Comparison of Clinical and Parasitological Data from Controlled Human Malaria Infection Trials

Abstract

BackgroundExposing healthy human volunteers to Plasmodium falciparum-infected mosquitoes is an accepted tool to evaluate preliminary efficacy of malaria vaccines. To accommodate the demand of the malaria vaccine pipeline, controlled infections are carried out in an increasing number of centers worldwide. We assessed their safety and reproducibility.MethodsWe reviewed safety and parasitological data from 128 malaria-naïve subjects participating in controlled malaria infection trials conducted at the University of Oxford, UK, and the Radboud University Nijmegen Medical Center, The Netherlands. Results were compared to a report from the US Military Malaria Vaccine Program.ResultsWe show that controlled human malaria infection trials are safe and demonstrate a consistent safety profile with minor differences in the frequencies of arthralgia, fatigue, chills and fever between institutions. But prepatent periods show significant variation. Detailed analysis of Q-PCR data reveals highly synchronous blood stage parasite growth and multiplication rates.ConclusionsProcedural differences can lead to some variation in safety profile and parasite kinetics between institutions. Further harmonization and standardization of protocols will be useful for wider adoption of these cost-effective small-scale efficacy trials. Nevertheless, parasite growth rates are highly reproducible, illustrating the robustness of controlled infections as a valid tool for malaria vaccine development.

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

“…Furthermore, P. falciparum lysate-seropositive Tanzanians had a lower parasite load at the time of first detection by qPCR and at the time of the first peak of parasite load than seronegative Tanzanians. The first peak of blood-stage parasitemia can be used as a proxy for parasite liver load (16,35). Our results might therefore indicate the emergence of fewer parasites from the liver and hence better control of either initiation or progression of liver-stage infection in preexposed individuals within the Tanzanian cohort and in Tanzanians than in the Dutch cohort.…”

“…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.…”

“…CHMI trials have so far been performed in countries were malaria is not endemic in previously unexposed individuals (11,(16)(17)(18)(19). A logical next step is to study the potential differences in the acquisition, maintenance, or recall of immune responses in individuals from different transmission settings and genetic backgrounds (20,21).…”

Probability of Transmission of Malaria from Mosquito to Human Is Regulated by Mosquito Parasite Density in Naïve and Vaccinated Hosts

“…In the CHMI trials analysed here volunteers are bitten by infected mosquitoes until they have received 5 bites from mosquitoes with >10 residual-sporozoites [21]. This ensures that all control volunteers develop malaria [22] though precludes these volunteers being used to investigate factors influencing the probability of naïve human infection.…”

Workshop report: Malaria vaccine development in Europe–preparing for the future

“…CHMI studies lead to discomfort in the volunteers, particularly during the treatment of asexual parasitaemia [52,53]. For diagnosis, some centres therefore explore the possibility of using a quantitative polymerase chain reaction (qPCR) [54] along with the current gold standard, thick blood smear microscopy [55].…”