Maturation of human humoral immunity through repeat malaria challenges

Malaria continues to be among the world’s most virulent infectious diseases accounting for the death of ~0.4 million people a year. Unlike many viral infections, children usually have repeated clinical episodes, but by adulthood, the majority of individuals living in endemic areas are protected against disease, not parasite carriage. The reasons for this gradual response to the parasite are not well established. Eventually antibodies are produced in adults that reduce parasitemia and fever when passively transferred to children with malaria, indicating a role for antibody-mediated immunity. However, it has been difficult to study this slow development of immunity to natural infection in the field, since there is no way to control for parasite strain or exposure timing. Animal studies, while allowing controlled inoculations of specific parasite strains, are complicated to apply to human infections due to differences across host and parasite species. To address these limitations a clinical trial was carried out to systematically evaluate the immune response of malaria-naïve volunteers to an initial exposure to uninfected mosquitoes, followed 2 months later with Plasmodium falciparum (Pf)-infected mosquito bites and then 2-3 subsequent challenges each with the mosquitoes infected with the same strain of Pf. The use of the controlled human malaria infection (CHMI) model allowed control of the timing of parasite exposure and therefore the early response to sequential infections could be directly monitored. As observed with children in malaria endemic countries, the initially naïve volunteers continued to be susceptible through the multiple infectious challenges, but the time to a positive blood smear, termed patency, increased significantly overtime. Symptoms decreased significantly by the 3rd and 4th challenges indicating the beginning of clinical immunity and preliminary data indicates plasma from the two subjects with the longest patency delay reduced liver cell invasion consistent with the development of pre-erythrocytic immunity. This unique, well- controlled infection model allows  a carefully follow up of the production of antibody-secreting plasma cells and parasite-specific memory B cells from before parasite exposure through 3 to 4 challenges with mosquitoes infected with the same strain of P. falciparum. Preliminary analysis of the antibody repertoire of circulating plasma cells demonstrates marked clonal expansion followed by population collapse and the appearance of distinct clones. The hypothesis is that B cells stimulated by the parasite proliferate and differentiate preferentially into plasma cells, not memory cells. Such a model could explain the lack of a sustained memory response to infection and subsequent delay in the acquisition of immunity. Together the results will advance our understanding of the memory response to Plasmodium, which is critical for the development of protective immunity.

Project details

Vaccines (Immune Correlates)

May 2023 — Apr 2028

$801,244

United States