A PfSPZ vaccine immunization regimen equally protective against homologous and heterologous controlled human malaria infection

Abstract

Immunization with radiation-attenuated Plasmodium falciparum (Pf) sporozoites (SPZ) in PfSPZ Vaccine, has provided better vaccine efficacy (VE) against controlled human malaria infection (CHMI) with the same parasites as in the vaccine (homologous) than with genetically distant parasites (heterologous). We sought to identify an immunization regimen that provided similar VE against CHMI with homologous and heterologous Pf for at least 9 weeks in malaria-naïve adults. Such a regimen was identified in part 1 (optimization), an open label study, and confirmed in part 2 (verification), a randomized, double-blind, placebo-controlled study in which VE was assessed by cross-over repeat CHMI with homologous (PfNF54) and heterologous (Pf7G8) PfSPZ at 3 and 9-10 weeks. VE was calculated using Bayesian generalized linear regression. In part 1, vaccination with 9 × 105 PfSPZ on days 1, 8, and 29 protected 5/5 (100%) subjects against homologous CHMI at 3 weeks after the last immunization. In part 2, the same 3-dose regimen protected 5/6 subjects (83%) against heterologous CHMI at both 3 and 9-10 weeks after the last immunization. Overall VE was 78% (95% predictive interval: 57-92%), and against heterologous and homologous was 79% (95% PI: 54-95%) and 77% (95% PI: 50-95%) respectively. PfSPZ Vaccine was safe and well tolerated. A 4-week, 3-dose regimen of PfSPZ Vaccine provided similar VE for 9-10 weeks against homologous and heterologous CHMI. The trial is registered with ClinicalTrials.gov, NCT02704533.

Conflict of interest statement

NKC, SC, PR, LWPC, TLR, BKLS, and SLH are salaried, full-time employees of Sanaria, the developer and sponsor of Sanaria PfSPZ Vaccine and PfSPZ Challenge. SLH and BKLS also have financial interests in Sanaria. BKLS and SLH are inventors on patents and patent applications that have been assigned to Sanaria. BM and PGK received funding from DZIF to conduct the trial. All other authors declare no competing interests.

© 2022. The Author(s).

Figures

Fig. 1. Study flow Chart.

aOptimization of PfSPZ Vaccine regimen and (b) Verification of PfSPZ Vaccine regimen. *9 of the 45 subjects were allocated to a 7G8 safety analysis that will be published elsewhere. $One volunteer received only the first vaccination. #One volunteer received the 2nd vaccination on day 15 instead of day 8.

Fig. 2. Results of CHMIs to assess VE during Verification.

a First CHMI at 3 weeks (top row) and second CHMI at 9–10 weeks (bottom row) of the individual volunteers. The black indicates no parasitemia (protected); the white represents parasitaemia (not protected). b Kaplan-Meier plots for heterologous CHMIs with Pf7G8. Five of 6 vaccinees were protected at 3 weeks and at 9–10 weeks. Six of 6 CHMIs with PfSPZ Challenge (7G8) in the controls resulted in parasitemia (infected). c Kaplan-Meier plots for homologous CHMIs with PfNF54. Four of 6 vaccinees were protected at 3 weeks and 5/6 were protected at 9–10 weeks. Five of 6 CHMIs with PfSPZ Challenge (NF54) in the controls resulted in parasitemia (infected).

Fig. 3. Antibodies to PfCSP and PfSPZ and functional activity of sera against PfSPZ.

a, b Median and interquartile range of net OD 1.0 for IgG and IgM antibodies to PfCSP by ELISA one day prior to CHMI in malaria-naïve adults who were uninfected (protected) and infected during CHMI administered 3 weeks after the 3rd dose (CHMI 1). c, d Median and interquartile range of net IgG antibodies to PfSPZ by aIFA and net inhibition of PfSPZ invasion of hepatocytes by aISI one day prior to CHMI in malaria-naïve adults who were uninfected (protected) and infected during CHMI administered 3 weeks after the 3rd dose (CHMI 1). e, f Median and interquartile range of net OD 1.0 for IgG and IgM antibodies to PfCSP by ELISA the day prior to CHMI in adults who were uninfected (protected) and infected during CHMI administered 9–10 weeks after the 3rd dose (CHMI 2). g, h Median and interquartile range of net IgG antibodies to PfSPZ by aIFA and net inhibition of PfSPZ invasion of hepatocytes by aISI one day prior to CHMI in adults who were uninfected (protected) and infected during CHMI administered 9–10 weeks after the 3rd dose (CHMI 2). P values were calculated by Wilcoxon-Mann-Whitney test. For each panel, filled triangles are uninfected subjects and open triangles are infected subjects who received heterologous CHMI with PfSPZ Challenge (7G8) and filled circles are uninfected subjects and open circles are infected subjects who received homologous CHMI with PfSPZ Challenge (NF54).