KR20240011248A - 키메라 유두종바이러스 l1 단백질 - Google Patents
키메라 유두종바이러스 l1 단백질 Download PDFInfo
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Abstract
본 발명은 키메라 유두종 바이러스 L1 단백질 및 이를 인코딩하는 폴리뉴클레오티드에 관한 것이고, 또한, HPV 바이러스-유사 입자 및 이의 제조 방법에 관한 것이다. 상기 키메라 유두종 바이러스 L1 단백질은, 제1 유두종 바이러스 유형의 L1 단백질로부터 유래된 N-말단 단편으로서, 상기 N-말단 단편은 대응하는 HPV 유형의 L1 단백질의 면역원성을 유지하는, N-말단 단편; 및 제2 유두종 바이러스 유형의 L1 단백질로부터 유래된 C-말단 단편으로서, 상기 제2 유두종 바이러스 유형의 L1 단백질은 다른 HPV 유형의 L1 단백질에 비해 발현 수준 및 용해도가 더 우수한 것인, C-말단 단편;을 포함하고, 상기 키메라 유두종 바이러스 L1 단백질은 대응하는 HPV 유형의 L1 단백질의 면역원성을 가지고 있다. 상기 키메라 유두종 바이러스 L 단백질은 백신의 대량 생산을 위한 더 우수한 발현량 및 용해도를 가진다.
Description
본 발명은 유두종 바이러스(HPV) L1 단백질 및 이를 인코딩하는 폴리뉴클레오티드에 관한 것이고, HPV 바이러스 유사 입자 및 이의 제조 방법에 관한 것이다.
유두종 바이러스 (PV)는 파필로마비리다에(Papillomaviridae) 패밀리에 속하고 인간, 소, 개 및 토끼에 유두종을 일으킨다. 이 멤버 중 하나인 인간 유두종 바이러스 (HPV)는 외피 비보유 DNA 바이러스(non-enveloped DNA virus)이다. 이 바이러스의 게놈은 약 7.2-8kb 크기의 이중 가닥 닫힌 원형 DNA(closed circular DNA)이고, 8개의 오픈 리딩 프레임들(open reading frames)을 가지며, 이들의 기능에 따라 하기 3개의 부위들로 나누어질 수 있다: (1) 약 4.5kb인 초기 부위(E)로서, 바이러스 복제, 전사 및 형질전환과 관련된 총 6개의 비구조 단백질들인, E1, E2, E4-E7을 인코딩하는 것인, 초기 부위(E); (2) 약 2.5kb인 후기 부위(L)으로서, 주요 캡시드 단백질 L1(major capsid protein 1) 및 부 캡시드 단백질 L2(minor capsid protein)를 인코딩하는, 후기 부위(L); (3) L 부위의 끝과 E 부위의 시작 사이에 위치한 긴 규제 부위 (LCR)로서, 약 800-900 bp의 길이이고, 어떠한 단백질도 인코딩하지 않으며, DNA 복제 및 발현 조절 성분들로서 역할하는, 긴 규제 부위(LCR).
L1 단백질 및 L2 단백질은 HPV 감염 주기 후기에서 합성된다. L1 단백질은 주요 캡시드 단백질이고 55-60 kDa의 분자량을 가진다. L2 단백질은 부 캡시드 단백질이다. 72개의 L1 단백질 5량체들은 닫힌 원형 이중 가닥 DNA를 둘러싸는 20면체의 HPV 입자들의 외부 껍질(45-55nm의 직경)을 형성한다. L2 단백질은 L1 단백질의 내측에 위치한다(Structure of Small Virus-like Particles Assembled from the L1 Protein of Human Papillomavirus 16 Chen, X.S., R. L.Garcea, Mol.Cell.5(3):557-567, 2000).
PV 게놈에서 가장 보존된 유전자인 L1 단백질의 ORF는, 새로운 PV 유형들을 식별하기 위해 사용될 수 있다. 완전한 게놈(complete genome)이 클로닝되고, 이의 L1 ORF DNA 서열이 가장 가까운 것으로 알려진 PV 유형과 10%를 초과하여 상이하면 새로운 PV 유형으로 식별된다. 2% 내지 10%의 차이를 갖는 상동체들은 상이한 아형들로 정의되며, 2% 미만의 차이는 동일한 아형의 상이한 변이체들로 정의된다(E.-M. de Villiers et al. / Virology 324 (2004) 17-27).
HPV 감염의 후기 단계에서, 세포질에서 새로 합성된 L1 단백질들은 말단 분화된(terminally differentiated) 케라틴 세포의 핵에 운반되며, 여기서, L2 단백질들과 함께, 복제된 HPV 게놈 DNA를 패키징하여 감염성 바이러스들을 형성한다(Nelson, L.M, et al. 2002. Nuclear import strategies of high risk HPV16 L1 major capsid protein. J. Biol. Chem. 277: 23958-23964). 이는 L1 단백질의 핵 이동(nuclear import)이 HPV 감염 및 생산에서 매우 중요한 역할을 한다는 것을 시사한다. 바이러스가 핵에 진입하는 능력은 HPV L1 단백질의 C-말단에서 핵 위치 신호(nuclear localization signal; NLS)에 의해 결정되며, NLS는 염기성 아미노산의 풍부함(abundance)를 특징으로 한다(Garcia-Bustos, J., et al. 1991. Nuclear protein localization. Biochimica et Biophysica Acta 1071: 83-101).
15개의 고위험 (HR) HPV 유형들은 자궁 경부암, 항문암, 음경암, 질암, 외음부암 및 구인두암을 유발할 수 있고, 그 중 HPV-16 및 HPV-18은 현재까지 암의 가장 흔한 원인으로, 자궁 경부암의 약 70%를 차지하고, 다른 HR-HPV 유형들(유형 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 및 82)은 나머지 암들을 일으킨다. HPV-16은 HPV 양성 구인두암(OpC)의 약 95%를 차지한다. 지속성 저위험 유전자형 HPV-6 및 HPV-11은 대부분 항문 생식기 사마귀(anogenital warts) 및 호흡기 유두종(respiratory papillomas)을 일으키는 원인이지만, 암과 거의 관련이 없다(Human Papillomavirus in Cervical Cancer and Oropharyngeal Cancer: One Cause, Two Diseases Tara A. Bermanand John T. Schiller, PhD2 Cancer 2017;123:2219-29).
L1 단백질은 폭스바이러스, 배큘로바이러스, 또는 효모 시스템에 의해 재조합적으로 발현된 후, 자가-조립(self-assemble)되어 바이러스 캡시드와 유사한 대략 72개의 L1 단백질들을 함유하는 바이러스-유사 입자들(VLP)을 형성할 수 있다. VLP은 적응증(indication)을 갖지 않는다. VLP는 접종된 동물에서 중화 항체들을 유도하고 감염성 바이러스에 의한 후속 공격으로부터 실험 동물들을 보호한다. 따라서, VLP는 유두종 바이러스 백신에 대한 우수한 후보로 보인다(Structure of Small Virus-like Particles Assembled from the L1 Protein of Human Papillomavirus 16 Chen, X.S. , R. L. Garcea, Mol. Cell. 5(3):557-567, 2000).
2가 재조합 HPV 백신(bivalent recombinant HPV vaccine)인 Glaxo의 CERVARIX®는 HPV 유형 16 재조합 L1 단백질 및 HPV 유형 18 재조합 L1 단백질을 포함한다. L1 단백질은 야행성 나방(트리코플루시아니(Trichoplusiani))의 곤충 세포에서 재조합 배큘로바이러스 발현 벡터 시스템의 발현에 의해 얻어진다. L1 단백질은 9-25세 여성에서 HPV 유형 16 및 18에 의해 유발되는 자궁경부암, 등급 2 또는 3 자궁경부 상피내 종양(cervical intraepithelial neoplasia) (종양원성) 및 상피내 선암(adenocarcinoma in situ)을 예방하기 위한 바이러스-유사 입자들로 자가-조립된다(https://www.fda.gov/downloads/BiologicsBloodVaccines/Vaccines/ApprovedProducts/UCM186981.pdf).
GARDASIL®은 9-26세의 소녀 및 여성에서 HPV 유형 6, 11, 16 및 18에 의해 유발되는 자궁경부암, 생식기 사마귀(첨형 콘딜로마(condyloma acuminata)) 및 전암성 또는 증식성 이형성 병변들의 예방; 및 9-26세 소년 및 남성에서 HPV 유형 6, 11, 16 및 18에 의해 유발되는 항문암, 생식기 사마귀(첨형 콘딜로마) 및 전암성 또는 비정상 발달성 병변들의 예방을 위한 Merck로부터의 인간 유두종 바이러스 4가 (유형 6, 11, 16 및 18) 재조합 백신이다(https://www.fda.gov/vaccines-blood-biologics/vaccines/gardasil).
GARDASIL®9는 HPV 유형 6, 11, 16, 18, 31, 33, 45, 52 및 58의 L1 단백질의 바이러스-유사 입자들을 함유하는 Merck의 9가 재조합 인간 유두종 바이러스이며, 상기 L1 단백질은 사카로미세스 세리비시아(Saccharomyces cerevisiae)의 발효에 의해 생산되고 VLP로 자가-조립된다. 이는 HPV 유형 16, 18, 31, 33, 45, 52 및 58에 의해 유발되는 자궁경부암, 외음부암, 질암 및 항문암, HPV 유형 6 및 11에 의해 유발되는 생식기 사마귀 (첨형 콘딜로마) 및 HPV 유형 6, 11, 16, 18, 31, 33, 45, 52 및 58에 의해 유발되는 전암성 또는 증식성 이형성증의 예방을 위해 9-45세 소녀 및 여성에게 사용되고; HPV 유형 16, 18, 31, 33, 45, 52 및 58에 의해 유발되는 항문암, HPV 유형 6 및 11에 의해 유발되는 생식기 사마귀 (첨형 콘딜로마) 및 HPV 유형 6, 11, 16, 18, 31, 33, 45, 52 및 58에 의해 유발되는 전암성 또는 발달성 비정상 병변들의 예방을 위해 9-45세의 소년 및 남성에게 사용된다(https://www.fda.gov/vaccines-blood-biologics/vaccines /gardasil-9).
GARDASIL®9에 대한 지침은 HPV 유형 16 및 18이 자궁 경부암의 약 70%를 차지하는 원인이고, 나머지 20%는 유형 31, 33, 45, 52 및 58에 기인하므로, GARDASIL®9이 자궁 경부암의 90%를 예방한다고 발표했다(https://www.fda.gov/ BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm426445.htm).
바이러스-유사 입자의 산업적 생산은 HPV 백신 개발에 중요하다. 바이러스-유사 입자를 생산하기 위한 일반적인 시스템은 주로 진핵생물 발현 시스템 및 원핵생물 발현 시스템으로 분류된다.
일반적으로 사용되는 진핵생물 발현 시스템은 폭스바이러스 발현 시스템, 곤충 배큘로바이러스 발현 시스템, 및 효모 발현 시스템을 포함한다. 진핵생물 발현 시스템에서 발현되는 HPV L1 단백질은 이의 자연적인 형태가 덜 파괴(less disrupted)되기 때문에 바이러스-유사 입자로 자발적으로 조립될 수 있지만. 그 수율은 낮다. 원핵생물 발현 시스템에서 발현되는 HPV L1 단백질은 주로 대장균(E. coli) 발현 시스템으로, 높은 수율이지만 대부분 봉입체(inclusion bodies)의 형태이고, 이러한 형태의 단백질은 쉽게 정제될 수 없으므로 생산 공정을 복잡하게 한다.
따라서, HPV 바이러스-유사 입자의 높은 수율을 얻을 필요가 여전히 있다.
일 양태에서, 본 발명은 키메라 유두종 바이러스 L1 단백질을 제공하는데, 상기 키메라 유두종 바이러스 L1 단백질은, 이의 N-말단에서 C-말단 방향으로, a. 제1 유두종 바이러스 유형의 L1 단백질로부터 유래된 N-말단 단편으로서, 상기 N-말단 단편은 대응하는 인간 유두종 바이러스 유형의 L1 단백질의 면역원성을 유지하는, N-말단 단편; b. 제2 유두종 바이러스 유형의 L1 단백질로부터 유래된 C-말단 단편으로서, 상기 제2 유두종 바이러스 유형의 L1 단백질은 다른 유형의 L1 단백질들에 비해 더 우수한 발현 수준 및 용해도를 갖는 것인, C-말단 단편;을 포함하고, 상기 키메라 유두종 바이러스 L1 단백질은 제1 유두종 바이러스 유형의 L1 단백질의 면역원성을 가진다.
또 다른 양태에서, 본 발명은 키메라 유두종 바이러스 L1 단백질을 포함하는 유두종 바이러스-유사 입자를 제공한다.
또 다른 양태에서, 본 발명은 유두종 바이러스-관련 질병 또는 감염을 예방을 위한 면역원성 조성물을 제공하는데, 상기 면역원성 조성물은 앞서 기재된 유두종 바이러스-유사 입자들 및 아쥬반트들(adjuvants)을 포함한다.
또 다른 양태에서, 본 발명은 키메라 유두종 바이러스 L1 단백질을 인코딩하는 분리된 폴리뉴클레오티드를 제공한다.
추가 양태에서, 본 발명은 키메라 유두종 바이러스 L1 단백질을 인코딩하는 폴리뉴클레오티드를 포함하는 벡터를 제공한다.
추가 양태에서, 본 발명은 키메라 유두종 바이러스 L1 단백질을 인코딩하는 폴리뉴클레오티드를 포함하는 배큘로바이러스를 제공한다.
또 다른 양태에서, 본 발명은 앞서 기재된 상기 폴리뉴클레오티드, 또는 상기 배큘로바이러스를 포함하는 숙주 세포를 제공한다.
또 다른 양태에서, 본 발명은 유두종 바이러스-유사 입자를 제조하는 방법을 제공하는데, 상기 방법은 상기 키메라 유두종 바이러스 L1 단백질들을 발현시키고 상기 바이러스-유사 입자들로 조립하기 위해 앞서 기재된 숙주 세포를 배양하는 단계; 및 상기 유두종 바이러스-유사 입자들을 정제하는 단계를 포함한다.
도 1a: HPV 6 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1b: HPV 11 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1c: HPV 16 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1d: HPV 18 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1e: HPV 31 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1f: HPV 35 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1g: HPV 39 L1: 59C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1h: HPV 45 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1i: HPV 51 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1j: HPV 52 L1: 33C의 L1 단백질의 발현: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1k: HPV 56 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1l: HPV 58 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 2a: HPV 6 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2b: HPV 11 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사 바이러스-유사 입자.
도 2c: HPV 16 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2d: HPV 18 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2e: HPV 31 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2f: HPV 35 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2g: HPV 39 L1: 59C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2h: HPV 45 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2i: HPV 51 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2j: HPV 52 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2k: HPV 56 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2l: HPV 58 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 3: C-말단 절단된 HPV 16L1 (1-474)의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1b: HPV 11 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1c: HPV 16 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1d: HPV 18 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1e: HPV 31 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1f: HPV 35 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1g: HPV 39 L1: 59C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1h: HPV 45 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1i: HPV 51 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1j: HPV 52 L1: 33C의 L1 단백질의 발현: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1k: HPV 56 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 1l: HPV 58 L1: 33C의 L1 단백질의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
도 2a: HPV 6 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2b: HPV 11 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사 바이러스-유사 입자.
도 2c: HPV 16 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2d: HPV 18 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2e: HPV 31 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2f: HPV 35 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2g: HPV 39 L1: 59C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2h: HPV 45 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2i: HPV 51 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2j: HPV 52 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2k: HPV 56 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 2l: HPV 58 L1: 33C 바이러스-유사 입자의 투과 전자 현미경 검사.
도 3: C-말단 절단된 HPV 16L1 (1-474)의 발현. M: 마커; L: 세포 용해물; E-S: 용해물의 원심분리 후 수집된 상층액.
특정 구현예
일 양태에서, 본 발명은 키메라 유두종 바이러스 L1 단백질을 제공하는데, 상기 키메라 유두종 바이러스 L1 단백질은, 이의 N-말단에서 C-말단 방향으로, a. 대응하는 인간 유두종 바이러스 유형의 L1 단백질로부터 유래된 N-말단 단편으로서, 상기 N-말단 단편은 대응하는 HPV 유형의 L1 단백질의 면역원성을 유지하는, N-말단 단편; 및 b. 제2 유두종 바이러스 유형의 L1 단백질로부터 유래된 C-말단 단편으로서, 상기 제2 유형의 L1 단백질은 다른 유형의 L1 단백질들에 비해 더 우수한 발현 수준 및 용해도를 갖는 것인, C-말단 단편;을 포함하고, 상기 키메라 유두종 바이러스 L1 단백질은 제1 유두종 바이러스 유형의 L1 단백질의 면역원성을 가진다.
일 구현예에서, 상기 N-말단 단편은 α5 부위 내의 임의의 아미노산 위치에서 제1 유두종 바이러스 유형의 L1 단백질의 천연 서열(natural sequence)의 C-말단을 절단하여 얻어진 단편, 및 상기 C-말단을 절단하여 얻어진 단편과 적어도 98%의 동일성을 갖는 단편이고, 상기 C-말단 단편은 α5 부위 내의 임의의 아미노산 위치에서 제2 유두종 바이러스 유형의 L1 단백질의 천연 서열의 N-말단을 절단하여 얻어진 단편, 및 상기 N-말단을 절단하여 얻어진 단편에 추가 돌연변이, 결실 및/또는 추가로부터 생성된 기능적 변이체들이다.
또 다른 구현예에서, 상기 N-말단 단편은 α5 부위 내의 임의의 아미노산 위치에서 제1 유두종 바이러스 유형의 L1 단백질의 천연 서열의 C-말단을 절단하여 얻어진 단편과 적어도 98.5%, 99%, 99.5% 또는 100%의 동일성을 가진다.
일 구현예에서, 상기 C-말단 단편은 하나 또는 복수의 핵 위치 서열들(nuclear localization sequences)을 포함한다.
일 구현예에서, 상기 유두종 바이러스 L1 단백질은 HPV L1 단백질이다.
일 구현예에서, 상기 제2 유두종 바이러스 유형의 L1 단백질은 HPV 유형 1, 2, 3, 4, 6, 7, 10, 11, 13, 16, 18, 22, 26, 28, 31, 32, 33, 35, 39, 42, 44, 45, 51, 52, 53, 56, 58, 59, 60, 63, 66, 68, 73 또는 82의 L1 단백질들로부터 선택된다.
바람직하게는, 상기 제2 유두종 바이러스 유형의 L1 단백질은 HPV 유형 16, 28, 33, 59 또는 68의 L1 단백질들로부터 선택된다.
보다 바람직하게는, 상기 제2 유두종 바이러스 유형의 L1 단백질은 HPV 유형 33 또는 HPV 유형 59의 L1 단백질들로부터 선택된다.
일 구현예에서, 상기 제2 유두종 바이러스 유형의 L1 단백질은 HPV 유형 33 L1 단백질이고, 상기 C-말단 단편은 서열 번호: 2, 또는 m1개의 아미노산 길이를 갖는 이의 단편, 바람직하게는 서열 번호: 2의 아미노산 1 내지 m1 위치를 커버(cover)하는 단편 - m1은 8 내지 26의 정수임 - 이거나; 상기 C-말단 단편은 서열 번호: 132, 또는 m2개의 아미노산 길이를 갖는 이의 단편, 바람직하게는 서열 번호: 132의 아미노산 1 내지 m2 위치를 커버하는 단편 - m2는 13 내지 31의 정수임 - 이다.
일 구현예에서, HPV 유형 33 L1 단백질의 C-말단 단편은 핵 위치 서열을 가진다. 또 다른 구현예에서, HPV 유형 33 L1 단백질의 C-말단 단편은 2개의 핵 위치 서열들을 가진다. 일부 구현예에서, 키메라 유두종 바이러스 L1 단백질은 HPV 유형 33 L1 단백질의 하나 또는 복수의 C-말단 단편들을 포함한다. 상기 HPV 유형 33 L1 단백질의 복수의 C-말단 단편들은 동일하거나 상이할 수 있다. 일 구현예에서 서열 번호: 2의 아미노산 번호: 7-8 (KR)을 가지는 아미노산 서열 및 아미노산 번호: 20-23 (KRKK)를 가지는 아미노산 서열들 HPV 유형 33 L1 단백질의 C-말단 단편의 핵 위치 서열이다.
또 다른 구현예에서, 상기 제2 유두종 바이러스 유형의 L1 단백질은 HPV 유형 59 L1 단백질이며, 상기 C-말단 단편은 서열 번호: 13, 또는 n개의 아미노산 길이를 갖는 이의 단편, 바람직하게는 서열 번호: 13의 아미노산 1 내지 n 위치를 커버하는 단편이고; 이때, n은 16 내지 38의 정수이다.
일 구현예에서, HPV 유형 59 L1 단백질의 C-말단 단편은 핵 위치 서열을 가진다. 또 다른 구현예에서, HPV 유형 59 L1 단백질의 C-말단 단편은 2개의 핵 위치 서열들을 가진다. 일부 구현예에서, 키메라 유두종 바이러스 L1 단백질은 HPV 유형 59 L1 단백질의 하나 또는 복수의 C-말단 단편들을 포함한다. 상기 HPV 유형 59 L1 단백질의 복수의 C-말단 단편들은 동일하거나 상이할 수 있다.
일 구현예에서, 상기 제1 유두종 바이러스 유형의 L1 단백질은 HPV 유형 6, 11, 16, 18, 31, 35, 39, 45, 51, 52, 56 또는 58의 L1 단백질들로부터 선택된다.
일 구현예에서, 상기 N-말단 단편의 C-말단은 상기 C-말단 단편의 N-말단에 직접 또는 링커(linker)를 통해 연결된다.
링커는 상기 N-말단 단편의 면역원성에 영향을 미치지 않고 단백질의 발현 수준 또는 용해도에 영향을 미치지 않는다. 일 구현예에서, 상기 N-말단 단편 및 상기 C-말단 단편은 1, 2, 3, 4, 5, 6, 7, 8, 9 또는 10개의 아미노산을 포함하는 링커를 통해 연결된다. 일 구현예에서, 링커는 인공 서열이다. 또 다른 구현예에서, 링커는 HPV L1 단백질에서의 자연 발생 서열이다. 또 다른 구현예에서, 링커는 HPV 유형 33 L1 단백질의 부분 서열일 수 있다. 또 다른 구현예에서, 링커는 HPV 유형 59 L1 단백질의 부분 서열일 수 있다.
일 구현예에서, 상기 N-말단 단편의 C-말단이 상기 C-말단 단편의 N-말단에 연결될 때 연결 지점의 플러스 또는 마이너스 4개 아미노산 위치의 범위 내에서, 하기 연속적인 아미노산 서열이 존재하고: RKFL; 바람직하게는, 연결 지점의 플러스 또는 마이너스 6개 아미노산 위치 범위 내에서 하기 연속적인 아미노산 서열이 존재한다: LGRKFL.
일 양태에서, 본 발명은 앞서 기재된 키메라 유두종 바이러스 L1 단백질을 포함하는, 유두종 바이러스-유사 입자를 제공한다. 일 구현예에서, 유두종 바이러스-유사 입자는 HPV 바이러스-유사 입자이고, 일 구현예에서, 상기 HPV 바이러스-유사 입자는 상기 키메라 HPV L1 단백질의 72개의 5량체들을 포함하는 20면체이다. 일 구현예에서, 상기 HPV 바이러스-유사 입자는 이황화 결합을 정확하게(correctly) 형성하고, 따라서 우수한 자연적 형태(natural conformation)을 가진다. 일 구현예에서, HPV 바이러스-유사 입자들은 생체 내(in vivo) 발현 시스템에서 자가-조립(self-assemble)된다.
일 양태에서, 본 발명은 유두종 바이러스-관련 질병 또는 감염의 예방을 위한 면역원성 조성물을 제공하는데, 상기 면역원성 조성물은 앞서 기재된 유두종 바이러스-유사 입자 및 아쥬반트들을 포함한다. 상기 예방은 치료로 간주될 수 있고 상호 교환적으로 사용될 수 있다.
일 양태에서, 전술한 면역원성 조성물은 대상체에 투여된다. 일 구현예에서, 대상체는 인간이다. 일 구현예에서, 대상체는 토끼이다. 일 구현예에서, 대상체는 개다.
일 양태에서, 본 발명은 앞서 기재된 키메라 유두종 바이러스 L1 단백질을 인코딩하는, 분리된 폴리뉴클레오티드를 제공한다. 일 구현예에서, 폴리뉴클레오티드는 다양한 발현 시스템들에 대해 코돈-최적화된 폴리뉴클레오티드이다. 일 구현예에서, 폴리뉴클레오티드는 곤충 배큘로바이러스 발현 시스템에 대해 코돈-최적화된 폴리뉴클레오티드이다.
일 양태에서, 본 발명은 앞서 기재된 폴리뉴클레오티드를 포함하는, 벡터를 제공한다. 일 구현예에서, 벡터는 배큘로바이러스 발현 시스템에 대한 전달 벡터(transfer vector)일 수 있다. 또 다른 구현예에서, 벡터는 배큘로바이러스 발현 시스템에 대한 발현 벡터일 수 있다. 다른 구현예에서, 벡터는 배큘로바이러스 발현 시스템에 대한 재조합 벡터일 수 있다.
일 양태에서, 본 발명은 앞서 기재된 폴리뉴클레오티드를 배큘로바이러스를 포함하는, 제공한다.
일 양태에서, 본 발명은 세포는 앞서 기재된 폴리뉴클레오티드, 벡터, 또는 배큘로바이러스를 포함하는, 숙주 세포를 제공한다. 일 구현예에서, 숙주 세포는 곤충 세포이며, 바람직하게는, 상기 곤충 세포는 Sf9 세포, Sf21 세포, Hi5 세포 및 S2 세포로부터 선택된다.
일 양태에서, 본 발명은 앞서 기재된 유두종 바이러스-유사 입자를 제조하는 방법을 제공하는데, 상기 방법은 바이러스-유사 입자들로 조립되는 상기 키메라 유두종 바이러스 L1 단백질들을 발현시키기 위해 숙주 세포를 배양하는 단계; 및 상기 유두종 바이러스-유사 입자들을 정제하는 단계를 포함한다.
일 구현예에서, 숙주 세포는 곤충 세포이다. 일 구현예에서, 숙주 세포는 Hi5 세포이다. 일 구현예에서, 키메라 유두종 L1 단백질들은 숙주 세포들에서 HPV 바이러스-유사 입자들로 자가-조립되는 키메라 HPV L1 단백질들이다. 일 구현예에서, 키메라 HPV L1 단백질들은 숙주 세포에서 상기 키메라 HPV L1 단백질의 72개의 5랑체들을 포함하는 20면체를 갖는 HPV 바이러스-유사 입자들로 자가-조립된다. 일 구현예에서, HPV 바이러스-유사 입자들은 이황화 결합을 정확하게 형성하고, 따라서 우수한 자연적 형태 가진다.
일 구현예에서, 정제는 양이온 교환 크로마토그래피를 사용하여 수행된다. 일 구현예에서, 정제는 강한 양이온 교환 크로마토그래피(strong cation exchange chromatography)를 사용하여 수행된다. 또 다른 구현예에서, 정제는 약한 양이온 교환 크로마토그래피(weak cation exchange chromatography)를 사용하여 수행된다. 일 구현예에서, 정제는 다중 양이온 교환 크로마토그래피의 조합을 사용하여 수행된다. 일 구현예에서, 정제는 HS 강한 양이온 교환 크로마토그래피를 사용하여 수행된다. 또 다른 구현예에서, 정제는 MMA 이온 교환 크로마토그래피를 사용하여 수행된다. 또 다른 구현예에서, 정제는 HS-MMA 2단계 크로마토그래피를 사용하여 수행된다.
진핵생물 발현 시스템에 의해 발현되는 유두종바이러스 L1 단백질은 자발적으로 바이러스-유사 입자로 조립될 수 있지만, 낮은 발현 수준으로 대량 생산에 적합하지 않다.
각 HPV 유형의 L1 단백질의 서열들은 https://www.uniprot.org에서 쉽게 얻을 수 있다. 제공된 HPV 유형에 대해, L1 단백질은 상이한 균주로부터 유래되어, 이의 아미노산 서열은 다양한 버전을 가질 수 있고, 천연 서열의 임의의 버전이 본 발명에서 사용될 수 있다. 본 발명의 구상 및 설계 동안 사용되는 제공된 유형의 HPV L1 단백질의 서열은 하기 실시예들에서 사용되는 서열과 상이할 수 있지만, 이러한 차이는 본 발명자들의 결정 및 결론에 영향을 미치지 않는다.
L1 단백질의 C-말단이 주요 중화 항원 에피토프(neutralizing antigenic epitope)를 함유하지 않는 것은 당업자에게 일반적으로 받아들여 지고, 따라서, HPV L1 단백질의 C-말단을 절단함으로써 발현을 증가시키는 시도가 이루어졌는데, 예를 들면, Glaxo의 US 특허 제US6361778B1호는 HPV16 L1 단백질의 C-말단이 1-34개의 아미노산들, 바람직하게는 26개의 아미노산들에 의해 절단되어, VLP의 생산이 몇 배, 바람직하게는 적어도 10배, 특히 약 10 내지 100배로 증가되는 것을 기술한다. 이에 영감을 받아, 본 발명자들은 HPV 16 L1 단백질의 C-말단을 31개의 아미노산들에 의해 절단하는 것을 시도하였고 절단된 단백질을 HPV 16 L1(1-474)로 명명하였다. 상기 단백질은 높은 발현 수준을 갖지만, 용해도가 낮고 추출 및 정제되기 어렵다(비교 실시예 참조).
이 절단으로 인한 단백질의 낮은 용해도는 C-말단에 위치한 핵 위치 서열의 결실로 인한 것일 수 있지만, 본 발명은 이러한 추측에 제한되지 않는다. 연구 및 생산 동안, 본 발명자는 HPV 유형 16 L1 단백질, HPV 유형 28 L1 단백질, HPV 유형 33 L1 단백질, HPV 유형 59 L1 단백질 및 HPV 유형 68 L1 단백질이 다른 HPV 유형 L1 단백질들보다 더 우수한 발현 수준 및 용해도를 가지는 것을 발견했다. 이 발견에 영감을 받아, 본 발명자들은 추출가능성이 낮거나 용해성이 낮은 특정 HPV 유형 L1 단백질들의 C-말단을 더 우수한 발현 수준 및 용해도를 갖는 특정 HPV 유형 L1 단백질의 C 말단으로 대체했다. 즉, 발명자들은 키메라 단백질을 작제하였는데, 상기 키메라 단백질은. N-말단에서 C-말단 방향으로, 제1 유두종 바이러스 유형의 L1 단백질(예를 들면, HPV L1 단백질)로부터 유래된 N-말단 단편으로서, 상기 제1 유두종 바이러스 유형(예를 들면, HPV)의 면역원성을 제공하는, N-말단 단편, 및 제2 유두종 바이러스 유형의 L1 단백질(예를 들면, HPV L1 단백질)로부터 유래된 C-말단 단편으로서, 더 우수한 발현 수준 및 용해도의 특성들을 제공하는, C-말단 단편을 포함한다. 이 2개의 단편들은 직접 또는 링커를 통해 연결될 수 있다.
제1 HPV 유형의 L1 단백질의 면역원성을 유지하고 VLP의 형성을 보장하는데 적절한 HPV L1 단백질의 N-말단 단편의 길이가 결정된다. 하기 보고 내용은 일반적인 HPV 유형의 에피토프 연구들에 관한 것이다.
Sunanda Baidya et, al 은 L1 단백질의 에피토프들 48EEYDLQFIFQLCKITLTA65, 45RHGEEYDLQFIFQLCKITLTA65, 63LPDPNKF69, 79PETQRLVWAC88, 36PVPGQYDA43, 77YNPETQRLVWAC88, 188DTGYGAMD195, 36PVPGQYDATK45, 45KQDIPKVSAYQYRVFRV61, 130RDNVSVDYKQTQLCI144 및 49YSRHVEEYDLQFIF62는 HPV 16 및 HPV 18 백신을 설계하기 위한 툴(tool)로 사용될 수 있음을 보고했다(Epitope design of L1 protein for vaccine production against Human Papilloma Virus types 16 and 18, Bioinformation 13(3): 86-93 March 2017 참고, 이의 전문은 여기에 참조로 포함됨).
Katharina Slupetzky et al은 HPV-16의 aa 282-286 및 351-355 근처 부위들이 중화 에피토프들에 기여하고 후자는 면역 우세 부위(immunodominant site)임을 보고했다(Chimeric papilloma virus-like particles expressing a foreign epitope on capsid surface loops, Journal of General Virology (2001), 82, 2799-2804 참고, 이의 전문은 여기서 참조로 포함됨).
Brooke Bishop et al은 HPV 11, 16, 18 및 35 L1 단백질의 하기 3개의 변이체들을 제조했고: 각각, N-말단에서 9개의 아미노산들의 결실, α4(HPV 16의 아미노산 잔기 404-436에 대응)의 결실, 및 C-말단에서 31개의 아미노산들의 결실, 전자의 2개의 변이체들은 VLP로 조립될 수 없었지만, 후자의 변이체에서는 이러현 현상이 보고되지 않았다(Crystal Structures of Four Types of Human Papillomavirus L1 Capsid Proteins UNDERSTANDING THE SPECIFICITY OF NEUTRALIZING MONOCLONAL ANTIBODIES, The Journal of Biological Chemistry, 282, 31803-31811, 이의 전문은 여기서 참조로 포함됨). 각 유형의 HPV L1 단백질의 α-나선, β-접힘 시트(β-fold sheets) 및 루프 부위는 당해 기술 분야에서 흔히 사용되는 서열 분석 소프트웨어에 의해 편리하게 결정될 수 있다. 여기서 α-나선 부위들은 α1 부위, α2 부위, α3 부위, α4 부위 및 α5 부위를 함유한다.
본 발명자들은 14개의 HPV 유형(유형 6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58 및 59)의 L1 단백질의 서열 정렬을 수행한 후, 앞서 인용된 문헌(Crystal Structures of Four Types of Human Papillomavirus L1 Capsid Proteins UNDERSTANDING THE SPECIFICITY OF NEUTRALIZING MONOCLONAL ANTIBODIES, The Journal of Biological Chemistry, 282,31803-31811)에 따라 2차 구조 예측을 수행했고, 그 결과는 하기에 나타난다, 여기서 아래쪽을 가리키는 화살표들 사이의 부분은 본 문헌에서 변이체들을 제조하기 위해 제거되었던 부위들에 대응한다.
서열 정렬을 위해 본 발명자에 의해 사용된 방법들 외에도, 예측을 위해 사용될 수 있는 단백질 이차 구조 예측 소프트웨어는 하기를 포함하지만, 이에 제한되지 않는다.
1. JPred: http://www.compbio.dundee.ac.uk/jpred/index.html
2. ProtPredicct: http://predictprotein.org
3. PsiPred: http://bioinf.cs.ucl.ac.uk/psipred
4. SCRATCH-1D: http://download.igb.uci.edu
5. Nnpredict: http://www.cmpharm.ucsf.edu/~nomi/nnpredict
6. Predictprotein: http://www.embl-heidelberg.de/predictprotein/SOPMA
http://www.ibcp.fr/predict.html
7. SSPRED: http://www.embl-heidelberg.de/sspred/ssprd_info.html.
본 발명의 일 구현예에서, 본 발명자들은 제1 유형으로부터 유래된 HPV L1 단백질의 N-말단 단편의 길이를 하기 방식으로 결정한다: L1 단백질의 천연 서열은 α5 부위 및 이의 근처 부위들 내에서 절단되고, N-말단에서 α5 부위 내에서 새로 생성된 C-말단까지의 서열이 유지된다. 이러한 절단된 서열은 제1 유형의 면역원성을 보장하고 VLP를 형성할 수 있다.
제1 유형으로부터 유래된 HPV L1 단백질의 N-말단 단편은 제1 유형의 면역원성을 유지하고 VLP를 형성할 수 있는 한, 더 변형될 수 있다.
제2 유형으로부터 유래된 HPV L1 단백질의 C-말단 단편의 길이는 하기 방식으로 결정된다: L1 단백질의 천연 서열은 α5 부위 및 이의 근처 부위들 내에서 절단된 다음, α5 부위 내에서 새로 생성된 N-말단에서 C-말단까지의 서열이 유지된다. 이러한 절단된 서열은 주요 중화 항원 에피토프를 가지지 않아, 생성된 키메라 단백질의 면역원성을 방해하지 않는다.
제2 유형으로부터 유래된 HPV L1 단백질의 C-말단 단편은 추가 돌연변이, 결실 및/또는 추가될 수 있으며, 바람직하게는, 이의 핵 국소화 서열들 중 적어도 하나를 보유한다. Yang et al은 107개의 HPV 아형들의 핵 위치 서열들을 예측하였다(Yang et al. Predicting the nuclear localization signals of 107 types of HPV L1 proteins by bioinformatic analysis. Geno. Prot. Bioinfo. Vol. 4 No. 1 2006, 이의 전문은 여기에 참조로 포함된다). 각 유형의 HPV L1 단백질의 핵 위치 서열은 당해 기술분야에서 일반적으로 사용되는 서열 분석 소프트웨어에 의해 편리하게 결정될 수 있다.
앞서 기재된 N-말단 단편 및 C-말단 단편의 연결은 전자의 새로 생성된 C-말단 및 후자의 새로 생성된 N-말단에서 발생한다. 이는 직접 연결 또는 링커를 통한 연결일 수 있다. 연결이 발생하는 위치는 좌표에서 원점(origin coordinate)으로 정의되고, 원점의 N-말단 쪽은 음수로 정의되는 반면, C-말단 쪽은 양수로 정의된다.
하기는 HPV6 L1 단백질의 아미노산 453-469의 서열 및 다른 HPV 유형들의 L1 단백질들의 대응하는 서열들을 보여준다. 이 서열들은 각각 α5 부위가 중첩된다. 이 서열들이 매우 유사한 것을 볼 수 있다 괄호 안의 숫자는 나열된 서열의 마지막 아미노산 잔기의 위치를 나타내며, HPV 유형 45의 경우, 추가적인 26개의 아미노산들이 일부 HPV 유형 45 균주의 L1 단백질의 N-말단에 존재하는 반면, 다른 HPV 유형 45 균주의 L1 단백질의 N-말단에서는, 상기 추가적인 26개의 아미노산들이 존재하지 않고, 따라서 숫자가 (478)+26으로 표시된다.
HPV6 ELDQYPLGRKFLLQSGY(469)
HPV11 ELDQFPLGRKFLLQSGY(470)
HPV16 DLDQFPLGRKFLLQAGL(474)
HPV18 DLDQYPLGRKFLVQAGL(475)
HPV31 DLDQFPLGRKFLLQAGY(475)
HPV35 DLDQFPLGRKFLLQAGL(472)
HPV39 ELDQFPLGRKFLLQARV (474)
HPV45 DLDQYPLGRKFLVQAGL(478)+26
HPV51 DLDQFALGRKFLLQVGV(474)
HPV52 DLDQFPLGRKFLLQAGL(478)
HPV56 DLDQFPLGRKFLMQLGTRS(474)
HPV58 DLDQFPLGRKFLLQSGL(473)
HPV33 DLDQFPLGRKFLLQAGL(473)KAKPKLKRAAPTSTRTSSAKRKKVKK 여기서 위치 480-481에서 KR 및 위치 493-496에서 KRKK는 핵 위치 서열이다.
HPV59 DLDQFPLGRKFLLQLGA(475)RPKPTIGPRKRAAPAPTSTPSPKRVKRRKSSRK, 여기서 위치 484-486에서 RKR 및 위치 498-504에서 KRVKRRK는 핵 위치 서열들이다.
본 발명의 일 구현예에서, 발명자들은 HPV 유형들 사이의 α5 부위 및 근처 부위들의 서열 유사성 활용하여 상이한 HPV 유형들 사이의 L1 단백질의 C-말단 치환을 완료했다.
본 발명의 가장 바람직한 구현예에서, 본 발명자들은 각 HPV 유형의 L1 단백질은 유사한 위치에서 테트라펩티드 RKFL, 또는 더 유리하게는, 헥사펩티드 LGRKFL을 가지고 있음을 주목했다. 본 발명자들은 이 고도로 보존된 서열을 능숙하게 사용하여, 이 올리고펩티드 내의 임의의 아미노산 위치에서 키메라 단백질 연결 지점을 설계했다 한편, 키메라 단백질의 N-말단에서 시작하여 RKFL 또는 LGRKFL까지의 서열은 제1 유형의 L1 단백질로부터 유래된 N-말단 단편의 서열과 동일한 반면에, RKFL 또는 LGRKFL에서 시작하여 키메라 단백질의 C-말단까지의 서열은 제2 유형의 L1 단백질로부터 유래된 C-말단 단편의 서열과 동일하다.
따라서, 생성된 키메라 단백질은 천연 HPV L1 단백질과 높은 정도의 유사도를 유지하고, 생산 및 후속 의료 또는 예방 절차에서도 잘 수행될 것으로 예상될 수 있다.
당업자는, 소정의 HPV 유형에 대해 상이한 천연 서열들을 가진 상이한 균주들이 존재하므로, 상이한 균주들을 사용하여 작제된 키메라 단백질들 또한 본 발명의 범위 내에 포함되는 것을 이해할 것이다.
당업자는, 상이한 HPV 유형들의 L1 단백질 사이의 높은 정도의 유사도 때문에, 키메라 단백질의 작제 동안에 제1 HPV 유형의 L1 단백질로부터 유래된 N-말단 단편이 더 많은 아미노산 잔기들로 C-말단을 향해 연장되거나, 제2 HPV 유형의 L1 단백질로부터 유래된 C-말단 단편이 더 많은 아미노산 잔기들로 N-말단을 향해 연장되는 경우, 대응하는 위치들에서 동일하거나 유사한 아미노산들로 인해 본 발명과 구조적으로 동일한 키메라 단백질이 형성될 수 있는 것이 이해될 것이다. 이렇게 형성된 키메라 단백질들도 본 발명의 범위 내에 속한다.
당업자는, 앞서 기재된 구현예들의 키메라 단백질들을 기초로 하여, 키메라 단백질들의 변이체들이 아미노산 잔기들의 돌연변이, 결실 및/또는 추가에 의해 형성될 수 있는 것이 이해될 것이다. 이 변이체들은 제1 HPV 유형의 L1 단백질의 면역원성을 가질 수 있고, VLP를 형성할 수 있으며, 우수한 수율 및 용해도를 가질 수 있다. 이렇게 형성된 키메라 단백질 또한 본 발명의 범위에 속한다.
본 발명의 유익한 효과
바이러스-유사 입자들을 생산하는데 일반적으로 사용되는 발현 시스템들은 진핵생물 발현 시스템 및 원핵생물 발현 시스템들로 분류된다. 진핵생물 발현 시스템들에 의해 발현되는 유두종 바이러스 L 단백질들은 바이러스-유사 입자들로 자발적으로 조립될 수 있지만, 낮은 발현 수준으로 대량 생산에 적합하지 않는 단점을 가진다 원핵생물 발현 시스템에 의해 발현되는 유두종 바이러스 L 단백질은 본래 발현 시스템에 의해 발현된 유두종 바이러스 L 단백질은 자연적 형태가 흔히 파괴되어 바이러스-유사 입자들을 얻기 위해 생체 외(in vitro) 처리를 필요로 하고, 낮은 수율을 갖기 때문에 산업화에 사용하기 어렵다.
본 발명은 유두종 바이러스 (예를 들면, 인간 유두종 바이러스)의 L 단백질의 C-말단을 변형하는데, 예를 들면, HPV 유형 16 L1 단백질, HPV 유형 28 L1 단백질, HPV 유형 33 L1 단백질, HPV 유형 59 L1 단백질 또는 HPV 유형 68 L1 단백질의 C-말단 단편으로 대체함으로써 변형하며, 발현 시스템(예를 들면, 숙주 세포들, 예를 들어 곤충 세포들)에서 사용되어 발현 시스템(예를 들면, 숙주 세포들, 예를 들어 곤충 세포들)에서 유두종 바이러스 L 단백질의 발현 수준 및 용해도를 개선할 수 있다. 이는 HPV 백신과 같은 백신의 대량 생산을 위해 사용될 수 있다.
본 발명자들은 HPV 유형 16 L1 단백질, HPV 유형 28 L1 단백질, HPV 유형 33 L1 단백질, HPV 유형 59 L1 단백질 및 HPV 유형 68 L1 단백질이 다른 HPV 유형의 L1 단백질들에 비해 증가된 발현 수준 및 용해도를 가지고, 상기 증가된 단백질 발현 수준 및 용해도는 HPV L1 단백질의 C-말단 서열에 의존하는 것을 발견했다. 107개의 HPV 유형 L1 단백질 중에서, 대부분은 C-말단에 핵 위치 서열들을 가지고 있고, C-말단 서열들은 일부 유사점을 가진다.
현재 발현할 수 없는 유두종 바이러스 L 단백질들의 경우, 발현 수준이 매우 낮거나 발현 후 불용성이기 때문에, 이들의 C-말단 단편들을 HPV 유형 16 L1 단백질, HPV 유형 28 L1 단백질, HPV 유형 33 L1 단백질, HPV 유형 59 L1 단백질 또는 HPV 유형 68 L1 단백질의 C-말단 단편으로 대체하는 것은 가용성 발현 및 후속 정제를 가능하게 한다. 이 전략은 다가 백신들 (예를 들면, HPV 백신들)의 대량 생산에 사용되어, 넓은 범위의 유두종 바이러스, 특히 HPV에 대해 더 포괄적인 보호를 가능하게 한다.
