Controlled Human Malaria Infections by Intradermal Injection of Cryopreserved Plasmodium falciparum Sporozoites

Abstract

Controlled human malaria infection with sporozoites is a standardized and powerful tool for evaluation of malaria vaccine and drug efficacy but so far only applied by exposure to bites of Plasmodium falciparum (Pf)-infected mosquitoes. We assessed in an open label Phase 1 trial, infection after intradermal injection of respectively 2,500, 10,000, or 25,000 aseptic, purified, vialed, cryopreserved Pf sporozoites (PfSPZ) in three groups (N = 6/group) of healthy Dutch volunteers. Infection was safe and parasitemia developed in 15 of 18 volunteers (84%), 5 of 6 volunteers in each group. There were no differences between groups in time until parasitemia by microscopy or quantitative polymerase chain reaction, parasite kinetics, clinical symptoms, or laboratory values. This is the first successful infection by needle and syringe with PfSPZ manufactured in compliance with regulatory standards. After further optimization, the use of such PfSPZ may facilitate and accelerate clinical development of novel malaria drugs and vaccines.

Impact of Malaria Preexposure on Antiparasite Cellular and Humoral Immune Responses after Controlled Human Malaria Infection

“…In line with such an effect of preexisting antisporozoite immunity would be the observation that those Tanzanian volunteers with a longer prepatancy by qPCR also had higher baseline antibody titers against the sporozoite antigen CSP. However, the first detection by qPCR in both the Dutch and Tanzanians after intradermal PfSPZ injection was uncharacteristically late compared to that for infection by mosquito bite routinely conducted in The Netherlands and elsewhere (11,16,18,19,23,24,35). This is likely due to less efficient liver-stage infection by this route and hence a low initial blood-stage load that reaches the qPCR detection limit only later.…”

“…The availability of aseptic, purified, cryopreserved, live P. falciparum sporozoites (PfSPZs; PfSPZ Challenge) (22) opens up opportunities to carry out CHMI trials in countries where malaria is endemic, since it bypasses the need for infecting local Anopheles mosquitoes with P. falciparum or importing P. falciparum-infected mosquitoes to the trial site. The first PfSPZ Challenge trial in malaria-naive Dutch volunteers demonstrated an infectivity rate of 83% after intradermal injections, independent of the dose given (23). Recently, PfSPZ Challenge was used for the first time during a CHMI trial in healthy adult male Tan-isolation lysis buffer to serve as an internal control.…”

Immunization with Apical Membrane Antigen 1 Confers Sterile Infection-Blocking Immunity against Plasmodium Sporozoite Challenge in a Rodent Model

“…The sporozoite dose was based on counts conducted at vialing; the pRBC dose was determined immediately prior to infection. The process of cryopreservation is associated with a loss of sporozoite viability, and our challenge dose of 10 3 cryopreserved sporozoites corresponds to a challenge dose of approximately 140 freshly dissected sporozoites (56). We have previously established that 100% of mice inoculated with as few as 50 cryopreserved P. yoelii sporozoites developed blood-stage parasitemia (S. Schussek, submitted for publication).…”

Artesunate versus Chloroquine Infection–Treatment–Vaccination Defines Stage-Specific Immune Responses Associated with Prolonged Sterile Protection against Both Pre-erythrocytic and Erythrocytic Plasmodium yoelii Infection

“…In comparison, the alternative infection-treatment-vaccination (ITV) strategy, which involves administration of wild type (wt) malaria parasites under drug treatment, requires significantly less spz to elicit protection (8)(9)(10), suggesting that irr-spz are not as immunogenic as wt spz under drug coverage. For example, infection of naive individuals via 3 doses of 15 bites each of mosquitoes infected with wt P. falciparum under chloroquine (CQ) coverage induces long-term protection against challenge (11,12). Despite these promising results, the severity of CQ resistance in the African continent precludes the use of CQ-ITV as an immunization strategy.…”