Thursday, April 3, 2025
4/3/2025
mRNA-LNP vaccines targeting multiple stages and multiple species of human malaria parasite - Project Summary Malaria remains a major public health problem with an estimated ¼ billion clinical cases and mortality to a total of 627,000 in 2022. More than 90% of the global malaria burden is due to infection by Plasmodium falciparum and P. vivax, often co-endemic in Asia, Pacific, Central and South America, with growing evidence in parts of Africa. The P. falciparum malaria vaccine RTS,S/AS01, approved by the WHO in 2021 and R21/Matrix-M approved in 2023 are significant steps toward malaria control. However, both vaccines exhibit partially protective efficacy of short duration, and emphasize the need for additional tools such as more effective and improved vaccines to interrupt malaria transmission. It is widely recognized that combination vaccines targeting antigenically distinct life cycle stages (sporozoites, erythrocytic asexual parasites and male and female gametocytes) in P. falciparum and P. vivax will provide effective immune protection against infection and reduce transmission. The primary focus of the proposed studies is to develop combination vaccines targeting infection by sporozoites and mosquito transmission by gametocytes of P. falciparum and P. vivax. P. falciparum circumsporozoite protein (PfCSP) is the leading pre-erythrocytic vaccine (PEV) candidate. In addition to Pfs25, pre-clinical studies and limited phase 1 trials have identified Pfs230 as another strong candidate for the development of a transmission-blocking vaccine (TBV). Orthologous antigens (PvCSP and Pvs25) in P. vivax have also been identified as strong PEV and TBV candidates. The mRNA-LNP approach shown to be relatively safe and effective offers the flexibility to combine several antigens in a multivalent vaccine. Our published studies on effective immunogenicity of mRNA-LNP vaccines encoding PfCSP and Pfs25 provide the basis and a solid foundation to develop proposed mRNA-LNP combination vaccines. In specific aim 1 we will evaluate protective efficacy of Pfs25 and Pfs230 TBV antigens, individually or in combination with PfCSP. The potency of PfCSP mRNA-LNP will be compared to RTS,S/AS01 as a benchmark. Immunogenicity of Pvs25 and chPvCSP (a chimeric P. vivax CSP representing all three allelic types) combination will be assessed in studies in specific aim 2. Studies in specific aim 3 will evaluate a combination of TBVs (aim 3a) and PEVs (aim 3b) of both Plasmodium species. Finally, immunogenicity of select combinations of TBVs and PEVs will be validated in rhesus macaques in specific aim 4. Vaccine combinations targeting different stages in: (i) P. falciparum and P. vivax, and (ii) validated in mice and nonhuman primates, will serve as a guide for designing future clinical trials aimed at reducing disease burden and interrupting malaria transmission to achieve the long-term goal of global malaria elimination.
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