Naturally acquired antibody response to a Plasmodium falciparum chimeric vaccine candidate GMZ2.6c and its components (MSP-3, GLURP, and Pfs48/45) in individuals living in Brazilian malaria-endemic areas

Abstract

Background The GMZ2.6c malaria vaccine candidate is a multi-stage Plasmodium falciparum chimeric protein which contains a fragment of the sexual-stage Pfs48/45-6C protein genetically fused to GMZ2, a fusion protein of GLURP and MSP-3, that has been shown to be well tolerated, safe and immunogenic in clinical trials performed in a malaria-endemic area of Africa. However, there is no data available on the antigenicity or immunogenicity of GMZ2.6c in humans. Considering that circulating parasites can be genetically distinct in different malaria-endemic areas and that host genetic factors can influence the immune response to vaccine antigens, it is important to verify the antigenicity, immunogenicity and the possibility of associated protection in individuals living in malaria-endemic areas with different epidemiological scenarios. Herein, the profile of antibody response against GMZ2.6c and its components (MSP-3, GLURP and Pfs48/45) in residents of the Brazilian Amazon naturally exposed to malaria, in areas with different levels of transmission, was evaluated. Methods This study was performed using serum samples from 352 individuals from Cruzeiro do Sul and Mâncio Lima, in the state of Acre, and Guajará, in the state of Amazonas. Specific IgG, IgM, IgA and IgE antibodies and IgG subclasses were detected by Enzyme-Linked Immunosorbent Assay. Results The results showed that GMZ2.6c protein was widely recognized by naturally acquired antibodies from individuals of the Brazilian endemic areas with different levels of transmission. The higher prevalence of individuals with antibodies against GMZ2.6c when compared to its individual components may suggest an additive effect of GLURP, MSP-3, and Pfs48/45 when inserted in a same construct. Furthermore, naturally malaria-exposed individuals predominantly had IgG1 and IgG3 cytophilic anti-GMZ2.6c antibodies, an important fact considering that the acquisition of anti-malaria protective immunity results from a delicate balance between cytophilic/non-cytophilic antibodies. Interestingly, anti-GMZ2.6c antibodies seem to increase with exposure to malaria infection and may contribute to parasite immunity. Conclusions The data showed that GMZ2.6c protein is widely recognized by naturally acquired antibodies from individuals living in malaria-endemic areas in Brazil and that these may contribute to parasite immunity. These data highlight the importance of GMZ2.6c as a candidate for an anti-malarial vaccine.

Plasmodium 6-Cysteine Proteins: Functional Diversity, Transmission-Blocking Antibodies and Structural Scaffolds

“…A number of 6-cysteine multi-antigen vaccine candidates are under investigation, including Pfs48/45-GLURP ( Theisen et al., 2014 ; Roeffen et al., 2015 ; Singh et al., 2015 ; Singh et al., 2017a ; Singh et al., 2017b ; Singh et al., 2021a ), Pfs48/45-GLURP-MSP3 ( Baldwin et al., 2016 ; Mistarz et al., 2017 ), Pfs230-Pfs48/45 ( Singh et al., 2019 ; Singh et al., 2020 ; Singh et al., 2021b ) and Pfs230-Pfs25 ( Menon et al., 2017 ; Healy et al., 2021 ). A recent study found a higher prevalence of naturally infected individuals with antibodies against a Pfs48/45-GLURP-MSP3-based vaccine than against the individual proteins, suggesting the combination of antigens has an additive effect on immune response ( Baptista et al., 2022 ). Moreover, animal immunization with the Pfs230-Pfs48/45 chimera elicited transmission-blocking antibody responses three-fold higher than the single antigens alone ( Singh et al., 2019 ), suggesting further investigation of 6-cysteine antigen combinations is warranted.…”

B-Cell Epitope Mapping of the Plasmodium falciparum Malaria Vaccine Candidate GMZ2.6c in a Naturally Exposed Population of the Brazilian Amazon

“…Serum samples from 303 malaria-exposed individuals identified as responders to GLURP 27−500 ( n = 258), MSP-3 155–249 ( n = 170), and/or Pf s48/45 291–428 ( n = 108) recombinants ( Table S1 ), as previously described [ 20 ], were used to investigate specific naturally acquired antibody response to GLURP, MSP-3, and Pf s48/45 epitopes. In addition, serum samples from 5 individuals of the laboratory staff (Rio de Janeiro, Brazil) who had neither history of malaria nor contact with malaria transmission areas were included in our study (Rio de Janeiro controls).…”

“…Previous studies showed that GMZ2.6c protein was widely recognized by naturally acquired antibodies from individuals of Brazilian endemic areas and that its components (MSP-3, GLURP, and Pf s48/45) are immunogenic in natural infection by P. falciparum. Moreover, anti-GMZ2.6c antibodies seem to increase with exposure to malaria infection and may contribute to parasite immunity [ 20 ]. Considering that antibodies recognize several antigenic determinants of the protein, identifying the contribution of different immunodominant B-cell epitopes of antimalarial vaccine candidates that induce specific immune responses may be an important tool for understanding protective immunity.…”

Host-parasite interactions during Plasmodium infection: Implications for immunotherapies

“…GMZ2.6c vaccine efficacy can be enhanced by using TLR4 agonists which have been reported to induce parasite-specific antibodies and T-cell-mediated immunity in mice models ( 170 ). Recently, one study reported that the GMZ2.6c vaccine is recognized by naturally acquired antibodies in individuals living in malaria-endemic regions of Brazil with different levels of transmission ( 171 ). Another chimeric multistage TBV, ProC6C was prepared by combining Pf s230- Pf s48/45 fusion protein with the Pf CSP linker sequence.…”