Understanding Human-Derived Antibodies Generated by Polymorphic Malaria Vaccine Against Merozoite Surface Protein 2

Understanding Human-Derived Antibodies Generated by Polymorphic Malaria Vaccine Against Merozoite... MSP2, vaccine, malaria (See the Major Article by Feng et al, on pages 35–43.) There is a continuing need for an effective malaria vaccine to enhance control and elimination efforts. This has been highlighted in the 2017 World Health Organization annual report, indicating that in multiple areas recent advances in reducing disease burden are stalling and reversing [1]. One continuing challenge in the development of effective antimalarial vaccine is the phenomenon of exceptional rates of genetic polymorphism and subsequent antigenic diversity in leading vaccine candidates [2]. Key target antigens of human immunity to malaria and leading vaccine candidate antigens (eg, AMA1, MSP1), have evolved significant polymorphisms in order to evade immunity. This has presented a persistent challenge in malaria vaccine development as it significantly impacts on how practically efficacious a logically designed, laboratory-derived vaccine is [3]. Antigenic polymorphisms in protein domains of high immunogenicity have evolved to be a crucial immune evasion mechanism of the parasite. Several trials of putative blood-stage vaccines have demonstrated evidence of strain-specific efficacy, which ultimately contributes towards rendering a vaccine effective or ineffective [4–6]. Naturally acquired immunity to malaria is typically slow to develop and requires repeated exposure to malaria over time; this slow acquisition is attributed, in part, to the requirement for the development of a sufficiently broad repertoire of antibodies against diverse strains [7, 8]. Current vaccine strategies to overcome antigenic diversity and vaccine escape include the incorporation of multiple alleles, developing antigens with modified sequences to enhance effective immunogenicity, or targeting conserved or less-diverse regions and epitopes [3]. Knowledge regarding the specificity and cross-reactivity of naturally acquired or vaccine-induced human immune responses to vaccine candidates is still limited. The conditions and approaches that favor the development of cross-reactive responses that may limit immune escape through antigenic diversity are largely unknown. In this issue of the Journal of Infectious Disease, Feng, Boyle et al use the well-characterized merozoite surface protein, MSP2, as a model to better understand the specificity and function of human-derived antibodies generated by vaccines compared with naturally acquired responses, determine whether an MSP2 combination vaccine successfully generated functional antibodies to multiple Plasmodium falciparum strains, and evaluate the overall specificity of vaccine-induced antibodies. Using a cohort of samples from a phase 1 bivalent vaccine trial with MSP2, Feng, Boyle et al provide direct evidence that vaccination with a multivalent vaccine induces cross-reactive and functional antibodies to the polymorphic malaria antigen, MSP2, in humans. This vaccine-induced response contrasted with the highly strain-specific nature of naturally acquired antibodies that enables immune escape. They show that vaccine-induced cytophilic antibodies are functional by examining mediation of opsonic phagocytosis, with a significant increase observed in activity following vaccination in sera from patients receiving the active vaccine, but not with placebo controls. Furthermore, they demonstrate an increase in the ability of postvaccination serum to activate complement via the classical complement pathway. Using competition enzyme-linked immunosorbent assay (ELISA), they show that the majority of antibody responses in vaccine recipients were highly cross-reactive to 2 distinct alleles of MSP2, in contrast to antibodies derived from naturally exposed individuals. Using an MSP2-peptide array and pools of “high responders” from vaccines, they epitope mapped vaccine-induced antibodies and showed that these antibodies predominately targeted the conserved epitopes at the C-terminal region of MSP2. Among naturally exposed individuals, antibodies targeting this region were also observed, but at significantly lower levels than those observed when examining strain-specific regions, or seen when using vaccine-derived samples. Finally, using a C-terminal–targeted monoclonal antibody, they confirm that this region of MSP2 is the target of functional antibodies, and definitively demonstrate that anti-MSP2 vaccine-induced antibodies can promote opsonic phagocytosis against multiple P. falciparum