Assessment of malaria whole organism vaccines

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications, trials & patents

Abstract

From our publications, we report the following FY2022 advances: 1. Silva JC, Dwivedi A, Moser KA, Sissoko MS, Epstein JE, Healy SA, Lyke KE, Mordmuller B, Kremsner PG, Duffy PE, Murshedkar T, Sim BKL, Richie TL, Hoffman SL. Plasmodium falciparum 7G8 challenge provides conservative prediction of efficacy of PfNF54-based PfSPZ Vaccine in Africa. 2022. Nature Communications. June 13. Controlled human malaria infection (CHMI) has supported Plasmodium falciparum (Pf) malaria vaccine development by providing preliminary estimates of vaccine efficacy (VE). Because CHMIs generally use Pf strains similar to vaccine strains, VE against antigenically heterogeneous Pf in the field has been required to establish VE. We increased the stringency of CHMI by selecting a Brazilian isolate, Pf7G8, which is genetically distant from the West African parasite (PfNF54) in our PfSPZ vaccines. Using two regimens to identically immunize US and Malian adults, VE over 24 weeks in the field was as good as or better than VE against CHMI at 24 weeks in the US. To explain this finding, here we quantify differences in the genome, proteome, and predicted CD8 T cell epitopes of PfNF54 relative to 704 Pf isolates from Africa and Pf7G8. We show that Pf7G8 is more distant from PfNF54 than any African isolates tested. We propose VE against Pf7G8 CHMI for providing pivotal data for malaria vaccine licensure for travelers to Africa, and potentially for endemic populations, because the genetic distance of Pf7G8 from the Pf vaccine strain makes it a stringent surrogate for Pf parasites in Africa. In unpublished work, we continued progress on our IND clinical trials registered at clinicaltrials.gov: WOCBP PfSPZ Vaccine in Mali, Africa #19-I-N113 This is a randomized, double blind, placebo-controlled study to assess the safety, tolerability, immunogenicity, and protective efficacy of PfSPZ Vaccine in healthy women of child bearing potential (WOCBP). Enrolled women receive pregnancy prevention during vaccination, but report plans to become pregnant in the near future. The study assesses safety, tolerability and efficacy of PfSPZ Vaccine primary series in healthy Malian WOCBP when administered at 1, 8, 29 days at two different doses (9 x105and 1.8 x106) after receiving antimalarials to clear parasitemia. This study enrolled in FY19; Year 1 results indicated that both regimens were efficacious. Based on this success, follow up of the entire cohort continued for a second year to assess efficacy of the vaccine over two successive malaria seasons, without a Year 2 booster dose. Analysis is ongoing. PfSPZ CVac-Mali #19-I-0099 In FY19 annual report, we reported the CVac-PYR2 #17-I-0067 study of Chemoprophyaxis Vaccination (CVac) at NIH: high dose PfSPZ-CVac PfSPZ Challenge NF54 with either pyrimethamine (PYR) or chloroquine (CQ) were safe and well-tolerated. In both PfSPZ-CVac-PYR and PfSPZ-CVac-CQ groups, high levels of sterile immunity against homologous (NF54) and heterologous (7G8) CHMI were observed 3 months after last dose. The unprecedented results from #17-I-0067 justified a Phase 2 efficacy PfSPZ Cvac trial that began in Bancoumana, Mali (PfSPZ CVac-Mali #19-I-0099) in FY2019. The study began screening participants in May 2019. After favorable results in the pilot phase study, the main phase proceeded with these arms that received 3 vaccinations approximately 1 month apart while on PYR treatment: 1. Arm 1b: PfSPZ-CVac (PYR) with PYR administered on day 0 (n=90) 2. Arm 2b: PfSPZ-CVac (PYR) with PYR administered on days 2 and 3 (n=60) 3. Arm 4a: Normal saline control with PYR administered on day 0 (n=54) 4. Arm 4b: Normal saline control with PYR administered on days 2 and 3 (n=36) Per the a priori statistical plan, a blinded analysis of the efficacy results was performed by the study statistician after Year 1 efficacy follow up, who reported that at least one of the PfSPZ CVac regimens showed significant efficacy. Based on this finding, the study remains blinded and is continuing for a second year in which subjects receive a booster dose of PfSPZ CVac or placebo saline. Subjects in PfSPZ Cvac arm(s) that were efficacious in FY19 were boosted with PfSPZ CVac, while other subjects received placebo saline; booster dose administration was completed 13 August 2020, and follow up continued into FY21 to assess protection in a second year after a booster dose. We expect efficacy analyses to be completed in FY22.