Will mosaic vaccine immunogens expand immune response breadth to rival HIV-1 strain diversity?

Abstract

HIV-1 displays the most genetic diversity of any virus studied to date [1]. Within an infected individual, the virus constantly mutates, outpacing host immune responses and increasing the number of distinct isolates that may be transmitted. Contending with such extreme diversity poses an unprecedented challenge for HIV-1 vaccine development. Although few HIV-1 preventive vaccine efficacy trials have been conducted to date, thus far only partial efficacy in reducing infection risk has been observed in one study in a low-risk setting (RV144; vaccine efficacy = 30%) [2]. Serum binding antibodies specific for HIV-1 Env were shown to correlate with reduced infection risk in this study [3]. To date, no HIV-1 vaccine has definitively reduced viral load after infection or slowed disease progression. Expanding cellular and antibody immune response breadth will likely be necessary for achieving high levels of vaccine efficacy in the face of HIV-1’s extraordinary genetic diversity. The first HIV vaccines containing mosaic antigen inserts will enter human testing later this year. This approach represents one of several in silico-based strategies to increase the cross reactivity of vaccine responses for diverse HIV-1 isolates. The original aim of mosaic antigens was to expand vaccine cellular response breadth (number of responses to distinct T-cell epitopes) and depth (number of responses to a given T-cell epitope). In nonhuman primate studies, vaccine-induced T-cell responses have been correlated with reduced viral loads [4–7]. In humans, a recombinant adenovirus serotype 5 vector (Ad5) vaccine inducing significant cellular responses was shown to exert immune pressure on HIV-1 divergence in infected individuals [8,9]. Vaccineinduced cellular responses were of limited breadth and depth and this may explain why the vaccine was not effective in reducing viral loads for infected vaccine recipients [10]. Increased breadth and depth for T-cell responses may help prevent infection or may block escape pathways and lead to earlier control of viral replication or slower disease progression for vaccinated individuals who become infected. Mosaic antigen sequences encode composite full-length HIV-1 proteins that optimize coverage of potential T-cell epitopes [11]. Mosaic protein sequences are generated from a genetic algorithm in which natural sequences are repeatedly recombined in silico with the goal of computationally ‘evolving’ a protein sequence made up of the peptides most frequently represented in the database. Mosaic antigens may be generated based on a set of sequences from a single clade or from the entire M group sequence collection. The inclusion of multiple mosaic antigens into a polyvalent cocktail enables even greater coverage of T-cell epitopes and may potentially block viral escape pathways [12]. Consensus sequences are another strategy to improve T-cell response breadth. In this strategy, computational methods are used to generate a sequence representing “The first HIV vaccines containing mosaic antigen inserts will enter human testing later this year.”