strains. Taken together, these studies provide strong evidence that vaccination with a bivalent vaccine can induce cross-reactive and functional antibodies in humans to the (typically polymorphic) malaria vaccine antigen MSP2. This contrasts with the highly allele/strain-specific nature of naturally acquired antibodies. This study provides new insights into how vaccine-induced responses in humans can differ from responses induced with naturally acquired immunity. This is clearly an important insight, which has implications for future strategic decisions on malaria vaccines targeting not only the blood stages, but also the pre-erythrocytic and transmission stages. In this case, MSP2 vaccine-induced antibodies are cross-reactive and functional at the C-terminus of MSP2. The scope of this study does not encompass investigation of the specific mechanisms mediating the preferential induction of cross-reactive antibodies following vaccination. The authors reason that this could be due to a differential antigenic load of conserved versus polymorphic epitopes when different alleles are used as part of a bivalent moiety, protein conformation differences in antigens when present in a vaccine compared to natural infection, adjuvant driven, or due to the administration route of the vaccine. Studies on influenza responses in mice have found that the route of administration and form of antigen can modulate immunodominance immunodominance of the specific antigen regions in the antibody response [9]. Extensive further examination and characterization of the mechanism of differential immunity are required if this phenomenon is to be exploited in vaccine development to overcome the confounding factors, that is antigenic diversity, parasite polymorphisms, and pathogen escape. An important priority in future malaria vaccine development is not just to identify the antigenic diversity circulating within the target parasite population, but also to understand the contribution of genetic/allelic diversity to targeted epitopes within each candidate antigen. Although there are indeed multiple diverse alleles of many candidate antigens circulating within distinct populations, not all polymorphisms will mediate antigenic escape; hence, these should be individually identified and characterized to enable logical vaccine design. Rigorous investigation of available candidates, as well as the examination of novel (relatively) conserved antigenic targets, are essential to develop a framework for the selection and prioritization of antigens for further development within a development pipeline. This study makes important observations and provides key insights into addressing these issues in the immediate future. Notes Financial support. F. A. and A. M. B. are supported by the UK Medical Research Council (grant number MR/N00227X/1). Potential conflicts of interest.  All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. World Malaria Report (WHO). World Malaria Report . Geneva: WHO, 2017. 2. Hamilton WL, Claessens A, Otto TD, et al.   Extreme mutation bias and high AT content in Plasmodium falciparum. Nucleic Acids Res  2017; 45: 1889– 901. Google Scholar PubMed  3. Ouattara A, Barry AE, Dutta S, Remarque EJ, Beeson JG, Plowe CV. Designing malaria vaccines to circumvent antigen variability. Vaccine  2015; 33: 7506– 12. Google Scholar CrossRef Search ADS PubMed  4. Neafsey DE, Juraska M, Bedford T, et al.   Genetic diversity and protective efficacy of the RTS,S/AS01 malaria vaccine. N Engl J Med  2015; 373: 2025– 37. Google Scholar CrossRef Search ADS PubMed  5. Epstein JE, Paolino KM, Richie TL, et al.   Protection against Plasmodium falciparum malaria by PfSPZ vaccine. JCI Insight  2017; 2: e89154. Google Scholar CrossRef Search ADS PubMed  6. Genton B, Betuela I, Felger I, et al.   A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1-2b trial in Papua New Guinea. J Infect Dis  2002; 185: 820– 7. Google Scholar CrossRef Search ADS PubMed  7. Conway DJ, Cavanagh DR, Tanabe K, et al.   A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses. Nat Med  2000; 6: 689– 92. Google Scholar CrossRef Search ADS PubMed  8. Bull PC, Lowe BS, Kortok M, Molyneux CS, Newbold CI, Marsh K. Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nat Med  1998; 4: 358– 60. Google Scholar CrossRef Search ADS PubMed  9. Angeletti D, Gibbs JS, Angel M, et al.   Defining B cell immunodominance to viruses. Nat Immunol  2017; 18: 456– 63. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Infectious Diseases Oxford University Press

Understanding Human-Derived Antibodies Generated by Polymorphic Malaria Vaccine Against Merozoite Surface Protein 2

