Gemma Moncunill1,2, Maxmillian Mpina3, Augusto J Nhabomba2, Ruth Aguilar1, Aintzane Ayestaran1, Héctor Sanz1, Joseph J Campo1,2, Chenjerai Jairoce2, Diana Barrios1, Yan Dong4, Núria Díez-Padrisa1, José F Fernandes5, Salim Abdulla6, Jahit Sacarlal2,7, Nana A Williams1, Jaroslaw Harezlak4, Benjamin Mordmüller5,8, Selidji T Agnandji5, John J Aponte1,2, Claudia Daubenberger9,10, Clarissa Valim11,12, Carlota Dobaño1,2. 1. ISGlobal, Barcelona Centre for International Health Research, Hospital Clínic-Universitat de Barcelona, Catalonia, Spain. 2. Centro de Investigação em Saúde de Manhiça, Maputo, Mozambique. 3. Ifakara Health Institute, Bagamoyo Research and Training Centre, Tanzania. 4. Department of Epidemiology and Biostatistics, School of Public Health, Indiana University, Bloomington. 5. Centre de Recherches Médicales de Lambaréné, Albert Schweitzer Hospital, Gabon. 6. Ifakara Health Institute, Dar es Salaam, Tanzania. 7. Faculdade de Medicina da Universidade Eduardo Mondlane, Maputo, Mozambique. 8. Institute of Tropical Medicine, German Center for Infection Research, University of Tübingen, Germany. 9. Swiss Tropical and Public Health Institute, Basel. 10. University of Basel, Switzerland. 11. Department of Osteopathic Medical Specialties, Michigan State University, East Lansing. 12. Department of Immunology and Infectious Diseases, Harvard T. H. Chan School of Public Health, Boston, Massachusetts.
Abstract
BACKGROUND: The RTS,S/AS01E malaria vaccine has moderate efficacy, lower in infants than children. Current efforts to enhance RTS,S/AS01E efficacy would benefit from learning about the vaccine-induced immunity and identifying correlates of malaria protection, which could, for instance, inform the choice of adjuvants. Here, we sought cellular immunity-based correlates of malaria protection and risk associated with RTS,S/AS01E vaccination. METHODS: We performed a matched case-control study nested within the multicenter African RTS,S/AS01E phase 3 trial. Children and infant samples from 57 clinical malaria cases (32 RTS,S/25 comparator vaccinees) and 152 controls without malaria (106 RTS,S/46 comparator vaccinees) were analyzed. We measured 30 markers by Luminex following RTS,S/AS01E antigen stimulation of cells 1 month postimmunization. Crude concentrations and ratios of antigen to background control were analyzed. RESULTS: Interleukin (IL) 2 and IL-5 ratios were associated with RTS,S/AS01E vaccination (adjusted P ≤ .01). IL-5 circumsporozoite protein (CSP) ratios, a helper T cell type 2 cytokine, correlated with higher odds of malaria in RTS,S/AS01E vaccinees (odds ratio, 1.17 per 10% increases of CSP ratios; P value adjusted for multiple testing = .03). In multimarker analysis, the helper T cell type 1 (TH1)-related markers interferon-γ, IL-15, and granulocyte-macrophage colony-stimulating factor protected from subsequent malaria, in contrast to IL-5 and RANTES, which increased the odds of malaria. CONCLUSIONS: RTS,S/AS01E-induced IL-5 may be a surrogate of lack of protection, whereas TH1-related responses may be involved in protective mechanisms. Efforts to develop second-generation vaccine candidates may concentrate on adjuvants that modulate the immune system to support enhanced TH1 responses and decreased IL-5 responses.
BACKGROUND: The RTS,S/AS01E malaria vaccine has moderate efficacy, lower in infants than children. Current efforts to enhance RTS,S/AS01E efficacy would benefit from learning about the vaccine-induced immunity and identifying correlates of malaria protection, which could, for instance, inform the choice of adjuvants. Here, we sought cellular immunity-based correlates of malaria protection and risk associated with RTS,S/AS01E vaccination. METHODS: We performed a matched case-control study nested within the multicenter African RTS,S/AS01E phase 3 trial. Children and infant samples from 57 clinical malaria cases (32 RTS,S/25 comparator vaccinees) and 152 controls without malaria (106 RTS,S/46 comparator vaccinees) were analyzed. We measured 30 markers by Luminex following RTS,S/AS01E antigen stimulation of cells 1 month postimmunization. Crude concentrations and ratios of antigen to background control were analyzed. RESULTS: Interleukin (IL) 2 and IL-5 ratios were associated with RTS,S/AS01E vaccination (adjusted P ≤ .01). IL-5 circumsporozoite protein (CSP) ratios, a helper T cell type 2 cytokine, correlated with higher odds of malaria in RTS,S/AS01E vaccinees (odds ratio, 1.17 per 10% increases of CSP ratios; P value adjusted for multiple testing = .03). In multimarker analysis, the helper T cell type 1 (TH1)-related markers interferon-γ, IL-15, and granulocyte-macrophage colony-stimulating factor protected from subsequent malaria, in contrast to IL-5 and RANTES, which increased the odds of malaria. CONCLUSIONS: RTS,S/AS01E-induced IL-5 may be a surrogate of lack of protection, whereas TH1-related responses may be involved in protective mechanisms. Efforts to develop second-generation vaccine candidates may concentrate on adjuvants that modulate the immune system to support enhanced TH1 responses and decreased IL-5 responses.
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