Chemoprophylaxis Vaccination: Phase I Study to Explore Stage-specific Immunity to Plasmodium falciparum in US Adults

Abstract

Background: Chemoprophylaxis vaccination with sporozoites (CVac) with chloroquine induces protection against a homologous Plasmodium 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 evaluated CVac regimens using primaquine and/or chloroquine as the partner drug to discern whether blood-stage parasite exposure impacts protection against homologous controlled human malaria infection.

Methods: In a Phase I, randomized, partial double-blind, placebo-controlled study of 36 malaria-naive 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 postexposure primaquine (CVac-primaquine/chloroquine arm). Drug control subjects received primaquine, chloroquine, and uninfected mosquito bites. After a chloroquine washout, subjects, including treatment-naive 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 1 subject in the study remained blood-smear negative, while only 1 subject (primaquine/chloroquine arm) remained polymerase chain reaction-negative. Upon challenge, compared to infectivity controls, 3/3 chloroquine arm subjects displayed delayed patent parasitemia (P = .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 postexposure does not completely prevent blood-stage parasitemia. Unlike previous studies, CVac-chloroquine did not produce sterile immunity.

Clinical trials registration: NCT01500980.

Keywords: Plasmodium falciparum; chemoprophylaxis vaccination with sporozoites; chloroquine; malaria; primaquine.

Published by Oxford University Press for the Infectious Diseases Society of America 2019.

Figures

Figure 1.

Trial profile. The boxes outlined in red represent the receipt of Pf SPZ+ mosquito bites, and those outlined in blue represent the receipt of Pf SPZ- mosquito bites. All CVac subjects received CQ from 8 days prior to the first iteration of mosquito bites to 20 days following the third mosquito bite exposure. Approximately 5 weeks elapsed between the discontinuation of CQ and CHMI to allow drug concentrations to decrease to subtherapeutic concentrations. “Received CVac” was defined as undergoing Pf SPZ± mosquito bites and receiving PQ/placebo. The EOS was defined as the final post-CHMI study visit (study Day 182; 35 days post-CHMI). LTF visits at 3 and 6 months post-CHMI were optional. Abbreviations: -, noninfectious mosquito bites; +, infectious mosquito bites; CHMI, controlled human malaria infection; CQ, chloroquine; CVac, chemoprophylaxis vaccination with sporozoites; EOS, end of study; LTF, long-term follow-up; Pf, Plasmodium falciparum; PQ, primaquine; SPZ, sporozoites.

Figure 2.

CVac-phase parasite densities for all study arms. The estimated mean parasites/mL by qRT-PCR are shown for the combined pilot phase PQ/CQ arm (blue line), main phase PQ/CQ Arm (orange line), CQ arm (black line), and drug control arm (green line) following the first, second, and third PfSPZ± mosquito bite exposures. Time is shown relative to each PfSPZ± mosquito bite exposure, which were spaced 28 days apart. The cumulative number of subjects positive in each arm by thick blood smear and/or qRT-PCR over eligible subjects during that CVac are shown for each corresponding CVac phase. Abbreviations: -, noninfectious mosquito bites; +, infectious mosquito bites; CQ, chloroquine; CVac, chemoprophylaxis vaccination with sporozoites; Pf, Plasmodium falciparum; PQ, primaquine; qRT-PCR, qualitative real-time polymerase chain reaction; SPZ, sporozoites.

Figure 3.

Kaplan-Meier curve showing the percentage of subjects who remained TBS-negative following homologous CHMI. The pilot phase PQ/CQ arm (blue line), main phase PQ/CQ arm (orange line), CQ arm (black line), drug control arm (green line), and infectivity control arm (red line) are shown. The P value reported is for the log-rank test, comparing all 5 arms. The CQ arm compared to the combined controls (drug and infectivity controls; n = 12) is P = .004 and compared to the infectivity controls alone (n = 6) is P = .01. The CQ arm compared to the combined PQ/CQ arms (pilot and main) is P = .74. Abbreviations: CHMI, controlled human malaria infection; CQ, chloroquine; PQ, primaquine; TBS, thick blood smear.