KR102228308B1 - Vaccine composition for preventing swine mycoplasmal pneumonia and pleuropneumonia - Google Patents
Vaccine composition for preventing swine mycoplasmal pneumonia and pleuropneumonia Download PDFInfo
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- KR102228308B1 KR102228308B1 KR1020190010607A KR20190010607A KR102228308B1 KR 102228308 B1 KR102228308 B1 KR 102228308B1 KR 1020190010607 A KR1020190010607 A KR 1020190010607A KR 20190010607 A KR20190010607 A KR 20190010607A KR 102228308 B1 KR102228308 B1 KR 102228308B1
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- South Korea
- Prior art keywords
- serotype
- vaccine composition
- mycoplasma
- multivalent vaccine
- porcine
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Abstract
본 발병은 돼지 마이코플라즈마균 및 흉막폐렴균에 의한 폐렴 발생을 예방할 수 있는 다가 백신 조성물에 관한 것이다. 본 발명에 따른 다가 백신 조성물은 마이코플라즈마 하이오뉴모니애 (Mycoplasma hyopneumoniae, Mhp) 및 마이코플라즈마 하이오뉴모니애 부착 단백질 P97, 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App) 혈청형 1형, 혈청형 2형, 혈청형 5형 및 각 흉막폐렴균에서 분비되는 독소 1,2 및 3형(ApxI, Ⅱ 및 Ⅲ)을 혼합함으로써 돼지 마이코플라즈마균 및 흉막폐렴균에 의한 폐렴의 동시 예방이 가능하고, 상용 백신보다 우수한 방어 효과를 나타낼 수 있다. 나아가, 초기 방어능이 뛰어나고, 백신 접종 후 부작용이 없으며, 최근 유행하는 혈청형을 포함하고 있어 효과적으로 자돈 폐사율을 감소시킴과 동시에 만성 호흡기 증상으로 인한 개체의 증체성 저하를 막아 양돈 산업에 유용하게 사용될 수 있다.The present outbreak relates to a multivalent vaccine composition capable of preventing the occurrence of pneumonia caused by porcine mycoplasma and pleural pneumonia. The multivalent vaccine composition according to the present invention is Mycoplasma hyopneumoniae (Mycoplasma hyopneumoniae , Mhp) and Mycoplasma hyopneumoniae adhesion protein P97, Actinobacillosis pleuropneumoniae (App) serotype 1, serotype 2, serotype 5 and secreted from each pleural pneumococcus By mixing the toxins 1,2 and 3 (ApxI, II and III), it is possible to simultaneously prevent pneumonia caused by porcine mycoplasma and pleural pneumococcus, and can exhibit superior protective effects than commercial vaccines. Furthermore, it has excellent initial defense ability, has no side effects after vaccination, and contains a recently prevalent serotype, so it can effectively reduce piglet mortality and at the same time prevent the decrease in body gain due to chronic respiratory symptoms, so it can be usefully used in the pig farming industry. have.
Description
본 발병은 돼지 마이코플라즈마균 및 흉막폐렴균에 의한 폐렴 발생을 예방할 수 있는 다가 백신 조성물에 관한 것이다.The present outbreak relates to a multivalent vaccine composition capable of preventing the occurrence of pneumonia caused by porcine mycoplasma and pleural pneumonia.
돼지 호흡기 복합증후군 (Porcine Respiratory Disease Complex, PRDC)은 자돈 폐사율의 증가와 만성 호흡기 증상으로 인해 증체성이 떨어져 양돈 산업에 막대한 경제적 손실을 초래하는 질병이다. Porcine Respiratory Disease Complex (PRDC) is a disease that causes enormous economic losses to the pig industry due to an increase in pig mortality and chronic respiratory symptoms.
돼지 호흡기 복합증후군의 세균성 원인 중 원발성 인자 (1차 감염인자)는 돼지 마이코플라즈마균 (Mycoplasma hyopneumoniae, Mhp)이고, 2차 감염인자는 돼지 흉막폐렴균 (Actinobacillosis pleuropneumoniae , App)이다. 이 중, 돼지 마이코플라즈마균은 호흡기 섬모세포에 집락화를 시작으로 감염을 일으키며, 단일 감염되었을 때는 건성 기침 등의 증상만을 나타내나, 다른 호흡기 병원체와 복합 감염되는 경우 심각한 호흡기 증상을 유발 및 대식세포의 활성을 떨어뜨리고, 다른 병원체의 침입을 방어하는 1차 방어 기능을 상실하게 하는 등 추가 병원균 감염의 위험성을 더욱 증가시킨다. 주로 어린 일령의 돼지에 감염되어 증체효과를 저하시키기 때문에 보통 1주령에 백신을 접종한다. 그러나, 최근 15~18주령에 많이 이환된다는 보고에 의해 마이코플라즈균의 추가 백신접종이 고려되고 있다.Among the bacterial causes of pig respiratory complex syndrome, the primary factor (primary infectious factor) is pig Mycoplasma (Mycoplasma). hyopneumoniae , Mhp), and the secondary infection factor is porcine pleural pneumonia ( Actinobacillosis pleuropneumoniae , App). Among them, porcine mycoplasma bacteria cause infection by colonization of respiratory ciliary cells, and when a single infection shows only symptoms such as dry cough, but when combined with other respiratory pathogens, it causes serious respiratory symptoms and causes macrophages to become infected. It further increases the risk of infection with additional pathogens, such as reducing activity and losing the primary defense function of defending against invasion of other pathogens. The vaccine is usually given at 1 week of age because it is mainly infected with young pigs and lowers the weight gain effect. However, due to the recent report that the disease is highly affected at the age of 15-18 weeks, additional vaccination of Mycoplasma bacteria is being considered.
마이코플라즈마 하이오뉴모니애의 감염은 병원체가 호흡기 상피세포의 섬모에 부착하면서 개시된다. 부착인자 (Adhesin) P97은 마이코플라즈마 하이오뉴모니애의 막 표면 단백질로 면역원성이 높은 항원으로 알려져 있다(Klinkert, et al., 1985, Zhang, et al., 1995, Minion, et al., 2000). P97의 C말단에는 반복되는 구간으로 구성된 R1과 R2 부위가 존재하며, 그 중 R1 부위는 숙주 호흡기 섬모의 부착부위(AAKPV/E)에 결합한다. 결합된 마이코플라즈마 하이오뉴모니애는 성장에 필요한 아미노산을 숙주로부터 얻을 수 있으며, 상처난 조직에 침입하기 위하여 숙주의 분자들을 다양하게 배열할 수 있게 된다. 한편, 숙주는 항체를 생산하여 돼지 섬모에 마이코플라즈마 하이오뉴모니애가 부착하는 것을 방해하거나 부착된 병원체의 성장을 저해할 수 있다. 그러나, 선행 연구에 따르면 기존의 상용 백신은 P97에 대한 항체를 유도할 수 없는 것으로 보고된 바 있다(Conceicao, et al., 2006, Okamba, et al., 2010). Infection of Mycoplasma hyopneumoniae begins when pathogens attach to the cilia of respiratory epithelial cells. Adhesin P97 is a membrane surface protein of Mycoplasma hyopneumoniae and is known as an antigen with high immunogenicity (Klinkert, et al., 1985, Zhang, et al., 1995, Minion, et al., 2000). ). At the C-terminus of P97, there are R1 and R2 sites composed of repeating sections, of which the R1 site binds to the attachment site of the host respiratory cilia (AAKPV/E). The bound Mycoplasma hyopneumoniae can obtain amino acids necessary for growth from the host, and variously arrange the host molecules in order to invade the wounded tissue. On the other hand, the host can produce antibodies to prevent the attachment of Mycoplasma hyopneumoniae to porcine cilia or inhibit the growth of the attached pathogen. However, according to previous studies, it has been reported that conventional commercial vaccines cannot induce antibodies against P97 (Conceicao, et al., 2006, Okamba, et al., 2010).
흉막폐렴균의 경우, 육성 출하기에 감염되어 급성 호흡기 증상으로 인해 높은 폐사율을 나타내기 때문에, 단독 백신의 경우 주로 7~10주령에 접종한다. 흉막폐렴균은 15가지의 혈청형 (serotype)으로 분류되어 있고 혈청형 간의 교차방어 (cross protection)가 없기 때문에 각 지역 (나라)에서 유행하는 혈청형을 포함시켜 백신을 접종하여야 유행하는 혈청형에 대한 효과가 있다. 기존 흉막폐렴균 백신은 App 혈청형 2형, App 혈청형 5형만을 포함하며 최근 국내에서 유행하는 App 혈청형 1형은 포함하지 않기 때문에 최근의 변화된 현실을 반영하지 못하고 있다. 따라서 기존의 백신에 국내에서 유행하는 혈청형인 App 혈청형 1형이 포함된 백신의 개발이 고려되고 있다.In the case of pleural pneumococcus, it is infected during the growing delivery period and shows a high mortality rate due to acute respiratory symptoms. Therefore, in the case of a single vaccine, it is mainly inoculated at 7-10 weeks of age. Since pleural pneumonia is classified into 15 serotypes and there is no cross protection between serotypes, serotypes prevalent in each region (country) must be included and vaccination against prevalent serotypes. It works. Existing pleural pneumococcal vaccines contain only
각각의 흉막폐렴균은 Apx toxin이라고 하는 병원성 인자를 분비하는데, App 혈청형에 따라 분비되는 Apx toxin의 종류가 다르다. Apx toxin은 type 1부터 4까지 있고, 이에 상용화된 일부 백신에서는 Apx toxin은 대장균에서 재조합 단백질의 형태로 생산하여 포함하였으나 그 효과가 크지 못한 부분에 대해서는 이미 보고된 바 있다 ( Yan Ke-Xia, et al., 2007). 이에 Apx toxin을 재조합 단백질의 형태가 아닌 App에서 분비된 native toxin을 정제하여 사용하는 것이 고려되고 있다.Each pleural pneumococcus secretes a pathogenic factor called Apx toxin, and the types of Apx toxin secreted according to the App serotype are different. Apx toxins range from
돼지 마이코플라즈마균 및 흉막폐렴균은 각각 기침, 폐렴 등의 호흡기 증상을 유발하여 증체효과가 약 15~30% 감소될 정도로 위험성이 매우 높은 병원균이다. 전세계적으로 상용화되고 있는 돼지 마이코플라즈마 백신은 돼지 마이코플라즈마균을 사용한 불활화 백신이다. 그러나, 기존의 마이코플라즈마불활화 백신은 임상증상 완화 및 증체율 저하를 막을 수는 있지만 감염에 대한 방어를 하지 못하며, 호흡기도 내 집락 형성 및 폐병변 형성을 방어하지 못한다고 알려져 있다. 또한, 기존 국내에서 제조 및 판매되는 다가 백신은 농장에서는 실제 효과를 볼 수 없어 거의 사용되지 않는 실정이다. Porcine mycoplasma bacteria and pleural pneumonia are pathogens with high risk, which cause respiratory symptoms such as cough and pneumonia, respectively, reducing the weight gain effect by about 15 to 30%. The swine mycoplasma vaccine that is commercially available worldwide is an inactivated vaccine using swine mycoplasma bacteria. However, it is known that the existing mycoplasma inactivation vaccine can alleviate clinical symptoms and prevent decrease in body weight gain, but cannot protect against infection, and cannot protect colony formation and lung lesion formation in the respiratory tract. In addition, existing multivalent vaccines manufactured and sold in Korea are rarely used on farms because they cannot see actual effects.
