Letvin Vaccine Discovery Consortium

OVERVIEW:

T-cell vaccines for AIDS often employ viral vectors that carry HIV-1 and other genes into the body and into cells. However, some of the vectors are constructed using natural viruses that infect humans. As a result, some individuals have preexisting immunity to the vector. Data from the Merck-STEP trial suggest that preexisting anti-viral vector immunity may impact the performance of an HIV-1 vaccine, and some researchers suspect that it could perhaps enhance an individual’s risk of acquiring HIV-1. However, more research needs to be done to clarify this issue.

Researchers in the Letvin VDC are studying the biology of anti-vector immunity and exploring ways to make better vectors from recombinant adenoviruses (rAd) and mycobacteria (rMyco). Investigators in the Letvin VDC rAd team are generating novel Ad vectors from adenoviral strains that are not commonly found in the human population and strains that are targeted to the mucosa. Investigators in the rMyco team are exploring the potential of mycobacteria with gene deletions to act as novel vectors with enhanced immunogenicity. The goal is to create novel vector-based vaccines that elicit durable systemic and mucosal cellular immune responses that will not be suppressed by preexisting anti-vector immunity.

RESEARCH OBJECTIVES:

1. Develop novel rAd vectors that evade preexisting anti-Ad5 immunity, and study the biology of anti-vector immunity;

2. Develop novel rAd vectors targeted to mucosa and improve prime-boost combinations of vaccines;

3. Develop novel rMyco vectors with enhanced immunogenicity; and

4. Establish an administrative core to facilitate the proposed studies.

PROGRESS:

The rAd team has made substantial progress towards the original project goals of developing vectors for clinical production. They have generated a portfolio of novel, human rare serotype, non-Ad5 vectors that evade preexisting anti-Ad5 immunity. The portfolio includes the replication incompetent rAd26 and rAd28 vectors, the replication competent rcAd26 vectors, HVR-chimeric rAd5 vectors, and prototype chimeric rAd35/41 vectors. Preclinical studies of these vectors have been completed in mice. Immunogenicity of the rcAd26 vectors was also tested in a pilot nonhuman primate study with promising results. Immunogenicity of the replication incompetent rAd28 vector was found to be superior to that of the chimeric rAd35/41 vectors. A nonhuman primate study will proceed to test the rAd28 vector in a heterologous, intramuscular prime-boost regimen in a rhesus macaque challenge model. The rAd team is developing the rcAd26 and rAd28 vectors as the lead clinical candidate vectors.

To help clarify issues raised by the STEP results, and to study the biology of preexisting anti-vector immunity and how it might affect vaccine performance, VDC researchers have assessed Ad vector-specific cellular and humoral immunity following rAd5-Gag immunization in human samples from the Merck phase I studies. No correlation was found between baseline Ad5-specific T-cell responses and neutralizing antibody (NAb) titers, thus challenging the hypothesis that anamnestic Ad5-specific CD4+ T cell responses following rAd5 vaccination were responsible for the enhancement of HIV-1 acquisition in the Ad5 seropositive subjects in the STEP study. VDC researchers have also found that natural infection by Ad5 and vaccination with rAd5 vectors have different immunogenicity profiles resulting in the generation of NAbs that target different proteins of the viral capsid. Studies have been completed in mice and are ongoing with human samples to confirm and delineate the differences in CD4 and CD8 epitopes between Ad5 and other rare Ad serotypes, and the extent of cross-reactive Ad immunity. These results provide reassurance to the vaccine community and will facilitate clinical development of rare serotype replication-incompetent and competent Ad vectors for HIV-1.

The rMyco team is developing second generation Bacillus Calmette-Guerin (BCG) vectors with improved immunogenicity and safety. In a pilot nonhuman primate study the first generation rBCG-SIV vectors provided effective priming for a rAd5-SIV boost. To augment vector immunogenicity, genome-wide screens were performed to identify BCG genes that are responsible for immune evasion, and molecular biology to improve transgene expression and secretion. Using different approaches, the VDC researchers have identified and characterized over 100 rMyco mutants that are associated with increased antigen presentation in the MHC class I and/or class II pathways. When benchmarked against industry-standard vaccine vectors, some of the mutants demonstrated superior immunogenicity. The rMyco team has designed a streamlined roadmap towards clinical vector production. Preclinical studies to test the immunogenicity of lead candidate rBCG mutants in nonhuman primates have been designed. Appropriate mutations will be combined to generate a set of rBCG vectors that are optimized for vaccine-elicited immune responses.

The Letvin VDC will also test the novel rMyco and rAd vectors in prime-boost combinations in preclinical studies to assess their effectiveness as vaccines against HIV-1.