The Hard Way towards an Antibody-Based HIV-1 Env Vaccine: Lessons from Other Viruses

Abstract

Although effective antibody-based vaccines have been developed against multiple viruses, such approaches have so far failed for the human immunodeficiency virus type 1 (HIV-1). Despite the success of anti-retroviral therapy (ART) that has turned HIV-1 infection into a chronic disease and has reduced the number of new infections worldwide, a vaccine against HIV-1 is still urgently needed. We discuss here the major reasons for the failure of “classical” vaccine approaches, which are mostly due to the biological properties of the virus itself. HIV-1 has developed multiple mechanisms of immune escape, which also account for vaccine failure. So far, no vaccine candidate has been able to induce broadly neutralizing antibodies (bnAbs) against primary patient viruses from different clades. However, such antibodies were identified in a subset of patients during chronic infection and were shown to protect from infection in animal models and to reduce viremia in first clinical trials. Their detailed characterization has guided structure-based reverse vaccinology approaches to design better HIV-1 envelope (Env) immunogens. Furthermore, conserved Env epitopes have been identified, which are promising candidates in view of clinical applications. Together with new vector-based technologies, considerable progress has been achieved in recent years towards the development of an effective antibody-based HIV-1 vaccine.

Presentation of HIV-1 Envelope Trimers on the Surface of Silica Nanoparticles

“…Unfortunately, the novel Env immunogens were less immunogenic than expected and the affinity against unmutated common ancestors of bnAbs is rather low. 6,7 Presenting Env on the surface of nanoparticles mimics the natural virus structure and is a promising attempt to optimize the immunogenicity and deliver the immunogen to the lymph node, as well as initiate and maintain the affinity maturation processes in their germinal centers. 8,9 Particulate formulations bring 2 key benefits.…”

Stabilized diverse HIV-1 envelope trimers for vaccine design

“…After infection in vivo, HIV-1 rapidly generates viral variants enabling viral escape from immune recognition [30][31][32]. Common mechanisms of HIV-1 immune evasion include sequence diversity, conformational metastability and the glycan shield [33][34][35], all of which pose major challenges to HIV-1 vaccine development. Traditional vaccine approaches have thus far failed to overcome the challenge of HIV-1 diversity despite remarkable success against a large array of pathogens with limited variability [36].…”

Antigenic Variability

“…HCV, HIV, and influenza exhibit this pattern, with bnAB, already a minority of the humoral response, functionally limited by the low accessibility of targeted epitopes or the limited neutralization window afforded by receptor binding-induced conformational change (6). Ongoing research into mapping the antigenic determinants of broad neutralization and eliciting the complementary antibodies, either through reverse-vaccinology or truncation of variable epitopes from vaccine immunogens, provides a basis for rationale vaccine design (26). However, challenges in reconstituting affinity maturation through reverse vaccinology, reduced immunogenicity of variable-epitope deleted immunogens, and the occlusion of conserved epitopes in situ suggest effective vaccine design for antigenically variable pathogens may need to target, rather than circumvent, the hypervariable epitopes.…”