Assessment of malaria whole organism vaccines

National Institute Of Allergy And Infectious Diseases

Investigators

Linked publications & trials

Abstract

From our publications, we report the following FY21 advances: 1. Sissoko MS, Healy SA, Katile A, Zaidi I, Hu Z, Kamate B, Samake Y, Sissoko K, Mwakingwe-Omari A, Lane J, Imeru A, Mohan R, Thera I, Guindo CO, Dolo A, Niare K, Koita F, Niangaly A, Rausch KM, Zeguime A, Guindo MA, Bah A, Abebe Y, James ER, Manoj A, Murshedkar T, KC N, Sim BKL, Billingsley PF, Richie TL, Hoffman SL, Doumbo O, Duffy PE. Three dose regimen of PfSPZ Vaccine protects adult Malians against Plasmodium falciparum through an intense transmission season: a randomized, controlled phase I trial. 2021. Lancet Infectious Diseases. In press. We conducted a phase 1 clinical trial in Mali, West Africa to assess the safety, immunogenicity and protective efficacy of a three-dose regimen of Sanaria PfSPZ Vaccine, an attenuated, Plasmodium falciparum (Pf) sporozoite (SPZ) vaccine, administered via direct venous inoculation (DVI), against homologous controlled human malaria infection (CHMI) and natural Pf infection. We recruited 1850-year-old healthy, non-pregnant Malians for an open-label, dose-escalation (45x105, 9x105, 18x106 PfSPZ) pilot study (n=55) and thereafter a randomised, double-blind, placebo-controlled main trial of 18x106 PfSPZ or normal saline (NS) (n=120). Primary outcome was safety and tolerability and secondary outcome was vaccine efficacy (VE) against homologous PfSPZ CHMI or against naturally transmitted Pf infection. Adverse events and laboratory abnormalities post-vaccination in all dosing arms were few, mainly mild, and did not differ significantly between vaccine arms (all p>005). Unexpected, severe transaminitis, presumed due to artesunate/amodiaquine, occurred in four subjects (2 vaccinees, 2 controls). During PfSPZ CHMI, 5 weeks after 3rd dose of 18106 PfSPZ, 0/29 vaccinees and 1/15 controls became blood smear (BS)-positive; 0/29 vaccinees and 8/15 (533%) controls became PCR-positive (VE 1, 95%CI 0.73-1; p<0001). In the main trial, 32/55 (582%) vaccinees and 42/54 (778%) controls became BS-positive during 24-week surveillance post-vaccination. VE (1-hazard ratio) was 051 per-protocol (95%CI 020070; log-rank p=0004) and 039 mITT (95%CI 004062; p=0033); VE (1-risk ratio) was 024 per-protocol (95%CI 002041; p=0031) and 022 mITT (95%CI 001-039; p=0041). Antibody and V2 T-cell responses were significantly higher in PfSPZ Vaccinees who remained uninfected. A three-dose regimen of PfSPZ Vaccine was safe, well-tolerated, and conferred 51% VE against intense natural Pf transmission, similar to 52% VE reported for the five-dose regimen. 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. 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. Coelho CH, Duffy PE: Unwanted Feedback: Malaria Antibodies Hinder Vaccine Boosting. Cell Host Microbe 2020, 28:504-506. Whole-organism vaccination is a promising approach to prevent malaria. In this issue of Cell Host & Microbe, we commented on a recent study by McNamara and colleagues that identified epitope masking as a hindrance to antibody boosting after repeated administration of attenuated Plasmodium falciparum sporozoite vaccine. 4. In unpublished work, we continued progress on our IND clinical trials registered at clinicaltrials.gov: Two regimens of PfSPZ Vaccine in Mali, Africa #18-I-N084 This study (N=210 enrolled) explored two accelerated regimens of vaccination, a regimen used in the previous study (0, 8, 16 wks) and a shortened regimen (0, 1, 4 wks) in Ouelessebougou, Mali. Vaccinations started in Jun 2018 with the 3rd vaccination administered in Sep 2018, then participants followed to assess vaccine efficacy against natural transmission during the rainy season. In FY19, a booster vaccination was successfully administered to 142 participants who completed long-term follow-up in FY20. Preliminary analyses indicate that infection risk was lower in vaccinees than controls, but efficacy was not statistically significant for either regimen. We hypothesize that vaccine efficacy was compromised because subjects did not receive antimalarials to clear parasitemia before vaccination. 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: Arm 1b: PfSPZ-CVac (PYR) with PYR administered on day 0 (n=90) Arm 2b: PfSPZ-CVac (PYR) with PYR administered on days 2 and 3 (n=60) Arm 4a: Normal saline control with PYR administered on day 0 (n=54) 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.