A strategy for accelerating the development of preventive AIDS vaccines

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An effective vaccine against HIV-1 is urgently needed. Many candidate vaccines are currently in or are approaching clinical trials. The selection of vaccines for advanced development is now based on safety and immunogenicity in humans and on the ability of analogous vaccines to protect macaques against SIV. In the next few years, however, many candidates will complete phase II testing and must be prioritized, because phase III efficacy trials are costly, lengthy, and the capacity to conduct them is limited. Given the complexity of HIV pathogenesis and the unconfirmed predictive value of vaccine-induced immune responses in non-human primate challenge studies, AIDS vaccine clinical trials conducted in at-risk populations with clinically relevant endpoints may be the best way to judge the true biological significance of human immune responses to vaccines as well as guiding, accelerating, and prioritizing efficient vaccine development. Phase IIB test of concept trials have recently been proposed to evaluate vaccine candidates for preliminary evidence of efficacy in trials smaller than pivotal efficacy trials [1–3]. The co-primary endpoints are the prevention of HIV infection and a reduction of viral load in vaccinated individuals who acquire HIV [1]. Phase IIB test of concept trials are still large (numbers approximately 2500–8500) and time-consuming (3.5–5 years).
None of the current vaccine candidates is likely to prevent infection completely, because they do not induce potent neutralizing antibodies against primary HIV isolates [4,5]. The failure to protect by antibodies against the HIV envelope may be the result of HIV antigenic variation, a lack of neutralization potency, or additional factors [6]. Most of the current candidate vaccines [7] are designed to induce cell-mediated immunity, which is expected to decrease the HIV viral load in vaccinated individuals who become infected, thereby potentially slowing or preventing progression to AIDS and decreasing infectiousness [8–11]. In HIV-infected individuals, the time to key clinical events in HIV-1 disease progression was significantly longer for those with viral load setpoints 0.5–1.25 log10 copies/ml lower than the reference group [12,13]. Studies in non-human primates have demonstrated that vaccine-induced viral load reduction accompanies increased survival [14]. By quantifying the anticipated clinical benefits of reducing the viral load at setpoint, Gupta and colleagues [15] have supported the use of virological end points in HIV-1 vaccine trials.
Given the hypothesis that the primary effect of current vaccines will be to reduce viral load, we propose a more efficient strategy for determining the value of various vaccine approaches: screening test of concept (STOC) trials. The primary endpoint of a STOC trial is plasma HIV-RNA viral load at setpoint in individuals who acquire HIV. Approximately 30 total HIV infections are required to detect a 1.0 log10 reduction in viral load with adequate statistical power. Data from these trials can demonstrate biological plausibility that a cell-mediated immunity-based vaccine has a meaningful effect, although if the reduction were only 1.0 log10, the next step might be to begin an interactive process, improving the vaccine and conducting another trial. Along with evidence of efficacy in animal models, safety and immunogenicity data, and feasibility of vaccine manufacture and distribution, these trials could serve to accelerate promising candidates to phase III trials, or limit the use of resources on less effective candidates.
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