Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children
Abstract Background RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. Antibodies play the major role in vaccine-induced immunity, but knowledge on the induction, decay, and determinants of antibody fun...
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| Format: | Article |
| Language: | English |
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BMC
2022-08-01
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| Series: | BMC Medicine |
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| Online Access: | https://doi.org/10.1186/s12916-022-02466-2 |
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| author | Gaoqian Feng Liriye Kurtovic Paul A. Agius Elizabeth H. Aitken Jahit Sacarlal Bruce D. Wines P. Mark Hogarth Stephen J. Rogerson Freya J. I. Fowkes Carlota Dobaño James G. Beeson |
| author_facet | Gaoqian Feng Liriye Kurtovic Paul A. Agius Elizabeth H. Aitken Jahit Sacarlal Bruce D. Wines P. Mark Hogarth Stephen J. Rogerson Freya J. I. Fowkes Carlota Dobaño James G. Beeson |
| author_sort | Gaoqian Feng |
| collection | DOAJ |
| description | Abstract Background RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. Antibodies play the major role in vaccine-induced immunity, but knowledge on the induction, decay, and determinants of antibody function is limited, especially among children. Antibodies that promote opsonic phagocytosis and other cellular functions appear to be important contributors to RTS,S immunity. Methods We studied a phase IIb trial of RTS,S/AS02 conducted in young children in malaria-endemic regions of Mozambique. We evaluated the induction of antibodies targeting the circumsporozoite protein (CSP, vaccine antigen) that interact with Fcγ-receptors (FcRγs) and promote phagocytosis (neutrophils, monocytes, THP-1 cells), antibody-dependent respiratory burst (ADRB) by neutrophils, and natural killer (NK) cell activity, as well as the temporal kinetics of responses over 5 years of follow-up (ClinicalTrials.gov registry number NCT00197041). Results RTS,S vaccination induced CSP-specific IgG with FcγRIIa and FcγRIII binding activity and promoted phagocytosis by neutrophils, THP-1 monocytes, and primary human monocytes, neutrophil ADRB activity, and NK cell activation. Responses were highly heterogenous among children, and the magnitude of neutrophil phagocytosis by antibodies was relatively modest, which may reflect modest vaccine efficacy. Induction of functional antibodies was lower among children with higher malaria exposure. Functional antibody magnitude and the functional activity of antibodies largely declined within a year post-vaccination, and decay were highest in the first 6 months, consistent with the decline in vaccine efficacy over that time. Decay rates varied for different antibody parameters and decay was slower for neutrophil phagocytosis. Biostatistical modelling suggested IgG1 and IgG3 contribute in promoting FcγR binding and phagocytosis, and IgG targeting the NANP-repeat and C-terminal regions CSP were similarly important for functional activities. Conclusions Results provide new insights to understand the modest and time-limited efficacy of RTS,S in children and the induction of antibody functional activities. Improving the induction and maintenance of antibodies that promote phagocytosis and cellular functions, and combating the negative effect of malaria exposure on vaccine responses are potential strategies for improving RTS,S efficacy and longevity. |
| first_indexed | 2024-12-10T19:21:27Z |
| format | Article |
| id | doaj.art-eb4e7695506a424fa850de98df36ef95 |
| institution | Directory Open Access Journal |
| issn | 1741-7015 |
| language | English |
| last_indexed | 2024-12-10T19:21:27Z |
| publishDate | 2022-08-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Medicine |
| spelling | doaj.art-eb4e7695506a424fa850de98df36ef952022-12-22T01:36:28ZengBMCBMC Medicine1741-70152022-08-0120111810.1186/s12916-022-02466-2Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young childrenGaoqian Feng0Liriye Kurtovic1Paul A. Agius2Elizabeth H. Aitken3Jahit Sacarlal4Bruce D. Wines5P. Mark Hogarth6Stephen J. Rogerson7Freya J. I. Fowkes8Carlota Dobaño9James G. Beeson10Burnet InstituteBurnet InstituteBurnet InstitutePeter Doherty Institute, The University of MelbourneCentro de Investigação em Saúde de ManhiçaBurnet InstituteBurnet InstituteDepartment of Medicine, The University of MelbourneBurnet InstituteCentro de Investigação em Saúde de ManhiçaBurnet InstituteAbstract Background RTS,S is the first malaria vaccine recommended for implementation among young children at risk. However, vaccine efficacy is modest and short-lived. Antibodies play the major role in vaccine-induced immunity, but knowledge on the induction, decay, and determinants of antibody function is limited, especially among children. Antibodies that promote opsonic phagocytosis and other cellular functions appear to be important contributors to RTS,S immunity. Methods We studied a phase IIb trial of RTS,S/AS02 conducted in young children in malaria-endemic regions of Mozambique. We evaluated the induction of antibodies targeting the circumsporozoite protein (CSP, vaccine antigen) that interact with Fcγ-receptors (FcRγs) and promote phagocytosis (neutrophils, monocytes, THP-1 cells), antibody-dependent respiratory burst (ADRB) by neutrophils, and natural killer (NK) cell activity, as well as the temporal kinetics of responses over 5 years of follow-up (ClinicalTrials.gov registry number NCT00197041). Results RTS,S vaccination induced CSP-specific IgG with FcγRIIa and FcγRIII binding activity and promoted phagocytosis by neutrophils, THP-1 monocytes, and primary human monocytes, neutrophil ADRB activity, and NK cell activation. Responses were highly heterogenous among children, and the magnitude of neutrophil phagocytosis by antibodies was relatively modest, which may reflect modest vaccine efficacy. Induction of functional antibodies was lower among children with higher malaria exposure. Functional antibody magnitude and the functional activity of antibodies largely declined within a year post-vaccination, and decay were highest in the first 6 months, consistent with the decline in vaccine efficacy over that time. Decay rates varied for different antibody parameters and decay was slower for neutrophil phagocytosis. Biostatistical modelling suggested IgG1 and IgG3 contribute in promoting FcγR binding and phagocytosis, and IgG targeting the NANP-repeat and C-terminal regions CSP were similarly important for functional activities. Conclusions Results provide new insights to understand the modest and time-limited efficacy of RTS,S in children and the induction of antibody functional activities. Improving the induction and maintenance of antibodies that promote phagocytosis and cellular functions, and combating the negative effect of malaria exposure on vaccine responses are potential strategies for improving RTS,S efficacy and longevity.https://doi.org/10.1186/s12916-022-02466-2MalariaPhagocytosisNeutrophilsMonocytesVaccinesChildren |
| spellingShingle | Gaoqian Feng Liriye Kurtovic Paul A. Agius Elizabeth H. Aitken Jahit Sacarlal Bruce D. Wines P. Mark Hogarth Stephen J. Rogerson Freya J. I. Fowkes Carlota Dobaño James G. Beeson Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children BMC Medicine Malaria Phagocytosis Neutrophils Monocytes Vaccines Children |
| title | Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children |
| title_full | Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children |
| title_fullStr | Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children |
| title_full_unstemmed | Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children |
| title_short | Induction, decay, and determinants of functional antibodies following vaccination with the RTS,S malaria vaccine in young children |
| title_sort | induction decay and determinants of functional antibodies following vaccination with the rts s malaria vaccine in young children |
| topic | Malaria Phagocytosis Neutrophils Monocytes Vaccines Children |
| url | https://doi.org/10.1186/s12916-022-02466-2 |
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