Systems analysis of protective immune responses to RTS, S malaria vaccination in humans
Systems analysis of protective immune responses to RTS, S malaria vaccination in humans
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DOI：
10.1073/pnas.1621489114
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发表时间：
2017-02-28
影响因子：
11.1
通讯作者：
Pulendran, Bali
中科院分区：
文献类型：
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作者：
Kazmin, Dmitri;Nakaya, Helder I.;Pulendran, Bali
RTS，S是一种先进的疟疾候选疫苗，可显著保护人类免受恶性疟原虫感染。对驱动疫苗免疫的分子机制知之甚少。在这里，我们应用系统生物学方法来研究受试者接受RTS，S（RRR）的连续三次免疫接种，或在接受RTS，S/AS 01的两次免疫接种后，与腺病毒35（Ad 35）（ARR）载体表达环子孢子蛋白的初次免疫接种的免疫应答。随后的控制人类疟疾挑战（CHMI）的疫苗接种者与疟原虫感染的蚊子，3周后的最后一次免疫接种，导致类似的50%的保护，在两组疫苗接种者。攻毒前环子孢子蛋白（CSP）特异性抗体滴度与RRR组的保护作用相关。相反，ARR诱导较低的抗体应答，并且在用Ad 35引发后2周，保护与多功能CD 4（+）T细胞应答相关。在RRR队列中，在PBMC中检测到的B和浆细胞的分子特征与攻毒前和保护性抗体滴度高度相关。相比之下，先天免疫和树突状细胞激活的早期特征与ARR队列中的保护作用高度相关。对于这两种疫苗方案，自然杀伤（NK）细胞签名与保护呈负相关并预测保护。这些结果表明，针对恶性疟原虫的保护性免疫可以通过多种机制来实现，并突出了系统方法在定义与疫苗接种保护相关的分子中的实用性。
RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS, S (RRR), or in those receiving two immunizations of RTS, S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in similar to 50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4(+) T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination.