title: Systems analysis of protective immune responses to RTS,S malaria vaccination in humans.
abstract: RTS,S is an advanced malaria vaccine candidate and confers significant protection againstPlasmodium falciparuminfection 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 withPlasmodium-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 againstP. falciparumcan be achieved via multiple mechanisms and highlight the utility of systems approaches in defining molecular correlates of protection to vaccination.
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30329.
authors.forename: Dmitri
authors.initials: D
authors.lastname: Kazmin
authors.affiliation: School of Pharmaceutical Sciences, University of Sao Paulo, São Paulo 05508, Brazil.
authors.forename: Helder I
authors.initials: HI
authors.lastname: Nakaya
authors.affiliation: School of Industrial and Systems Engineering, Georgia Institute of Technology, Atlanta, GA 30332.
authors.forename: Eva K
authors.initials: EK
authors.lastname: Lee
authors.affiliation: Center for Genome Engineering, University of Minnesota, Minneapolis, MN 55108.
authors.forename: Matthew J
authors.initials: MJ
authors.lastname: Johnson
authors.affiliation: GSK Vaccines, Rixensart 1330, Belgium.
authors.forename: Robbert
authors.initials: R
authors.lastname: van der Most
authors.affiliation: GSK Vaccines, Rockville, MD 20850.
authors.forename: Robert A
authors.initials: RA
authors.lastname: van den Berg
authors.affiliation: GSK Vaccines, Rockville, MD 20850.
authors.forename: W Ripley
authors.initials: WR
authors.lastname: Ballou
authors.affiliation: GSK Vaccines, Rixensart 1330, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: Jongert
authors.affiliation: Program for Appropriate Technology in Health-Malaria Vaccine Initiative, Washington, DC 20001.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Wille-Reece
authors.affiliation: Program for Appropriate Technology in Health-Malaria Vaccine Initiative, Washington, DC 20001.
authors.forename: Christian
authors.initials: C
authors.lastname: Ockenhouse
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109.
authors.forename: Alan
authors.initials: A
authors.lastname: Aderem
authors.affiliation: Center for Infectious Disease Research, Seattle, WA 98109.
authors.forename: Daniel E
authors.initials: DE
authors.lastname: Zak
authors.affiliation: Crucell, Leiden 2333, The Netherlands.
authors.forename: Jerald
authors.initials: J
authors.lastname: Sadoff
authors.affiliation: Crucell, Leiden 2333, The Netherlands.
authors.forename: Jenny
authors.initials: J
authors.lastname: Hendriks
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30329.
authors.forename: Jens
authors.initials: J
authors.lastname: Wrammert
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30329; bpulend@emory.edu rahmed@emory.edu.
authors.forename: Rafi
authors.initials: R
authors.lastname: Ahmed
authors.affiliation: Emory Vaccine Center, Emory University, Atlanta, GA 30329; bpulend@emory.edu rahmed@emory.edu.|Department of Pathology, Emory University School of Medicine, Atlanta, GA 30322.
authors.forename: Bali
authors.initials: B
authors.lastname: Pulendran
mesh_terms: D056704:Adaptive Immunity / Q000187:drug effects*; D000256:Adenoviridae / Q000235:genetics / Q000276:immunology; D000913:Antibodies, Protozoan / Q000096:biosynthesis*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation; D005822:Genetic Vectors / Q000737:chemistry / Q000276:immunology; D006801:Humans; D007113:Immunity, Innate / Q000187:drug effects*; D007117:Immunization, Secondary / Q000379:methods; D000071497:Immunogenicity, Vaccine; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D017780:Malaria Vaccines / Q000008:administration & dosage*; D016778:Malaria, Falciparum / Q000276:immunology* / Q000469:parasitology / Q000517:prevention & control; D010963:Plasmodium falciparum / Q000276:immunology / Q000472:pathogenicity; D015800:Protozoan Proteins / Q000008:administration & dosage* / Q000235:genetics / Q000276:immunology; D014611:Vaccination / Q000379:methods; D014614:Vaccines, Synthetic / Q000008:administration & dosage*
chemical_list: D000913:Antibodies, Protozoan; D017780:Malaria Vaccines; D015800:Protozoan Proteins; C577001:RTS,S-AS01 vaccine; D014614:Vaccines, Synthetic; C041595:circumsporozoite protein, Protozoan
keywords: immune; malaria; systems biology; systems vaccinology; vaccine