Anneth-Mwasi Tumbo1,2,3, Tobias Schindler2,3, Jean-Pierre Dangy2,3, Nina Orlova-Fink2,3, Jose Raso Bieri4, Maximillian Mpina1,2,3,4, Florence A Milando1, Omar Juma1, Ali Hamad1,4, Elizabeth Nyakarungu1,4, Mwajuma Chemba1,4, Ali Mtoro1,4, Kamaka Ramadhan1,4, Ally Olotu1,4, Damas Makweba5,6,7, Stephen Mgaya6,7, Kenneth Stuart8, Matthieu Perreau9, Jack T Stapleton10, Said Jongo1,4, Stephen L Hoffman11, Marcel Tanner2,3, Salim Abdulla1,4, Claudia Daubenberger12,13. 1. Department of Intervention and Clinical Trials, Ifakara Health Institute, Bagamoyo, Tanzania. 2. Department of Medical Parasitology and Infection Biology, Clinical Immunology Unit, Swiss Tropical and Public Health Institute, Socinstr. 57, 4002, Basel, Switzerland. 3. University of Basel, Basel, Switzerland. 4. Equatorial Guinea Malaria Vaccine Initiative, Malabo, Bioko Norte, Equatorial Guinea. 5. Dar-Es-Salaam Institute of Technology, Dar-Es-Salaam, Tanzania. 6. Tanzania Education and Research Networks, Dar-Es-Salaam, Tanzania. 7. Tanzania Commission for Science and Technology, Dar-Es-Salaam, Tanzania. 8. Center for Global Infectious Disease Research, Seattle Children's Research Institute, 307 Westlake Avenue, N. Suite 500, Seattle, WA, 98109, USA. 9. Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland. 10. Iowa City Veterans Administration and the University of Iowa, 200 Hawkins Drive, Iowa City, IA, 52242, USA. 11. Sanaria Inc, Rockville, MD, 20850, USA. 12. Department of Medical Parasitology and Infection Biology, Clinical Immunology Unit, Swiss Tropical and Public Health Institute, Socinstr. 57, 4002, Basel, Switzerland. Claudia.Daubenberger@swisstph.ch. 13. University of Basel, Basel, Switzerland. Claudia.Daubenberger@swisstph.ch.
Abstract
BACKGROUND: Diverse vaccination outcomes and protection levels among different populations 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, post vaccination with PfSPZ Vaccine and after CHMI 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 pre-patent periods and parasite multiplication rates, (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 regions revealed the predominance of genotypes 1, 2 and 5. 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, a tendency for higher protection levels was detected in the HPgV-1 positive group (62.5%) compared to the negative one (51.6%) following CHMI. HPgV-1 viremia levels were not significantly altered after CHMI. CONCLUSIONS: HPgV-1 infection did not alter PfSPZ Vaccine elicited levels of PfCSP-specific antibody responses and parasite multiplication rates. Ongoing HPgV-1 infection appears to improve to some degree 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.
BACKGROUND: Diverse vaccination outcomes and protection levels among different populations 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 humanmalaria infections (CHMI). METHODS:HPgV-1 prevalence was quantified by RT-qPCR in plasma samples of 96 individuals before, post vaccination with PfSPZ Vaccine and after CHMI 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 pre-patent periods and parasite multiplication rates, (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 regions revealed the predominance of genotypes 1, 2 and 5. 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, a tendency for higher protection levels was detected in the HPgV-1 positive group (62.5%) compared to the negative one (51.6%) following CHMI. HPgV-1 viremia levels were not significantly altered after CHMI. CONCLUSIONS:HPgV-1 infection did not alter PfSPZ Vaccine elicited levels of PfCSP-specific antibody responses and parasite multiplication rates. Ongoing HPgV-1 infection appears to improve to some degree 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.
Entities:
Keywords:
Antibody response; Controlled human malaria infection; Human pegivirus; Immune activation; Malaria; PfSPZ vaccine
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