대량 생산 목적을 위해 곤충 세포에서 HPV L1 단백질의 발현 수준 및 용해도를 증가시킬 필요가 있다. 또한, HPV L 단백질에 의해 조립된 바이러스-유사 입자들은 정확한 이황화 결합을 형성하지 못하기 때문에 효모 세포들에서 우수한 형태(good conformation)가 부족하다.
곤충 세포에서 발현이 낮고 불용성인 HPV L1 단백질의 경우, 발현 수준 및 용해도의 상당한 증가는 이의 C-말단 단편을 HPV 유형 33 또는 59 L1 단백질의 C-말단 단편으로 변형한 후에 발생할 수 있으며, 이에 따라, HPV 백신의 대량 생산에 사용될 수 있다.
HPV 유형 16 단백질, HPV 유형 28 L1 단백질, HPV 유형 68 L1 단백질 등과 같은 다른 HPV 유형의 L1 단백질들과 비교시, 곤충 세포에서 더 우수한 발현 및 용해도를 갖는 HPV L1 단백질의 경우, 백신들의 대량 생산을 달성하기 위해 발현 수준과 용해도를 더욱 개선할 필요가 있다. 본 발명에서, 예를 들면, HPV 유형 16 L1 단백질의 C-말단 단편을 HPV 유형 33 L1 단백질의 C-말단 단편으로 변형한 후에, 변형된 키메라 HPV 유형 16 단백질의 발현 수준 및 용해도가 개선되는데, 이는 HPV 백신들의 대량 생산에 도움이 된다.
요약하자면, 키메라 HPV L1 단백질들은 변형되지 않은 HPV L1 단백질에 비해 곤충 세포에서 훨씬 더 높은 발현 수준과 용해도를 보여주었다. 이는 HPV 백신들의 대량 생산을 위해 사용될 수 있다. 또한, 키메라 HPV L1 단백질들은 곤충 세포들에서 정확하게 이황화 결합들을 형성하여, 곤충 세포들에서 우수한 형태룰 가진 HPV 바이러스-유사 입자로 조립될 수 있다. 이는 HPV 바이러스-유사 입자들의 면역원성을 개선하고 더 나은 면역 반응들을 일으킬 수 있다.
정의
달리 명시되지 않는 한, 본 명세서에서 사용되는 모든 기술적 및 과학적 용어들은 본 발명이 속하는 기술 분야에서 통상의 기술자가 일반적으로 이해하는 의미를 가진다. 본 발명을 이해를 용이하게 하기 위해, 하기 용어들은 이들의 일반적인 의미에 대해 하기에서 인용된다.
본 명세서 및 첨부된 청구범위에서 사용될 때, 단수 형태 "하나(a/an)", "또 다른(another)" 및 "상기(said/the)"는 문맥이 달리 명확하게 나타내지 않는 한, 복수의 지시 대상을 포함한다. 달리 명시적으로 명시되지 않는 한, 용어 "포함하다/포함하다/가진다(include/comprise/have)", "예를 들면(for example):" 등은 제한이 아니라 포함을 전달하기 위한 것이다.
용어 "면역원성(immunogenicity)"은 물질(예를 들면, 단백질 또는 펩티드)의 면역 반응을 일으키는 능력, 즉, 항체의 생산을 일으키는 능력, 특히, 체액성 또는 세포-매개 반응을 일으키는 능력을 지칭한다.
용어 "항체(antibody)"는 항원에 결합하는 이뮤노글로불린 분자를 지칭한다. 항체는 다중클론성 혼합물 또는 단일클론일 수 있다. 항체는 천연 기원 또는 재조합 기원의 온전한 이뮤노글로불린일 수 있고 온전한 이뮤노글로불린의 면역반응성 부분일 수 있다. 항체는 예를 들면, Fv, Fab', F(ab')2 및 단일 사슬을 포함하여 다양한 형태들로 존재할 수 있다.
용어 "항원성(antigenicity)"은 물질(예를 들면, 단백질 또는 펩티드)이, 항원에 특이적으로 결합하는 항체의 생산을 일으키는 능력을 지칭한다.
용어 "에피토프(epitope)"는 항체 또는 T 세포 수용체에 특이적으로 결합하는 임의의 단백질 결정 클러스터(protein determinant cluster)를 포함한다. 에피토프 결정인자들은 전형적으로 분자의 화학적 활성 표면 그룹(예를 들면, 아미노산 또는 당측 사슬, 또는 이들의 조합)으로 이루어지고, 전형적으로 특정 3차원 구조적 특징들 및 특정 전하 특징들을 가진다.
용어 "아형(subtype)" 또는 "유형(type)"은 본 명세서에서 상호 교환적으로 사용되어 유형마다(type to type) 면역 시스템에 의해 별개의 항원으로 인식되도록 하는 바이러스의 유전적 변이체를 지칭한다. 예를 들면, HPV 16은 HPV33과 면역학적으로 구별된다.
본 명세서에서 사용되는 용어 "HPV L1 단백질(HPV L1 protein)", "HPV" 및 "인간 유두종 바이러스(human papilloma virus)"는 유두종 바이러스 패밀리의 비외피 이중 가닥 DNA 바이러스를 지칭한다. 이들의 게놈은 원형이고 대략 8 킬로 염기쌍의 크기이다. 대부분의 HPV는, "초기" 부위(E1-E2)에서 6개 및 "후기" 부위(L1(주요 캡시드 단백질) 및 L2(부 캡시드 단백질))에서 2개인, 8개의 주요 단백질들을 인코딩한다. 120개 초과의 HPV 유형들이 확인되었고 이들은 숫자(예를 들면, HPV-16, HPV-18 등)로 라벨링되어 있다.
용어 "HPV" 또는 "HPV 바이러스(HPV virus)"는 일반적으로 파필로마비리다에(Papillomaviridae) 패밀리의 유두종 바이러스들을 지칭하고, 일반적으로 하기 3개의 부위들로 나눌 수 있는 대략 8 kb 크기의 이중 가닥 닫힌 원형 DNA 게놈을 가진 비외피 DNA 바이러스들이다: (i) 초기 부위 (E)로서, 바이러스 복제, 전사 및 변형과 관련된 비구조 단백질들을 인코딩하는 6개의 오픈 리딩 프레임 E1, E2, E4-E7, 및 오픈 리딩 프레임 E3 및 E8을 함유하는, 초기 부위 (E); (ii) 후기 부위 (L)로서, 주요 캡시드 단백질 L1 및 부 캡시드 단백질 L2을 인코딩하는 리딩 프레임을 함유하는, 후기 부위 (L); 및 (iii) 긴 조절 부위 (LCR)로서, 어떠한 단백질도 인코딩하지 않지만, 복제 원점 및 다중 전사 인자 결합 위치들을 가지는, 긴 조절 부위 (LCR).
용어 "HPV L1 단백질(HPV L1 protein)" 및 "HPV L2 단백질(HPV L2 protein)"은 HPV 유전자의 후기 부위 (L)에 의해 인코딩되고 HPV 감염 주기 후기에서 합성되는 단백질을 지칭한다. L2 단백질은 부 캡시드 단백질이다. 72개의 L1 5량체들은 20면체의 HPV 입자들의 외부 껍질을 형성하고, 닫힌 원형 이중 가닥 DNA 마이크로염색체를 감싼다(enclose). L2 단백질은 L1 단백질 내부에 있다.
용어 "바이러스-유사 입자(virus-like particle)"는 바이러스 핵산 없이, 하나 또는 복수의 바이러스 구조 단백질들을 함유하는 빈 입자(hollow particle)를 지칭한다.
"HPV 슈도바이러스(HPV pseudovirus)"는 HPV VLP의 비특이적 핵산 캡슐화 특성을 활용함으로써, HPV의 생체 외 중화에 이상적인 모델이고, HPV 슈도바이러스는 유리 DNA를 랩핑(wrapping)하거나 외인성 플라스미드를 세포 내에서 발현되는 HPV L1 및 L2로 구성된 VLP에 도입함으로써 형성된다.
"슈도바이러스 중화 분석(pseudovirus neutralization assay)"은 항체의 중화 활성을 평가하는 방법이다. 면역화된 동물 혈청을 일정량의 슈도바이러스와 함께 인큐베이팅하고, 세포들을 감염시키면, 혈청 중화 항체들이 증가하면서 발현 세포의 양이 감소하여, 특정 범위의 선형 음성 상관관계를 보여준다. 따라서, 혈청에서 항체의 중화 활성은 세포의 양의 변화를 측정함으로써 평가될 수 있다.
용어 "이의 단편(fragment thereof)" 또는 "이의 변이체(variant thereof)"는 본 발명의 뉴클레오티드 또는 아미노산 서열의 결실, 삽입 및/또는 치환을 지칭한다. 바람직하게는, 본 발명에 의해 제공되는 폴리펩티드의 단편 또는 변이체에는 동물 또는 인간에서 체액성- 및/또는 세포성-면역 반응을 일으킬 수 있다.
용어 "키메라(chimeric)"는 상이한 모분자들에서 유래된 폴리펩티드 또는 뉴클레오티드의 서열들이 각각 -CO-NH- 또는 3', 5'-포스포디에스터 결합에 의해 함께 연결되는 것을 의미한다. 바람직하게는, 이들은 추가적인 링커 서열들에 의해 스페이싱(spaced)되지 않고, 서로 직접적으로 인접해 있다.
용어 "절단(truncation)"은 폴리펩티드의 N- 및/또는 C-말단으로부터 하나 또는 복수의 아미노산들의 제거 또는 폴리펩티드의 내부에서 하나 또는 복수의 아미노산들의 결실을 의미한다.
용어 "핵 위치 서열(nuclear localization sequence)"은 단백질을 핵으로 안내하는 아미노산 서열을 지칭한다. 일부 HPV L1 단백질에서, 염기성 잔기들(즉, 핵 위치 서열들)의 2개의 긴밀한(tight) 클러스터들(예를 들면, 하나는 KRKR, KRKK, KRKRK, KRKKRK, KRVKRRK 등이고, 다른 하나는 KR, RKR, KRK 등이다)은 이들 사이에 10-14개 아미노산의 스페이서 부위를 갖는다. 상기 염기성 잔기들의 클러스터들은 핵 위치 서열들에 속한다. 일부 다른 HPV L1 단백질에서 핵 국소화 서열은 아르기닌 및/또는 라이신에 의해 형성된 염기성 잔기들의 긴밀한 클러스터이다. 핵 위치 서열은 앞서 기재된 염기성 잔기들의 클러스터의 예시들을 포함하나, 이에 제한되지 않는다. Jun Yang et al, Predicting the Nuclear Localization Signals of 107 Types of HPV L1 Proteins by Bioinformatic Analysis, Genomics, Proteomics & Bioinformatics Volume 4, Issue 1, 2006, Pages 34-41 참고, 이의 전문은 여기서 참조로 포함된다.
용어 "기능적 변이체(functional variant)"는 절단, 돌연변이, 결실 및/또는 추가 후에, 원하는 활성 또는 특징들을 유지하는 폴리펩티드 또는 단백질의 버전을 지칭한다.
2개의 폴리펩티드 또는 핵산의 서열들 사이의 "서열 동일성(sequence identity)"는 총 잔기 수의 백분율로서 상기 서열들 사이의 동일한 잔기들의 수를 지칭하고, 비교되는 분자들 중 더 작은 분자의 크기를 기준으로 계산된다. 퍼센트 동일성을 계산할 때, 비교되는 서열은 서열들 사이의 최대 매치(match)를 생성하는 방식으로 매칭되고, 매치에서 빈 위치들(존재하는 경우)은 특정 알고리즘에 의해 해결된다. 2개의 서열들 사이의 동일성을 결정하는 바람직한 컴퓨터 프로그램 방법들은, GAP, BLASTP, BLASTN 및 FASTA를 포함하는 GCG 프로그램 패키지들을 포함하나, 이에 제한되지 않는다(Altschul et al, 1990, J. Mol. Biol. 215: 403-410). 상기 프로그램들은 미국 국립 생명공학 정보 센터(NCBI) 및 기타 출처에서 공개적으로 이용가능하다. 잘 알려진 Smith Waterman 알고리즘 또한 동일성을 결정하기 위해 사용될 수 있다.
중요하지 않은 아미노산들(non-critical amino acids)은 단백질의 정상적인 기능에 영향을 미치지 않고 보존적으로 치환될 수 있다. 보존적 치환은 아미노산들을 화학적으로 또는 기능적으로 유사한 아미노산들로 대체하는 것을 의미한다. 유사한 아미노산을 제공하는 보존적 치환들에 대한 표들은 당업계에 잘 알려져 있다. 예를 들면, 일부 구현예에서, 표 1-3에서 제공된 아미노산 그룹들은 서로에 대해 보존적 치환으로 간주된다.
[표 1] 일부 구현예에서, 서로에 대해 보존적 치환으로 간주되는 선택된 아미노산의 그룹들
[표 2] 일부 구현예에서, 서로에 대해 보존적 치환으로 간주되는 다른 선택된 아미노산의 그룹들
[표 3] 일부 구현예에서, 서로에 대해 보존성 치환으로 간주되는 다른 선택된 아미노산의 그룹들
용어 "아미노산(amino acids)"은 20개의 일반적인 자연 발생 아미노산들을 지칭한다. 자연 발생 아미노산은 알라닌 (Ala; A), 아르기닌 (Arg; R), 아스파라진 (Asn; N), 아스파르트산 (Asp; D), 시스테인 (Cys; C), 글루탐산 (Glu; E), 글루타민 (Gln; Q), 글리신(Gly; G), 히스티딘 (His; H), 이소류신 (Ile; I), 류신 (Leu; L), 라이신 (Lys; K), 메티오닌 (Met; M), 페닐알라닌 (Phe; F), 프롤린(Pro; P), 세린 (Ser; S), 트레오닌 (Thr; T), 트립토판 (Trp; W), 티로신 (Tyr; Y) 및 발린 (Val; V)을 포함한다.
용어 "아쥬반트(adjuvant)"는 면역 반응을 향상시키는 화합물 또는 혼합물을 지칭한다. 특히, 백신은 아쥬반트를 포함할 수 있다. 본 발명에서 사용되는 아쥬반트는 하기 중 하나 또는 복수를 포함하나, 이에 제한되지 않는다: 미네랄-함유 아쥬반트 조성물, 오일-에멀젼 아쥬반트, 사포닌 아쥬반트 제형, 박테리아 또는 미생물의 유도체.
용어 "벡터(vector)"는 이와 연결된 또 다른 핵산을 증식시킬 수 있는 핵산 분자를 의미한다. 상기 용어는 자가 복제 핵산 구조물로서의 벡터, 및 벡터가 도입된 숙주 세포의 게놈에 통합된 벡터를 포함한다. 특정 벡터는 이러한 벡터가 작동 가능하게 연결된 핵산들의 발현을 지시할 수 있다.
용어 "숙주 세포(host cell)"는 외인성 핵산이 도입된 세포, 및 이러한 세포의 자손을 지칭한다. 숙주 세포는 "형질전환체(transformants)"(또는 "형질전환된 세포(transformed cells)"), "형질주입체(transfectants)"(또는 "형질주입된 세포(transfected cells)") 또는 "감염체(infectants)"(또는 "감염된 세포(infected cells)")를 포함하며, 이들 각각은 1차 형질전환, 형질주입 또는 감염된 세포 및 이들로부터 유래된 자손을 포함한다. 이러한 자손은 핵산 함량의 관점에서 모세포와 동일하지 않을 수 있고 돌연변이를 함유할 수 있다.
투여량은 바람직하게는, 개체에게 "예방적으로 유효한 양(prophylactically effective amount)"(본 명세서에서 예방은 치료로 간주될 수 있고, 이 둘은 상호 교환적으로 사용될 수 있다)이며, 이는 개체에게 이점을 나타내기에 충분하다.
실시예
실시예 1 키메라 유전자의 작제
실시예 1.1: HPV6 L1의 C-말단이 HPV33 L1의 C-말단으로 치환된 키메라 유전자의 작제
1.1.1 주형으로서 pFB-HPV6 L1의 작제
합성 서열의 양 끝에 KpnI 및 XbaI 절단 자리를 가진 HPV6 L1 유전자는 Thermo Fisher[구 Invitrogen (Shanghai) Trading Co.]에 의해 합성되었으며, 그 서열은 서열 번호: 5에 나타난다. 합성된 유전자 단편을 KpnI 및 XbaI 절단 자리에서 pcDNA3 벡터(판매업체: Thermo Fisher)와 연결시켜 HPV6 L1의 아미노산 1-500을 인코딩하는 뉴클레오티드 서열을 포함하는 플라스미드 pcDNA3-HPV6-L1을 얻었다.
얻어진 pcDNA3-HPV6-L1 플라스미드를 KpnI 및 XbaI로 이중 효소 분해하여 HPV6 L1(1-500)의 유전자 단편을 얻었다. 이후, 단편을 KpnI/ XbaI 이중 분해 pFastBacTM1 벡터(판매업체: Thermo Fisher)와 연결시켜, pFB-HPV6 L1로 명명된 HPV6 L1(1-500) 유전자 단편을 함유하는 bacmid 벡터()를 얻었다.
1.1.2 주형으로서 pFB-HPV33 L1의 작제
합성 서열의 양 끝에 KpnI 및 XbaI 절단 자리를 가진 HPV33 L1 유전자는 Thermo Fisher (구 Invitrogen (Shanghai) Trading Co.)에 의해 합성되었으며, 그 서열은 서열 번호: 6에 나타난다. 합성된 유전자 단편을 KpnI 및 XbaI 절단 자리에서 pcDNA3 벡터(판매업체: Thermo Fisher)와 연결시켜 HPV33 L1의 아미노산 1-499를 인코딩하는 뉴클레오티드 서열을 포함하는 플라스미드 pcDNA3-HPV33-L1을 얻었다.
상기 pcDNA3-HPV33-L1 플라스미드를 KpnI 및 XbaI로 이중 효소 분해하여 HPV33 L1(1-499) 유전자의 단편을 얻었다. 이후, 단편을 KpnI 및 XbaI 이중 분해 pFastBacTM1 벡터(판매업체: Thermo Fisher)와 연결시켜, pFB-HPV33 L1로 명명된 HPV33 L1(1-499) 유전자 단편을 함유하는 bacmid 벡터를 얻었다.
1.1.3 pFB-HPV6 L1 33C의 작제
HPV6 L1 C-말단이 HPV33 L1 C-말단으로 치환된 키메라 유전자: 작제된 재조합 플라스미드 pFB-HPV6 L1을 유전자 주형으로 사용하고 프라이머 F1 및 R1을 사용하여 1426 bp 유전자 단편으로 증폭했다, 프라이머 서열 F1은 서열 번호: 7에 나타나고 R1은 서열 번호: 8에 나타난다.
이 유전자 단편은 HPV6 L1의 아미노산 1-469를 인코딩하는 단편, HPV33 L1의 아미노산 474-499를 인코딩하는 유전자 단편과 중첩되는 10개의 염기, 및 KpnI 제한 자리 (GGTAC^C)의 단편을 인코딩하는 단편을 함유하고, 증폭된 서열은 하기 서열 번호: 9에 나타난다.
PCR 증폭 매개변수: 5분 동안 94℃에서 사전-변성(pre-denaturation); 10초 동안 98℃에서 변성, 15s 동안 69℃에서 어닐링(annealing), 72℃에서 1 kb/1분, 30 사이클 동안 수행; 5 분 동안 72 ℃에서 신장(extension); 16℃에서 종료.
재조합 플라스미드 pFB-HPV33 L1을 프라이머 F2 및 R2를 사용하여 101 bp 길이의 유전자 단편을 증폭시키는 유전자 주형으로 사용하였고, F2의 프라이머 서열은 서열 번호: 10에 나타나고 및 R2의 프라이머 서열은 서열 번호: 11에 나타난다.
이 유전자 단편은 HPV33 L1의 26개의 C-말단 아미노산(474-499)을 인코딩하는 유전자 단편, HPV6 L1의 아미노산 1-469의 C-말단을 인코딩하는 유전자 단편과 중첩되는 10 bp 염기, 및 Xbal (T^CTAGA) 제한 자리를 함유하고, 증폭된 서열은 서열 번호: 12에 나타난다.
PCR 증폭 매개변수: 5분 동안 94℃에서 사전-변성; 10 s 동안 98℃에서 변성, 15s 동안 69℃에서 어닐링, 72℃에서 1kb/1분, 30 사이클 동안 수행; 5 분 동안 72 ℃에서 신장; 16℃에서 종료.
PCR 연결 서열(ligating sequences):
연결 프라이머(ligating primer)는 F1 및 R2이고, 상기 프라이머를 사용하여 증폭된 단편들(F1 및 R1의 증폭된 단편, F2 및 R2의 증폭된 단편)을 주형으로 사용했다.
PCR 연결 매개변수: 5분 동안 94 ℃에서 사전-변성; 10 s 동안 98℃에서 변성, 15 s 동안 52℃에서 어닐링, 72℃에서 1kb/1분, 5 사이클 동안 수행; 10 s 동안 98℃에서 변성, 15 s 동안 68℃에서 어닐링, 72℃에서 1kb/1분, 25사이클 동안 수행; 5분 동안 72 ℃에서 신장; 16℃에서 종료.
최종 생성물은 HPV6 L1의 아미노산 1-469 및 HPV33 L1의 26개의 C-말단 아미노산들(aa 474-499)을 인코딩하는 뉴클레오티드 서열인 서열 번호: 4였고, 양 끝에 KpnI 및 XbaI 절단 자리를 가진다(이하 연결 서열로 지칭함). pFastBacTM1 벡터 및 연결 서열 단편을 Kpnl+Xbal 효소로 이중 분해하고, 연결 서열을 pFastBacTM1 벡터에 클로닝하여 재조합 HPV6 L1: 33C을 얻었는데, 이는 HPV6 L1의 C-말단이 HPV33 L1의 C-말단으로 치환된 키메라 유전자이다.
실시예 1.2 HPV11 L1의 C-말단이 HPV33 L1의 C-말단으로 치환된 키메라 유전자의 작제
실험 방법 및 절차는 실시예 1.1과 동일하며, 관련 서열은 부록 2 참고.
실시예 1.3 HPV16 L1의 C-말단이 HPV33 L1의 C-말단으로 치환된 키메라 유전자의 작제
실험 방법 및 절차는 실시예 1.1과 동일하며, 관련 서열은 부록 3 참고.
실시예 1.4 HPV18 L1의 C-말단이 HPV33 L1의 C-말단으로 치환된 키메라 유전자의 작제
실험 방법 및 절차는 실시예 1.1과 동일하며, 관련 서열은 부록 4 참고.
실시예 1.5 HPV31 L1의 C-말단이 HPV33 L1의 C-말단으로 치환된 키메라 유전자의 작제
실험 방법 및 절차는 실시예 1.1과 동일하며, 관련 서열은 부록 5 참고.
실시예 1.6 HPV35 L1의 C-말단이 HPV33 L1의 C-말단으로 치환된 키메라 유전자의 작제
실험 방법 및 절차는 실시예 1.1과 동일하며, 관련 서열은 부록 6 참고.
실시예 1.7 HPV39 L1의 C-말단이 HPV59 L1의 C-말단으로 치환된 키메라 유전자의 작제
1.7.1 주형으로 사용되는 pFB-HPV39 L1의 작제
합성 서열의 양 끝에 KpnI 및 XbaI 절단 자리를 가진 HPV39 L1 유전자는 Thermo Fisher[구 Invitrogen (Shanghai) Trading Co.]에 의해 합성되었으며, 그 서열은 서열 번호: 83에 나타난다. 합성된 유전자 단편을 KpnI 및 XbaI 절단 자리에서 pcDNA3 벡터(판매업체: Thermo Fisher)와 연결시켜 HPV39 L1의 아미노산 1-505를 인코딩하는 뉴클레오티드 서열을 함유하는 플라스미드 pcDNA3-HPV39-L1을 얻었다.
상기 pcDNA3-HPV39-L1 플라스미드를 KpnI 및 XbaI로 이중 분해하여 HPV39 L1(1-505) 유전자의 단편을 얻었다. 이후, 단편을 KpnI 및 XbaI 이중 분해 pFastBacTM1 벡터(판매업체: Thermo Fisher)와 연결시켜, pFB-HPV39 L1로 명명된 HPV39 L1(1-505) 유전자 단편을 함유하는 bacmid 벡터를 얻었다.
1.7.2 주형으로서 pFB-HPV59L1의 작제
HPV59L1의 아미노산 1-508을 인코딩하는 뉴클레오티드 서열을 함유하는 플라스미드 pcDNA3-HPV59-L1을 얻기 위해 HPV59L1 유전자는 Thermo Fisher(구 Invitrogen (Shanghai) Trading Co.)에 의해 합성되었다.
pcDNA3-HPV59-L1 플라스미드를 KpnI 및 XbaI로 이중 분해하여 HPV59L1(1-508) 유전자의 단편을 얻었다. 이후, 단편을 KpnI / XbaI로 이중 분해 pFastBacTM1 벡터(판매업체: Thermo Fisher)와 연결시켜 pFB-HPV59L1로 명명된 HPV59L1(1-508) 유전자 단편을 함유하는 bacmid 벡터를 얻었다.
1.7.3 pFB-HPV39 L1: 59C의 작제
HPV39 L1 C-말단이 HPV59 L1 C-말단으로 치환된 키메라 유전자: 작제된 재조합 플라스미드 pFB-HPV39 L1을 유전자 주형으로 사용하고 프라이머 F1 및 R1을 사용하여 1428 bp 유전자 단편으로 증폭했다, 프라이머 서열 F1은 서열 번호: 85에 나타나고 프라이머 서열 R1은 서열 번호: 86에 나타난다.
이 단편은 HPV39 L1의 아미노산 1-469를 인코딩하는 단편, HPV59 L1의 아미노산 471-508을 인코딩하는 단편과 중첩되는 12개의 염기, 및 KpnI 제한 자리 (GGTAC^C)의 세그멘트를 함유하고, 증폭된 서열은 서열 번호: 87에 나타난다.
PCR 증폭 매개변수: 5분 동안 94℃에서 사전-변성; 10 s 동안 98℃에서 변성, 15s 동안 69℃에서 어닐링, 72℃에서 1kb/1분, 30 사이클 동안 수행; 5 분 동안 72 ℃에서 신장; 16℃에서 종료.
재조합 플라스미드 pFB-HPV59 L1을 유전자 주형으로 사용하고 프라이머 F2 및 R2를 사용하여 139bp 길이의 유전자 단편을 증폭하였다. 프라이머 서열 F2는 서열 번호: 88에 나타나고 R2는 서열 번호: 89에 나타난다.
이 유전자 단편은 HPV59L1의 38개의 C-말단 아미노산(471-508)을 인코딩하는 유전자 단편, HPV39 L1의 아미노산 1-469를 인코딩하는 유전자 단편과 중첩되는 12 bp 염기, 및 Xbal(T^CTAGA) 제한 자리를 함유하고, 증폭된 서열은 서열 번호: 90에 나타난다.
PCR 증폭 매개변수: 5분 동안 94℃에서 사전-변성; 10s 동안 98℃에서 변성, 15s 동안 69℃에서 어닐링, 72℃에서 1kb/1분, 30 사이클 동안 수행, 5분 동안 72℃에서 신장; 16℃에서 종료.
PCR 연결 서열
연결 프라이머는 F1 및 R2였고, 상기 프라이머를 사용하여 증폭된 단편들(F1 및 R1 증폭된 단편들, F2 및 R2 증폭된 단편들)을 주형으로 사용했다.
PCR 연결 매개변수: 5분 동안 94℃에서 사전-변성; 10s 동안 98℃에서 변성, 15s 동안 52℃에서 어닐링, 72℃에서 1kb/1분, 5 사이클 동안 수행, 10s 동안 98℃에서 변성, 15s 동안 68℃에서 어닐링, 72℃에서 1kb/1분, 25 사이클 동안 수행; 5분 동안 72℃에서 신장, 16℃에서 종료.
최종 생성물은 HPV39 L1의 아미노산 1-469 및 HPV59 L1의 38개의 C-말단 아미노산(471-508)을 인코딩하는 뉴클레오티드 서열인 서열 번호: 82였고, 양 끝에 KpnI 및 XbaI 효소 절단 자리를 가진다(이후 연결 서열로 지칭함).
pFastBacTM1 벡터 및 연결 서열 단편을 Kpnl+Xbal 효소로 이중 분해하고, 연결 서열을 pFastBacTM1 벡터에 클로닝하여 pFB-HPV39 L1: 59C을 얻었는데, 이는 HPV39 L1의 C-말단이 HPV59 L1의 C-말단으로 치환된 키메라 유전자이다.
실시예 1.8 HPV45L1의 C-말단이 HPV33 L1의 C-말단으로 치환된 키메라 유전자의 작제.
실험 방법 및 절차는 실시예 1.1과 동일하며, 관련 서열은 부록 8 참고.
실시예 1.9 HPV51L1의 C-말단이 HPV33 L1의 C-말단으로 치환된 키메라 유전자의 작제
실험 방법 및 절차는 실시예 1.1과 동일하며, 관련 서열은 부록 9 참고.
실시예 1.10 HPV52L1의 C-말단이 HPV33 L1의 C-말단으로 치환된 키메라 유전자의 작제.
실험 방법 및 절차는 실시예 1.1과 동일하며, 관련 서열은 부록 10 참고.
실시예 1.11 HPV56L1의 C-말단이 HPV33L1의 C-말단으로 치환된 키메라 유전자의 작제
실험 방법 및 절차는 실시예 1.1과 동일하며, 관련 서열은 부록 11 참고.
실시예 1.12 HPV58L1의 C-말단이 HPV33 L1의 C-말단으로 치환된 키메라 유전자의 작제
실험 방법 및 절차는 실시예 1.1과 동일하며, 관련 서열은 부록 12 참고.
실시예 2: 재조합 배큘로바이러스 패키징
실시예 2.1: HPV6 L1: 33C 재조합 배큘로바이러스 패키징
실시예 1에서 작제한 pFB-HPV6 L1: 33C의 재조합 플라스미드를 정확하게 동정 및 시퀀싱하여, DH10Bac 박테리아 컴피턴트 세포(Bac-to-Bac® kit, Thermo Fisher에서 구입)에 형질전환하였고, 증식을 위해 37℃에서 배양하고, 획선 배양(streak culture)을 위해 평평한 디쉬(flat dish)에 인큐베이팅했다. 흰 콜로니를 선택하였고, 밤새 인큐베이팅했다. 박테리아 배양액을 수집하고 재조합 배큘로바이러스 DNA를 알칼린 용해법을 사용하여 추출했다.
재조합 배큘로 바이러스 DNA를 양이온성 형질주입 시약(Sino Biological에서 구입)을 사용하여 곤충 세포 SF9에 형질주입함으로써 재조합 배큘로바이러스 독성 균주(recombinant baculovirus virulent strains)를 패키징했다. 절차는 하기와 같다.
a. 대수기(log phase)에 있는 SF9 세포를 0.6Х106 세포/디쉬의 밀도로 디쉬에 접종했다. 세포가 디쉬 벽에 부착되도록 SF9 세포로 접종된 디쉬를 2시간 동안 실온에서 방치했다.
b. 20μL의 추출된 플라스미드 Bacmid DNA를 200 μL Grace's Medium (혈청 없음, 첨가제 없음, Gibico에서 구입)에 첨가하고 5회 혼합 및 반전(invert)시켰다.
c. 25 μL의 0.2x TF1(형질주입 시약, Sino Biological에서 구입)을 Grace's Medium에 적가하고 부드럽게 혼합했다.
d. b와 c를 혼합했다. 15-45 분 동안 실온에서 인큐베이팅했다.
e. DNA를 cellfectin(Sino Biological에서 구입)과 함께 배양하는 동안, 세포 상층액을 제거하고 0.8 mL의 Grace Medium(혈청 첨가제 없음)을 디쉬에 첨가했다.
f. d의 DNA 및 형질주입 시약의 인큐베이팅된 혼합물을 디쉬에 적가했다.
g. 2시간 동안 27℃에서 인큐베이팅했다.
h. 세포 배양 배지를 제거하고 2.5mL 완전 성장 배지/디쉬 (SCD6 SF + 10% FBS)(SCD6 SF는 Sino Biological에서 구입, FBS는 Gibico에서 구입)를 첨가했다.
i. 7일 동안 27℃에서 배양했고 바이러스 감염이 일어났는지 여부를 관찰했다.
통상적으로 7-11일 동안 배양한 후에, 형질주입된 세포에서 뚜렷한 병변이 관찰되면, 바이러스 상층액을 수집했다. 바이러스 상층액, 즉 HPV6 L1: 33C의 P1 세대 바이러스 균주를 파이펫으로 무균적으로 수집했다. 2 x 106 세포/mL 밀도에서 SF9 세포를 HPV6 L1: 33C의 P1 세대 바이러스 균주를 사용하여 1:50 (V/V)의 비로 감염시키고, 3일 동안 27 ℃에서 배양하고, 실온에서 10분 동안 1000g ± 200g로 원심분리하였다. 수집된 바이러스 상층액은 P2 세대 바이러스였고 숙주 세포 감염 및 생산에 사용될 수 있다.
실시예 2.2: HPV11 L1: 33C 재조합 배큘로바이러스의 패키징
실험 방법 및 절차는 실시예 2.1과 동일하였다.
실시예 2.3: HPV 16L1: 33C 재조합 배큘로바이러스의 패키징
실험 방법과 절차는 실시예 2.1과 동일하였다.
실시예 2.4: HPV18 L1: 33C 재조합 배큘로바이러스의 패키징
실험 방법과 절차는 실시예 2.1과 동일하였다.
실시예 2.5: HPV31 L1: 33C 재조합 배큘로바이러스의 패키징
실험 방법과 절차는 실시예 2.1과 동일하였다.
실시예 2.6: HPV35 L1: 33C 재조합 배큘로바이러스의 패키징
실험 방법과 절차는 실시예 2.1과 동일하였다.
실시예 2.7: HPV39 L1: 59C 재조합 배큘로바이러스의 패키징
실험 방법과 절차는 실시예 2.1과 동일하였다.
실시예 2.8: HPV45 L1: 33C 재조합 배큘로바이러스의 패키징
실험 방법과 절차는 실시예 2.1과 동일하였다.
실시예 2.9: HPV51 L1: 33C 재조합 배큘로바이러스의 패키징
실험 방법과 절차는 실시예 2.1과 동일하였다.
실시예 2.10: HPV52 L1: 33C 재조합 배큘로바이러스의 패키징
실험 방법과 절차는 실시예 2.1과 동일하였다.
실시예 2.11: HPV56 L1: 33C 재조합 배큘로바이러스의 패키징
실험 방법과 절차는 실시예 2.1과 동일하였다.
실시예 2.12: HPV58 L1: 33C 재조합 배큘로바이러스의 패키징
실험 방법과 절차는 실시예 2.1과 동일하였다.
실시예 3 키메라 단백질의 발현
실시예 3.1: HPV6 L1: 33C의 발현
High Five 세포들에 실시예 2에서 얻은 HPV6L1: 33C 재조합 유전자를 함유하는 배큘로바이러스를 1:200 (V/V)의 비로 감염시켰고, 실온에서 1000g ± 100g로 원심분리하여 세포 침전물을 수집했다. PBS 또는 MOPS 완충액(pH6.0-7.0, 염농도 100mM-1M)을 사용하고 세포를 3분 동안 저온에서 초음파 처리하여 분해시켰고, 10분 동안 >10,000g로 원심분리하고, SDS-PAGE를 위해 상층액을 수집했다 레인 1: 마커 (마커는 14.4 kDa 내지 116 kDa 범위의 분자량을 갖는 7개의 정제된 단백질들의 혼합물, Thermo Scientific 제조); 레인 2: 세포 용해물; 원심분리에 의해 수집된 용해물의 상층액.
그 결과는 도 1a에 나타난다. 이 방법에 의해 제조된 The HPV6 L1: 33C L1 단백질은 >100 mg/L의 수율을 가지고 대략 56 KD의 단백질 크기를 가지며, 이는 대량 생산에 사용될 수 있다.
실시예 3.2: HPV11 L1: 33C의 발현 및 생산
실험 방법 및 절차는 실시예 3.1과 동일하였다.
그 결과는 도 1b에 나타난다. 이 방법에 의해 제조된 HPV11 L1: 33C L1 단백질은 >100 mg/L의 수율을 가지고 대략 56 KD의 단백질 크기를 가지며, 이는 대량 생산에 사용될 수 있다.
실시예 3.3: HPV 16L1: 33C의 발현 및 생산
실험 방법 및 절차는 실시예 3.1과 동일하였다.
그 결과는 도 1c에 나타난다. 이 방법에 의해 제조된 HPV 16L1: 33C L1 단백질은 >100 mg/L의 수율을 가지고 대략 56 KD의 단백질 크기를 가지며, 이는 대량 생산에 사용될 수 있다.
실시예 3.4: HPV18 L1: 33C의 발현 및 생산
실험 방법 및 절차는 실시예 3.1과 동일하였다.
그 결과는 도 1d에 나타난다. 이 방법에 의해 제조된 HPV 18 L1: 33C L1 단백질은 >100 mg/L의 수율을 가지고 대략 56 KD의 단백질 크기를 가지며, 이는 대량 생산에 사용될 수 있다.
실시예 3.5: HPV31 L1: 33C의 발현 및 생산
실험 방법 및 절차는 실시예 3.1과 동일하였다.
그 결과는 도 1e에 나타난다. 이 방법에 의해 제조된 HPV31 L1: 33C L1 단백질은 >100 mg/L의 수율을 가지고 대략 56 KD의 단백질 크기를 가지며, 이는 대량 생산에 사용될 수 있다.
실시예 3.6: HPV35 L1: 33C의 발현 및 생산
실험 방법 및 절차는 실시예 3.1과 동일하였다.
결과는 도 1f에 나타난다. 이 방법에 의해 제조된 HPV35 L1: 33C L1 단백질은 >100 mg/L의 수율을 가지고 대략 56 KD의 단백질 크기를 가지며, 이는 대량 생산에 사용될 수 있다.
실시예 3.7: HPV39 L1: 59C의 발현 및 생산
실험 방법 및 절차는 실시예 3.1과 동일하였다.
결과는 도 1g에 나타난다. 이 방법에 의해 제조된 HPV39 L1: 59C L1 단백질은 >100 mg/L의 수율을 가지고 대략 56 KD의 단백질 크기를 가지며, 이는 대량 생산에 사용될 수 있다.
실시예 3.8: HPV45 L1: 33C의 발현 및 생산
실험 방법 및 절차는 실시예 3.1과 동일하였다.
결과는 도 1h에 나타난다. 이 방법에 의해 제조된 HPV45 L1: 33C L1 단백질은 >100 mg/L의 수율을 가지고 대략 56 KD의 단백질 크기를 가지며, 이는 대량 생산에 사용될 수 있다.
실시예 3.9: HPV51 L1: 33C의 발현 및 생산
실험 방법 및 절차는 실시예 3.1과 동일하였다.
결과는 도 1i에 나타난다. 이 방법에 의해 제조된 HPV51 L1: 33C L1 단백질은 >100 mg/L의 수율을 가지고 대략 56 KD의 단백질 크기를 가지며, 이는 대량 생산에 사용될 수 있다.
실시예 3.10: HPV52 L1: 33C의 발현 및 생산
실험 방법 및 절차는 실시예 3.1과 동일하였다.
결과는 도 1j에 나타난다. 이 방법에 의해 제조된 HPV52 L1: 33C L1 단백질은 >100 mg/L의 수율을 가지고 대략 56 KD의 단백질 크기를 가지며, 이는 대량 생산에 사용될 수 있다.
실시예 3.11: HPV56 L1: 33C의 발현 및 생산
실험 방법 및 절차는 실시예 3.1과 동일하였다.
결과는 도 1k에 나타난다. 이 방법에 의해 제조된 HPV56 L1: 33C L1 단백질은 >100 mg/L의 수율을 가지고 대략 56 KD의 단백질 크기를 가지며, 이는 대량 생산에 사용될 수 있다.
실시예 3.12: HPV58 L1: 33C의 발현 및 생산
실험 방법 및 절차는 실시예 3.1과 동일하였다.
결과는 도 1l에 나타난다. 이 방법에 의해 제조된 HPV58 L1: 33C L1 단백질은 >100 mg/L의 수율을 가지고 대략 56 KD의 단백질 크기를 가지며, 이는 대량 생산에 사용될 수 있다.
실시예 4 정제된 바이러스-유사 입자의 제조
실시예 4.1: 정제된 HPV6 L1: 33C 바이러스-유사 입자의 제조
HPV6 L1: 33C 바이러스-유사 입자를 2단계 크로마토그래피 방법, 즉, HS-MMA 방법으로 정제하였고, 실시예 3에서 수집된 상층액을 정제하여, 최종적으로 고순도의 바이러스-유사 입자들을 얻었다.
1 단계 크로마토그래피:
배지: Thermo Fisher에 의해 제조된 POROS® 50 HS 강한 양이온 교환 배지를 사용하였다.
배지 부피: 150mL의 배지 부피, 30mL/분의 선형 유속.
크로마토그래피 조건: 평형 완충액(pH 6.2, 염 농도는 50mM 포스페이트, 0.5 M NaCl); 세척 완충액(염 농도는 50 mM 포스페이트, 0.75 M NaCl, pH 6.2).
크로마토그래피 컬럼을 먼저 5 CV의 평형 완충액으로 평형화한 다음, 샘플을 로딩했다. 로딩 후, 컬럼을 각각 5 CV의 평형 완충액 및 세척 완충액으로 용출시켜 단백질 불순물을 제거하였다.
용출 조건: pH 6.2, 50 mM 아르기닌 하이드로클로라이드, 및 용출 염 농도 1.25 M의 NaCl을 함유하는 50mM 포스페이트 완충액을 사용했다.
2 단계 크로마토그래피.
배지: Bestchrom (Shanghai) Biosciences Co., Ltd에 의해 제조된 MMA 이온 교환 배지를 사용했다.
배지 부피: 배지 부피는 150mL이고, 선형 유속은 30mL/분이다.
크로마토그래피 조건: 평형 완충액: 50 mM PB, 1.25 M NaCl, pH 6.2. 크로마토그래피 컬럼을 먼저 4CV 평형 버퍼로 평형화한 다음, 샘플을 로딩했다. 로딩 후, 단백질 불순물을 5CV 평형 버퍼로 세척(rinsed off)한 다음, 표적 단백질을 용출 완충액으로 용출하여 수집하였다.
용출 조건: 100 mM NaAC, 150 mM NaCl, 0.01% Tween 80, pH 4.5.
실시예 4.2: 정제된 HPV11 L1: 33C 바이러스-유사 입자의 제조
실험 방법 및 절차는 실시예 4.1과 동일하였다.
실시예 4.3: HPV 16L1: 33C 바이러스-유사 입자의 정제 및 제조
실험 방법 및 절차는 실시예 4.1과 동일하였다.
실시예 4.4: HPV18 L1: 33C 바이러스-유사 입자의 정제 및 제조
실험 방법 및 절차는 실시예 4.1과 동일하였다.
실시예 4.5: HPV31 L1: 33C 바이러스-유사 입자의 정제 및 제조
실험 방법 및 절차는 실시예 4.1과 동일하였다.
실시예 4.6: 정제된 HPV35 L1: 33C 바이러스-유사 입자의 제조
실험 방법 및 절차는 실시예 4.1과 동일하였다.
실시예 4.7: 정제된 HPV39 L1: 59C 바이러스-유사 입자의 제조
실험 방법 및 절차는 실시예 4.1과 동일하였다.
실시예 4.8: 정제된 HPV45 L1: 33C 바이러스-유사 입자의 제조
실험 방법 및 절차는 실시예 4.1과 동일하였다.
실시예 4.9: 정제된 HPV51 L1: 33C 바이러스-유사 입자의 제조
실험 방법 및 절차는 실시예 4.1과 동일하였다.
실시예 4.10: 정제된 HPV52 L1: 33C 바이러스-유사 입자의 제조
실험 방법 및 절차는 실시예 4.1과 동일하였다.
실시예 4.11: 정제된 HPV56 L1: 33C 바이러스-유사 입자의 제조
실험 방법 및 절차는 실시예 4.1과 동일하였다.
실시예 4.12: 정제된 HPV58 L1: 33C 바이러스-유사 입자의 제조
실험 방법 및 절차는 실시예 4.1과 동일하였다.
실시예 5 바이러스-유사 입자의 형태학적 관찰
실시예 5.1: HPV6 L1: 33C 바이러스-유사 입자의 형태학적 관찰
투과 전자 현미경 검사를 위해 10 μL 샘플을 취하였다 샘플을 탄소 코팅된 구리 그리드 상에 2분 동안 고정시켰고, 잔류액을 여과지로 흡수시킨 후, 포스포텅스텐산(phosphotungstic acid)(Beijing Electron Microscopy China Technology Co., Ltd., 농도 2%, pH 6.5)으로 매회 30초 동안 2회 염색하고, 잔류 염색액을 여과지로 흡수시켰고, 샘플을 건조한 다음, 투과 전자 현미경 관찰을 수행했다. 투과 전자 현미경 (브랜드: Hitachi, Model No.: H-7650)은 80KV이고 80,000x의 배율을 가진다.
전자 현미경 관찰은 도 2a에 나타난다. 도 2a에서 볼 수 있듯이, C-말단 변형된 HPV6 L1: 33C는 대략 60 nm의 평균 직경을 갖는 균일한 크기의 바이러스-유사 입자를 형성할 수 있다.
