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Unanticipated results from two recent candidate HIV-1 vaccine regimens in large-scale international trials highlight the importance of understanding the optimal earliest immune defense against HIV-1 infection. Presented here are key findings in these vaccine studies that have relevance to the development of future HIV-1 vaccines that can control acute HIV-1 infection.
Although the marked success of combination antiretroviral therapy in controlling HIV-1 offers hope for longer and better quality of life for millions of infected people, full deployment of treatment in regions where HIV-1 has hit hardest is unlikely to eradicate the virus and its disease sequelae. Unquestionably, a safe and efficacious HIV-1 vaccine is crucial to halt the HIV-1 epidemic. Of the more than fifty vaccine regimens entering clinical trials over the past two decades, only four have undergone evaluation in larger scale, test of concept (Phase IIb) or efficacy (Phase III) trials. The unanticipated outcomes of the two most recent expanded trials, the Step Study  and the Thai Trial , underscore the importance of understanding how the immune system responds to early events in HIV-1 infection in order to better guide vaccine development.
The multicenter Step Study evaluated a Merck Ad5/HIV trivalent subtype B vaccine in HIV-1-uninfected persons reporting high-risk activities and residing in regions where HIV-1 subtype B predominates. No significant reduction in the vaccine group, compared to the placebo group, was observed in HIV-1 acquisition rates . In fact, the initial analyses revealed an increased infection rate in uncircumcised male vaccine recipients with pre-existing adenovirus serotype 5 neutralizing antibodies , but detailed regression analyses with additional data indicate that circumcision status in the vaccinees was the significant baseline risk factor associated with higher infection rates (S. Buchbinder, unpublished). Moreover, while the T cell-based vaccine regimen was assumed to have a greater impact on control of viremia post-infection than on prevention of infection, the vaccine failed to lower set point viremia despite eliciting remarkably high HIV-specific CD8+ T cell response rates .
A wide range of investigations ensued in an attempt to explain the lack of vaccine efficacy, and a few key issues have emerged as relevant to control of acute viremia. A chief consideration has been the incorporation of the appropriate HIV-1 genes or proteins into the vaccine candidate. The selection of vaccine antigens for HIV-1 has been largely empirical, but common approaches include expression of HIV-1 structural genes, particularly gag for those vaccines intended to induce primarily CD8+ T cells and env for those intended to induce neutralizing antibodies. The MRKAd5/HIV trivalent vaccine, intended to induce a T cell response, encoded HIV-1 Gag, Pol and Nef, but did not encode Env because of its high variability and the desire to exclude functional antibodies in this test of concept study. While HIV-specific CD8+ T cells are able to exert control of viral replication during acute infection in the absence of Env-specific neutralizing antibodies [4–6], it remains unclear if the combination of effector responses, previously primed by vaccination, may offer benefit over either response alone in containing initial bursts of infection in mucosal epithelium. In progress is an expanded Phase II vaccine trial (HVTN 505) evaluating an envelope-containing vaccine regimen using a HIV-1 DNA prime and replication-incompetent Ad5/HIV boost, and results may yield further insights into the role of Env antigens in HIV-1 protection.
An additional consideration is the understanding of the epitope specificities that are important to elicit in a protective HIV-1 vaccine. Detailed studies of immune responses in acute HIV-1 infection have revealed the emergence of circulating HIV-1-specific CD8+ T cells as viremia peaks, and rapid viral escape mutations can occur within or upstream of the targeted epitopes [6–9]. Thus, viral epitopes first recognized in acute infection are unlikely to represent those commonly seen in chronic infection. Advances in the early diagnosis of HIV infection and implementation of these screening tests into large scale vaccine trials will permit better understanding of whether a vaccine is exerting pressure on incoming virus or whether escape is occurring very early within the epitopes originally recognized. Furthermore, although Gag-specific CD8+ T cells have been associated with lower levels of plasma HIV-1 RNA , the range and specificities of these responses may be important in generating effective vaccine-induced protection. In the Step Study, participants who acquired HIV-1 infection (cases) mounted similar frequencies of Gag-specific CD8+ T cell responses following vaccination compared to matched controls who did not acquire infection (40% vs. 42%, respectively) . Some cases mounted vaccine-induced CD8+ T cells recognizing as many as six Gag epitopes, but on average only one Gag epitope was recognized, and these were located within both variable and conserved regions of the protein (McElrath, unpublished findings). Although no vaccine effect was demonstrated on post-infection viral load, viral sequence analysis suggests that immune pressure was exerted by the vaccine on the early founder viruses . Taken together, it is likely that T cell-inducing vaccines will need to either elicit broader responses or target certain antigen specificities associated with conserved or functional sequences in order to contain early bursts of viremia and rapid viral escape mutation. In this regard, new vaccine designs employing conserved sequences and antigenic mosaic sequences may have utility, as they have the potential to induce T cell responses to high frequency viral strains, a greater number of epitopes and more variants within a given epitope [12–14]. Clinical trials will soon evaluate these approaches.