따라서, 돼지 호흡기 복합증후군의 원발성 인자 및 2차 감염인자에 해당하는 돼지 마이코플라즈마균과 흉막폐렴균을 모두 방어하는 다가 백신에 대한 개발이 필요하다. Therefore, it is necessary to develop a multivalent vaccine that protects both porcine mycoplasma and pleural pneumonia, which are the primary and secondary infectious factors of porcine respiratory complex syndrome.
이에 본 발명자들은 돼지 호흡기 복합증후군 (PRDC)을 예방하는 백신을 개발하기 위하여, 이의 대표적 감염인자인 돼지 마이코플라즈마균과 돼지 흉막폐렴균을 동시에 예방할 수 있는 새로운 복합 백신을 개발하던 중, 마이코플라즈마 하이오뉴모니애 (Mycoplasma hyopneumoniae, 마이코플라즈마균, Mhp) 및 마이코플라즈마 하이오뉴모니애 부착 단백질 P97, 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, 흉막폐렴균, App) 혈청형 1형, 혈청형 2형, 혈청형 5형 및 각 흉막폐렴균에서 분비되는 독소 1, 2 및 3형(ApxI, II, III)를 정제하여 혼합한 백신이 기존의 상용 백신 대비 현저히 우수한 면역 반응을 나타내는 것을 확인하고 본 발명을 완성하였다.Accordingly, in order to develop a vaccine that prevents porcine respiratory complex syndrome (PRDC), the present inventors were developing a new combination vaccine capable of simultaneously preventing pig mycoplasma bacteria and pig pleural pneumonia, which are representative infection factors thereof, Mycoplasma hyopneumoniae. A ( Mycoplasma hyopneumoniae , Mycoplasma bacteria, Mhp) and Mycoplasma hyopneumoniae adhesion protein P97, Actinobacillosis pleuropneumoniae (Pleuropneumoniae, App)
따라서 본 발명의 목적은 (ⅰ) 돼지 마이코플라즈마 하이오뉴모니애 (Mycoplasma hyopneumoniae, Mhp) 균주, (ⅱ) 돼지 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App) 혈청형 1형, 혈청형 2형 및 혈청형 5형 균주; (ⅲ) 돼지 마이코플라즈마 하이오뉴모니애 유래 재조합 P97 단백질; 및 (ⅳ) 돼지 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App) 독소 1,2 및 3형(ApxI, Ⅱ 및 Ⅲ); 을 포함하는 돼지 마이코플라즈마균 및 흉막폐렴균에 의한 폐렴 예방을 위한 다가 백신 조성물 및 상기 다가 백신 조성물을 이용한 돼지 마이코플라즈마균 및 흉막폐렴균에 의한 폐렴 예방 방법을 제공하는 것이다. Therefore, the object of the present invention is (i) Pig Mycoplasma hyopneumoniae (Mhp) strain, (ii) Pig Actinobacillosis pleuropneumoniae (App)
상기와 같은 목적을 달성하기 위하여, 본 발명은 (ⅰ) 돼지 마이코플라즈마 하이오뉴모니애 (Mycoplasma hyopneumoniae, Mhp) 균주, (ⅱ) 돼지 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App) 혈청형 1형, 혈청형 2형 및 혈청형 5형 균주; (ⅲ) 돼지 마이코플라즈마 하이오뉴모니애 유래 재조합 P97 단백질; 및 (ⅳ) 돼지 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App) 독소 1,2 및 3형(ApxI, Ⅱ 및 Ⅲ); 을 포함하는 돼지 마이코플라즈마균 및 흉막폐렴균에 의한 폐렴 예방을 위한 다가 백신 조성물을 제공한다. In order to achieve the above object, the present invention is (i) Pig Mycoplasma High-Opneumoniae ( Mycoplasma hyopneumoniae , Mhp) strain, (ii) Actinobacillosis porcine Actinobacillosis pleuropneumoniae , App)
또한, 본 발명은 본 발명에 따른 다가 백신 조성물을 돼지에 접종하는 단계; 를 포함하는 돼지 마이코플라즈마균 및 흉막폐렴균에 의한 폐렴 예방 방법을 제공하는 것이다.In addition, the present invention comprises the steps of inoculating pigs with the multivalent vaccine composition according to the present invention; It is to provide a method for preventing pneumonia caused by porcine mycoplasma and pleural pneumococcus, including.
본 발명에 따른 다가 백신 조성물은 마이코플라즈마 하이오뉴모니애 (Mycoplasma hyopneumoniae, Mhp) 및 마이코플라즈마 하이오뉴모니애 부착 단백질 P97, 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App) 혈청형 1형, 혈청형 2형, 혈청형 5형 및 각 흉막폐렴균에서 분비되는 독소 1,2 및 3형(ApxI, Ⅱ 및 Ⅲ)을 혼합함으로써 돼지 마이코플라즈마균 및 흉막폐렴균에 의한 폐렴의 동시 예방이 가능하고, 상용 백신보다 우수한 방어 효과를 나타낼 수 있다. 나아가, 초기 방어능이 뛰어나고, 백신 접종 후 부작용이 없으며, 최근 유행하는 혈청형을 포함하고 있어 효과적으로 자돈 폐사율을 감소시킴과 동시에 만성 호흡기 증상으로 인한 개체의 증체성 저하를 막아 양돈 산업에 유용하게 사용될 수 있다.The multivalent vaccine composition according to the present invention includes Mycoplasma hyopneumoniae (Mhp) and Mycoplasma hyopneumoniae adhesion protein P97, Actinobacillosis. pleuropneumoniae , App)
도 1은 본 발명에 따른 다가 백신의 개요를 나타낸 도이다.
도 2는 Mhp IDEXX kit를 사용하여 본 발명에 따른 다가 백신 (Test vaccine)의 돼지 마이코플라즈마균 (Mycoplasma hyopneumoniae, Mhp)에 대한 면역 형성능 평가 결과를 나타낸 도이다. 대조군으로 PBS 및 상용 백신 (Commercial vaccine)을 사용하였다.
도 3은 접종 항원 (재조합 P97)을 ELISA 항원으로 사용하여 Indirect ELISA 방법으로 본 발명에 따른 다가 백신의 재조합 P97에 대한 면역 형성능 평가 결과를 나타낸 도이다.
도 4는 돼지 흉막폐렴균 (Actinobacillosis pleuropneumoniae)에 대한 면역 형성능 예비 실험 결과를 나타낸 것으로, 마우스에 App 1형 및 App 5형을 불활화하여 접종 후 얻은 혈청을 App1, 2, 5에서 분리한 OMP (Outer Membrane Protein)를 ELISA 항원으로 사용하여 Indirect ELISA 방법으로 본 발명에 따른 다가 백신의 App에 대한 면역 형성능을 확인하기 위한 예비 실험 결과를 나타낸 도이다.
도 5 내지 6은 각각 App 1형 (도 5), App 2형 (도 6)에서 분리한 OMP를 ELISA 항원으로 사용하여 Indirect ELISA 방법으로 본 발명에 따른 다가 백신의 App에 대한 면역 형성능 평가 결과를 나타낸 도이다.
도 7은 ApxII를 ELISA 항원으로 사용하여 Indirect ELISA 방법으로 본 발명에 따른 다가 백신의 재조합 Apx 독소에 대한 면역 형성능 평가 결과를 나타낸 도이다.
도 8은 본 발명에 따른 다가 백신 접종에 따른 부작용을 확인하기 위하여 백신 접종 후 돼지의 체중 변화를 측정한 결과를 나타낸 도이다.
도 9는 본 발명에 따른 다가 백신 접종에 따른 부작용을 확인하기 위하여 백신 접종 후 돼지의 체온 변화를 측정한 결과를 나타낸 도이다.
도 10은 흉막폐렴균 공격접종에 대한 본 발명에 따른 다가 백신의 방어능을 평가한 결과를 나타낸 도이다.
