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      Differential Patterns of IgG Subclass Responses to Plasmodium falciparum Antigens in Relation to Malaria Protection and RTS,S Vaccination

      1 , 2 , * , 1 , 1 , 1 , 3 , 2 , 1 , 4 , 1 , 1 , 1 , 1 , 5 , 6 , 4 , 4 , 7 , 8 , 9 , 9 , 8 , 8 , 10 , 11 , 12 , 12 , 9 , 13 , 14 , 4 , 15 , 2 , 1 , 2 , 1 , 2 , *
      Frontiers in Immunology
      Frontiers Media S.A.
      Malaria, Plasmodium falciparum, antibody, IgG subclass, naturally acquired immunity, protection, vaccine, children

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          Naturally acquired immunity (NAI) to Plasmodium falciparum malaria is mainly mediated by IgG antibodies but the subclasses, epitope targets and effector functions have not been unequivocally defined. Dissecting the type and specificity of antibody responses mediating NAI is a key step toward developing more effective vaccines to control the disease. We investigated the role of IgG subclasses to malaria antigens in protection against disease and the factors that affect their levels, including vaccination with RTS,S/AS01E. We analyzed plasma and serum samples at baseline and 1 month after primary vaccination with RTS,S or comparator in African children and infants participating in a phase 3 trial in two sites of different malaria transmission intensity: Kintampo in Ghana and Manhiça in Mozambique. We used quantitative suspension array technology (qSAT) to measure IgG 1−4 responses to 35 P. falciparum pre-erythrocytic and blood stage antigens. Our results show that the pattern of IgG response is predominantly IgG1 or IgG3, with lower levels of IgG2 and IgG4. Age, site and RTS,S vaccination significantly affected antibody subclass levels to different antigens and susceptibility to clinical malaria. Univariable and multivariable analysis showed associations with protection mainly for cytophilic IgG3 levels to selected antigens, followed by IgG1 levels and, unexpectedly, also with IgG4 levels, mainly to antigens that increased upon RTS,S vaccination such as MSP5 and MSP1 block 2, among others. In contrast, IgG2 was associated with malaria risk. Stratified analysis in RTS,S vaccinees pointed to novel associations of IgG4 responses with immunity mainly involving pre-erythrocytic antigens upon RTS,S vaccination. Multi-marker analysis revealed a significant contribution of IgG3 responses to malaria protection and IgG2 responses to malaria risk. We propose that the pattern of cytophilic and non-cytophilic IgG antibodies is antigen-dependent and more complex than initially thought, and that mechanisms of both types of subclasses could be involved in protection. Our data also suggests that RTS,S efficacy is significantly affected by NAI, and indicates that RTS,S vaccination significantly alters NAI.

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          Most cited references55

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          Gamma-globulin and acquired immunity to human malaria.

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            Properties of mouse and human IgG receptors and their contribution to disease models.

            Impressive advances in defining the properties of receptors for the Fc portion of immunoglobulins (FcR) have been made over the past several years. Ligand specificities were systematically analyzed for both human and mouse FcRs that revealed novel receptors for specific IgG subclasses. Expression patterns were redefined using novel specific anti-FcR mAbs that revealed major differences between human and mouse systems. The in vivo roles of IgG receptors have been addressed using specific FcR knockout mice or in mice expressing a single FcR, and have demonstrated a predominant contribution of mouse activating IgG receptors FcγRIII and FcγRIV to models of autoimmunity (eg, arthritis) and allergy (eg, anaphylaxis). Novel blocking mAbs specific for these activating IgG receptors have enabled, for the first time, the investigation of their roles in vivo in wild-type mice. In parallel, the in vivo properties of human FcRs have been reported using transgenic mice and models of inflammatory and allergic reactions, in particular those of human activating IgG receptor FcγRIIA (CD32A). Importantly, these studies led to the identification of specific cell populations responsible for the induction of various inflammatory diseases and have revealed, in particular, the unexpected contribution of neutrophils and monocytes to the induction of anaphylactic shock.
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              A phase 3 trial of RTS,S/AS01 malaria vaccine in African infants.