Understanding correlates of protection with T-cell inducing vaccines may require more extensive analysis of the anti-viral functional properties of the T cells elicited. In recent years, extensive efforts to standardize and validate immunogenicity measurements have been undertaken in order to clearly define response rates, magnitude and antigen specificity of the responding T cells [15, 16]. These assays are robust, highly sensitive and reliable when applied in early trials to screen vaccine candidates and to compare vaccine regimens, and they have utility for bridging immunogenicity results from the previous Phase I/II studies to the larger trials. However, they may not be sufficient as the benchmark for predicting vaccine efficacy. Additional approaches to be incorporated into future studies include, alone or in combination, analyses of T cell suppression of viral replication, proliferation and cytolysis, and broader immunologic functions at the transcriptional and proteomic levels [3, 17–19]. Key factors in moving these platforms forward will be scaling them for performance in small specimen numbers, making them cost-effective, and building the capacity to manipulate the resulting large databases for timely comparative analyses.
The ALVAC vCP1531 (four doses) in combination with AIDSVAX B/E (two boosts concurrent with doses three and four of ALVA vCP1531) showed low-level efficacy in reducing HIV-1 acquisition in a community-randomized trial in Thailand of subjects at relatively low risk of HIV-1 infection . Although serious efforts are underway to discover how this vaccine may have elicited low-level protection, the prototypic high-titer broadly reactive neutralizing antibodies and class I MHC restricted CTL responses commonly thought to provide vaccine-induced protection are unlikely to be major contributors in this trial. In fact, in previous studies with this and similar regimens, and in analysis of a subset of Thai Trial subjects, the most consistent immune responses have been CD4+ T cell lymphoproliferation, antibody-directed cell-mediated cytotoxicity (ADCC), antibodies binding to HIV-1 gp120, and low-titer neutralizing antibody activities [2, 20–22].
The Thai Trial findings indicate that pre-existing, circulating CD4+ T cells induced by vaccination do not necessarily enhance HIV-1 infection and suggest that the vector prime may be important in inducing B cell help for antibody production. It remains an unanswered question whether the functional properties of memory CD4+ T and B cells induced by the prime-boost regimen are distinct from those induced by subunit Env protein alone, and thus more likely to elicit protective immunity. In addition, induction of low-titer Env-specific antibodies with properties such as HIV-1 binding, ADCC or interference with HIV-1 spread, may be more easily generated than broadly-reactive neutralizing activities with current vaccine strategies, and these activities should be fully characterized. These may afford a greater degree of protection than previously recognized at mucosal surfaces following HIV-1 exposure, as has been suggested in retrovirus challenge studies in antibody-treated macaques .
The study results also raise the possibility that immune activities, both innate and acquired, may be more successful in eliminating initial infection than in controlling viremia after acute infection. In acute HIV-1 infection, most often a single founder virus establishes mucosal infection . In the vaginal mucosa, HIV-1 can rapidly enter CD4+ cells by fusion or Langerhans’ cells by receptor-mediated endocytosis, suggesting that effective vaccine strategies are needed for both entry pathways . Selective activation of innate immunity with specific viral vectors, cytokines and adjuvants may be advantageous in increasing antigen presentation and adaptive immune effector responses. However, the benefit may be outweighed by the inflammatory response, which can result in greater virus replication from activated target cells. Furthermore, NK cells have not been shown to mediate immunological memory following vaccination, but NK functions in acute infection have been identified in association with control of viremia . Whether vaccination can elicit NK cells with heightened antiviral activities, particularly mediating cytolysis and ADCC, will need further examination.
Results from recent large scale HIV vaccine studies underscore the need to better understand many aspects of the immune response in acute infection that can guide HIV vaccine development. Foremost is gaining knowledge of the distinct repertoire of innate and adaptive mucosal immune responses providing the first wave of attack following HIV-1 transmission. Detailed studies in the macaque model following mucosal SIV exposure can also guide these efforts, particularly in identifying vaccine formulations that can effectively induce desired mucosal immune responses. Early detection of infection will permit better elucidation of a vaccine’s effect during acute infection, particularly in identifying T cell epitope specificities and functional properties that control viremia. Identifying co-factors such as risk activities, circumcision status, co-infections, and non-vaccine prevention modalities (e.g., microbicides, pre-exposure prophylaxis) that can modify vaccine effects and determining the mechanism for these activities will be important in the design of future trials. Finally, building on the modest success of the recent Thai Trial will require further understanding of the diverse roles that antibodies can play in preventing acute infection, and future efforts to optimize these activities at mucosal surfaces will be the next steps to explore.
This article was submitted as a part of a supplement detailing the Acute HIV Infection Meeting held September 22–23, 2009 in Boston, MA. This meeting was funded by the NIHNIAID.
No author has a commercial or other association that might pose a conflict of interest.