Evaluation of Novel Preerythrocytic Anti-infection Malaria Vaccine Candidates

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

From our collaborative publication this year, we report the following advances in FY2021: 1. Daniel S, Pichugin A, Torano H, Renn JP, Kwan J, Cowles M, Conteh S, Lambert LE, Alani N, MacDonald NJ, Dai W, Highsmith K, Anderson C, Gorres JP, Musgrove J, Butler B, Althubaiti N, Dixit S, Zarling-Bejma S, Krzych U, Duffy PE. Plasmodium pre-erythrocytic vaccine antigens enhance sterile protection in mice induced by circumsporozoite protein. 2021. Infection and Immunity. In press. Previously, we identified highly expressed liver stage proteins that could potentially be used in combination with CSP and are referred to as pre-erythrocytic vaccine antigens (PEVA). Here, we developed heterologous prime-boost CSP vaccination models to confer partial sterilizing immunity against Plasmodium yoelii (Py)(protein prime/adenovirus 5 (Ad5) boost) and P. berghei (Pb) (DNA prime/Ad5 boost) in mice. When combined as individual antigens with PyCSP, 3 of 8 PyPEVA significantly enhanced sterile protection against sporozoite challenge, compared to PyCSP alone. Similar results were obtained when 3 PbPEVA and PbCSP were combined in a single vaccine regimen. In general, PyCSP antibody responses were similar after CSP alone versus CSP+PEVA vaccinations. Both Py and Pb CSP+PEVA combination vaccines induced robust CD8+ T cell responses including signature IFN- increases. In the Pb model system, IFN- responses were significantly higher in hepatic than splenic CD8+ T cells. The addition of novel antigens may enhance the degree and duration of sterile protective immunity conferred by a human vaccine such as RTS,S. 2. Mwakingwe-Omari A, Healy SA, Lane J, Cook DM, Kalhori S, Wyatt C, Kolluri A, Marte-Salcedo O, Imeru A, Nason M, et al: Two chemoattenuated PfSPZ malaria vaccines induce sterile hepatic immunity. Nature 2021. We optimized regimens for chemoprophylaxis vaccination (CVac), for which aseptic, purified, cryopreserved, infectious Plasmodium falciparum sporozoites (PfSPZ) were inoculated under prophylactic cover with pyrimethamine (PYR) (Sanaria PfSPZ-CVac(PYR)) or chloroquine (CQ) (PfSPZ-CVac(CQ))which kill liver-stage and blood-stage parasites, respectivelyand we assessed vaccine efficacy against homologous and heterologous controlled human malaria infection (CHMI) three months after immunization. We reported that a fourfold increase in the dose of PfSPZ-CVac(PYR) from 5.12 104 to 2 105 PfSPZs transformed a minimal vaccine efficacy (low dose, two out of nine (22.2%) participants protected against homologous CHMI), to a high-level vaccine efficacy with seven out of eight (87.5%) individuals protected against homologous and seven out of nine (77.8%) protected against heterologous CHMI. Increased protection was associated with V2 T cell and antibody responses. At the higher dose, PfSPZ-CVac(CQ) protected six out of six (100%) participants against heterologous CHMI three months after immunization. All homologous (four out of four) and heterologous (eight out of eight) infectivity control participants showed parasitaemia. PfSPZ-CVac(CQ) and PfSPZ-CVac(PYR) induced a durable, sterile vaccine efficacy against a heterologous South American strain of P. falciparum, which has a genome and predicted CD8 T cell immunome that differs more strongly from the African vaccine strain than other analysed African P. falciparum strains. 3. Hobbs CV, Sahu T, Neal J, Conteh S, Voza T, Borkowsky W, Langhorne J, Duffy PE: Determinants of Malaria Protective Immunity in Mice Immunized with Live Sporozoites during Trimethoprim-Sulfamethoxazole Prophylaxis. Am J Trop Med Hyg 2020. Trimethoprim-sulfamethoxazole (TMP-SMX) is a drug widely used in HIV-exposed uninfected and infected children in malaria-endemic areas, and is known to have antimalarial effects. Using rodent malaria models, we previously showed that repeated Plasmodium exposure during TMP-SMX administration, or chemoprophylaxis vaccination (CVac), induces CD8 T-cell-dependent preerythrocytic immunity. However, humoral immune responses have been shown to be important in models of preerythrocytic immunity. We demonstrated that antibody-mediated responses contribute to protective immunity induced by CVac immune sera using TMP-SMX in models of homologous, but not heterologous, parasite species. Clinical studies must account for potential anti-Plasmodium antibody induced during TMP-SMX prophylaxis. Our unpublished progress during this reporting period includes the following advances: In FY2019, we down-selected to 2 PyPEVA candidates to pursue the PfPEVA orthologues. The two candidates selected were SHMT and 305w (now termed TBP). In FY2020, we pursued expression of both PyPEVA and PfPEVA in E. coli instead of insect cells. Stability of the protein was increased by modifying the N-terminal amino acid to increase the half-life of the protein in E. coli and as a result, protein expression was observed for PySHMT, PfSHMT and PfTBP. Refolding conditions to achieve soluble protein of PySHMT and PfSHMT have been identified and are in development for TBP orthologues. In FY2021, we scaled up expression and refolding of PfTBP and PyTBP. We have initiated combination studies in thicket rats to examine sterile protection of PyPEVA (PySHMT and PyTBP) with PyCSP.