Eur. J. Immunol. 2013. 43: 3087–3089

News & EFIS Toward an effective AIDS vaccine development For the past 30 years, the world has been waiting for an effective vaccine against human immunodeficiency virus type 1 (HIV-1), and tremendous efforts have been invested worldwide to reach this long-awaited goal [1]. However, the HIV-1 genetic diversity poses a demanding challenge for the design of such a vaccine. Here, we present the latest research reported at the AIDS Vaccine 2013 meeting, which took place this past October in Barcelona, Spain (Fig. 1).

AIDS vaccine development – lessons learned Although our knowledge of HIV-1 biology and pathogenesis has increased dramatically over the past 30 years, an effective vaccine, targeting T-cell mediated and/or antibody responses, remains elusive. What we learn from failed attempts can be equally informative for refining and advancing the search for a HIV vaccine with optimal anti-HIV immune responses for maximum protection.

Cell-Mediated Immunity Disappointing results from the STEP trial, in which the cellular immunity induced by the rAd5 (Gag/Pol/Nef) vaccine failed to provide any protection against HIV, revealed a possible reason why the vaccine did not effectively work; many of the CD8+ T-cell responses were targeted to variable epitopes [2]. The CD8+ T-cell responses were low in magnitude and narrow, directing to a median of three epitopes [3]. Even though a few vaccine recipients who targeted at least three Gag epitopes showed lower viral load, most vaccinees had CD8+ T-cell responses to only one Gag epitope. These results from the STEP trial have provided insights into the current design of

Figure 1. Entrance to the AIDS Vaccine 2013 meeting in Barcelona.

T-cell vaccines [4] and emphasized the importance of efficacy trials. The HVTN505 Phase IIb trial, using a DNA (Gag/Pol/Nef/Env)/ rAd5 (Gag/Pol/Env) prime boost approach, started in 2009 but ended in April this year, due to the lack of efficacy in either preventing HIV-1 infection or reducing viral load in vaccinees. The study enrolled 2504 men and transgender women in the United States. 27 out of 1250 vaccine recipients were infected with HIV-1, compared with 21 infections among 1244 placebo recipients after at least 28 weeks of enrollment [5]. The immune responses were analyzed for 40 vaccine and 10 placebo recipients selected randomly

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from uninfected study subjects who were enrolled in the study for at least 24 months. When compared with the results from the moderately successful RV144 trial, where the canarypox-based prime and rgp120 boost vaccine elicited protective non-neutralizing antibodies [6], the frequency and magnitude of IgG antibody responses to the Env gp120 V1-V2 loop, a positive correlate of protection, were considerably lower than those observed in the RV144 trial. Moreover, predominant CD8+ T-cell responses targeted Env, which may have undermined the responses to more protective epitopes in Gag, or possibly in Pol and Nef as well. Detailed immune analyses are necessary to understand the




lack of efficacy in the HVTN505 trial and to move forward for a new and improved vaccine design.

Humoral Immunity Neutralizing Antibodies Approximately 20% of the individuals infected with HIV-1 develop cross-reactive, broadly neutralizing antibodies (BnAbs) over two to four years of infection. The immune response of one such individual has been followed for over three years after the transmission of the virus [7]; the BnAbs isolated from this individual, termed CH103, showed that they target the CD4 binding site on gp120, and furthermore CH103 showed high binding affinity for the envelope expressed on the transmitted virus when the antibodies were in the form of the unmutated germline precursor. As disease progressed, replicating HIV-1 accumulated escape mutations in the CD4-binding site epitope [7]. The diversification of the CH103 epitope regions led to further development of the neutralization breadth of CH103 antibodies through somatic mutations and affinity maturations [7]. Thus, transmitted HIV-1 and broadly neutralizing antibodies “co-evolved”, and the CH103 antibodies conferred a broadly neutralizing activity even though the unmutated common ancestor did not bind to the heterologous HIV-1 envelope. Future vaccine design will require the identification of target immunogens that would elicit “polyreactive” B-cell responses and induce the ancestors of BnAbs.

