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Classic preventive vaccines are designed to mimic the effects of natural exposure to microbes. They provide a high level of long-lasting protection against infection in the vast majority of recipients and serve as freestanding preventive measures. Although a classic preventive vaccine remains the ultimate goal of efforts to develop a vaccine for protection against the human immunodeficiency virus (HIV), the enormous genetic diversity and other unique features of the HIV envelope protein have thus far thwarted attempts to identify an effective candidate. However, we have learned from studies of HIV pathogenesis in humans and from animal models that a vaccine that induces strong T-cell–mediated immune responses in the absence of broadly neutralizing antibodies may prove beneficial even if infection is not completely prevented. Vaccine-induced T-cell responses may blunt initial viremia and prevent the early and massive destruction of memory CD4+ T cells that help control infection and prolong disease-free survival. Furthermore, secondary transmission may also be reduced if the vaccine helps to control viral replication; efficiency of transmission is directly related to plasma virus levels. T-cell vaccines represent uncharted territory, and their use may have outcomes that challenge researchers and regulators alike. If proven successful, a disease-modifying HIV vaccine would also present new challenges for the entire public health community, since it would not be a stand-alone preventive measure, as are most classic preventive vaccines. Instead, it would need to be delivered in the context of a comprehensive HIV-prevention program. OB S T AC L E S T O VAC C I NE DE V E L OPM E N T The development of more than two dozen antiretroviral therapies to combat HIV infection has resulted in a dramatic decrease in morbidity and mortality associated with the acquired immunodeficiency syndrome (AIDS) in developed countries and, increasingly, in low- and middle-income countries as these therapies become more widely available. Despite ongoing prevention efforts, however, HIV continues to spread unabated in many parts of the world, with an estimated 14,000 new infections occurring daily. A safe and effective HIV vaccine would be an enormously valuable tool in the campaign to stop the spread of HIV. Most viruses against which successful vaccines have been developed undergo some level of initial replication and dispersal from the portal of entry before the virus reaches its target organ and triggers pathogenic sequelae. During this period, the virus remains vulnerable to eradication by the immune system. When prior immunization or exposure to a virus has elicited virus-specific immunologic memory, the increased speed and intensity of the immune response can prevent or mitigate disease. The nature of the interaction between HIV and the immune system is complex, and the relevance of different immune responses to the control of infection is only partially understood (Fig. 1). The primary stage of HIV infection begins with a burst

This report summarizes the discussions and recommendations from a consultation held in New York City, USA (31 January-2 February 2006) organized by the joint World Health Organization-United Nations Programme on HIV/AIDS HIV Vaccine Initiative and the International AIDS Vaccine Initiative. The consultation discussed issues related to the design and implementation of phase IIB 'test of concept' trials (phase IIB-TOC), also referred to as 'proof of concept' trials, in evaluating candidate HIV vaccines and their implications for future approval and licensure. The results of a single phase IIB-TOC trial would not be expected to provide sufficient evidence of safety or efficacy required for licensure. In many instances, phase IIB-TOC trials may be undertaken relatively early in development, before manufacturing processes and capacity are developed sufficiently to distribute the vaccine on a large scale. However, experts at this meeting considered the pressure that could arise, particularly in regions hardest hit by AIDS, if a phase IIB-TOC trial showed high levels of efficacy. The group largely agreed that full-scale phase III trials would still be necessary to demonstrate that the vaccine candidate was safe and effective, but emphasized that governments and organizations conducting trials should consider these issues in advance. The recommendations from this meeting should be helpful for all organizations involved in HIV vaccine trials, in particular for the national regulatory authorities in assessing the utility of phase IIB-TOC trials in the overall HIV vaccine research and development process. (c) 2007 Lippincott Williams & Wilkins.

Development of a safe and preventive HIV-1 vaccine is a high priority. Recent advances in HIV vaccine development include an improved understanding of HIV envelope structure, development of techniques that enable a detailed analysis of vaccine-induced immune responses in humans, expansion of the pipeline of promising candidate vaccines, and completion of the first vaccine efficacy trials. A common feature of several preventive vaccine strategies in early clinical trials is their ability to attenuate clinical disease rather than completely prevent HIV infection in nonhuman primates. One or more candidate vaccines will likely advance into efficacy trials within the next few years, while efforts to identify new designs that induce broadly neutralizing antibodies continue with incremental success.

Recent advances in HIV vaccine development include initiation of the first efficacy trials and substantial expansion of the preclinical pipeline. Several preclinical candidate vaccines have induced strong cellular immune responses and provided impressive protection against AIDS in non-human primate models; however, candidates that induce broadly neutralizing antibodies remain elusive.

