Pfs230 yields higher malaria transmission-blocking vaccine activity than Pfs25 in humans but not mice

Abstract

AbstractBackgroundVaccines that block human-to-mosquito Plasmodium transmission 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 significant serum functional activity in both US and Malian adults. However, antibody titers declined rapidly, and transmission-reducing activity required four vaccine doses. Functional immunogenicity and durability must be improved before advancing TBV further in clinical development. We hypothesized that the pre-fertilization 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 titers were measured by ELISA and transmission-reducing activity was assess 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 U.S. adults, two vaccine doses induced complement-dependent activity in 4 of 5 Pfs230D1-EPA/Alhydrogel® recipients but no significant activity in five 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. The rhesus model is more predictive of the functional human immune response to Pfs230D1 than is the mouse model.Trial RegistrationClinicalTrials.govNCT02334462FundingThis work was supported by the Intramural Research Program of the National Institute of Allergy and Infectious Diseases, National Institutes of Health.