A Pvs25 mRNA vaccine induces complete and durable transmission-blocking immunity to Plasmodium vivax.
A Pvs25 mRNA vaccine induces complete and durable transmission-blocking immunity to Plasmodium vivax.
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Pvs25 mRNA疫苗诱导对间日疟原虫的完全和持久的传播阻断免疫
DOI：
10.1038/s41541-023-00786-9
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发表时间：
2023-12-14
期刊：
影响因子：
9.2
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中科院分区：
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间日疟原虫（Plasmodium vivax，P. vivax）是非洲以外的主要疟疾寄生虫，并且没有针对它的疫苗。阻断寄生虫传播的疫苗（transmission-blocking vaccine，TBV）被认为是非常期望的，以减少间日疟原虫的传播并加速其消除。然而，由于不能培养寄生虫以及迄今为止开发的疫苗的低免疫原性，针对该病原体的TBV的开发受到阻碍。Pvs 25是间日疟原虫最先进的TBV候选抗原。然而，在之前的I期临床试验中，基于Pvs 25的TBV疫苗产生低抗体应答或具有不可接受的安全性。由于核苷修饰的mRNA-lipid nanoparticle（mRNA-LNP）疫苗平台在人类中被证明是安全有效的，我们在小鼠中产生并测试了编码几种版本的Pvs 25的mRNA-LNP疫苗。我们发现，在初免-加强免疫接种方案中，所有Pvs 25 mRNA-LNP疫苗均引起强烈的抗原特异性抗体应答。此外，当与用Montanide伊萨-51佐剂配制的Pvs 25重组蛋白疫苗相比时，全长Pvs 25 mRNA-LNP疫苗诱导更强和更持久的功能性免疫。第二次接种后7个月，疫苗诱导的抗体在直接膜饲养测定中保留了完全阻断间日疟原虫传播的能力，而蛋白质/伊萨-51疫苗诱导的阻断活性显著下降。总之，我们报告了靶向间日疟原虫的mRNA疫苗，并证明Pvs 25 mRNA-LNP优于佐剂化的Pvs 25蛋白疫苗，表明它是在非人灵长类动物中进一步测试的有希望的候选者。
Plasmodium vivax (P. vivax) is the major malaria parasite outside of Africa and no vaccine is available against it. A vaccine that interrupts parasite transmission (transmission-blocking vaccine, TBV) is considered highly desirable to reduce the spread of P. vivax and to accelerate its elimination. However, the development of a TBV against this pathogen has been hampered by the inability to culture the parasite as well as the low immunogenicity of the vaccines developed to date. Pvs25 is the most advanced TBV antigen candidate for P. vivax. However, in previous phase I clinical trials, TBV vaccines based on Pvs25 yielded low antibody responses or had unacceptable safety profiles. As the nucleoside-modified mRNA–lipid nanoparticle (mRNA–LNP) vaccine platform proved to be safe and effective in humans, we generated and tested mRNA–LNP vaccines encoding several versions of Pvs25 in mice. We found that in a prime-boost vaccination schedule, all Pvs25 mRNA–LNP vaccines elicited robust antigen-specific antibody responses. Furthermore, when compared with a Pvs25 recombinant protein vaccine formulated with Montanide ISA-51 adjuvant, the full-length Pvs25 mRNA–LNP vaccine induced a stronger and longer-lasting functional immunity. Seven months after the second vaccination, vaccine-induced antibodies retained the ability to fully block P. vivax transmission in direct membrane feeding assays, whereas the blocking activity induced by the protein/ISA-51 vaccine dropped significantly. Taken together, we report on mRNA vaccines targeting P. vivax and demonstrate that Pvs25 mRNA–LNP outperformed an adjuvanted Pvs25 protein vaccine suggesting that it is a promising candidate for further testing in non-human primates.
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