Pfs25 mRNA-LNP(University of Washington/Acuitas Therapeutics/The Johns Hopkins University)

Malaria is a deadly disease responsible for between 550,000 and 627,000 deaths annually. There is a pressing need to develop vaccines focused on malaria elimination. The complex lifecycle of Plasmodium falciparum provides opportunities not only to target the infectious sporozoite stage, introduced by anopheline mosquitoes, but also the sexual stages, which are ingested by mosquitoes during blood feeding, leading to parasite transmission. It is widely recognized that a vaccine targeting multiple stages would induce efficacious transmission reducing immunity. Technological advancements offer new vaccine platforms, such as mRNA-LNPs, which can be used to develop highly effective malarial vaccines. We evaluated the immunogenicity of two leading P. falciparum vaccine candidates, Pfs25 and PfCSP, delivered as mRNA-LNP vaccines. Both vaccines induced extremely potent immune responses when administered alone or in combination, which were superior to Pfs25 and PfCSP DNA vaccine formulations. Purified IgGs from Pfs25 mRNA-LNPs immunized mice were highly potent in reducing malaria transmission to mosquitoes. Additionally, mice after three and four immunizations with PfCSP mRNA-LNP provided evidence for varying degrees of protection against sporozoite challenge. The comparison of immune responses and stage-specific functional activity induced by each mRNA-LNP vaccine, administered alone or in combination, also supports the development of an effective combination vaccine without any risk of immune interference for targeting malaria parasites at various life cycle stages. A combination of vaccines targeting both the infective stage and sexual/midgut stages is expected to interrupt malaria transmission, which is critical for achieving elimination goals.

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.