Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure

Background: Leading malaria vaccine, RTS,S, is based on the circumsporozoite protein (CSP) of sporozoites. RTS,S confers partial protection against malaria in children, but efficacy wanes relatively quickly after primary immunization. Vaccine efficacy has some association with anti-CSP IgG; however,...

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Autores: Kurtovic, Liriye, Agius, Paul A., Feng, Gaoqian, Drew, Damien R., Ubillos, Itziar, Sacarlal, Jahit, Aponte, John J., Fowkes, Freya J. I., Dobaño, Carlota, 1969-, Beeson, James G.
Formato: artículo
Estado:Versión publicada
Fecha de publicación:2019
País:España
Recursos:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/134891
Acesso em linha:https://hdl.handle.net/2445/134891
Access Level:acceso abierto
Palavra-chave:Vacuna de la malària
Infants
Malaria vaccine
Children
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spelling Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposureKurtovic, LiriyeAgius, Paul A.Feng, GaoqianDrew, Damien R.Ubillos, ItziarSacarlal, JahitAponte, John J.Fowkes, Freya J. I.Dobaño, Carlota, 1969-Beeson, James G.Vacuna de la malàriaInfantsMalaria vaccineChildrenBackground: Leading malaria vaccine, RTS,S, is based on the circumsporozoite protein (CSP) of sporozoites. RTS,S confers partial protection against malaria in children, but efficacy wanes relatively quickly after primary immunization. Vaccine efficacy has some association with anti-CSP IgG; however, it is unclear how these antibodies function, and how functional antibodies are induced and maintained over time. Recent studies identified antibodycomplement interactions as a potentially important immune mechanism against sporozoites. Here, we investigated whether RTS,S vaccine-induced antibodies could function by interacting with complement. Methods: Serum samples were selected from children in a phase IIb trial of RTS,S/AS02A conducted at two study sites of high and low malaria transmission intensity in Manhiça, Mozambique. Samples following primary immunization and 5-year post-immunization follow-up time points were included. Vaccine-induced antibodies were characterized by isotype, subclass, and epitope specificity, and tested for the ability to fix and activate complement. We additionally developed statistical methods to model the decay and determinants of functional antibodies after vaccination. Results: RTS,S vaccination induced anti-CSP antibodies that were mostly IgG1, with some IgG3, IgG2, and IgM. Complement-fixing antibodies were effectively induced by vaccination, and targeted the central repeat and Cterminal regions of CSP. Higher levels of complement-fixing antibodies were associated with IgG that equally recognized both the central repeat and C-terminal regions of CSP. Older age and higher malaria exposure were significantly associated with a poorer induction of functional antibodies. There was a marked decay in functional complement-fixing antibodies within months after vaccination, as well as decays in IgG subclasses and IgM. Statistical modeling suggested the decay in complement-fixing antibodies was mostly attributed to the waning of anti-CSP IgG1, and to a lesser extent IgG3. Conclusions: We demonstrate for the first time that RTS,S can induce complement-fixing antibodies in young malaria-exposed children. The short-lived nature of functional responses mirrors the declining vaccine efficacy of RTS,S over time. The negative influence of age and malaria exposure on functional antibodies has implications for understanding vaccine efficacy in different settings. These findings provide insights into the mechanisms and longevity of vaccine-induced immunity that will help inform the future development of highly efficacious and longlasting malaria vaccines.BioMed Central2019201920192019info:eu-repo/semantics/articleinfo:eu-repo/semantics/publishedVersion14 p.application/pdfhttps://hdl.handle.net/2445/134891Articles publicats en revistes (ISGlobal)reponame:Recercat. Dipósit de la Recerca de Catalunyainstname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)InglésReproducció del document publicat a: http://dx.doi.org/10.1186/s12916-019-1277-xBMC medicine, 2019, vol. 17, num. 45http://dx.doi.org/10.1186/s12916-019-1277-xcc by (c) Kurtovic et al., 2019http://creativecommons.org/licenses/by/3.0/es/info:eu-repo/semantics/openAccessoai:recercat.cat:2445/1348912026-05-29T05:05:01Z
dc.title.none.fl_str_mv Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure
title Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure
spellingShingle Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure
Kurtovic, Liriye
Vacuna de la malària
Infants
Malaria vaccine
Children
title_short Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure
title_full Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure
title_fullStr Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure
title_full_unstemmed Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure
title_sort Induction and decay of functional complement-fixing antibodies by the RTS,S malaria vaccine in children, and a negative impact of malaria exposure
dc.creator.none.fl_str_mv Kurtovic, Liriye
Agius, Paul A.
Feng, Gaoqian
Drew, Damien R.