실시예 5.2: HPV11 L1: 33C 바이러스-유사 입자의 형태학적 관찰
실험 방법 및 절차는 실시예 5.1과 동일하였다.
전자 현미경 관찰은 도 2b에 나타난다. 도 2b에서 볼 수 있듯이, C-말단 변형된 HPV11 L1: 33C는 대략 약 60nm의 평균 직경을 갖는 균일한 크기의 바이러스-유사 입자를 형성할 수 있다.
실시예 5.3: HPV 16L1: 33C 바이러스-유사 입자의 형태학적 관찰
실험 방법 및 절차는 실시예 5.1과 동일하였다.
전자 현미경 관찰은 도 2c에 나타난다. 도 2c에서 볼 수 있듯이, C-말단 변형된 HPV 16L1: 33C는 대략 60nm의 평균 직경을 갖는 균일한 크기의 바이러스-유사 입자를 형성할 수 있다.
실시예 5.4: HPV18 L1: 33C 바이러스-유사 입자의 형태학적 관찰
실험 방법 및 절차는 실시예 5.1과 동일하였다.
전자 현미경 관찰은 도 2d에 나타난다. 도 2d에서 볼 수 있듯이, C-말단 변형된 HPV18 L1: 33C는 대략 60nm의 평균 직경을 갖는 균일한 크기의 바이러스-유사 입자를 형성할 수 있다.
실시예 5.5: HPV31 L1: 33C 바이러스-유사 입자의 형태학적 관찰
실험 방법 및 절차는 실시예 5.1과 동일하였다.
전자 현미경 관찰은 도 2e에 나타난다. 도 2e에서 볼 수 있듯이 C-말단 변형된 HPV31 L1: 33C는 대략 60nm의 평균 직경을 갖는 균일한 크기의 바이러스-유사 입자를 형성할 수 있다.
실시예 5.6: HPV35 L1: 33C 바이러스-유사 입자의 형태학적 관찰
실험 방법 및 절차는 실시예 5.1과 동일하였다.
전자 현미경 관찰은 도 2f에 나타난다. 도 2f에서 볼 수 있듯이, C-말단 변형된 HPV35 L1: 33C는 대략 60nm의 평균 직경을 갖는 균일한 크기의 바이러스-유사 입자를 형성할 수 있다.
실시예 5.7: HPV39 L1: 59C 바이러스-유사 입자의 형태학적 관찰
실험 방법 및 절차는 실시예 5.1과 동일하였다.
전자 현미경 관찰은 도 2g에 나타난다. 도 2g에서 볼 수 있듯이, C-말단 변형된 HPV39 L1: 59C는 대략 60nm의 평균 직경을 갖는 균일한 크기의 바이러스-유사 입자를 형성할 수 있다.
실시예 5.8: HPV45 L1: 33C 바이러스-유사 입자의 형태학적 관찰
실험 방법 및 절차는 실시예 5.1과 동일하였다.
전자 현미경 관찰은 도 2h에 나타난다. 도 2h에서 볼 수 있듯이, C-말단 변형된 HPV45 L1: 33C는 대략 60nm의 평균 직경을 갖는 균일한 크기의 바이러스-유사 입자를 형성할 수 있다.
실시예 5.9: HPV51 L1: 33C 바이러스-유사 입자의 형태학적 관찰
실험 방법 및 절차는 실시예 5.1과 동일하였다.
전자 현미경 관찰은 도 2i에 나타난다. 도 2I에서 볼 수 있듯이, C-말단 변형된 HPV51 L1: 33C는 대략 60nm의 평균 직경을 갖는 균일한 크기의 바이러스-유사 입자를 형성할 수 있다.
실시예 5.10: HPV52 L1: 33C 바이러스-유사 입자의 형태학적 관찰
실험 방법 및 절차는 실시예 5.1과 동일하였다.
전자 현미경 관찰은 도 2j에 나타난다. 도 2J에서 볼 수 있듯이, C-말단 변형된 HPV52 L1: 33C는 대략 60nm의 평균 직경을 갖는 균일한 크기의 바이러스-유사 입자를 형성할 수 있다.
실시예 5.11: HPV56 L1: 33C 바이러스-유사 입자의 형태학적 관찰
실험 방법 및 절차는 실시예 5.1과 동일하였다.
전자 현미경 관찰은 도 2k에 나타난다. 도 2k에서 볼 수 있듯이, C-말단 변형된 HPV56 L1: 33C는 대략 60nm의 평균 직경을 갖는 균일한 크기의 바이러스-유사 입자를 형성할 수 있다.
실시예 5.12: HPV58 L1: 33C 바이러스-유사 입자의 형태학적 관찰
실험 방법 및 절차는 실시예 5.1과 동일하였다.
전자 현미경 관찰은 도 2l에 나타난다. 도 2l에서 볼 수 있듯이, C-말단 변형된 HPV58 L1: 33C는 대략 60nm의 평균 직경을 갖는 균일한 크기의 바이러스-유사 입자를 형성할 수 있다.
실시예 6 동물에서 바이러스-유사 입자의 면역원성 평가
실시예 6.1: 동물에서 HPV6 L1: 33C 바이러스-유사 입자의 면역원성 평가
6.1.1 슈도바이러스-중화 세포의 모델링
HPV는 생체 외에서 배양하기 어렵고 숙주 특이성이 강하기 때문에, 인간 이외의 유기체에서 번식시키기 어렵고, 따라서 적합한 동물 모델이 부족하다. 그러므로, 백신 면역보호성의 평가를 위한 적절하고 효과적인 생체 외 중화 실험 모델을 확립하는 것이 필요하다.
HPV 슈도바이러스는 생체 외 중화에서 HPV에 대한 이상적인 모델이다: HPV VLP의 핵산을 비특이적으로 캡슐화하는 특징 덕분에, 유리 DNA를 캡슐화하거나 외인성 플라스미드를 도입함으로써, 세포에서 발현되는 HPV L1 및 L2로 구성된 VLP들로부터 HPV 슈도바이러스를 형성할 수 있다.
면역화된 동물 혈청 샘플의 면역원성을 슈도바이러스 중화 분석으로 분석했다. HPV6 바이러스-유사 입자로 면역화된 동물은 HPV6에 대한 중화 항체를 생성할 수 있고, 이는 HPV6 슈도바이러스를 중화할 수 있다. 면역화된 동물 혈청을 특정한 양의 슈도바이러스과 함께 인큐베이팅하고 세포를 감염시키면, 혈청에서 중화 항체가 증가함에 따라 GFP 형광을 발현할 수 있는 세포의 수는 감소했고, 특정 범위의 선형 음의 상관관계를 나타냈다. 따라서, 혈청에서 항체의 중화 활성은 GFP를 발현하는 세포의 수의 변화를 검출함으로써 평가될 수 있다.
슈도바이러스의 작제 방법: HPV6 pCMV3-3-HPV6 L1+L2 (Uniprot P69898의 L1 서열, Uniprot Q84297의 L2 서열) 플라스미드 (Sino Biological로부터 구입) 및 형광 플라스미드(PSEU-GFP Spark, Sino Biological에서 구입)를 293FT 부착 세포 (Thermo Fisher에서 구입)에 함께-형질주입했다. 구체적인 방법은 공개된 문헌 (Pastrana D V, Buck C B, Pang Y S, Thompson C D, Castle P E, FitzGerald P C, Kjaer S K, Lowy D R, Schiller J T. Reactivity of human sera in a sensitive, high-throughput pseudovirus-based papilloma virus neutralization assay for HPV16 and HPV18. [J] Virology 2004,321:205-216.)을 참조한다. 슈도바이러스 상층액을 수집하고 분취(aliquoted)했고, 스톡(stock)용으로 -80℃ 냉장고에 저장하였다.
6.1.2 동물에서 HPV6 L1: 33C 바이러스-유사 입자의 면역 보호 평가
마우스의 면역화 절차: HPV6 L1: 33C 바이러스-유사 입자를 알루미늄 포스페이트 아쥬반트 상에 흡착시키고, 혼합했고, 이를 총 10마리의 마우스에, 마우스 당 0.15 μg/200 μL의 투여량으로 마우스를 면역화하는데 사용했다.
0일, 7일, 및 21일차에, 마우스를 희석된 샘플들로 면역화하였고, 대조군 마우스를 블랭크 혈청(blank serum)으로 면역화하였다. 28일차에 마우스의 눈으로부터 혈액을 수집했고, 슈도바이러스 중화 역가 분석을 위해 혈청을 분리했다.
마우스의 EC50 분석:
30분 동안 56℃에서 뮤린 혈청을 비활성화하였고, 5분 동안 6000g으로 원심분리하고, 분석을 위해 상층액을 수집했다. 분석 4-8시간 전에, 293FT 세포를 15,000 세포/웰의 밀도로 96웰 플레이트에 접종했고, 5% CO2 인큐베이터에서 37℃에서 인큐베이팅하였다. 면역 후 뮤린 혈청 및 블랭크 대조군 혈청을 각각 중화 배지로 순차적으로 희석한 다음, 6.1에서 제조한 HPV6 슈도바이러스와 1:1의 부피비로 혼합하고, 1시간 동안 2-8℃에서 인큐베이팅한 다음, 100 μL/웰의 혼합물을 미리 4-8시간 동안 접종시킨 293FT 세포에 첨가했다. 각 샘플에 대해 2개의 복제웰(in replicate)을 설정하고, 동시에 블랭크 혈청 대조군 웰, 슈도바이러스 양성 대조군 웰 및 슈도바이러스 음성 대조군 웰을 설정했다. 슈도바이러스에 감염된 세포를 62-96 시간 동안 5% CO2를 갖는 CO2 인큐베이터에서 37 ℃에서 인큐베이팅하였고, ELISPOT 분석기 (모델 NO.:S6 Universal-V Analyzer, 제조업체: CTL)에서 형광 스캐닝 촬영(photographed)하고 카운팅했다. 각 뮤린 혈청 샘플의 중화 억제에 기초하여, Reed Muench 방법에 따라 각 뮤린 혈청 샘플에 대해 50% 중화 억제에서 혈청의 최대 희석량, 즉, 반수 유효 희석량(half efficacy dilution) EC50을 계산했다.
HPV6 혈청 슈도바이러스 중화 역가 분석의 결과는 표 4에 나타난다.
[표 4] 마우스에서 혈청 중화 역가 분석의 EC50 (GMT±SEM)
주석:
1. 동물의 수, N = 10.
2. GMT(Geometric Mean Titer): 기하 평균 역가.
3. SEM(Standard Error of Mean): 표준 오차.
상기 평가 결과는 본 발명에 의해 제조된 HPV6 L1: 33C 바이러스-유사 입자가 우수한 면역원성을 갖고 동물에서 높은 역가를 갖는 중화 항체를 생산할 수 있으며, HPV 감염을 예방하기 위한 백신으로 제조하는데 사용될 수 있음을 보여준다.
실시예 6.2: 동물에서 HPV11 L1: 33C 바이러스-유사 입자의 면역원성 평가
실험 방법 및 절차는 실시예 6.1과 동일하였다. L1 서열은 Uniprot P04012로부터 유래됐고, L2 서열은 Uniprot P04013으로부터 유래됐다.
HPV11 혈청 슈도바이러스 역가 분석의 결과는 표 5에 나타난다.
[표 5] 마우스에서 혈청 중화 역가 분석의 EC50(GMT±SEM)
상기 평가 결과는 본 발명에 의해 제조된 HPV11 L1: 33C 바이러스-유사 입자가 우수한 면역원성을 갖고, 동물에서 높은 역가의 중화 항체를 생산할 수 있으며, HPV 감염을 예방하기 위한 백신으로 제조하는데 사용될 수 있음을 보여준다.
실시예 6.3: 동물에서 HPV 16L1: 33C 바이러스-유사 입자의 면역원성 평가
실험 방법 및 절차는 실시예 6.1과 동일하였다. L1 서열은 Uniprot P03101로부터 유래됐고, L2 서열은 Uniprot P03107로부터 유래됐다.
HPV16 혈청 슈도바이러스 중화 역가 분석은 표 6에 나타난다.
[표 6] 마우스에서 혈청 중화 역가 분석의 EC50 (GMT±SEM)
상기 평가 결과는 본 발명에 의해 제조된 HPV 16L1: 33C 바이러스-유사 입자가 우수한 면역원성을 갖고 동물에서 높은 역가의 중화 항체를 생산할 수 있으며, HPV 감염을 예방하기 위한 백신으로 제조하는데 사용될 수 있음을 보여준다.
실시예 6.4: 동물에서 HPV18 L1: 33C 바이러스-유사 입자의 면역원성 평가
실험 방법 및 절차는 실시예 6.1과 동일하였다. L1 서열은 Uniprot Q80B70로부터 유래됐고, L2 서열은 Uniprot P06793으로부터 유래됐다.
HPV18 혈청 슈도바이러스 중화 역가 분석의 결과는 표 7에 나타난다.
[표 7] 마우스에서 혈청 중화 역가 분석의 EC50 (GMT±SEM)
상기 평과 결과는 본 발명에 의해 제조된 HPV18 L1: 33C 바이러스-유사 입자가 우수한 면역원성을 갖고, 동물에서 높은 역가의 중화 항체를 생산할 수 있으며, HPV 감염을 예방하기 위한 백신으로 제조하는데 사용될 수 있음을 보여준다.
실시예 6.5: 동물에서 HPV31 L1: 33C 바이러스-유사 입자의 면역원성 평가
실험 방법 및 절차는 실시예 6.1과 동일하였다. L1 서열은 Uniprot P17388로부터 유래됐고, L2 서열은 Uniprot P17389로부터 유래됐다.
HPV31 혈청 슈도바이러스 중화 역가 분석의 결과는 표 8에 나타난다.
[표 8] 마우스에서 혈청 중화 역가 분석의 EC50 (GMT±SEM)
상기 평가 결과는 본 발명에 의해 제조된 HPV31 L1: 33C 바이러스-유사 입자가 우수한 면역원성을 갖고, 동물에서 높은 역가의 중화 항체를 생산할 수 있으며, HPV 감염을 예방하기 위한 백신으로 제조하는데 사용될 수 있음을 보여준다.
실시예 6.6: 동물에서 HPV35 L1: 33C 바이러스-유사 입자의 면역원성 평가
실험 방법 및 절차는 실시예 6.1과 동일하였다. L1 서열은 Uniprot P27232로부터 유래됐고, L2 서열은 Uniprot P27234로부터 유래됐다.
HPV35 혈청 슈도바이러스 중화 역가 분석의 결과는 표 9에 나타난다.
[표 9] 마우스에서 혈청 중화 역가 분석의 EC50 (GMT±SEM)
상기 평가 결과는 본 발명에 의해 제조된 HPV35 L1: 33C 바이러스-유사 입자가 우수한 면역원성을 갖고, 동물에서 높은 역가의 중화 항체를 생산할 수 있으며, HPV 감염을 예방하기 위한 백신으로 제조하는데 사용될 수 있음을 보여준다.
실시예 6.7: 동물에서 HPV39 L1: 59C 바이러스-유사 입자의 면역원성 평가
실험 방법 및 절차는 실시예 6.1과 동일하였다. L1 서열은 Uniprot P24838로부터 유래됐고, L2 서열은 Uniprot P24839로부터 유래됐다.
HPV39 혈청 슈도바이러스 중화 역가 분석의 결과는 표 10에 나타난다.
[표 10] 마우스에서 혈청 중화 역가 분석의 EC50 (GMT±SEM)
상기 평가 결과는 본 발명에 의해 제조된 HPV39 L1: 59C 바이러스-유사 입자가 우수한 면역원성을 갖고, 동물에서 높은 역가의 중화 항체를 생산할 수 있으며, HPV 감염을 예방하기 위한 백신을 제조하는데 사용될 수 있음을 보여준다.
실시예 6.8: 동물에서 HPV45 L1: 33C 바이러스-유사 입자의 면역원성 평가
실험 방법 및 절차는 실시예 6.1과 동일하였다. L1 서열은 Uniprot P36741로부터 유래됐고, L2 서열은 Uniprot P36761로부터 유래됐다.
HPV45 혈청 슈도바이러스 중화 역가 분석의 결과는 표 11에 나타난다.
[표 11] 마우스에서 혈청 중화 역가 분석의 EC50 (GMT±SEM)
상기 평가 결과는 본 발명에 의해 제조된 HPV45 L1: 33C 바이러스-유사 입자가 우수한 면역원성을 갖고, 동물에서 높은 역가의 중화 항체를 생산할 수 있으며, HPV 감염을 예방하기 위한 백신으로 제조하는 데 사용될 수 있음을 보여준다.
실시예 6.9: 동물에서 HPV51 L1: 33C 바이러스-유사 입자의 면역원성 평가
실험 방법 및 절차는 실시예 6.1과 동일하였다. L1 서열은 Uniprot P26536으로부터 유래됐고, L2 서열은 Uniprot P26539로부터 유래됐다.
HPV51 혈청 슈도바이러스 중화 역가 분석의 결과는 표 12에 나타난다.
[표 12] 마우스에서 혈청 중화 역가 분석의 EC50 (GMT±SEM)
상기 평가 결과는 본 발명에 의해 제조된 HPV51 L1: 33C 바이러스-유사 입자가 우수한 면역원성을 갖고, 동물에서 높은 역가의 중화 항체를 생산할 수 있으며, HPV 감염을 예방하기 위한 백신으로 제조하는데 사용될 수 있음을 보여준다.
실시예 6.10: 동물에서 HPV52 L1: 33C 바이러스-유사 입자의 면역원성 평가
실험 방법 및 절차는 실시예 6.1과 동일하였다. L1 서열은 Uniprot Q05138로부터 유래됐고, L2 서열은 Uniprot F8S4U2로부터 유래됐다.
HPV52 혈청 슈도바이러스 중화 역가 분석의 결과는 표 13에 나타난다.
[표 13] 마우스에서 혈청 중화 역가 분석의 EC50 (GMT±SEM)
상기 평가 결과는 본 발명에 의해 제조된 HPV52 L1: 33C 바이러스-유사 입자는 우수한 면역원성을 갖고, 동물에서 높은 역가의 중화 항체를 생산할 수 있으며, HPV 감염을 예방하기 위한 백신으로 제조하는데 사용될 수 있음을 보여준다.
실시예 6.11: 동물에서 HPV56 L1: 33C 바이러스-유사 입자의 면역원성 평가
실험 방법 및 절차는 실시예 6.1과 동일하였다. L1 서열은 Uniprot P36743로부터 유래됐고, L2 서열은 Uniprot P36765로부터 유래됐다.
HPV56 혈청 슈도바이러스 중화 역가 분석의 결과는 표 14에 나타난다.
[표 14] 마우스에서 혈청 중화 역가 분석의 EC50 (GMT±SEM)
상기 평가 결과는 본 발명에 의해 제조된 HPV56 L1: 33C 바이러스-유사 입자는 우수한 면역원성을 갖고, 동물에서 높은 역가의 중화 항체를 생산할 수 있으며, HPV 감염을 예방하기 위한 백신으로 제조하는 데 사용될 수 있음을 보여준다.
실시예 6.12: 동물에서 HPV58 L1: 33C 바이러스-유사 입자의 면역원성 평가
실험 방법 및 절차는 실시예 6.1과 동일하였다. L1 서열은 Uniprot P26535로부터 유래됐고, L2 서열은 Uniprot B6ZB12로부터 유래됐다.
HPV58 혈청 슈도바이러스 중화 역가 분석의 결과는 표 15에 나타난다.
[표 15] 마우스에서 혈청 중화 역가 분석의 EC50 (GMT±SEM)
상기 평가 결과는 본 발명에 의해 제조된 HPV58 L1: 33C 바이러스-유사 입자는 우수한 면역원성을 갖고, 동물에서 높은 역가의 중화 항체를 생산할 수 있으며, HPV 감염을 예방하기 위한 백신으로 제조하는 데 사용될 수 있음을 보여준다.
비교 실시예 1: C-말단 절단된 HPV16 L1의 발현(aa 1-474)
본 발명자들은 HPV16 L1의 C-말단을 31개의 아미노산들로 절단하는 것을 시도하였고, 이를 HPV16 L1(1-474) (서열 번호: 27)로 명명했다. 하지만, 본 연구에서, 절단된 HPV16 L1(1-474) 단백질은 높은 발현을 갖지만, 매우 낮은 용해도를 가지고, 추출하고 정제하기 어려운 것을 발견했으며, 발현 및 추출의 상세한 결과는 도 3에 나타난다.
본 발명은 전술한 예시 및 구현예로 상세히 설명되었지만, 이는 이해를 용이하게 하기 위한 것이다. 당업자는 첨부된 청구범위의 정신 또는 범위에 벗어나지 않고 본 발명의 기술적 해결방안에 다양한 수정 및 개선을 할 수 있는 것이 명백하다.
부록 1:서열 목록-키메라 인간 유두종 바이러스 유형 6 L1 단백질
부록 2:서열 목록-키메라 인간 유두종 바이러스 유형 11 L1 단백질
부록 3:서열 목록-키메라 인간 유두종 바이러스 유형 16 L1 단백질
부록 4: 서열 목록-키메라 인간 유두종 바이러스 유형 18 L1 단백질
부록 5:서열 목록-키메라 인간 유두종 바이러스 유형 31 L1 단백질
부록 6:서열 목록-키메라 인간 유두종 바이러스 유형 35 L1 단백질
부록 7:서열 목록-키메라 인간 유두종 바이러스 유형 39 L1 단백질
부록 8:서열 목록-키메라 인간 유두종 바이러스 유형 45 L1 단백질
부록 9:서열 목록-키메라 인간 유두종 바이러스 유형 51 L1 단백질
부록 10:서열 목록-키메라 인간 유두종 바이러스 유형 52 L1 단백질
부록 11:서열 목록-키메라 인간 유두종 바이러스 유형 56 L1 단백질
부록 12:서열 목록-키메라 인간 유두종 바이러스 유형 58 L1 단백질
<110> SinoCellTech Ltd.
<120> CHIMERIC PAPILLOMAVIRUS L1 PROTEIN
<130> CIE200063PCT
<160> 156
<170> BiSSAP 1.3.6
<210> 1
<211> 469
<212> PRT
<213> Homo sapiens 0601 Amino acid sequence of HPV type 6 L1 protein aa 1-469
<400> 1
Met Trp Arg Pro Ser Asp Ser Thr Val Tyr Val Pro Pro Pro Asn Pro
1 5 10 15
Val Ser Lys Val Val Ala Thr Asp Ala Tyr Val Thr Arg Thr Asn Ile
20 25 30
Phe Tyr His Ala Ser Ser Ser Arg Leu Leu Ala Val Gly His Pro Tyr
35 40 45
Phe Ser Ile Lys Arg Ala Asn Lys Thr Val Val Pro Lys Val Ser Gly
50 55 60
Tyr Gln Tyr Arg Val Phe Lys Val Val Leu Pro Asp Pro Asn Lys Phe
65 70 75 80
Ala Leu Pro Asp Ser Ser Leu Phe Asp Pro Thr Thr Gln Arg Leu Val
85 90 95
Trp Ala Cys Thr Gly Leu Glu Val Gly Arg Gly Gln Pro Leu Gly Val
100 105 110
Gly Val Ser Gly His Pro Phe Leu Asn Lys Tyr Asp Asp Val Glu Asn
115 120 125
Ser Gly Ser Gly Gly Asn Pro Gly Gln Asp Asn Arg Val Asn Val Gly
130 135 140
Met Asp Tyr Lys Gln Thr Gln Leu Cys Met Val Gly Cys Ala Pro Pro
145 150 155 160
Leu Gly Glu His Trp Gly Lys Gly Lys Gln Cys Thr Asn Thr Pro Val
165 170 175
Gln Ala Gly Asp Cys Pro Pro Leu Glu Leu Ile Thr Ser Val Ile Gln
180 185 190
Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala Met Asn Phe Ala Asp
195 200 205
Leu Gln Thr Asn Lys Ser Asp Val Pro Ile Asp Ile Cys Gly Thr Thr
210 215 220
Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ala Ala Asp Pro Tyr Gly Asp
225 230 235 240
Arg Leu Phe Phe Phe Leu Arg Lys Glu Gln Met Phe Ala Arg His Phe
245 250 255
Phe Asn Arg Ala Gly Glu Val Gly Glu Pro Val Pro Asp Thr Leu Ile
260 265 270
Ile Lys Gly Ser Gly Asn Arg Thr Ser Val Gly Ser Ser Ile Tyr Val
275 280 285
Asn Thr Pro Ser Gly Ser Leu Val Ser Ser Glu Ala Gln Leu Phe Asn
290 295 300
Lys Pro Tyr Trp Leu Gln Lys Ala Gln Gly His Asn Asn Gly Ile Cys
305 310 315 320
Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp Thr Thr Arg Ser Thr
325 330 335
Asn Met Thr Leu Cys Ala Ser Val Thr Thr Ser Ser Thr Tyr Thr Asn
340 345 350
Ser Asp Tyr Lys Glu Tyr Met Arg His Val Glu Glu Tyr Asp Leu Gln
355 360 365
Phe Ile Phe Gln Leu Cys Ser Ile Thr Leu Ser Ala Glu Val Met Ala
370 375 380
Tyr Ile His Thr Met Asn Pro Ser Val Leu Glu Asp Trp Asn Phe Gly
385 390 395 400
Leu Ser Pro Pro Pro Asn Gly Thr Leu Glu Asp Thr Tyr Arg Tyr Val
405 410 415
Gln Ser Gln Ala Ile Thr Cys Gln Lys Pro Thr Pro Glu Lys Glu Lys
420 425 430
Pro Asp Pro Tyr Lys Asn Leu Ser Phe Trp Glu Val Asn Leu Lys Glu
435 440 445
Lys Phe Ser Ser Glu Leu Asp Gln Tyr Pro Leu Gly Arg Lys Phe Leu
450 455 460
Leu Gln Ser Gly Tyr
465
<210> 2
<211> 26
<212> PRT
<213> Homo sapiens 0602 Amino acid sequence of HPV type 33 L1 protein aa 474-499
<400> 2
Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr
1 5 10 15
Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
20 25
<210> 3
<211> 495
<212> PRT
<213> Artificial Sequence
<220>
<223> 0603 Amino acid sequence of chimeric HPV type 6 L1 protein
<400> 3
Met Trp Arg Pro Ser Asp Ser Thr Val Tyr Val Pro Pro Pro Asn Pro
1 5 10 15
Val Ser Lys Val Val Ala Thr Asp Ala Tyr Val Thr Arg Thr Asn Ile
20 25 30
Phe Tyr His Ala Ser Ser Ser Arg Leu Leu Ala Val Gly His Pro Tyr
35 40 45
Phe Ser Ile Lys Arg Ala Asn Lys Thr Val Val Pro Lys Val Ser Gly
50 55 60
Tyr Gln Tyr Arg Val Phe Lys Val Val Leu Pro Asp Pro Asn Lys Phe
65 70 75 80
Ala Leu Pro Asp Ser Ser Leu Phe Asp Pro Thr Thr Gln Arg Leu Val
85 90 95
Trp Ala Cys Thr Gly Leu Glu Val Gly Arg Gly Gln Pro Leu Gly Val
100 105 110
Gly Val Ser Gly His Pro Phe Leu Asn Lys Tyr Asp Asp Val Glu Asn
115 120 125
Ser Gly Ser Gly Gly Asn Pro Gly Gln Asp Asn Arg Val Asn Val Gly
130 135 140
Met Asp Tyr Lys Gln Thr Gln Leu Cys Met Val Gly Cys Ala Pro Pro
145 150 155 160
Leu Gly Glu His Trp Gly Lys Gly Lys Gln Cys Thr Asn Thr Pro Val
165 170 175
Gln Ala Gly Asp Cys Pro Pro Leu Glu Leu Ile Thr Ser Val Ile Gln
180 185 190
Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala Met Asn Phe Ala Asp
195 200 205
Leu Gln Thr Asn Lys Ser Asp Val Pro Ile Asp Ile Cys Gly Thr Thr
210 215 220
Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ala Ala Asp Pro Tyr Gly Asp
225 230 235 240
Arg Leu Phe Phe Phe Leu Arg Lys Glu Gln Met Phe Ala Arg His Phe
245 250 255
Phe Asn Arg Ala Gly Glu Val Gly Glu Pro Val Pro Asp Thr Leu Ile
260 265 270
Ile Lys Gly Ser Gly Asn Arg Thr Ser Val Gly Ser Ser Ile Tyr Val
275 280 285
Asn Thr Pro Ser Gly Ser Leu Val Ser Ser Glu Ala Gln Leu Phe Asn
290 295 300
Lys Pro Tyr Trp Leu Gln Lys Ala Gln Gly His Asn Asn Gly Ile Cys
305 310 315 320
Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp Thr Thr Arg Ser Thr
325 330 335
Asn Met Thr Leu Cys Ala Ser Val Thr Thr Ser Ser Thr Tyr Thr Asn
340 345 350
Ser Asp Tyr Lys Glu Tyr Met Arg His Val Glu Glu Tyr Asp Leu Gln
355 360 365
Phe Ile Phe Gln Leu Cys Ser Ile Thr Leu Ser Ala Glu Val Met Ala
370 375 380
Tyr Ile His Thr Met Asn Pro Ser Val Leu Glu Asp Trp Asn Phe Gly
385 390 395 400
Leu Ser Pro Pro Pro Asn Gly Thr Leu Glu Asp Thr Tyr Arg Tyr Val
405 410 415
Gln Ser Gln Ala Ile Thr Cys Gln Lys Pro Thr Pro Glu Lys Glu Lys
420 425 430
Pro Asp Pro Tyr Lys Asn Leu Ser Phe Trp Glu Val Asn Leu Lys Glu
435 440 445
Lys Phe Ser Ser Glu Leu Asp Gln Tyr Pro Leu Gly Arg Lys Phe Leu
450 455 460
Leu Gln Ser Gly Tyr Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro
465 470 475 480
Thr Ser Thr Arg Thr Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
485 490 495
<210> 4
<211> 1488
<212> DNA
<213> Artificial Sequence
<220>
<223> 0604 Nucleotide sequence of chimeric HPV type 6 L1 protein
<400> 4
atgtggagac catctgacag cacagtctat gtgcctcctc caaaccctgt gagcaaggtg 60
gtggctacag atgcctatgt gaccaggacc aacatcttct accatgcctc ctccagcaga 120
ctgctggctg tgggacaccc atacttcagc atcaagaggg ctaacaagac agtggtgcca 180
aaggtgtctg gctaccaata cagggtgttc aaggtggtgc tgcctgaccc aaacaagttt 240
gccctgcctg actcctccct gtttgaccca accacccaga gactggtgtg ggcttgtact 300
ggattggagg tgggcagggg acaaccactg ggagtgggag tgtctggaca cccattcctg 360
aacaaatatg atgatgtgga gaactctggc tctggaggca accctggaca agacaacagg 420
gtgaatgtgg ggatggacta caagcagacc caactttgta tggtgggctg tgcccctcca 480
ctgggagaac actggggcaa gggcaagcag tgtaccaaca cacctgtcca ggctggagac 540
tgtcctccat tggaactgat tacctctgtg attcaggatg gagatatggt ggacacaggc 600
tttggagcta tgaactttgc tgacctccaa accaacaagt ctgatgtgcc aattgacatc 660
tgtggcacca cttgtaaata ccctgactac ctccaaatgg ctgctgaccc atatggagac 720
agactgttct tcttcctgag gaaggaacag atgtttgcca gacacttctt caacagggct 780
ggagaggtgg gagaacctgt gcctgacacc ctgattatca agggctctgg caacaggacc 840
tctgtgggct ccagcatcta tgtgaacaca ccatctggct ccctggtgtc ctctgaggct 900
caacttttca acaagccata ctggctccaa aaggctcaag gacacaacaa tggcatctgt 960
tggggcaacc aactttttgt gacagtggtg gacaccacca ggagcaccaa tatgaccctg 1020
tgtgcctctg tgaccacctc cagcacctac accaactctg actacaagga atatatgagg 1080
catgtggagg aatatgacct ccaattcatc ttccaacttt gtagcatcac cctgtctgct 1140
gaggtgatgg cttacatcca cacaatgaac ccatctgtgt tggaggactg gaactttgga 1200
ctgagccctc ctccaaatgg caccttggag gacacctaca gatatgtcca gagccaggct 1260
atcacttgtc agaagccaac acctgagaag gagaagcctg acccatacaa gaacctgtcc 1320
ttctgggagg tgaacctgaa agagaagttc tcctctgaac tggaccaata cccactgggc 1380
aggaagttcc tgctccaatc tggctacaaa gccaagccaa aactgaaaag ggctgcccca 1440
accagcacca ggacctcctc tgccaagagg aagaaggtga agaagtaa 1488
<210> 5
<211> 1522
<212> DNA
<213> Artificial Sequence
<220>
<223> 0605 Synthetic HPV6 L1 gene
<400> 5
ctgggtacca tgtggagacc atctgacagc acagtctatg tgcctcctcc aaaccctgtg 60
agcaaggtgg tggctacaga tgcctatgtg accaggacca acatcttcta ccatgcctcc 120
tccagcagac tgctggctgt gggacaccca tacttcagca tcaagagggc taacaagaca 180
gtggtgccaa aggtgtctgg ctaccaatac agggtgttca aggtggtgct gcctgaccca 240
aacaagtttg ccctgcctga ctcctccctg tttgacccaa ccacccagag actggtgtgg 300
gcttgtactg gattggaggt gggcagggga caaccactgg gagtgggagt gtctggacac 360
ccattcctga acaaatatga tgatgtggag aactctggct ctggaggcaa ccctggacaa 420
gacaacaggg tgaatgtggg gatggactac aagcagaccc aactttgtat ggtgggctgt 480
gcccctccac tgggagaaca ctggggcaag ggcaagcagt gtaccaacac acctgtccag 540
gctggagact gtcctccatt ggaactgatt acctctgtga ttcaggatgg agatatggtg 600
gacacaggct ttggagctat gaactttgct gacctccaaa ccaacaagtc tgatgtgcca 660
attgacatct gtggcaccac ttgtaaatac cctgactacc tccaaatggc tgctgaccca 720
tatggagaca gactgttctt cttcctgagg aaggaacaga tgtttgccag acacttcttc 780
aacagggctg gagaggtggg agaacctgtg cctgacaccc tgattatcaa gggctctggc 840
aacaggacct ctgtgggctc cagcatctat gtgaacacac catctggctc cctggtgtcc 900
tctgaggctc aacttttcaa caagccatac tggctccaaa aggctcaagg acacaacaat 960
ggcatctgtt ggggcaacca actttttgtg acagtggtgg acaccaccag gagcaccaat 1020
atgaccctgt gtgcctctgt gaccacctcc agcacctaca ccaactctga ctacaaggaa 1080
tatatgaggc atgtggagga atatgacctc caattcatct tccaactttg tagcatcacc 1140
ctgtctgctg aggtgatggc ttacatccac acaatgaacc catctgtgtt ggaggactgg 1200
aactttggac tgagccctcc tccaaatggc accttggagg acacctacag atatgtccag 1260
agccaggcta tcacttgtca gaagccaaca cctgagaagg agaagcctga cccatacaag 1320
aacctgtcct tctgggaggt gaacctgaaa gagaagttct cctctgaact ggaccaatac 1380
ccactgggca ggaagttcct gctccaatct ggctacaggg gcaggtccag catcaggaca 1440
ggagtgaaga gacctgctgt gagcaaggca tctgctgccc caaagaggaa gagggctaag 1500
accaagaggt aaactcgagc tc 1522
<210> 6
<211> 1519
<212> DNA
<213> Artificial Sequence
<220>
<223> 0606 Synthetic HPV33 L1 gene
<400> 6
ctgggtacca tgagtgtgtg gagaccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtgagcagga ccagcatcta ctactatgct 120
ggctccagca gactgctggc tgtgggacac ccatacttca gcatcaagaa cccaaccaat 180
gccaagaaac tgctggtgcc aaaggtgtct ggactccaat acagggtgtt cagggtgaga 240
ctgcctgacc caaacaagtt tggctttcct gacacctcct tctacaaccc tgacacccag 300
agactggtgt gggcttgtgt gggattggag attggcaggg gacaaccact gggagtgggc 360
atctctggac acccactgct gaacaagttt gatgacacag agacaggcaa caaataccct 420
ggacaacctg gagcagacaa cagggagtgt ctgagtatgg actacaagca gacccaactt 480
tgtctgctgg gctgtaagcc tccaacagga gaacactggg gcaagggagt ggcttgtacc 540
aatgctgccc ctgccaatga ctgtcctcca ttggaactga taaacaccat cattgaggat 600
ggagatatgg tggacacagg ctttggctgt atggacttca agaccctcca agccaacaag 660
tctgatgtgc caattgacat ctgtggcagc acttgtaaat accctgacta cctgaaaatg 720
acctctgaac catatggaga ctccctgttc ttcttcctga ggagggaaca gatgtttgtg 780
agacacttct tcaacagggc tggcaccctg ggagaggctg tgcctgatga cctctacatc 840
aagggctctg gcaccacagc cagcatccag tcctctgcct tctttccaac accatctggc 900
agtatggtga cctctgagag ccaacttttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caggtgtttg tgacagtggt ggacaccacc 1020
aggagcacca atatgaccct gtgtacccag gtgacctctg acagcaccta caagaatgag 1080
aacttcaagg aatacatcag gcatgtggag gaatatgacc tccaatttgt gttccaactt 1140
tgtaaggtga ccctgacagc agaggtgatg acctacatcc atgctatgaa ccctgacatc 1200
ttggaggact ggcagtttgg actgacacct cctccatctg cctccctcca agacacctac 1260
aggtttgtga ccagccaggc tatcacttgt cagaagacag tgcctccaaa ggagaaggag 1320
gacccactgg gcaaatacac cttctgggag gtggacctga aagagaagtt ctctgctgac 1380
ctggaccagt ttccactggg caggaagttc ctgctccaag caggactgaa agccaagcca 1440
aaactgaaaa gggctgcccc aaccagcacc aggacctcct ctgccaagag gaagaaggtg 1500
aagaagtaaa ctcgagctc 1519
<210> 7
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 0607 HPV6L1 F1
<400> 7
cttggtacca tgtggagacc atctgacagc acagt 35
<210> 8
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 0608 HPV6L1 R1
<400> 8
gcttggcttt gtagccagat tggagcagga acttcc 36
<210> 9
<211> 1426
<212> DNA
<213> Artificial Sequence
<220>
<223> 0609 HPV6L1 amplified sequence 1
<400> 9
cttggtacca tgtggagacc atctgacagc acagtctatg tgcctcctcc aaaccctgtg 60
agcaaggtgg tggctacaga tgcctatgtg accaggacca acatcttcta ccatgcctcc 120
tccagcagac tgctggctgt gggacaccca tacttcagca tcaagagggc taacaagaca 180
gtggtgccaa aggtgtctgg ctaccaatac agggtgttca aggtggtgct gcctgaccca 240
aacaagtttg ccctgcctga ctcctccctg tttgacccaa ccacccagag actggtgtgg 300
gcttgtactg gattggaggt gggcagggga caaccactgg gagtgggagt gtctggacac 360
ccattcctga acaaatatga tgatgtggag aactctggct ctggaggcaa ccctggacaa 420
gacaacaggg tgaatgtggg gatggactac aagcagaccc aactttgtat ggtgggctgt 480
gcccctccac tgggagaaca ctggggcaag ggcaagcagt gtaccaacac acctgtccag 540
gctggagact gtcctccatt ggaactgatt acctctgtga ttcaggatgg agatatggtg 600
gacacaggct ttggagctat gaactttgct gacctccaaa ccaacaagtc tgatgtgcca 660
attgacatct gtggcaccac ttgtaaatac cctgactacc tccaaatggc tgctgaccca 720
tatggagaca gactgttctt cttcctgagg aaggaacaga tgtttgccag acacttcttc 780
aacagggctg gagaggtggg agaacctgtg cctgacaccc tgattatcaa gggctctggc 840
aacaggacct ctgtgggctc cagcatctat gtgaacacac catctggctc cctggtgtcc 900
tctgaggctc aacttttcaa caagccatac tggctccaaa aggctcaagg acacaacaat 960
ggcatctgtt ggggcaacca actttttgtg acagtggtgg acaccaccag gagcaccaat 1020
atgaccctgt gtgcctctgt gaccacctcc agcacctaca ccaactctga ctacaaggaa 1080
tatatgaggc atgtggagga atatgacctc caattcatct tccaactttg tagcatcacc 1140
ctgtctgctg aggtgatggc ttacatccac acaatgaacc catctgtgtt ggaggactgg 1200
aactttggac tgagccctcc tccaaatggc accttggagg acacctacag atatgtccag 1260
agccaggcta tcacttgtca gaagccaaca cctgagaagg agaagcctga cccatacaag 1320
aacctgtcct tctgggaggt gaacctgaaa gagaagttct cctctgaact ggaccaatac 1380
ccactgggca ggaagttcct gctccaatct ggctacaaag ccaagc 1426
<210> 10
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 0610 HPV6L1 F2
<400> 10
atctggctac aaagccaagc caaaactgaa aaggg 35
<210> 11
<211> 37
<212> DNA
<213> Artificial Sequence
<220>
<223> 0611 HPV6L1 R2
<400> 11
ctgtctagat ttacttcttc accttcttcc tcttggc 37
<210> 12
<211> 101
<212> DNA
<213> Artificial Sequence
<220>
<223> 0612 HPV6L1 amplified sequence 2
<400> 12
atctggctac aaagccaagc caaaactgaa aagggctgcc ccaaccagca ccaggacctc 60
ctctgccaag aggaagaagg tgaagaagta aatctagaca g 101
<210> 13
<211> 38
<212> PRT
<213> Homo sapiens 0613 Amino acid sequence of HPV type 59 L1 protein aa 471-508
<400> 13
Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile Gly Pro Arg Lys Arg
1 5 10 15
Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro Lys Arg Val Lys Arg
20 25 30
Arg Lys Ser Ser Arg Lys
35
<210> 14
<211> 470
<212> PRT
<213> Homo sapiens 1101 Amino acid sequence of HPV type 11 L1 protein aa 1-470
<400> 14
Met Trp Arg Pro Ser Asp Ser Thr Val Tyr Val Pro Pro Pro Asn Pro
1 5 10 15
Val Ser Lys Val Val Ala Thr Asp Ala Tyr Val Lys Arg Thr Asn Ile
20 25 30
Phe Tyr His Ala Ser Ser Ser Arg Leu Leu Ala Val Gly His Pro Tyr
35 40 45
Tyr Ser Ile Lys Lys Val Asn Lys Thr Val Val Pro Lys Val Ser Gly
50 55 60
Tyr Gln Tyr Arg Val Phe Lys Val Val Leu Pro Asp Pro Asn Lys Phe
65 70 75 80
Ala Leu Pro Asp Ser Ser Leu Phe Asp Pro Thr Thr Gln Arg Leu Val
85 90 95
Trp Ala Cys Thr Gly Leu Glu Val Gly Arg Gly Gln Pro Leu Gly Val
100 105 110
Gly Val Ser Gly His Pro Leu Leu Asn Lys Tyr Asp Asp Val Glu Asn
115 120 125
Ser Gly Gly Tyr Gly Gly Asn Pro Gly Gln Asp Asn Arg Val Asn Val
130 135 140
Gly Met Asp Tyr Lys Gln Thr Gln Leu Cys Met Val Gly Cys Ala Pro
145 150 155 160
Pro Leu Gly Glu His Trp Gly Lys Gly Thr Gln Cys Ser Asn Thr Ser
165 170 175
Val Gln Asn Gly Asp Cys Pro Pro Leu Glu Leu Ile Thr Ser Val Ile
180 185 190
Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala Met Asn Phe Ala
195 200 205
Asp Leu Gln Thr Asn Lys Ser Asp Val Pro Leu Asp Ile Cys Gly Thr
210 215 220
Val Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ala Ala Asp Pro Tyr Gly
225 230 235 240
Asp Arg Leu Phe Phe Tyr Leu Arg Lys Glu Gln Met Phe Ala Arg His
245 250 255
Phe Phe Asn Arg Ala Gly Thr Val Gly Glu Pro Val Pro Asp Asp Leu
260 265 270
Leu Val Lys Gly Gly Asn Asn Arg Ser Ser Val Ala Ser Ser Ile Tyr
275 280 285
Val His Thr Pro Ser Gly Ser Leu Val Ser Ser Glu Ala Gln Leu Phe
290 295 300
Asn Lys Pro Tyr Trp Leu Gln Lys Ala Gln Gly His Asn Asn Gly Ile
305 310 315 320
Cys Trp Gly Asn His Leu Phe Val Thr Val Val Asp Thr Thr Arg Ser
325 330 335
Thr Asn Met Thr Leu Cys Ala Ser Val Ser Lys Ser Ala Thr Tyr Thr
340 345 350
Asn Ser Asp Tyr Lys Glu Tyr Met Arg His Val Glu Glu Phe Asp Leu
355 360 365
Gln Phe Ile Phe Gln Leu Cys Ser Ile Thr Leu Ser Ala Glu Val Met
370 375 380
Ala Tyr Ile His Thr Met Asn Pro Ser Val Leu Glu Asp Trp Asn Phe
385 390 395 400
Gly Leu Ser Pro Pro Pro Asn Gly Thr Leu Glu Asp Thr Tyr Arg Tyr
405 410 415
Val Gln Ser Gln Ala Ile Thr Cys Gln Lys Pro Thr Pro Glu Lys Glu
420 425 430
Lys Gln Asp Pro Tyr Lys Asp Met Ser Phe Trp Glu Val Asn Leu Lys
435 440 445
Glu Lys Phe Ser Ser Glu Leu Asp Gln Phe Pro Leu Gly Arg Lys Phe
450 455 460
Leu Leu Gln Ser Gly Tyr
465 470
<210> 15
<211> 26
<212> PRT
<213> Homo sapiens 1102 Amino acid sequence of HPV type 33 L1 protein aa 474-499
<400> 15
Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr
1 5 10 15
Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
20 25
<210> 16
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> 1103 Amino acid sequence of chimeric HPV type 11 L1 protein
<400> 16
Met Trp Arg Pro Ser Asp Ser Thr Val Tyr Val Pro Pro Pro Asn Pro
1 5 10 15
Val Ser Lys Val Val Ala Thr Asp Ala Tyr Val Lys Arg Thr Asn Ile
20 25 30
Phe Tyr His Ala Ser Ser Ser Arg Leu Leu Ala Val Gly His Pro Tyr
35 40 45
Tyr Ser Ile Lys Lys Val Asn Lys Thr Val Val Pro Lys Val Ser Gly
50 55 60
Tyr Gln Tyr Arg Val Phe Lys Val Val Leu Pro Asp Pro Asn Lys Phe
65 70 75 80
Ala Leu Pro Asp Ser Ser Leu Phe Asp Pro Thr Thr Gln Arg Leu Val
85 90 95
Trp Ala Cys Thr Gly Leu Glu Val Gly Arg Gly Gln Pro Leu Gly Val
100 105 110
Gly Val Ser Gly His Pro Leu Leu Asn Lys Tyr Asp Asp Val Glu Asn
115 120 125
Ser Gly Gly Tyr Gly Gly Asn Pro Gly Gln Asp Asn Arg Val Asn Val
130 135 140
Gly Met Asp Tyr Lys Gln Thr Gln Leu Cys Met Val Gly Cys Ala Pro
145 150 155 160
Pro Leu Gly Glu His Trp Gly Lys Gly Thr Gln Cys Ser Asn Thr Ser
165 170 175
Val Gln Asn Gly Asp Cys Pro Pro Leu Glu Leu Ile Thr Ser Val Ile
180 185 190
Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala Met Asn Phe Ala
195 200 205
Asp Leu Gln Thr Asn Lys Ser Asp Val Pro Leu Asp Ile Cys Gly Thr
210 215 220
Val Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ala Ala Asp Pro Tyr Gly
225 230 235 240
Asp Arg Leu Phe Phe Tyr Leu Arg Lys Glu Gln Met Phe Ala Arg His
245 250 255
Phe Phe Asn Arg Ala Gly Thr Val Gly Glu Pro Val Pro Asp Asp Leu
260 265 270
Leu Val Lys Gly Gly Asn Asn Arg Ser Ser Val Ala Ser Ser Ile Tyr
275 280 285
Val His Thr Pro Ser Gly Ser Leu Val Ser Ser Glu Ala Gln Leu Phe
290 295 300
Asn Lys Pro Tyr Trp Leu Gln Lys Ala Gln Gly His Asn Asn Gly Ile
305 310 315 320
Cys Trp Gly Asn His Leu Phe Val Thr Val Val Asp Thr Thr Arg Ser
325 330 335
Thr Asn Met Thr Leu Cys Ala Ser Val Ser Lys Ser Ala Thr Tyr Thr
340 345 350
Asn Ser Asp Tyr Lys Glu Tyr Met Arg His Val Glu Glu Phe Asp Leu
355 360 365
Gln Phe Ile Phe Gln Leu Cys Ser Ile Thr Leu Ser Ala Glu Val Met
370 375 380
Ala Tyr Ile His Thr Met Asn Pro Ser Val Leu Glu Asp Trp Asn Phe
385 390 395 400
Gly Leu Ser Pro Pro Pro Asn Gly Thr Leu Glu Asp Thr Tyr Arg Tyr
405 410 415
Val Gln Ser Gln Ala Ile Thr Cys Gln Lys Pro Thr Pro Glu Lys Glu
420 425 430
Lys Gln Asp Pro Tyr Lys Asp Met Ser Phe Trp Glu Val Asn Leu Lys
435 440 445
Glu Lys Phe Ser Ser Glu Leu Asp Gln Phe Pro Leu Gly Arg Lys Phe
450 455 460
Leu Leu Gln Ser Gly Tyr Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala
465 470 475 480
Pro Thr Ser Thr Arg Thr Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
485 490 495
<210> 17
<211> 1492
<212> DNA
<213> Artificial Sequence
<220>
<223> 1104 Nucleotide sequence of chimeric HPV type 11 L1 protein
<400> 17
atgtggagac catctgacag cacagtctat gtgcctcctc caaaccctgt gagcaaggtg 60
gtggctacag atgcctatgt gaagaggacc aacatcttct accatgcctc ctccagcaga 120
ctgctggctg tgggacaccc atactacagc atcaagaagg tgaacaagac agtggtgcca 180
aaggtgtctg gctaccaata cagggtgttc aaggtggtgc tgcctgaccc aaacaagttt 240
gccctgcctg actcctccct gtttgaccca accacccaga gactggtgtg ggcttgtact 300
ggattggagg tgggcagggg acaaccactg ggagtgggag tgtctggaca cccactgctg 360
aacaaatatg atgatgtgga gaactctgga ggctatggag gcaaccctgg acaagacaac 420
agggtgaatg tggggatgga ctacaagcag acccaacttt gtatggtggg ctgtgcccct 480
ccactgggag aacactgggg caagggcacc cagtgtagca acacctctgt ccagaatgga 540
gactgtcctc cattggaact gattacctct gtgattcagg atggagatat ggtggacaca 600
ggctttggag ctatgaactt tgctgacctc caaaccaaca agtctgatgt gccactggac 660
atctgtggca cagtgtgtaa ataccctgac tacctccaaa tggctgctga cccatatgga 720
gacagactgt tcttctacct gaggaaggaa cagatgtttg ccagacactt cttcaacagg 780
gctggcacag tgggagaacc tgtgcctgat gacctgctgg tgaagggagg caacaacagg 840
tcctctgtgg catccagcat ctatgtgcat acaccatctg gctccctggt gtcctctgag 900