              The candidate malaria vaccine RTS,S/AS01 reduced episodes of both clinical and severe malaria in children 5 to 17 months of age by approximately 50% in an ongoing phase 3 trial. We studied infants 6 to 12 weeks of age recruited for the same trial. We administered RTS,S/AS01 or a comparator vaccine to 6537 infants who were 6 to 12 weeks of age at the time of the first vaccination in conjunction with Expanded Program on Immunization (EPI) vaccines in a three-dose monthly schedule. Vaccine efficacy against the first or only episode of clinical malaria during the 12 months after vaccination, a coprimary end point, was analyzed with the use of Cox regression. Vaccine efficacy against all malaria episodes, vaccine efficacy against severe malaria, safety, and immunogenicity were also assessed. The incidence of the first or only episode of clinical malaria in the intention-to-treat population during the 14 months after the first dose of vaccine was 0.31 per person-year in the RTS,S/AS01 group and 0.40 per person-year in the control group, for a vaccine efficacy of 30.1% (95% confidence interval [CI], 23.6 to 36.1). Vaccine efficacy in the per-protocol population was 31.3% (97.5% CI, 23.6 to 38.3). Vaccine efficacy against severe malaria was 26.0% (95% CI, -7.4 to 48.6) in the intention-to-treat population and 36.6% (95% CI, 4.6 to 57.7) in the per-protocol population. Serious adverse events occurred with a similar frequency in the two study groups. One month after administration of the third dose of RTS,S/AS01, 99.7% of children were positive for anti-circumsporozoite antibodies, with a geometric mean titer of 209 EU per milliliter (95% CI, 197 to 222). The RTS,S/AS01 vaccine coadministered with EPI vaccines provided modest protection against both clinical and severe malaria in young infants. (Funded by GlaxoSmithKline Biologicals and the PATH Malaria Vaccine Initiative; RTS,S ClinicalTrials.gov number, NCT00866619.).

                Author and article information

                Front Immunol
                Front Immunol
                Front. Immunol.
                Frontiers in Immunology
                Frontiers Media S.A.
                15 March 2019
                : 10
                [1] 1ISGlobal, Hospital Clínic - Universitat de Barcelona , Barcelona, Spain
                [2] 2Centro de Investigação em Saúde de Manhiça (CISM) , Manhiça, Mozambique
                [3] 3Spanish Consortium for Research in Epidemiology and Public Health (CIBERESP) , Barcelona, Spain
                [4] 4Kintampo Health Research Centre , Kintampo, Ghana
                [5] 5Department of Osteopathic Medical Specialties, Michigan State University , East Lansing, MI, United States
                [6] 6Department of Immunology and Infectious Diseases, Harvard T.H. Chen School of Public Health , Boston, MA, United States
                [7] 7Disease Control Department, London School of Hygiene and Tropical Medicine , London, United Kingdom
                [8] 8Malaria Vaccine Branch, Walter Reed Army Institute of Research , Silver Spring, MD, United States
                [9] 9Malaria Group, International Centre for Genetic Engineering and Biotechnology (ICGEB) , New Delhi, India
                [10] 10Unité Biologie Intégrée du Globule Rouge, Laboratoire d'Excellence GR-Ex, UMR_S1134, Inserm, INTS, Université Sorbonne Paris Cité, Université Paris Diderot , Paris, France
                [11] 11Infection and Immunity Program, Monash Biomedicine Discovery Institute, Department of Microbiology, Monash University , Melbourne, VIC, Australia
                [12] 12Burnet Institute , Melbourne, VIC, Australia
                [13] 13Laboratory of Malaria and Vaccine Research, School of Biotechnology, Jawaharlal Nehru University , New Delhi, India
                [14] 14Ashworth Laboratories, Centre for Immunity, Infection and Evolution, School of Biological Sciences, Institute of Immunology and Infection Research, University of Edinburgh , Edinburgh, United Kingdom
                [15] 15Noguchi Memorial Institute for Medical Research, University of Ghana , Accra, Ghana
                Author notes

                Edited by: Abhay Satoskar, The Ohio State University, United States

                Reviewed by: Dolores Correa, National Institute of Pediatrics, Mexico; Shinjiro Hamano, Nagasaki University, Japan

                *Correspondence: Carlota Dobaño carlota.dobano@ 123456isglobal.org

                This article was submitted to Microbial Immunology, a section of the journal Frontiers in Immunology

                Copyright © 2019 Dobaño, Santano, Vidal, Jiménez, Jairoce, Ubillos, Dosoo, Aguilar, Williams, Díez-Padrisa, Ayestaran, Valim, Asante, Owusu-Agyei, Lanar, Chauhan, Chitnis, Dutta, Angov, Gamain, Coppel, Beeson, Reiling, Gaur, Cavanagh, Gyan, Nhabomba, Campo and Moncunill.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                Page count
                Figures: 11, Tables: 0, Equations: 0, References: 70, Pages: 19, Words: 10872
                Original Research

                malaria,plasmodium falciparum,antibody,igg subclass,naturally acquired immunity,protection,vaccine,children


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