An HIV vaccine has thus far been elusive. Drs. Margaret Johnston and Anthony Fauci remain cautiously optimistic that a substantial increase in our understanding of HIV infection and disease will lead to creative ideas about how to design an effective HIV vaccine. Dr. Anthony Fauci discusses the 30-year search for an HIV vaccine, recent setbacks, and prospects for future success. Dr. Fauci is the director of the National Institute of Allergy and Infectious Diseases, Bethesda, MD.

The need to broaden research directed at answering fundamental questions in HIV vaccine discovery through laboratory, nonhuman primate (NHP), and clinical research has recently been emphasized. In addition, the importance of attracting and retaining young researchers, developing better NHP models, and more closely linking NHP and clinical research is being stressed. In an era of a level budget for biomedical research at the U.S. National Institutes of Health (NIH), HIV/AIDS vaccine research efforts will need to be carefully prioritized such that resources to energize HIV vaccine discovery can be identified. This article summarizes progress and challenges in HIV vaccine research, the priorities arising from a recent summit at NIAID, and the actions needed, some already under way, to address those priorities.

Because of a unique combination of challenges facing human immunodeficiency virus vaccine developers, a number of traditional and novel vaccine designs are being evaluated essentially in parallel. Monomeric proteins, poxvirus vectors, peptides, and particle-based candidate vaccines have entered or will soon enter human trials. Other designs are at earlier stages of development. All candidates evaluated to date in phase I/II human trials have proven safe and immunogenic. One or more of the most promising designs will soon progress to 'test of concept' clinical trials to determine efficacy.

Since our natural immune response to HIV infection is ineffective, a key goal for an HIV vaccine is to induce a response different from that induced by natural infection — an “unnatural immunity,” involving production of broadly neutralizing antibodies.

Developing a vaccine against the human immunodeficiency virus (HIV) poses an exceptional challenge. There are no documented cases of immune-mediated clearance of HIV from an infected individual, and no known correlates of immune protection. Although non-human primate models of lentivirus infection have provided valuable data about HIV pathogenesis, such models do not predict HIV vaccine efficacy in humans. The combined lack of a predictive animal model and undefined biomarkers of immune protection against HIV necessitate that vaccines to this pathogen be tested directly in clinical trials. Adaptive clinical trial designs can accelerate vaccine development by rapidly screening out poor vaccines while extending the evaluation of efficacious ones, thereby improving the characterization of promising vaccine candidates and the identification of correlates of immune protection.

Since the discovery of human immunodeficiency virus (HIV) in 1983, significant progress has been made toward the discovery, development, and licensing of anti-HIV drugs. In vitro screens against whole virus are now being complemented by screens against specific viral targets, resulting in the development of clinical candidates acting at several critical stages of the viral life cycle. Despite these advances, clinical therapy remains largely palliative. In addition, it has recently been recognized that HIV resistance to most drugs may pose even greater obstacles. Moreover, emerging data on immunopathogenesis raise the possibility that even if virus was eliminated from an infected individual, the patient's immune system might not be capable of restoration to normal function. In the face of such obstacles, deeper insights into the pathogenic mechanisms of disease, aggressive exploitation of those mechanisms for therapeutic gain, and continued commitment of both public and private sectors to support and collaborate in this research are needed.

Since the identification of HIV in 1984, the search for a safe and effective vaccine has been relentless. While investigator-initiated research has provided substantial information regarding HIV disease and pathogenesis, and over two dozen drugs are licensed in the USA to treat HIV, the global epidemic continues unabated. Early in HIV vaccine research, the pharmaceutical industry took the initiative to produce products for clinical testing. As the likelihood of a quick success decreased, private investment waned. The public sector responded with novel mechanisms to engage industry while continuing to support academic investigators. HIV vaccine research continues to rely on the creativity of individual investigators, as well as collaborations that vary in size and complexity and offer opportunities for the efficient use of resources and accelerated progress.

Although animal models have been useful in guiding vaccine development, HIV/AIDS models have not yielded a clear correlate of immunity nor given consistent results on the potential efficacy of various vaccine approaches. Further development and improved uniformity in the use of animal models would maximize their potential to meet the urgent worldwide need for a safe and effective HIV vaccine.

Several lines of evidence now argue strongly that a successful HIV vaccine does not need to block infection completely. It has to mimic what already occurs in a minority of unvaccinated individuals--namely, rapid clearance of infection or reduction of viral load to a level that does not produce symptoms or permit transmission to others. The various vaccine candidates are reviewed.