gctcaacttt tcaacaagcc atactggctc caaaaggctc aaggacacaa caatggcatc 960
tgttggggca accacctgtt tgtgacagtg gtggacacca ccaggagcac caatatgacc 1020
ctgtgtgcct ctgtgagcaa gtctgccacc tacaccaact ctgactacaa ggaatatatg 1080
aggcatgtgg aggagtttga cctccaattc atcttccaac tttgtagcat caccctgtct 1140
gctgaggtga tggcttacat ccacacaatg aacccatctg tgttggagga ctggaacttt 1200
ggactgagcc ctcctccaaa tggcaccttg gaggacacct acagatatgt ccagagccag 1260
gctatcactt gtcagaagcc aacacctgag aaggagaagc aggacccata caaggatatg 1320
agtttctggg aggtgaacct gaaagagaag ttctcctctg aactggacca gtttccactg 1380
ggcaggaagt tcctgctcca atctggctac aaagccaagc caaaactgaa aagggctgcc 1440
ccaaccagca ccaggacctc ctctgccaag aggaagaagg tgaagaagta aa 1492
<210> 18
<211> 1525
<212> DNA
<213> Artificial Sequence
<220>
<223> 1105 Synthetic HPV11 L1 gene
<400> 18
ctgggtacca tgtggagacc atctgacagc acagtctatg tgcctcctcc aaaccctgtg 60
agcaaggtgg tggctacaga tgcctatgtg aagaggacca acatcttcta ccatgcctcc 120
tccagcagac tgctggctgt gggacaccca tactacagca tcaagaaggt gaacaagaca 180
gtggtgccaa aggtgtctgg ctaccaatac agggtgttca aggtggtgct gcctgaccca 240
aacaagtttg ccctgcctga ctcctccctg tttgacccaa ccacccagag actggtgtgg 300
gcttgtactg gattggaggt gggcagggga caaccactgg gagtgggagt gtctggacac 360
ccactgctga acaaatatga tgatgtggag aactctggag gctatggagg caaccctgga 420
caagacaaca gggtgaatgt ggggatggac tacaagcaga cccaactttg tatggtgggc 480
tgtgcccctc cactgggaga acactggggc aagggcaccc agtgtagcaa cacctctgtc 540
cagaatggag actgtcctcc attggaactg attacctctg tgattcagga tggagatatg 600
gtggacacag gctttggagc tatgaacttt gctgacctcc aaaccaacaa gtctgatgtg 660
ccactggaca tctgtggcac agtgtgtaaa taccctgact acctccaaat ggctgctgac 720
ccatatggag acagactgtt cttctacctg aggaaggaac agatgtttgc cagacacttc 780
ttcaacaggg ctggcacagt gggagaacct gtgcctgatg acctgctggt gaagggaggc 840
aacaacaggt cctctgtggc atccagcatc tatgtgcata caccatctgg ctccctggtg 900
tcctctgagg ctcaactttt caacaagcca tactggctcc aaaaggctca aggacacaac 960
aatggcatct gttggggcaa ccacctgttt gtgacagtgg tggacaccac caggagcacc 1020
aatatgaccc tgtgtgcctc tgtgagcaag tctgccacct acaccaactc tgactacaag 1080
gaatatatga ggcatgtgga ggagtttgac ctccaattca tcttccaact ttgtagcatc 1140
accctgtctg ctgaggtgat ggcttacatc cacacaatga acccatctgt gttggaggac 1200
tggaactttg gactgagccc tcctccaaat ggcaccttgg aggacaccta cagatatgtc 1260
cagagccagg ctatcacttg tcagaagcca acacctgaga aggagaagca ggacccatac 1320
aaggatatga gtttctggga ggtgaacctg aaagagaagt tctcctctga actggaccag 1380
tttccactgg gcaggaagtt cctgctccaa tctggctaca ggggcaggac ctctgccagg 1440
acaggcatca agagacctgc tgtgagcaag ccaagcacag ccccaaagag gaagaggacc 1500
aagaccaaga agtaaactcg agctc 1525
<210> 19
<211> 1519
<212> DNA
<213> Artificial Sequence
<220>
<223> 1106 Synthetic HPV33 L1 gene
<400> 19
ctgggtacca tgagtgtgtg gagaccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtgagcagga ccagcatcta ctactatgct 120
ggctccagca gactgctggc tgtgggacac ccatacttca gcatcaagaa cccaaccaat 180
gccaagaaac tgctggtgcc aaaggtgtct ggactccaat acagggtgtt cagggtgaga 240
ctgcctgacc caaacaagtt tggctttcct gacacctcct tctacaaccc tgacacccag 300
agactggtgt gggcttgtgt gggattggag attggcaggg gacaaccact gggagtgggc 360
atctctggac acccactgct gaacaagttt gatgacacag agacaggcaa caaataccct 420
ggacaacctg gagcagacaa cagggagtgt ctgagtatgg actacaagca gacccaactt 480
tgtctgctgg gctgtaagcc tccaacagga gaacactggg gcaagggagt ggcttgtacc 540
aatgctgccc ctgccaatga ctgtcctcca ttggaactga taaacaccat cattgaggat 600
ggagatatgg tggacacagg ctttggctgt atggacttca agaccctcca agccaacaag 660
tctgatgtgc caattgacat ctgtggcagc acttgtaaat accctgacta cctgaaaatg 720
acctctgaac catatggaga ctccctgttc ttcttcctga ggagggaaca gatgtttgtg 780
agacacttct tcaacagggc tggcaccctg ggagaggctg tgcctgatga cctctacatc 840
aagggctctg gcaccacagc cagcatccag tcctctgcct tctttccaac accatctggc 900
agtatggtga cctctgagag ccaacttttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caggtgtttg tgacagtggt ggacaccacc 1020
aggagcacca atatgaccct gtgtacccag gtgacctctg acagcaccta caagaatgag 1080
aacttcaagg aatacatcag gcatgtggag gaatatgacc tccaatttgt gttccaactt 1140
tgtaaggtga ccctgacagc agaggtgatg acctacatcc atgctatgaa ccctgacatc 1200
ttggaggact ggcagtttgg actgacacct cctccatctg cctccctcca agacacctac 1260
aggtttgtga ccagccaggc tatcacttgt cagaagacag tgcctccaaa ggagaaggag 1320
gacccactgg gcaaatacac cttctgggag gtggacctga aagagaagtt ctctgctgac 1380
ctggaccagt ttccactggg caggaagttc ctgctccaag caggactgaa agccaagcca 1440
aaactgaaaa gggctgcccc aaccagcacc aggacctcct ctgccaagag gaagaaggtg 1500
aagaagtaaa ctcgagctc 1519
<210> 20
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 1107 HPV11L1 F1
<400> 20
cttggtacca tgtggagacc atctgacagc acagt 35
<210> 21
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 1108 HPV11L1 R1
<400> 21
gcttggcttt gtagccagat tggagcagga acttcc 36
<210> 22
<211> 1429
<212> DNA
<213> Artificial Sequence
<220>
<223> 1109 HPV11L1 amplified sequence 1
<400> 22
cttggtacca tgtggagacc atctgacagc acagtctatg tgcctcctcc aaaccctgtg 60
agcaaggtgg tggctacaga tgcctatgtg aagaggacca acatcttcta ccatgcctcc 120
tccagcagac tgctggctgt gggacaccca tactacagca tcaagaaggt gaacaagaca 180
gtggtgccaa aggtgtctgg ctaccaatac agggtgttca aggtggtgct gcctgaccca 240
aacaagtttg ccctgcctga ctcctccctg tttgacccaa ccacccagag actggtgtgg 300
gcttgtactg gattggaggt gggcagggga caaccactgg gagtgggagt gtctggacac 360
ccactgctga acaaatatga tgatgtggag aactctggag gctatggagg caaccctgga 420
caagacaaca gggtgaatgt ggggatggac tacaagcaga cccaactttg tatggtgggc 480
tgtgcccctc cactgggaga acactggggc aagggcaccc agtgtagcaa cacctctgtc 540
cagaatggag actgtcctcc attggaactg attacctctg tgattcagga tggagatatg 600
gtggacacag gctttggagc tatgaacttt gctgacctcc aaaccaacaa gtctgatgtg 660
ccactggaca tctgtggcac agtgtgtaaa taccctgact acctccaaat ggctgctgac 720
ccatatggag acagactgtt cttctacctg aggaaggaac agatgtttgc cagacacttc 780
ttcaacaggg ctggcacagt gggagaacct gtgcctgatg acctgctggt gaagggaggc 840
aacaacaggt cctctgtggc atccagcatc tatgtgcata caccatctgg ctccctggtg 900
tcctctgagg ctcaactttt caacaagcca tactggctcc aaaaggctca aggacacaac 960
aatggcatct gttggggcaa ccacctgttt gtgacagtgg tggacaccac caggagcacc 1020
aatatgaccc tgtgtgcctc tgtgagcaag tctgccacct acaccaactc tgactacaag 1080
gaatatatga ggcatgtgga ggagtttgac ctccaattca tcttccaact ttgtagcatc 1140
accctgtctg ctgaggtgat ggcttacatc cacacaatga acccatctgt gttggaggac 1200
tggaactttg gactgagccc tcctccaaat ggcaccttgg aggacaccta cagatatgtc 1260
cagagccagg ctatcacttg tcagaagcca acacctgaga aggagaagca ggacccatac 1320
aaggatatga gtttctggga ggtgaacctg aaagagaagt tctcctctga actggaccag 1380
tttccactgg gcaggaagtt cctgctccaa tctggctaca aagccaagc 1429
<210> 23
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 1110 HPV11L1 F2
<400> 23
atctggctac aaagccaagc caaaactgaa aaggg 35
<210> 24
<211> 37
<212> DNA
<213> Artificial Sequence
<220>
<223> 1111 HPV11L1 R2
<400> 24
ctgtctagat ttacttcttc accttcttcc tcttggc 37
<210> 25
<211> 101
<212> DNA
<213> Artificial Sequence
<220>
<223> 1112 HPV11L1 amplified sequence 2
<400> 25
atctggctac aaagccaagc caaaactgaa aagggctgcc ccaaccagca ccaggacctc 60
ctctgccaag aggaagaagg tgaagaagta aatctagaca g 101
<210> 26
<211> 38
<212> PRT
<213> Homo sapiens 1113 Amino acid sequence of HPV type 59 L1 protein aa 471-508
<400> 26
Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile Gly Pro Arg Lys Arg
1 5 10 15
Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro Lys Arg Val Lys Arg
20 25 30
Arg Lys Ser Ser Arg Lys
35
<210> 27
<211> 474
<212> PRT
<213> Homo sapiens 1601 Amino acid sequence of HPV type 16 L1 protein aa 1-474
<400> 27
Met Ser Leu Trp Leu Pro Ser Glu Ala Thr Val Tyr Leu Pro Pro Val
1 5 10 15
Pro Val Ser Lys Val Val Ser Thr Asp Glu Tyr Val Ala Arg Thr Asn
20 25 30
Ile Tyr Tyr His Ala Gly Thr Ser Arg Leu Leu Ala Val Gly His Pro
35 40 45
Tyr Phe Pro Ile Lys Lys Pro Asn Asn Asn Lys Ile Leu Val Pro Lys
50 55 60
Val Ser Gly Leu Gln Tyr Arg Val Phe Arg Ile His Leu Pro Asp Pro
65 70 75 80
Asn Lys Phe Gly Phe Pro Asp Thr Ser Phe Tyr Asn Pro Asp Thr Gln
85 90 95
Arg Leu Val Trp Ala Cys Val Gly Val Glu Val Gly Arg Gly Gln Pro
100 105 110
Leu Gly Val Gly Ile Ser Gly His Pro Leu Leu Asn Lys Leu Asp Asp
115 120 125
Thr Glu Asn Ala Ser Ala Tyr Ala Ala Asn Ala Gly Val Asp Asn Arg
130 135 140
Glu Cys Ile Ser Met Asp Tyr Lys Gln Thr Gln Leu Cys Leu Ile Gly
145 150 155 160
Cys Lys Pro Pro Ile Gly Glu His Trp Gly Lys Gly Ser Pro Cys Thr
165 170 175
Asn Val Ala Val Asn Pro Gly Asp Cys Pro Pro Leu Glu Leu Ile Asn
180 185 190
Thr Val Ile Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala Met
195 200 205
Asp Phe Thr Thr Leu Gln Ala Asn Lys Ser Glu Val Pro Leu Asp Ile
210 215 220
Cys Thr Ser Ile Cys Lys Tyr Pro Asp Tyr Ile Lys Met Val Ser Glu
225 230 235 240
Pro Tyr Gly Asp Ser Leu Phe Phe Tyr Leu Arg Arg Glu Gln Met Phe
245 250 255
Val Arg His Leu Phe Asn Arg Ala Gly Ala Val Gly Glu Asn Val Pro
260 265 270
Asp Asp Leu Tyr Ile Lys Gly Ser Gly Ser Thr Ala Asn Leu Ala Ser
275 280 285
Ser Asn Tyr Phe Pro Thr Pro Ser Gly Ser Met Val Thr Ser Asp Ala
290 295 300
Gln Ile Phe Asn Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn
305 310 315 320
Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp Thr
325 330 335
Thr Arg Ser Thr Asn Met Ser Leu Cys Ala Ala Ile Ser Thr Ser Glu
340 345 350
Thr Thr Tyr Lys Asn Thr Asn Phe Lys Glu Tyr Leu Arg His Gly Glu
355 360 365
Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr
370 375 380
Ala Asp Val Met Thr Tyr Ile His Ser Met Asn Ser Thr Ile Leu Glu
385 390 395 400
Asp Trp Asn Phe Gly Leu Gln Pro Pro Pro Gly Gly Thr Leu Glu Asp
405 410 415
Thr Tyr Arg Phe Val Thr Ser Gln Ala Ile Ala Cys Gln Lys His Thr
420 425 430
Pro Pro Ala Pro Lys Glu Asp Pro Leu Lys Lys Tyr Thr Phe Trp Glu
435 440 445
Val Asn Leu Lys Glu Lys Phe Ser Ala Asp Leu Asp Gln Phe Pro Leu
450 455 460
Gly Arg Lys Phe Leu Leu Gln Ala Gly Leu
465 470
<210> 28
<211> 26
<212> PRT
<213> Homo sapiens 1602 Amino acid sequence of HPV type 33 L1 protein aa 474-499
<400> 28
Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr
1 5 10 15
Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
20 25
<210> 29
<211> 500
<212> PRT
<213> Artificial Sequence
<220>
<223> 1603 Amino acid sequence of chimeric HPV type 16 L1 protein
<400> 29
Met Ser Leu Trp Leu Pro Ser Glu Ala Thr Val Tyr Leu Pro Pro Val
1 5 10 15
Pro Val Ser Lys Val Val Ser Thr Asp Glu Tyr Val Ala Arg Thr Asn
20 25 30
Ile Tyr Tyr His Ala Gly Thr Ser Arg Leu Leu Ala Val Gly His Pro
35 40 45
Tyr Phe Pro Ile Lys Lys Pro Asn Asn Asn Lys Ile Leu Val Pro Lys
50 55 60
Val Ser Gly Leu Gln Tyr Arg Val Phe Arg Ile His Leu Pro Asp Pro
65 70 75 80
Asn Lys Phe Gly Phe Pro Asp Thr Ser Phe Tyr Asn Pro Asp Thr Gln
85 90 95
Arg Leu Val Trp Ala Cys Val Gly Val Glu Val Gly Arg Gly Gln Pro
100 105 110
Leu Gly Val Gly Ile Ser Gly His Pro Leu Leu Asn Lys Leu Asp Asp
115 120 125
Thr Glu Asn Ala Ser Ala Tyr Ala Ala Asn Ala Gly Val Asp Asn Arg
130 135 140
Glu Cys Ile Ser Met Asp Tyr Lys Gln Thr Gln Leu Cys Leu Ile Gly
145 150 155 160
Cys Lys Pro Pro Ile Gly Glu His Trp Gly Lys Gly Ser Pro Cys Thr
165 170 175
Asn Val Ala Val Asn Pro Gly Asp Cys Pro Pro Leu Glu Leu Ile Asn
180 185 190
Thr Val Ile Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala Met
195 200 205
Asp Phe Thr Thr Leu Gln Ala Asn Lys Ser Glu Val Pro Leu Asp Ile
210 215 220
Cys Thr Ser Ile Cys Lys Tyr Pro Asp Tyr Ile Lys Met Val Ser Glu
225 230 235 240
Pro Tyr Gly Asp Ser Leu Phe Phe Tyr Leu Arg Arg Glu Gln Met Phe
245 250 255
Val Arg His Leu Phe Asn Arg Ala Gly Ala Val Gly Glu Asn Val Pro
260 265 270
Asp Asp Leu Tyr Ile Lys Gly Ser Gly Ser Thr Ala Asn Leu Ala Ser
275 280 285
Ser Asn Tyr Phe Pro Thr Pro Ser Gly Ser Met Val Thr Ser Asp Ala
290 295 300
Gln Ile Phe Asn Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn
305 310 315 320
Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp Thr
325 330 335
Thr Arg Ser Thr Asn Met Ser Leu Cys Ala Ala Ile Ser Thr Ser Glu
340 345 350
Thr Thr Tyr Lys Asn Thr Asn Phe Lys Glu Tyr Leu Arg His Gly Glu
355 360 365
Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr
370 375 380
Ala Asp Val Met Thr Tyr Ile His Ser Met Asn Ser Thr Ile Leu Glu
385 390 395 400
Asp Trp Asn Phe Gly Leu Gln Pro Pro Pro Gly Gly Thr Leu Glu Asp
405 410 415
Thr Tyr Arg Phe Val Thr Ser Gln Ala Ile Ala Cys Gln Lys His Thr
420 425 430
Pro Pro Ala Pro Lys Glu Asp Pro Leu Lys Lys Tyr Thr Phe Trp Glu
435 440 445
Val Asn Leu Lys Glu Lys Phe Ser Ala Asp Leu Asp Gln Phe Pro Leu
450 455 460
Gly Arg Lys Phe Leu Leu Gln Ala Gly Leu Lys Ala Lys Pro Lys Leu
465 470 475 480
Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr Ser Ser Ala Lys Arg Lys
485 490 495
Lys Val Lys Lys
500
<210> 30
<211> 1504
<212> DNA
<213> Artificial Sequence
<220>
<223> 1604 Nucleotide sequence of chimeric HPV type 16 L1 protein
<400> 30
atgagtctgt ggctgccatc tgaggctaca gtctacctgc ctcctgtgcc tgtgagcaag 60
gtggtgagca cagatgaata tgtggcaagg accaacatct actaccatgc tggcaccagc 120
agactgctgg ctgtgggaca cccatacttt ccaatcaaga agccaaacaa caacaagatt 180
ctggtgccaa aggtgtctgg actccaatac agggtgttca ggattcacct gcctgaccca 240
aacaagtttg gctttcctga cacctccttc tacaaccctg acacccagag actggtgtgg 300
gcttgtgtgg gagtggaggt gggcagggga caaccactgg gagtgggcat ctctggacac 360
ccactgctga acaaactgga tgacacagag aatgcctctg cctatgctgc caatgctgga 420
gtggacaaca gggagtgtat cagtatggac tacaagcaga cccaactttg tctgattggc 480
tgtaagcctc caattggaga acactggggc aagggcagcc catgtaccaa tgtggctgtg 540
aaccctggag actgtcctcc attggaactg ataaacacag tgattcagga tggagatatg 600
gtggacacag gctttggagc tatggacttc accaccctcc aagccaacaa gtctgaggtg 660
ccactggaca tctgtaccag catctgtaaa taccctgact acatcaagat ggtgtctgaa 720
ccatatggag actccctgtt cttctacctg aggagggaac agatgtttgt gagacacctg 780
ttcaacaggg ctggagcagt gggagagaat gtgcctgatg acctctacat caagggctct 840
ggcagcacag ccaacctggc atccagcaac tactttccaa caccatctgg cagtatggtg 900
acctctgatg cccagatttt caacaagcca tactggctcc aaagggctca aggacacaac 960
aatggcatct gttggggcaa ccaacttttt gtgacagtgg tggacaccac caggagcacc 1020
aatatgagtc tgtgtgctgc catcagcacc tctgagacca cctacaagaa caccaacttc 1080
aaggaatacc tgagacatgg agaggaatat gacctccaat tcatcttcca actttgtaag 1140
attaccctga cagcagatgt gatgacctac atccacagta tgaacagcac catcttggag 1200
gactggaact ttggactcca acctcctcct ggaggcacct tggaggacac ctacaggttt 1260
gtgaccagcc aggctattgc ctgtcagaaa cacacacctc ctgccccaaa ggaggaccca 1320
ctgaaaaaat acaccttctg ggaggtgaac ctgaaagaga agttctctgc tgacctggac 1380
cagtttccac tgggcaggaa gttcctgctc caagcaggac tgaaagccaa gccaaaactg 1440
aaaagggctg ccccaaccag caccaggacc tcctctgcca agaggaagaa ggtgaagaag 1500
taaa 1504
<210> 31
<211> 1537
<212> DNA
<213> Artificial Sequence
<220>
<223> 1605 Synthetic HPV16 L1 gene
<400> 31
ctgggtacca tgagtctgtg gctgccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtggcaagga ccaacatcta ctaccatgct 120
ggcaccagca gactgctggc tgtgggacac ccatactttc caatcaagaa gccaaacaac 180
aacaagattc tggtgccaaa ggtgtctgga ctccaataca gggtgttcag gattcacctg 240
cctgacccaa acaagtttgg ctttcctgac acctccttct acaaccctga cacccagaga 300
ctggtgtggg cttgtgtggg agtggaggtg ggcaggggac aaccactggg agtgggcatc 360
tctggacacc cactgctgaa caaactggat gacacagaga atgcctctgc ctatgctgcc 420
aatgctggag tggacaacag ggagtgtatc agtatggact acaagcagac ccaactttgt 480
ctgattggct gtaagcctcc aattggagaa cactggggca agggcagccc atgtaccaat 540
gtggctgtga accctggaga ctgtcctcca ttggaactga taaacacagt gattcaggat 600
ggagatatgg tggacacagg ctttggagct atggacttca ccaccctcca agccaacaag 660
tctgaggtgc cactggacat ctgtaccagc atctgtaaat accctgacta catcaagatg 720
gtgtctgaac catatggaga ctccctgttc ttctacctga ggagggaaca gatgtttgtg 780
agacacctgt tcaacagggc tggagcagtg ggagagaatg tgcctgatga cctctacatc 840
aagggctctg gcagcacagc caacctggca tccagcaact actttccaac accatctggc 900
agtatggtga cctctgatgc ccagattttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caactttttg tgacagtggt ggacaccacc 1020
aggagcacca atatgagtct gtgtgctgcc atcagcacct ctgagaccac ctacaagaac 1080
accaacttca aggaatacct gagacatgga gaggaatatg acctccaatt catcttccaa 1140
ctttgtaaga ttaccctgac agcagatgtg atgacctaca tccacagtat gaacagcacc 1200
atcttggagg actggaactt tggactccaa cctcctcctg gaggcacctt ggaggacacc 1260
tacaggtttg tgaccagcca ggctattgcc tgtcagaaac acacacctcc tgccccaaag 1320
gaggacccac tgaaaaaata caccttctgg gaggtgaacc tgaaagagaa gttctctgct 1380
gacctggacc agtttccact gggcaggaag ttcctgctcc aagcaggact gaaagccaag 1440
ccaaagttca ccctgggcaa gaggaaggct acaccaacca cctccagcac cagcaccaca 1500
gccaagagga agaagaggaa actgtaaact cgagctc 1537
<210> 32
<211> 1519
<212> DNA
<213> Artificial Sequence
<220>
<223> 1606 Synthetic HPV33 L1 gene
<400> 32
ctgggtacca tgagtgtgtg gagaccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtgagcagga ccagcatcta ctactatgct 120
ggctccagca gactgctggc tgtgggacac ccatacttca gcatcaagaa cccaaccaat 180
gccaagaaac tgctggtgcc aaaggtgtct ggactccaat acagggtgtt cagggtgaga 240
ctgcctgacc caaacaagtt tggctttcct gacacctcct tctacaaccc tgacacccag 300
agactggtgt gggcttgtgt gggattggag attggcaggg gacaaccact gggagtgggc 360
atctctggac acccactgct gaacaagttt gatgacacag agacaggcaa caaataccct 420
ggacaacctg gagcagacaa cagggagtgt ctgagtatgg actacaagca gacccaactt 480
tgtctgctgg gctgtaagcc tccaacagga gaacactggg gcaagggagt ggcttgtacc 540
aatgctgccc ctgccaatga ctgtcctcca ttggaactga taaacaccat cattgaggat 600
ggagatatgg tggacacagg ctttggctgt atggacttca agaccctcca agccaacaag 660
tctgatgtgc caattgacat ctgtggcagc acttgtaaat accctgacta cctgaaaatg 720
acctctgaac catatggaga ctccctgttc ttcttcctga ggagggaaca gatgtttgtg 780
agacacttct tcaacagggc tggcaccctg ggagaggctg tgcctgatga cctctacatc 840
aagggctctg gcaccacagc cagcatccag tcctctgcct tctttccaac accatctggc 900
agtatggtga cctctgagag ccaacttttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caggtgtttg tgacagtggt ggacaccacc 1020
aggagcacca atatgaccct gtgtacccag gtgacctctg acagcaccta caagaatgag 1080
aacttcaagg aatacatcag gcatgtggag gaatatgacc tccaatttgt gttccaactt 1140
tgtaaggtga ccctgacagc agaggtgatg acctacatcc atgctatgaa ccctgacatc 1200
ttggaggact ggcagtttgg actgacacct cctccatctg cctccctcca agacacctac 1260
aggtttgtga ccagccaggc tatcacttgt cagaagacag tgcctccaaa ggagaaggag 1320
gacccactgg gcaaatacac cttctgggag gtggacctga aagagaagtt ctctgctgac 1380
ctggaccagt ttccactggg caggaagttc ctgctccaag caggactgaa agccaagcca 1440
aaactgaaaa gggctgcccc aaccagcacc aggacctcct ctgccaagag gaagaaggtg 1500
aagaagtaaa ctcgagctc 1519
<210> 33
<211> 34
<212> DNA
<213> Artificial Sequence
<220>
<223> 1607 HPV16L1 F1
<400> 33
cttggtacca tgagtctgtg gctgccatct gagg 34
<210> 34
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 1608 HPV16L1 R1
<400> 34
gcttggcttt cagtcctgct tggagcagga acttcc 36
<210> 35
<211> 1441
<212> DNA
<213> Artificial Sequence
<220>
<223> 1609 HPV16L1 amplified sequence 1
<400> 35
cttggtacca tgagtctgtg gctgccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtggcaagga ccaacatcta ctaccatgct 120
ggcaccagca gactgctggc tgtgggacac ccatactttc caatcaagaa gccaaacaac 180
aacaagattc tggtgccaaa ggtgtctgga ctccaataca gggtgttcag gattcacctg 240
cctgacccaa acaagtttgg ctttcctgac acctccttct acaaccctga cacccagaga 300
ctggtgtggg cttgtgtggg agtggaggtg ggcaggggac aaccactggg agtgggcatc 360
tctggacacc cactgctgaa caaactggat gacacagaga atgcctctgc ctatgctgcc 420
aatgctggag tggacaacag ggagtgtatc agtatggact acaagcagac ccaactttgt 480
ctgattggct gtaagcctcc aattggagaa cactggggca agggcagccc atgtaccaat 540
gtggctgtga accctggaga ctgtcctcca ttggaactga taaacacagt gattcaggat 600
ggagatatgg tggacacagg ctttggagct atggacttca ccaccctcca agccaacaag 660
tctgaggtgc cactggacat ctgtaccagc atctgtaaat accctgacta catcaagatg 720
gtgtctgaac catatggaga ctccctgttc ttctacctga ggagggaaca gatgtttgtg 780
agacacctgt tcaacagggc tggagcagtg ggagagaatg tgcctgatga cctctacatc 840
aagggctctg gcagcacagc caacctggca tccagcaact actttccaac accatctggc 900
agtatggtga cctctgatgc ccagattttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caactttttg tgacagtggt ggacaccacc 1020
aggagcacca atatgagtct gtgtgctgcc atcagcacct ctgagaccac ctacaagaac 1080
accaacttca aggaatacct gagacatgga gaggaatatg acctccaatt catcttccaa 1140
ctttgtaaga ttaccctgac agcagatgtg atgacctaca tccacagtat gaacagcacc 1200
atcttggagg actggaactt tggactccaa cctcctcctg gaggcacctt ggaggacacc 1260
tacaggtttg tgaccagcca ggctattgcc tgtcagaaac acacacctcc tgccccaaag 1320
gaggacccac tgaaaaaata caccttctgg gaggtgaacc tgaaagagaa gttctctgct 1380
gacctggacc agtttccact gggcaggaag ttcctgctcc aagcaggact gaaagccaag 1440
c 1441
<210> 36
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 1610 HPV16L1 F2
<400> 36
agcaggactg aaagccaagc caaaactgaa aaggg 35
<210> 37
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 1611 HPV16L1 R2
<400> 37
ctgtctagat ttacttcttc accttcttcc tcttgg 36
<210> 38
<211> 101
<212> DNA
<213> Artificial Sequence
<220>
<223> 1612 HPV16L1 amplified sequence 2
<400> 38
agcaggactg aaagccaagc caaaactgaa aagggctgcc ccaaccagca ccaggacctc 60
ctctgccaag aggaagaagg tgaagaagta aatctagaca g 101
<210> 39
<211> 38
<212> PRT
<213> Homo sapiens 1613 Amino acid sequence of HPV type 59 L1 protein aa 471-508
<400> 39
Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile Gly Pro Arg Lys Arg
1 5 10 15
Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro Lys Arg Val Lys Arg
20 25 30
Arg Lys Ser Ser Arg Lys
35
<210> 40
<211> 470
<212> PRT
<213> Homo sapiens 1801 Amino acid sequence of HPV type 18 L1 protein aa 1-470
<400> 40
Met Ala Leu Trp Arg Pro Ser Asp Asn Thr Val Tyr Leu Pro Pro Pro
1 5 10 15
Ser Val Ala Arg Val Val Asn Thr Asp Asp Tyr Val Thr Arg Thr Ser
20 25 30
Ile Phe Tyr His Ala Gly Ser Ser Arg Leu Leu Thr Val Gly Asn Pro
35 40 45
Tyr Phe Arg Val Pro Ala Gly Gly Gly Asn Lys Gln Asp Ile Pro Lys
50 55 60
Val Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val Gln Leu Pro Asp Pro
65 70 75 80
Asn Lys Phe Gly Leu Pro Asp Thr Ser Ile Tyr Asn Pro Glu Thr Gln
85 90 95
Arg Leu Val Trp Ala Cys Ala Gly Val Glu Ile Gly Arg Gly Gln Pro
100 105 110
Leu Gly Val Gly Leu Ser Gly His Pro Phe Tyr Asn Lys Leu Asp Asp
115 120 125
Thr Glu Ser Ser His Ala Ala Thr Ser Asn Val Ser Glu Asp Val Arg
130 135 140
Asp Asn Val Ser Val Asp Tyr Lys Gln Thr Gln Leu Cys Ile Leu Gly
145 150 155 160
Cys Ala Pro Ala Ile Gly Glu His Trp Ala Lys Gly Thr Ala Cys Lys
165 170 175
Ser Arg Pro Leu Ser Gln Gly Asp Cys Pro Pro Leu Glu Leu Lys Asn
180 185 190
Thr Val Leu Glu Asp Gly Asp Met Val Asp Thr Gly Tyr Gly Ala Met
195 200 205
Asp Phe Ser Thr Leu Gln Asp Thr Lys Cys Glu Val Pro Leu Asp Ile
210 215 220
Cys Gln Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ser Ala Asp
225 230 235 240
Pro Tyr Gly Asp Ser Met Phe Phe Cys Leu Arg Arg Glu Gln Leu Phe
245 250 255
Ala Arg His Phe Trp Asn Arg Ala Gly Thr Met Gly Asp Thr Val Pro
260 265 270
Gln Ser Leu Tyr Ile Lys Gly Thr Gly Met Arg Ala Ser Pro Gly Ser
275 280 285
Cys Val Tyr Ser Pro Ser Pro Ser Gly Ser Ile Val Thr Ser Asp Ser
290 295 300
Gln Leu Phe Asn Lys Pro Tyr Trp Leu His Lys Ala Gln Gly His Asn
305 310 315 320
Asn Gly Val Cys Trp His Asn Gln Leu Phe Val Thr Val Val Asp Thr
325 330 335
Thr Arg Ser Thr Asn Leu Thr Ile Cys Ala Ser Thr Gln Ser Pro Val
340 345 350
Pro Gly Gln Tyr Asp Ala Thr Lys Phe Lys Gln Tyr Ser Arg His Val
355 360 365
Glu Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Thr Ile Thr Leu
370 375 380
Thr Ala Asp Val Met Ser Tyr Ile His Ser Met Asn Ser Ser Ile Leu
385 390 395 400
Glu Asp Trp Asn Phe Gly Val Pro Pro Pro Pro Thr Thr Ser Leu Val
405 410 415
Asp Thr Tyr Arg Phe Val Gln Ser Val Ala Ile Thr Cys Gln Lys Asp
420 425 430
Ala Ala Pro Ala Glu Asn Lys Asp Pro Tyr Asp Lys Leu Lys Phe Trp
435 440 445
Asn Val Asp Leu Lys Glu Lys Phe Ser Leu Asp Leu Asp Gln Tyr Pro
450 455 460
Leu Gly Arg Lys Phe Leu
465 470
<210> 41
<211> 26
<212> PRT
<213> Homo sapiens 1802 Amino acid sequence of HPV type 33 L1 protein aa 474-499
<400> 41
Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr
1 5 10 15
Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
20 25
<210> 42
<211> 496
<212> PRT
<213> Artificial Sequence
<220>
<223> 1803 Amino acid sequence of chimeric HPV type 18 L1 protein
<400> 42
Met Ala Leu Trp Arg Pro Ser Asp Asn Thr Val Tyr Leu Pro Pro Pro
1 5 10 15
Ser Val Ala Arg Val Val Asn Thr Asp Asp Tyr Val Thr Arg Thr Ser
20 25 30
Ile Phe Tyr His Ala Gly Ser Ser Arg Leu Leu Thr Val Gly Asn Pro
35 40 45
Tyr Phe Arg Val Pro Ala Gly Gly Gly Asn Lys Gln Asp Ile Pro Lys
50 55 60
Val Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val Gln Leu Pro Asp Pro
65 70 75 80
Asn Lys Phe Gly Leu Pro Asp Thr Ser Ile Tyr Asn Pro Glu Thr Gln
85 90 95
Arg Leu Val Trp Ala Cys Ala Gly Val Glu Ile Gly Arg Gly Gln Pro
100 105 110
Leu Gly Val Gly Leu Ser Gly His Pro Phe Tyr Asn Lys Leu Asp Asp
115 120 125
Thr Glu Ser Ser His Ala Ala Thr Ser Asn Val Ser Glu Asp Val Arg
130 135 140
Asp Asn Val Ser Val Asp Tyr Lys Gln Thr Gln Leu Cys Ile Leu Gly
145 150 155 160
Cys Ala Pro Ala Ile Gly Glu His Trp Ala Lys Gly Thr Ala Cys Lys
165 170 175
Ser Arg Pro Leu Ser Gln Gly Asp Cys Pro Pro Leu Glu Leu Lys Asn
180 185 190
Thr Val Leu Glu Asp Gly Asp Met Val Asp Thr Gly Tyr Gly Ala Met
195 200 205
Asp Phe Ser Thr Leu Gln Asp Thr Lys Cys Glu Val Pro Leu Asp Ile
210 215 220
Cys Gln Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ser Ala Asp
225 230 235 240
Pro Tyr Gly Asp Ser Met Phe Phe Cys Leu Arg Arg Glu Gln Leu Phe
245 250 255
Ala Arg His Phe Trp Asn Arg Ala Gly Thr Met Gly Asp Thr Val Pro
260 265 270
Gln Ser Leu Tyr Ile Lys Gly Thr Gly Met Arg Ala Ser Pro Gly Ser
275 280 285
Cys Val Tyr Ser Pro Ser Pro Ser Gly Ser Ile Val Thr Ser Asp Ser
290 295 300
Gln Leu Phe Asn Lys Pro Tyr Trp Leu His Lys Ala Gln Gly His Asn
305 310 315 320
Asn Gly Val Cys Trp His Asn Gln Leu Phe Val Thr Val Val Asp Thr
325 330 335
Thr Arg Ser Thr Asn Leu Thr Ile Cys Ala Ser Thr Gln Ser Pro Val
340 345 350
Pro Gly Gln Tyr Asp Ala Thr Lys Phe Lys Gln Tyr Ser Arg His Val
355 360 365
Glu Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Thr Ile Thr Leu
370 375 380
Thr Ala Asp Val Met Ser Tyr Ile His Ser Met Asn Ser Ser Ile Leu
385 390 395 400
Glu Asp Trp Asn Phe Gly Val Pro Pro Pro Pro Thr Thr Ser Leu Val
405 410 415
Asp Thr Tyr Arg Phe Val Gln Ser Val Ala Ile Thr Cys Gln Lys Asp
420 425 430
Ala Ala Pro Ala Glu Asn Lys Asp Pro Tyr Asp Lys Leu Lys Phe Trp
435 440 445
Asn Val Asp Leu Lys Glu Lys Phe Ser Leu Asp Leu Asp Gln Tyr Pro
450 455 460
Leu Gly Arg Lys Phe Leu Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala
465 470 475 480
Pro Thr Ser Thr Arg Thr Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
485 490 495
<210> 43
<211> 1492
<212> DNA
<213> Artificial Sequence
<220>
<223> 1804 Nucleotide sequence of chimeric HPV type 18 L1 protein
<400> 43
atggccctct ggagaccatc cgataacaca gtgtacttgc ccccacccag cgtcgcccgg 60
gtggtgaaca cagacgacta cgtcaccaga acctcaatct tctaccacgc cgggtccagc 120
cggctgctga ccgtgggcaa cccctacttc cgcgtgcccg ccggcggcgg aaacaaacaa 180
gacatcccca aagtcagcgc ctatcagtac cgggtgttcc gcgtccaact gcccgatccc 240
aacaagttcg gcctgcccga cacctccatc tacaaccccg agacccagag gctggtctgg 300
gcttgcgccg gcgtcgagat cgggaggggc caacccctgg gcgtggggtt gtccggccac 360
cccttctaca acaagctgga cgataccgag tccagccacg cagcaaccag caacgtctcc 420
gaagatgtgc gcgataacgt cagcgtggac tacaaacaaa cccaactgtg catcctggga 480
tgcgcacccg ccatcggcga gcattgggcc aaggggaccg cctgcaagag caggcccctg 540
agccaagggg actgtccacc cctggagttg aagaataccg tgctcgagga cggcgacatg 600
gtggacaccg gctacggcgc tatggatttc tccaccctcc aggacaccaa gtgcgaagtg 660
cccctcgaca tctgccaaag catctgcaag taccccgact acctccagat gagcgccgac 720
ccctacggcg acagcatgtt cttctgtctc agaagggaac aattgttcgc ccgccacttc 780
tggaaccggg ccggcacaat gggagataca gtcccccaga gcctgtacat caaggggacc 840
ggaatgaggg ccagccccgg gtcctgcgtc tacagcccaa gcccctccgg gagcatcgtc 900
acaagcgata gccaactctt caacaagccc tactggctcc acaaagccca aggccacaat 960
aacggggtgt gttggcacaa ccagctgttc gtgaccgtcg tggacacaac caggtccaca 1020
aacctgacca tctgcgccag cacccaaagc cccgtgcccg gccagtacga cgccacaaag 1080
ttcaaacaat actctcggca cgtggaagag tacgacctcc aattcatctt ccaactctgc 1140
accatcaccc tcaccgccga cgtgatgagc tacatccact ccatgaactc ctccatcctg 1200
gaagactgga atttcggcgt gccaccaccc cctaccacct ccctcgtcga cacctacaga 1260
ttcgtgcaga gcgtggccat cacatgccag aaagacgccg cccccgccga gaacaaagac 1320
ccatacgaca aactgaaatt ctggaacgtc gacctgaaag agaaattcag cctggatctg 1380
gaccagtacc cattgggcag gaagttcctc aaagccaagc caaaactgaa aagggctgcc 1440
ccaaccagca ccaggacctc ctctgccaag aggaagaagg tgaagaagta aa 1492
<210> 44
<211> 1543
<212> DNA
<213> Artificial Sequence
<220>
<223> 1805 Synthetic HPV18 L1 gene
<400> 44
ctgggtacca tggccctctg gagaccatcc gataacacag tgtacttgcc cccacccagc 60
gtcgcccggg tggtgaacac agacgactac gtcaccagaa cctcaatctt ctaccacgcc 120
gggtccagcc ggctgctgac cgtgggcaac ccctacttcc gcgtgcccgc cggcggcgga 180
aacaaacaag acatccccaa agtcagcgcc tatcagtacc gggtgttccg cgtccaactg 240
cccgatccca acaagttcgg cctgcccgac acctccatct acaaccccga gacccagagg 300
ctggtctggg cttgcgccgg cgtcgagatc gggaggggcc aacccctggg cgtggggttg 360
tccggccacc ccttctacaa caagctggac gataccgagt ccagccacgc agcaaccagc 420
aacgtctccg aagatgtgcg cgataacgtc agcgtggact acaaacaaac ccaactgtgc 480
atcctgggat gcgcacccgc catcggcgag cattgggcca aggggaccgc ctgcaagagc 540
aggcccctga gccaagggga ctgtccaccc ctggagttga agaataccgt gctcgaggac 600
ggcgacatgg tggacaccgg ctacggcgct atggatttct ccaccctcca ggacaccaag 660
tgcgaagtgc ccctcgacat ctgccaaagc atctgcaagt accccgacta cctccagatg 720
agcgccgacc cctacggcga cagcatgttc ttctgtctca gaagggaaca attgttcgcc 780
cgccacttct ggaaccgggc cggcacaatg ggagatacag tcccccagag cctgtacatc 840
aaggggaccg gaatgagggc cagccccggg tcctgcgtct acagcccaag cccctccggg 900
agcatcgtca caagcgatag ccaactcttc aacaagccct actggctcca caaagcccaa 960
ggccacaata acggggtgtg ttggcacaac cagctgttcg tgaccgtcgt ggacacaacc 1020
aggtccacaa acctgaccat ctgcgccagc acccaaagcc ccgtgcccgg ccagtacgac 1080
gccacaaagt tcaaacaata ctctcggcac gtggaagagt acgacctcca attcatcttc 1140
caactctgca ccatcaccct caccgccgac gtgatgagct acatccactc catgaactcc 1200
tccatcctgg aagactggaa tttcggcgtg ccaccacccc ctaccacctc cctcgtcgac 1260
