Current status of HIV/AIDS vaccine development
Recently, considerable progress has been achieved in the field of HIV vaccine development Citation[1,2], and it has been suggested that the immune correlates of protection against viral infection comprise a complicated combination of viral and host immunological and genetic factors Citation[3]. It is well known that some HIV-1-infected individuals do not exhibit disease progression as long as HIV-1 replication is well controlled by host immunity Citation[4]. Despite great efforts to understand the immune status of such long-term nonprogressors and macaques immunized with live-attenuated simian immunodeficiency virus (SIV) vaccine, we still suffer from lack of sufficient knowledge on potential immune correlates of protection. In addition, the structural features and variability of the envelope (Env) glycoprotein (gp) of HIV-1 are responsible for our inability to elicit potent broadly neutralizing antibodies against HIV-1 by active immunization.
History of HIV vaccine efficacy trials
The history of efficacy trials for preventive HIV vaccines is marked by a series of paradigm shifts in immune correlation. First, Vaxgen Co. (CA, USA) tested a genetically engineered surface Env gp120 vaccine in humans. Despite induction of effective virus-neutralizing antibodies during the initial phases of the trial, a large-scale Phase III trial revealed the ineffectiveness of the vaccine Citation[5]. This failure changed the strategy of HIV vaccine research from antibodytargeted to cell-mediated immunity-targeted. Considering the cell-associated features of HIV-1, cell-mediated immunity, especially that conferred by virus-specific cytotoxic T lymphocytes (CTLs), should be an important arm of the host immune system in regards to HIV infections. Indeed, it has been suggested that immunodeficiency virus-specific cellular immunity effectively controls viral replication during the natural course of infection Citation[6,7]. Based on these considerations, various vaccine modalities, including live viral vectors and DNA, have been tested to elicit strong CTL and type 1 T-helper cell responses in nonhuman primate models. Although the DNA vaccine was not sufficiently immunogenic in macaques, boosting in DNA-primed individuals with viral vector vaccines, such as vaccinia virus Citation[7], Sendaivirus Citation[8] and adenovirus Citation[9], amplified CTL responses and resulted in effective control of immunodeficiency virus replication. Among such viral vectors, vaccination with adenovirus type 5 (Ad5) elicited the strongest CTL induction. However, in 2007, the Merck (NJ, USA) STEP trial testing the efficacy of a recombinant (r)Ad5 vaccine was discontinued at Phase IIb because the vaccine failed to provide protective immunity Citation[10]. Instead, the vaccinated group showed a significantly higher HIV-1 infection rate than the placebo group, which indicated that rAd5 immunization may have some unknown enhancing effect on HIV-1 infection. This trial provided key findings that T-cell vaccine approaches may involve risks and limitations, and that the chimeric simian human immunodeficiency virus macaque AIDS model is not suitable for evaluation of the protective immunity of candidate vaccines Citation[11]. The results do not necessarily mean that T-cell vaccines have no potential applications, but rather that this paradigm seemed to have reached a deadlock.
In September 2009, RV144, a large-scale efficacy trial conducted in Thailand, reported a partial reduction in the HIV-1 infection rate among the vaccinees who received the canarypox/gp120 prime–boost vaccine Citation[12]. The results indicated only a limited effect but first demonstrated the possibility of prevention of HIV infection through active immunization. Although there was no clear correlation of protection with a virus-specific, cell-mediated immune response and neutralizing antibody levels in the vaccinees, detailed analysis of the host responses is expected. Taking into account the vaccine formulation of the gp120 boost, some types of antibody-mediated reaction other than neutralization may be involved in this partial protection. This might generate a novel paradigm of immune correlates of protection against HIV-1 infection.
Bacillus Calmette–Guérin vector for HIV vaccine development
Mycobacterium bovis bacillus Calmette–Guérin (BCG) is a unique vector in the field of vaccine research because of its safety record, affordability and easy antigen delivery to the professional antigen-presenting cells, and thereby to the T cells. Most of the current candidate T-cell vaccines utilized DNA vaccines for priming HIV-specific cellular responses. However, because of its low immunogenicity in humans and product cost issues, an alternative vector is needed for global use. Therefore, BCG has been extensively studied as a primer of heterologous vaccination regimens.
The characteristic responses to BCG involve the induction of innate immunity by cellular components via Toll-like receptors, a strong and long-lasting type 1 T-helper cell response and triggering of the CTL priming. As we reported in 2005, a prime–boost regimen combining rBCG–SIVgag with a nonreplicating vaccinia virus Dairen I strain (DIs), which was similar to modified vaccinia Ankara (MVA) and expressed SIV Gag, induced a long-lasting and effective cellular immunity that was able to control a highly pathogenic simian human immunodeficiency virus after mucosal challenge in macaques Citation[13]. This indicated that the BCG/DIs prime–boost regimen may have the potential to serve as an effective and safe anti-HIV vaccine. Recent studies in macaques subjected to BCG/Ad5 Citation[14] and BCG/MVA Citation[15] regimens strongly support the effectiveness of the BCG vector. In the latter study, a hemolysin-expressing BCG strain, which was devised for more efficient antigen presentation to CTL precursors, elicited robust and broad-range HIV-1-specific T-cell responses along with recruitment of multiple T-cell clonotypes into the memory pool.
Another strategy for enhancing the potential of the BCG vector is codon optimization. Owing to the limitation on the dose that can be delivered in humans, the rBCG construct should be capable of optimal foreign antigen expression. To address this issue, we applied a codon-optimization strategy to the rBCG system and successfully generated a rBCG harboring the codon-optimized SIV gag gene with a tenfold higher expression than the native gag gene Citation[16]. In the macaque study, a low-dose (106 bacilli) injection of this construct, in comparison with that of the native gag gene construct, induced optimal priming of Gag-specific CD4+ and CD8+ T cells, and prolonged the maintenance of memory T-cell response after vaccinia DIs boost Citation[17]. These results imply that the quality of the priming vaccine is a critical factor for inducing a desirable immune response against immunodeficiency viruses.
These rBCG-/viral vector-based combination regimens are expected to progress to human clinical study because, as McShane et al. reported, the BCG/MVA-antigen 85A prime–boost vaccine, which is quite similar to the rBCG-based HIV vaccines, efficiently induced anti-TB T-cell responses in humans and proceeded to a Phase IIb trial in July 2009, indicating the advantage of BCG over other T-cell vaccine vectors with regard to human immunogenicity Citation[18].
Future prospects
Recent studies in macaques have confirmed the effectiveness of T-cell vaccines. A DNA-prime and rAd5-boost regimen induced broad SIV-specific cellular responses without neutralizing antibodies and protected rhesus macaques from heterologous mucosal SIV challenge Citation[19]. Furthermore, a rhesus cytomegalovirus vector expressing SIV Gag, Rev-Tat-Nef and Env persistently infected rhesus macaques, and primed and maintained robust SIV-specific CD4+ and CD8+ effector memory T-cell responses in the absence of neutralizing antibodies Citation[20]. These reports suggest that T-cell vaccines may have a greater potential than previously estimated. Although the importance of the induction of broadly neutralizing antibodies by vaccines cannot be denied, cellular immunity-targeted candidate vaccines, whose efficacy has been tested in a macaque-SIV study, should also be clinically tested. Such human trials would provide a greater insight into the paradigm of immune correlation, and help achieve the ultimate goal of establishing a dual humoral and cellular immune barrier against HIV infection at the site of viral entry, especially at mucosal sites.
Financial & competing interests disclosure
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
No writing assistance was utilized in the production of this manuscript.
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