JP5269803B2 - デング熱の4種の血清型に対する免疫付与のプロトコル - Google Patents
デング熱の4種の血清型に対する免疫付与のプロトコル Download PDFInfo
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Description
(a)デング熱第一血清型ワクチンウイルスを含む一価ワクチンの第一投与、
(b)デング熱の4種の血清型ワクチンウイルスを含む四価ワクチンの第二投与、
を含み、
第二投与(b)が第一投与(a)の少なくとも30日後から最長12ヶ月後の間に行われる、方法に関する。
(a)デング熱第一血清型ワクチンウイルスを含む一価ワクチンの第一投与、
(b)デング熱の4種の血清型ワクチンウイルスを含む四価ワクチンの第二投与、
を含み、かつ
第二投与(b)が第一投与(a)の少なくとも30日後、最長で12ヶ月後に行われることを含む方法に関する。
(a)VDV1またはVDV2ワクチンウイルスを含む一価ワクチンが入った第一容器、
(b)4つのChimerivaxTMDEN−1、2、3および4を含む四価ワクチンが入った第二容器を含む。
「デング熱ウイルス」または「DEN」は、フラビウイルス科フラビウイルス属に属するプラス一本鎖RNAウイルスである。ゲノムRNAは5’末端にI型キャップを含み、3’末端にポリ−Aテールを欠く。ゲノム構成は以下の要素を含む:5’非コード領域(NCR)、構造タンパク質(カプシド(C)、前膜/膜(prM/M)、エンベロープ(E))および非構造タンパク質(NS1−NS2A−NS2B−NS3−NS4A−NS4B−NS5)、および3’NCR。ウイルスゲノムRNAはカプシドタンパク質と結合してヌクレオカプシドを形成する。他のフラビウイルスの場合と同様に、DENウイルスゲノムは、単一のポリタンパク質に翻訳される連続したコード領域をコードしている。
(a)VDV1 (b)CYD DEN−1、2、3および4
(a)VDV2 (b)CYD DEN−1、2、3および4。
(a)VDV1またはVDV2ワクチンウイルスを含む一価ワクチンが入った第一容器、および
(b)4種のChimeriVaxTMDEN−1、2、3および4を含む四価ワクチンが入った第二容器
を含む。
ウイルス血症および免疫原性についてサルをモデルに試験した。特にウイルス血症は、ヒトの疾病の毒性および重症度に関連する一つの要因として認定され、したがって考慮されるべき重要なパラメーターを構成する。免疫原性に関しては、付与された防御を評価する上で主要なパラメーターである。
サルにおける実験は、動物実験に関する欧州指針にしたがって行われた。免疫付与はモーリタニア由来のカニクイザル(Macaca fascicularis)で実施された。サルを免疫付与前6週間隔離した。
免疫付与後のウイルス血症を定量リアルタイムRT−PCR(qRT−PCR)によりモニターした。DEN1およびDEN2株のNS5遺伝子に位置するプライマーおよびプローブの2組のセットをVDV−1 RNAおよびVDV−2 RNAの定量にそれぞれ用いた。YFウイルスのNS5遺伝子に位置する2つのプライマーおよび1つのプローブの3組目のセットをCYD RNAを定量するために用いた。最後に、YF NS5 RNA陽性サンプルにおける血清型を同定するために、E(DEN)/NS1(YF)遺伝子の接合点に位置する各種CYD血清型に特異的なプライマーおよびプローブの4組のセットを使用した(表1参照)。RT−PCRアッセイの内部基準として含まれる一連の合成RNAを産生するために、各PCRによって標的とされた領域を含む7つのプラスミドを、T7プロモーターの制御下でインビトロにおいて転写した。これらの合成RNAを分光分析により測定し、得られたRNA量をRNAコピー数に変換し、GEQ(ゲノム等量)として表した。
log10SN50=d+f/N(X+N/2)
式中、
dは100%中和(すなわち6つの陰性複製物、すなわち感染の徴候を示さない複製物)を生じさせる希釈率であり、
fはlog10で示される希釈係数であり(たとえば、1:4の希釈係数なら、f=0.6)、
Nは複製物/希釈率の数であり(N=6)、
Xは感染の徴候を示さないウェルの合計数、ただし希釈率dを除く、
ウイルス検出限界は10SN50(すなわち1.0log10SN50)である。
log10PRNT50=log10SN50+0.2
年齢および体重の等しい1群4匹のサル、計2群に免疫付与した(表2参照)。
−本発明に係る投与経路により、四価ワクチンによる同一の2回の免疫付与を含む系によって得られた中和抗体応答において質的かつ量的に増加が得られる。
−最初に一価VDV2免疫付与後に行われる1回のCYD−1、2、3、4免疫付与は、四価ワクチンを2回免疫付与することを含む系とは違って、すべてのサルで4種の血清型に対して高いレベルの応答を誘導する。
−予想通り、VDV2を用いて行われる最初の免疫付与は、ほとんど血清型2のみに向けられる応答を引き起こすが、数匹において、血清型1および4に対して交差反応が低レベルで起こった。
−ウイルス血症は最初の免疫付与後にVDV2で観察され、第二投与(b)後CYD−4によって優勢的に引き起こされる(群1)。ナイーブな動物において四価ワクチンを用いて第一投与した後誘導されるウイルス血症において目立った違いは観察されなかった(群2)。したがって、本発明によって提案された系は、第二投与後血清型1、3および4のウイルス血症の発症を促進しないと結論づけることができる。
Claims (8)
- デング熱ウイルスに対する免疫付与のためのワクチン組成物であって、
(a)VDV1株およびVDV2株からなる群より選択される、デング熱の第一の血清型に対するワクチンウイルスを含む一価ワクチン、
(b)デング熱の4種の血清型に対するワクチンウイルスを含む四価ワクチンを含み、該四価ワクチンは、一価ワクチンの投与の少なくとも30日後、最長で12ヶ月後に投与され、かつ
該四価ワクチンは、同一の用量の血清型1−4のワクチンデングウイルスのそれぞれを含む、ワクチン組成物。 - 四価ワクチンに用いられるワクチンウイルスがChimerivax(商標)DEN−
1、2、3および4である、請求項1に記載のワクチン組成物。 - 血清型1、2、3および4のデング熱ワクチンウイルスの量が103から106CCID50の範囲内である、請求項1または2に記載のワクチン組成物。
- 一価ワクチンがVDV1株またはVDV2株を104CCID50含み、四価ワクチンがChimerivax(商標)DEN−1、2、3および4を105CCID50含む、請求項1ないし3のいずれか一項に記載のワクチン組成物。
- 第二投与(b)が第一投与(a)の30日後から60日後までに行われる、請求項1ないし4のいずれか一項に記載のワクチン組成物。
- 少なくとも、
(a)VDV1株およびVDV2株からなる群より選択される、デング熱の第一の血清型のワクチンウイルスを含む一価ワクチンが入った第一容器、