acctacagat tcgtgcagag cgtggccatc acatgccaga aagacgccgc ccccgccgag 1320
aacaaagacc catacgacaa actgaaattc tggaacgtcg acctgaaaga gaaattcagc 1380
ctggatctgg accagtaccc attgggcagg aagttcctcg tgcaagccgg cctcaggaga 1440
aaaccaacaa tcgggcccag gaagaggagc gcccccagcg caaccaccag cagcaagccc 1500
gcaaaaaggg tcagagtgag ggcacgcaaa taaactcgag ctc 1543
<210> 45
<211> 1519
<212> DNA
<213> Artificial Sequence
<220>
<223> 1806 Synthetic HPV33 L1 gene
<400> 45
ctgggtacca tgagtgtgtg gagaccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtgagcagga ccagcatcta ctactatgct 120
ggctccagca gactgctggc tgtgggacac ccatacttca gcatcaagaa cccaaccaat 180
gccaagaaac tgctggtgcc aaaggtgtct ggactccaat acagggtgtt cagggtgaga 240
ctgcctgacc caaacaagtt tggctttcct gacacctcct tctacaaccc tgacacccag 300
agactggtgt gggcttgtgt gggattggag attggcaggg gacaaccact gggagtgggc 360
atctctggac acccactgct gaacaagttt gatgacacag agacaggcaa caaataccct 420
ggacaacctg gagcagacaa cagggagtgt ctgagtatgg actacaagca gacccaactt 480
tgtctgctgg gctgtaagcc tccaacagga gaacactggg gcaagggagt ggcttgtacc 540
aatgctgccc ctgccaatga ctgtcctcca ttggaactga taaacaccat cattgaggat 600
ggagatatgg tggacacagg ctttggctgt atggacttca agaccctcca agccaacaag 660
tctgatgtgc caattgacat ctgtggcagc acttgtaaat accctgacta cctgaaaatg 720
acctctgaac catatggaga ctccctgttc ttcttcctga ggagggaaca gatgtttgtg 780
agacacttct tcaacagggc tggcaccctg ggagaggctg tgcctgatga cctctacatc 840
aagggctctg gcaccacagc cagcatccag tcctctgcct tctttccaac accatctggc 900
agtatggtga cctctgagag ccaacttttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caggtgtttg tgacagtggt ggacaccacc 1020
aggagcacca atatgaccct gtgtacccag gtgacctctg acagcaccta caagaatgag 1080
aacttcaagg aatacatcag gcatgtggag gaatatgacc tccaatttgt gttccaactt 1140
tgtaaggtga ccctgacagc agaggtgatg acctacatcc atgctatgaa ccctgacatc 1200
ttggaggact ggcagtttgg actgacacct cctccatctg cctccctcca agacacctac 1260
aggtttgtga ccagccaggc tatcacttgt cagaagacag tgcctccaaa ggagaaggag 1320
gacccactgg gcaaatacac cttctgggag gtggacctga aagagaagtt ctctgctgac 1380
ctggaccagt ttccactggg caggaagttc ctgctccaag caggactgaa agccaagcca 1440
aaactgaaaa gggctgcccc aaccagcacc aggacctcct ctgccaagag gaagaaggtg 1500
aagaagtaaa ctcgagctc 1519
<210> 46
<211> 34
<212> DNA
<213> Artificial Sequence
<220>
<223> 1807 HPV18L1 F1
<400> 46
cttggtacca tggccctctg gagaccatcc gata 34
<210> 47
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 1808 HPV18L1 R1
<400> 47
gcttggcttt gaggaacttc ctgcccaatg ggtac 35
<210> 48
<211> 1429
<212> DNA
<213> Artificial Sequence
<220>
<223> 1809 HPV18L1 amplified sequence 1
<400> 48
cttggtacca tggccctctg gagaccatcc gataacacag tgtacttgcc cccacccagc 60
gtcgcccggg tggtgaacac agacgactac gtcaccagaa cctcaatctt ctaccacgcc 120
gggtccagcc ggctgctgac cgtgggcaac ccctacttcc gcgtgcccgc cggcggcgga 180
aacaaacaag acatccccaa agtcagcgcc tatcagtacc gggtgttccg cgtccaactg 240
cccgatccca acaagttcgg cctgcccgac acctccatct acaaccccga gacccagagg 300
ctggtctggg cttgcgccgg cgtcgagatc gggaggggcc aacccctggg cgtggggttg 360
tccggccacc ccttctacaa caagctggac gataccgagt ccagccacgc agcaaccagc 420
aacgtctccg aagatgtgcg cgataacgtc agcgtggact acaaacaaac ccaactgtgc 480
atcctgggat gcgcacccgc catcggcgag cattgggcca aggggaccgc ctgcaagagc 540
aggcccctga gccaagggga ctgtccaccc ctggagttga agaataccgt gctcgaggac 600
ggcgacatgg tggacaccgg ctacggcgct atggatttct ccaccctcca ggacaccaag 660
tgcgaagtgc ccctcgacat ctgccaaagc atctgcaagt accccgacta cctccagatg 720
agcgccgacc cctacggcga cagcatgttc ttctgtctca gaagggaaca attgttcgcc 780
cgccacttct ggaaccgggc cggcacaatg ggagatacag tcccccagag cctgtacatc 840
aaggggaccg gaatgagggc cagccccggg tcctgcgtct acagcccaag cccctccggg 900
agcatcgtca caagcgatag ccaactcttc aacaagccct actggctcca caaagcccaa 960
ggccacaata acggggtgtg ttggcacaac cagctgttcg tgaccgtcgt ggacacaacc 1020
aggtccacaa acctgaccat ctgcgccagc acccaaagcc ccgtgcccgg ccagtacgac 1080
gccacaaagt tcaaacaata ctctcggcac gtggaagagt acgacctcca attcatcttc 1140
caactctgca ccatcaccct caccgccgac gtgatgagct acatccactc catgaactcc 1200
tccatcctgg aagactggaa tttcggcgtg ccaccacccc ctaccacctc cctcgtcgac 1260
acctacagat tcgtgcagag cgtggccatc acatgccaga aagacgccgc ccccgccgag 1320
aacaaagacc catacgacaa actgaaattc tggaacgtcg acctgaaaga gaaattcagc 1380
ctggatctgg accagtaccc attgggcagg aagttcctca aagccaagc 1429
<210> 49
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 1810 HPV18L1 F2
<400> 49
gaagttcctc aaagccaagc caaaactgaa aaggg 35
<210> 50
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 1811 HPV18L1 R2
<400> 50
ctgtctagat ttacttcttc accttcttcc tcttgg 36
<210> 51
<211> 101
<212> DNA
<213> Artificial Sequence
<220>
<223> 1812 HPV18L1 amplified sequence 2
<400> 51
gaagttcctc aaagccaagc caaaactgaa aagggctgcc ccaaccagca ccaggacctc 60
ctctgccaag aggaagaagg tgaagaagta aatctagaca g 101
<210> 52
<211> 38
<212> PRT
<213> Homo sapiens 1813 Amino acid sequence of HPV type 59 L1 protein aa 471-508
<400> 52
Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile Gly Pro Arg Lys Arg
1 5 10 15
Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro Lys Arg Val Lys Arg
20 25 30
Arg Lys Ser Ser Arg Lys
35
<210> 53
<211> 475
<212> PRT
<213> Homo sapiens 3101 Amino acid sequence of HPV type 31 L1 protein aa 1-475
<400> 53
Met Ser Leu Trp Arg Pro Ser Glu Ala Thr Val Tyr Leu Pro Pro Val
1 5 10 15
Pro Val Ser Lys Val Val Ser Thr Asp Glu Tyr Val Thr Arg Thr Asn
20 25 30
Ile Tyr Tyr His Ala Gly Ser Ala Arg Leu Leu Thr Val Gly His Pro
35 40 45
Tyr Tyr Ser Ile Pro Lys Ser Asp Asn Pro Lys Lys Ile Val Val Pro
50 55 60
Lys Val Ser Gly Leu Gln Tyr Arg Val Phe Arg Val Arg Leu Pro Asp
65 70 75 80
Pro Asn Lys Phe Gly Phe Pro Asp Thr Ser Phe Tyr Asn Pro Glu Thr
85 90 95
Gln Arg Leu Val Trp Ala Cys Val Gly Leu Glu Val Gly Arg Gly Gln
100 105 110
Pro Leu Gly Val Gly Ile Ser Gly His Pro Leu Leu Asn Lys Phe Asp
115 120 125
Asp Thr Glu Asn Ser Asn Arg Tyr Ala Gly Gly Pro Gly Thr Asp Asn
130 135 140
Arg Glu Cys Ile Ser Met Asp Tyr Lys Gln Thr Gln Leu Cys Leu Leu
145 150 155 160
Gly Cys Lys Pro Pro Ile Gly Glu His Trp Gly Lys Gly Ser Pro Cys
165 170 175
Ser Asn Asn Ala Ile Thr Pro Gly Asp Cys Pro Pro Leu Glu Leu Lys
180 185 190
Asn Ser Val Ile Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala
195 200 205
Met Asp Phe Thr Ala Leu Gln Asp Thr Lys Ser Asn Val Pro Leu Asp
210 215 220
Ile Cys Asn Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Lys Met Val Ala
225 230 235 240
Glu Pro Tyr Gly Asp Thr Leu Phe Phe Tyr Leu Arg Arg Glu Gln Met
245 250 255
Phe Val Arg His Phe Phe Asn Arg Ser Gly Thr Val Gly Glu Ser Val
260 265 270
Pro Thr Asp Leu Tyr Ile Lys Gly Ser Gly Ser Thr Ala Thr Leu Ala
275 280 285
Asn Ser Thr Tyr Phe Pro Thr Pro Ser Gly Ser Met Val Thr Ser Asp
290 295 300
Ala Gln Ile Phe Asn Lys Pro Tyr Trp Met Gln Arg Ala Gln Gly His
305 310 315 320
Asn Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp
325 330 335
Thr Thr Arg Ser Thr Asn Met Ser Val Cys Ala Ala Ile Ala Asn Ser
340 345 350
Asp Thr Thr Phe Lys Ser Ser Asn Phe Lys Glu Tyr Leu Arg His Gly
355 360 365
Glu Glu Phe Asp Leu Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu
370 375 380
Ser Ala Asp Ile Met Thr Tyr Ile His Ser Met Asn Pro Ala Ile Leu
385 390 395 400
Glu Asp Trp Asn Phe Gly Leu Thr Thr Pro Pro Ser Gly Ser Leu Glu
405 410 415
Asp Thr Tyr Arg Phe Val Thr Ser Gln Ala Ile Thr Cys Gln Lys Ser
420 425 430
Ala Pro Gln Lys Pro Lys Glu Asp Pro Phe Lys Asp Tyr Val Phe Trp
435 440 445
Glu Val Asn Leu Lys Glu Lys Phe Ser Ala Asp Leu Asp Gln Phe Pro
450 455 460
Leu Gly Arg Lys Phe Leu Leu Gln Ala Gly Tyr
465 470 475
<210> 54
<211> 26
<212> PRT
<213> Homo sapiens 3102 Amino acid sequence of HPV type 33 L1 protein aa 474-499
<400> 54
Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr
1 5 10 15
Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
20 25
<210> 55
<211> 501
<212> PRT
<213> Artificial Sequence
<220>
<223> 3103 Amino acid sequence of chimeric HPV type 31 L1 protein
<400> 55
Met Ser Leu Trp Arg Pro Ser Glu Ala Thr Val Tyr Leu Pro Pro Val
1 5 10 15
Pro Val Ser Lys Val Val Ser Thr Asp Glu Tyr Val Thr Arg Thr Asn
20 25 30
Ile Tyr Tyr His Ala Gly Ser Ala Arg Leu Leu Thr Val Gly His Pro
35 40 45
Tyr Tyr Ser Ile Pro Lys Ser Asp Asn Pro Lys Lys Ile Val Val Pro
50 55 60
Lys Val Ser Gly Leu Gln Tyr Arg Val Phe Arg Val Arg Leu Pro Asp
65 70 75 80
Pro Asn Lys Phe Gly Phe Pro Asp Thr Ser Phe Tyr Asn Pro Glu Thr
85 90 95
Gln Arg Leu Val Trp Ala Cys Val Gly Leu Glu Val Gly Arg Gly Gln
100 105 110
Pro Leu Gly Val Gly Ile Ser Gly His Pro Leu Leu Asn Lys Phe Asp
115 120 125
Asp Thr Glu Asn Ser Asn Arg Tyr Ala Gly Gly Pro Gly Thr Asp Asn
130 135 140
Arg Glu Cys Ile Ser Met Asp Tyr Lys Gln Thr Gln Leu Cys Leu Leu
145 150 155 160
Gly Cys Lys Pro Pro Ile Gly Glu His Trp Gly Lys Gly Ser Pro Cys
165 170 175
Ser Asn Asn Ala Ile Thr Pro Gly Asp Cys Pro Pro Leu Glu Leu Lys
180 185 190
Asn Ser Val Ile Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala
195 200 205
Met Asp Phe Thr Ala Leu Gln Asp Thr Lys Ser Asn Val Pro Leu Asp
210 215 220
Ile Cys Asn Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Lys Met Val Ala
225 230 235 240
Glu Pro Tyr Gly Asp Thr Leu Phe Phe Tyr Leu Arg Arg Glu Gln Met
245 250 255
Phe Val Arg His Phe Phe Asn Arg Ser Gly Thr Val Gly Glu Ser Val
260 265 270
Pro Thr Asp Leu Tyr Ile Lys Gly Ser Gly Ser Thr Ala Thr Leu Ala
275 280 285
Asn Ser Thr Tyr Phe Pro Thr Pro Ser Gly Ser Met Val Thr Ser Asp
290 295 300
Ala Gln Ile Phe Asn Lys Pro Tyr Trp Met Gln Arg Ala Gln Gly His
305 310 315 320
Asn Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp
325 330 335
Thr Thr Arg Ser Thr Asn Met Ser Val Cys Ala Ala Ile Ala Asn Ser
340 345 350
Asp Thr Thr Phe Lys Ser Ser Asn Phe Lys Glu Tyr Leu Arg His Gly
355 360 365
Glu Glu Phe Asp Leu Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu
370 375 380
Ser Ala Asp Ile Met Thr Tyr Ile His Ser Met Asn Pro Ala Ile Leu
385 390 395 400
Glu Asp Trp Asn Phe Gly Leu Thr Thr Pro Pro Ser Gly Ser Leu Glu
405 410 415
Asp Thr Tyr Arg Phe Val Thr Ser Gln Ala Ile Thr Cys Gln Lys Ser
420 425 430
Ala Pro Gln Lys Pro Lys Glu Asp Pro Phe Lys Asp Tyr Val Phe Trp
435 440 445
Glu Val Asn Leu Lys Glu Lys Phe Ser Ala Asp Leu Asp Gln Phe Pro
450 455 460
Leu Gly Arg Lys Phe Leu Leu Gln Ala Gly Tyr Lys Ala Lys Pro Lys
465 470 475 480
Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr Ser Ser Ala Lys Arg
485 490 495
Lys Lys Val Lys Lys
500
<210> 56
<211> 1507
<212> DNA
<213> Artificial Sequence
<220>
<223> 3104 Nucleotide sequence of chimeric HPV type 31 L1 protein
<400> 56
atgagcctgt ggaggcccag cgaggccacc gtgtacctgc cccccgtgcc cgtgagcaag 60
gtggtgagca ccgacgagta cgtgaccagg accaacatct actaccacgc cggcagcgcc 120
aggctgctga ccgtgggcca cccctactac agcatcccca agagcgacaa ccccaagaag 180
atcgtggtgc ccaaggtgag cggcctgcag tacagggtgt tcagggtgag gctgcccgac 240
cccaacaagt tcggcttccc cgacaccagc ttctacaacc ccgagaccca gaggctggtg 300
tgggcctgcg tgggcctgga ggtgggcagg ggccagcccc tgggcgtggg catcagcggc 360
caccccctgc tgaacaagtt cgacgacacc gagaacagca acaggtacgc cggcggcccc 420
ggcaccgaca acagggagtg catcagcatg gactacaagc agacccagct gtgcctgctg 480
ggctgcaagc cccccatcgg cgagcactgg ggcaagggca gcccctgcag caacaacgcc 540
atcacccccg gcgactgccc ccccctggag ctgaagaaca gcgtgatcca ggacggcgac 600
atggtggaca ccggcttcgg cgccatggac ttcaccgccc tgcaggacac caagagcaac 660
gtgcccctgg acatctgcaa cagcatctgc aagtaccccg actacctgaa gatggtggcc 720
gagccctacg gcgacaccct gttcttctac ctgaggaggg agcagatgtt cgtgaggcac 780
ttcttcaaca ggagcggcac cgtgggcgag agcgtgccca ccgacctgta catcaagggc 840
agcggcagca ccgccaccct ggccaacagc acctacttcc ccacccccag cggcagcatg 900
gtgaccagcg acgcccagat cttcaacaag ccctactgga tgcagagggc ccagggccac 960
aacaacggca tctgctgggg caaccagctg ttcgtgaccg tggtggacac caccaggagc 1020
accaacatga gcgtgtgcgc cgccatcgcc aacagcgaca ccaccttcaa gagcagcaac 1080
ttcaaggagt acctgaggca cggcgaggag ttcgacctgc agttcatctt ccagctgtgc 1140
aagatcaccc tgagcgccga catcatgacc tacatccaca gcatgaaccc cgccatcctg 1200
gaggactgga acttcggcct gaccaccccc cccagcggca gcctggagga cacctacagg 1260
ttcgtgacca gccaggccat cacctgccag aagtccgccc cccagaagcc caaggaggac 1320
cccttcaagg actacgtgtt ctgggaggtg aacctgaagg agaagttcag cgccgacctg 1380
gaccagttcc ccctgggcag gaagttcctg ctgcaggccg gctacaaagc caagccaaaa 1440
ctgaaaaggg ctgccccaac cagcaccagg acctcctctg ccaagaggaa gaaggtgaag 1500
aagtaaa 1507
<210> 57
<211> 1534
<212> DNA
<213> Artificial Sequence
<220>
<223> 3105 Synthetic HPV31 L1 gene
<400> 57
ctgggtacca tgagcctgtg gaggcccagc gaggccaccg tgtacctgcc ccccgtgccc 60
gtgagcaagg tggtgagcac cgacgagtac gtgaccagga ccaacatcta ctaccacgcc 120
ggcagcgcca ggctgctgac cgtgggccac ccctactaca gcatccccaa gagcgacaac 180
cccaagaaga tcgtggtgcc caaggtgagc ggcctgcagt acagggtgtt cagggtgagg 240
ctgcccgacc ccaacaagtt cggcttcccc gacaccagct tctacaaccc cgagacccag 300
aggctggtgt gggcctgcgt gggcctggag gtgggcaggg gccagcccct gggcgtgggc 360
atcagcggcc accccctgct gaacaagttc gacgacaccg agaacagcaa caggtacgcc 420
ggcggccccg gcaccgacaa cagggagtgc atcagcatgg actacaagca gacccagctg 480
tgcctgctgg gctgcaagcc ccccatcggc gagcactggg gcaagggcag cccctgcagc 540
aacaacgcca tcacccccgg cgactgcccc cccctggagc tgaagaacag cgtgatccag 600
gacggcgaca tggtggacac cggcttcggc gccatggact tcaccgccct gcaggacacc 660
aagagcaacg tgcccctgga catctgcaac agcatctgca agtaccccga ctacctgaag 720
atggtggccg agccctacgg cgacaccctg ttcttctacc tgaggaggga gcagatgttc 780
gtgaggcact tcttcaacag gagcggcacc gtgggcgaga gcgtgcccac cgacctgtac 840
atcaagggca gcggcagcac cgccaccctg gccaacagca cctacttccc cacccccagc 900
ggcagcatgg tgaccagcga cgcccagatc ttcaacaagc cctactggat gcagagggcc 960
cagggccaca acaacggcat ctgctggggc aaccagctgt tcgtgaccgt ggtggacacc 1020
accaggagca ccaacatgag cgtgtgcgcc gccatcgcca acagcgacac caccttcaag 1080
agcagcaact tcaaggagta cctgaggcac ggcgaggagt tcgacctgca gttcatcttc 1140
cagctgtgca agatcaccct gagcgccgac atcatgacct acatccacag catgaacccc 1200
gccatcctgg aggactggaa cttcggcctg accacccccc ccagcggcag cctggaggac 1260
acctacaggt tcgtgaccag ccaggccatc acctgccaga agtccgcccc ccagaagccc 1320
aaggaggacc ccttcaagga ctacgtgttc tgggaggtga acctgaagga gaagttcagc 1380
gccgacctgg accagttccc cctgggcagg aagttcctgc tgcaggccgg ctacagggcc 1440
aggcccaagt tcaaggccgg caagaggagc gcccccagcg ccagcaccac cacccccgcc 1500
aagaggaaga agaccaagaa gtaaactcga gctc 1534
<210> 58
<211> 1519
<212> DNA
<213> Artificial Sequence
<220>
<223> 3106 Synthetic HPV33 L1 gene
<400> 58
ctgggtacca tgagtgtgtg gagaccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtgagcagga ccagcatcta ctactatgct 120
ggctccagca gactgctggc tgtgggacac ccatacttca gcatcaagaa cccaaccaat 180
gccaagaaac tgctggtgcc aaaggtgtct ggactccaat acagggtgtt cagggtgaga 240
ctgcctgacc caaacaagtt tggctttcct gacacctcct tctacaaccc tgacacccag 300
agactggtgt gggcttgtgt gggattggag attggcaggg gacaaccact gggagtgggc 360
atctctggac acccactgct gaacaagttt gatgacacag agacaggcaa caaataccct 420
ggacaacctg gagcagacaa cagggagtgt ctgagtatgg actacaagca gacccaactt 480
tgtctgctgg gctgtaagcc tccaacagga gaacactggg gcaagggagt ggcttgtacc 540
aatgctgccc ctgccaatga ctgtcctcca ttggaactga taaacaccat cattgaggat 600
ggagatatgg tggacacagg ctttggctgt atggacttca agaccctcca agccaacaag 660
tctgatgtgc caattgacat ctgtggcagc acttgtaaat accctgacta cctgaaaatg 720
acctctgaac catatggaga ctccctgttc ttcttcctga ggagggaaca gatgtttgtg 780
agacacttct tcaacagggc tggcaccctg ggagaggctg tgcctgatga cctctacatc 840
aagggctctg gcaccacagc cagcatccag tcctctgcct tctttccaac accatctggc 900
agtatggtga cctctgagag ccaacttttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caggtgtttg tgacagtggt ggacaccacc 1020
aggagcacca atatgaccct gtgtacccag gtgacctctg acagcaccta caagaatgag 1080
aacttcaagg aatacatcag gcatgtggag gaatatgacc tccaatttgt gttccaactt 1140
tgtaaggtga ccctgacagc agaggtgatg acctacatcc atgctatgaa ccctgacatc 1200
ttggaggact ggcagtttgg actgacacct cctccatctg cctccctcca agacacctac 1260
aggtttgtga ccagccaggc tatcacttgt cagaagacag tgcctccaaa ggagaaggag 1320
gacccactgg gcaaatacac cttctgggag gtggacctga aagagaagtt ctctgctgac 1380
ctggaccagt ttccactggg caggaagttc ctgctccaag caggactgaa agccaagcca 1440
aaactgaaaa gggctgcccc aaccagcacc aggacctcct ctgccaagag gaagaaggtg 1500
aagaagtaaa ctcgagctc 1519
<210> 59
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> 3107 HPV31L1 F1
<400> 59
cttggtacca tgagcctgtg gaggcccagc gag 33
<210> 60
<211> 38
<212> DNA
<213> Artificial Sequence
<220>
<223> 3108 HPV31L1 R1
<400> 60
gcttggcttt gtagccggcc tgcagcagga acttcctg 38
<210> 61
<211> 1444
<212> DNA
<213> Artificial Sequence
<220>
<223> 3109 HPV31L1 amplified sequence 1
<400> 61
cttggtacca tgagcctgtg gaggcccagc gaggccaccg tgtacctgcc ccccgtgccc 60
gtgagcaagg tggtgagcac cgacgagtac gtgaccagga ccaacatcta ctaccacgcc 120
ggcagcgcca ggctgctgac cgtgggccac ccctactaca gcatccccaa gagcgacaac 180
cccaagaaga tcgtggtgcc caaggtgagc ggcctgcagt acagggtgtt cagggtgagg 240
ctgcccgacc ccaacaagtt cggcttcccc gacaccagct tctacaaccc cgagacccag 300
aggctggtgt gggcctgcgt gggcctggag gtgggcaggg gccagcccct gggcgtgggc 360
atcagcggcc accccctgct gaacaagttc gacgacaccg agaacagcaa caggtacgcc 420
ggcggccccg gcaccgacaa cagggagtgc atcagcatgg actacaagca gacccagctg 480
tgcctgctgg gctgcaagcc ccccatcggc gagcactggg gcaagggcag cccctgcagc 540
aacaacgcca tcacccccgg cgactgcccc cccctggagc tgaagaacag cgtgatccag 600
gacggcgaca tggtggacac cggcttcggc gccatggact tcaccgccct gcaggacacc 660
aagagcaacg tgcccctgga catctgcaac agcatctgca agtaccccga ctacctgaag 720
atggtggccg agccctacgg cgacaccctg ttcttctacc tgaggaggga gcagatgttc 780
gtgaggcact tcttcaacag gagcggcacc gtgggcgaga gcgtgcccac cgacctgtac 840
atcaagggca gcggcagcac cgccaccctg gccaacagca cctacttccc cacccccagc 900
ggcagcatgg tgaccagcga cgcccagatc ttcaacaagc cctactggat gcagagggcc 960
cagggccaca acaacggcat ctgctggggc aaccagctgt tcgtgaccgt ggtggacacc 1020
accaggagca ccaacatgag cgtgtgcgcc gccatcgcca acagcgacac caccttcaag 1080
agcagcaact tcaaggagta cctgaggcac ggcgaggagt tcgacctgca gttcatcttc 1140
cagctgtgca agatcaccct gagcgccgac atcatgacct acatccacag catgaacccc 1200
gccatcctgg aggactggaa cttcggcctg accacccccc ccagcggcag cctggaggac 1260
acctacaggt tcgtgaccag ccaggccatc acctgccaga agtccgcccc ccagaagccc 1320
aaggaggacc ccttcaagga ctacgtgttc tgggaggtga acctgaagga gaagttcagc 1380
gccgacctgg accagttccc cctgggcagg aagttcctgc tgcaggccgg ctacaaagcc 1440
aagc 1444
<210> 62
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 3110 HPV31L1 F2
<400> 62
ggccggctac aaagccaagc caaaactgaa aaggg 35
<210> 63
<211> 41
<212> DNA
<213> Artificial Sequence
<220>
<223> 3111 HPV31L1 R2
<400> 63
ctgtctagat ttacttcttc accttcttcc tcttggcaga g 41
<210> 64
<211> 101
<212> DNA
<213> Artificial Sequence
<220>
<223> 3112 HPV31L1 amplified sequence 2
<400> 64
ggccggctac aaagccaagc caaaactgaa aagggctgcc ccaaccagca ccaggacctc 60
ctctgccaag aggaagaagg tgaagaagta aatctagaca g 101
<210> 65
<211> 38
<212> PRT
<213> Homo sapiens 3113 Amino acid sequence of HPV type 59 L1 protein aa 471-508
<400> 65
Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile Gly Pro Arg Lys Arg
1 5 10 15
Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro Lys Arg Val Lys Arg
20 25 30
Arg Lys Ser Ser Arg Lys
35
<210> 66
<211> 472
<212> PRT
<213> Homo sapiens 3501 Amino acid sequence of HPV type 35 L1 protein aa 1-472
<400> 66
Met Ser Leu Trp Arg Ser Asn Glu Ala Thr Val Tyr Leu Pro Pro Val
1 5 10 15
Ser Val Ser Lys Val Val Ser Thr Asp Glu Tyr Val Thr Arg Thr Asn
20 25 30
Ile Tyr Tyr His Ala Gly Ser Ser Arg Leu Leu Ala Val Gly His Pro
35 40 45
Tyr Tyr Ala Ile Lys Lys Gln Asp Ser Asn Lys Ile Ala Val Pro Lys
50 55 60
Val Ser Gly Leu Gln Tyr Arg Val Phe Arg Val Lys Leu Pro Asp Pro
65 70 75 80
Asn Lys Phe Gly Phe Pro Asp Thr Ser Phe Tyr Asp Pro Ala Ser Gln
85 90 95
Arg Leu Val Trp Ala Cys Thr Gly Val Glu Val Gly Arg Gly Gln Pro
100 105 110
Leu Gly Val Gly Ile Ser Gly His Pro Leu Leu Asn Lys Leu Asp Asp
115 120 125
Thr Glu Asn Ser Asn Lys Tyr Val Gly Asn Ser Gly Thr Asp Asn Arg
130 135 140
Glu Cys Ile Ser Met Asp Tyr Lys Gln Thr Gln Leu Cys Leu Ile Gly
145 150 155 160
Cys Arg Pro Pro Ile Gly Glu His Trp Gly Lys Gly Thr Pro Cys Asn
165 170 175
Ala Asn Gln Val Lys Ala Gly Glu Cys Pro Pro Leu Glu Leu Leu Asn
180 185 190
Thr Val Leu Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala Met
195 200 205
Asp Phe Thr Thr Leu Gln Ala Asn Lys Ser Asp Val Pro Leu Asp Ile
210 215 220
Cys Ser Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Lys Met Val Ser Glu
225 230 235 240
Pro Tyr Gly Asp Met Leu Phe Phe Tyr Leu Arg Arg Glu Gln Met Phe
245 250 255
Val Arg His Leu Phe Asn Arg Ala Gly Thr Val Gly Glu Thr Val Pro
260 265 270
Ala Asp Leu Tyr Ile Lys Gly Thr Thr Gly Thr Leu Pro Ser Thr Ser
275 280 285
Tyr Phe Pro Thr Pro Ser Gly Ser Met Val Thr Ser Asp Ala Gln Ile
290 295 300
Phe Asn Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn Asn Gly
305 310 315 320
Ile Cys Trp Ser Asn Gln Leu Phe Val Thr Val Val Asp Thr Thr Arg
325 330 335
Ser Thr Asn Met Ser Val Cys Ser Ala Val Ser Ser Ser Asp Ser Thr
340 345 350
Tyr Lys Asn Asp Asn Phe Lys Glu Tyr Leu Arg His Gly Glu Glu Tyr
355 360 365
Asp Leu Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr Ala Asp
370 375 380
Val Met Thr Tyr Ile His Ser Met Asn Pro Ser Ile Leu Glu Asp Trp
385 390 395 400
Asn Phe Gly Leu Thr Pro Pro Pro Ser Gly Thr Leu Glu Asp Thr Tyr
405 410 415
Arg Tyr Val Thr Ser Gln Ala Val Thr Cys Gln Lys Pro Ser Ala Pro
420 425 430
Lys Pro Lys Asp Asp Pro Leu Lys Asn Tyr Thr Phe Trp Glu Val Asp
435 440 445
Leu Lys Glu Lys Phe Ser Ala Asp Leu Asp Gln Phe Pro Leu Gly Arg
450 455 460
Lys Phe Leu Leu Gln Ala Gly Leu
465 470
<210> 67
<211> 26
<212> PRT
<213> Homo sapiens 3502 Amino acid sequence of HPV type 33 L1 protein aa 474-499
<400> 67
Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr
1 5 10 15
Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
20 25
<210> 68
<211> 498
<212> PRT
<213> Artificial Sequence
<220>
<223> 3503 Amino acid sequence of chimeric HPV type 35 L1 protein
<400> 68
Met Ser Leu Trp Arg Ser Asn Glu Ala Thr Val Tyr Leu Pro Pro Val
1 5 10 15
Ser Val Ser Lys Val Val Ser Thr Asp Glu Tyr Val Thr Arg Thr Asn
20 25 30
Ile Tyr Tyr His Ala Gly Ser Ser Arg Leu Leu Ala Val Gly His Pro
35 40 45
Tyr Tyr Ala Ile Lys Lys Gln Asp Ser Asn Lys Ile Ala Val Pro Lys
50 55 60
Val Ser Gly Leu Gln Tyr Arg Val Phe Arg Val Lys Leu Pro Asp Pro
65 70 75 80
Asn Lys Phe Gly Phe Pro Asp Thr Ser Phe Tyr Asp Pro Ala Ser Gln
85 90 95
Arg Leu Val Trp Ala Cys Thr Gly Val Glu Val Gly Arg Gly Gln Pro
100 105 110
Leu Gly Val Gly Ile Ser Gly His Pro Leu Leu Asn Lys Leu Asp Asp
115 120 125
Thr Glu Asn Ser Asn Lys Tyr Val Gly Asn Ser Gly Thr Asp Asn Arg
130 135 140
Glu Cys Ile Ser Met Asp Tyr Lys Gln Thr Gln Leu Cys Leu Ile Gly
145 150 155 160
Cys Arg Pro Pro Ile Gly Glu His Trp Gly Lys Gly Thr Pro Cys Asn
165 170 175
Ala Asn Gln Val Lys Ala Gly Glu Cys Pro Pro Leu Glu Leu Leu Asn
180 185 190
Thr Val Leu Gln Asp Gly Asp Met Val Asp Thr Gly Phe Gly Ala Met
195 200 205
Asp Phe Thr Thr Leu Gln Ala Asn Lys Ser Asp Val Pro Leu Asp Ile
210 215 220
Cys Ser Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Lys Met Val Ser Glu
225 230 235 240
Pro Tyr Gly Asp Met Leu Phe Phe Tyr Leu Arg Arg Glu Gln Met Phe
245 250 255
Val Arg His Leu Phe Asn Arg Ala Gly Thr Val Gly Glu Thr Val Pro
260 265 270
Ala Asp Leu Tyr Ile Lys Gly Thr Thr Gly Thr Leu Pro Ser Thr Ser
275 280 285
Tyr Phe Pro Thr Pro Ser Gly Ser Met Val Thr Ser Asp Ala Gln Ile
290 295 300
Phe Asn Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn Asn Gly
305 310 315 320
Ile Cys Trp Ser Asn Gln Leu Phe Val Thr Val Val Asp Thr Thr Arg
325 330 335
Ser Thr Asn Met Ser Val Cys Ser Ala Val Ser Ser Ser Asp Ser Thr
340 345 350
Tyr Lys Asn Asp Asn Phe Lys Glu Tyr Leu Arg His Gly Glu Glu Tyr
355 360 365
Asp Leu Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr Ala Asp
370 375 380
Val Met Thr Tyr Ile His Ser Met Asn Pro Ser Ile Leu Glu Asp Trp
385 390 395 400
Asn Phe Gly Leu Thr Pro Pro Pro Ser Gly Thr Leu Glu Asp Thr Tyr
405 410 415
Arg Tyr Val Thr Ser Gln Ala Val Thr Cys Gln Lys Pro Ser Ala Pro
420 425 430
Lys Pro Lys Asp Asp Pro Leu Lys Asn Tyr Thr Phe Trp Glu Val Asp
435 440 445
Leu Lys Glu Lys Phe Ser Ala Asp Leu Asp Gln Phe Pro Leu Gly Arg
450 455 460
Lys Phe Leu Leu Gln Ala Gly Leu Lys Ala Lys Pro Lys Leu Lys Arg
465 470 475 480
Ala Ala Pro Thr Ser Thr Arg Thr Ser Ser Ala Lys Arg Lys Lys Val
485 490 495
Lys Lys
<210> 69
<211> 1498
<212> DNA
<213> Artificial Sequence
<220>
<223> 3504 Nucleotide sequence of chimeric HPV type 35 L1 protein
<400> 69
atgagtctgt ggaggagcaa tgaggctaca gtctacctgc ctcctgtgtc tgtgagcaag 60
gtggtgagca cagatgaata tgtgaccagg accaacatct actaccatgc tggctccagc 120
agactgctgg ctgtgggaca cccatactat gccatcaaga agcaggacag caacaagatt 180
gctgtgccaa aggtgtctgg actccaatac agggtgttca gggtgaaact gcctgaccca 240
aacaagtttg gctttcctga cacctccttc tatgaccctg ccagccagag actggtgtgg 300
gcttgtactg gagtggaggt gggcagggga caaccactgg gagtgggcat ctctggacac 360
ccactgctga acaaactgga tgacacagag aacagcaaca aatatgtggg caactctggc 420
acagacaaca gggagtgtat cagtatggac tacaagcaga cccaactttg tctgattggc 480
tgtagacctc caattggaga acactggggc aagggcacac catgtaatgc caaccaggtg 540
aaggctggag agtgtcctcc attggaactg ctgaacacag tgctccaaga tggagatatg 600
gtggacacag gctttggagc tatggacttc accaccctcc aagccaacaa gtctgatgtg 660
ccactggaca tctgttccag catctgtaaa taccctgact acctgaaaat ggtgtctgaa 720
ccatatggag atatgctgtt cttctacctg aggagggaac agatgtttgt gagacacctg 780
ttcaacaggg ctggcacagt gggagagaca gtgcctgctg acctctacat caagggcacc 840
acaggcaccc tgccaagcac ctcctacttt ccaacaccat ctggcagtat ggtgacctct 900
gatgcccaga ttttcaacaa gccatactgg ctccaaaggg ctcaaggaca caacaatggc 960
atctgttgga gcaaccaact ttttgtgaca gtggtggaca ccaccaggag caccaatatg 1020
agtgtgtgtt ctgctgtgtc ctcctctgac agcacctaca agaatgacaa cttcaaggaa 1080
tacctgagac atggagagga atatgacctc caattcatct tccaactttg taagattacc 1140
ctgacagcag atgtgatgac ctacatccac agtatgaacc caagcatctt ggaggactgg 1200
aactttggac tgacacctcc tccatctggc accttggagg acacctacag atatgtgacc 1260
agccaggctg tgacttgtca gaagccatct gccccaaagc caaaggatga cccactgaaa 1320
aactacacct tctgggaggt ggacctgaaa gagaagttct ctgctgacct ggaccagttt 1380
ccactgggca ggaagttcct gctccaagca ggactgaaag ccaagccaaa actgaaaagg 1440
gctgccccaa ccagcaccag gacctcctct gccaagagga agaaggtgaa gaagtaaa 1498
<210> 70
<211> 1528
<212> DNA
<213> Artificial Sequence
<220>
<223> 3505 Synthetic HPV35 L1 gene
<400> 70
ctgggtacca tgagtctgtg gaggagcaat gaggctacag tctacctgcc tcctgtgtct 60
gtgagcaagg tggtgagcac agatgaatat gtgaccagga ccaacatcta ctaccatgct 120
ggctccagca gactgctggc tgtgggacac ccatactatg ccatcaagaa gcaggacagc 180
aacaagattg ctgtgccaaa ggtgtctgga ctccaataca gggtgttcag ggtgaaactg 240
cctgacccaa acaagtttgg ctttcctgac acctccttct atgaccctgc cagccagaga 300
ctggtgtggg cttgtactgg agtggaggtg ggcaggggac aaccactggg agtgggcatc 360
tctggacacc cactgctgaa caaactggat gacacagaga acagcaacaa atatgtgggc 420
aactctggca cagacaacag ggagtgtatc agtatggact acaagcagac ccaactttgt 480
ctgattggct gtagacctcc aattggagaa cactggggca agggcacacc atgtaatgcc 540
aaccaggtga aggctggaga gtgtcctcca ttggaactgc tgaacacagt gctccaagat 600
ggagatatgg tggacacagg ctttggagct atggacttca ccaccctcca agccaacaag 660
tctgatgtgc cactggacat ctgttccagc atctgtaaat accctgacta cctgaaaatg 720
gtgtctgaac catatggaga tatgctgttc ttctacctga ggagggaaca gatgtttgtg 780
agacacctgt tcaacagggc tggcacagtg ggagagacag tgcctgctga cctctacatc 840
aagggcacca caggcaccct gccaagcacc tcctactttc caacaccatc tggcagtatg 900
gtgacctctg atgcccagat tttcaacaag ccatactggc tccaaagggc tcaaggacac 960
aacaatggca tctgttggag caaccaactt tttgtgacag tggtggacac caccaggagc 1020
accaatatga gtgtgtgttc tgctgtgtcc tcctctgaca gcacctacaa gaatgacaac 1080
ttcaaggaat acctgagaca tggagaggaa tatgacctcc aattcatctt ccaactttgt 1140
aagattaccc tgacagcaga tgtgatgacc tacatccaca gtatgaaccc aagcatcttg 1200
gaggactgga actttggact gacacctcct ccatctggca ccttggagga cacctacaga 1260
tatgtgacca gccaggctgt gacttgtcag aagccatctg ccccaaagcc aaaggatgac 1320
ccactgaaaa actacacctt ctgggaggtg gacctgaaag agaagttctc tgctgacctg 1380
gaccagtttc cactgggcag gaagttcctg ctccaagcag gactgaaagc cagaccaaac 1440
ttcagactgg gcaagagggc tgcccctgcc agcaccagca agaagtccag caccaagagg 1500
aggaaggtga agagctaaac tcgagctc 1528
<210> 71
<211> 1519
<212> DNA
<213> Artificial Sequence
<220>
<223> 3506 Synthetic HPV33 L1 gene
<400> 71
ctgggtacca tgagtgtgtg gagaccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtgagcagga ccagcatcta ctactatgct 120
ggctccagca gactgctggc tgtgggacac ccatacttca gcatcaagaa cccaaccaat 180
gccaagaaac tgctggtgcc aaaggtgtct ggactccaat acagggtgtt cagggtgaga 240
ctgcctgacc caaacaagtt tggctttcct gacacctcct tctacaaccc tgacacccag 300
agactggtgt gggcttgtgt gggattggag attggcaggg gacaaccact gggagtgggc 360
atctctggac acccactgct gaacaagttt gatgacacag agacaggcaa caaataccct 420
ggacaacctg gagcagacaa cagggagtgt ctgagtatgg actacaagca gacccaactt 480
tgtctgctgg gctgtaagcc tccaacagga gaacactggg gcaagggagt ggcttgtacc 540
aatgctgccc ctgccaatga ctgtcctcca ttggaactga taaacaccat cattgaggat 600
ggagatatgg tggacacagg ctttggctgt atggacttca agaccctcca agccaacaag 660
tctgatgtgc caattgacat ctgtggcagc acttgtaaat accctgacta cctgaaaatg 720
acctctgaac catatggaga ctccctgttc ttcttcctga ggagggaaca gatgtttgtg 780
agacacttct tcaacagggc tggcaccctg ggagaggctg tgcctgatga cctctacatc 840
aagggctctg gcaccacagc cagcatccag tcctctgcct tctttccaac accatctggc 900
agtatggtga cctctgagag ccaacttttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caggtgtttg tgacagtggt ggacaccacc 1020
aggagcacca atatgaccct gtgtacccag gtgacctctg acagcaccta caagaatgag 1080
aacttcaagg aatacatcag gcatgtggag gaatatgacc tccaatttgt gttccaactt 1140
tgtaaggtga ccctgacagc agaggtgatg acctacatcc atgctatgaa ccctgacatc 1200
ttggaggact ggcagtttgg actgacacct cctccatctg cctccctcca agacacctac 1260
aggtttgtga ccagccaggc tatcacttgt cagaagacag tgcctccaaa ggagaaggag 1320
gacccactgg gcaaatacac cttctgggag gtggacctga aagagaagtt ctctgctgac 1380
ctggaccagt ttccactggg caggaagttc ctgctccaag caggactgaa agccaagcca 1440
