Given that we do not have an established immunological correlate of efficacy for an HIV vaccine, we believe that the successful development of an HIV vaccine requires multiple phase IIb hypothesis-generating studies with different HIV vaccine candidates. Using this approach, the hypothesis might be, for example, that broadly neutralizing antibodies confer protection against HIV infection or that T-cell immunity blocks infection at mucosal sites.
The key to progress stemming from phase II trials depends on two elements. First, a positive efficacy signal (such as that in the phase IIb RV144 trial) is essential if further testing of the product in question is to proceed. Such protective responses provide a proof-of-concept for the vaccine candidate. Second, an efficacy signal in a phase II trial might allow the identification of immunological correlates of protection and a strong rationale to proceed to a definitive phase III efficacy trial. The recently licensed vaccine against human papillomavirus (HPV) adopted this approach. A phase II proof-of-concept study with an HPV16 vaccine manufactured by Merck revealed striking efficacy against acquisition of HPV16 infection that correlated with an increase in anti-HPV16 antibodies (9
). This observation laid the foundation for a definitive efficacy study with a multivalent HPV vaccine that contains a mixture of capsids from multiple HPV strains.
In the selection of vaccine candidates to enter phase IIb trials for the evaluation of efficacy signals, a rational approach is to prioritize and select candidates based on the hypothesis that the immune responses that they have been demonstrated to trigger will provide protection from established infection. The supporting evidence that should be required to advance a product into a phase IIb study is the validation of a robust response in prior human trials. Although success in nonhuman primate challenge studies can provide some information for prioritization, they have been minimally helpful to date in selecting optimal candidates for advanced testing in humans.
Priority should be given to the selection of vaccine candidates for efficacy trial testing if (1) the candidates test new hypotheses and therefore elicit immune responses that are significantly different, qualitatively or quantitatively, from previous candidates and (2) the candidates are predicted to provide protection based on current understanding of immunopathogenesis. In effect, phase IIb trials, in addition to providing insights into the clinical efficacy of the vaccine candidates, should also explore the different facets of the immune response that may confer protection. Such vaccine candidates may include those that induce neutralizing antibody responses, non-neutralizing antibodies that may interdict transmission at mucosal surfaces, innate immune responses, cell-mediated immune responses directed toward specific viral gene products, or a unique combination of these responses. In other words, the goal of these coordinated trials would be to “fill in the immunological space.”
A key ingredient in developing such coordinated studies is the nature of the study populations and the required degree of efficacy needed to develop an immune correlate. Phase II trials should be powered to demonstrate modest but significant effects, preferably protection from HIV acquisition that is >40% with a lower bound above 0%, and designed to allow for prospective and timely immunological analyses of blood and mucosal samples. Previous phase IIb trials such as the RV144 Thai trial were designed to allow for retrospective immunological analyses that may extend for two years after the completion of the trial, thus precluding rapid access to information that can be important for the design of new clinical trials that test other vaccine candidates. Moreover, the trials should be conducted in populations with a sufficiently high incidence of HIV infection that additional trials or adaptations of the trial can be performed and results obtained rapidly. Future approaches to clinical trial design should take these important issues into consideration.