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.

DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection

“…Hence, sequential and adaptive study designs can be used. Infection is highly reproducible and therefore the number of participants and infection controls can be minimised compared with natural exposure and mosquito-mediated CHMI 10, 19. Also, the fully infectious dose is small enough to allow at least three replication cycles following the hepatic stage, hence activity against asexual blood stages can be assessed as wel.…”

“…Other limitations of CHMI studies are related to their model character and the study population. CHMI is optimised to infect all inoculated volunteers, which is more stringent than in naturally acquired infection, in which only a fraction of bites of infected mosquitoes will lead to malaria 19 . Such non-physiological inoculates are required to ascertain that the prophylactic effect of the drug is measured and not infectiveness of the inoculum.…”

Experimental Determination of the Force of Malaria Infection Reveals a Non-Linear Relationship to Mosquito Sporozoite Loads

“…A recent study used data from human vaccine trials and rodent malaria transmission blocking studies to determine whether there was a relationship between mosquito salivary load and infection [53]. Both mice and humans in these studies were subjected to multiple mosquito bites, between 5-12 in the human studies and 1-10 in the rodent studies, and thus it is not possible to directly determine the probability that a single infected mosquito bite will initiate malaria infection.…”

Vital role forPlasmodium bergheiKinesin8B in axoneme assembly during male gamete formation and mosquito transmission

“…Since as few as 10 sporozoites would be sufficient to complete the life cycle (Churcher et al, 2017), we tested the ability of the parasites to infect mice. Since as few as 10 sporozoites would be sufficient to complete the life cycle (Churcher et al, 2017), we tested the ability of the parasites to infect mice.…”

“…Since as few as 10 sporozoites would be sufficient to complete the life cycle (Churcher et al, 2017), we tested the ability of the parasites to infect mice. A. stephensi mosquitoes, fed 21 days prior on mice infected with ΔPbkin8B, wt or Pbkin8B-gfp parasites, were allowed to bite naïve 6-to 8-week-old female Tucks Ordinary mice.…”