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Immune systems rather than antigenic epitopes elicit and produce protective antibodies against HIV
Vaccine 35 (2017) 1985–1986
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Letter to the Editor Immune systems rather than antigenic epitopes elicit and produce protective antibodies against HIV
It is common parlance to refer to viral antigens and their epitopes as immunogens capable of producing antibodies (Abs) against the virus that harbours them. Words have an insiduous capacity to fashion our thinking and terms like immunogen and immunogenicity do suggest that epitopes are able to generate immune responses, although they only trigger in the host a series of reactions with B-cell receptors that eventually leads to the immune system (IS) producing a variety of antibodies. Although everyone in the field is well aware that antigens are different from immunogens, it seems that in many cases investigators do not use appropriate experimental tools for studying and controlling the immunogenicity of proteins rather than their antigenicity. For many years, much of HIV vaccine research concentrated on elucidating the structure of HIV epitopes present on the virus glycoprotein spikes because these epitopes were considered to be potential vaccine immunogens capable of inducing protective Abs against virus infection. The approach known as structurebased reverse vaccinology (SBRV) analysed the structure of complexes between HIV epitopes and neutralizing monoclonal Abs (nMabs) in an attempt to design epitopes by reverse molecular engineering that would elicit nAbs when used as vaccine immunogens [1]. Investigators using this approach called it vaccine design because they assumed that if an antigenic epitope did bind strongly to a nMab, it would also be able to induce similar neutralizing Abs when used as a vaccine [2]. They also assumed that when an antigenic epitope binds to a free Ab molecule, the recognition process is exactly the same as when the same epitope (which is then an immunogen) binds to the cognate B-cell receptor embedded in a lipid membrane. There is, however, evidence that lipids present in B-cell membranes may contribute to the binding observed when a protein antigen interacts with a B-cell receptor, which means that the same antigen is likely to bind more weakly to the corresponding free Ab molecule. It is also known that when an Ab binds to a free viral peptide, the binding may be weaker than when that Ab binds to the same peptide embedded in a viral membrane, because of additional hydrophobic interactions with membrane lipids [3]. An additional problem with the SBRV approach was that it ignored the fact that all Abs are polyspecific or even heterospecific and that the antigenic and immunogenic properties of a protein antigen may be located in different parts of the molecule [4]. Since they were focusing on only one of the epitopes recognized by a polyspecific nMab, the investigators assumed that this epitope was the immunogen that elicited the nAb and should therefore be able to elicit similar nAbs when used as a vaccine [5]. Although many structures of nMabs-epitope complexes were elucidated in this manner, the insights derived from http://dx.doi.org/10.1016/j.vaccine.2017.03.017 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.
these immunochemical studies did not lead to an effective HIV vaccine [6,7]. It was found, for instance, that strongly neutralizing Abs often possessed very long CDR-H3 but it was not feasible to reverse engineer that property in a vaccine immunogen so that the IS would elicit such nAbs [8]. Many properties of the IS are known to control the types of Abs that are produced, for instance the host Ab gene repertoire, the presence of helper and suppressor T cells, self tolerance and numerous other immunoregulatory mechanisms in the host [9]. However, vaccine designers using the SBRV approach tended to ignore these factors because they focused their attention on recognition processes between single epitope-paratope pairs which made it impossible for them to figure out how to intervene in the IS so that it would produce neutralizing Abs. When it was discovered 20 years later that HIV Env epitopes recognized by affinity-matured Abs obtained from HIV-infected individuals did not bind the germline predecessors of these Abs [10], it became obvious that potential vaccine immunogens would only be discovered if one took into account the slow but extensive Ab maturation that is required for obtaining nAbs. Finding potential HIV vaccine immunogens by SBRV appeared no longer feasible and a huge research effort was initiated to analyze the innumerable maturation pathways that allow individual immune systems to transform non-neutralizing germline Abs into protective Abs [11]. Our understanding of antibody maturation processes increased dramatically but the complexity that emerged was daunting because it indicated that several sequential immunizations with particular Env immunogens would be needed to drive the immune responses of genetically heterogeneous human vaccinees towards highly mutated antiHIV bnAbs [12]. Since rational vaccine design based on antigenicity studies was unable to reveal which immunogens may lead to a protective immune response [7], it became increasingly evident that only in vivo empirical, experimental immunogenicity studies might be able to provide the required information. Unfortunately, most animal models are poorly predictive of responses in humans and testing a huge variety of HIV vaccine immunogens in humans is not a practical alternative. The most promising approach for evaluating HIV vaccine immunogens developed in recent years is the use of human Ig knockin (KI) mice that have incorporated human Ig variable regions in the corresponding mouse loci [13]. The remarkable results that have been obtained indicate that KI mice are the best model system for testing HIV vaccine immunogens as well as novel adjuvants and T cell help. The use of KI mice might also be able to conclusively establish whether the existence of self-reactivity in nAbs leads to host tolerance and controls the immune responses induced by particular Env immunogens [13]. Immune correlates of protection are often believed to be essential information for guiding HIV vaccine development although they can be inferred only retrospectively after an efficacious
1986
Letter to the Editor / Vaccine 35 (2017) 1985–1986
vaccine has been obtained empirically [2]. At the moment, only correlates of HIV-1 decreased transmission risk (i.e. not protection) involving multiple immune responses observed during the RV144 vaccine trial have been investigated [14] and their usefulness for further improving vaccine regimens will need to be confirmed after a more effective vaccine has been developed. This reminds us that the prescriptive, empirical knowledge required for producing an efficacious HIV vaccine cannot be obtained beforehand by deducing immunogenicity from antigenicity [7]. The current, huge investment in curiosity-driven basic research aimed at understanding HIV-Ab interactions will no doubt greatly increase our factual knowledge of the enormous complexity of the IS and of HIV. However, it also cannot be excluded, as was often observed in vaccinology in the past, that applied vaccine research may succeed even if we lack a complete understanding of the complex immunological mechanisms that would underlie the mode of action of an ideal HIV vaccine. Conflicts of interest None. References [1] Van Regenmortel MHV. Two meanings of reverse vaccinology and the empirical nature of vaccine science. Vaccine 2011;29:7875. [2] Van Regenmortel MHV. Basic research in HIV vaccinology is hampered by reductionist thinking. Front Immunol 2012;3:194. doi: http://dx.doi.org/ 10.3389/fimmu.2012.00194. [3] Scherer EM, Leaman DP, Zwick M, McMichael AJ, Burton DR. Aromatic residues at the edge of the antibody combining site facilitate viral glycoprotein recognition through membrane interactions. Proc Natl Acad Sci USA 2010;107: 1529–34.
[4] Van Regenmortel MHV. Specificity, polyspecificity and heterospecificity of antibody-antigen recognition. J Mol Recogn 2014;27:627–39. [5] Van Regenmortel MHV. An outdated notion of antibody specificity is one of the major detrimental assumptions of the structure-based reverse vaccinology paradigm, which prevented it from helping to develop an effective HIV-1 vaccine. Front Immunol 5:593. http://dx.doi.org/10.3389/fimmu.2014.00593. [6] Pejchal R, Wilson IA. Structure-based vaccine design in HIV: blind men and the elephant? Curr Pharm Des 2010;16:3744–53. [7] Van Regenmortel MHV. Structure-based reverse vaccinology failed in the case of HIV because it disregarded accepted immunological theory. Int J Mol Sci 2016;17:1591. doi: http://dx.doi.org/10.3390/ijms17091591. [8] Yu L, Guan Y. Immunologic basis for long HCDR3s in broadly neutralizing antibodies against HIV-1. Front Immunol 2014;5:250. [9] Berzofsky JA. Intrinsic and extrinsic factors in protein antigenic structure. Science 1985;27:932–40. [10] Xiao X, Chen W, Feng Y, Prabakaran P, Wang Y, Dimitrov DS. Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: implications for evasion of immune responses and design of vaccine immunogens. Biochem Biophys Res Commun 2009;390: 404–9. [11] Mascola JR, Haynes BF. HIV-1 neutralizing antibodies: understanding nature’s pathways. Immunol Rev 2013;254:225–44. [12] Stamatatos L, Pancera M, McGuire AT. Germline-targeting immunogens. Immunol Rev 2017;275:203–16. [13] Verkoczy L, Alt FW, Tian M. Human Ig knocking mice to study the development and regulation of broadly neutralizing antibodies. Immunol Rev 2017;275:89–107. [14] Tomaras GD, Plotkin SA. Complex immune correlates of protection in HIV-1 vaccine efficacy trials. Immunol Rev 2017;275:245–61.
