HIV vaccine development has been slow and difficult. Although a priority from the moment HIV was discovered to be the cause of AIDS in 1986, only three products have completed efficacy testing in a series of five clinical efficacy trials Citation[1]. Of these, only one, RV 144, the Thai efficacy trial of a canarypox prime and envelope subunit boost, demonstrated modest efficacy to protect against infection Citation[2]. However, that result was transforming and spurred fundamental changes in the HIV vaccine development field. The last three efficacy trials have yielded entirely unexpected results and emphasize the critical importance of human clinical trials. The notion that a vaccine could protect from HIV infection had been questioned and we still do not know what is needed to afford protective immunity. However, advances in nonhuman primate models, neutralizing antibody design and an appreciation for the urgent need to conduct more clinical efficacy trials to evaluate conceptually distinct products has brought new hope and vigor to the vaccine development enterprise.
The first two efficacy trials evaluated the VaxGen (CA, USA) HIV envelope subunit proteins and failed to protect in high-risk intravenous drug users or men who have sex with men in Thailand or the USA Citation[3,4]. Induction of neutralizing antibodies is widely regarded as the critical determinant of protection for many licensed vaccines, but no HIV immunogen induces a neutralizing antibody against the wild-type strains transmitted between humans Citation[5]. The VaxGen efficacy studies examined the hypothesis that a neutralizing antibody induced by the gp120 envelope of a lab-adapted strain of HIV would afford protection or limit viral replication after infection. The failure of these studies combined with the inability to devise envelope vaccines capable of inducing the desired profile of neutralizing responses directed attention to vaccines designed to induce T-cell immunity.
The next two efficacy trials, the Step study conducted in the USA and the Caribbean and a companion study in South Africa (Phambili), were designed to induce CD8+ T-cell immunity with end points for both protection from infection but also reduction of early viral load. The product employed an attenuated adenovirus type 5 vector and lacked an envelope component to focus immune responses on more conserved regions of the HIV genome. The Step study was halted for futility and post hoc analysis identified an excess of HIV cases among vaccine recipients who were not circumcised and had baseline antibody to adenovirus type 5 Citation[6]. The reason for these observations remains unknown but the impact of the Step study on the HIV vaccine development community was substantial. Vaccine research funding was applied with greater focus on development of improved animal models and more basic understanding of the pathophysiology of transmission Citation[7]. There was despair that a vaccine could ever protect against the acquisition of HIV and some argued that no vaccine under development at the time could achieve this goal Citation[8,9].
The current climate of cautious optimism is a result of the unexpected and encouraging results of RV 144, the Thai vaccine efficacy trial. It has been observed that the efficacy of 31% at the end of 3.5 years of participation is modest but statistically significant and, using alternate statistical approaches, is likely to be real Citation[10]. Furthermore, it has been noted that the effect seen in the study appeared early and then clearly waned over time. An intense evaluation of vaccine-induced immune responses is underway to seek a correlate of immune protection that could guide rational vaccine development. While we await that information, some useful observations can be gained from data already available. The ALVAC prime/gp120 boost tested in RV 144 did not produce any neutralizing antibodies against wild-type HIV strains and did not produce CD8+ T-cell responses detectable by intracellular cytokine staining Citation[2]. Thus the two mechanisms most experts felt were critical to afford protection from acquisition and disease progression, neutralizing antibodies and CD8+ cytotoxic T lymphocytes, respectively, did not account for the observed benefit. This infers that other effector mechanisms contributed to the modest acquisition benefit and has sparked particular interest in non-neutralizing antibody mechanisms, such as antibody-dependent cellular cytotoxicity, dependent cell-mediated viral inhibition and inhibition across mucosal barriers.
Taken together, Step and RV 144 have each produced startling and unexpected results emphasizing the crucial need for human efficacy testing to validate animal models and to definitively examine hypothesized mechanisms of protection. At this time there is only a single ongoing HIV vaccine efficacy trial. The VRC vaccine product that combines a DNA prime and Ad5 boost is being tested in the USA and Caribbean among circumcised men who have sex with men who are also adenovirus type 5-antibody-negative. The reason for limiting the enrollment to volunteers without antibody to the vector is the safety concern that in Step was associated with the presence of antibody to adenovirus type 5 at entry. Furthermore, prevalence of the antibody to the Ad5 vector is variable, but in many communities hit hard by the HIV epidemic prevalence can be as high as 80% Citation[11]. This product, if successful, will lead to testing of new vaccines with similar conceptual framework but without the use of adenovirus type 5 so that the product could be tested globally.
There are several new candidate vaccines in early development that should enter efficacy trials in the next 3–5 years. These are heterologous prime and boost regimens, meaning the initial vaccine uses a different vector rather than the boost vaccine. Examples include DNA-prime and pox virus-boost designs, and combinations of rare serotype adenovirus vectors alone with pox virus boost. The ephemeral responses within RV 144 are most consistent with antibody-mediated mechanisms of protection. In consequence, vector-prime and protein-boost regimens are now considering extended boosts and those regimens lacking a protein subunit are considering the need to add this as a component to their vaccine strategy. The optimal design of these proteins is a clear priority for study. Meanwhile, the pox-prime/protein-boost approach examined in RV 144 will be optimized and repeated in efficacy trials. A repeat trial in higher risk volunteers in Thailand is planned with a canarypox prime and protein boost for 2014. A similar pox/protein efficacy trial in high-risk heterosexual volunteers is in development for execution in South Africa in 2014.
As the HIV vaccine field looks to the future, it is clear that more basic and nonhuman primates (NHP) research will be important to develop and test new concepts. A new generation of NHP experiments has evolved to better simulate the relative inefficient transmission of HIV. The use of repeat, mucosal exposure of NHP to Simian immunodeficiency virus (SIV) at doses that, although substantially greater than those in human exposures, are modestly inefficient are beginning to show rewards. New candidate vaccines tested in these new NHP study designs have shown protection from infection and reduced viremia postinfection and identify potential correlates for these outcomes Citation[12,13].
It is even more clear that the pace and scope of human clinical trials must be increased substantially. Only human trials can provide unequivocal insights into vaccine protection from HIV, and validate the concepts arising from preclinical research. The challenge is managing both a vigorous clinical trials strategy and a robust basic and animal model research program. The inclusion of sample collections to determine a human correlate of protection is highly desirable but also adds substantially to costs. Given our current state of knowledge, testing more vaccine products with distinct profiles of induced immunity will be more informative than any other enterprise. However, human clinical trials must be performed more efficiently than has been accomplished to date. This will require relatively small studies among high-risk populations designed to reliably determine that the product has efficacy but not achieve the precision of safety and benefit estimates required for licensure. The need for strategic coordination to ensure that concepts entered into efficacy testing are complementary and advance the field as a whole will be critical. Finally, new HIV prevention modalities will be entering standard practice globally Citation[14,15]. These interventions are welcome and need to be integrated into HIV vaccine trial designs. Although clinical trials may be larger in consequence, synergies between vaccine-induced protective effect and these other interventions may be observed. Ultimately, a multifaceted approach to HIV epidemic control is needed and finding a successful vaccine will be a critical cornerstone.
Financial & competing interests disclosure
The author has 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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