Limitations to the structure‐based design of HIV‐1 vaccine immunogens

Abstract

In spite of 25 years of intensive research, no effective human immunodeficiency virus type 1 (HIV-1) vaccine has yet been developed. One reason for this is that investigators have concentrated mainly on the structural analysis of HIV-1 antigens because they assumed that it should be possible to deduce vaccine-relevant immunogens from the structure of viral antigens bound to neutralizing monoclonal antibodies. This unwarranted assumption arises from misconceptions regarding the nature of protein epitopes and from the belief that it is justified to extrapolate from the antigenicity to the immunogenicity of proteins. Although the structure of the major HIV-1 antigenic sites has been elucidated, this knowledge has been of little use for designing an HIV-1 vaccine. Little attention has been given to the fact that protective immune responses tend to be polyclonal and involve antibodies directed to several different epitopes. It is concluded that only trial and error, empirical investigations using numerous immunization protocols may eventually allow us to identify which mixtures of immunogens are likely to be the best candidates for an HIV-1 vaccine.

Envelope Variants Circulating as Initial Neutralization Breadth Developed in Two HIV-Infected Subjects Stimulate Multiclade Neutralizing Antibodies in Rabbits

“…One active area of research for the past decade or more has been to design Env proteins that are more effective in presenting these neutralization determinants; to date, these approaches have not significantly increased the neutralization breadth of NAbs elicited through vaccination (73)(74)(75). An alternative approach that we have taken is to vaccinate with natural quasispecies sequences that have evolved during the development of breadth.…”

Development of prophylactic vaccines against HIV-1

“…Although the complex and unusual nature of many bNmAb epitopes present unprecedented challenges in vaccine antigen design, the large and rapidly growing number of bNmAb-epitope structures encourages optimism that one or more epitopes will be translated into a viable vaccine antigen. However, translating antigenicity in vitro into immunogenicity in vivo is unpredictable and will be a major hurdle to overcome [68-71]. Concerns have been expressed that too much emphasis on basic research towards reductionist structure-based vaccine design will end in frustration and failure [69], but there are equally serious concerns within the vaccine research community that too much emphasis on empirical clinical trials will soak up available funding with an uncertain long-term outcome.…”

Paradigm Changes and the Future of HIV Vaccine Research: A Summary of a Workshop Held in Baltimore on 20 November 2013

“…In HIV vaccine research, there is evidence that several prevalent paradigms have not helped the development of the field, and this may partly explain why after 25 years of intensive research efforts, it has not been possible to develop an effective vaccine using classical strategies [3][4][5][6]. One such paradigm is the assumption that HIV-1 epitopes identified by crystallography of complexes of HIV Env bound to affinity -matured neutralizing (n) Mabs are likely to be effective vaccine immunogens able to induce a protective immune response.…”