Systems analysis of protective immune responses to RTS,S malaria vaccination in humans

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 114; no. 9; pp. 2425 - 2430
• Main Authors: Kazmin, Dmitri, Nakaya, Helder I., Lee, Eva K., Johnson, Matthew J., van der Most, Robbert, van den Berg, Robert A., Ballou, W. Ripley, Jongert, Erik, Wille-Reece, Ulrike, Ockenhouse, Christian, Aderem, Alan, Zak, Daniel E., Sadoff, Jerald, Hendriks, Jenny, Wrammert, Jens, Ahmed, Rafi, Pulendran, Bali
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 28.02.2017
• Subjects: Adaptive Immunity - drug effects; Adenoviridae; Adenoviridae - genetics; Adenoviridae - immunology; Antibodies, Protozoan - biosynthesis; B-Lymphocytes - drug effects; B-Lymphocytes - immunology; B-Lymphocytes - metabolism; Biological Sciences; CD4-Positive T-Lymphocytes - drug effects; CD4-Positive T-Lymphocytes - immunology; CD4-Positive T-Lymphocytes - metabolism; Dendritic Cells - drug effects; Dendritic Cells - immunology; Dendritic Cells - metabolism; Gene Expression Profiling; Gene Expression Regulation; Genetic Vectors - chemistry; Genetic Vectors - immunology; Humans; Immunity (Disease); Immunity, Innate - drug effects; Immunization; Immunization, Secondary - methods; Immunogenicity, Vaccine; Killer Cells, Natural - drug effects; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Malaria; Malaria Vaccines - administration & dosage; Malaria, Falciparum - immunology; Malaria, Falciparum - parasitology; Malaria, Falciparum - prevention & control; Parasitic protozoa; Plasmodium falciparum; Plasmodium falciparum - immunology; Plasmodium falciparum - pathogenicity; Proteins; Protozoan Proteins - administration & dosage; Protozoan Proteins - genetics; Protozoan Proteins - immunology; Systematic biology; Systems analysis; Vaccination - methods; Vaccines; Vaccines, Synthetic - administration & dosage; Vector-borne diseases; systems biology; systems vaccinology; vaccine; immune; malaria
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1621489114

RTS,S is an advanced malaria vaccine candidate and confers significant protection against Plasmodium falciparum infection in humans. Little is known about the molecular mechanisms driving vaccine immunity. Here, we applied a systems biology approach to study immune responses in subjects receiving three consecutive immunizations with RTS,S (RRR), or in those receiving two immunizations of RTS,S/AS01 following a primary immunization with adenovirus 35 (Ad35) (ARR) vector expressing circumsporozoite protein. Subsequent controlled human malaria challenge (CHMI) of the vaccinees with Plasmodium-infected mosquitoes, 3 wk after the final immunization, resulted in ∼50% protection in both groups of vaccinees. Circumsporozoite protein (CSP)-specific antibody titers, prechallenge, were associated with protection in the RRR group. In contrast, ARR-induced lower antibody responses, and protection was associated with polyfunctional CD4⁺ T-cell responses 2 wk after priming with Ad35. Molecular signatures of B and plasma cells detected in PBMCs were highly correlated with antibody titers prechallenge and protection in the RRR cohort. In contrast, early signatures of innate immunity and dendritic cell activation were highly associated with protection in the ARR cohort. For both vaccine regimens, natural killer (NK) cell signatures negatively correlated with and predicted protection. These results suggest that protective immunity against P. falciparum can be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination.