Characterising the circulation of gametocytes and mosquito infectivity in induced blood stage malaria

BACKGROUND: Understanding the influence of gametocyte dynamics on transmission of Plasmodium falciparum from humans to mosquitoes may support malaria elimination initiatives. METHODS: Longitudinal parasitemia, gametocytemia and mosquito transmission data from 91 participants in 9 controlled human malaria infection studies conducted in Brisbane, Australia (n=8) and Nijmegen, Netherlands (n=1) were analysed to explore the relationship of parasite and participant characteristics on gametocytes and transmission. Transmission potential estimated using Poisson probabilities was compared to transmission to Anopheles stephensi mosquitoes assessed using direct and membrane feeding assays across 5 clinical trials and 30 participants. RESULTS: Maximum gametocyte density overtime per participant was positively correlated with asexual parasitemia at time of first treatment (ρ minimum=0.44, maximum=0.89). Median maximum gametocyte densities occurring 19-21 days post inoculation were 1087 gametocytes/mL for female and 219 gametocytes/mL for male gametocytes. Both female and male gametocyte densities were higher among individuals who infected mosquitoes, as were pre-treatment parasite growth rates and parasite densities. Infectivity rates varied between 53-54% for direct skin, 29-33% for direct membrane, 54-100% for membrane after serum replacement and 89-100% for enriched membrane feeding assays. Potential for transmission was correctly predicted for 71-74% of direct and 50-78% of membrane after serum replacement feeding assays. CONCLUSIONS: This study confirms that transmissible gametocyte densities can be consistently achieved in controlled infections. Higher asexual densities and growth rates were associated with higher gametocyte densities and higher transmission. Detailed understanding of how low level gametocytemia contributes to transmission will guide both experimental infection studies and interventions to interrupt transmission.