도 11 내지 16은 공격접종 수행군 (도 11 내지 14) 및 공격접종 비수행군 (도 15 및 도 16)간의 폐 병변 발생 정도를 비교한 결과를 나타낸 도이다. 1 is a diagram showing an overview of a multivalent vaccine according to the present invention.
Figure 2 is a pig Mycoplasma (Mycoplasma) of the multivalent vaccine (Test vaccine) according to the present invention using the Mhp IDEXX kit hyopneumoniae , Mhp) is a diagram showing the results of the evaluation of immune formation ability. As a control, PBS and a commercial vaccine were used.
3 is a diagram showing the results of evaluating the immunity-forming ability of the multivalent vaccine according to the present invention against recombinant P97 by an Indirect ELISA method using an inoculation antigen (recombinant P97) as an ELISA antigen.
Figure 4 is a pig pleural pneumonia ( Actinobacillosis pleuropneumoniae ) shows the results of preliminary immunity-forming ability for mice. Serum obtained after inoculation by inactivating
5 to 6 show the results of evaluating the immunity formation ability of the App of the multivalent vaccine according to the present invention by the Indirect ELISA method using OMP isolated from
7 is a diagram showing the results of evaluating the ability to form immunity against the recombinant Apx toxin of the multivalent vaccine according to the present invention by an Indirect ELISA method using ApxII as an ELISA antigen.
Figure 8 is a diagram showing the result of measuring the weight change of the pig after vaccination in order to check the side effects of the multivalent vaccination according to the present invention.
9 is a diagram showing the results of measuring changes in body temperature of pigs after vaccination in order to check the side effects of the multivalent vaccination according to the present invention.
10 is a diagram showing the results of evaluating the protective ability of the multivalent vaccine according to the present invention against pleural pneumococcal challenge vaccination.
11 to 16 are diagrams showing the results of comparing the degree of occurrence of lung lesions between the challenge vaccination group (FIGS. 11 to 14) and the challenge vaccination group (FIGS. 15 and 16).
이하, 본 발명을 상세히 설명한다. Hereinafter, the present invention will be described in detail.
본 발명은 (ⅰ) 돼지 마이코플라즈마 하이오뉴모니애 (Mycoplasma hyopneumoniae, Mhp) 균주, (ⅱ) 돼지 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App) 혈청형 1형, 혈청형 2형 및 혈청형 5형 균주; (ⅲ) 돼지 마이코플라즈마 하이오뉴모니애 유래 재조합 P97 단백질; 및 (ⅳ) 돼지 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App) 독소 1,2 및 3형(ApxI, Ⅱ 및 Ⅲ); 을 포함하는 돼지 마이코플라즈마균 및 흉막폐렴균에 의한 폐렴 예방을 위한 다가 백신 조성물을 제공한다.The present invention is (i) pig Mycoplasma hyopneumoniae (Mhp) strain, (ii) pig Actinobacillosis pleuropneumoniae (App)
본 명세서에서 용어 “돼지 마이코플라즈마균”은 “Mhp”, “돼지 마이코플라즈마 하이오뉴모니애” 또는 “마이코플라즈마 하이오뉴모니애”와 혼용되어 사용되며, 용어 “돼지 흉막폐렴균”은 “App”, “돼지 액티노바실러스 플레로뉴모니애” 또는 “액티노바실러스 플레로뉴모니애”와 혼용되어 사용된다.In the present specification, the term “swine mycoplasma bacteria” is used interchangeably with “Mhp”, “swine mycoplasma hyopneumoniae” or “mycoplasma hyopneumoniae”, and the term “swine pleural pneumonia” is “App”, It is used interchangeably with "Swine Actinobacillus pleronneumoniae" or "Actinovacillus pleronneumoniae".
본 발명에 따른 다가 백신 돼지 마이코플라즈마성 폐렴과 흉막페렴 을 예방하기 위하여 돼지 마이코플라즈마 하이오뉴모니애와 돼지 마이코플라즈마 하이오뉴모니애의 초기감염에 중요한 부착인자 (adhesin)로 알려진 재조합 단백질 P97을 포함하며, 동시에 돼지흉막폐렴을 예방하기 위하여 돼지 흉막폐렴균의 국내 유행 혈청형인 돼지 액티노바실러스 플레로뉴모니애 혈청형 1형, 혈청형 2형, 혈청형 5형 균주 (whole bacterin)와 이들 균주에서 분비되는 독소 1,2 및 3형(ApxI, Ⅱ 및 Ⅲ)을 정제하여 혼합한 백신인 것을 특징으로 한다.In order to prevent pig mycoplasma pneumonia and pleural pneumonia according to the present invention, the multivalent vaccine according to the present invention comprises a recombinant protein P97 known as an important adhesion factor (adhesin) for early infection of pig mycoplasma hyopneumoniae and pig mycoplasma hyopneumoniae, and , At the same time, to prevent swine pleural pneumonia, pig Actinobacillus pleuropneumoniae
본 발명에 있어서, 백신에 포함되는 재조합 단백질 P97은 돼지 마이코플라즈마 하이오뉴모니애 유래 P97 단백질과 E. coli heat-labile enterotoxin subunit B 유전자 (eltb)를 융합하여 제조될 수 있다. 보다 구체적으로, E. coli 의 eltb와 마이코플라즈마 하이오뉴모니애 P97 유전자의 C-말단 반복 서열인 R1과 R1R2를 융합시키고, LTB와 융합된 P97 유전자인 ltbR1과 ltbR1R2를 중합효소연쇄반응(PCR)에 의해 증폭하여 제조될 수 있다. 상기 재조합 단백질 P97은 하기 서열번호 1로 표시되는 아미노산 서열로 이루어진 것을 특징으로 할 수 있다.In the present invention, the recombinant protein P97 contained in the vaccine is a P97 protein derived from porcine mycoplasma hyopneumoniae and E. coli. It can be prepared by fusing the heat-labile enterotoxin subunit B gene (eltb). More specifically, E. coli It can be prepared by fusing the C-terminal repeat sequences of R1 and R1R2 of the eltb of the mycoplasma hyopneumoniae P97 gene, and amplifying ltbR1 and ltbR1R2, the P97 genes fused with LTB, by polymerase chain reaction (PCR). have. The recombinant protein P97 may be characterized by consisting of an amino acid sequence represented by SEQ ID NO: 1.
MHHHHHHSSGLVPRGSGMKETAAAKFERQHMDSPDLGTDDDDKAMADIGSEFAPQTITELCSEYRNTQIYTINDKILSYTESMAGKREMVIITFKSGATFQVEVPGSQHIDSQKKAIERMKDTLRIAYLTETKIDKLCVWNNKTPNSIAAISLEGIPTKEGKREEVDKKVKELDNKIKGILPQPPAAKPEAAKPVAAKPEAAKPVAAKPEAAKPEAAKPVAAKPEAAKPVAAKPEAAKPVATNEGTPNQGKKAEGAPNQGKKAEGAPSQGKKAEGASNQQSPTTELTNYLPELGKKIDEIIKKQGKNWKTEVELIEDNIAGDAKLLYFVLRDDSKSGDPKKSSLKVKITVKQSNNNQELKSKQACGRTRAPPPPPLRSGC (서열번호 1)MHHHHHHSSGLVPRGSGMKETAAAKFERQHMDSPDLGTDDDDKAMADIGSEFAPQTITELCSEYRNTQIYTINDKILSYTESMAGKREMVIITFKSGATFQVEVPGSQHIDSQKKAIERMKDTLRIAYLTETKIDKLCVWNNKTPNSIAAISLEGIPTKEGKREEVDKKVKELDNKIKGILPQPPAAKPEAAKPVAAKPEAAKPVAAKPEAAKPEAAKPVAAKPEAAKPVAAKPEAAKPVATNEGTPNQGKKAEGAPNQGKKAEGAPSQGKKAEGASNQQSPTTELTNYLPELGKKIDEIIKKQGKNWKTEVELIEDNIAGDAKLLYFVLRDDSKSGDPKKSSLKVKITVKQSNNNQELKSKQACGRTRAPPPPPLRSGC (SEQ ID NO: 1)
본 발명의 재조합 단백질 P97은 서열번호 1의 아미노산 서열과 적어도 70%, 80%, 90%, 95%, 98% 또한 바람직하게는 적어도 99%의 상동성을 가지는 폴리펩타이드를 모두 포함할 수 있다. "상동성 (homology)"은 단백질 또는 폴리뉴클레오티드 서열들 간 유사도의 측정을 의미한다. 이들 폴리펩타이드는 서열번호 1의 아미노산 서열과 비교하여 적어도 하나의 아미노산의 결실, 부가 또는 치환을 가질 수 있다. 점수로 매겨진 두 가지 서열들 간 상동성의 정도는 일치도의 퍼센트 (percentage of identities) 및/또는 서열의 치환을 보존하는 것에 근거한다.The recombinant protein P97 of the present invention may include all of the polypeptides having homology of at least 70%, 80%, 90%, 95%, 98% and preferably at least 99% with the amino acid sequence of SEQ ID NO: 1. “Homology” refers to the measurement of similarity between protein or polynucleotide sequences. These polypeptides may have deletions, additions or substitutions of at least one amino acid compared to the amino acid sequence of SEQ ID NO: 1. The degree of homology between the two scoring sequences is based on the percentage of identities and/or preserving substitutions of the sequences.
본 발명의 재조합 단백질들은 백신의 제조에 사용되는 경우, 정제된 단백질 형태로 백신에 첨가되거나 대장균에서 발현하여 정제되지 않은 상태인 용균액 상태로 포함될 수 있다.When the recombinant proteins of the present invention are used in the manufacture of a vaccine, they may be added to the vaccine in the form of a purified protein, or expressed in E. coli and included in an unpurified lysate state.