Marc H.V. Van Regenmortel IREBS, CNRS, Université de Strasbourg, 67400 Illkirch, France E-mail address: [email protected]
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Letter to the Editor Immune systems rather than antigenic epitopes elicit and produce protective antibodies against HIV
It is common parlance to refer to viral antigens and their epitopes as immunogens capable of producing antibodies (Abs) against the virus that harbours them. Words have an insiduous capacity to fashion our thinking and terms like immunogen and immunogenicity do suggest that epitopes are able to generate immune responses, although they only trigger in the host a series of reactions with B-cell receptors that eventually leads to the immune system (IS) producing a variety of antibodies. Although everyone in the field is well aware that antigens are different from immunogens, it seems that in many cases investigators do not use appropriate experimental tools for studying and controlling the immunogenicity of proteins rather than their antigenicity. For many years, much of HIV vaccine research concentrated on elucidating the structure of HIV epitopes present on the virus glycoprotein spikes because these epitopes were considered to be potential vaccine immunogens capable of inducing protective Abs against virus infection. The approach known as structurebased reverse vaccinology (SBRV) analysed the structure of complexes between HIV epitopes and neutralizing monoclonal Abs (nMabs) in an attempt to design epitopes by reverse molecular engineering that would elicit nAbs when used as vaccine immunogens [1]. Investigators using this approach called it vaccine design because they assumed that if an antigenic epitope did bind strongly to a nMab, it would also be able to induce similar neutralizing Abs when used as a vaccine [2]. They also assumed that when an antigenic epitope binds to a free Ab molecule, the recognition process is exactly the same as when the same epitope (which is then an immunogen) binds to the cognate B-cell receptor embedded in a lipid membrane. There is, however, evidence that lipids present in B-cell membranes may contribute to the binding observed when a protein antigen interacts with a B-cell receptor, which means that the same antigen is likely to bind more weakly to the corresponding free Ab molecule. It is also known that when an Ab binds to a free viral peptide, the binding may be weaker than when that Ab binds to the same peptide embedded in a viral membrane, because of additional hydrophobic interactions with membrane lipids [3]. An additional problem with the SBRV approach was that it ignored the fact that all Abs are polyspecific or even heterospecific and that the antigenic and immunogenic properties of a protein antigen may be located in different parts of the molecule [4]. Since they were focusing on only one of the epitopes recognized by a polyspecific nMab, the investigators assumed that this epitope was the immunogen that elicited the nAb and should therefore be able to elicit similar nAbs when used as a vaccine [5]. Although many structures of nMabs-epitope complexes were elucidated in this manner, the insights derived from http://dx.doi.org/10.1016/j.vaccine.2017.03.017 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.
these immunochemical studies did not lead to an effective HIV vaccine [6,7]. It was found, for instance, that strongly neutralizing Abs often possessed very long CDR-H3 but it was not feasible to reverse engineer that property in a vaccine immunogen so that the IS would elicit such nAbs [8]. Many properties of the IS are known to control the types of Abs that are produced, for instance the host Ab gene repertoire, the presence of helper and suppressor T cells, self tolerance and numerous other immunoregulatory mechanisms in the host [9]. However, vaccine designers using the SBRV approach tended to ignore these factors because they focused their attention on recognition processes between single epitope-paratope pairs which made it impossible for them to figure out how to intervene in the IS so that it would produce neutralizing Abs. When it was discovered 20 years later that HIV Env epitopes recognized by affinity-matured Abs obtained from HIV-infected individuals did not bind the germline predecessors of these Abs [10], it became obvious that potential vaccine immunogens would only be discovered if one took into account the slow but extensive Ab maturation that is required for obtaining nAbs. Finding potential HIV vaccine immunogens by SBRV appeared no longer feasible and a huge research effort was initiated to analyze the innumerable maturation pathways that allow individual immune systems to transform non-neutralizing germline Abs into protective Abs [11]. Our understanding of antibody maturation processes increased dramatically but the complexity that emerged was daunting because it indicated that several sequential immunizations with particular Env immunogens would be needed