Ubillos, Itziar
Sacarlal, Jahit
Aponte, John J.
Fowkes, Freya J. I.
Dobaño, Carlota, 1969-
Beeson, James G.
author Kurtovic, Liriye
author_facet Kurtovic, Liriye
Agius, Paul A.
Feng, Gaoqian
Drew, Damien R.
Ubillos, Itziar
Sacarlal, Jahit
Aponte, John J.
Fowkes, Freya J. I.
Dobaño, Carlota, 1969-
Beeson, James G.
author_role author
author2 Agius, Paul A.
Feng, Gaoqian
Drew, Damien R.
Ubillos, Itziar
Sacarlal, Jahit
Aponte, John J.
Fowkes, Freya J. I.
Dobaño, Carlota, 1969-
Beeson, James G.
author2_role author
author
author
author
author
author
author
author
author
dc.subject.none.fl_str_mv Vacuna de la malària
Infants
Malaria vaccine
Children
topic Vacuna de la malària
Infants
Malaria vaccine
Children
description Background: Leading malaria vaccine, RTS,S, is based on the circumsporozoite protein (CSP) of sporozoites. RTS,S confers partial protection against malaria in children, but efficacy wanes relatively quickly after primary immunization. Vaccine efficacy has some association with anti-CSP IgG; however, it is unclear how these antibodies function, and how functional antibodies are induced and maintained over time. Recent studies identified antibodycomplement interactions as a potentially important immune mechanism against sporozoites. Here, we investigated whether RTS,S vaccine-induced antibodies could function by interacting with complement. Methods: Serum samples were selected from children in a phase IIb trial of RTS,S/AS02A conducted at two study sites of high and low malaria transmission intensity in Manhiça, Mozambique. Samples following primary immunization and 5-year post-immunization follow-up time points were included. Vaccine-induced antibodies were characterized by isotype, subclass, and epitope specificity, and tested for the ability to fix and activate complement. We additionally developed statistical methods to model the decay and determinants of functional antibodies after vaccination. Results: RTS,S vaccination induced anti-CSP antibodies that were mostly IgG1, with some IgG3, IgG2, and IgM. Complement-fixing antibodies were effectively induced by vaccination, and targeted the central repeat and Cterminal regions of CSP. Higher levels of complement-fixing antibodies were associated with IgG that equally recognized both the central repeat and C-terminal regions of CSP. Older age and higher malaria exposure were significantly associated with a poorer induction of functional antibodies. There was a marked decay in functional complement-fixing antibodies within months after vaccination, as well as decays in IgG subclasses and IgM. Statistical modeling suggested the decay in complement-fixing antibodies was mostly attributed to the waning of anti-CSP IgG1, and to a lesser extent IgG3. Conclusions: We demonstrate for the first time that RTS,S can induce complement-fixing antibodies in young malaria-exposed children. The short-lived nature of functional responses mirrors the declining vaccine efficacy of RTS,S over time. The negative influence of age and malaria exposure on functional antibodies has implications for understanding vaccine efficacy in different settings. These findings provide insights into the mechanisms and longevity of vaccine-induced immunity that will help inform the future development of highly efficacious and longlasting malaria vaccines.
publishDate 2019
dc.date.none.fl_str_mv 2019
2019
2019
2019
dc.type.none.fl_str_mv info:eu-repo/semantics/article
info:eu-repo/semantics/publishedVersion
format article
status_str publishedVersion
dc.identifier.none.fl_str_mv https://hdl.handle.net/2445/134891
url https://hdl.handle.net/2445/134891
dc.language.none.fl_str_mv Inglés
language_invalid_str_mv Inglés
dc.relation.none.fl_str_mv Reproducció del document publicat a: http://dx.doi.org/10.1186/s12916-019-1277-x
BMC medicine, 2019, vol. 17, num. 45
http://dx.doi.org/10.1186/s12916-019-1277-x
dc.rights.none.fl_str_mv cc by (c) Kurtovic et al., 2019
http://creativecommons.org/licenses/by/3.0/es/
info:eu-repo/semantics/openAccess
rights_invalid_str_mv cc by (c) Kurtovic et al., 2019
http://creativecommons.org/licenses/by/3.0/es/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv 14 p.
application/pdf
dc.publisher.none.fl_str_mv BioMed Central
publisher.none.fl_str_mv BioMed Central
dc.source.none.fl_str_mv Articles publicats en revistes (ISGlobal)
reponame:Recercat. Dipósit de la Recerca de Catalunya
instname:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
instname_str Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
reponame_str Recercat. Dipósit de la Recerca de Catalunya
collection Recercat. Dipósit de la Recerca de Catalunya
repository.name.fl_str_mv
repository.mail.fl_str_mv
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