T Cell Regulatory and Suppression Mechanisms in Malaria

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Our published work in FY2023 included: Kc N, Church LWP, Riyahi P, Chakravarty S, Seder RA, Epstein JE, Lyke KE, Mordmller B, Kremsner PG, Sissoko MS, Healy S, Duffy PE, Jongo SA, Nchama VUNN, Abdulla S, Mpina M, Sirima SB, Laurens MB, Steinhardt LC, Oneko M, Li M, Murshedkar T, Billingsley PF, Sim BKL, Richie TL, Hoffman SL. Increased levels of anti-PfCSP antibodies in post-pubertal females versus males immunized with PfSPZ Vaccine does not translate into increased protective efficacy. 2022. Frontiers in Immunology Oct 25.13:1006716. doi: 10.3389/fimmu.2022.1006716. While prior research has shown differences in the risk of malaria infection and sickness between males and females, little is known about sex differences in vaccine-induced immunity to malaria. Identifying such differences could elucidate important aspects of malaria biology and facilitate development of improved approaches to malaria vaccination. Using a standardized ELISA, IgG antibodies to the major sporozoite surface protein PfCSP were measured before and two weeks after administration of PfSPZ Vaccine to 5-month to 61-year-olds across 11 clinical trials conducted in Germany, the US and five African countries, to determine differences in vaccine elicited antibody response between males and females, and whether these differences were associated with differential protection against naturally transmitted Pf malaria (Africa) or controlled human malaria infection (Germany, the US and Africa). Females 11 years of age made significantly higher levels of antibodies to PfCSP than did males in most trials, while there was no indication of such differences in infants or children. Although adult females had higher levels of antibodies, there was no evidence of improved protection compared to males. In 2 of the 7 trials with sufficient data, protected males had significantly higher levels of antibodies than unprotected males, and in 3 other trials protected females had higher levels of antibodies than did unprotected females. We concluded PfSPZ Vaccine induced higher levels of antibodies in post-pubertal females but showed equivalent protection in males and females. Increased antibody levels in post-pubertal females did not contribute substantially to improved protection. We hypothesize that while antibodies to PfCSP (and PfSPZ) may potentially contribute directly to protection, they primarily correlate with other, potentially protective immune mechanisms, such as antibody dependent and antibody independent cellular responses in the liver. Richie TL, Church LWP, Murshedkar T, Billingsley PF, James ER, Healy SA, Diawara H, Sissoko MS, Sagara I, Cook DM, Mordmller B, Chakravarty S, Kapulu M, Kreidenweiss A, Vaughan A, Kublin J, Murphy S, Jongo S, Tanner M, Sirima S, Laurens M, Daubenberger C, Silva J, Lyke KE, Abdulla S, Dicko A, Kappe S, Sim BKL, Kremsner PG, Duffy PE, Hoffman SL. Sporozoite Immunization: Innovative Translational Science to Support the Fight Against Malaria. 2023. Expert Review of Vaccines. In press. doi:10.1080/14760584.2023.2245890 A highly effective malaria vaccine is urgently needed, especially for Plasmodium falciparum (Pf), the deadliest human malaria parasite. Sporozoites (SPZ), the parasite stage transmitted by Anopheles mosquitoes to humans, are the only vaccine immunogen achieving > 90% efficacy against Pf infection. We and our partners in the PfSPZ Consortium reviewed > 30 clinical trials of PfSPZ vaccines in the U.S.A., Europe, Africa, and Asia, based on first-hand knowledge of the trials and PubMed searches of 'sporozoites,' 'malaria,' and 'vaccines.' First generation (radiation-attenuated) PfSPZ vaccines are safe, well tolerated, 80-100% efficacious against homologous controlled human malaria infection (CHMI). However, trials in endemic areas have achieved lower albeit significant protection against naturally occurring infection; LMIV in collaboration with Mali and Sanaria scientists demonstrated 18-19 months protection without boosting in Africa. Future studies should seek to understand immunological mechanisms that may explain reduced efficacy of PfSPZ Vaccine in Africa, using samples and data from the trials we have conducted. Our unpublished progress during this reporting period includes the following advances: We identified a subset of KLRC1+ Vd2 T cell and genes that are upregulated during PfSPZ vaccinations and associate with sterile immunity. In parallel, using a mouse model of whole SPZ vaccination, we identified the corresponding subset of gd T cells that play this role in SPZ-immunized mice and that are required to generate protective CD8 T cells.