PfSPZ-CVac efficacy against malaria increases from 0% to 75% when administered in the absence of erythrocyte stage parasitemia: A randomized, placebo-controlled trial with controlled human malaria infection

Abstract

PfSPZ-CVac combines ‘PfSPZ Challenge’, which consists of infectious Plasmodium falciparum sporozoites (PfSPZ), with concurrent antimalarial chemoprophylaxis. In a previously-published PfSPZ-CVac study, three doses of 5.12x10 ⁴ PfSPZ-CVac given 28 days apart had 100% vaccine efficacy (VE) against controlled human malaria infection (CHMI) 10 weeks after the last immunization, while the same dose given as three injections five days apart had 63% VE. Here, we conducted a dose escalation trial of similarly condensed schedules. Of the groups proceeding to CHMI, the first study group received three direct venous inoculations (DVIs) of a dose of 5.12x10 ⁴ PfSPZ-CVac seven days apart and the next full dose group received three DVIs of a higher dose of 1.024x10 ⁵ PfSPZ-CVac five days apart. CHMI (3.2x10 ³ PfSPZ Challenge) was performed by DVI 10 weeks after the last vaccination. In both CHMI groups, transient parasitemia occurred starting seven days after each vaccination. For the seven-day interval group, the second and third vaccinations were therefore administered coincident with parasitemia from the prior vaccination. Parasitemia was associated with systemic symptoms which were severe in 25% of subjects. VE in the seven-day group was 0% (7/7 infected) and in the higher-dose, five-day group was 75% (2/8 infected). Thus, the same dose of PfSPZ-CVac previously associated with 63% VE when given on a five-day schedule in the prior study had zero VE here when given on a seven-day schedule, while a double dose given on a five-day schedule here achieved 75% VE. The relative contributions of the five-day schedule and/or the higher dose to improved VE warrant further investigation. It is notable that administration of PfSPZ-CVac on a schedule where vaccine administration coincided with blood-stage parasitemia was associated with an absence of sterile protective immunity.

Clinical trials registration: NCT02773979.

Author summary

The world needs a protective malaria vaccine. One approach is to repeatedly administer whole sporozoites, the parasite form that is transmitted from mosquitos to humans. Without treatment, sporozoites enter the liver, grow for a week, and then infect red blood cells, causing clinical disease. Here, we gave a vaccine consisting of sporozoites with a drug that prevents red blood cell infections to eliminate clinical illness. This approach was protective in other studies so we initially evaluated a faster schedule where the vaccine was given weekly. Surprisingly, there was no protection observed. We determined that weekly intervals led the second and third vaccine doses to be administered just as the previous dose of sporozoites was transitioning from the liver to the blood stage. Even though blood stage infection was stopped in this study by the co-administered drug (chloroquine), we hypothesized that it was problematic to administer a vaccine during blood stage infection. Therefore, we gave the vaccinations every five days so that upon the second and third doses, there were no blood-stage parasites present. With five-day spacing and a higher dose, the vaccine protected 75% of participants. These findings suggest that blood-stage infections may hinder formation of protective responses to malaria.