본 발명에 있어서, 상기 재조합 단백질 P97을 암호화하는 폴리뉴클레오티드는 서열번호 2로 표시되는 염기서열로 이루어지거나 서열번호 2의 염기서열과 적어도 70%, 80%, 90%, 95%, 98% 또한 바람직하게는 적어도 99%의 상동성을 가지는 폴리뉴클레오티드로, 서열번호 2의 생물학적 활성을 유지할 수 있는 모든 폴리뉴클레오티드를 포함할 수 있다. In the present invention, the polynucleotide encoding the recombinant protein P97 consists of the nucleotide sequence represented by SEQ ID NO: 2, or at least 70%, 80%, 90%, 95%, 98% and the base sequence of SEQ ID NO: 2 are also preferred. Preferably, it is a polynucleotide having at least 99% homology, and may include all polynucleotides capable of maintaining the biological activity of SEQ ID NO: 2.
본 발명에 따른 다가 백신 조성물에 포함되는 마이코플라즈마 하이오뉴모니애 균주 및 돼지 액티노바실러스 플레로뉴모니애 균주는 불활화 된 것을 특징으로 할 수 있으며, 불활화는 당 분야에 공지된 방법을 제한 없이 사용할 수 있다.The Mycoplasma hyopneumoniae strain and the pig Actinobacillus pleuropneumoniae strain contained in the multivalent vaccine composition according to the present invention may be characterized as being inactivated, and the inactivation limits methods known in the art. Can be used without.
본 발명의 일 실시예에서, 마이코플라즈마는 Binary ethyleneimine (BEI)과 같은 불활화 시약을 사용하여 불활화 후 중화시약인 sodium thiosulfate (SigmaAldrich, St. Louis, MO, USA)를 넣어 중화시켰다. 이후, 불활화된 배양액 일부를 새 배지에 첨가하여 37℃에서 배양하였으며, 적어도 일주일 이상 배양하여 불활화가 잘 되었는지 확인하였다. 흉막폐렴균의 경우, 포르말린을 사용하여 불활화시켰으며, 불활화된 배양액은 여과(filtration)나 원심분리법으로 농축하여 사용하였다.In an embodiment of the present invention, mycoplasma was neutralized by adding sodium thiosulfate (SigmaAldrich, St. Louis, MO, USA) as a neutralizing reagent after inactivation using an inactivation reagent such as Binary ethyleneimine (BEI). Thereafter, a part of the inactivated culture medium was added to a new medium and cultured at 37° C., and cultured for at least one week to confirm whether inactivation was well performed. In the case of pleural pneumonia, formalin was used to inactivate, and the inactivated culture was concentrated by filtration or centrifugation.
본 발명에 따른 다가 백신 조성물의 마이코플라즈마 하이오뉴모니애는 5.0x106 내지 5.0x1010 CCU (Colour-changing units)/ml의 농도로 백신에 포함될 수 있으며, 바람직하게는 5.0x107 내지 5.0x109 CCU/ml, 더욱 바람직하게는 2.5x108 내지 7.5x108 CCU/ml의 농도로 포함될 수 있다. 이 때, 백신 접종량은 2ml이다. 또한, 본 발명에 따른 다가 백신 조성물의 액티노바실러스 플레로뉴모니애 혈청형 1형, 혈청형 2형, 혈청형 5형 균주는 각각 1.0x108 내지 1.0x1011 CFU (Colony-forming units)/ml의 농도로 백신에 포함될 수 있으며, 바람직하게는 1.0x108 내지 5.0x1010 CFU/ml, 더욱 바람직하게는 1.0x109 내지 5.0x109 CFU/ml 의 농도로 포함될 수 있다. 이 때, 백신 접종량은 2ml이다.Mycoplasma hyopneumoniae of the multivalent vaccine composition according to the present invention may be included in the vaccine at a concentration of 5.0x10 6 to 5.0x10 10 CCU (Colour-changing units)/ml, preferably 5.0x10 7 to 5.0x10 9 It may be contained in a concentration of CCU/ml, more preferably 2.5x10 8 to 7.5x10 8 CCU/ml. At this time, the vaccination amount is 2ml. In addition,
본 발명에 따른 다가 백신 조성물은 돼지 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App)의 독소 1,2 및3형을 포함하는 것을 특징으로 한다.The multivalent vaccine composition according to the present invention is characterized by comprising the
상기 ApxI, Ⅱ 및 Ⅲ는 액티노바실러스 플레로뉴모니애 혈청형 1형, 혈청형 2형 및 혈청형 5형 각각에서 분비를 유도하여 얻은 독소로, 본 발명의 일 실시예에서는 상기 각 독소를 정제하여 본 발명에 따른 다가 백신 조성물에 혼합하여 사용하고 있다. 상기 ApxI, Ⅱ 및 Ⅲ는 액티노바실러스 플레로뉴모니애의 중요 병원성 인자로, 다가 백신 접종에 따른 생존율과 증체율 증가에 핵심적 역할을 수행함을 특징으로 한다.The ApxI, Ⅱ, and Ⅲ are toxins obtained by inducing secretion from each of
본 발명에 따른 다가 백신 조성물의 ApxI, Ⅱ 및 Ⅲ는 1 내지 100 ug/ml의 용량으로 백신에 포함될 수 있으며, 바람직하게는 5 내지 50 ug/ml, 더욱 바람직하게는 10 내지 30 ug/ml의 용량으로 포함될 수 있다.ApxI, II and III of the multivalent vaccine composition according to the present invention may be included in the vaccine at a dose of 1 to 100 ug/ml, preferably 5 to 50 ug/ml, more preferably 10 to 30 ug/ml. Can be included as a dose.
본 발명의 다가 백신 조성물은 상기 백신의 면역원성을 증진시켜 최소한의 투여로도 보호 면역을 유도할 수 있는 면역강화제로서, 보조제 혼합물 및 하나 이상의 약제학적 또는 수의학적으로 허용되는 담체, 부형제 또는 희석제를 포함할 수 있다. 상기 “약제학적 또는 수의학적으로 허용되는” 이란 생리학적으로 허용되고 동물에게 투여될 때, 통상적으로 위장장애, 현기증과 같은 알레르기 반응 또는 이와 유사한 반응을 일으키지 않는 조성물을 말한다. 상기 담체, 부형제 및 희석제의 예로는, 락토즈, 덱스트로즈, 수크로즈, 솔비톨, 만니톨, 자일리톨, 에리스리톨, 말티톨, 전분, 아카시아 고무, 알지네이트, 젤라틴, 칼슘 포스페이트, 칼슘 실리케이트, 셀룰로즈, 메틸 셀룰로즈, 폴리비닐피롤리돈, 물, 메틸하이드록시벤조에이트, 프로필하이드록시벤조에이트, 탈크, 마그네슘 스테아레이트 및 광물유를 들 수 있다. 또한, 충진제, 항응집제, 윤활제, 습윤제, 향료, 유화제 및 방부제 등을 추가로 포함할 수 있다. 사용하기에 적합한 담체로는 식염수, 인산염 완충 식염수, 최소 필수 배지 (MEM) 또는 HEPES 완충액의 MEM을 포함하는 수성 매질을 들 수 있으나, 이에 제한되는 것은 아니다. 본 발명의 일 실시예에서는 안전성 및 면역지속성을 고려하여 IMS 계열 부형제인 IMS1313을 사용하였다.The multivalent vaccine composition of the present invention is an immunity enhancing agent capable of inducing protective immunity with minimal administration by enhancing the immunogenicity of the vaccine. A mixture of adjuvants and one or more pharmaceutically or veterinarily acceptable carriers, excipients, or diluents are used. Can include. The term "pharmaceutically or veterinary acceptable" refers to a composition that is physiologically acceptable and does not usually cause an allergic reaction such as gastrointestinal disorder or dizziness or a similar reaction when administered to an animal. Examples of the carrier, excipient and diluent include lactose, dextrose, sucrose, sorbitol, mannitol, xylitol, erythritol, maltitol, starch, gum acacia, alginate, gelatin, calcium phosphate, calcium silicate, cellulose, methyl cellulose, Polyvinylpyrrolidone, water, methylhydroxybenzoate, propylhydroxybenzoate, talc, magnesium stearate, and mineral oils. In addition, fillers, anti-aggregating agents, lubricants, wetting agents, flavoring agents, emulsifying agents, and preservatives may additionally be included. Suitable carriers for use include, but are not limited to, saline, phosphate buffered saline, minimal essential medium (MEM), or an aqueous medium including MEM in HEPES buffer. In one embodiment of the present invention, IMS1313, an IMS-based excipient, was used in consideration of safety and immune persistence.
또한, 본 발명의 다가 백신 조성물은 포유동물에 투여된 후 활성 성분의 신속, 지속 또는 지연된 방출을 제공할 수 있도록 당업계에 공지된 방법을 사용하여 제형화될 수 있다. 제형은 분말, 과립, 정제, 에멀젼, 시럽, 에어로졸, 연질 또는 경질 젤라틴 캅셀, 멸균 주사용액, 멸균 분말 등의 형태일 수 있다. 본 발명의 다가 백신 조성물은 근육, 피하, 경피, 정맥, 비강내, 복강내 또는 경구 경로로 투여될 수 있고 바람직하게는 근육내 또는 피하 경로로 투여될 수 있다. 백신의 투여량은 투여 경로, 동물의 연령, 성별, 체중 및 중증도 등의 여러 인자에 따라 적절히 선택될 수 있다. In addition, the multivalent vaccine composition of the present invention may be formulated using methods known in the art to provide rapid, sustained or delayed release of the active ingredient after administration to a mammal. The formulation may be in the form of powder, granule, tablet, emulsion, syrup, aerosol, soft or hard gelatin capsule, sterile injectable solution, sterile powder, and the like. The multivalent vaccine composition of the present invention may be administered by intramuscular, subcutaneous, transdermal, intravenous, intranasal, intraperitoneal or oral route, preferably intramuscular or subcutaneous route. The dosage of the vaccine may be appropriately selected according to various factors such as the route of administration, the age, sex, weight and severity of the animal.