(b)同一の用量の血清型1−4のワクチンデングウイルスのそれぞれを含むものである、デング熱の4種の血清型に対するワクチンウイルスを含む四価ワクチンが入った第二容器、
を含む箱を含む、デング熱ウイルスに対する免疫付与キット。 - 少なくとも、
(a)VDV1株およびVDV2株からなる群より選択される、デング熱の第一の血清型のワクチンウイルスを含む一価ワクチンが入った第一容器、
(b)Chimerivax(商標)DEN−1、2、3および4を含む四価ワクチンが入った第二容器、
を含む、請求項6に記載の免疫付与キット。 - 一価ワクチンがVDV1株またはVDV2株を104CCID50含み、かつ四価ワクチンがChimerivax(商標)DEN−1、2、3および4を105CCID50含む、請求項7に記載の免疫付与キット。
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US20080193477A1 (en) * | 2005-08-10 | 2008-08-14 | Acambis Inc. | Vaccination Against Dengue Virus Infection |
FR2903605A1 (fr) * | 2006-07-12 | 2008-01-18 | Sanofi Pasteur Sa | Methode d'immunisation contre les quatres serotypes de la dengue |
FR2906724B1 (fr) * | 2006-10-04 | 2009-03-20 | Sanofi Pasteur Sa | Methode d'immunisation contre les 4 serotypes de la dengue. |
WO2009109550A1 (en) | 2008-03-05 | 2009-09-11 | Sanofi Pasteur | Process for stabilizing an adjuvant containing vaccine composition |
EP2143440A1 (fr) * | 2008-07-09 | 2010-01-13 | Sanofi Pasteur | Agent stabilisant et composition vaccinale comprenant un ou plusieurs flavivirus vivants atténués |
AU2010256845B2 (en) * | 2009-06-01 | 2016-09-22 | Takeda Vaccines, Inc. | Compositions and methods for administration of vaccines against dengue virus |
CA2770888C (en) * | 2009-08-31 | 2020-04-14 | Gen-Probe Incorporated | Dengue virus assay |
EP2353609A1 (en) | 2010-02-04 | 2011-08-10 | Sanofi Pasteur | Immunization compositions and methods |
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JP2015524422A (ja) | 2012-07-24 | 2015-08-24 | サノフィ・パスツールSanofipasteur | ワクチン組成物 |
WO2014083194A1 (en) | 2012-11-30 | 2014-06-05 | Sanofi Pasteur | Methods for inducing antibodies |
WO2014204892A1 (en) * | 2013-06-21 | 2014-12-24 | Merck Sharp & Dohme Corp. | Dengue virus vaccine compositions and methods of use thereof |
TW201620546A (zh) * | 2014-09-02 | 2016-06-16 | 賽諾菲巴斯德公司 | 疫苗組合物 |
BR112017028212A2 (pt) | 2015-07-03 | 2018-09-11 | Sanofi Pasteur | vacinação concomitante contra dengue e febre amarela |
US10004795B2 (en) | 2015-09-08 | 2018-06-26 | Fundacao Butantan | Process for preparing an attenuated tetravalent dengue vaccine |
SG11202002933TA (en) | 2017-10-05 | 2020-04-29 | Sanofi Pasteur | Compositions for booster vaccination against dengu |
CA3111332A1 (en) | 2018-09-05 | 2020-03-12 | Takeda Vaccines, Inc. | Dengue vaccine unit dose and administration thereof |
BR112022001476A2 (pt) | 2019-08-16 | 2023-10-03 | Takeda Vaccines Inc | Uso de uma vacina contra hepatite a e uma composição de vacina contra dengue ou uma dose unitária de uma composição de vacina contra dengue, combinação de vacina e kit |
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WO2023158989A1 (en) | 2022-02-15 | 2023-08-24 | Takeda Vaccines, Inc. | Dengue vaccine batch mixing process |
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IL198466A0 (en) | 2011-08-01 |
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ZA200902540B (en) | 2010-07-28 |
FR2909286B1 (fr) | 2012-06-08 |
AU2007327367B2 (en) | 2013-05-09 |
BRPI0718927A2 (pt) | 2014-04-08 |
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