Focusing the immune response on protective epitopes: A new approach to vaccine design using classical immunologic principles

Abstract

Protective antibodies (Abs) are needed to reduce the size of a virus inoculum and block infection of target cells. Since sera from some HIV-infected individuals have broad neutralizing activity and several human monoclonal Abs neutralize a broad spectrum of primary isolates, it is clear that the human B-cell repertoire includes genes capable of coding for broadly protective Abs. The epitopes that are known to induce broadly neutralizing Abs include the membrane proximal external region of gp41, the CD4 binding site on gp120, complex glycans on gp120, the CD4-induced epitope in and around the gp120 bridging sheet, and the V3 loop of gp120.

Despite the extensive information on HIV neutralizing Abs, it has proven difficult to induce broadly neutralizing Ab responses against HIV by immunization. This is due to several factors including the predominant induction of non-neutralizing rather than neutralizing Abs, the masking of neutralization-sensitive epitopes, the high mutation rate of HIV leading to antigenic variability, the physicochemical characteristics of the virus membrane, and the variable affinities of the different gp120 proteins for the virus receptors.

While various forms of the HIV envelope proteins have been used as immunogens, the best, albeit modest, results in terms of generating broadly neutralizing Abs have been achieved with strategies utilizing a DNA prime and either a recombinant adenovirus or protein boost. An alternative immunization approach is the construction and use of an immunogen that will focus the immune response on one or a few epitopes that are known to induce neutralizing Abs. An advantage of this approach is the potential to induce an immune response with a larger proportion of neutralizing Abs. To test the concept of "immunofocusing vaccines," we developed an immunization regimen designed to focus the immune response on the V3 loop of the HIV envelope. For this, we used both classical immunologic approaches and more recent data that stress the importance of the conformation of B cell epitopes to prime and selectively stimulate memory B cells.

Here, we report the results of experiments in rabbits in which animals were primed with gp120 DNA and boosted with a V3-fusion protein in order to preferentially induce anti-V3 Abs. The results provide a proof-of-principle that it is possible to focus the immune response on a neutralizing epitope and induce a vigorous neutralizing anti-HIV Ab response. The results suggest that immunofocusing vaccine regimens do indeed, target Abs to particular epitopes. This approach can now be employed to provide a platform for inducing Abs of greater potency and breadth by defining the best combinations of strains from which to build the priming and boosting immunogens and by designing immunogens that will optimally present several neutralizing epitopes.

This abstract was published in Cancer Immunity, a Cancer Research Institute journal that ceased publication in 2013 and is now provided online in association with Cancer Immunology Research.