또한, 본 발명의 다가 백신 조성물은 재조합 단백질 P97의 제조와 같이 본 발명에 특이적인 방법을 제외하고는 당해 기술 분야의 표준 방법에 의해 제조될 수 있다. 가령, 유기체는 완전 배지와 같은 배양 배지에서 증식시킬 수 있고, 유기체의 증식은 색 변화 단위 (CCU)를 측정하는 것과 같은 표준 기술로 모니터하고 충분히 높은 역가가 성취된 네 경우 수거될 수 있다. 스톡은 제형화를 위해 백신에 포함되기 전에 통상적인 방법에 의해 추가로 농축되거나 동결건조시킬 수 있다.In addition, the multivalent vaccine composition of the present invention can be prepared by standard methods in the art, except for methods specific to the present invention, such as the production of recombinant protein P97. For example, organisms can be grown in a culture medium such as complete media, and the growth of organisms can be monitored with standard techniques such as measuring color change units (CCU) and collected in four cases where a sufficiently high titer has been achieved. The stock can be further concentrated or lyophilized by conventional methods before being included in a vaccine for formulation.
본 발명에 따른 다가 백신 조성물은 돼지 마이코플라즈마 백신과 돼지 흉막폐렴 백신을 혼합함으로써 돼지 호흡기 복합 증후군의 원발성 인자 및 2차 감염인자를 모두 방어하여 기존 상용 백신보다 더욱 효과적인 면역 반응을 유도할 수 있고, 육성후반기의 호흡기전염병 예방 및 증체 저하 방지에 효율적이다. 본 발명의 일 실시예에서는, 기존 상용백신을 사용하여 본 발명에 따른 다가 백신과의 방어능을 비교한 결과, 다가 백신 투여군의 폐병변 발생율이 대조군 및 상용백신군보다 큰 수치로 개선됨을 확인하였다. The multivalent vaccine composition according to the present invention can induce a more effective immune response than conventional commercial vaccines by mixing a pig mycoplasma vaccine and a pig pleural pneumonia vaccine to protect both the primary factor and the secondary infectious factor of the pig respiratory complex syndrome. It is effective in preventing respiratory infectious diseases in the second half and reducing weight gain. In one embodiment of the present invention, as a result of comparing the protective ability with the multivalent vaccine according to the present invention using an existing commercial vaccine, it was confirmed that the incidence of lung lesions in the multivalent vaccine-administered group was improved to a higher value than that of the control group and the commercial vaccine group. .
또한 본 발명은 본 발명에 따른 다가 백신을 돼지에 접종하는 단계; 를 포함하는 돼지 마이코플라즈마균 및 흉막폐렴균에 의한 폐렴 예방 방법을 제공한다. In addition, the present invention comprises the steps of inoculating pigs with the multivalent vaccine according to the present invention; It provides a method for preventing pneumonia caused by porcine mycoplasma and pleural pneumococcus, including.
상기 돼지는 마이코플라즈마 및/또는 흉막폐렴균에 감염될 가능성이 있는 개체를 제한 없이 포함할 수 있으며, 이와 같은 감염 예방 방법은 다른 당 분야에 공지된 치료 방법 또는 예방 방법과 함께 병행하여 이용할 수 있다. 본 발명에서 사용되는 용어 "접종"은 임의의 적절한 방법으로 개체에게 소정의 본 발명의 조성물을 제공하는 것을 의미한다.The pig may include, without limitation, an individual who may be infected with mycoplasma and/or pleural pneumonia, and such a method for preventing infection may be used in combination with treatment methods or prevention methods known in the art. As used herein, the term "inoculation" means providing a given composition of the present invention to an individual by any suitable method.
본 발명에 따른 다가 백신 조성물은 1~5주령에 1차, 4~7주령에 2차 접종을 실시할 수 있다. The multivalent vaccine composition according to the present invention can be given a primary inoculation at 1-5 weeks of age and a secondary inoculation at 4-7 weeks of age.
이하, 본 발명을 실시예에 의하여 더욱 상세하게 설명한다. 단, 하기 실시예들은 본 발명을 더욱 쉽게 이해할 수 있도록 예시하는 것으로 본 발명의 내용이 실시예에 의해 한정되는 것은 아니다.Hereinafter, the present invention will be described in more detail by examples. However, the following examples are illustrative to make the present invention easier to understand, and the contents of the present invention are not limited by the examples.
실시예 1. 본 발명에 따른 다가 백신의 개발Example 1. Development of a multivalent vaccine according to the present invention
1-1. 마이코플라즈마 하이오뉴모니애 불활화 균주의 준비1-1. Preparation of Mycoplasma hyopneumoniae inactivated strain
마이코플라즈마 하이오뉴모니애 (Mycoplasma hyopneumoniae, Mhp) 균주를 국내의 양돈농가에서 분리하였으며, 단백질 패턴 분석을 통하여 분리된 균주 중 분리주인 Mhp HID3117과 HID3138을 Friis 배지를 사용하여 37℃의 조건에서 배양하였다. 배양된 균액은 pH 를 약 7.8까지 높인 후 Binary ethyleneimine (BEI) (U.S. Pat. No. 5,565,205)와 같은 불활화 시약을 이용하여 균의 불활화를 진행하였다. BEI는 배양액에 2-bromoethylaminehydrobromide (BEA)(SigmaAldrich, St. Louis, MO, USA)를 첨가하여 제조하였으며, 그 뒤, BEI는 중화시약인 sodium thiosulfate (SigmaAldrich, St. Louis, MO, USA)를 넣어 중화시켰다. 불활화된 배양액 일부를 새 배지에 첨가하여 37℃에서 배양하였으며, 적어도 일주일 이상 배양하여 불활화가 잘 되었는지 확인하였다. 불활화된 배양액은 여과 (filtration)나 원심분리법으로 농축하였다. Mycoplasma Hi-Onewmoniae ( Mycoplasma hyopneumoniae , Mhp) strains were isolated from domestic pig farms, and the isolates Mhp HID3117 and HID3138, which were isolated through protein pattern analysis, were cultured at 37℃ using Friis medium. After raising the pH of the cultured bacteria solution to about 7.8, the bacteria were inactivated using an inactivation reagent such as Binary ethyleneimine (BEI) (US Pat. No. 5,565,205). BEI was prepared by adding 2-bromoethylaminehydrobromide (BEA) (SigmaAldrich, St. Louis, MO, USA) to the culture medium, and then BEI was prepared by adding sodium thiosulfate (SigmaAldrich, St. Louis, MO, USA), a neutralizing reagent, to the culture medium. Neutralized. Part of the inactivated culture medium was added to a new medium and cultured at 37° C., and cultured for at least one week to confirm whether the inactivation was well performed. The inactivated culture solution was concentrated by filtration or centrifugation.
