Strong off-target antibody reactivity to malarial antigens induced by RTS,S/AS01E vaccination is associated with protection

Macià, Dídac; Campo, Joseph J.; Moncunill, Gemma; Jairoce, Chenjerai; Nhabomba, Augusto; Mpina, Maximilian; Sorgho, Hermann; Dosoo, David; Ousmane, Traore; Kusi, Kwadwo Asamoah; Williams, Nana Aba; Oberai, Amit; Randall, Arlo; Sanz, Héctor; Valim, Clarissa; Asante, Kwaku Poku; Owusu‐Agyei, Seth; Tinto, Halidou; Agnandji, Selidji Todagbé; Kariuki, Simon; Gyan, Ben; Daubenberger, Claudia; Mordmüller, Benjamin; Petrone, Paula; Dobaño, Carlota

doi:10.1172/jci.insight.158030

Cited by 9 publications

(8 citation statements)

References 29 publications

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“…Overall, our data show that the total polyclonal binding antibody titers resulting from immunization were not directly associated with sterile protection in this study. It is possible that protection is associated with specific functional antibody subsets within the polyclonal antibody mixture based on either on-target epitope specificity ( 40 ), antibody isotype ( 10 , 11 ), or off-target cross-reactivity ( 41 ). We and others had previously shown that the composition of the polyclonal antibody response can be diverse enough to include antibodies capable of inhibiting the parasite as well as those that do not have a detectable impact on the course of infection despite their ability to bind the antigen ( 24 , 42 – 46 ).…”

Section: Discussionmentioning

confidence: 99%

Coimmunization with Preerythrocytic Antigens alongside Circumsporozoite Protein Can Enhance Sterile Protection against Plasmodium Sporozoite Infection

et al. 2023

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Section: Discussionmentioning

confidence: 99%

Coimmunization with Preerythrocytic Antigens alongside Circumsporozoite Protein Can Enhance Sterile Protection against Plasmodium Sporozoite Infection

et al. 2023

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“…One unexpected finding was the antibody response to CSP after infection with blood stage parasites; we hypothesize that the abundance of low complexity, highly immunogenic repeat regions shared by CSP and some blood stage antigens may have resulted in a degree of cross-reactivity ( 52 ). Unexpected blood stage antigen reactivity has been observed previously after RTS’S vaccination ( 53 ).…”

Section: Discussionmentioning

confidence: 65%

The acquisition of humoral immune responses targeting Plasmodium falciparum sexual stages in controlled human malaria infections

et al. 2022

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Individuals infected with P. falciparum develop antibody responses to intra-erythrocytic gametocyte proteins and exported gametocyte proteins present on the surface of infected erythrocytes. However, there is currently limited knowledge on the immunogenicity of gametocyte antigens and the specificity of gametocyte-induced antibody responses. In this study, we assessed antibody responses in participants of two controlled human malaria infection (CHMI) studies by ELISA, multiplexed bead-based antibody assays and protein microarray. By comparing antibody responses in participants with and without gametocyte exposure, we aimed to disentangle the antibody response induced by asexual and sexual stage parasites. We showed that after a single malaria infection, a significant anti-sexual stage humoral response is induced in malaria-naïve individuals, even after exposure to relatively low gametocyte densities (up to ~1,600 gametocytes/mL). In contrast to antibody responses to well-characterised asexual blood stage antigens that were detectable by day 21 after infection, responses to sexual stage antigens (including transmission blocking vaccine candidates Pfs48/45 and Pfs230) were only apparent at 51 days after infection. We found antigens previously associated with early gametocyte or anti-gamete immunity were highly represented among responses linked with gametocyte exposure. Our data provide detailed insights on the induction and kinetics of antibody responses to gametocytes and identify novel antigens that elicit antibody responses exclusively in individuals with gametocyte exposure. Our findings provide target identification for serological assays for surveillance of the malaria infectious reservoir, and support vaccine development by describing the antibody response to leading vaccine antigens after primary infection.

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“…Overall, our data show that the total polyclonal binding Ab levels resulting from immunization were an insufficient predictor of sterile protection in this study. It is possible that protection is associated with functional antibody subsets either based on on-target epitope specificity 34 , antibody isotype 9,10 or off-target cross-reactivity 35 . We and others had previously shown that the character of the polyclonal Ab response can be diverse enough to include antibodies capable of inhibiting the parasite as well as those that don't have a detectable impact on the course of infection despite their ability to bind the antigen 22,[36][37][38][39][40] .…”

Section: Discussionmentioning

confidence: 99%

Co-immunization with pre-erythrocytic antigens alongside circumsporozoite protein can enhance sterile protection against Plasmodium sporozoite infection.

Sather¹,

Вигдорович²,

Patel³

et al. 2022

Preprint

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Malaria-causing Plasmodium parasites have a complex life cycle and present numerous antigen targets that may contribute to protective immune responses. The currently recommended vaccine—RTS,S—functions by targeting the P. falciparum circumsporozoite protein (CSP), which is the most abundant surface protein of the sporozoite form responsible for initiating infection of the human host. Despite showing only moderate efficacy, RTS,S has established a strong foundation for the development of next-generation subunit vaccines. Our previous work characterizing the sporozoite surface proteome identified additional non-CSP antigens that may be useful as immunogens individually or in combination with CSP. In this study, we examined eight such antigens using the rodent malaria parasite P. yoelii as a model system. We demonstrate that despite conferring weak protection individually, co-immunizing each of several of these antigens alongside CSP, could significantly enhance the sterile protection achieved by CSP immunization alone. Thus, our work provides compelling evidence that a multi-antigen pre-erythrocytic vaccine approach may enhance protection compared to CSP-only vaccines. This lays the groundwork for further studies aimed at testing the identified antigen combinations in human vaccination trials that assess efficacy with controlled human malaria infection.

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Strong off-target antibody reactivity to malarial antigens induced by RTS,S/AS01E vaccination is associated with protection

Abstract: Conflict of interest: JJC, AR, and AO are employees of Antigen Discovery, Inc. (ADI), a company that carries patents (US Patent 10174311 and US Patent 20160320404) related to the protein array analyses used here and the location where the arrays were conducted.

Cited by 9 publications

References 29 publications

Coimmunization with Preerythrocytic Antigens alongside Circumsporozoite Protein Can Enhance Sterile Protection against Plasmodium Sporozoite Infection

Coimmunization with Preerythrocytic Antigens alongside Circumsporozoite Protein Can Enhance Sterile Protection against Plasmodium Sporozoite Infection

The acquisition of humoral immune responses targeting Plasmodium falciparum sexual stages in controlled human malaria infections

Co-immunization with pre-erythrocytic antigens alongside circumsporozoite protein can enhance sterile protection against Plasmodium sporozoite infection.

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