Malaria Transmission Blocking Vaccine Discovery

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

Antigen discovery has focused on using human serum samples collected from individuals that are naturally exposed to malaria and appear to develop effective immunity that prevents gametocytemia or blocks parasite transmission to mosquitoes, as tools to identify candidate vaccine antigens. Specifically, serum samples or antibodies that have activity of interest are compared to sera/antibodies that lack this activity, for their ability to select or recognize individual recombinant proteins constructs of P. falciparum. Recombinant proteins identified through differential screening are then prepared as immunogens and tested for their ability to induce effective anti-gametocyte or transmission-blocking antibodies. From our publications this year, we report the following advances in FY2022: 1. Duffy PE. The virtues and vices of Pfs230from vaccine concept to vaccine candidate. 2022. AJTMH. Jul 11. This review article summarized progress in the development of the malaria transmission blocking vaccine Pfs230D1 at LMIV/NIAID, which provides a model approach for malaria transmission blocking vaccine discovery in future. Pfs230 is currently the target of the most advanced candidate for a malaria transmission-blocking vaccine, Pfs230D1-EPA. First identified by its orthologue in the avian malaria parasite Plasmodium gallinaceum, the large cysteine-rich 14-domain Pfs230 antigen is displayed on the surface of gametes that emerge in the mosquito midgut. Gametes lacking Pfs230 cannot bind to red blood cells nor develop further into oocysts. Human antibodies against the Pfs230D1-EPA vaccine developed at LMIV lyse gametes in the presence of complement, which largely explains serum transmission-blocking activity in Pfs230D1 antisera. The proteinprotein conjugate vaccine Pfs230D1-EPA developed at LMIV that incorporates the first domain of the Pfs230 antigen induced greater serum transmission-reducing activity versus a similarly manufactured Pfs25 vaccine in U.S. trials, and is currently in phase II field trials in Mali. 2. Huang W, Mabrouk M, Zhou L, Baba M, Tachibana M, Torii M, Takashima E, Locke E, Plieskatt J, King CR, Coelho CH, Duffy PE, Long C, Tsuboi T, Miura K, Wu Y, Ishino T, Lovell JF. Vaccine co-display of CSP and Pfs230 on liposomes targeting two Plasmodium falciparum differentiation stages. 2022. Communications Biology. Aug 1. The sporozoite surface Circumsporozoite Protein (CSP) is the target of leading anti-infective P. falciparum pre-erythrocytic vaccines. Pfs230, a sexual-stage P. falciparum surface protein, is currently in trials as the basis for a transmission-blocking vaccine, which inhibits parasite development in the mosquito vector. In this study led by LMIV colleagues at SUNY-Buffalo, recombinant full-length CSP and a Pfs230 fragment (Pfs230D1+) were co-displayed on immunogenic liposomes (containing cobalt-porphyrin phospholipid (CoPoP), monophosphoryl lipid A and QS-21) to induce immunity against both infection and transmission. Bivalent liposomes induced humoral and cellular responses against both CSP and Pfs230D1+, and vaccine-induced antibodies reduced parasite numbers in mosquito midguts in a standard membrane feeding assay. Mice immunized with liposome-displayed antigens or that passively received antibodies from immunized rabbits had reduced parasite liver burden following challenge with transgenic sporozoites expressing P. falciparum CSP. This demonstrates the feasibility to incorporate CSP and Pfs230 antigens in a single immunogen that induces functional antibodies against both targets.