Requirements for empirical immunogenicity trials, rather than structure-based design, for developing an effective HIV vaccine.

The claim that it is possible to rationally design a structure-based HIV-1 vaccine is based on misconceptions regarding the nature of protein epitopes and of immunological specificity. Attempts to use reverse vaccinology to generate an HIV-1 vaccine on the basis of the structure of viral epitopes bound to monoclonal neutralizing antibodies have failed so far because it was not possible to extrapolate from an observed antigenic structure to the immunogenic structure required in a vaccine. Vaccine immunogenicity depends on numerous extrinsic factors such as the host immunoglobulin gene repertoire, the presence of various cellular and regulatory mechanisms in the immunized host and the process of antibody affinity maturation. All these factors played a role in the appearance of the neutralizing antibody used to select the epitope to be investigated as potential vaccine immunogen, but they cannot be expected to be present in identical form in the host to be vaccinated. It is possible to rationally design and optimize an epitope to fit one particular antibody molecule or to improve the paratope binding efficacy of a monoclonal antibody intended for passive immunotherapy. What is not possible is to rationally design an HIV-1 vaccine immunogen that will elicit a protective polyclonal antibody response of predetermined efficacy. An effective vaccine immunogen can only be discovered by investigating experimentally the immunogenicity of a candidate molecule and demonstrating its ability to induce a protective immune response. It cannot be discovered by determining which epitopes of an engineered antigen molecule are recognized by a neutralizing monoclonal antibody. This means that empirical immunogenicity trials rather than structural analyses of antigens offer the best hope of discovering an HIV-1 vaccine.