Non-neutralizing Antibodies The moderately successful RV144 trial brought unexpected results. The ALVAC (canary pox vector-Env/Gag/Pol)/ rgp120 prime boost vaccine did not have an effect on viral load, although it was designed to induce cell-mediated immunity to kill infected cells [6]. Instead, it provided modest protection against acquisition of HIV-1. The analysis of immune correlates of protection revealed that the level of IgG3 antibodies to V1/V2 regions of Env gp120, a glycoprotein forming spikes on the viral envelope, was associated with prevention of infection [8]. The trial also identified a direct correlation between IgA specific to Env and risk of infection [8]. The findings suggested for the first time the involvement of non-neutralizing antibod-

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ies, through Fc receptor-mediated mechanisms, in protection instead of neutralizing antibodies the scientific community had been seeking. Since the trial was not designed to specifically elicit IgG antibody responses, the mechanism of V1/V2specific IgG3 antibody induction needs further investigation. Undoubtedly, the unexpected results from the RV144 trial have influenced immunogen design in successive clinical trials.

Vaccine Strategies Different strategies have been used in the development of a HIV-1 vaccine to induce protective immune responses against infection, some of which have been tested in the past six efficacy trials. Paradigms have been shifting based on results from previous clinical trials. A few cutting-edge strategies and approaches to induce effective CD8+ T-cell responses are highlighted below.

Immunogen Design: Env for T-cell vaccines Although Env was a successful target for a reduced risk of infection in the RV144 trial [7], it elicits Th2 responses rather than the Th1 responses which are the aim of CD8+ T-cell vaccine strategy. The induction of Th1 versus Th2 responses should be kept separate, and Env immunogens should be excluded from vaccines aiming to induce CD8+ T-cell responses. The rationale for the exclusion of Env immunogen from vaccines is as follows: i) CD8+ T-cell responses to Env have been nonprotective compared with those to Gag, possibly due to rapid immune escape [9], and ii) protective responses to Gag or other epitope regions may be compromised by the strong responses to Env. Therefore, the inclusion of Env immunogen could do more harm than good and needs to be carefully designed when included for synergistic induction of antibody responses and CD8+ T-cell responses.

Stimulation of CD8+ T cells Macaque models of simian immunodeficiency virus (SIV) infection have previously established the importance of CD8+ T-cell responses for the immune control of viral replication. Some of the earlier studies showed that the depletion of CD8+ T cells results in increased viral load in SIVinfected macaques [10,11]. In humans, the crucial role of CD8+ T cells is indicated

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in associations between HLA class I alleles and viral load, as typically observed in elite controllers who have HLA-B*57 alleles [12]. More recently, studies of SIVinfected macaques indicated that CMVbased vaccines induce effector memory T cells which suppressed virus replication [13]. Surprisingly, many of the epitopes are presented by MHC class II molecules. Based on the macaque models, the goal of the CD8+ T-cell vaccine model is to achieve a high frequency and magnitude of CD8+ effector memory T cells against multiple epitopes. Antigen sensitivity is another key factor to be considered in the design for a successful vaccine. High antigen sensitivity of CD8+ cells, or functional avidity, has been correlated with their ability to suppress virus replication [14], which would be a necessary characteristic of vaccineinduced CD8+ T cells. Additionally, conserved and protective epitopes with low entropy should be targeted for vaccines to circumvent viral escape and variability problems and accompanying shift in immunnodominance [15]. Escape mutations in the conserved epitopes tend to sacrifice viral fitness or require multiple compensatory mutations [16], possibly resulting in low viral set-point as reported in HLA-B*57+ elite controllers.

Conserved-Region Vaccines: CD8+ T-cell responses optimization An effective vaccine should focus on immunodominant epitopes that are associated with a high fitness cost to prevent immune escape, and on the complex patterns of virus evolution induced by CD8+ T-cell responses. Therefore, such a vaccine should target functionally conserved regions of HIV-1. Targeting the conserved regions also has an advantage of a better coverage of the viral genetic diversity in globally circulating viruses. Conserved-Region Vaccines (HIVconsv) are designed based on these rationales, and a Phase I clinical trial HIVCORE002 has recently been conducted using the HIVconsv for the first time [17]. The novel multi-clade immunogen in this trial was a chimeric protein derived from the 14 most conserved regions of HIV-1 Gag, Pol, Vif, and Env and provides the coverage of clades A, B, C, and D [17]. By focusing on “regions in the HIV-1 proteome” rather than particular epitopes, the vaccine can target regions conserved in the majority of HIV subtypes and avoid directing the immune responses to epitopes restricted by particular HLA