1-2. 액티노바실러스 플레로뉴모니애 불활화 균주의 준비1-2. Preparation of Actinobacillus pleuropneumoniae inactivated strain
액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App) 혈청형 1형, 혈청형 2형 및 혈청형 5형 균주 균주를 국내의 양돈농가에서 분리하였으며, PCR 분석을 통하여 확인하였고, 분리된 균주 중 분리주인 App 혈청형 1형 HID7501, App 혈청형 2형 HID7509, App 혈청형 5형 HID7521을 Columbia broth에서 8시간 배양 후 4℃ 16,000Xg에서 30분간 원심분리하여 균을 회수하고 PBS에 다시 부유시켰다. 포르말린을 2% 농도로 처리하여 4시간 동안 불활화 후 5,000Xg으로 원심분리하여 불활화된 bacterin을 회수하고 PBS로 세척하는 과정을 3회 반복하였다. 불활화된 배양액의 일부를 TSB.NAD 배지에서 배양하여 불활화가 잘 되었는지 확인하였다. Actinobacillosis pleuropneumoniae , App)
1-3. 본 발명에 따른 다가 백신의 조성1-3. The composition of the multivalent vaccine according to the present invention
마이코플라즈마 하이오뉴모니애 (Mycoplasma hyopneumoniae, 마이코플라즈마균, 이하 Mhp)와 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, 흉막폐렴균, 이하 App) 1, 2, 5형에 대한 불활화 백신을 개발하였다. 구체적으로, 상기 실시예 1-1 및 1-2에서 준비한 마이코플라즈마 하이오뉴모니애 및 액티노바실러스 플레로뉴모니애 불활화 균주에 더하여, Mhp의 초기감염에 중요한 부착인자 (adhesin)로 알려진 재조합 단백질인 P97 (서열번호 1)과 흉막폐렴균에서 분비되는 독소인 독소 1,2 및 3형(ApxI, Ⅱ 및 Ⅲ)을 정제하여 혼합하였다. 본 발명에 따른 다가 백신의 구체적인 조성은 하기와 같다.Mycoplasma Hi-Onewmoniae ( Mycoplasma hyopneumoniae , Mycoplasma bacteria, hereinafter Mhp) and Actinobacillosis pleuropneumoniae (Pleural pneumonia, hereinafter App) 1, 2, 5 inactivated vaccines were developed. Specifically, in addition to the Mycoplasma hyopneumoniae and Actinobacillus pleuropneumoniae inactivated strains prepared in Examples 1-1 and 1-2, recombinant known as an important adhesion factor (adhesin) for early infection of Mhp Protein P97 (SEQ ID NO: 1) and
유래 재조합 단백질 P97Myco Plasma High-O-Nu-Monia
Derived recombinant protein P97
(IMS1313을 제외한 백신 조성물 1ml:IMS1313 1ml)1:1 ratio with vaccine composition excluding IMS1313
(1 ml of vaccine composition excluding IMS1313: 1 ml of IMS1313)
실시예Example 2. 본 발명에 따른 다가 백신 효과의 검증 (면역 2. Verification of the effect of the multivalent vaccine according to the present invention (immune 형성능Formation ability 평가) evaluation)
2-1. 실험 설계2-1. Experimental Design
상기 실시예 1-3에서 제조한 개발백신의 면역원성을 측정하기 위해 약 15~18일령의 마이코플라즈마 하이오뉴모니애 음성 자돈을 확보하였다. 모든 자돈은 온/습도가 관리되는 환경에서 4~5마리씩 분리 사육하였고, 약 5~7일간 순화시켰다. 임상실험은 표 2와 같이 개발백신군 (Group 1), 상용백신군 (Group 2) 및 대조군 (Group 3)으로 그룹을 나누어 수행하였고, 상용백신으로는 돼지 마이코플라즈마, 흉막폐렴 예방 혼합백신인 상용백신을 사용하고, 대조군에는 동량의 PBS를 투여하였다. 백신 접종 및 채혈 일정은 표 3과 같다. 실험 시작 7주 후 안락사하여 폐를 분리하고, 흉막폐렴균에 의한 폐병변 정도를 분석하였다. 모든 실험은 강원대학교 실험동물윤리위원회의 승인 하에 진행하였다 (KW-180611-2).In order to measure the immunogenicity of the developed vaccine prepared in Example 1-3, Mycoplasma hyopneumoniae negative piglets of about 15 to 18 days old were obtained. All piglets were reared separately from 4 to 5 pigs in a temperature/humidity controlled environment and allowed to acclimatize for about 5 to 7 days. As shown in Table 2, the clinical trial was carried out by dividing the group into a developed vaccine group (Group 1), a commercial vaccine group (Group 2), and a control group (Group 3), and as a commercial vaccine, a combination vaccine for preventing pig mycoplasma and pleural pneumonia was carried out. A vaccine was used, and the same amount of PBS was administered to the control group. The vaccination and blood collection schedule are shown in Table 3. The lungs were separated by
개체수Population
(각 10(10 each
55
CFU) CFU)
(CCU)(CCU)
(CFU)(CFU)
(ug)(ug)
2-2. 2-2. Mhp에Mhp 대한 면역 Against immunity 형성능Formation ability 평가 evaluation
상기 실시예 2-1의 실험모델에 대하여 Mhp IDEXX kit를 사용하여 Mhp (Mycoplasma hyopneumoniae)에 대한 면역 형성능 실험을 수행하였다. PBS, 상용백신, 개발백신 (본 발명에 따른 다가 백신) 접종 후 Mhp에 대한 항체가를 흡광도로 측정하였다. 그 결과를 도 2에 나타내었다.For the experimental model of Example 2-1, an immune-forming ability test for Mhp (Mycoplasma hyopneumoniae) was performed using the Mhp IDEXX kit. After inoculation of PBS, commercial vaccine, and development vaccine (multivalent vaccine according to the present invention), the antibody titer against Mhp was measured by absorbance. The results are shown in FIG. 2.
도 2에 나타낸 바와 같이, 접종 4주차부터 개발백신군에서 대조군과 상용백신군에 비하여 유의한 수준으로 항체가 높게 형성되었고, 2차 접종 후 개발백신군에서 월등한 수준으로 항체가 형성됨을 확인하였다.As shown in FIG. 2, it was confirmed that the antibody was formed at a significantly higher level in the development vaccine group than in the control group and the commercial vaccine group from the 4th week of inoculation, and the antibody was formed at a superior level in the development vaccine group after the second inoculation. .
2-3. 재조합 단백질 P97에 대한 면역 형성능 평가2-3. Evaluation of immune-forming ability against recombinant protein P97
P97은 Mhp의 부착단백질로 Mhp 초기 감염에 중요하게 작용한다. 상기 실시예 2-1의 실험모델에서 각 시기별로 샘플을 채취한 후, 접종 항원 (재조합 P97)을 ELISA 항원으로 사용하여 Indirect ELISA 방법으로 재조합 단백질 P97에 대한 면역 형성능 실험을 수행하였다. 그 결과를 도 3에 나타내었다.P97 is an adhesion protein of Mhp and plays an important role in early infection of Mhp. In the experimental model of Example 2-1, samples were collected at each time period, and then an inoculation antigen (recombinant P97) was used as an ELISA antigen to perform an immune-forming ability test for the recombinant protein P97 by the Indirect ELISA method. The results are shown in FIG. 3.
도 3에 나타낸 바와 같이, 대조군과 상용백신군은 P97을 포함하지 않아 항체가 형성되지 않았으나 개발백신군은 높은 수준으로 항체가 형성됨을 확인하였다. As shown in Figure 3, the control group and the commercial vaccine group did not contain P97 antibody was not formed, but it was confirmed that the antibody was formed at a high level in the development vaccine group.
2-4. App에 대한 면역 형성능 평가2-4. Evaluation of immunity-forming ability for App
App에 대한 면역 형성능 평가의 본실험에 앞서, ELISA를 위한 최적 항원 선정을 위해 다음과 같은 예비실험을 수행하였다. 선행문헌 (미국등록특허 US 6,656,477 B1)을 통하여 App 전체 박테린을 항원으로 사용한 것보다 OMP를 항원으로 사용하는 것이 예민도가 높음을 확인하고, OMP를 항원으로 하여 하기 표 4와 같은 실험군으로 예비시험을 수행하였다. 구체적으로, App1, 2, 5형에서 각각 분리한 OMP를 ELISA 항원으로 사용하여 Indirect ELISA 방법으로 재조합 App 항원에 대한 면역 형성능 실험을 수행하였다. 그 결과를 도 4에 나타내었다.Prior to the main experiment of evaluating the ability to form immunity for App, the following preliminary experiment was performed to select the optimal antigen for ELISA. Through prior literature (US Patent US 6,656,477 B1), it was confirmed that the sensitivity of using OMP as an antigen was higher than that of using the entire App bacterin as an antigen, and a preliminary test in the experimental group shown in Table 4 below using OMP as an antigen. Was performed. Specifically, the OMP isolated from App1, 2, and 5 types was used as an ELISA antigen, and an immunogenic ability test for the recombinant App antigen was performed by the Indirect ELISA method. The results are shown in FIG. 4.
도 4에 나타낸 바와 같이, App를 접종한 마우스의 혈청에서 대조군에 비하여 높은 수준으로 항체가 형성되었다. 그러나 App 혈청형에 관계없이 분리된 모든 OMP에서 App5는 동일한 수준의 항체를 보임을 확인하였다. 상기 결과를 바탕으로, App 검출을 위하여 App1 OMP, App2 OMP를 사용하여 돼지 혈청에서 App에 대한 항체를 측정하기로 결정하고 본실험을 수행하였다.As shown in Fig. 4, antibodies were formed at a higher level than in the control group in the serum of the mice inoculated with App. However, it was confirmed that App5 showed the same level of antibodies in all isolated OMPs regardless of App serotype. Based on the above results, it was decided to measure the antibody against App in pig serum using App1 OMP and App2 OMP for App detection, and this experiment was performed.
본실험은 상기 실시예 2-1의 실험모델에서 각 시기별로 샘플을 채취한 후, App1, 2형에서 분리한 OMP를 ELISA 항원으로 사용하여 Indirect ELISA 방법으로 재조합 App 항원에 대한 면역 형성능 실험을 수행하였다. 그 결과를 도 5 및 도 6에 나타내었다.In this experiment, samples were collected at each time in the experimental model of Example 2-1, and then the OMP isolated from App1 and
도 5 및 도 6에 나타낸 바와 같이, App1, 2형에서 분리한 OMP를 ELISA 항원으로 사용한 두 경우 모두에서, 개발백신군 투여 시 대조군, 상용백신군과 비교하여 6주차 (2차 접종 2주 후)부터 높은 수준으로 App 항체가 형성됨을 확인하였다. 한편, 실험 시작 6주차에 App1, 2, 5형을 혼합하여 공격접종을 수행하였는바, 7주차 실험 결과 대조군에서 공격접종에 의해 항체가가 증가한 것을 확인할 수 있다.5 and 6, in both cases where the OMP isolated from App1 and
2-5. App 독소에 대한 면역 형성능 평가2-5. Evaluation of immunity-forming ability against App toxin
상기 실시예 2-1의 실험모델에서 각 시기별로 샘플을 분리한 후, ApxII를 ELISA항원으로 사용하여 Indirect ELISA 방법으로 Apx 독소에 대한 면역 형성능 실험을 수행하였다. 그 결과를 도 7에 나타내었다.After separating samples for each period in the experimental model of Example 2-1, an immunogenic ability test against Apx toxin was performed by an Indirect ELISA method using ApxII as an ELISA antigen. The results are shown in FIG. 7.
도 7에 나타낸 바와 같이, 개발백신군에서 대조군, 상용백신군과 비교하여 6주차 (2차 접종 2주 후)부터 높은 수준으로 App 항체가 형성되었다. 상기 실시예 2-4의 결과와 마찬가지로, 실험 시작 6주차의 공격접종에 의해 7주차의 대조군에서 항체가가 증가하였다.As shown in FIG. 7, the App antibody was formed at a high level from the 6th week (2 weeks after the second inoculation) compared to the control group and the commercial vaccine group in the development vaccine group. As with the results of Example 2-4, antibody titers were increased in the control group at
실시예 3. 본 발명에 따른 다가 백신의 안전성 평가Example 3. Safety evaluation of the multivalent vaccine according to the present invention
3-1. 체중 측정 결과3-1. Weight measurement result
본 발명에 따른 다가 백신의 부작용 (식사거부 등의 증상 확인 목적)을 확인하기 위하여 접종 6주까지의 체중을 관찰하였다. 그 결과를 도 8에 나타내었다.In order to check the side effects of the multivalent vaccine according to the present invention (for the purpose of confirming symptoms such as refusal to eat), the body weight up to 6 weeks of inoculation was observed. The results are shown in FIG. 8.