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© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
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Abstract

MSP2, vaccine, malaria (See the Major Article by Feng et al, on pages 35–43.) There is a continuing need for an effective malaria vaccine to enhance control and elimination efforts. This has been highlighted in the 2017 World Health Organization annual report, indicating that in multiple areas recent advances in reducing disease burden are stalling and reversing [1]. One continuing challenge in the development of effective antimalarial vaccine is the phenomenon of exceptional rates of genetic polymorphism and subsequent antigenic diversity in leading vaccine candidates [2]. Key target antigens of human immunity to malaria and leading vaccine candidate antigens (eg, AMA1, MSP1), have evolved significant polymorphisms in order to evade immunity. This has presented a persistent challenge in malaria vaccine development as it significantly impacts on how practically efficacious a logically designed, laboratory-derived vaccine is [3]. Antigenic polymorphisms in protein domains of high immunogenicity have evolved to be a crucial immune evasion mechanism of the parasite. Several trials of putative blood-stage vaccines have demonstrated evidence of strain-specific efficacy, which ultimately contributes towards rendering a vaccine effective or ineffective [4–6]. Naturally acquired immunity to malaria is typically slow to develop and requires repeated exposure to malaria over time; this slow acquisition is attributed, in part, to the requirement for the development of a sufficiently broad repertoire of antibodies against diverse strains [7, 8]. Current vaccine strategies to overcome antigenic diversity and vaccine escape include the incorporation of multiple alleles, developing antigens with modified sequences to enhance effective immunogenicity, or targeting conserved or less-diverse regions and epitopes [3]. Knowledge regarding the specificity and cross-reactivity of naturally acquired or vaccine-induced human immune responses to vaccine candidates is still limited. The conditions and approaches that favor the development of cross-reactive responses that may limit immune escape through antigenic diversity are largely unknown. In this issue of the Journal of Infectious Disease, Feng, Boyle et al use the well-characterized merozoite surface protein, MSP2, as a model to better understand the specificity and function of human-derived antibodies generated by vaccines compared with naturally acquired responses, determine whether an MSP2 combination vaccine successfully generated functional antibodies to multiple Plasmodium falciparum strains, and evaluate the overall specificity of vaccine-induced antibodies. Using a cohort of samples from a phase 1 bivalent vaccine trial with MSP2, Feng, Boyle et al provide direct evidence that vaccination with a multivalent vaccine induces cross-reactive and functional antibodies to the polymorphic malaria antigen, MSP2, in humans. This vaccine-induced response contrasted with the highly strain-specific nature of naturally acquired antibodies that enables immune escape. They show that vaccine-induced cytophilic antibodies are functional by examining mediation of opsonic phagocytosis, with a significant increase observed in activity following vaccination in sera from patients receiving the active vaccine, but not with placebo controls. Furthermore, they demonstrate an increase in the ability of postvaccination serum to activate complement via the classical complement pathway. Using competition enzyme-linked immunosorbent assay (ELISA), they show that the majority of antibody responses in vaccine recipients were highly cross-reactive to 2 distinct alleles of MSP2, in contrast to antibodies derived from naturally exposed individuals. Using an MSP2-peptide array and pools of “high responders” from vaccines, they epitope mapped vaccine-induced antibodies and showed that these antibodies predominately targeted the conserved epitopes at the C-terminal region of MSP2. Among naturally exposed individuals, antibodies targeting this region were also observed, but at significantly lower levels than those observed when examining strain-specific regions, or seen when using vaccine-derived samples. Finally, using a C-terminal–targeted monoclonal antibody, they confirm that this region of MSP2 is the target of functional antibodies, and definitively demonstrate that anti-MSP2 vaccine-induced antibodies can promote opsonic phagocytosis against multiple P. falciparum strains. Taken together, these studies provide strong evidence that vaccination with a bivalent vaccine can induce