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alleles. The trial, conducted in Oxford, involved row-risk healthy volunteers who received either placebo or HIVconsv in plasmid DNA, replication-deficient chimpanzee adenovirus, or replication-deficient modified vaccinia virus Ankara [17]. Post-vaccination immune analyses indicated strong immune responses against HIVconsv peptides. The responses were directed to approximately 10 epitopes per vaccine recipient, suggesting a breadth of CD8+ T-cell responses. Further analyses revealed that the majority of the responses targeted known HLA-matched CD8+ T-cell epitopes, but 40% of the responses were towards unknown epitopes. Another important attribute for an effective CD8+ T-cell vaccine, polyfunctional responses, was also demonstrated for CD8+ T cells elicited by HIVconsv [17]. Upon stimulation with HIVconsv peptide pools, vaccineinduced CD8+ T cells produced IFN-γ, TNF-α, and IL-2 in addition to the expression of CD107a. The effectiveness of artificial peptides as vaccine immunogens was tested by the ability of vaccine-elicited T cells to suppress HIV-1 replication in vitro. For this experiment, CD8+ T cells from vaccine recipients were co-cultured with autologous CD4+ T cells infected with eight different HIV-1 isolates covering clades A, B, and C [17]. Remarkably, one vaccine recipient inhibited all eight viruses tested, and another suppressed the replication of six out of eight virus isolates. The assays demonstrated that 15 out of 23 vaccinees suppressed viruses from both clades A and B. More unexpected, as well as intriguing, finding from this study came from the analysis of the specificities of CD8+ T-cell responses to HIV-1 proteins. Overall, responses to both Gag and Pol corresponded well with virus suppression and were stronger than those to Env and Vif combined [17]. An immunological comparison revealed that Pol-specific CD8+ T-cell responses were associated with a stronger virus inhibition than those to Gag-specific CD8+ T cells. Consistent with these data, the one vaccinee from this study who suppressed all eight viruses showed Pol-specific responses only and none towards Gag [17]. These results may be due to the HIVconsv immuno-

gen design, in which well-conserved Pol regions are present more frequently than any other proteins. Even so, this study successfully demonstrated the effectiveness of Pol-specific CD8+ T cells in the control of virus replication and Pol epitopes as a good vaccine target.

cal science fields to achieve an AIDS-free world.

Looking to the future

Center for AIDS Research, Kumamoto University, Kumamoto, Japan

Since the first clinical trial in 1988, more than 200 trials have been conducted. In the 2003 efficacy trial, VaxGen Env gp120induced antibodies did not protect HIV infection in vaccine recipients [18]. The next efficacy trial, the STEP study [2], was aimed at inducing CD8+ T-cell responses and excluded Env immunogens. This trial also ended in disappointment in 2007. Two years later, RV144, the first and only vaccine that showed some degree of protection, surprisingly mediated its effect through non-neutralizing antibodies [6]. Building on the past trials and modest efficacy in RV144, vaccines aiming at only CD8+ T-cell responses have been shifting to those eliciting broadly neutralizing and non-neutralizing antibodies as well in order to seek for combinations of immune responses. However, the recent HVTN505 trial to induce both CD8+ T-cell and antibody responses failed to provide any protection: No prevention of infection and no reduction in set-point viral load. Based on previous success and failure, the scientific community is exploring new modalities and paradigms for vaccine development. Innovative efforts include, but are not limited to i) testing for new vectors, such as CMV [13] and Sendai virus vectors and ii) immunogen design, including HIVconsv universal immunogens for CD8+ T-cell responses, mosaic immunogens for a maximum coverage of diverse viral sequences, and structurebased design of Env immunogens. Translational research and clinical trials will continue to play an instrumental role in integrating the knowledge built up from the past studies and basic science research. As in the theme of the conference, Progress, Partnership, and Perseverance, research efforts continue in both basic and clini-

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Conflict of interest: The authors declare no financial or commercial conflict of interest. Keiko Sakai and Masafumi Takiguchi

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Abbreviation: antibody




Full correspondence: Prof. Masafumi Takiguchi, Center for AIDS Research, Kumamoto University, 2-2-1 Honjo, Chuo-ku, Kumamoto, 860-0811, Japan Fax: +81 96 373 6532 e-mail: [email protected]


Toward an effective AIDS vaccine development.

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