Author:
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Ubillos, Itziar; Ayestaran, Aintzane; Nhabomba, Augusto J.; Dosoo, David; Vidal, Marta; Jiménez, Alfons; Jairoce, Chenjerai; Sanz, Héctor; Aguilar, Ruth; Williams, Nana A.; Díez-Padrisa, Núria; Mpina, Maximilian; Sorgho, Hermann; Agnandji, Selidji Todagbe; Kariuki, Simon; Mordmüller, Benjamin; Daubenberger, Claudia; Asante, Kwaku Poku; Owusu-Agyei, Seth; Sacarlal, Jahit; Aide, Pedro Carlos Paulino; Aponte, John J.; Dutta, Sheetij; Gyan, Ben; Campo, Joseph J.; Valim, Clarissa; Moncunill, Gemma; Dobaño, Carlota, 1969-
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Abstract:
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Background: The RTS,S/AS01E vaccine provides partial protection against malaria in African children, but immune
responses have only been partially characterized and do not reliably predict protective efficacy. We aimed to
evaluate comprehensively the immunogenicity of the vaccine at peak response, the factors affecting it, and the
antibodies associated with protection against clinical malaria in young African children participating in the multicenter
phase 3 trial for licensure.
Methods: We measured total IgM, IgG, and IgG1–4 subclass antibodies to three constructs of the Plasmodium falciparum
circumsporozoite protein (CSP) and hepatitis B surface antigen (HBsAg) that are part of the RTS,S vaccine, by quantitative
suspension array technology. Plasma and serum samples were analyzed in 195 infants and children from two sites in
Ghana (Kintampo) and Mozambique (Manhiça) with different transmission intensities using a case-control study design.
We applied regression models and machine learning techniques to analyze immunogenicity, correlates of protection, and
factors affecting them.
Results: RTS,S/AS01E induced IgM and IgG, predominantly IgG1 and IgG3, but also IgG2 and IgG4, subclass responses.
Age, site, previous malaria episodes, and baseline characteristics including antibodies to CSP and other antigens reflecting
malaria exposure and maternal IgGs, nutritional status, and hemoglobin concentration, significantly affected vaccine
immunogenicity. We identified distinct signatures of malaria protection and risk in RTS,S/AS01E but not in comparator
vaccinees. IgG2 and IgG4 responses to RTS,S antigens post-vaccination, and anti-CSP and anti-P. falciparum antibody levels
pre-vaccination, were associated with malaria risk over 1-year follow-up. In contrast, antibody responses to HBsAg (all
isotypes, subclasses, and timepoints) and post-vaccination IgG1 and IgG3 to CSP C-terminus and NANP were associated
with protection. Age and site affected the relative contribution of responses in the correlates identified. Conclusions: Cytophilic IgG responses to the C-terminal and NANP repeat regions of CSP and anti-HBsAg antibodies
induced by RTS,S/AS01E vaccination were associated with malaria protection. In contrast, higher malaria exposure at
baseline and non-cytophilic IgG responses to CSP were associated with disease risk. Data provide new correlates of
vaccine success and failure in African children and reveal key insights into the mode of action that can guide
development of more efficacious next-generation vaccines. |