aaactgaaaa gggctgcccc aaccagcacc aggacctcct ctgccaagag gaagaaggtg 1500
aagaagtaaa ctcgagctc 1519
<210> 72
<211> 34
<212> DNA
<213> Artificial Sequence
<220>
<223> 3507 HPV35L1 F1
<400> 72
cttggtacca tgagtctgtg gaggagcaat gagg 34
<210> 73
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 3508 HPV35L1 R1
<400> 73
gcttggcttt cagtcctgct tggagcagga acttcc 36
<210> 74
<211> 1435
<212> DNA
<213> Artificial Sequence
<220>
<223> 3509 HPV35L1 amplified sequence 1
<400> 74
cttggtacca tgagtctgtg gaggagcaat gaggctacag tctacctgcc tcctgtgtct 60
gtgagcaagg tggtgagcac agatgaatat gtgaccagga ccaacatcta ctaccatgct 120
ggctccagca gactgctggc tgtgggacac ccatactatg ccatcaagaa gcaggacagc 180
aacaagattg ctgtgccaaa ggtgtctgga ctccaataca gggtgttcag ggtgaaactg 240
cctgacccaa acaagtttgg ctttcctgac acctccttct atgaccctgc cagccagaga 300
ctggtgtggg cttgtactgg agtggaggtg ggcaggggac aaccactggg agtgggcatc 360
tctggacacc cactgctgaa caaactggat gacacagaga acagcaacaa atatgtgggc 420
aactctggca cagacaacag ggagtgtatc agtatggact acaagcagac ccaactttgt 480
ctgattggct gtagacctcc aattggagaa cactggggca agggcacacc atgtaatgcc 540
aaccaggtga aggctggaga gtgtcctcca ttggaactgc tgaacacagt gctccaagat 600
ggagatatgg tggacacagg ctttggagct atggacttca ccaccctcca agccaacaag 660
tctgatgtgc cactggacat ctgttccagc atctgtaaat accctgacta cctgaaaatg 720
gtgtctgaac catatggaga tatgctgttc ttctacctga ggagggaaca gatgtttgtg 780
agacacctgt tcaacagggc tggcacagtg ggagagacag tgcctgctga cctctacatc 840
aagggcacca caggcaccct gccaagcacc tcctactttc caacaccatc tggcagtatg 900
gtgacctctg atgcccagat tttcaacaag ccatactggc tccaaagggc tcaaggacac 960
aacaatggca tctgttggag caaccaactt tttgtgacag tggtggacac caccaggagc 1020
accaatatga gtgtgtgttc tgctgtgtcc tcctctgaca gcacctacaa gaatgacaac 1080
ttcaaggaat acctgagaca tggagaggaa tatgacctcc aattcatctt ccaactttgt 1140
aagattaccc tgacagcaga tgtgatgacc tacatccaca gtatgaaccc aagcatcttg 1200
gaggactgga actttggact gacacctcct ccatctggca ccttggagga cacctacaga 1260
tatgtgacca gccaggctgt gacttgtcag aagccatctg ccccaaagcc aaaggatgac 1320
ccactgaaaa actacacctt ctgggaggtg gacctgaaag agaagttctc tgctgacctg 1380
gaccagtttc cactgggcag gaagttcctg ctccaagcag gactgaaagc caagc 1435
<210> 75
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 3510 HPV35L1 F2
<400> 75
agcaggactg aaagccaagc caaaactgaa aaggg 35
<210> 76
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 3511 HPV35L1 R2
<400> 76
ctgtctagat ttacttcttc accttcttcc tcttgg 36
<210> 77
<211> 101
<212> DNA
<213> Artificial Sequence
<220>
<223> 3512 HPV35L1 amplified sequence 2
<400> 77
agcaggactg aaagccaagc caaaactgaa aagggctgcc ccaaccagca ccaggacctc 60
ctctgccaag aggaagaagg tgaagaagta aatctagaca g 101
<210> 78
<211> 38
<212> PRT
<213> Homo sapiens 3513 Amino acid sequence of HPV type 59 L1 protein aa 471-508
<400> 78
Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile Gly Pro Arg Lys Arg
1 5 10 15
Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro Lys Arg Val Lys Arg
20 25 30
Arg Lys Ser Ser Arg Lys
35
<210> 79
<211> 469
<212> PRT
<213> Homo sapiens 3901 Amino acid sequence of HPV type 39 L1 protein aa 1-469
<400> 79
Met Ala Met Trp Arg Ser Ser Asp Ser Met Val Tyr Leu Pro Pro Pro
1 5 10 15
Ser Val Ala Lys Val Val Asn Thr Asp Asp Tyr Val Thr Arg Thr Gly
20 25 30
Ile Tyr Tyr Tyr Ala Gly Ser Ser Arg Leu Leu Thr Val Gly His Pro
35 40 45
Tyr Phe Lys Val Gly Met Asn Gly Gly Arg Lys Gln Asp Ile Pro Lys
50 55 60
Val Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val Thr Leu Pro Asp Pro
65 70 75 80
Asn Lys Phe Ser Ile Pro Asp Ala Ser Leu Tyr Asn Pro Glu Thr Gln
85 90 95
Arg Leu Val Trp Ala Cys Val Gly Val Glu Val Gly Arg Gly Gln Pro
100 105 110
Leu Gly Val Gly Ile Ser Gly His Pro Leu Tyr Asn Arg Gln Asp Asp
115 120 125
Thr Glu Asn Ser Pro Phe Ser Ser Thr Thr Asn Lys Asp Ser Arg Asp
130 135 140
Asn Val Ser Val Asp Tyr Lys Gln Thr Gln Leu Cys Ile Ile Gly Cys
145 150 155 160
Val Pro Ala Ile Gly Glu His Trp Gly Lys Gly Lys Ala Cys Lys Pro
165 170 175
Asn Asn Val Ser Thr Gly Asp Cys Pro Pro Leu Glu Leu Val Asn Thr
180 185 190
Pro Ile Glu Asp Gly Asp Met Ile Asp Thr Gly Tyr Gly Ala Met Asp
195 200 205
Phe Gly Ala Leu Gln Glu Thr Lys Ser Glu Val Pro Leu Asp Ile Cys
210 215 220
Gln Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ser Ala Asp Val
225 230 235 240
Tyr Gly Asp Ser Met Phe Phe Cys Leu Arg Arg Glu Gln Leu Phe Ala
245 250 255
Arg His Phe Trp Asn Arg Gly Gly Met Val Gly Asp Ala Ile Pro Ala
260 265 270
Gln Leu Tyr Ile Lys Gly Thr Asp Ile Arg Ala Asn Pro Gly Ser Ser
275 280 285
Val Tyr Cys Pro Ser Pro Ser Gly Ser Met Val Thr Ser Asp Ser Gln
290 295 300
Leu Phe Asn Lys Pro Tyr Trp Leu His Lys Ala Gln Gly His Asn Asn
305 310 315 320
Gly Ile Cys Trp His Asn Gln Leu Phe Leu Thr Val Val Asp Thr Thr
325 330 335
Arg Ser Thr Asn Phe Thr Leu Ser Thr Ser Ile Glu Ser Ser Ile Pro
340 345 350
Ser Thr Tyr Asp Pro Ser Lys Phe Lys Glu Tyr Thr Arg His Val Glu
355 360 365
Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Thr Val Thr Leu Thr
370 375 380
Thr Asp Val Met Ser Tyr Ile His Thr Met Asn Ser Ser Ile Leu Asp
385 390 395 400
Asn Trp Asn Phe Ala Val Ala Pro Pro Pro Ser Ala Ser Leu Val Asp
405 410 415
Thr Tyr Arg Tyr Leu Gln Ser Ala Ala Ile Thr Cys Gln Lys Asp Ala
420 425 430
Pro Ala Pro Glu Lys Lys Asp Pro Tyr Asp Gly Leu Lys Phe Trp Asn
435 440 445
Val Asp Leu Arg Glu Lys Phe Ser Leu Glu Leu Asp Gln Phe Pro Leu
450 455 460
Gly Arg Lys Phe Leu
465
<210> 80
<211> 38
<212> PRT
<213> Homo sapiens 3902 Amino acid sequence of HPV type 59 L1 protein aa 471-508
<400> 80
Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile Gly Pro Arg Lys Arg
1 5 10 15
Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro Lys Arg Val Lys Arg
20 25 30
Arg Lys Ser Ser Arg Lys
35
<210> 81
<211> 507
<212> PRT
<213> Artificial Sequence
<220>
<223> 3903 Amino acid sequence of chimeric HPV type 39 L1 protein
<400> 81
Met Ala Met Trp Arg Ser Ser Asp Ser Met Val Tyr Leu Pro Pro Pro
1 5 10 15
Ser Val Ala Lys Val Val Asn Thr Asp Asp Tyr Val Thr Arg Thr Gly
20 25 30
Ile Tyr Tyr Tyr Ala Gly Ser Ser Arg Leu Leu Thr Val Gly His Pro
35 40 45
Tyr Phe Lys Val Gly Met Asn Gly Gly Arg Lys Gln Asp Ile Pro Lys
50 55 60
Val Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val Thr Leu Pro Asp Pro
65 70 75 80
Asn Lys Phe Ser Ile Pro Asp Ala Ser Leu Tyr Asn Pro Glu Thr Gln
85 90 95
Arg Leu Val Trp Ala Cys Val Gly Val Glu Val Gly Arg Gly Gln Pro
100 105 110
Leu Gly Val Gly Ile Ser Gly His Pro Leu Tyr Asn Arg Gln Asp Asp
115 120 125
Thr Glu Asn Ser Pro Phe Ser Ser Thr Thr Asn Lys Asp Ser Arg Asp
130 135 140
Asn Val Ser Val Asp Tyr Lys Gln Thr Gln Leu Cys Ile Ile Gly Cys
145 150 155 160
Val Pro Ala Ile Gly Glu His Trp Gly Lys Gly Lys Ala Cys Lys Pro
165 170 175
Asn Asn Val Ser Thr Gly Asp Cys Pro Pro Leu Glu Leu Val Asn Thr
180 185 190
Pro Ile Glu Asp Gly Asp Met Ile Asp Thr Gly Tyr Gly Ala Met Asp
195 200 205
Phe Gly Ala Leu Gln Glu Thr Lys Ser Glu Val Pro Leu Asp Ile Cys
210 215 220
Gln Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ser Ala Asp Val
225 230 235 240
Tyr Gly Asp Ser Met Phe Phe Cys Leu Arg Arg Glu Gln Leu Phe Ala
245 250 255
Arg His Phe Trp Asn Arg Gly Gly Met Val Gly Asp Ala Ile Pro Ala
260 265 270
Gln Leu Tyr Ile Lys Gly Thr Asp Ile Arg Ala Asn Pro Gly Ser Ser
275 280 285
Val Tyr Cys Pro Ser Pro Ser Gly Ser Met Val Thr Ser Asp Ser Gln
290 295 300
Leu Phe Asn Lys Pro Tyr Trp Leu His Lys Ala Gln Gly His Asn Asn
305 310 315 320
Gly Ile Cys Trp His Asn Gln Leu Phe Leu Thr Val Val Asp Thr Thr
325 330 335
Arg Ser Thr Asn Phe Thr Leu Ser Thr Ser Ile Glu Ser Ser Ile Pro
340 345 350
Ser Thr Tyr Asp Pro Ser Lys Phe Lys Glu Tyr Thr Arg His Val Glu
355 360 365
Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Thr Val Thr Leu Thr
370 375 380
Thr Asp Val Met Ser Tyr Ile His Thr Met Asn Ser Ser Ile Leu Asp
385 390 395 400
Asn Trp Asn Phe Ala Val Ala Pro Pro Pro Ser Ala Ser Leu Val Asp
405 410 415
Thr Tyr Arg Tyr Leu Gln Ser Ala Ala Ile Thr Cys Gln Lys Asp Ala
420 425 430
Pro Ala Pro Glu Lys Lys Asp Pro Tyr Asp Gly Leu Lys Phe Trp Asn
435 440 445
Val Asp Leu Arg Glu Lys Phe Ser Leu Glu Leu Asp Gln Phe Pro Leu
450 455 460
Gly Arg Lys Phe Leu Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile
465 470 475 480
Gly Pro Arg Lys Arg Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro
485 490 495
Lys Arg Val Lys Arg Arg Lys Ser Ser Arg Lys
500 505
<210> 82
<211> 1525
<212> DNA
<213> Artificial Sequence
<220>
<223> 3904 Nucleotide sequence of chimeric HPV type 39 L1 protein
<400> 82
atggctatgt ggaggtcctc tgacagtatg gtctacctgc ctcctccatc tgtggctaag 60
gtggtgaaca cagatgacta tgtgaccagg acaggcatct actactatgc tggctccagc 120
agactgctga cagtgggaca cccatacttc aaggtgggga tgaatggagg caggaagcag 180
gacatcccaa aggtgtctgc ctaccaatac agggtgttca gggtgaccct gcctgaccca 240
aacaagttca gcatccctga tgcctccctc tacaaccctg agacccagag actggtgtgg 300
gcttgtgtgg gagtggaggt gggcagggga caaccactgg gagtgggcat ctctggacac 360
ccactctaca acagacagga tgacacagag aacagcccat tctccagcac caccaacaag 420
gacagcaggg acaatgtgtc tgtggactac aagcagaccc aactttgtat cattggctgt 480
gtgcctgcca ttggagaaca ctggggcaag ggcaaggctt gtaagccaaa caatgtgagc 540
acaggagact gtcctccatt ggaactggtg aacacaccaa ttgaggatgg agatatgatt 600
gacacaggct atggagctat ggactttgga gccctccaag agaccaagtc tgaggtgcca 660
ctggacatct gtcagagcat ctgtaaatac cctgactacc tccaaatgag tgctgatgtc 720
tatggagaca gtatgttctt ctgtctgagg agggaacaac tttttgccag acacttctgg 780
aacaggggag ggatggtggg agatgccatc cctgcccaac tctacatcaa gggcacagac 840
atcagggcta accctggctc ctctgtctac tgtccaagcc catctggcag tatggtgacc 900
tctgacagcc aacttttcaa caagccatac tggctgcaca aggctcaagg acacaacaat 960
ggcatctgtt ggcacaacca acttttcctg acagtggtgg acaccaccag gagcaccaac 1020
ttcaccctga gcaccagcat tgagtccagc atcccaagca cctatgaccc aagcaagttc 1080
aaggaataca ccaggcatgt ggaggaatat gacctccaat tcatcttcca actttgtact 1140
gtgaccctga ccacagatgt gatgagttac atccacacaa tgaactccag catcctggac 1200
aactggaact ttgctgtggc tcctcctcca tctgcctccc tggtggacac ctacagatac 1260
ctccaatctg ctgccatcac ttgtcagaag gatgcccctg cccctgagaa gaaggaccca 1320
tatgatggac tgaagttctg gaatgtggac ctgagggaga agttctcctt ggaactggac 1380
cagtttccac tgggcaggaa gttcctgctc caacttggag ccagaccaaa gccaaccatt 1440
ggaccaagga agagggctgc ccctgcccca accagcacac caagcccaaa gagggtgaag 1500
aggaggaagt ccagcaggaa gtaaa 1525
<210> 83
<211> 1537
<212> DNA
<213> Artificial Sequence
<220>
<223> 3905 Synthetic HPV39 L1 gene
<400> 83
ctgggtacca tggctatgtg gaggtcctct gacagtatgg tctacctgcc tcctccatct 60
gtggctaagg tggtgaacac agatgactat gtgaccagga caggcatcta ctactatgct 120
ggctccagca gactgctgac agtgggacac ccatacttca aggtggggat gaatggaggc 180
aggaagcagg acatcccaaa ggtgtctgcc taccaataca gggtgttcag ggtgaccctg 240
cctgacccaa acaagttcag catccctgat gcctccctct acaaccctga gacccagaga 300
ctggtgtggg cttgtgtggg agtggaggtg ggcaggggac aaccactggg agtgggcatc 360
tctggacacc cactctacaa cagacaggat gacacagaga acagcccatt ctccagcacc 420
accaacaagg acagcaggga caatgtgtct gtggactaca agcagaccca actttgtatc 480
attggctgtg tgcctgccat tggagaacac tggggcaagg gcaaggcttg taagccaaac 540
aatgtgagca caggagactg tcctccattg gaactggtga acacaccaat tgaggatgga 600
gatatgattg acacaggcta tggagctatg gactttggag ccctccaaga gaccaagtct 660
gaggtgccac tggacatctg tcagagcatc tgtaaatacc ctgactacct ccaaatgagt 720
gctgatgtct atggagacag tatgttcttc tgtctgagga gggaacaact ttttgccaga 780
cacttctgga acaggggagg gatggtggga gatgccatcc ctgcccaact ctacatcaag 840
ggcacagaca tcagggctaa ccctggctcc tctgtctact gtccaagccc atctggcagt 900
atggtgacct ctgacagcca acttttcaac aagccatact ggctgcacaa ggctcaagga 960
cacaacaatg gcatctgttg gcacaaccaa cttttcctga cagtggtgga caccaccagg 1020
agcaccaact tcaccctgag caccagcatt gagtccagca tcccaagcac ctatgaccca 1080
agcaagttca aggaatacac caggcatgtg gaggaatatg acctccaatt catcttccaa 1140
ctttgtactg tgaccctgac cacagatgtg atgagttaca tccacacaat gaactccagc 1200
atcctggaca actggaactt tgctgtggct cctcctccat ctgcctccct ggtggacacc 1260
tacagatacc tccaatctgc tgccatcact tgtcagaagg atgcccctgc ccctgagaag 1320
aaggacccat atgatggact gaagttctgg aatgtggacc tgagggagaa gttctccttg 1380
gaactggacc agtttccact gggcaggaag ttcctgctcc aagccagggt gaggaggaga 1440
ccaaccattg gaccaaggaa gagacctgct gccagcacct cctcctcctc tgccaccaaa 1500
cacaagagga agagggtgag caagtaaact cgagctc 1537
<210> 84
<211> 1546
<212> DNA
<213> Artificial Sequence
<220>
<223> 3906 Synthetic HPV59 L1 gene
<400> 84
ctgggtacca tggctctgtg gaggtcctct gacaacaagg tctacctgcc tcctccatct 60
gtggctaagg tggtgagcac agatgaatat gtgaccagga ccagcatctt ctaccatgct 120
ggctccagca gactgctgac agtgggacac ccatacttca aggtgccaaa gggaggcaat 180
ggcagacagg atgtgccaaa ggtgtctgcc taccaataca gggtgttcag ggtgaaactg 240
cctgacccaa acaagtttgg actgcctgac aacacagtct atgacccaaa cagccagaga 300
ctggtgtggg cttgtgtggg agtggagatt ggcaggggac aaccactggg agtgggactg 360
tctggacacc cactctacaa caaactggat gacacagaga actctcatgt ggcatctgct 420
gtggacacca aggacaccag ggacaatgtg tctgtggact acaagcagac ccaactttgt 480
atcattggct gtgtgcctgc cattggagaa cactggacca agggcacagc ctgtaagcca 540
accacagtgg tccagggaga ctgtcctcca ttggaactga taaacacacc aattgaggat 600
ggagatatgg tggacacagg ctatggagct atggacttca aactgctcca agacaacaag 660
tctgaggtgc cactggacat ctgtcagagc atctgtaaat accctgacta cctccaaatg 720
agtgctgatg cctatggaga cagtatgttc ttctgtctga ggagggaaca ggtgtttgcc 780
agacacttct ggaacaggtc tggcacaatg ggagaccaac ttcctgagtc cctctacatc 840
aagggcacag acatcagggc taaccctggc tcctacctct acagcccaag cccatctggc 900
tctgtggtga cctctgacag ccaacttttc aacaagccat actggctgca caaggctcaa 960
ggactgaaca atggcatctg ttggcacaac caacttttcc tgacagtggt ggacaccacc 1020
aggagcacca acctgtctgt gtgtgccagc accacctcca gcatcccaaa tgtctacaca 1080
ccaacctcct tcaaggaata tgccaggcat gtggaggagt ttgacctcca attcatcttc 1140
caactttgta agattaccct gaccacagag gtgatgagtt acatccacaa tatgaacacc 1200
accatcttgg aggactggaa ctttggagtg acacctcctc caacagcctc cctggtggac 1260
acctacaggt ttgtccagtc tgctgctgtg acttgtcaga aggacacagc ccctcctgtg 1320
aagcaggacc catatgacaa actgaagttc tggcctgtgg acctgaaaga gaggttctct 1380
gctgacctgg accagtttcc actgggcagg aagttcctgc tccaacttgg agccagacca 1440
aagccaacca ttggaccaag gaagagggct gcccctgccc caaccagcac accaagccca 1500
aagagggtga agaggaggaa gtccagcagg aagtaaactc gagctc 1546
<210> 85
<211> 38
<212> DNA
<213> Artificial Sequence
<220>
<223> 3907 HPV39L1 F1
<400> 85
cttggtacca tggctatgtg gaggtcctct gacagtat 38
<210> 86
<211> 38
<212> DNA
<213> Artificial Sequence
<220>
<223> 3908 HPV39L1 R1
<400> 86
tccaagttgg agcaggaact tcctgcccag tggaaact 38
<210> 87
<211> 1428
<212> DNA
<213> Artificial Sequence
<220>
<223> 3909 HPV39L1 amplified sequence 1
<400> 87
cttggtacca tggctatgtg gaggtcctct gacagtatgg tctacctgcc tcctccatct 60
gtggctaagg tggtgaacac agatgactat gtgaccagga caggcatcta ctactatgct 120
ggctccagca gactgctgac agtgggacac ccatacttca aggtggggat gaatggaggc 180
aggaagcagg acatcccaaa ggtgtctgcc taccaataca gggtgttcag ggtgaccctg 240
cctgacccaa acaagttcag catccctgat gcctccctct acaaccctga gacccagaga 300
ctggtgtggg cttgtgtggg agtggaggtg ggcaggggac aaccactggg agtgggcatc 360
tctggacacc cactctacaa cagacaggat gacacagaga acagcccatt ctccagcacc 420
accaacaagg acagcaggga caatgtgtct gtggactaca agcagaccca actttgtatc 480
attggctgtg tgcctgccat tggagaacac tggggcaagg gcaaggcttg taagccaaac 540
aatgtgagca caggagactg tcctccattg gaactggtga acacaccaat tgaggatgga 600
gatatgattg acacaggcta tggagctatg gactttggag ccctccaaga gaccaagtct 660
gaggtgccac tggacatctg tcagagcatc tgtaaatacc ctgactacct ccaaatgagt 720
gctgatgtct atggagacag tatgttcttc tgtctgagga gggaacaact ttttgccaga 780
cacttctgga acaggggagg gatggtggga gatgccatcc ctgcccaact ctacatcaag 840
ggcacagaca tcagggctaa ccctggctcc tctgtctact gtccaagccc atctggcagt 900
atggtgacct ctgacagcca acttttcaac aagccatact ggctgcacaa ggctcaagga 960
cacaacaatg gcatctgttg gcacaaccaa cttttcctga cagtggtgga caccaccagg 1020
agcaccaact tcaccctgag caccagcatt gagtccagca tcccaagcac ctatgaccca 1080
agcaagttca aggaatacac caggcatgtg gaggaatatg acctccaatt catcttccaa 1140
ctttgtactg tgaccctgac cacagatgtg atgagttaca tccacacaat gaactccagc 1200
atcctggaca actggaactt tgctgtggct cctcctccat ctgcctccct ggtggacacc 1260
tacagatacc tccaatctgc tgccatcact tgtcagaagg atgcccctgc ccctgagaag 1320
aaggacccat atgatggact gaagttctgg aatgtggacc tgagggagaa gttctccttg 1380
gaactggacc agtttccact gggcaggaag ttcctgctcc aacttgga 1428
<210> 88
<211> 37
<212> DNA
<213> Artificial Sequence
<220>
<223> 3910 HPV39L1 F2
<400> 88
aggaagttcc tgctccaact tggagccaga ccaaagc 37
<210> 89
<211> 40
<212> DNA
<213> Artificial Sequence
<220>
<223> 3911 HPV39L1 R2
<400> 89
ctgtctagat ttacttcctg ctggacttcc tcctcttcac 40
<210> 90
<211> 139
<212> DNA
<213> Artificial Sequence
<220>
<223> 3912 HPV39L1 amplified sequence 2
<400> 90
aggaagttcc tgctccaact tggagccaga ccaaagccaa ccattggacc aaggaagagg 60
gctgcccctg ccccaaccag cacaccaagc ccaaagaggg tgaagaggag gaagtccagc 120
aggaagtaaa tctagacag 139
<210> 91
<211> 26
<212> PRT
<213> Homo sapiens 3913 Amino acid sequence of HPV type 33 L1 protein aa 474-499
<400> 91
Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr
1 5 10 15
Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
20 25
<210> 92
<211> 478
<212> PRT
<213> Homo sapiens 4501 Amino acid sequence of HPV type 45 L1 protein aa 1-478
<400> 92
Met Ala Leu Trp Arg Pro Ser Asp Ser Thr Val Tyr Leu Pro Pro Pro
1 5 10 15
Ser Val Ala Arg Val Val Asn Thr Asp Asp Tyr Val Ser Arg Thr Ser
20 25 30
Ile Phe Tyr His Ala Gly Ser Ser Arg Leu Leu Thr Val Gly Asn Pro
35 40 45
Tyr Phe Arg Val Val Pro Ser Gly Ala Gly Asn Lys Gln Ala Val Pro
50 55 60
Lys Val Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val Ala Leu Pro Asp
65 70 75 80
Pro Asn Lys Phe Gly Leu Pro Asp Ser Thr Ile Tyr Asn Pro Glu Thr
85 90 95
Gln Arg Leu Val Trp Ala Cys Val Gly Met Glu Ile Gly Arg Gly Gln
100 105 110
Pro Leu Gly Ile Gly Leu Ser Gly His Pro Phe Tyr Asn Lys Leu Asp
115 120 125
Asp Thr Glu Ser Ala His Ala Ala Thr Ala Val Ile Thr Gln Asp Val
130 135 140
Arg Asp Asn Val Ser Val Asp Tyr Lys Gln Thr Gln Leu Cys Ile Leu
145 150 155 160
Gly Cys Val Pro Ala Ile Gly Glu His Trp Ala Lys Gly Thr Leu Cys
165 170 175
Lys Pro Ala Gln Leu Gln Pro Gly Asp Cys Pro Pro Leu Glu Leu Lys
180 185 190
Asn Thr Ile Ile Glu Asp Gly Asp Met Val Asp Thr Gly Tyr Gly Ala
195 200 205
Met Asp Phe Ser Thr Leu Gln Asp Thr Lys Cys Glu Val Pro Leu Asp
210 215 220
Ile Cys Gln Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ser Ala
225 230 235 240
Asp Pro Tyr Gly Asp Ser Met Phe Phe Cys Leu Arg Arg Glu Gln Leu
245 250 255
Phe Ala Arg His Phe Trp Asn Arg Ala Gly Val Met Gly Asp Thr Val
260 265 270
Pro Thr Asp Leu Tyr Ile Lys Gly Thr Ser Ala Asn Met Arg Glu Thr
275 280 285
Pro Gly Ser Cys Val Tyr Ser Pro Ser Pro Ser Gly Ser Ile Thr Thr
290 295 300
Ser Asp Ser Gln Leu Phe Asn Lys Pro Tyr Trp Leu His Lys Ala Gln
305 310 315 320
Gly His Asn Asn Gly Ile Cys Trp His Asn Gln Leu Phe Val Thr Val
325 330 335
Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Leu Cys Ala Ser Thr Gln
340 345 350
Asn Pro Val Pro Asn Thr Tyr Asp Pro Thr Lys Phe Lys His Tyr Ser
355 360 365
Arg His Val Glu Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Thr
370 375 380
Ile Thr Leu Thr Ala Glu Val Met Ser Tyr Ile His Ser Met Asn Ser
385 390 395 400
Ser Ile Leu Glu Asn Trp Asn Phe Gly Val Pro Pro Pro Pro Thr Thr
405 410 415
Ser Leu Val Asp Thr Tyr Arg Phe Val Gln Ser Val Ala Val Thr Cys
420 425 430
Gln Lys Asp Thr Thr Pro Pro Glu Lys Gln Asp Pro Tyr Asp Lys Leu
435 440 445
Lys Phe Trp Thr Val Asp Leu Lys Glu Lys Phe Ser Ser Asp Leu Asp
450 455 460
Gln Tyr Pro Leu Gly Arg Lys Phe Leu Val Gln Ala Gly Leu
465 470 475
<210> 93
<211> 26
<212> PRT
<213> Homo sapiens 4502 Amino acid sequence of HPV type 33 L1 protein aa 474-499
<400> 93
Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr
1 5 10 15
Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
20 25
<210> 94
<211> 504
<212> PRT
<213> Artificial Sequence
<220>
<223> 4503 Amino acid sequence of chimeric HPV type 45 L1 protein
<400> 94
Met Ala Leu Trp Arg Pro Ser Asp Ser Thr Val Tyr Leu Pro Pro Pro
1 5 10 15
Ser Val Ala Arg Val Val Asn Thr Asp Asp Tyr Val Ser Arg Thr Ser
20 25 30
Ile Phe Tyr His Ala Gly Ser Ser Arg Leu Leu Thr Val Gly Asn Pro
35 40 45
Tyr Phe Arg Val Val Pro Ser Gly Ala Gly Asn Lys Gln Ala Val Pro
50 55 60
Lys Val Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val Ala Leu Pro Asp
65 70 75 80
Pro Asn Lys Phe Gly Leu Pro Asp Ser Thr Ile Tyr Asn Pro Glu Thr
85 90 95
Gln Arg Leu Val Trp Ala Cys Val Gly Met Glu Ile Gly Arg Gly Gln
100 105 110
Pro Leu Gly Ile Gly Leu Ser Gly His Pro Phe Tyr Asn Lys Leu Asp
115 120 125
Asp Thr Glu Ser Ala His Ala Ala Thr Ala Val Ile Thr Gln Asp Val
130 135 140
Arg Asp Asn Val Ser Val Asp Tyr Lys Gln Thr Gln Leu Cys Ile Leu
145 150 155 160
Gly Cys Val Pro Ala Ile Gly Glu His Trp Ala Lys Gly Thr Leu Cys
165 170 175
Lys Pro Ala Gln Leu Gln Pro Gly Asp Cys Pro Pro Leu Glu Leu Lys
180 185 190
Asn Thr Ile Ile Glu Asp Gly Asp Met Val Asp Thr Gly Tyr Gly Ala
195 200 205
Met Asp Phe Ser Thr Leu Gln Asp Thr Lys Cys Glu Val Pro Leu Asp
210 215 220
Ile Cys Gln Ser Ile Cys Lys Tyr Pro Asp Tyr Leu Gln Met Ser Ala
225 230 235 240
Asp Pro Tyr Gly Asp Ser Met Phe Phe Cys Leu Arg Arg Glu Gln Leu
245 250 255
Phe Ala Arg His Phe Trp Asn Arg Ala Gly Val Met Gly Asp Thr Val
260 265 270
Pro Thr Asp Leu Tyr Ile Lys Gly Thr Ser Ala Asn Met Arg Glu Thr
275 280 285
Pro Gly Ser Cys Val Tyr Ser Pro Ser Pro Ser Gly Ser Ile Thr Thr
290 295 300
Ser Asp Ser Gln Leu Phe Asn Lys Pro Tyr Trp Leu His Lys Ala Gln
305 310 315 320
Gly His Asn Asn Gly Ile Cys Trp His Asn Gln Leu Phe Val Thr Val
325 330 335
Val Asp Thr Thr Arg Ser Thr Asn Leu Thr Leu Cys Ala Ser Thr Gln
340 345 350
Asn Pro Val Pro Asn Thr Tyr Asp Pro Thr Lys Phe Lys His Tyr Ser
355 360 365
Arg His Val Glu Glu Tyr Asp Leu Gln Phe Ile Phe Gln Leu Cys Thr
370 375 380
Ile Thr Leu Thr Ala Glu Val Met Ser Tyr Ile His Ser Met Asn Ser
385 390 395 400
Ser Ile Leu Glu Asn Trp Asn Phe Gly Val Pro Pro Pro Pro Thr Thr
405 410 415
Ser Leu Val Asp Thr Tyr Arg Phe Val Gln Ser Val Ala Val Thr Cys
420 425 430
Gln Lys Asp Thr Thr Pro Pro Glu Lys Gln Asp Pro Tyr Asp Lys Leu
435 440 445
Lys Phe Trp Thr Val Asp Leu Lys Glu Lys Phe Ser Ser Asp Leu Asp
450 455 460
Gln Tyr Pro Leu Gly Arg Lys Phe Leu Val Gln Ala Gly Leu Lys Ala
465 470 475 480
Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr Ser Ser
485 490 495
Ala Lys Arg Lys Lys Val Lys Lys
500
<210> 95
<211> 1516
<212> DNA
<213> Artificial Sequence
<220>
<223> 4504 Nucleotide sequence of chimeric HPV type 45 L1 protein
<400> 95
atggctctgt ggagaccatc tgacagcaca gtctacctgc ctcctccatc tgtggcaagg 60
gtggtgaaca cagatgacta tgtgagcagg accagcatct tctaccatgc tggctccagc 120
agactgctga cagtgggcaa cccatacttc agggtggtgc caagtggagc aggcaacaag 180
caggctgtgc caaaggtgtc tgcctaccaa tacagggtgt tcagggtggc tctgcctgac 240
ccaaacaagt ttggactgcc tgacagcacc atctacaacc ctgagaccca gagactggtg 300
tgggcttgtg tggggatgga gattggcagg ggacaaccac tgggcattgg actgtctgga 360
cacccattct acaacaaact ggatgacaca gagtctgccc atgctgccac agcagtgatt 420
acccaggatg tgagggacaa tgtgtctgtg gactacaagc agacccaact ttgtatcctg 480
ggctgtgtgc ctgccattgg agaacactgg gctaagggca ccctgtgtaa gcctgcccaa 540
ctccaacctg gagactgtcc tccattggaa ctgaaaaaca ccatcattga ggatggagat 600
atggtggaca caggctatgg agctatggac ttcagcaccc tccaagacac caagtgtgag 660
gtgccactgg acatctgtca gagcatctgt aaataccctg actacctcca aatgagtgct 720
gacccatatg gagacagtat gttcttctgt ctgaggaggg aacaactttt tgccagacac 780
ttctggaaca gggctggagt gatgggagac acagtgccaa cagacctcta catcaagggc 840
acctctgcca atatgaggga gacacctggc tcctgtgtct acagcccaag cccatctggc 900
agcatcacca cctctgacag ccaacttttc aacaagccat actggctgca caaggctcaa 960
ggacacaaca atggcatctg ttggcacaac caactttttg tgacagtggt ggacaccacc 1020
aggagcacca acctgaccct gtgtgccagc acccagaacc ctgtgccaaa cacctatgac 1080
ccaaccaagt tcaagcacta cagcaggcat gtggaggaat atgacctcca attcatcttc 1140
caactttgta ccatcaccct gacagcagag gtgatgagtt acatccacag tatgaactcc 1200
agcatcttgg agaactggaa ctttggagtg cctcctcctc caaccacctc cctggtggac 1260
acctacaggt ttgtccagtc tgtggctgtg acttgtcaga aggacaccac acctcctgag 1320
aagcaggacc catatgacaa actgaagttc tggacagtgg acctgaaaga gaagttctcc 1380
tctgacctgg accaataccc actgggcagg aagttcctgg tccaggctgg actgaaagcc 1440
aagccaaaac tgaaaagggc tgccccaacc agcaccagga cctcctctgc caagaggaag 1500
aaggtgaaga agtaaa 1516
<210> 96
<211> 1552
<212> DNA
<213> Artificial Sequence
<220>
<223> 4505 Synthetic HPV45 L1 gene
<400> 96
ctgggtacca tggctctgtg gagaccatct gacagcacag tctacctgcc tcctccatct 60
gtggcaaggg tggtgaacac agatgactat gtgagcagga ccagcatctt ctaccatgct 120
ggctccagca gactgctgac agtgggcaac ccatacttca gggtggtgcc aagtggagca 180
ggcaacaagc aggctgtgcc aaaggtgtct gcctaccaat acagggtgtt cagggtggct 240
ctgcctgacc caaacaagtt tggactgcct gacagcacca tctacaaccc tgagacccag 300
agactggtgt gggcttgtgt ggggatggag attggcaggg gacaaccact gggcattgga 360
ctgtctggac acccattcta caacaaactg gatgacacag agtctgccca tgctgccaca 420
gcagtgatta cccaggatgt gagggacaat gtgtctgtgg actacaagca gacccaactt 480
tgtatcctgg gctgtgtgcc tgccattgga gaacactggg ctaagggcac cctgtgtaag 540
cctgcccaac tccaacctgg agactgtcct ccattggaac tgaaaaacac catcattgag 600
gatggagata tggtggacac aggctatgga gctatggact tcagcaccct ccaagacacc 660
aagtgtgagg tgccactgga catctgtcag agcatctgta aataccctga ctacctccaa 720
atgagtgctg acccatatgg agacagtatg ttcttctgtc tgaggaggga acaacttttt 780
gccagacact tctggaacag ggctggagtg atgggagaca cagtgccaac agacctctac 840
atcaagggca cctctgccaa tatgagggag acacctggct cctgtgtcta cagcccaagc 900
ccatctggca gcatcaccac ctctgacagc caacttttca acaagccata ctggctgcac 960
aaggctcaag gacacaacaa tggcatctgt tggcacaacc aactttttgt gacagtggtg 1020
gacaccacca ggagcaccaa cctgaccctg tgtgccagca cccagaaccc tgtgccaaac 1080
acctatgacc caaccaagtt caagcactac agcaggcatg tggaggaata tgacctccaa 1140
ttcatcttcc aactttgtac catcaccctg acagcagagg tgatgagtta catccacagt 1200
atgaactcca gcatcttgga gaactggaac tttggagtgc ctcctcctcc aaccacctcc 1260
ctggtggaca cctacaggtt tgtccagtct gtggctgtga cttgtcagaa ggacaccaca 1320
cctcctgaga agcaggaccc atatgacaaa ctgaagttct ggacagtgga cctgaaagag 1380
aagttctcct ctgacctgga ccaataccca ctgggcagga agttcctggt ccaggctgga 1440
ctgaggagga gaccaaccat tggaccaagg aagagacctg ctgccagcac cagcacagcc 1500
agcagacctg ccaagagggt gaggattagg agcaagaagt aaactcgagc tc 1552
<210> 97
<211> 1519
<212> DNA
<213> Artificial Sequence
<220>
<223> 4506 Synthetic HPV33 L1 gene
<400> 97
ctgggtacca tgagtgtgtg gagaccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtgagcagga ccagcatcta ctactatgct 120
ggctccagca gactgctggc tgtgggacac ccatacttca gcatcaagaa cccaaccaat 180
gccaagaaac tgctggtgcc aaaggtgtct ggactccaat acagggtgtt cagggtgaga 240
ctgcctgacc caaacaagtt tggctttcct gacacctcct tctacaaccc tgacacccag 300
agactggtgt gggcttgtgt gggattggag attggcaggg gacaaccact gggagtgggc 360
atctctggac acccactgct gaacaagttt gatgacacag agacaggcaa caaataccct 420
ggacaacctg gagcagacaa cagggagtgt ctgagtatgg actacaagca gacccaactt 480
tgtctgctgg gctgtaagcc tccaacagga gaacactggg gcaagggagt ggcttgtacc 540
aatgctgccc ctgccaatga ctgtcctcca ttggaactga taaacaccat cattgaggat 600
ggagatatgg tggacacagg ctttggctgt atggacttca agaccctcca agccaacaag 660
tctgatgtgc caattgacat ctgtggcagc acttgtaaat accctgacta cctgaaaatg 720
acctctgaac catatggaga ctccctgttc ttcttcctga ggagggaaca gatgtttgtg 780
agacacttct tcaacagggc tggcaccctg ggagaggctg tgcctgatga cctctacatc 840
aagggctctg gcaccacagc cagcatccag tcctctgcct tctttccaac accatctggc 900
agtatggtga cctctgagag ccaacttttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caggtgtttg tgacagtggt ggacaccacc 1020
aggagcacca atatgaccct gtgtacccag gtgacctctg acagcaccta caagaatgag 1080
aacttcaagg aatacatcag gcatgtggag gaatatgacc tccaatttgt gttccaactt 1140
tgtaaggtga ccctgacagc agaggtgatg acctacatcc atgctatgaa ccctgacatc 1200
ttggaggact ggcagtttgg actgacacct cctccatctg cctccctcca agacacctac 1260
aggtttgtga ccagccaggc tatcacttgt cagaagacag tgcctccaaa ggagaaggag 1320
gacccactgg gcaaatacac cttctgggag gtggacctga aagagaagtt ctctgctgac 1380
ctggaccagt ttccactggg caggaagttc ctgctccaag caggactgaa agccaagcca 1440
aaactgaaaa gggctgcccc aaccagcacc aggacctcct ctgccaagag gaagaaggtg 1500
aagaagtaaa ctcgagctc 1519
<210> 98
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> 4507 HPV45L1 F1
<400> 98
cttggtacca tggctctgtg gagaccatct gac 33
<210> 99
<211> 32
<212> DNA
<213> Artificial Sequence
<220>
<223> 4508 HPV45L1 R1
<400> 99
gcttggcttt cagtccagcc tggaccagga ac 32
<210> 100
<211> 1453
<212> DNA
<213> Artificial Sequence
<220>
<223> 4509 HPV45L1 amplified sequence 1
<400> 100
cttggtacca tggctctgtg gagaccatct gacagcacag tctacctgcc tcctccatct 60
gtggcaaggg tggtgaacac agatgactat gtgagcagga ccagcatctt ctaccatgct 120
ggctccagca gactgctgac agtgggcaac ccatacttca gggtggtgcc aagtggagca 180
ggcaacaagc aggctgtgcc aaaggtgtct gcctaccaat acagggtgtt cagggtggct 240
ctgcctgacc caaacaagtt tggactgcct gacagcacca tctacaaccc tgagacccag 300
agactggtgt gggcttgtgt ggggatggag attggcaggg gacaaccact gggcattgga 360
ctgtctggac acccattcta caacaaactg gatgacacag agtctgccca tgctgccaca 420
gcagtgatta cccaggatgt gagggacaat gtgtctgtgg actacaagca gacccaactt 480
tgtatcctgg gctgtgtgcc tgccattgga gaacactggg ctaagggcac cctgtgtaag 540
cctgcccaac tccaacctgg agactgtcct ccattggaac tgaaaaacac catcattgag 600
gatggagata tggtggacac aggctatgga gctatggact tcagcaccct ccaagacacc 660
aagtgtgagg tgccactgga catctgtcag agcatctgta aataccctga ctacctccaa 720
atgagtgctg acccatatgg agacagtatg ttcttctgtc tgaggaggga acaacttttt 780
gccagacact tctggaacag ggctggagtg atgggagaca cagtgccaac agacctctac 840
atcaagggca cctctgccaa tatgagggag acacctggct cctgtgtcta cagcccaagc 900
ccatctggca gcatcaccac ctctgacagc caacttttca acaagccata ctggctgcac 960
aaggctcaag gacacaacaa tggcatctgt tggcacaacc aactttttgt gacagtggtg 1020
gacaccacca ggagcaccaa cctgaccctg tgtgccagca cccagaaccc tgtgccaaac 1080
acctatgacc caaccaagtt caagcactac agcaggcatg tggaggaata tgacctccaa 1140
ttcatcttcc aactttgtac catcaccctg acagcagagg tgatgagtta catccacagt 1200
