HIV-1 Vaccine Trials: Evolving Concepts and Designs

Abstract

An effective prophylactic HIV-1 vaccine is needed to eradicate the HIV/AIDS pandemic but designing such a vaccine is a challenge. Despite many advances in vaccine technology and approaches to generate both humoral and cellular immune responses, major phase-II and -III vaccine trials against HIV/AIDS have resulted in only moderate successes. The modest achievement of the phase-III RV144 prime-boost trial in Thailand re-emphasized the importance of generating robust humoral and cellular responses against HIV. While antibody-directed approaches are being pursued by some groups, others are attempting to develop vaccines targeting cell-mediated immunity, since evidence show CTLs to be important for the control of HIV replication. Phase-I and -IIa multi-epitope vaccine trials have already been conducted with vaccine immunogens consisting of known CTL epitopes conserved across HIV subtypes, but have so far fallen short of inducing robust and consistent anti-HIV CTL responses. The concepts leading to the development of T-cell epitope-based vaccines, the outcomes of related clinical vaccine trials and efforts to enhance the immunogenicity of cell-mediated approaches are summarized in this review. Moreover, we describe a novel approach based on the identification of SIV and FIV antigens which contain conserved HIV-specific T-cell epitopes and represent an alternative method for developing an effective HIV vaccine against global HIV isolates.

Conserved epitopes on HIV-1, FIV and SIV p24 proteins are recognized by HIV-1 infected subjects

“…Being conserved, these sequences are most likely essential for viral fitness, and thus less likely to mutate. 13 In summary, by evaluating IFNg production, CFSE proliferation, and cytotoxin production in both HIV C and HIV ¡ subjects (Fig. 8), we can conclude that the large 13-15mer peptides, HIV Hp15-1 and FIV Fp14-4, and small 9-10mers Hp15-2/3a, Fp14-1b, Fp14-3/4e, and Fp14-3/4f induce robust CMI responses without enhancement of infection.…”

“…10,11 In addition, HLA allotypes responsive to T-cell epitopes have correlated to a delay in AIDS progression and/or lower HIV-1 viral set point in HIV C longterm survivors and elite controllers when compared to HIV C rapid progressors. 12,13 Nevertheless, it is currently unclear as to which epitopes detected at what stage of HIV infection may be useful as vaccine immunogens or in immunotherapy.…”

Evolutionarily Conserved Epitopes on Human Immunodeficiency Virus Type 1 (HIV-1) and Feline Immunodeficiency Virus Reverse Transcriptases Detected by HIV-1-Infected Subjects

“…Computational analyses identify potential conserved epitopes that are later tested for relevant biological activity. These analyses have been used to select conserved HIV/FIV sequences such as the one previously described for HIV/FIV integrase (16). The current FIV approach simultaneously compares both HIV/FIV epitope sequences and immunological responses.…”

“…However, phase I and II vaccine trials consisting of cross-subtype-conserved CTL-associated peptide epitopes have shown minimal CMI responses (16)(17)(18). Therefore, a thorough selection of potent anti-HIV T-cell-associated epitopes, which are conserved among HIV-1 subtypes and do not mutate without negatively affecting viral fitness (19)(20)(21), would be valuable for an effective HIV-1 vaccine.…”

Recombinant and epitope-based vaccines on the road to the market and implications for vaccine design and production

“…During the past 3 decades of HIV vaccine research, only 3 candidate vaccines have completed phase-III clinical trials with moderate success, reflecting the need for additional research and development of innovative approaches. 24 In 2009, a Phase-III trial known as RV144 was completed in Thailand, which assessed a "prime-boost" combination of 2 vaccines: ALVAC Ò HIV vaccine (the prime; a viral vector expressing genetically engineered versions of Gag, Env, and Pol proteins) and AIDSVAX Ò B/E vaccine (the boost; a bivalent gp120 envelope protein vaccine).…”