Optimizing malaria transmission-blocking vaccines with improved platforms

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

In FY2021, LMIV scientists published 1 review article discussing conjugate or particle vaccines. Duffy PE: Transmission-Blocking Vaccines: Harnessing Herd Immunity for Malaria Elimination. Expert Rev Vaccines 2021, 20:185-198. We described the concept and biology behind TBV and provided an update on clinical development of the leading vaccine candidate antigens including Pfs25, Pvs25, Pfs230, and Pfs48/45, as well as novel vaccine platforms including nanoparticles. In unpublished work, we report below our progress on other ongoing projects: Further evaluation of OMPC as a delivery platform for Transmission Blocking Vaccine antigens In FY2021, we completed the evaluation of OMPC as a delivery platform for TBV antigens. In our previous report, we described a qualitatively different, Th1-biased immune response was observed for OMPC conjugates as opposed to a Th2 response of EPA conjugates. Based on these findings, we initiated evaluation of OMPC conjugates of Pfs25 and Pfs230 in nonhuman primates to determine their efficacy in this model and to evaluate the duration of immune response. In this study, OMPC conjugates were compared to EPA conjugates of these antigens in ALFQ adjuvant from WRAIR. Pfs230 conjugates of both OMPC and EPA showed superior transmission blocking activity compared to Pfs25 conjugates after two vaccinations. These results recapitulated the observation in humans where Pfs230 induced stronger functional immune response than Pfs25. This study also showed that a third vaccination may be needed to achieve a durable immune response that lasts at least a year. Some of the results from these studies are currently under review for publication. Evaluation of mRNA technology for malaria antigens In FY2021, we continued the collaboration with CureVac, Germany to test the immunogenicity of LMIVs malaria antigens in CureVacs RNActive technology platform. Antigen delivery using mRNA has generated considerable excitement in the vaccine field as a technology that can rapidly generate vaccine candidates for clinical testing. This technology is now well-established for COVID-19 vaccines. We worked with CureVac to construct mRNA for our TBV and PMV antigens. In FY2019, CureVac generated a series of mRNA constructs for LMIVs TBV and pregnancy malaria antigens and tested their expression in mammalian cells. As part of this continuing collaboration, mouse immunogenicity studies have been completed at LMIV to test the immunogenicity and functional activity of these mRNA constructs. Theresults so far suggest that mRNA is a viable platform for malaria vaccine development. Among the various mRNA constructs of Pfs25 and Pfs230 evaluated in mice, we have assessed constructs consisting of membrane anchor elements such and GPI anchor or trans membrane domain to induce immune response in mice. Immune response generated gave high transmission blocking functional activity by standard membrane feeding assay. . Additional studies are planned to evaluate the T-cell responses to these vaccine candidates. Understanding T-cell epitope requirements for TBV boosting To further test that boosting of antibody responses in animal immunized with a conjugate vaccine is not dependent on the presence of a conjugated vaccine, but a monomeric form of the vaccine is enough, we conducted vaccination studies in Rhesus macaques immunized with Pfs230D1-EPA or monomeric Pfs230D1M formulated in Matrix-M, the results showed that monomer was sufficient to induce high titers after a fourth boost Pfs230 vaccination.