atgaactcca gcatcttgga gaactggaac tttggagtgc ctcctcctcc aaccacctcc 1260
ctggtggaca cctacaggtt tgtccagtct gtggctgtga cttgtcagaa ggacaccaca 1320
cctcctgaga agcaggaccc atatgacaaa ctgaagttct ggacagtgga cctgaaagag 1380
aagttctcct ctgacctgga ccaataccca ctgggcagga agttcctggt ccaggctgga 1440
ctgaaagcca agc 1453
<210> 101
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 4510 HPV45L1 F2
<400> 101
ggctggactg aaagccaagc caaaactgaa aaggg 35
<210> 102
<211> 37
<212> DNA
<213> Artificial Sequence
<220>
<223> 4511 HPV45L1 R2
<400> 102
ctgtctagat ttacttcttc accttcttcc tcttggc 37
<210> 103
<211> 101
<212> DNA
<213> Artificial Sequence
<220>
<223> 4512 HPV45L1 amplified sequence 2
<400> 103
ggctggactg aaagccaagc caaaactgaa aagggctgcc ccaaccagca ccaggacctc 60
ctctgccaag aggaagaagg tgaagaagta aatctagaca g 101
<210> 104
<211> 38
<212> PRT
<213> Homo sapiens 4513 Amino acid sequence of HPV type 59 L1 protein aa 471-508
<400> 104
Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile Gly Pro Arg Lys Arg
1 5 10 15
Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro Lys Arg Val Lys Arg
20 25 30
Arg Lys Ser Ser Arg Lys
35
<210> 105
<211> 474
<212> PRT
<213> Homo sapiens 5101 Amino acid sequence of HPV type 51 L1 protein aa 1-474
<400> 105
Met Ala Leu Trp Arg Thr Asn Asp Ser Lys Val Tyr Leu Pro Pro Ala
1 5 10 15
Pro Val Ser Arg Ile Val Asn Thr Glu Glu Tyr Ile Thr Arg Thr Gly
20 25 30
Ile Tyr Tyr Tyr Ala Gly Ser Ser Arg Leu Ile Thr Leu Gly His Pro
35 40 45
Tyr Phe Pro Ile Pro Lys Thr Ser Thr Arg Ala Ala Ile Pro Lys Val
50 55 60
Ser Ala Phe Gln Tyr Arg Val Phe Arg Val Gln Leu Pro Asp Pro Asn
65 70 75 80
Lys Phe Gly Leu Pro Asp Pro Asn Leu Tyr Asn Pro Asp Thr Asp Arg
85 90 95
Leu Val Trp Gly Cys Val Gly Val Glu Val Gly Arg Gly Gln Pro Leu
100 105 110
Gly Val Gly Leu Ser Gly His Pro Leu Phe Asn Lys Tyr Asp Asp Thr
115 120 125
Glu Asn Ser Arg Ile Ala Asn Gly Asn Ala Gln Gln Asp Val Arg Asp
130 135 140
Asn Thr Ser Val Asp Asn Lys Gln Thr Gln Leu Cys Ile Ile Gly Cys
145 150 155 160
Ala Pro Pro Ile Gly Glu His Trp Gly Ile Gly Thr Thr Cys Lys Asn
165 170 175
Thr Pro Val Pro Pro Gly Asp Cys Pro Pro Leu Glu Leu Val Ser Ser
180 185 190
Val Ile Gln Asp Gly Asp Met Ile Asp Thr Gly Phe Gly Ala Met Asp
195 200 205
Phe Ala Ala Leu Gln Ala Thr Lys Ser Asp Val Pro Leu Asp Ile Ser
210 215 220
Gln Ser Val Cys Lys Tyr Pro Asp Tyr Leu Lys Met Ser Ala Asp Thr
225 230 235 240
Tyr Gly Asn Ser Met Phe Phe His Leu Arg Arg Glu Gln Ile Phe Ala
245 250 255
Arg His Tyr Tyr Asn Lys Leu Val Gly Val Gly Glu Asp Ile Pro Asn
260 265 270
Asp Tyr Tyr Ile Lys Gly Ser Gly Asn Gly Arg Asp Pro Ile Glu Ser
275 280 285
Tyr Ile Tyr Ser Ala Thr Pro Ser Gly Ser Met Ile Thr Ser Asp Ser
290 295 300
Gln Ile Phe Asn Lys Pro Tyr Trp Leu His Arg Ala Gln Gly His Asn
305 310 315 320
Asn Gly Ile Cys Trp Asn Asn Gln Leu Phe Ile Thr Cys Val Asp Thr
325 330 335
Thr Arg Ser Thr Asn Leu Thr Ile Ser Thr Ala Thr Ala Ala Val Ser
340 345 350
Pro Thr Phe Thr Pro Ser Asn Phe Lys Gln Tyr Ile Arg His Gly Glu
355 360 365
Glu Tyr Glu Leu Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr
370 375 380
Thr Glu Val Met Ala Tyr Leu His Thr Met Asp Pro Thr Ile Leu Glu
385 390 395 400
Gln Trp Asn Phe Gly Leu Thr Leu Pro Pro Ser Ala Ser Leu Glu Asp
405 410 415
Ala Tyr Arg Phe Val Arg Asn Ala Ala Thr Ser Cys Gln Lys Asp Thr
420 425 430
Pro Pro Gln Ala Lys Pro Asp Pro Leu Ala Lys Tyr Lys Phe Trp Asp
435 440 445
Val Asp Leu Lys Glu Arg Phe Ser Leu Asp Leu Asp Gln Phe Ala Leu
450 455 460
Gly Arg Lys Phe Leu Leu Gln Val Gly Val
465 470
<210> 106
<211> 26
<212> PRT
<213> Homo sapiens 5102 Amino acid sequence of HPV type 33 L1 protein aa 474-499
<400> 106
Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr
1 5 10 15
Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
20 25
<210> 107
<211> 500
<212> PRT
<213> Artificial Sequence
<220>
<223> 5103 Amino acid sequence of chimeric HPV type 51 L1 protein
<400> 107
Met Ala Leu Trp Arg Thr Asn Asp Ser Lys Val Tyr Leu Pro Pro Ala
1 5 10 15
Pro Val Ser Arg Ile Val Asn Thr Glu Glu Tyr Ile Thr Arg Thr Gly
20 25 30
Ile Tyr Tyr Tyr Ala Gly Ser Ser Arg Leu Ile Thr Leu Gly His Pro
35 40 45
Tyr Phe Pro Ile Pro Lys Thr Ser Thr Arg Ala Ala Ile Pro Lys Val
50 55 60
Ser Ala Phe Gln Tyr Arg Val Phe Arg Val Gln Leu Pro Asp Pro Asn
65 70 75 80
Lys Phe Gly Leu Pro Asp Pro Asn Leu Tyr Asn Pro Asp Thr Asp Arg
85 90 95
Leu Val Trp Gly Cys Val Gly Val Glu Val Gly Arg Gly Gln Pro Leu
100 105 110
Gly Val Gly Leu Ser Gly His Pro Leu Phe Asn Lys Tyr Asp Asp Thr
115 120 125
Glu Asn Ser Arg Ile Ala Asn Gly Asn Ala Gln Gln Asp Val Arg Asp
130 135 140
Asn Thr Ser Val Asp Asn Lys Gln Thr Gln Leu Cys Ile Ile Gly Cys
145 150 155 160
Ala Pro Pro Ile Gly Glu His Trp Gly Ile Gly Thr Thr Cys Lys Asn
165 170 175
Thr Pro Val Pro Pro Gly Asp Cys Pro Pro Leu Glu Leu Val Ser Ser
180 185 190
Val Ile Gln Asp Gly Asp Met Ile Asp Thr Gly Phe Gly Ala Met Asp
195 200 205
Phe Ala Ala Leu Gln Ala Thr Lys Ser Asp Val Pro Leu Asp Ile Ser
210 215 220
Gln Ser Val Cys Lys Tyr Pro Asp Tyr Leu Lys Met Ser Ala Asp Thr
225 230 235 240
Tyr Gly Asn Ser Met Phe Phe His Leu Arg Arg Glu Gln Ile Phe Ala
245 250 255
Arg His Tyr Tyr Asn Lys Leu Val Gly Val Gly Glu Asp Ile Pro Asn
260 265 270
Asp Tyr Tyr Ile Lys Gly Ser Gly Asn Gly Arg Asp Pro Ile Glu Ser
275 280 285
Tyr Ile Tyr Ser Ala Thr Pro Ser Gly Ser Met Ile Thr Ser Asp Ser
290 295 300
Gln Ile Phe Asn Lys Pro Tyr Trp Leu His Arg Ala Gln Gly His Asn
305 310 315 320
Asn Gly Ile Cys Trp Asn Asn Gln Leu Phe Ile Thr Cys Val Asp Thr
325 330 335
Thr Arg Ser Thr Asn Leu Thr Ile Ser Thr Ala Thr Ala Ala Val Ser
340 345 350
Pro Thr Phe Thr Pro Ser Asn Phe Lys Gln Tyr Ile Arg His Gly Glu
355 360 365
Glu Tyr Glu Leu Gln Phe Ile Phe Gln Leu Cys Lys Ile Thr Leu Thr
370 375 380
Thr Glu Val Met Ala Tyr Leu His Thr Met Asp Pro Thr Ile Leu Glu
385 390 395 400
Gln Trp Asn Phe Gly Leu Thr Leu Pro Pro Ser Ala Ser Leu Glu Asp
405 410 415
Ala Tyr Arg Phe Val Arg Asn Ala Ala Thr Ser Cys Gln Lys Asp Thr
420 425 430
Pro Pro Gln Ala Lys Pro Asp Pro Leu Ala Lys Tyr Lys Phe Trp Asp
435 440 445
Val Asp Leu Lys Glu Arg Phe Ser Leu Asp Leu Asp Gln Phe Ala Leu
450 455 460
Gly Arg Lys Phe Leu Leu Gln Val Gly Val Lys Ala Lys Pro Lys Leu
465 470 475 480
Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr Ser Ser Ala Lys Arg Lys
485 490 495
Lys Val Lys Lys
500
<210> 108
<211> 1504
<212> DNA
<213> Artificial Sequence
<220>
<223> 5104 Nucleotide sequence of chimeric HPV type 51 L1 protein
<400> 108
atggctctgt ggaggaccaa tgacagcaag gtctacctgc ctcctgcccc tgtgagcagg 60
attgtgaaca cagaggaata catcaccagg acaggcatct actactatgc tggctccagc 120
agactgatta ccctgggaca cccatacttt ccaatcccaa agaccagcac cagggctgcc 180
atcccaaagg tgtctgcctt ccaatacagg gtgttcaggg tccaacttcc tgacccaaac 240
aagtttggac tgcctgaccc aaacctctac aaccctgaca cagacagact ggtgtggggc 300
tgtgtgggag tggaggtggg caggggacaa ccactgggag tgggactgtc tggacaccca 360
ctgttcaaca aatatgatga cacagagaac agcaggattg ccaatggcaa tgcccaacag 420
gatgtgaggg acaacacctc tgtggacaac aagcagaccc aactttgtat cattggctgt 480
gcccctccaa ttggagaaca ctggggcatt ggcaccactt gtaagaacac acctgtgcct 540
cctggagact gtcctccatt ggaactggtg tcctctgtga ttcaggatgg agatatgatt 600
gacacaggct ttggagctat ggactttgct gccctccaag ccaccaagtc tgatgtgcca 660
ctggacatca gccagtctgt gtgtaaatac cctgactacc tgaaaatgag tgctgacacc 720
tatggcaaca gtatgttctt ccacctgagg agggaacaga tttttgccag acactactac 780
aacaaactgg tgggagtggg agaggacatc ccaaatgact actacatcaa gggctctggc 840
aatggcaggg acccaattga gtcctacatc tactctgcca caccatctgg cagtatgatt 900
acctctgaca gccagatttt caacaagcca tactggctgc acagggctca aggacacaac 960
aatggcatct gttggaacaa ccaacttttc atcacttgtg tggacaccac caggagcacc 1020
aacctgacca tcagcacagc cacagcagca gtgagcccaa ccttcacacc aagcaacttc 1080
aagcaataca tcagacatgg agaggaatat gaactccaat tcatcttcca actttgtaag 1140
attaccctga ccacagaggt gatggcttac ctgcacacaa tggacccaac catcttggaa 1200
cagtggaact ttggactgac cctgcctcca tctgcctcct tggaggatgc ctacaggttt 1260
gtgaggaatg ctgccacctc ctgtcagaag gacacacctc cacaggctaa gcctgaccca 1320
ctggctaaat acaagttctg ggatgtggac ctgaaagaga ggttctccct ggacctggac 1380
cagtttgccc tgggcaggaa gttcctgctc caagtgggag tcaaagccaa gccaaaactg 1440
aaaagggctg ccccaaccag caccaggacc tcctctgcca agaggaagaa ggtgaagaag 1500
taaa 1504
<210> 109
<211> 1534
<212> DNA
<213> Artificial Sequence
<220>
<223> 5105 Synthetic HPV51 L1 gene
<400> 109
ctgggtacca tggctctgtg gaggaccaat gacagcaagg tctacctgcc tcctgcccct 60
gtgagcagga ttgtgaacac agaggaatac atcaccagga caggcatcta ctactatgct 120
ggctccagca gactgattac cctgggacac ccatactttc caatcccaaa gaccagcacc 180
agggctgcca tcccaaaggt gtctgccttc caatacaggg tgttcagggt ccaacttcct 240
gacccaaaca agtttggact gcctgaccca aacctctaca accctgacac agacagactg 300
gtgtggggct gtgtgggagt ggaggtgggc aggggacaac cactgggagt gggactgtct 360
ggacacccac tgttcaacaa atatgatgac acagagaaca gcaggattgc caatggcaat 420
gcccaacagg atgtgaggga caacacctct gtggacaaca agcagaccca actttgtatc 480
attggctgtg cccctccaat tggagaacac tggggcattg gcaccacttg taagaacaca 540
cctgtgcctc ctggagactg tcctccattg gaactggtgt cctctgtgat tcaggatgga 600
gatatgattg acacaggctt tggagctatg gactttgctg ccctccaagc caccaagtct 660
gatgtgccac tggacatcag ccagtctgtg tgtaaatacc ctgactacct gaaaatgagt 720
gctgacacct atggcaacag tatgttcttc cacctgagga gggaacagat ttttgccaga 780
cactactaca acaaactggt gggagtggga gaggacatcc caaatgacta ctacatcaag 840
ggctctggca atggcaggga cccaattgag tcctacatct actctgccac accatctggc 900
agtatgatta cctctgacag ccagattttc aacaagccat actggctgca cagggctcaa 960
ggacacaaca atggcatctg ttggaacaac caacttttca tcacttgtgt ggacaccacc 1020
aggagcacca acctgaccat cagcacagcc acagcagcag tgagcccaac cttcacacca 1080
agcaacttca agcaatacat cagacatgga gaggaatatg aactccaatt catcttccaa 1140
ctttgtaaga ttaccctgac cacagaggtg atggcttacc tgcacacaat ggacccaacc 1200
atcttggaac agtggaactt tggactgacc ctgcctccat ctgcctcctt ggaggatgcc 1260
tacaggtttg tgaggaatgc tgccacctcc tgtcagaagg acacacctcc acaggctaag 1320
cctgacccac tggctaaata caagttctgg gatgtggacc tgaaagagag gttctccctg 1380
gacctggacc agtttgccct gggcaggaag ttcctgctcc aagtgggagt ccagaggaag 1440
ccaagacctg gactgaaaag acctgcctcc tctgcctcct cctcctcctc ctcctctgcc 1500
aagaggaaga gggtgaagaa gtaaactcga gctc 1534
<210> 110
<211> 1519
<212> DNA
<213> Artificial Sequence
<220>
<223> 5106 Synthetic HPV33 L1 gene
<400> 110
ctgggtacca tgagtgtgtg gagaccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtgagcagga ccagcatcta ctactatgct 120
ggctccagca gactgctggc tgtgggacac ccatacttca gcatcaagaa cccaaccaat 180
gccaagaaac tgctggtgcc aaaggtgtct ggactccaat acagggtgtt cagggtgaga 240
ctgcctgacc caaacaagtt tggctttcct gacacctcct tctacaaccc tgacacccag 300
agactggtgt gggcttgtgt gggattggag attggcaggg gacaaccact gggagtgggc 360
atctctggac acccactgct gaacaagttt gatgacacag agacaggcaa caaataccct 420
ggacaacctg gagcagacaa cagggagtgt ctgagtatgg actacaagca gacccaactt 480
tgtctgctgg gctgtaagcc tccaacagga gaacactggg gcaagggagt ggcttgtacc 540
aatgctgccc ctgccaatga ctgtcctcca ttggaactga taaacaccat cattgaggat 600
ggagatatgg tggacacagg ctttggctgt atggacttca agaccctcca agccaacaag 660
tctgatgtgc caattgacat ctgtggcagc acttgtaaat accctgacta cctgaaaatg 720
acctctgaac catatggaga ctccctgttc ttcttcctga ggagggaaca gatgtttgtg 780
agacacttct tcaacagggc tggcaccctg ggagaggctg tgcctgatga cctctacatc 840
aagggctctg gcaccacagc cagcatccag tcctctgcct tctttccaac accatctggc 900
agtatggtga cctctgagag ccaacttttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caggtgtttg tgacagtggt ggacaccacc 1020
aggagcacca atatgaccct gtgtacccag gtgacctctg acagcaccta caagaatgag 1080
aacttcaagg aatacatcag gcatgtggag gaatatgacc tccaatttgt gttccaactt 1140
tgtaaggtga ccctgacagc agaggtgatg acctacatcc atgctatgaa ccctgacatc 1200
ttggaggact ggcagtttgg actgacacct cctccatctg cctccctcca agacacctac 1260
aggtttgtga ccagccaggc tatcacttgt cagaagacag tgcctccaaa ggagaaggag 1320
gacccactgg gcaaatacac cttctgggag gtggacctga aagagaagtt ctctgctgac 1380
ctggaccagt ttccactggg caggaagttc ctgctccaag caggactgaa agccaagcca 1440
aaactgaaaa gggctgcccc aaccagcacc aggacctcct ctgccaagag gaagaaggtg 1500
aagaagtaaa ctcgagctc 1519
<210> 111
<211> 34
<212> DNA
<213> Artificial Sequence
<220>
<223> 5107 HPV51L1 F1
<400> 111
cttggtacca tggctctgtg gaggaccaat gaca 34
<210> 112
<211> 32
<212> DNA
<213> Artificial Sequence
<220>
<223> 5108 HPV51L1 R1
<400> 112
gcttggcttt gactcccact tggagcagga ac 32
<210> 113
<211> 1441
<212> DNA
<213> Artificial Sequence
<220>
<223> 5109 HPV51L1 amplified sequence 1
<400> 113
cttggtacca tggctctgtg gaggaccaat gacagcaagg tctacctgcc tcctgcccct 60
gtgagcagga ttgtgaacac agaggaatac atcaccagga caggcatcta ctactatgct 120
ggctccagca gactgattac cctgggacac ccatactttc caatcccaaa gaccagcacc 180
agggctgcca tcccaaaggt gtctgccttc caatacaggg tgttcagggt ccaacttcct 240
gacccaaaca agtttggact gcctgaccca aacctctaca accctgacac agacagactg 300
gtgtggggct gtgtgggagt ggaggtgggc aggggacaac cactgggagt gggactgtct 360
ggacacccac tgttcaacaa atatgatgac acagagaaca gcaggattgc caatggcaat 420
gcccaacagg atgtgaggga caacacctct gtggacaaca agcagaccca actttgtatc 480
attggctgtg cccctccaat tggagaacac tggggcattg gcaccacttg taagaacaca 540
cctgtgcctc ctggagactg tcctccattg gaactggtgt cctctgtgat tcaggatgga 600
gatatgattg acacaggctt tggagctatg gactttgctg ccctccaagc caccaagtct 660
gatgtgccac tggacatcag ccagtctgtg tgtaaatacc ctgactacct gaaaatgagt 720
gctgacacct atggcaacag tatgttcttc cacctgagga gggaacagat ttttgccaga 780
cactactaca acaaactggt gggagtggga gaggacatcc caaatgacta ctacatcaag 840
ggctctggca atggcaggga cccaattgag tcctacatct actctgccac accatctggc 900
agtatgatta cctctgacag ccagattttc aacaagccat actggctgca cagggctcaa 960
ggacacaaca atggcatctg ttggaacaac caacttttca tcacttgtgt ggacaccacc 1020
aggagcacca acctgaccat cagcacagcc acagcagcag tgagcccaac cttcacacca 1080
agcaacttca agcaatacat cagacatgga gaggaatatg aactccaatt catcttccaa 1140
ctttgtaaga ttaccctgac cacagaggtg atggcttacc tgcacacaat ggacccaacc 1200
atcttggaac agtggaactt tggactgacc ctgcctccat ctgcctcctt ggaggatgcc 1260
tacaggtttg tgaggaatgc tgccacctcc tgtcagaagg acacacctcc acaggctaag 1320
cctgacccac tggctaaata caagttctgg gatgtggacc tgaaagagag gttctccctg 1380
gacctggacc agtttgccct gggcaggaag ttcctgctcc aagtgggagt caaagccaag 1440
c 1441
<210> 114
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 5110 HPV51L1 F2
<400> 114
agtgggagtc aaagccaagc caaaactgaa aaggg 35
<210> 115
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 5111 HPV51L1 R2
<400> 115
ctgtctagat ttacttcttc accttcttcc tcttgg 36
<210> 116
<211> 101
<212> DNA
<213> Artificial Sequence
<220>
<223> 5112 HPV51L1 amplified sequence 2
<400> 116
agtgggagtc aaagccaagc caaaactgaa aagggctgcc ccaaccagca ccaggacctc 60
ctctgccaag aggaagaagg tgaagaagta aatctagaca g 101
<210> 117
<211> 38
<212> PRT
<213> Homo sapiens 5113 Amino acid sequence of HPV type 59 L1 protein aa 471-508
<400> 117
Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile Gly Pro Arg Lys Arg
1 5 10 15
Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro Lys Arg Val Lys Arg
20 25 30
Arg Lys Ser Ser Arg Lys
35
<210> 118
<211> 478
<212> PRT
<213> Homo sapiens 5201 Amino acid sequence of HPV type 52 L1 protein aa 1-478
<400> 118
Met Ser Val Trp Arg Pro Ser Glu Ala Thr Val Tyr Leu Pro Pro Val
1 5 10 15
Pro Val Ser Lys Val Val Ser Thr Asp Glu Tyr Val Ser Arg Thr Ser
20 25 30
Ile Tyr Tyr Tyr Ala Gly Ser Ser Arg Leu Leu Thr Val Gly His Pro
35 40 45
Tyr Phe Ser Ile Lys Asn Thr Ser Ser Gly Asn Gly Lys Lys Val Leu
50 55 60
Val Pro Lys Val Ser Gly Leu Gln Tyr Arg Val Phe Arg Ile Lys Leu
65 70 75 80
Pro Asp Pro Asn Lys Phe Gly Phe Pro Asp Thr Ser Phe Tyr Asn Pro
85 90 95
Glu Thr Gln Arg Leu Val Trp Ala Cys Thr Gly Leu Glu Ile Gly Arg
100 105 110
Gly Gln Pro Leu Gly Val Gly Ile Ser Gly His Pro Leu Leu Asn Lys
115 120 125
Phe Asp Asp Thr Glu Thr Ser Asn Lys Tyr Ala Gly Lys Pro Gly Ile
130 135 140
Asp Asn Arg Glu Cys Leu Ser Met Asp Tyr Lys Gln Thr Gln Leu Cys
145 150 155 160
Ile Leu Gly Cys Lys Pro Pro Ile Gly Glu His Trp Gly Lys Gly Thr
165 170 175
Pro Cys Asn Asn Asn Ser Gly Asn Pro Gly Asp Cys Pro Pro Leu Gln
180 185 190
Leu Ile Asn Ser Val Ile Gln Asp Gly Asp Met Val Asp Thr Gly Phe
195 200 205
Gly Cys Met Asp Phe Asn Thr Leu Gln Ala Ser Lys Ser Asp Val Pro
210 215 220
Ile Asp Ile Cys Ser Ser Val Cys Lys Tyr Pro Asp Tyr Leu Gln Met
225 230 235 240
Ala Ser Glu Pro Tyr Gly Asp Ser Leu Phe Phe Phe Leu Arg Arg Glu
245 250 255
Gln Met Phe Val Arg His Phe Phe Asn Arg Ala Gly Thr Leu Gly Asp
260 265 270
Pro Val Pro Gly Asp Leu Tyr Ile Gln Gly Ser Asn Ser Gly Asn Thr
275 280 285
Ala Thr Val Gln Ser Ser Ala Phe Phe Pro Thr Pro Ser Gly Ser Met
290 295 300
Val Thr Ser Glu Ser Gln Leu Phe Asn Lys Pro Tyr Trp Leu Gln Arg
305 310 315 320
Ala Gln Gly His Asn Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val
325 330 335
Thr Val Val Asp Thr Thr Arg Ser Thr Asn Met Thr Leu Cys Ala Glu
340 345 350
Val Lys Lys Glu Ser Thr Tyr Lys Asn Glu Asn Phe Lys Glu Tyr Leu
355 360 365
Arg His Gly Glu Glu Phe Asp Leu Gln Phe Ile Phe Gln Leu Cys Lys
370 375 380
Ile Thr Leu Thr Ala Asp Val Met Thr Tyr Ile His Lys Met Asp Ala
385 390 395 400
Thr Ile Leu Glu Asp Trp Gln Phe Gly Leu Thr Pro Pro Pro Ser Ala
405 410 415
Ser Leu Glu Asp Thr Tyr Arg Phe Val Thr Ser Thr Ala Ile Thr Cys
420 425 430
Gln Lys Asn Thr Pro Pro Lys Gly Lys Glu Asp Pro Leu Lys Asp Tyr
435 440 445
Met Phe Trp Glu Val Asp Leu Lys Glu Lys Phe Ser Ala Asp Leu Asp
450 455 460
Gln Phe Pro Leu Gly Arg Lys Phe Leu Leu Gln Ala Gly Leu
465 470 475
<210> 119
<211> 26
<212> PRT
<213> Homo sapiens 5202 Amino acid sequence of HPV type 33 L1 protein aa 474-499
<400> 119
Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr
1 5 10 15
Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
20 25
<210> 120
<211> 504
<212> PRT
<213> Artificial Sequence
<220>
<223> 5203 Amino acid sequence of chimeric HPV type 52 L1 protein
<400> 120
Met Ser Val Trp Arg Pro Ser Glu Ala Thr Val Tyr Leu Pro Pro Val
1 5 10 15
Pro Val Ser Lys Val Val Ser Thr Asp Glu Tyr Val Ser Arg Thr Ser
20 25 30
Ile Tyr Tyr Tyr Ala Gly Ser Ser Arg Leu Leu Thr Val Gly His Pro
35 40 45
Tyr Phe Ser Ile Lys Asn Thr Ser Ser Gly Asn Gly Lys Lys Val Leu
50 55 60
Val Pro Lys Val Ser Gly Leu Gln Tyr Arg Val Phe Arg Ile Lys Leu
65 70 75 80
Pro Asp Pro Asn Lys Phe Gly Phe Pro Asp Thr Ser Phe Tyr Asn Pro
85 90 95
Glu Thr Gln Arg Leu Val Trp Ala Cys Thr Gly Leu Glu Ile Gly Arg
100 105 110
Gly Gln Pro Leu Gly Val Gly Ile Ser Gly His Pro Leu Leu Asn Lys
115 120 125
Phe Asp Asp Thr Glu Thr Ser Asn Lys Tyr Ala Gly Lys Pro Gly Ile
130 135 140
Asp Asn Arg Glu Cys Leu Ser Met Asp Tyr Lys Gln Thr Gln Leu Cys
145 150 155 160
Ile Leu Gly Cys Lys Pro Pro Ile Gly Glu His Trp Gly Lys Gly Thr
165 170 175
Pro Cys Asn Asn Asn Ser Gly Asn Pro Gly Asp Cys Pro Pro Leu Gln
180 185 190
Leu Ile Asn Ser Val Ile Gln Asp Gly Asp Met Val Asp Thr Gly Phe
195 200 205
Gly Cys Met Asp Phe Asn Thr Leu Gln Ala Ser Lys Ser Asp Val Pro
210 215 220
Ile Asp Ile Cys Ser Ser Val Cys Lys Tyr Pro Asp Tyr Leu Gln Met
225 230 235 240
Ala Ser Glu Pro Tyr Gly Asp Ser Leu Phe Phe Phe Leu Arg Arg Glu
245 250 255
Gln Met Phe Val Arg His Phe Phe Asn Arg Ala Gly Thr Leu Gly Asp
260 265 270
Pro Val Pro Gly Asp Leu Tyr Ile Gln Gly Ser Asn Ser Gly Asn Thr
275 280 285
Ala Thr Val Gln Ser Ser Ala Phe Phe Pro Thr Pro Ser Gly Ser Met
290 295 300
Val Thr Ser Glu Ser Gln Leu Phe Asn Lys Pro Tyr Trp Leu Gln Arg
305 310 315 320
Ala Gln Gly His Asn Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val
325 330 335
Thr Val Val Asp Thr Thr Arg Ser Thr Asn Met Thr Leu Cys Ala Glu
340 345 350
Val Lys Lys Glu Ser Thr Tyr Lys Asn Glu Asn Phe Lys Glu Tyr Leu
355 360 365
Arg His Gly Glu Glu Phe Asp Leu Gln Phe Ile Phe Gln Leu Cys Lys
370 375 380
Ile Thr Leu Thr Ala Asp Val Met Thr Tyr Ile His Lys Met Asp Ala
385 390 395 400
Thr Ile Leu Glu Asp Trp Gln Phe Gly Leu Thr Pro Pro Pro Ser Ala
405 410 415
Ser Leu Glu Asp Thr Tyr Arg Phe Val Thr Ser Thr Ala Ile Thr Cys
420 425 430
Gln Lys Asn Thr Pro Pro Lys Gly Lys Glu Asp Pro Leu Lys Asp Tyr
435 440 445
Met Phe Trp Glu Val Asp Leu Lys Glu Lys Phe Ser Ala Asp Leu Asp
450 455 460
Gln Phe Pro Leu Gly Arg Lys Phe Leu Leu Gln Ala Gly Leu Lys Ala
465 470 475 480
Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr Ser Ser
485 490 495
Ala Lys Arg Lys Lys Val Lys Lys
500
<210> 121
<211> 1516
<212> DNA
<213> Artificial Sequence
<220>
<223> 5204 Nucleotide sequence of chimeric HPV type 52 L1 protein
<400> 121
atgagcgtgt ggaggcccag cgaggccacc gtgtacctgc cccccgtgcc cgtgagcaag 60
gtggtgagca ccgacgagta cgtgagcagg accagcatct actactacgc cggcagcagc 120
aggctgctga ccgtgggcca cccctacttc agcatcaaga acaccagcag cggcaacggc 180
aagaaggtgc tggtgcccaa ggtgagcggc ctgcagtaca gggtgttcag gatcaagctg 240
cccgacccca acaagttcgg cttccccgac accagcttct acaaccccga gacccagagg 300
ctggtgtggg cctgcaccgg cctggagatc ggcaggggcc agcccctggg cgtgggcatc 360
agcggccacc ccctgctgaa caagttcgac gacaccgaga ccagcaacaa gtacgccggc 420
aagcccggca tcgacaacag ggagtgcctg agcatggact acaagcagac ccagctgtgc 480
atcctgggct gcaagccccc catcggcgag cactggggca agggcacccc ctgcaacaac 540
aacagcggca accccggcga ctgccccccc ctgcagctga tcaacagcgt gatccaggac 600
ggcgacatgg tggacaccgg cttcggctgc atggacttca acaccctgca ggccagcaag 660
agcgacgtgc ccatcgacat ctgcagcagc gtgtgcaagt accccgacta cctgcagatg 720
gccagcgagc cctacggcga cagcctgttc ttcttcctga ggagggagca gatgttcgtg 780
aggcacttct tcaacagggc cggcaccctg ggcgaccccg tgcccggcga cctgtacatc 840
cagggcagca acagcggcaa caccgccacc gtgcagagca gcgccttctt ccccaccccc 900
agcggcagca tggtgaccag cgagagccag ctgttcaaca agccctactg gctgcagagg 960
gcccagggcc acaacaacgg catctgctgg ggcaaccagc tgttcgtgac cgtggtggac 1020
accaccagga gcaccaacat gaccctgtgc gccgaggtga agaaggagag cacctacaag 1080
aacgagaact tcaaggagta cctgaggcac ggcgaggagt tcgacctgca gttcatcttc 1140
cagctgtgca agatcaccct gaccgccgac gtgatgacct acatccacaa gatggacgcc 1200
accatcctgg aggactggca gttcggcctg accccccccc ccagcgccag cctggaggac 1260
acctacaggt tcgtgaccag caccgccatc acctgccaga agaacacccc ccccaagggc 1320
aaggaggacc ccctgaagga ctacatgttc tgggaggtgg acctgaagga gaagttcagc 1380
gccgacctgg accagttccc cctgggcagg aagttcctgc tgcaggccgg cctgaaagcc 1440
aagccaaaac tgaaaagggc tgccccaacc agcaccagga cctcctctgc caagaggaag 1500
aaggtgaaga agtaaa 1516
<210> 122
<211> 1531
<212> DNA
<213> Artificial Sequence
<220>
<223> 5205 Synthetic HPV52 L1 gene
<400> 122
ctgggtacca tgagcgtgtg gaggcccagc gaggccaccg tgtacctgcc ccccgtgccc 60
gtgagcaagg tggtgagcac cgacgagtac gtgagcagga ccagcatcta ctactacgcc 120
ggcagcagca ggctgctgac cgtgggccac ccctacttca gcatcaagaa caccagcagc 180
ggcaacggca agaaggtgct ggtgcccaag gtgagcggcc tgcagtacag ggtgttcagg 240
atcaagctgc ccgaccccaa caagttcggc ttccccgaca ccagcttcta caaccccgag 300
acccagaggc tggtgtgggc ctgcaccggc ctggagatcg gcaggggcca gcccctgggc 360
gtgggcatca gcggccaccc cctgctgaac aagttcgacg acaccgagac cagcaacaag 420
tacgccggca agcccggcat cgacaacagg gagtgcctga gcatggacta caagcagacc 480
cagctgtgca tcctgggctg caagcccccc atcggcgagc actggggcaa gggcaccccc 540
tgcaacaaca acagcggcaa ccccggcgac tgcccccccc tgcagctgat caacagcgtg 600
atccaggacg gcgacatggt ggacaccggc ttcggctgca tggacttcaa caccctgcag 660
gccagcaaga gcgacgtgcc catcgacatc tgcagcagcg tgtgcaagta ccccgactac 720
ctgcagatgg ccagcgagcc ctacggcgac agcctgttct tcttcctgag gagggagcag 780
atgttcgtga ggcacttctt caacagggcc ggcaccctgg gcgaccccgt gcccggcgac 840
ctgtacatcc agggcagcaa cagcggcaac accgccaccg tgcagagcag cgccttcttc 900
cccaccccca gcggcagcat ggtgaccagc gagagccagc tgttcaacaa gccctactgg 960
ctgcagaggg cccagggcca caacaacggc atctgctggg gcaaccagct gttcgtgacc 1020
gtggtggaca ccaccaggag caccaacatg accctgtgcg ccgaggtgaa gaaggagagc 1080
acctacaaga acgagaactt caaggagtac ctgaggcacg gcgaggagtt cgacctgcag 1140
ttcatcttcc agctgtgcaa gatcaccctg accgccgacg tgatgaccta catccacaag 1200
atggacgcca ccatcctgga ggactggcag ttcggcctga cccccccccc cagcgccagc 1260
ctggaggaca cctacaggtt cgtgaccagc accgccatca cctgccagaa gaacaccccc 1320
cccaagggca aggaggaccc cctgaaggac tacatgttct gggaggtgga cctgaaggag 1380
aagttcagcg ccgacctgga ccagttcccc ctgggcagga agttcctgct gcaggccggc 1440
ctgcaggcca ggcccaagct gaagaggccc gccagcagcg cccccaggac cagcaccaag 1500
aagaagaagg tgaagaggta aactcgagct c 1531
<210> 123
<211> 1519
<212> DNA
<213> Artificial Sequence
<220>
<223> 5206 Synthetic HPV33 L1 gene
<400> 123
ctgggtacca tgagtgtgtg gagaccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtgagcagga ccagcatcta ctactatgct 120
ggctccagca gactgctggc tgtgggacac ccatacttca gcatcaagaa cccaaccaat 180
gccaagaaac tgctggtgcc aaaggtgtct ggactccaat acagggtgtt cagggtgaga 240
ctgcctgacc caaacaagtt tggctttcct gacacctcct tctacaaccc tgacacccag 300
agactggtgt gggcttgtgt gggattggag attggcaggg gacaaccact gggagtgggc 360
atctctggac acccactgct gaacaagttt gatgacacag agacaggcaa caaataccct 420
ggacaacctg gagcagacaa cagggagtgt ctgagtatgg actacaagca gacccaactt 480
tgtctgctgg gctgtaagcc tccaacagga gaacactggg gcaagggagt ggcttgtacc 540
aatgctgccc ctgccaatga ctgtcctcca ttggaactga taaacaccat cattgaggat 600
ggagatatgg tggacacagg ctttggctgt atggacttca agaccctcca agccaacaag 660
tctgatgtgc caattgacat ctgtggcagc acttgtaaat accctgacta cctgaaaatg 720
acctctgaac catatggaga ctccctgttc ttcttcctga ggagggaaca gatgtttgtg 780
agacacttct tcaacagggc tggcaccctg ggagaggctg tgcctgatga cctctacatc 840
aagggctctg gcaccacagc cagcatccag tcctctgcct tctttccaac accatctggc 900
agtatggtga cctctgagag ccaacttttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caggtgtttg tgacagtggt ggacaccacc 1020
aggagcacca atatgaccct gtgtacccag gtgacctctg acagcaccta caagaatgag 1080
aacttcaagg aatacatcag gcatgtggag gaatatgacc tccaatttgt gttccaactt 1140
tgtaaggtga ccctgacagc agaggtgatg acctacatcc atgctatgaa ccctgacatc 1200
ttggaggact ggcagtttgg actgacacct cctccatctg cctccctcca agacacctac 1260
aggtttgtga ccagccaggc tatcacttgt cagaagacag tgcctccaaa ggagaaggag 1320
gacccactgg gcaaatacac cttctgggag gtggacctga aagagaagtt ctctgctgac 1380
ctggaccagt ttccactggg caggaagttc ctgctccaag caggactgaa agccaagcca 1440
aaactgaaaa gggctgcccc aaccagcacc aggacctcct ctgccaagag gaagaaggtg 1500
aagaagtaaa ctcgagctc 1519
<210> 124
<211> 34
<212> DNA
<213> Artificial Sequence
<220>
<223> 5207 HPV52L1 F1
<400> 124
cttggtacca tgagcgtgtg gaggcccagc gagg 34
<210> 125
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 5208 HPV52L1 R1
<400> 125
gcttggcttt caggccggcc tgcagcagga acttc 35
<210> 126
<211> 1453
<212> DNA
<213> Artificial Sequence
<220>
<223> 5209 HPV52L1 amplified sequence 1
<400> 126
cttggtacca tgagcgtgtg gaggcccagc gaggccaccg tgtacctgcc ccccgtgccc 60
gtgagcaagg tggtgagcac cgacgagtac gtgagcagga ccagcatcta ctactacgcc 120
ggcagcagca ggctgctgac cgtgggccac ccctacttca gcatcaagaa caccagcagc 180
ggcaacggca agaaggtgct ggtgcccaag gtgagcggcc tgcagtacag ggtgttcagg 240
atcaagctgc ccgaccccaa caagttcggc ttccccgaca ccagcttcta caaccccgag 300
acccagaggc tggtgtgggc ctgcaccggc ctggagatcg gcaggggcca gcccctgggc 360
gtgggcatca gcggccaccc cctgctgaac aagttcgacg acaccgagac cagcaacaag 420
tacgccggca agcccggcat cgacaacagg gagtgcctga gcatggacta caagcagacc 480
cagctgtgca tcctgggctg caagcccccc atcggcgagc actggggcaa gggcaccccc 540
tgcaacaaca acagcggcaa ccccggcgac tgcccccccc tgcagctgat caacagcgtg 600
atccaggacg gcgacatggt ggacaccggc ttcggctgca tggacttcaa caccctgcag 660
gccagcaaga gcgacgtgcc catcgacatc tgcagcagcg tgtgcaagta ccccgactac 720
ctgcagatgg ccagcgagcc ctacggcgac agcctgttct tcttcctgag gagggagcag 780
atgttcgtga ggcacttctt caacagggcc ggcaccctgg gcgaccccgt gcccggcgac 840
ctgtacatcc agggcagcaa cagcggcaac accgccaccg tgcagagcag cgccttcttc 900
cccaccccca gcggcagcat ggtgaccagc gagagccagc tgttcaacaa gccctactgg 960
ctgcagaggg cccagggcca caacaacggc atctgctggg gcaaccagct gttcgtgacc 1020
gtggtggaca ccaccaggag caccaacatg accctgtgcg ccgaggtgaa gaaggagagc 1080
acctacaaga acgagaactt caaggagtac ctgaggcacg gcgaggagtt cgacctgcag 1140
ttcatcttcc agctgtgcaa gatcaccctg accgccgacg tgatgaccta catccacaag 1200
atggacgcca ccatcctgga ggactggcag ttcggcctga cccccccccc cagcgccagc 1260
ctggaggaca cctacaggtt cgtgaccagc accgccatca cctgccagaa gaacaccccc 1320
cccaagggca aggaggaccc cctgaaggac tacatgttct gggaggtgga cctgaaggag 1380
aagttcagcg ccgacctgga ccagttcccc ctgggcagga agttcctgct gcaggccggc 1440
ctgaaagcca agc 1453
<210> 127
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 5210 HPV52L1 F2
<400> 127
ggccggcctg aaagccaagc caaaactgaa aaggg 35
<210> 128
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 5211 HPV52L1 R2
<400> 128
ctgtctagat ttacttcttc accttcttcc tcttgg 36
<210> 129
<211> 101
<212> DNA
<213> Artificial Sequence
<220>
<223> 5212 HPV52L1 amplified sequence 2
<400> 129
ggccggcctg aaagccaagc caaaactgaa aagggctgcc ccaaccagca ccaggacctc 60
ctctgccaag aggaagaagg tgaagaagta aatctagaca g 101
<210> 130
<211> 38
<212> PRT
<213> Homo sapiens 5213 Amino acid sequence of HPV type 59 L1 protein aa 471-508
<400> 130
Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile Gly Pro Arg Lys Arg
1 5 10 15
Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro Lys Arg Val Lys Arg
20 25 30
Arg Lys Ser Ser Arg Lys
35
<210> 131
<211> 467
<212> PRT
<213> Homo sapiens 5601 Amino acid sequence of HPV type 56 L1 protein aa 1-467
<400> 131
Met Ala Thr Trp Arg Pro Ser Glu Asn Lys Val Tyr Leu Pro Pro Thr
1 5 10 15
Pro Val Ser Lys Val Val Ala Thr Asp Ser Tyr Val Lys Arg Thr Ser
20 25 30
Ile Phe Tyr His Ala Gly Ser Ser Arg Leu Leu Ala Val Gly His Pro
35 40 45
Tyr Tyr Ser Val Thr Lys Asp Asn Thr Lys Thr Asn Ile Pro Lys Val
50 55 60
Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val Arg Leu Pro Asp Pro Asn
65 70 75 80
Lys Phe Gly Leu Pro Asp Thr Asn Ile Tyr Asn Pro Asp Gln Glu Arg
85 90 95
Leu Val Trp Ala Cys Val Gly Leu Glu Val Gly Arg Gly Gln Pro Leu
100 105 110
Gly Ala Gly Leu Ser Gly His Pro Leu Phe Asn Arg Leu Asp Asp Thr
115 120 125
Glu Ser Ser Asn Leu Ala Asn Asn Asn Val Ile Glu Asp Ser Arg Asp
130 135 140
Asn Ile Ser Val Asp Gly Lys Gln Thr Gln Leu Cys Ile Val Gly Cys
145 150 155 160
Thr Pro Ala Met Gly Glu His Trp Thr Lys Gly Ala Val Cys Lys Ser
