Development of clinical immunity to Plasmodium vivax following repeat controlled human malaria infection.
Hou MM., Harding AC., Barber NM., Kundu P., Bach FA., Salkeld J., Themistocleous Y., Greenwood NM., Cho J-S., Barrett JR., Nugent FL., Rawlinson TA., Hodgson SH., Khozoee B., Mac Lochlainn DJ., Cowan RE., Poulton ID., Baker M., Kingham L., Mitton CH., Platt A., Lopez Ramon R., Ramos Lopez F., Thomas M., Skinner K., Quinkert D., Pipini D., Lias AM., Bardelli M., Edwards NJ., Donnellan FR., Biswas S., Rayner JC., Nielsen CM., Silk SE., Draper SJ., Nahrendorf W., Spence PJ., Minassian AM.
Clinical immunity to malaria can lead to asymptomatic infection, but the underlying mechanisms remain unclear. To examine the development of clinical immunity, we conducted a multi-cohort, repeat controlled human malaria infection (CHMI) study with Plasmodium vivax, and a heterologous rechallenge with P. falciparum (ClinicalTrials.gov NCT03797989). Malaria-naïve adults underwent CHMI up to three times, by administration of red blood cells infected with P. vivax PvW1 clone or P. falciparum 3D7 clone. Nineteen participants underwent primary CHMI with P. vivax, 12 returned for secondary homologous CHMI and 2 for tertiary homologous CHMI. Six participants who had completed P. vivax CHMI then underwent heterologous rechallenge with P. falciparum. We find that clinical immunity to P. vivax develops rapidly after a single CHMI, protecting participants against fever and laboratory abnormalities. This is underpinned by the attenuation of inflammatory cytokines and chemokines, as well as reduced coagulation and endothelium activation. In contrast, there is no evidence of anti-parasite immunity, suggesting that mechanisms of clinical immunity can operate independently of pathogen load to reduce the damage caused by malaria infection. In addition, we show that clinical immunity to P. vivax is parasite species-specific and provides no protection against CHMI with P. falciparum.