to drive the immune responses of genetically heterogeneous human vaccinees towards highly mutated antiHIV bnAbs [12]. Since rational vaccine design based on antigenicity studies was unable to reveal which immunogens may lead to a protective immune response [7], it became increasingly evident that only in vivo empirical, experimental immunogenicity studies might be able to provide the required information. Unfortunately, most animal models are poorly predictive of responses in humans and testing a huge variety of HIV vaccine immunogens in humans is not a practical alternative. The most promising approach for evaluating HIV vaccine immunogens developed in recent years is the use of human Ig knockin (KI) mice that have incorporated human Ig variable regions in the corresponding mouse loci [13]. The remarkable results that have been obtained indicate that KI mice are the best model system for testing HIV vaccine immunogens as well as novel adjuvants and T cell help. The use of KI mice might also be able to conclusively establish whether the existence of self-reactivity in nAbs leads to host tolerance and controls the immune responses induced by particular Env immunogens [13]. Immune correlates of protection are often believed to be essential information for guiding HIV vaccine development although they can be inferred only retrospectively after an efficacious
1986
Letter to the Editor / Vaccine 35 (2017) 1985–1986
vaccine has been obtained empirically [2]. At the moment, only correlates of HIV-1 decreased transmission risk (i.e. not protection) involving multiple immune responses observed during the RV144 vaccine trial have been investigated [14] and their usefulness for further improving vaccine regimens will need to be confirmed after a more effective vaccine has been developed. This reminds us that the prescriptive, empirical knowledge required for producing an efficacious HIV vaccine cannot be obtained beforehand by deducing immunogenicity from antigenicity [7]. The current, huge investment in curiosity-driven basic research aimed at understanding HIV-Ab interactions will no doubt greatly increase our factual knowledge of the enormous complexity of the IS and of HIV. However, it also cannot be excluded, as was often observed in vaccinology in the past, that applied vaccine research may succeed even if we lack a complete understanding of the complex immunological mechanisms that would underlie the mode of action of an ideal HIV vaccine. Conflicts of interest None. References [1] Van Regenmortel MHV. Two meanings of reverse vaccinology and the empirical nature of vaccine science. Vaccine 2011;29:7875. [2] Van Regenmortel MHV. Basic research in HIV vaccinology is hampered by reductionist thinking. Front Immunol 2012;3:194. doi: http://dx.doi.org/ 10.3389/fimmu.2012.00194. [3] Scherer EM, Leaman DP, Zwick M, McMichael AJ, Burton DR. Aromatic residues at the edge of the antibody combining site facilitate viral glycoprotein recognition through membrane interactions. Proc Natl Acad Sci USA 2010;107: 1529–34.
[4] Van Regenmortel MHV. Specificity, polyspecificity and heterospecificity of antibody-antigen recognition. J Mol Recogn 2014;27:627–39. [5] Van Regenmortel MHV. An outdated notion of antibody specificity is one of the major detrimental assumptions of the structure-based reverse vaccinology paradigm, which prevented it from helping to develop an effective HIV-1 vaccine. Front Immunol 5:593. http://dx.doi.org/10.3389/fimmu.2014.00593. [6] Pejchal R, Wilson IA. Structure-based vaccine design in HIV: blind men and the elephant? Curr Pharm Des 2010;16:3744–53. [7] Van Regenmortel MHV. Structure-based reverse vaccinology failed in the case of HIV because it disregarded accepted immunological theory. Int J Mol Sci 2016;17:1591. doi: http://dx.doi.org/10.3390/ijms17091591. [8] Yu L, Guan Y. Immunologic basis for long HCDR3s in broadly neutralizing antibodies against HIV-1. Front Immunol 2014;5:250. [9] Berzofsky JA. Intrinsic and extrinsic factors in protein antigenic structure. Science 1985;27:932–40. [10] Xiao X, Chen W, Feng Y, Prabakaran P, Wang Y, Dimitrov DS. Germline-like predecessors of broadly neutralizing antibodies lack measurable binding to HIV-1 envelope glycoproteins: implications for evasion of immune responses and design of vaccine immunogens. Biochem Biophys Res Commun 2009;390: 404–9. [11] Mascola JR, Haynes BF. HIV-1 neutralizing antibodies: understanding nature’s pathways. Immunol Rev 2013;254:225–44. [12] Stamatatos L, Pancera M, McGuire AT. Germline-targeting immunogens. Immunol Rev 2017;275:203–16. [13] Verkoczy L, Alt FW, Tian M. Human Ig knocking mice to study the development and regulation of broadly neutralizing antibodies. Immunol Rev 2017;275:89–107. [14] Tomaras GD, Plotkin SA. Complex immune correlates of protection in HIV-1 vaccine efficacy trials. Immunol Rev 2017;275:245–61.
Marc H.V. Van Regenmortel IREBS, CNRS, Université de Strasbourg, 67400 Illkirch, France E-mail address: [email protected]