165 170 175
Thr Gln Val Thr Thr Gly Asp Cys Pro Pro Leu Ala Leu Ile Asn Thr
180 185 190
Pro Ile Glu Asp Gly Asp Met Ile Asp Thr Gly Phe Gly Ala Met Asp
195 200 205
Phe Lys Val Leu Gln Glu Ser Lys Ala Glu Val Pro Leu Asp Ile Val
210 215 220
Gln Ser Thr Cys Lys Tyr Pro Asp Tyr Leu Lys Met Ser Ala Asp Ala
225 230 235 240
Tyr Gly Asp Ser Met Trp Phe Tyr Leu Arg Arg Glu Gln Leu Phe Ala
245 250 255
Arg His Tyr Phe Asn Arg Ala Gly Lys Val Gly Glu Thr Ile Pro Ala
260 265 270
Glu Leu Tyr Leu Lys Gly Ser Asn Gly Arg Glu Pro Pro Pro Ser Ser
275 280 285
Val Tyr Val Ala Thr Pro Ser Gly Ser Met Ile Thr Ser Glu Ala Gln
290 295 300
Leu Phe Asn Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn Asn
305 310 315 320
Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp Thr Thr
325 330 335
Arg Ser Thr Asn Met Thr Ile Ser Thr Ala Thr Glu Gln Leu Ser Lys
340 345 350
Tyr Asp Ala Arg Lys Ile Asn Gln Tyr Leu Arg His Val Glu Glu Tyr
355 360 365
Glu Leu Gln Phe Val Phe Gln Leu Cys Lys Ile Thr Leu Ser Ala Glu
370 375 380
Val Met Ala Tyr Leu His Asn Met Asn Ala Asn Leu Leu Glu Asp Trp
385 390 395 400
Asn Ile Gly Leu Ser Pro Pro Val Ala Thr Ser Leu Glu Asp Lys Tyr
405 410 415
Arg Tyr Val Arg Ser Thr Ala Ile Thr Cys Gln Arg Glu Gln Pro Pro
420 425 430
Thr Glu Lys Gln Asp Pro Leu Ala Lys Tyr Lys Phe Trp Asp Val Asn
435 440 445
Leu Gln Asp Ser Phe Ser Thr Asp Leu Asp Gln Phe Pro Leu Gly Arg
450 455 460
Lys Phe Leu
465
<210> 132
<211> 31
<212> PRT
<213> Homo sapiens 5602 Amino acid sequence of HPV type 33 L1 protein aa 469-499
<400> 132
Leu Gln Ala Gly Leu Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro
1 5 10 15
Thr Ser Thr Arg Thr Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
20 25 30
<210> 133
<211> 498
<212> PRT
<213> Artificial Sequence
<220>
<223> 5603 Amino acid sequence of chimeric HPV type 56 L1 protein
<400> 133
Met Ala Thr Trp Arg Pro Ser Glu Asn Lys Val Tyr Leu Pro Pro Thr
1 5 10 15
Pro Val Ser Lys Val Val Ala Thr Asp Ser Tyr Val Lys Arg Thr Ser
20 25 30
Ile Phe Tyr His Ala Gly Ser Ser Arg Leu Leu Ala Val Gly His Pro
35 40 45
Tyr Tyr Ser Val Thr Lys Asp Asn Thr Lys Thr Asn Ile Pro Lys Val
50 55 60
Ser Ala Tyr Gln Tyr Arg Val Phe Arg Val Arg Leu Pro Asp Pro Asn
65 70 75 80
Lys Phe Gly Leu Pro Asp Thr Asn Ile Tyr Asn Pro Asp Gln Glu Arg
85 90 95
Leu Val Trp Ala Cys Val Gly Leu Glu Val Gly Arg Gly Gln Pro Leu
100 105 110
Gly Ala Gly Leu Ser Gly His Pro Leu Phe Asn Arg Leu Asp Asp Thr
115 120 125
Glu Ser Ser Asn Leu Ala Asn Asn Asn Val Ile Glu Asp Ser Arg Asp
130 135 140
Asn Ile Ser Val Asp Gly Lys Gln Thr Gln Leu Cys Ile Val Gly Cys
145 150 155 160
Thr Pro Ala Met Gly Glu His Trp Thr Lys Gly Ala Val Cys Lys Ser
165 170 175
Thr Gln Val Thr Thr Gly Asp Cys Pro Pro Leu Ala Leu Ile Asn Thr
180 185 190
Pro Ile Glu Asp Gly Asp Met Ile Asp Thr Gly Phe Gly Ala Met Asp
195 200 205
Phe Lys Val Leu Gln Glu Ser Lys Ala Glu Val Pro Leu Asp Ile Val
210 215 220
Gln Ser Thr Cys Lys Tyr Pro Asp Tyr Leu Lys Met Ser Ala Asp Ala
225 230 235 240
Tyr Gly Asp Ser Met Trp Phe Tyr Leu Arg Arg Glu Gln Leu Phe Ala
245 250 255
Arg His Tyr Phe Asn Arg Ala Gly Lys Val Gly Glu Thr Ile Pro Ala
260 265 270
Glu Leu Tyr Leu Lys Gly Ser Asn Gly Arg Glu Pro Pro Pro Ser Ser
275 280 285
Val Tyr Val Ala Thr Pro Ser Gly Ser Met Ile Thr Ser Glu Ala Gln
290 295 300
Leu Phe Asn Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn Asn
305 310 315 320
Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp Thr Thr
325 330 335
Arg Ser Thr Asn Met Thr Ile Ser Thr Ala Thr Glu Gln Leu Ser Lys
340 345 350
Tyr Asp Ala Arg Lys Ile Asn Gln Tyr Leu Arg His Val Glu Glu Tyr
355 360 365
Glu Leu Gln Phe Val Phe Gln Leu Cys Lys Ile Thr Leu Ser Ala Glu
370 375 380
Val Met Ala Tyr Leu His Asn Met Asn Ala Asn Leu Leu Glu Asp Trp
385 390 395 400
Asn Ile Gly Leu Ser Pro Pro Val Ala Thr Ser Leu Glu Asp Lys Tyr
405 410 415
Arg Tyr Val Arg Ser Thr Ala Ile Thr Cys Gln Arg Glu Gln Pro Pro
420 425 430
Thr Glu Lys Gln Asp Pro Leu Ala Lys Tyr Lys Phe Trp Asp Val Asn
435 440 445
Leu Gln Asp Ser Phe Ser Thr Asp Leu Asp Gln Phe Pro Leu Gly Arg
450 455 460
Lys Phe Leu Leu Gln Ala Gly Leu Lys Ala Lys Pro Lys Leu Lys Arg
465 470 475 480
Ala Ala Pro Thr Ser Thr Arg Thr Ser Ser Ala Lys Arg Lys Lys Val
485 490 495
Lys Lys
<210> 134
<211> 1498
<212> DNA
<213> Artificial Sequence
<220>
<223> 5604 Nucleotide sequence of chimeric HPV type 56 L1 protein
<400> 134
atggctacct ggagaccatc tgagaacaag gtctacctgc ctccaacacc tgtgagcaag 60
gtggtggcta cagactccta tgtgaagagg accagcatct tctaccatgc tggctccagc 120
agactgctgg ctgtgggaca cccatactac tctgtgacca aggacaacac caagaccaac 180
atcccaaagg tgtctgccta ccaatacagg gtgttcaggg tgagactgcc tgacccaaac 240
aagtttggac tgcctgacac caacatctac aaccctgacc aggagagact ggtgtgggct 300
tgtgtgggat tggaggtggg caggggacaa ccactgggag caggactgtc tggacaccca 360
ctgttcaaca gactggatga cacagagtcc agcaacctgg ctaacaacaa tgtgattgag 420
gacagcaggg acaacatctc tgtggatggc aagcagaccc aactttgtat tgtgggctgt 480
actcctgcta tgggagaaca ctggaccaag ggagcagtgt gtaagagcac ccaggtgacc 540
acaggagact gtcctccact ggctctgata aacacaccaa ttgaggatgg agatatgatt 600
gacacaggct ttggagctat ggacttcaag gtgctccaag agagcaaggc tgaggtgcca 660
ctggacattg tccagagcac ttgtaaatac cctgactacc tgaaaatgag tgctgatgcc 720
tatggagaca gtatgtggtt ctacctgagg agggaacaac tttttgccag acactacttc 780
aacagggctg gcaaggtggg agagaccatc cctgctgaac tctacctgaa aggcagcaat 840
ggcagggaac ctcctccatc ctctgtctat gtggctacac catctggcag tatgattacc 900
tctgaggctc aacttttcaa caagccatac tggctccaaa gggctcaagg acacaacaat 960
ggcatctgtt ggggcaacca actttttgtg acagtggtgg acaccaccag gagcaccaat 1020
atgaccatca gcacagccac agaacaactt agcaaatatg atgccaggaa gataaaccaa 1080
tacctgaggc atgtggagga atatgaactc caatttgtgt tccaactttg taagattacc 1140
ctgtctgctg aggtgatggc ttacctgcac aatatgaatg ccaacctgtt ggaggactgg 1200
aacattggac tgagccctcc tgtggctacc tccttggagg acaaatacag atatgtgagg 1260
agcacagcca tcacttgtca gagggaacaa cctccaacag agaagcagga cccactggct 1320
aaatacaagt tctgggatgt gaacctccaa gactccttca gcacagacct ggaccagttt 1380
ccactgggca ggaagttcct gctccaagca ggactgaaag ccaagccaaa actgaaaagg 1440
gctgccccaa ccagcaccag gacctcctct gccaagagga agaaggtgaa gaagtaaa 1498
<210> 135
<211> 1519
<212> DNA
<213> Artificial Sequence
<220>
<223> 5605 Synthetic HPV56 L1 gene
<400> 135
ctgggtacca tggctacctg gagaccatct gagaacaagg tctacctgcc tccaacacct 60
gtgagcaagg tggtggctac agactcctat gtgaagagga ccagcatctt ctaccatgct 120
ggctccagca gactgctggc tgtgggacac ccatactact ctgtgaccaa ggacaacacc 180
aagaccaaca tcccaaaggt gtctgcctac caatacaggg tgttcagggt gagactgcct 240
gacccaaaca agtttggact gcctgacacc aacatctaca accctgacca ggagagactg 300
gtgtgggctt gtgtgggatt ggaggtgggc aggggacaac cactgggagc aggactgtct 360
ggacacccac tgttcaacag actggatgac acagagtcca gcaacctggc taacaacaat 420
gtgattgagg acagcaggga caacatctct gtggatggca agcagaccca actttgtatt 480
gtgggctgta ctcctgctat gggagaacac tggaccaagg gagcagtgtg taagagcacc 540
caggtgacca caggagactg tcctccactg gctctgataa acacaccaat tgaggatgga 600
gatatgattg acacaggctt tggagctatg gacttcaagg tgctccaaga gagcaaggct 660
gaggtgccac tggacattgt ccagagcact tgtaaatacc ctgactacct gaaaatgagt 720
gctgatgcct atggagacag tatgtggttc tacctgagga gggaacaact ttttgccaga 780
cactacttca acagggctgg caaggtggga gagaccatcc ctgctgaact ctacctgaaa 840
ggcagcaatg gcagggaacc tcctccatcc tctgtctatg tggctacacc atctggcagt 900
atgattacct ctgaggctca acttttcaac aagccatact ggctccaaag ggctcaagga 960
cacaacaatg gcatctgttg gggcaaccaa ctttttgtga cagtggtgga caccaccagg 1020
agcaccaata tgaccatcag cacagccaca gaacaactta gcaaatatga tgccaggaag 1080
ataaaccaat acctgaggca tgtggaggaa tatgaactcc aatttgtgtt ccaactttgt 1140
aagattaccc tgtctgctga ggtgatggct tacctgcaca atatgaatgc caacctgttg 1200
gaggactgga acattggact gagccctcct gtggctacct ccttggagga caaatacaga 1260
tatgtgagga gcacagccat cacttgtcag agggaacaac ctccaacaga gaagcaggac 1320
ccactggcta aatacaagtt ctgggatgtg aacctccaag actccttcag cacagacctg 1380
gaccagtttc cactgggcag gaagttcctg atgcaacttg gcaccaggag caagcctgct 1440
gtggctacca gcaagaagag gtctgcccca accagcacca gcacacctgc caagaggaag 1500
aggaggtaaa ctcgagctc 1519
<210> 136
<211> 1519
<212> DNA
<213> Artificial Sequence
<220>
<223> 5606 Synthetic HPV33 L1 gene
<400> 136
ctgggtacca tgagtgtgtg gagaccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtgagcagga ccagcatcta ctactatgct 120
ggctccagca gactgctggc tgtgggacac ccatacttca gcatcaagaa cccaaccaat 180
gccaagaaac tgctggtgcc aaaggtgtct ggactccaat acagggtgtt cagggtgaga 240
ctgcctgacc caaacaagtt tggctttcct gacacctcct tctacaaccc tgacacccag 300
agactggtgt gggcttgtgt gggattggag attggcaggg gacaaccact gggagtgggc 360
atctctggac acccactgct gaacaagttt gatgacacag agacaggcaa caaataccct 420
ggacaacctg gagcagacaa cagggagtgt ctgagtatgg actacaagca gacccaactt 480
tgtctgctgg gctgtaagcc tccaacagga gaacactggg gcaagggagt ggcttgtacc 540
aatgctgccc ctgccaatga ctgtcctcca ttggaactga taaacaccat cattgaggat 600
ggagatatgg tggacacagg ctttggctgt atggacttca agaccctcca agccaacaag 660
tctgatgtgc caattgacat ctgtggcagc acttgtaaat accctgacta cctgaaaatg 720
acctctgaac catatggaga ctccctgttc ttcttcctga ggagggaaca gatgtttgtg 780
agacacttct tcaacagggc tggcaccctg ggagaggctg tgcctgatga cctctacatc 840
aagggctctg gcaccacagc cagcatccag tcctctgcct tctttccaac accatctggc 900
agtatggtga cctctgagag ccaacttttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caggtgtttg tgacagtggt ggacaccacc 1020
aggagcacca atatgaccct gtgtacccag gtgacctctg acagcaccta caagaatgag 1080
aacttcaagg aatacatcag gcatgtggag gaatatgacc tccaatttgt gttccaactt 1140
tgtaaggtga ccctgacagc agaggtgatg acctacatcc atgctatgaa ccctgacatc 1200
ttggaggact ggcagtttgg actgacacct cctccatctg cctccctcca agacacctac 1260
aggtttgtga ccagccaggc tatcacttgt cagaagacag tgcctccaaa ggagaaggag 1320
gacccactgg gcaaatacac cttctgggag gtggacctga aagagaagtt ctctgctgac 1380
ctggaccagt ttccactggg caggaagttc ctgctccaag caggactgaa agccaagcca 1440
aaactgaaaa gggctgcccc aaccagcacc aggacctcct ctgccaagag gaagaaggtg 1500
aagaagtaaa ctcgagctc 1519
<210> 137
<211> 33
<212> DNA
<213> Artificial Sequence
<220>
<223> 5607 HPV56L1 F1
<400> 137
cttggtacca tggctacctg gagaccatct gag 33
<210> 138
<211> 31
<212> DNA
<213> Artificial Sequence
<220>
<223> 5608 HPV56L1 R1
<400> 138
ctgcttggag caggaacttc ctgcccagtg g 31
<210> 139
<211> 1420
<212> DNA
<213> Artificial Sequence
<220>
<223> 5609 HPV56L1 amplified sequence 1
<400> 139
cttggtacca tggctacctg gagaccatct gagaacaagg tctacctgcc tccaacacct 60
gtgagcaagg tggtggctac agactcctat gtgaagagga ccagcatctt ctaccatgct 120
ggctccagca gactgctggc tgtgggacac ccatactact ctgtgaccaa ggacaacacc 180
aagaccaaca tcccaaaggt gtctgcctac caatacaggg tgttcagggt gagactgcct 240
gacccaaaca agtttggact gcctgacacc aacatctaca accctgacca ggagagactg 300
gtgtgggctt gtgtgggatt ggaggtgggc aggggacaac cactgggagc aggactgtct 360
ggacacccac tgttcaacag actggatgac acagagtcca gcaacctggc taacaacaat 420
gtgattgagg acagcaggga caacatctct gtggatggca agcagaccca actttgtatt 480
gtgggctgta ctcctgctat gggagaacac tggaccaagg gagcagtgtg taagagcacc 540
caggtgacca caggagactg tcctccactg gctctgataa acacaccaat tgaggatgga 600
gatatgattg acacaggctt tggagctatg gacttcaagg tgctccaaga gagcaaggct 660
gaggtgccac tggacattgt ccagagcact tgtaaatacc ctgactacct gaaaatgagt 720
gctgatgcct atggagacag tatgtggttc tacctgagga gggaacaact ttttgccaga 780
cactacttca acagggctgg caaggtggga gagaccatcc ctgctgaact ctacctgaaa 840
ggcagcaatg gcagggaacc tcctccatcc tctgtctatg tggctacacc atctggcagt 900
atgattacct ctgaggctca acttttcaac aagccatact ggctccaaag ggctcaagga 960
cacaacaatg gcatctgttg gggcaaccaa ctttttgtga cagtggtgga caccaccagg 1020
agcaccaata tgaccatcag cacagccaca gaacaactta gcaaatatga tgccaggaag 1080
ataaaccaat acctgaggca tgtggaggaa tatgaactcc aatttgtgtt ccaactttgt 1140
aagattaccc tgtctgctga ggtgatggct tacctgcaca atatgaatgc caacctgttg 1200
gaggactgga acattggact gagccctcct gtggctacct ccttggagga caaatacaga 1260
tatgtgagga gcacagccat cacttgtcag agggaacaac ctccaacaga gaagcaggac 1320
ccactggcta aatacaagtt ctgggatgtg aacctccaag actccttcag cacagacctg 1380
gaccagtttc cactgggcag gaagttcctg ctccaagcag 1420
<210> 140
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 5610 HPV56L1 F2
<400> 140
gaagttcctg ctccaagcag gactgaaagc caagcc 36
<210> 141
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 5611 HPV56L1 R2
<400> 141
ctgtctagat ttacttcttc accttcttcc tcttgg 36
<210> 142
<211> 116
<212> DNA
<213> Artificial Sequence
<220>
<223> 5612 HPV56L1 amplified sequence 2
<400> 142
gaagttcctg ctccaagcag gactgaaagc caagccaaaa ctgaaaaggg ctgccccaac 60
cagcaccagg acctcctctg ccaagaggaa gaaggtgaag aagtaaatct agacag 116
<210> 143
<211> 38
<212> PRT
<213> Homo sapiens 5613 Amino acid sequence of HPV type 59 L1 protein aa 471-508
<400> 143
Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile Gly Pro Arg Lys Arg
1 5 10 15
Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro Lys Arg Val Lys Arg
20 25 30
Arg Lys Ser Ser Arg Lys
35
<210> 144
<211> 473
<212> PRT
<213> Homo sapiens 5801 Amino acid sequence of HPV type 58 L1 protein aa 1-473
<400> 144
Met Ser Val Trp Arg Pro Ser Glu Ala Thr Val Tyr Leu Pro Pro Val
1 5 10 15
Pro Val Ser Lys Val Val Ser Thr Asp Glu Tyr Val Ser Arg Thr Ser
20 25 30
Ile Tyr Tyr Tyr Ala Gly Ser Ser Arg Leu Leu Ala Val Gly Asn Pro
35 40 45
Tyr Phe Ser Ile Lys Ser Pro Asn Asn Asn Lys Lys Val Leu Val Pro
50 55 60
Lys Val Ser Gly Leu Gln Tyr Arg Val Phe Arg Val Arg Leu Pro Asp
65 70 75 80
Pro Asn Lys Phe Gly Phe Pro Asp Thr Ser Phe Tyr Asn Pro Asp Thr
85 90 95
Gln Arg Leu Val Trp Ala Cys Val Gly Leu Glu Ile Gly Arg Gly Gln
100 105 110
Pro Leu Gly Val Gly Val Ser Gly His Pro Tyr Leu Asn Lys Phe Asp
115 120 125
Asp Thr Glu Thr Ser Asn Arg Tyr Pro Ala Gln Pro Gly Ser Asp Asn
130 135 140
Arg Glu Cys Leu Ser Met Asp Tyr Lys Gln Thr Gln Leu Cys Leu Ile
145 150 155 160
Gly Cys Lys Pro Pro Thr Gly Glu His Trp Gly Lys Gly Val Ala Cys
165 170 175
Asn Asn Asn Ala Ala Ala Thr Asp Cys Pro Pro Leu Glu Leu Phe Asn
180 185 190
Ser Ile Ile Glu Asp Gly Asp Met Val Asp Thr Gly Phe Gly Cys Met
195 200 205
Asp Phe Gly Thr Leu Gln Ala Asn Lys Ser Asp Val Pro Ile Asp Ile
210 215 220
Cys Asn Ser Thr Cys Lys Tyr Pro Asp Tyr Leu Lys Met Ala Ser Glu
225 230 235 240
Pro Tyr Gly Asp Ser Leu Phe Phe Phe Leu Arg Arg Glu Gln Met Phe
245 250 255
Val Arg His Phe Phe Asn Arg Ala Gly Lys Leu Gly Glu Ala Val Pro
260 265 270
Asp Asp Leu Tyr Ile Lys Gly Ser Gly Asn Thr Ala Val Ile Gln Ser
275 280 285
Ser Ala Phe Phe Pro Thr Pro Ser Gly Ser Ile Val Thr Ser Glu Ser
290 295 300
Gln Leu Phe Asn Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn
305 310 315 320
Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp Thr
325 330 335
Thr Arg Ser Thr Asn Met Thr Leu Cys Thr Glu Val Thr Lys Glu Gly
340 345 350
Thr Tyr Lys Asn Asp Asn Phe Lys Glu Tyr Val Arg His Val Glu Glu
355 360 365
Tyr Asp Leu Gln Phe Val Phe Gln Leu Cys Lys Ile Thr Leu Thr Ala
370 375 380
Glu Ile Met Thr Tyr Ile His Thr Met Asp Ser Asn Ile Leu Glu Asp
385 390 395 400
Trp Gln Phe Gly Leu Thr Pro Pro Pro Ser Ala Ser Leu Gln Asp Thr
405 410 415
Tyr Arg Phe Val Thr Ser Gln Ala Ile Thr Cys Gln Lys Thr Ala Pro
420 425 430
Pro Lys Glu Lys Glu Asp Pro Leu Asn Lys Tyr Thr Phe Trp Glu Val
435 440 445
Asn Leu Lys Glu Lys Phe Ser Ala Asp Leu Asp Gln Phe Pro Leu Gly
450 455 460
Arg Lys Phe Leu Leu Gln Ser Gly Leu
465 470
<210> 145
<211> 26
<212> PRT
<213> Homo sapiens 5802 Amino acid sequence of HPV type 33 L1 protein aa 474-499
<400> 145
Lys Ala Lys Pro Lys Leu Lys Arg Ala Ala Pro Thr Ser Thr Arg Thr
1 5 10 15
Ser Ser Ala Lys Arg Lys Lys Val Lys Lys
20 25
<210> 146
<211> 499
<212> PRT
<213> Artificial Sequence
<220>
<223> 5803 Amino acid sequence of chimeric HPV type 58 L1 protein
<400> 146
Met Ser Val Trp Arg Pro Ser Glu Ala Thr Val Tyr Leu Pro Pro Val
1 5 10 15
Pro Val Ser Lys Val Val Ser Thr Asp Glu Tyr Val Ser Arg Thr Ser
20 25 30
Ile Tyr Tyr Tyr Ala Gly Ser Ser Arg Leu Leu Ala Val Gly Asn Pro
35 40 45
Tyr Phe Ser Ile Lys Ser Pro Asn Asn Asn Lys Lys Val Leu Val Pro
50 55 60
Lys Val Ser Gly Leu Gln Tyr Arg Val Phe Arg Val Arg Leu Pro Asp
65 70 75 80
Pro Asn Lys Phe Gly Phe Pro Asp Thr Ser Phe Tyr Asn Pro Asp Thr
85 90 95
Gln Arg Leu Val Trp Ala Cys Val Gly Leu Glu Ile Gly Arg Gly Gln
100 105 110
Pro Leu Gly Val Gly Val Ser Gly His Pro Tyr Leu Asn Lys Phe Asp
115 120 125
Asp Thr Glu Thr Ser Asn Arg Tyr Pro Ala Gln Pro Gly Ser Asp Asn
130 135 140
Arg Glu Cys Leu Ser Met Asp Tyr Lys Gln Thr Gln Leu Cys Leu Ile
145 150 155 160
Gly Cys Lys Pro Pro Thr Gly Glu His Trp Gly Lys Gly Val Ala Cys
165 170 175
Asn Asn Asn Ala Ala Ala Thr Asp Cys Pro Pro Leu Glu Leu Phe Asn
180 185 190
Ser Ile Ile Glu Asp Gly Asp Met Val Asp Thr Gly Phe Gly Cys Met
195 200 205
Asp Phe Gly Thr Leu Gln Ala Asn Lys Ser Asp Val Pro Ile Asp Ile
210 215 220
Cys Asn Ser Thr Cys Lys Tyr Pro Asp Tyr Leu Lys Met Ala Ser Glu
225 230 235 240
Pro Tyr Gly Asp Ser Leu Phe Phe Phe Leu Arg Arg Glu Gln Met Phe
245 250 255
Val Arg His Phe Phe Asn Arg Ala Gly Lys Leu Gly Glu Ala Val Pro
260 265 270
Asp Asp Leu Tyr Ile Lys Gly Ser Gly Asn Thr Ala Val Ile Gln Ser
275 280 285
Ser Ala Phe Phe Pro Thr Pro Ser Gly Ser Ile Val Thr Ser Glu Ser
290 295 300
Gln Leu Phe Asn Lys Pro Tyr Trp Leu Gln Arg Ala Gln Gly His Asn
305 310 315 320
Asn Gly Ile Cys Trp Gly Asn Gln Leu Phe Val Thr Val Val Asp Thr
325 330 335
Thr Arg Ser Thr Asn Met Thr Leu Cys Thr Glu Val Thr Lys Glu Gly
340 345 350
Thr Tyr Lys Asn Asp Asn Phe Lys Glu Tyr Val Arg His Val Glu Glu
355 360 365
Tyr Asp Leu Gln Phe Val Phe Gln Leu Cys Lys Ile Thr Leu Thr Ala
370 375 380
Glu Ile Met Thr Tyr Ile His Thr Met Asp Ser Asn Ile Leu Glu Asp
385 390 395 400
Trp Gln Phe Gly Leu Thr Pro Pro Pro Ser Ala Ser Leu Gln Asp Thr
405 410 415
Tyr Arg Phe Val Thr Ser Gln Ala Ile Thr Cys Gln Lys Thr Ala Pro
420 425 430
Pro Lys Glu Lys Glu Asp Pro Leu Asn Lys Tyr Thr Phe Trp Glu Val
435 440 445
Asn Leu Lys Glu Lys Phe Ser Ala Asp Leu Asp Gln Phe Pro Leu Gly
450 455 460
Arg Lys Phe Leu Leu Gln Ser Gly Leu Lys Ala Lys Pro Lys Leu Lys
465 470 475 480
Arg Ala Ala Pro Thr Ser Thr Arg Thr Ser Ser Ala Lys Arg Lys Lys
485 490 495
Val Lys Lys
<210> 147
<211> 1501
<212> DNA
<213> Artificial Sequence
<220>
<223> 5804 Nucleotide sequence of chimeric HPV type 58 L1 protein
<400> 147
atgagcgtgt ggaggcccag cgaggccacc gtgtacctgc cccccgtgcc cgtgagcaag 60
gtggtgagca ccgacgagta cgtgagcagg accagcatct actactacgc cggcagcagc 120
aggctgctgg ccgtgggcaa cccctacttc agcatcaaga gccccaacaa caacaagaag 180
gtgctggtgc ccaaggtgag cggcctgcag tacagggtgt tcagggtgag gctgcccgac 240
cccaacaagt tcggcttccc cgacaccagc ttctacaacc ccgacaccca gaggctggtg 300
tgggcctgcg tgggcctgga gatcggcagg ggccagcccc tgggcgtggg cgtgagcggc 360
cacccctacc tgaacaagtt cgacgacacc gagaccagca acaggtaccc cgcccagccc 420
ggcagcgaca acagggagtg cctgagcatg gactacaagc agacccagct gtgcctgatc 480
ggctgcaagc cccccaccgg cgagcactgg ggcaagggcg tggcctgcaa caacaacgcc 540
gccgccaccg actgcccccc cctggagctg ttcaacagca tcatcgagga cggcgacatg 600
gtggacaccg gcttcggctg catggacttc ggcaccctgc aggccaacaa gagcgacgtg 660
cccatcgaca tctgcaacag cacctgcaag taccccgact acctgaagat ggccagcgag 720
ccctacggcg acagcctgtt cttcttcctg aggagggagc agatgttcgt gaggcacttc 780
ttcaacaggg ccggcaagct gggcgaggcc gtgcccgacg acctgtacat caagggcagc 840
ggcaacaccg ccgtgatcca gagcagcgcc ttcttcccca cccccagcgg cagcatcgtg 900
accagcgaga gccagctgtt caacaagccc tactggctgc agagggccca gggccacaac 960
aacggcatct gctggggcaa ccagctgttc gtgaccgtgg tggacaccac caggagcacc 1020
aacatgaccc tgtgcaccga ggtgaccaag gagggcacct acaagaacga caacttcaag 1080
gagtacgtga ggcacgtgga ggagtacgac ctgcagttcg tgttccagct gtgcaagatc 1140
accctgaccg ccgagatcat gacctacatc cacaccatgg acagcaacat cctggaggac 1200
tggcagttcg gcctgacccc cccccccagc gccagcctgc aggacaccta caggttcgtg 1260
accagccagg ccatcacctg ccagaagacc gcccccccca aggagaagga ggaccccctg 1320
aacaagtaca ccttctggga ggtgaacctg aaggagaagt tcagcgccga cctggaccag 1380
ttccccctgg gcaggaagtt cctgctgcag agcggcctga aagccaagcc aaaactgaaa 1440
agggctgccc caaccagcac caggacctcc tctgccaaga ggaagaaggt gaagaagtaa 1500
a 1501
<210> 148
<211> 1516
<212> DNA
<213> Artificial Sequence
<220>
<223> 5805 Synthetic HPV58 L1 gene
<400> 148
ctgggtacca tgagcgtgtg gaggcccagc gaggccaccg tgtacctgcc ccccgtgccc 60
gtgagcaagg tggtgagcac cgacgagtac gtgagcagga ccagcatcta ctactacgcc 120
ggcagcagca ggctgctggc cgtgggcaac ccctacttca gcatcaagag ccccaacaac 180
aacaagaagg tgctggtgcc caaggtgagc ggcctgcagt acagggtgtt cagggtgagg 240
ctgcccgacc ccaacaagtt cggcttcccc gacaccagct tctacaaccc cgacacccag 300
aggctggtgt gggcctgcgt gggcctggag atcggcaggg gccagcccct gggcgtgggc 360
gtgagcggcc acccctacct gaacaagttc gacgacaccg agaccagcaa caggtacccc 420
gcccagcccg gcagcgacaa cagggagtgc ctgagcatgg actacaagca gacccagctg 480
tgcctgatcg gctgcaagcc ccccaccggc gagcactggg gcaagggcgt ggcctgcaac 540
aacaacgccg ccgccaccga ctgccccccc ctggagctgt tcaacagcat catcgaggac 600
ggcgacatgg tggacaccgg cttcggctgc atggacttcg gcaccctgca ggccaacaag 660
agcgacgtgc ccatcgacat ctgcaacagc acctgcaagt accccgacta cctgaagatg 720
gccagcgagc cctacggcga cagcctgttc ttcttcctga ggagggagca gatgttcgtg 780
aggcacttct tcaacagggc cggcaagctg ggcgaggccg tgcccgacga cctgtacatc 840
aagggcagcg gcaacaccgc cgtgatccag agcagcgcct tcttccccac ccccagcggc 900
agcatcgtga ccagcgagag ccagctgttc aacaagccct actggctgca gagggcccag 960
ggccacaaca acggcatctg ctggggcaac cagctgttcg tgaccgtggt ggacaccacc 1020
aggagcacca acatgaccct gtgcaccgag gtgaccaagg agggcaccta caagaacgac 1080
aacttcaagg agtacgtgag gcacgtggag gagtacgacc tgcagttcgt gttccagctg 1140
tgcaagatca ccctgaccgc cgagatcatg acctacatcc acaccatgga cagcaacatc 1200
ctggaggact ggcagttcgg cctgaccccc ccccccagcg ccagcctgca ggacacctac 1260
aggttcgtga ccagccaggc catcacctgc cagaagaccg ccccccccaa ggagaaggag 1320
gaccccctga acaagtacac cttctgggag gtgaacctga aggagaagtt cagcgccgac 1380
ctggaccagt tccccctggg caggaagttc ctgctgcaga gcggcctgaa ggccaagccc 1440
aggctgaaga ggagcgcccc caccaccagg gcccccagca ccaagaggaa gaaggtgaag 1500
aagtaaactc gagctc 1516
<210> 149
<211> 1519
<212> DNA
<213> Artificial Sequence
<220>
<223> 5806 Synthetic HPV33 L1 gene
<400> 149
ctgggtacca tgagtgtgtg gagaccatct gaggctacag tctacctgcc tcctgtgcct 60
gtgagcaagg tggtgagcac agatgaatat gtgagcagga ccagcatcta ctactatgct 120
ggctccagca gactgctggc tgtgggacac ccatacttca gcatcaagaa cccaaccaat 180
gccaagaaac tgctggtgcc aaaggtgtct ggactccaat acagggtgtt cagggtgaga 240
ctgcctgacc caaacaagtt tggctttcct gacacctcct tctacaaccc tgacacccag 300
agactggtgt gggcttgtgt gggattggag attggcaggg gacaaccact gggagtgggc 360
atctctggac acccactgct gaacaagttt gatgacacag agacaggcaa caaataccct 420
ggacaacctg gagcagacaa cagggagtgt ctgagtatgg actacaagca gacccaactt 480
tgtctgctgg gctgtaagcc tccaacagga gaacactggg gcaagggagt ggcttgtacc 540
aatgctgccc ctgccaatga ctgtcctcca ttggaactga taaacaccat cattgaggat 600
ggagatatgg tggacacagg ctttggctgt atggacttca agaccctcca agccaacaag 660
tctgatgtgc caattgacat ctgtggcagc acttgtaaat accctgacta cctgaaaatg 720
acctctgaac catatggaga ctccctgttc ttcttcctga ggagggaaca gatgtttgtg 780
agacacttct tcaacagggc tggcaccctg ggagaggctg tgcctgatga cctctacatc 840
aagggctctg gcaccacagc cagcatccag tcctctgcct tctttccaac accatctggc 900
agtatggtga cctctgagag ccaacttttc aacaagccat actggctcca aagggctcaa 960
ggacacaaca atggcatctg ttggggcaac caggtgtttg tgacagtggt ggacaccacc 1020
aggagcacca atatgaccct gtgtacccag gtgacctctg acagcaccta caagaatgag 1080
aacttcaagg aatacatcag gcatgtggag gaatatgacc tccaatttgt gttccaactt 1140
tgtaaggtga ccctgacagc agaggtgatg acctacatcc atgctatgaa ccctgacatc 1200
ttggaggact ggcagtttgg actgacacct cctccatctg cctccctcca agacacctac 1260
aggtttgtga ccagccaggc tatcacttgt cagaagacag tgcctccaaa ggagaaggag 1320
gacccactgg gcaaatacac cttctgggag gtggacctga aagagaagtt ctctgctgac 1380
ctggaccagt ttccactggg caggaagttc ctgctccaag caggactgaa agccaagcca 1440
aaactgaaaa gggctgcccc aaccagcacc aggacctcct ctgccaagag gaagaaggtg 1500
aagaagtaaa ctcgagctc 1519
<210> 150
<211> 34
<212> DNA
<213> Artificial Sequence
<220>
<223> 5807 HPV58L1 F1
<400> 150
cttggtacca tgagcgtgtg gaggcccagc gagg 34
<210> 151
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 5808 HPV58L1 R1
<400> 151
gcttggcttt caggccgctc tgcagcagga acttcc 36
<210> 152
<211> 1438
<212> DNA
<213> Artificial Sequence
<220>
<223> 5809 HPV58L1 amplified sequence 1
<400> 152
cttggtacca tgagcgtgtg gaggcccagc gaggccaccg tgtacctgcc ccccgtgccc 60
gtgagcaagg tggtgagcac cgacgagtac gtgagcagga ccagcatcta ctactacgcc 120
ggcagcagca ggctgctggc cgtgggcaac ccctacttca gcatcaagag ccccaacaac 180
aacaagaagg tgctggtgcc caaggtgagc ggcctgcagt acagggtgtt cagggtgagg 240
ctgcccgacc ccaacaagtt cggcttcccc gacaccagct tctacaaccc cgacacccag 300
aggctggtgt gggcctgcgt gggcctggag atcggcaggg gccagcccct gggcgtgggc 360
gtgagcggcc acccctacct gaacaagttc gacgacaccg agaccagcaa caggtacccc 420
gcccagcccg gcagcgacaa cagggagtgc ctgagcatgg actacaagca gacccagctg 480
tgcctgatcg gctgcaagcc ccccaccggc gagcactggg gcaagggcgt ggcctgcaac 540
aacaacgccg ccgccaccga ctgccccccc ctggagctgt tcaacagcat catcgaggac 600
ggcgacatgg tggacaccgg cttcggctgc atggacttcg gcaccctgca ggccaacaag 660
agcgacgtgc ccatcgacat ctgcaacagc acctgcaagt accccgacta cctgaagatg 720
gccagcgagc cctacggcga cagcctgttc ttcttcctga ggagggagca gatgttcgtg 780
aggcacttct tcaacagggc cggcaagctg ggcgaggccg tgcccgacga cctgtacatc 840
aagggcagcg gcaacaccgc cgtgatccag agcagcgcct tcttccccac ccccagcggc 900
agcatcgtga ccagcgagag ccagctgttc aacaagccct actggctgca gagggcccag 960
ggccacaaca acggcatctg ctggggcaac cagctgttcg tgaccgtggt ggacaccacc 1020
aggagcacca acatgaccct gtgcaccgag gtgaccaagg agggcaccta caagaacgac 1080
aacttcaagg agtacgtgag gcacgtggag gagtacgacc tgcagttcgt gttccagctg 1140
tgcaagatca ccctgaccgc cgagatcatg acctacatcc acaccatgga cagcaacatc 1200
ctggaggact ggcagttcgg cctgaccccc ccccccagcg ccagcctgca ggacacctac 1260
aggttcgtga ccagccaggc catcacctgc cagaagaccg ccccccccaa ggagaaggag 1320
gaccccctga acaagtacac cttctgggag gtgaacctga aggagaagtt cagcgccgac 1380
ctggaccagt tccccctggg caggaagttc ctgctgcaga gcggcctgaa agccaagc 1438
<210> 153
<211> 35
<212> DNA
<213> Artificial Sequence
<220>
<223> 5810 HPV58L1 F2
<400> 153
gagcggcctg aaagccaagc caaaactgaa aaggg 35
<210> 154
<211> 36
<212> DNA
<213> Artificial Sequence
<220>
<223> 5811 HPV58L1 R2
<400> 154
ctgtctagat ttacttcttc accttcttcc tcttgg 36
<210> 155
<211> 101
<212> DNA
<213> Artificial Sequence
<220>
<223> 5812 HPV58L1 amplified sequence 2
<400> 155
gagcggcctg aaagccaagc caaaactgaa aagggctgcc ccaaccagca ccaggacctc 60
ctctgccaag aggaagaagg tgaagaagta aatctagaca g 101
<210> 156
<211> 38
<212> PRT
<213> Homo sapiens 5813 Amino acid sequence of HPV type 59 L1 protein aa 471-508
<400> 156
Leu Gln Leu Gly Ala Arg Pro Lys Pro Thr Ile Gly Pro Arg Lys Arg
1 5 10 15
Ala Ala Pro Ala Pro Thr Ser Thr Pro Ser Pro Lys Arg Val Lys Arg
20 25 30
Arg Lys Ser Ser Arg Lys
35
Claims (16)
- 키메라 유두종(papilloma) 바이러스 L1 단백질로서, 이의 N-말단에서 C-말단 방향으로,
a. 제1 유두종 바이러스 유형의 L1 단백질로부터 유래된 N-말단 단편으로서, 상기 N-말단 단편은 α5 부위 또는 이의 근처 부위들 내의 임의의 아미노산 위치에서 상기 제1 유두종 바이러스 유형의 L1 단백질의 천연 서열(natural sequence)의 C-말단을 절단하여 얻어진 단편이고, 상기 N-말단 단편은 제1 유두종 바이러스 유형의 L1 단백질의 면역원성을 유지하는, N-말단 단편; 및
b. 제2 유두종 바이러스 유형의 L1 단백질로부터 유래된 C-말단 단편으로서, 상기 C-말단 단편은 α5 부위 또는 이의 근처 부위들 내의 임의의 아미노산 위치에서 상기 제2 유두종 바이러스 유형의 L1 단백질의 천연 서열의 N-말단을 절단하여 얻어진 단편이고, 상기 제2 유두종 바이러스 유형의 L1 단백질은 다른 유형의 L1 단백질들에 비해 더 우수한 발현 수준 및 용해도를 가지며, 상기 제2 유두종 바이러스 유형은 HPV 유형 33 및 59로부터 선택되는 것인, C-말단 단편;을 포함하고,
상기 키메라 유두종 바이러스 L1 단백질은 제1 유두종 바이러스 유형의 L1 단백질의 면역원성을 갖고,
상기 N-말단 단편의 C-말단이 상기 C-말단 단편의 N-말단에 연결될 때, 연속적인 아미노산 서열 RKFL은 연결 지점으로부터 N-말단 또는 C-말단 방향으로 4개의 아미노산들의 범위 내에 존재하거나,
연속적인 아미노산 서열 LGRKFL은 연결 지점으로부터 N-말단 또는 C-말단 방향으로 6개의 아미노산들의 범위 내에 존재하는 것인, 키메라 유두종 바이러스 L1 단백질.
- 제1항에 있어서, 상기 유두종 바이러스 L1 단백질은 HPV L1 단백질인, 키메라 유두종 바이러스 L1 단백질.
- 제1항에 있어서, 상기 C-말단 단편은 서열 번호: 2 이거나; 상기 C-말단 단편은 서열 번호: 132 인 것인, 키메라 유두종 바이러스 L1 단백질.
- 제1항에 있어서, 상기 C-말단 단편은 서열 번호: 13 인 것인, 키메라 유두종 바이러스 L1 단백질.
- 제1항에 있어서, 상기 제1 유두종 바이러스 유형의 L1 단백질은 HPV 유형 6, 11, 16, 18, 31, 35, 39, 45, 51, 52, 56, 및 58의 L1 단백질들로부터 선택되거나,
하기 L1 단백질들로부터 선택되는 것인, 키메라 유두종 바이러스 L1 단백질:
서열 번호: 5에 나타낸 유전자에 의해 인코딩되는 HPV 유형 6 L1 단백질,
서열 번호: 18에 나타낸 유전자에 의해 인코딩되는 HPV 유형 11 L1 단백질,
서열 번호: 31에 나타낸 유전자에 의해 인코딩되는 HPV 유형 16 L1 단백질,
서열 번호: 44에 나타낸 유전자에 의해 인코딩되는 HPV 유형 18 L1 단백질,
서열 번호: 57에 나타낸 유전자에 의해 인코딩되는 HPV 유형 31 L1 단백질,
서열 번호: 70에 나타낸 유전자에 의해 인코딩되는 HPV 유형 35 L1 단백질,
서열 번호: 83에 나타낸 유전자에 의해 인코딩되는 HPV 유형 39 L1 단백질,
서열 번호: 96에 나타낸 유전자에 의해 인코딩되는 HPV 유형 45 L1 단백질,
서열 번호: 109에 나타낸 유전자에 의해 인코딩되는 HPV 유형 51 L1 단백질,
서열 번호: 122에 나타낸 유전자에 의해 인코딩되는 HPV 유형 52 L1 단백질,
서열 번호: 135에 나타낸 유전자에 의해 인코딩되는 HPV 유형 56 L1 단백질, 및
서열 번호: 148에 나타낸 유전자에 의해 인코딩되는 HPV 유형 58 L1 단백질.
- 제5항에 있어서, 상기 제1 유두종 바이러스 유형의 L1 단백질은 하기 단백질들로부터 선택되는 것인, 키메라 유두종 바이러스 L1 단백질:
서열 번호: 1에 나타낸 HPV 유형 6 L1 단백질,
서열 번호: 14에 나타낸 HPV 유형 11 L1 단백질,
서열 번호: 27에 나타낸 HPV 유형 16 L1 단백질,
서열 번호: 40에 나타낸 HPV 유형 18 L1 단백질,
서열 번호: 53에 나타낸 HPV 유형 31 L1 단백질,
서열 번호: 66에 나타낸 HPV 유형 35 L1 단백질,
서열 번호: 79에 나타낸 HPV 유형 39 L1 단백질,
서열 번호: 92에 나타낸 HPV 유형 45 L1 단백질,
서열 번호: 105에 나타낸 HPV 유형 51 L1 단백질,
서열 번호: 118에 나타낸 HPV 유형 52 L1 단백질,
서열 번호: 131에 나타낸 HPV 유형 56 L1 단백질, 및
서열 번호: 144에 나타낸 HPV 유형 58 L1 단백질.
- 제1항의 키메라 유두종 바이러스 L1 단백질을 포함하는, 유두종 바이러스-유사 입자.
- 유두종 바이러스-관련 질병 또는 감염을 예방하기 위한 면역원성 조성물로서, 제7항에 기재된 유두종 바이러스-유사 입자들 및 아쥬반트들(adjuvants)을 포함하는, 면역원성 조성물.
- 제1항의 키메라 유두종 바이러스 L1 단백질을 인코딩하는, 분리된 폴리뉴클레오티드.
- 제9항에 기재된 폴리뉴클레오티드를 포함하는, 벡터.
- 제10항에 있어서, 상기 벡터는 배큘로바이러스 벡터인, 벡터.
- 제9항에 기재된 폴리뉴클레오티드를 포함하는, 배큘로바이러스.
- 제9항에 기재된 폴리뉴클레오티드, 상기 폴리뉴클레오티드를 포함하는 벡터, 또는 상기 폴리뉴클레오티드를 포함하는 배큘로바이러스를 포함하는, 숙주 세포.
- 제13항에 있어서, 상기 숙주 세포는 곤충 세포, Sf9 세포, Sf21 세포, Hi5 세포 또는 S2 세포인, 숙주 세포.
- 제7항에 기재된 유두종 바이러스-유사 입자를 제조하는 방법으로서, 상기 방법은,
상기 키메라 유두종 바이러스 L1 단백질을 발현시키고 바이러스-유사 입자들로 조립하기 위해 제13항의 숙주 세포를 배양하는 단계; 및
상기 유두종 바이러스-유사 입자들을 정제하는 단계;를 포함하는, 방법.
- 제15항에 있어서, 상기 정제하는 단계는 양이온 교환 크로마토그래피, 또는 HS-MMA 2단계 크로마토그래피를 사용하여 수행되는 것인, 방법.
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KR1020227005645A KR102640490B1 (ko) | 2019-07-19 | 2020-07-17 | 키메라 유두종바이러스 l1 단백질 |
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