도 8에 나타낸 바와 같이, 모든 그룹간의 체중은 유사하게 증가하여 백신 접종 후 식욕저하 등의 부작용이 나타나지 않음을 확인하였다.As shown in FIG. 8, it was confirmed that the body weight between all groups increased similarly, and side effects such as decreased appetite after vaccination did not appear.
3-2. 체온 측정 결과3-2. Body temperature measurement result
본 발명에 따른 다가 백신의 부작용 (염증 등의 증상 확인 목적)을 확인하기 위하여 접종 6주까지의 체온을 관찰하였다. 그 결과를 도 9에 나타내었다.Body temperature up to 6 weeks of inoculation was observed in order to confirm the side effects of the multivalent vaccine according to the present invention (for the purpose of checking symptoms such as inflammation). The results are shown in FIG. 9.
도 9에 나타낸 바와 같이, 모든 그룹간의 체온의 차이가 관찰되지 않아 백신 접종 후 발열 등의 부작용이 나타나지 않음을 확인하였다. As shown in FIG. 9, since no difference in body temperature was observed between all groups, it was confirmed that side effects such as fever after vaccination did not appear.
실시예 4. 흉막폐렴균 공격접종에 대한 다가 백신의 방어능 평가Example 4. Evaluation of the protective ability of a multivalent vaccine against pleural pneumococcal challenge vaccination
본 발명에 따른 다가 백신의 효능을 검증하기 위하여 본 개발에 사용된 App 혈청형 1, 2, 5형 균주를 살아있는 상태로 비강으로 흘려주었고(총 3x105 cfu), 각 그룹 사이의 폐병변 발생 정도를 비교하였다. 폐병변 발생 정도를 정량화시킨 결과를 도 10에 나타내었다. 각 그룹간 폐병변을 육안으로 관찰한 사진은 도 11 내지 도 16에 나타내었다. In order to verify the efficacy of the multivalent vaccine according to the present invention, App serotypes 1, 2, and 5 strains used in this development were flown alive into the nasal cavity (total 3x10 5 cfu), and the degree of lung lesions between each group Was compared. The results of quantifying the degree of occurrence of lung lesions are shown in FIG. 10. The photographs of visual observation of lung lesions between each group are shown in FIGS. 11 to 16.
도 10에 나타낸 바와 같이, 대조군은 약 37%로 병변 발생율이 가장 높았고, 상용백신군은 약 20%였으나 이는 유의한 차이는 아니었으며, 한편 본 발명에 따른 다가 백신 (개발백신군)의 병변 발생율은 10% 미만으로 대조군과 비교하여 큰 수치로 개선됨을 확인하였다. 한편, 도 10에서 비공격접종군의 경우 병변 발생율이 0%로 나타남을 확인하였다. 또한, 도 11 내지 도 14에 나타낸 바와 같이, 육안으로 확인 시에도 대조군에서 비정상적인 병변이 관찰되고, 상용백신군에서도 일부 개체에서 비정상적인 병변이 관찰되나, 본 발명에 따른 다가 백신의 경우 병변 발생 정도가 현저히 낮음을 확인할 수 있었다. 한편, 도 15 및 16에 나타낸 바와 같이, 공격접종을 수행하지 않은 개체에서는 폐병변이 발생되지 않았다.As shown in Figure 10, the control group had the highest lesion incidence rate of about 37%, and the commercial vaccine group had the highest lesion incidence rate, but this was not a significant difference, while the lesion incidence rate of the multivalent vaccine (developed vaccine group) according to the present invention It was confirmed that less than 10% was improved by a large number compared to the control group. On the other hand, it was confirmed that the lesion incidence rate was 0% in the case of the non-attack vaccinated group in FIG. 10. In addition, as shown in Figs. 11 to 14, abnormal lesions are observed in the control group even when visually confirmed, and abnormal lesions are observed in some individuals even in the commercial vaccine group, but in the case of the multivalent vaccine according to the present invention, the degree of lesion occurrence is It was confirmed that it was remarkably low. On the other hand, as shown in Figs. 15 and 16, lung lesions did not occur in individuals who did not perform the challenge vaccination.
상기와 같은 결과를 통해, 본 발명에 따른 다가 백신 조성물은 마이코플라즈마 하이오뉴모니애 (Mycoplasma hyopneumoniae, Mhp) 및 마이코플라즈마 하이오뉴모니애 부착 단백질 P97, 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App) 혈청형 1형, 혈청형 2형, 혈청형 5형 및 각 흉막폐렴균에서 분비되는 독소 1,2 및 3형(ApxI, Ⅱ 및 Ⅲ)을 정제하여 혼합함으로써 돼지 호흡기 복합 증후군의 원발성 인자 및 2차 감염인자를 모두 방어하여 돼지 호흡기 복합 감염증, 구체적으로는 돼지 마이코플라즈마균 및 흉막폐렴균에 의한 폐렴 발생의 동시 예방이 가능하고, 기존 상용 백신보다 우수한 방어 효과를 나타낼 수 있음을 확인하였다. Through the results as described above, the multivalent vaccine composition according to the present invention is Mycoplasma high o pneumoniae ( Mycoplasma hyopneumoniae , Mhp) and Mycoplasma hyopneumoniae adhesion protein P97, Actinobacillosis pleuropneumoniae (App)
따라서, 본 발명에 따른 다가 백신 조성물은 초기 방어능이 뛰어나고, 백신 접종 후 부작용이 없으며, 최근 유행하는 혈청형을 포함하여 효과적으로 자돈 폐사율을 감소시킴과 동시에 만성 호흡기 증상으로 인한 증체성 저하를 막아 양돈 산업에 유용하게 사용될 수 있다.Therefore, the multivalent vaccine composition according to the present invention has excellent initial defense, has no side effects after vaccination, and effectively reduces piglet mortality, including recently prevalent serotypes, and at the same time prevents reduction in increase in weight due to chronic respiratory symptoms, thereby preventing the pig industry. It can be used usefully.
<110> Innovac KNU-Industry Cooperation Foundation <120> Vaccine composition for preventing swine mycoplasmal pneumonia and pleuropneumonia <130> INNO1-2P-1 <150> KR 10-2018-0165022 <151> 2018-12-19 <160> 2 <170> KoPatentIn 3.0 <210> 1 <211> 380 <212> PRT <213> Artificial Sequence <220> <223> Mycoplasma hyopneumoniae rP97m protein sequence <400> 1 Met His His His His His His Ser Ser Gly Leu Val Pro Arg Gly Ser 1 5 10 15 Gly Met Lys Glu Thr Ala Ala Ala Lys Phe Glu Arg Gln His Met Asp 20 25 30 Ser Pro Asp Leu Gly Thr Asp Asp Asp Asp Lys Ala Met Ala Asp Ile 35 40 45 Gly Ser Glu Phe Ala Pro Gln Thr Ile Thr Glu Leu Cys Ser Glu Tyr 50 55 60 Arg Asn Thr Gln Ile Tyr Thr Ile Asn Asp Lys Ile Leu Ser Tyr Thr 65 70 75 80 Glu Ser Met Ala Gly Lys Arg Glu Met Val Ile Ile Thr Phe Lys Ser 85 90 95 Gly Ala Thr Phe Gln Val Glu Val Pro Gly Ser Gln His Ile Asp Ser 100 105 110 Gln Lys Lys Ala Ile Glu Arg Met Lys Asp Thr Leu Arg Ile Ala Tyr 115 120 125 Leu Thr Glu Thr Lys Ile Asp Lys Leu Cys Val Trp Asn Asn Lys Thr 130 135 140 Pro Asn Ser Ile Ala Ala Ile Ser Leu Glu Gly Ile Pro Thr Lys Glu 145 150 155 160 Gly Lys Arg Glu Glu Val Asp Lys Lys Val Lys Glu Leu Asp Asn Lys 165 170 175 Ile Lys Gly Ile Leu Pro Gln Pro Pro Ala Ala Lys Pro Glu Ala Ala 180 185 190 Lys Pro Val Ala Ala Lys Pro Glu Ala Ala Lys Pro Val Ala Ala Lys 195 200 205 Pro Glu Ala Ala Lys Pro Glu Ala Ala Lys Pro Val Ala Ala Lys Pro 210 215 220 Glu Ala Ala Lys Pro Val Ala Ala Lys Pro Glu Ala Ala Lys Pro Val 225 230 235 240 Ala Thr Asn Glu Gly Thr Pro Asn Gln Gly Lys Lys Ala Glu Gly Ala 245 250 255 Pro Asn Gln Gly Lys Lys Ala Glu Gly Ala Pro Ser Gln Gly Lys Lys 260 265 270 Ala Glu Gly Ala Ser Asn Gln Gln Ser Pro Thr Thr Glu Leu Thr Asn 275 280 285 Tyr Leu Pro Glu Leu Gly Lys Lys Ile Asp Glu Ile Ile Lys Lys Gln 290 295 300 Gly Lys Asn Trp Lys Thr Glu Val Glu Leu Ile Glu Asp Asn Ile Ala 305 310 315 