Approaches to modulate vaccine-induced antibody responses

Abstract

Most successful licensed vaccines mediate protection by inducing antibody responses capable of protecting the individual from infection or disease. Despite the availability of many effective vaccines, we lack knowledge about fundamental aspects of B cell immunity and how we respond to complex real-world protein antigens. HIV-1 is a particularly difficult vaccine target since it has evolved multiple strategies to evade host antibody responses, such as conformational and glycan shielding. A consequence of this effective shielding is that the most immunogenic determinants of the envelope glycoprotein (Env) spike are those that the virus can readily mutate, which give rise to strain-specific antibodies. The conserved determinants of Env, which are targets for broadly neutralizing antibodies, tend to be less immunogenic. Another challenge has been the production of recombinant immunogens that mimic the functional HIV-1 Env spike but recent developments have improved this situation. In this thesis, I studied Env-specific immune responses induced by immunization with recombinant Env trimers to broaden our knowledge about B cell responses against this complex protein antigen.

In brief, I investigated basic B cell questions using HIV-1 Env as a model antigen in a series of mouse immunogenicity studies. In Paper I, we asked whether or not there is a competition between B cells that recognize distal epitopes on HIV-1 Env. The variable region 3 (V3) of Env is highly immunogenic. We therefore masked the V3 region with N-linked glycans to study if the elicited response would be re-distributed to other more conserved determinants on Env. The results indicated that there was no competition between B cells. Instead, we observed a total decrease in the antibody responses when the V3 region was shielded. Next, in Paper II, we manipulated the naïve B cell repertoire by pre-treating mice with recombinant BLyS to rescue additional B cells into the mature naïve B cell pool. The results showed that BLyS treatment expanded the naïve B cell population and resulted in improved neutralization capacity after Env immunization. In Paper III, we established protocols that would allow characterization of vaccine-induced antibody specificities. We describe staining protocols for Env-specific memory and germinal center B cells in mice. Finally, in Paper IV, we evaluated the effect of chemical cross-linking of HIV-1 Env trimers for the elicited antibody response after immunization. The results indicated a Th2 shift in the serum antibody isotype response compared to the response elicited in mice immunized with unfixed trimers.

In conclusion, the purpose of this thesis has been to evaluate strategies to manipulate or redirect the antibody response induced by recombinant HIV-1 Env immunogens. The results obtained in this thesis gave insights into several fundamental B cell questions of relevance to the vaccine field and to our understanding of basic B cell immunology.