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

Abstract

Over a century since Ronald Ross discovered that malaria is caused by the bite of an infectious mosquito it is still unclear how the number of parasites injected influences disease transmission. Currently it is assumed that all mosquitoes with salivary gland sporozoites are equally infectious irrespective of the number of parasites they harbour, though this has never been rigorously tested. Here we analyse >1000 experimental infections of humans and mice and demonstrate a dose-dependency for probability of infection and the length of the host pre-patent period. Mosquitoes with a higher numbers of sporozoites in their salivary glands following blood-feeding are more likely to have caused infection (and have done so quicker) than mosquitoes with fewer parasites. A similar dose response for the probability of infection was seen for humans given a pre-erythrocytic vaccine candidate targeting circumsporozoite protein (CSP), and in mice with and without transfusion of anti-CSP antibodies. These interventions prevented infection more efficiently from bites made by mosquitoes with fewer parasites. The importance of parasite number has widespread implications across malariology, ranging from our basic understanding of the parasite, how vaccines are evaluated and the way in which transmission should be measured in the field. It also provides direct evidence for why the only registered malaria vaccine RTS,S was partially effective in recent clinical trials.

Author Summary

Malaria is transmitted to humans by the bite of an infectious mosquito though it is unclear whether a mosquito with a high number of parasites is more infectious than one with only a few. Here we show that the greater the number of parasites within the salivary gland of the mosquito following blood-feeding the more likely it is to have transmitted the disease. A clear dose-response is seen with highly infected mosquitoes being more likely to have caused infection (and to have done so quicker) than lightly infected mosquitoes. This suggesting that mosquito-based methods for measuring transmission in the field need to be refined as they currently only consider whether a mosquito is infected or not (and not how heavily infected the mosquito is). Novel transmission reducing drugs and vaccines are tested by experimentally infecting people using infectious mosquitoes. This work indicates that it is important to further standardise infectious dose in malaria experimental infections to enable the efficacy of new interventions to be accurately compared. The work also provides direct evidence to suggest that the world’s first licenced malaria vaccine may be partially effective because it fails to provide protection against highly infected mosquitoes.