Pre-existing immunity to cytomegalovirus in macaques influences human CMV vaccine responses in preclinical models.
Pre-existing immunity to cytomegalovirus in macaques influences human CMV vaccine responses in preclinical models.
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猕猴预先存在的巨细胞病毒免疫力影响临床前模型中人类 CMV 疫苗的反应。
DOI：
10.1016/j.vaccine.2021.08.011
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发表时间：
2021
期刊：
影响因子：
5.5
通讯作者：
Permar,SallieR
中科院分区：
文献类型：
--
作者：
Webster,Helen;Valencia,Sarah;Kumar,Amit;Chan,Cliburn;Dennis,Maria;Roark,Hunter;Woods,Angela;John,Shinu;Carfi,Andrea;Permar,SallieR
人巨细胞病毒（HCMV）疫苗的开发是美国国立医学研究院的一级优先事项，因为HCMV是全球最常见的先天性感染和移植患者最常见的感染并发症。用于测试HCMV疫苗免疫原性的相关临床前非人灵长类动物模型是恒河猴和食蟹猴。然而，使用这些模型的一个复杂之处在于，物种特异性CMV变体在非人灵长类繁殖群体中是地方性的。我们假设恒河猴和食蟹猴对种特异性CMV的天然免疫力影响HCMV疫苗的免疫原性，并可能干扰我们充分解释疫苗免疫原性的能力。将包装在脂质纳米颗粒（LNP）中的编码HCMV糖蛋白（gB）和五聚体复合物（PC）的修饰的mRNA疫苗肌内递送至食蟹猴（n = 16，CyCMV血清阳性）和恒河猴（n = 24，RhCMV血清阳性）组。在两种动物中均存在对HCMV gB的高免疫前IgG结合反应，但对PC的免疫前结合反应主要存在于恒河猴中。然而，在两个物种中，在第二次HCMV mRNA疫苗接种后检测到PC和gB特异性血浆IgG水平至少对数增加。两个物种在第二次HCMV mRNA疫苗接种后4周时均产生高上皮细胞中和抗体应答，但成纤维细胞中和抗体有限。HCMV gB + PC mRNA/LNP疫苗在第二次接种后，在两个物种中也引起了对细胞相关gB的IgG结合应答，这是一种确定的保护性免疫相关性，并且在恒河猴中，这种接种前和接种后应答之间存在中等强度的直接相关性。基于恒河猴中预先存在的和疫苗后gB特异性结合应答之间的相关性，我们得出结论，种属特异性CMV变体特异性抗体应答有助于灵长类动物模型中对HCMV疫苗接种的抗体应答，表明在非人灵长类动物临床前模型中必须考虑预先存在的免疫力，并将影响HCMV疫苗血清阳性人疫苗接种者的免疫原性。
Development of a human cytomegalovirus (HCMV) vaccine is a Tier 1 priority by the National Institutes of Medicine, as HCMV is the most common congenital infection globally and most frequent infectious complication in transplant patients. Relevant preclinical non-human primate models used for testing HCMV vaccine immunogenicity are rhesus and cynomolgous monkeys. However, a complication in using these models is that species-specific CMV variants are endemic in non-human primate breeding colonies. We hypothesize that natural immunity to species-specific CMV in rhesus and cynomolgous monkeys impacts HCMV vaccine immunogenicity and may interfere with our ability to fully interpret vaccine immunogenicity. A modified mRNA vaccine encoding HCMV glycoprotein (gB) and the pentameric complex (PC) packaged in lipid nanoparticles (LNP) was delivered intramuscularly to groups of cynomolgous (n = 16, CyCMV-seropositive) and rhesus macaques (n = 24, RhCMV-seropositive). High pre-vaccination IgG binding responses to HCMV gB were present in both species, but pre-vaccination binding responses to PC were mostly present in rhesus macaques. Yet, at least a log increase in both PC and gB-specific plasma IgG levels was detected post-second HCMV mRNA vaccination in both species. Both species responded with high epithelial cell neutralizing antibody responses at 4 weeks post second HCMV mRNA vaccination, but limited fibroblast neutralizing antibodies. HCMV gB + PC mRNA/LNP vaccine also elicited IgG binding responses to cell-associated gB, an identified immune correlate of protection, in both species after the second vaccination, and there was a moderately strong direct correlation between this pre- and post-vaccination response in rhesus macaques. Based on the correlation between pre-existing and post-vaccine gB-specific binding responses in rhesus macaques, we conclude that species-specific CMV variant-specific antibody responses contribute to antibody responses to HCMV vaccination in primate models, indicating that pre-existing immunity must be taken into account in non-human primate preclinical models and will impact immunogenicity of HCMV vaccines seropositive human vaccinees.