320 Gly Asp Ala Lys Leu Leu Tyr Phe Val Leu Arg Asp Asp Ser Lys Ser 325 330 335 Gly Asp Pro Lys Lys Ser Ser Leu Lys Val Lys Ile Thr Val Lys Gln 340 345 350 Ser Asn Asn Asn Gln Glu Leu Lys Ser Lys Gln Ala Cys Gly Arg Thr 355 360 365 Arg Ala Pro Pro Pro Pro Pro Leu Arg Ser Gly Cys 370 375 380 <210> 2 <211> 1143 <212> DNA <213> Artificial Sequence <220> <223> Mycoplasma hyopneumoniae rP97m DNA sequence, <400> 2 atgcaccatc atcatcatca ttcttctggt ctggtgccac gcggttctgg tatgaaagaa 60 accgctgctg ctaaattcga acgccagcac atggacagcc cagatctggg taccgacgac 120 gacgacaagg ccatggctga tatcggatcc gaattcgctc cccagactat tacagaacta 180 tgttcggaat atcgcaacac acaaatatat acgataaatg acaaaatact atcatatacg 240 gaatcgatgg caggcaaaag agaaatggtt atcattacat ttaagagcgg cgcaacattt 300 caggtcgaag tcccgggcag tcaacatata gactcccaaa aaaaagccat tgaaaggatg 360 aaggacacat taagaatcgc atatctgacc gagaccaaaa ttgataaatt atgtgtatgg 420 aataataaaa cccccaattc aattgcggca atcagtctcg aggggatccc tacaaaagaa 480 ggtaaaagag aagaagtaga taaaaaagtt aaagaattag ataataaaat aaaaggtata 540 ttacctcagc ccccagcagc taaaccagaa gcagcaaaac cagtagcagc taaacctgaa 600 gcagcaaaac cagtagcggc taaacctgaa gcagcaaaac ctgaagcagc aaaaccagta 660 gcggctaaac ctgaagcagc aaaaccagta gcagctaaac ctgaagcagc aaaaccagtt 720 gctactaatg aaggaactcc taaccaaggc aaaaaagccg aaggcgctcc taaccaaggc 780 aaaaaagccg aaggcgcacc tagtcaaggg aaaaaagcag agggtgcttc taatcaacaa 840 agcccaacta ccgaattaac taattacctt cctgaattag gtaaaaaaat tgacgaaatc 900 attaaaaaac aaggtaaaaa ttggaaaaca gaggttgaac taatcgagga taatatcgct 960 ggagatgcta aattgctata ctttgtccta agggatgatt caaaatccgg tgatcctaaa 1020 aaatcaagtc taaaagttaa aataacagta aaacaaagta ataataatca ggaattaaaa 1080 tctaaacaag cttgcggccg cactcgagca ccaccaccac caccactgag atccggctgc 1140 taa 1143 <110> Innovac KNU-Industry Cooperation Foundation <120> Vaccine composition for preventing swine mycoplasmal pneumonia and pleuropneumonia <130> INNO1-2P-1 <150> KR 10-2018-0165022 <151> 2018-12-19 <160> 2 <170> KoPatentIn 3.0 <210> 1 <211> 380 <212> PRT <213> Artificial Sequence <220> <223> Mycoplasma hyopneumoniae rP97m protein sequence <400> 1 Met His His His His His His Ser Ser Gly Leu Val Pro Arg Gly Ser 1 5 10 15 Gly Met Lys Glu Thr Ala Ala Ala Lys Phe Glu Arg Gln His Met Asp 20 25 30 Ser Pro Asp Leu Gly Thr Asp Asp Asp Asp Lys Ala Met Ala Asp Ile 35 40 45 Gly Ser Glu Phe Ala Pro Gln Thr Ile Thr Glu Leu Cys Ser Glu Tyr 50 55 60 Arg Asn Thr Gln Ile Tyr Thr Ile Asn Asp Lys Ile Leu Ser Tyr Thr 65 70 75 80 Glu Ser Met Ala Gly Lys Arg Glu Met Val Ile Ile Thr Phe Lys Ser 85 90 95 Gly Ala Thr Phe Gln Val Glu Val Pro Gly Ser Gln His Ile Asp Ser 100 105 110 Gln Lys Lys Ala Ile Glu Arg Met Lys Asp Thr Leu Arg Ile Ala Tyr 115 120 125 Leu Thr Glu Thr Lys Ile Asp Lys Leu Cys Val Trp Asn Asn Lys Thr 130 135 140 Pro Asn Ser Ile Ala Ala Ile Ser Leu Glu Gly Ile Pro Thr Lys Glu 145 150 155 160 Gly Lys Arg Glu Glu Val Asp Lys Lys Val Lys Glu Leu Asp Asn Lys 165 170 175 Ile Lys Gly Ile Leu Pro Gln Pro Pro Ala Ala Lys Pro Glu Ala Ala 180 185 190 Lys Pro Val Ala Ala Lys Pro Glu Ala Ala Lys Pro Val Ala Ala Lys 195 200 205 Pro Glu Ala Ala Lys Pro Glu Ala Ala Lys Pro Val Ala Ala Lys Pro 210 215 220 Glu Ala Ala Lys Pro Val Ala Ala Lys Pro Glu Ala Ala Lys Pro Val 225 230 235 240 Ala Thr Asn Glu Gly Thr Pro Asn Gln Gly Lys Lys Ala Glu Gly Ala 245 250 255 Pro Asn Gln Gly Lys Lys Ala Glu Gly Ala Pro Ser Gln Gly Lys Lys 260 265 270 Ala Glu Gly Ala Ser Asn Gln Gln Ser Pro Thr Thr Glu Leu Thr Asn 275 280 285 Tyr Leu Pro Glu Leu Gly Lys Lys Ile Asp Glu Ile Ile Lys Lys Gln 290 295 300 Gly Lys Asn Trp Lys Thr Glu Val Glu Leu Ile Glu Asp Asn Ile Ala 305 310 315 320 Gly Asp Ala Lys Leu Leu Tyr Phe Val Leu Arg Asp Asp Ser Lys Ser 325 330 335 Gly Asp Pro Lys Lys Ser Ser Leu Lys Val Lys Ile Thr Val Lys Gln 340 345 350 Ser Asn Asn Asn Gln Glu Leu Lys Ser Lys Gln Ala Cys Gly Arg Thr 355 360 365 Arg Ala Pro Pro Pro Pro Leu Arg Ser Gly Cys 370 375 380 <210> 2 <211> 1143 <212> DNA <213> Artificial Sequence <220> <223> Mycoplasma hyopneumoniae rP97m DNA sequence, <400> 2 atgcaccatc atcatcatca ttcttctggt ctggtgccac gcggttctgg tatgaaagaa 60 accgctgctg ctaaattcga acgccagcac atggacagcc cagatctggg taccgacgac 120 gacgacaagg ccatggctga tatcggatcc gaattcgctc cccagactat tacagaacta 180 tgttcggaat atcgcaacac acaaatatat acgataaatg acaaaatact atcatatacg 240 gaatcgatgg caggcaaaag agaaatggtt atcattacat ttaagagcgg cgcaacattt 300 caggtcgaag tcccgggcag tcaacatata gactcccaaa aaaaagccat tgaaaggatg 360 aaggacacat taagaatcgc atatctgacc gagaccaaaa ttgataaatt atgtgtatgg 420 aataataaaa cccccaattc aattgcggca atcagtctcg aggggatccc tacaaaagaa 480 ggtaaaagag aagaagtaga taaaaaagtt aaagaattag ataataaaat aaaaggtata 540 ttacctcagc ccccagcagc taaaccagaa gcagcaaaac cagtagcagc taaacctgaa 600 gcagcaaaac cagtagcggc taaacctgaa gcagcaaaac ctgaagcagc aaaaccagta 660 gcggctaaac ctgaagcagc aaaaccagta gcagctaaac ctgaagcagc aaaaccagtt 720 gctactaatg aaggaactcc taaccaaggc aaaaaagccg aaggcgctcc taaccaaggc 780 aaaaaagccg aaggcgcacc tagtcaaggg aaaaaagcag agggtgcttc taatcaacaa 840 agcccaacta ccgaattaac taattacctt cctgaattag gtaaaaaaat tgacgaaatc 900 attaaaaaac aaggtaaaaa ttggaaaaca gaggttgaac taatcgagga taatatcgct 960 ggagatgcta aattgctata ctttgtccta agggatgatt caaaatccgg tgatcctaaa 1020 aaatcaagtc taaaagttaa aataacagta aaacaaagta ataataatca ggaattaaaa 1080 tctaaacaag cttgcggccg cactcgagca ccaccaccac caccactgag atccggctgc 1140 taa 1143
Claims (8)
(ⅱ) 돼지 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App) 혈청형 1형, 혈청형 2형 및 혈청형 5형 균주;
(ⅲ) 서열번호 1로 표시되는 아미노산 서열로 이루어진 돼지 마이코플라즈마 하이오뉴모니애 유래 재조합 P97 단백질; 및
(ⅳ) 돼지 액티노바실러스 플레로뉴모니애 (Actinobacillosis pleuropneumoniae, App) 독소 1,2 및 3형(ApxI, Ⅱ 및 Ⅲ); 을 포함하는 돼지 마이코플라즈마균 및 흉막폐렴균에 의한 폐렴 예방을 위한 다가 백신 조성물. (I) Pig Mycoplasma hyopneumoniae (Mhp) strain,
(Ii) Porcine Actinobacillosis pleuropneumoniae (App) serotype 1, serotype 2 and serotype 5 strains;
(Iii) a recombinant P97 protein derived from pig Mycoplasma hyopneumoniae consisting of the amino acid sequence represented by SEQ ID NO: 1; And
(Iv) Porcine Actinobacillosis pleuropneumoniae (App) toxins 1,2 and 3 (ApxI, II and III); A multivalent vaccine composition for the prevention of pneumonia caused by porcine mycoplasma bacteria and pleural pneumococcus comprising a.
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