Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice
Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice
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DOI：
10.1172/jci146221
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发表时间：
2021-04-01
影响因子：
15.9
通讯作者：
Duffy，Patrick E.
中科院分区：
文献类型：
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作者：
Healy，Sara A.;Anderson，Charles;Duffy，Patrick E.
研究基础阻断人-蚊疟原虫传播的疫苗是根除疟疾所必需的，几十年来，临床试验一直针对受精卵抗原Pfs 25。我们报道了在明矾佐剂中配制的Pfs 25蛋白-蛋白缀合物疫苗在美国和马里成年人中诱导血清功能活性。然而，抗体水平迅速下降，减少传播活动需要4剂疫苗。在进一步推进传播阻断疫苗的临床开发之前，必须提高功能性免疫原性和耐久性。我们假设，优选蛋白Pfs 230单独或与Pfs 25组合将提高功能activity. METHODS基于配子抗原Pfs 230或Pfs 25的传递阻断疫苗候选物与外蛋白A缀合，配制在铝凝胶中，并给予小鼠，恒河猴，和人类。通过ELISA测量抗体水平，并通过标准膜喂养试验评估减少传播的活性。TSPfs 25-EPA/Alhydrogel和Pfs 230 D1-EPA/Alhydrogel在小鼠中诱导类似的血清功能活性，但Pfs 230 D1-EPA在恒河猴中诱导显著更大的活性，该活性被补体增强。在美国成年人中，2个疫苗剂量诱导补体依赖性活性在4的5 Pfs 230 D1-EPA/Alhydrogel收件人，但没有显着的活性在5 Pfs 25-EPA收件人，并与Pfs 25-EPA的组合并没有增加活动超过Pfs 230 D1-EPA单独。恒河猴模型比小鼠模型更能预测对Pfs 230 D1的功能性人类免疫应答。REGISTRATIONClinicalTrials.gov
BACKGROUNDVaccines that block human-to-mosquitoPlasmodiumtransmission are needed for malaria eradication, and clinical trials have targeted zygote antigen Pfs25 for decades. We reported that a Pfs25 protein-protein conjugate vaccine formulated in alum adjuvant induced serum functional activity in both US and Malian adults. However, antibody levels declined rapidly, and transmission-reducing activity required 4 vaccine doses. Functional immunogenicity and durability must be improved before advancing transmission-blocking vaccines further in clinical development. We hypothesized that the prefertilization protein Pfs230 alone or in combination with Pfs25 would improve functional activity.METHODSTransmission-blocking vaccine candidates based on gamete antigen Pfs230 or Pfs25 were conjugated with Exoprotein A, formulated in Alhydrogel, and administered to mice, rhesus macaques, and humans. Antibody levels were measured by ELISA and transmission-reducing activity was assessed by the standard membrane feeding assay.RESULTSPfs25-EPA/Alhydrogel and Pfs230D1-EPA/Alhydrogel induced similar serum functional activity in mice, but Pfs230D1-EPA induced significantly greater activity in rhesus monkeys that was enhanced by complement. In US adults, 2 vaccine doses induced complement-dependent activity in 4 of 5 Pfs230D1-EPA/Alhydrogel recipients but no significant activity in 5 Pfs25-EPA recipients, and combination with Pfs25-EPA did not increase activity over Pfs230D1-EPA alone.CONCLUSIONThe complement-dependent functional immunogenicity of Pfs230D1-EPA represents a significant improvement over Pfs25-EPA in this comparative study. The rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model.TRIAL REGISTRATIONClinicalTrials.gov NCT02334462.FUNDINGIntramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.