cross-reactive and functional antibodies in humans to the (typically polymorphic) malaria vaccine antigen MSP2. This contrasts with the highly allele/strain-specific nature of naturally acquired antibodies. This study provides new insights into how vaccine-induced responses in humans can differ from responses induced with naturally acquired immunity. This is clearly an important insight, which has implications for future strategic decisions on malaria vaccines targeting not only the blood stages, but also the pre-erythrocytic and transmission stages. In this case, MSP2 vaccine-induced antibodies are cross-reactive and functional at the C-terminus of MSP2. The scope of this study does not encompass investigation of the specific mechanisms mediating the preferential induction of cross-reactive antibodies following vaccination. The authors reason that this could be due to a differential antigenic load of conserved versus polymorphic epitopes when different alleles are used as part of a bivalent moiety, protein conformation differences in antigens when present in a vaccine compared to natural infection, adjuvant driven, or due to the administration route of the vaccine. Studies on influenza responses in mice have found that the route of administration and form of antigen can modulate immunodominance immunodominance of the specific antigen regions in the antibody response [9]. Extensive further examination and characterization of the mechanism of differential immunity are required if this phenomenon is to be exploited in vaccine development to overcome the confounding factors, that is antigenic diversity, parasite polymorphisms, and pathogen escape. An important priority in future malaria vaccine development is not just to identify the antigenic diversity circulating within the target parasite population, but also to understand the contribution of genetic/allelic diversity to targeted epitopes within each candidate antigen. Although there are indeed multiple diverse alleles of many candidate antigens circulating within distinct populations, not all polymorphisms will mediate antigenic escape; hence, these should be individually identified and characterized to enable logical vaccine design. Rigorous investigation of available candidates, as well as the examination of novel (relatively) conserved antigenic targets, are essential to develop a framework for the selection and prioritization of antigens for further development within a development pipeline. This study makes important observations and provides key insights into addressing these issues in the immediate future. Notes Financial support. F. A. and A. M. B. are supported by the UK Medical Research Council (grant number MR/N00227X/1). Potential conflicts of interest.  All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. World Malaria Report (WHO). World Malaria Report . Geneva: WHO, 2017. 2. Hamilton WL, Claessens A, Otto TD, et al.   Extreme mutation bias and high AT content in Plasmodium falciparum. Nucleic Acids Res  2017; 45: 1889– 901. Google Scholar PubMed  3. Ouattara A, Barry AE, Dutta S, Remarque EJ, Beeson JG, Plowe CV. Designing malaria vaccines to circumvent antigen variability. Vaccine  2015; 33: 7506– 12. Google Scholar CrossRef Search ADS PubMed  4. Neafsey DE, Juraska M, Bedford T, et al.   Genetic diversity and protective efficacy of the RTS,S/AS01 malaria vaccine. N Engl J Med  2015; 373: 2025– 37. Google Scholar CrossRef Search ADS PubMed  5. Epstein JE, Paolino KM, Richie TL, et al.   Protection against Plasmodium falciparum malaria by PfSPZ vaccine. JCI Insight  2017; 2: e89154. Google Scholar CrossRef Search ADS PubMed  6. Genton B, Betuela I, Felger I, et al.   A recombinant blood-stage malaria vaccine reduces Plasmodium falciparum density and exerts selective pressure on parasite populations in a phase 1-2b trial in Papua New Guinea. J Infect Dis  2002; 185: 820– 7. Google Scholar CrossRef Search ADS PubMed  7. Conway DJ, Cavanagh DR, Tanabe K, et al.   A principal target of human immunity to malaria identified by molecular population genetic and immunological analyses. Nat Med  2000; 6: 689– 92. Google Scholar CrossRef Search ADS PubMed  8. Bull PC, Lowe BS, Kortok M, Molyneux CS, Newbold CI, Marsh K. Parasite antigens on the infected red cell surface are targets for naturally acquired immunity to malaria. Nat Med  1998; 4: 358– 60. Google Scholar CrossRef Search ADS PubMed  9. Angeletti D, Gibbs JS, Angel M, et al.   Defining B cell immunodominance to viruses. Nat Immunol  2017; 18: 456– 63. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

The Journal of Infectious DiseasesOxford University Press

Published: Mar 23, 2018

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