Role of Human Pegivirus Infections in Whole P. falciparum Sporozoite Vaccination and Controlled Human Malaria Infection in African Volunteers

Background: Diverse vaccination outcomes and protection levels pose a serious challenge to the development of an effective malaria vaccine. Co-infections are among many factors associated with immune dysfunction and sub-optimal vaccination outcomes. Chronic, asymptomatic viral infections can contribute to the modulation of vaccine efficacy through various mechanisms. Human Pegivirus-1 (HPgV-1) persists in immune cells thereby potentially modulating immune responses. We investigated whether Pegivirus infection influences vaccine-induced responses and protection in African volunteers undergoing whole P. falciparum sporozoites-based malaria vaccination and controlled human malaria infections (CHMI). Methods: HPgV-1 prevalence was quantified by RT-qPCR in plasma samples of 96 individuals before, during and post vaccination with PfSPZ Vaccine in cohorts from Tanzania and Equatorial Guinea. The impact of HPgV-1 infection was evaluated on (1) systemic cytokine and chemokine levels measured by Luminex, (2) PfCSP-specific antibody titers quantified by ELISA (3) asexual blood stage parasitemia and pre-patent periods with HPgV-1 infection status and (4) HPgV-1 RNA levels upon asexual blood stage parasitemia induced by CHMI. Results: The prevalence of HPgV-1 was 29.2% (28/96) and sequence analysis of the 5`UTR and E2 region revealed the predominance of genotypes 1, 2 and 5 in the positive volunteers. HPgV-1 infection was associated with elevated systemic levels of IL-2 and IL-17A. Comparable vaccine-induced anti-PfCSP antibody titers, asexual blood stage multiplication rates and pre-patent periods were observed in HPgV-1 positive and negative individuals. However, higher level of protection was detected in the HPgV-1 positive group (62.5%) than negative one (51.6%) following CHMI. Overall, HPgV-1 viremia levels were not significantly altered after CHMI. Conclusions: Although HPgV-1 infection did not alter vaccine-elicited levels of PfCSP-specific antibody responses and parasite multiplication rates, an ongoing infection appears to improve some degree of protection against CHMI in PfSPZ-vaccinated individuals. This is likely through modulation of immune system activation and systemic cytokines as higher levels of IL-2 and IL17A were observed in HPgV-1 infected individuals. CHMI is safe and well tolerated in HPgV-1 infected individuals. Identification of cell types and mechanisms of both silent and productive infection in individuals will help to unravel the biology of this widely present but largely under-researched virus.