A Meningococcal Outer Membrane Vesicle Vaccine with Overexpressed Mutant FHbp Elicits Higher Protective Antibody Responses in Infant Rhesus Macaques than a Licensed Serogroup B Vaccine
A Meningococcal Outer Membrane Vesicle Vaccine with Overexpressed Mutant FHbp Elicits Higher Protective Antibody Responses in Infant Rhesus Macaques than a Licensed Serogroup B Vaccine
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DOI：
10.1128/mbio.01231-19
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发表时间：
2019-05-01
期刊：
影响因子：
6.4
通讯作者：
Granoff, Dan M.
中科院分区：
文献类型：
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作者：
Beernink, Peter T.;Vianzon, Vianca;Granoff, Dan M.
MenB-4C(Bexsero；GlaxoSmithKline Biologals)是一种获得许可的针对B囊型脑膜炎球菌的疫苗。该疫苗包含洗涤剂提取的外膜囊泡(DOMV)和三种重组蛋白，其中一种是因子H结合蛋白(FHBP)。在以往的研究中，FHBP在基因减毒内毒素(LpxL1)的天然OMV(NOMV)中过表达和/或使用低因子H(FH)结合的突变FHBP抗原可增加血清杀菌抗体(SBA)的应答。在本研究中，我们用与猕猴FH低结合的高表达突变体(R41S)FHBP(NOMV-FHBP)免疫13只幼猴。对照组猕猴给予MenB-4C佐剂(n=13)或单独给予氢氧化铝佐剂(n=4)。NOMV-FHBP诱导的抗体几何平均滴度是MenB-4C的2倍(P=0.003)，抗FHBP抑制FH与FHBP的结合，而抗MenB-4C的FHBP抗体促进FH结合。MenB-4C对用于制备dOMV组分的NZ98/254株产生10倍以上的GMT，而NOMV-FHBP对突变株H44/76产生8倍以上的GMT，H44/76是NOMV-FHBP疫苗株的亲本。对于PORA与两种疫苗和不同FHBP序列变异体都不匹配的4株毒株，NOMV-FHBP诱导的SBA GMT是MenB-4C的6-14倍(P=0.0002)。用MenB-4C免疫的13只猕猴中有2只出现血清抗FH自身抗体(P=0.18)，而用NOMV-FHBP或佐剂免疫的17只猕猴中无一例出现抗FH自身抗体。因此，与含有结合FH的野生型FHBP的许可B组疫苗相比，突变的NOMV-FHBP方法有可能引起更高和更广泛的SBA反应。突变的NOMV-FHBP也可能引起抗FH自身抗体的风险较低。两者均含有能与宿主补体因子H(FH)结合的重组H因子结合蛋白(FHBP)。这些疫苗的局限性包括缺乏对某些脑膜炎球菌株的保护，以及可能引发针对FH的自身抗体。我们用基因减毒内毒素的天然外膜泡囊(NOMV)疫苗免疫幼猴，并产生了与FH低结合的突变体FHBP。与获得许可的B组脑膜炎球菌疫苗相比，NOMV-FHBP疫苗刺激了更高水平的保护性血清抗体，以对抗所测试的六种遗传多样性脑膜炎球菌菌株中的五种。使用许可疫苗免疫的13只猕猴中，有两只产生了抗FH自身抗体，但在17只接受NOMV-FHBP或阴性对照的猕猴中，0只出现了血清抗FH自身抗体。因此，在相关的非人灵长类动物模型中，NOMV-FHBP疫苗比许可疫苗产生了更强的保护性抗体，并可能产生抗FH自身抗体的风险较小。
MenB-4C (Bexsero; GlaxoSmithKline Biologicals) is a licensed meningococcal vaccine for capsular B strains. The vaccine contains detergent-extracted outer membrane vesicles (dOMV) and three recombinant proteins, of which one is factor H binding protein (FHbp). In previous studies, overexpression of FHbp in native OMV (NOMV) with genetically attenuated endotoxin (LpxL1) and/or by the use of mutant FHbp antigens with low factor H (FH) binding increased serum bactericidal antibody (SBA) responses. In this study, we immunized 13 infant macaques with 2 doses of NOMV with overexpressed mutant (R41S) FHbp with low binding to macaque FH (NOMV-FHbp). Control macaques received MenB-4C (n = 13) or aluminum hydroxide adjuvant alone (n = 4). NOMV-FHbp elicited a 2-fold higher IgG anti-FHbp geometric mean titer (GMT) than MenB-4C (P = 0.003), and the anti-FHbp repertoire inhibited binding of FH to FHbp, whereas anti-FHbp antibodies to MenB-4C enhanced FH binding. MenB-4C elicited a 10-fold higher GMT against strain NZ98/254, which was used to prepare the dOMV component, whereas NOMV-FHbp elicited an 8-fold higher GMT against strain H44/76, which was the parent of the mutant NOMV-FHbp vaccine strain. Against four strains with PorA mismatched to both of the vaccines and different FHbp sequence variants, NOMV-FHbp elicited 6- to 14-fold higher SBA GMTs than MenB-4C (P = 0.0002). Two of 13 macaques immunized with MenB-4C but 0 of 17 macaques immunized with NOMV-FHbp or adjuvant developed serum anti-FH autoantibodies (P = 0.18). Thus, the mutant NOMV-FHbp approach has the potential to elicit higher and broader SBA responses than a licensed group B vaccine that contains wild-type FHbp that binds FH. The mutant NOMV-FHbp also might pose less of a risk of eliciting anti-FH autoantibodies.IMPORTANCE There are two licensed meningococcal capsular B vaccines. Both contain recombinant factor H binding protein (FHbp), which can bind to host complement factor H (FH). The limitations of these vaccines include a lack of protection against some meningococcal strains and the potential to elicit autoantibodies to FH. We immunized infant macaques with a native outer membrane vesicle (NOMV) vaccine with genetically attenuated endotoxin and overproduced mutant FHbp with low binding to FH. The NOMV-FHbp vaccine stimulated higher levels of protective serum antibodies than a licensed meningococcal group B vaccine against five of six genetically diverse meningococcal strains tested. Two of 13 macaques immunized with the licensed vaccine, which contains FHbp that binds macaque FH, but 0 of 17 macaques given NOMV-FHbp or the negative control developed serum anti-FH autoantibodies Thus, in a relevant nonhuman primate model, the NOMV-FHbp vaccine elicited greater protective antibodies than the licensed vaccine and may pose less of a risk of anti-FH autoantibody.