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Chemoprophylaxis vaccination: Phase 1 study to explore stage-specific immunity to Plasmodium falciparum in U.S. adults.

BACKGROUND
Chemoprophylaxis vaccination with sporozoites (CVac) with chloroquine induces protection against homologous P. falciparum sporozoite (PfSPZ) challenge, but whether blood-stage parasite exposure is required for protection remains unclear. Chloroquine suppresses and clears blood-stage parasitemia, while other antimalarial drugs such as primaquine act against liver-stage parasites. Here, we evaluate CVac regimens using chloroquine or primaquine as the partner drug to discern whether blood stage parasite exposure impacts protection against homologous controlled human malaria infection.


METHODS
In a phase 1, randomized, partial double-blind, placebo-controlled study of 36 malaria-naïve adults, all CVac subjects received chloroquine prophylaxis and bites from 12-15 P. falciparum-infected mosquitoes (CVac-chloroquine arm) at 3 monthly iterations, and some received post-exposure primaquine (CVac-primaquine/chloroquine arm). Drug control subjects received primaquine, chloroquine, and uninfected mosquito bites. After chloroquine washout, subjects, including treatment-naïve infectivity controls, underwent homologous PfSPZ controlled human malaria infection and were monitored for parasitemia for 21 days.


RESULTS
No serious adverse events occurred. During CVac, all but one subject in the study remained blood smear-negative while only one subject (primaquine/chloroquine arm) remained PCR-negative. Upon challenge, compared to infectivity controls, 3/3 chloroquine arm subjects displayed delayed patent parasitemia (p=0.01) but not sterile protection, while 3/11 primaquine/chloroquine subjects remained blood smear negative.


CONCLUSIONS
CVac-primaquine/chloroquine is safe and induces sterile immunity to P. falciparum in some recipients, but a single 45 mg dose of primaquine post-exposure does not completely prevent blood-stage parasitemia. Unlike previous studies, CVac-chloroquine did not produce sterile immunity.


CLINICAL TRIALS REGISTRATION
ClinicalTrials.gov identifier NCT01500980.