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HIV Vaccine Research: Considerations for the New Millenium

Lecture by Anthony S. Fauci, M.D.,
Director
National Institute of Allergy and Infectious Diseases
National Institutes of Health
Bethesda, Maryland

32nd National Immunization Conference
July 22, 1998
Atlanta, Georgia

Introduction

The human immunodeficiency virus (HIV), the cause of the acquired immunodeficiency syndrome (AIDS), remains one of the greatest threats to global health. Although recent treatment advances have led to an encouraging downturn in the number of new AIDS cases and AIDS-related deaths in the United States and other developed countries, the epidemic continues to accelerate elsewhere in the world, notably in sub-Saharan Africa and on the Indian sub-continent.

In 1997 alone, approximately 5.8 million people worldwide were newly infected with HIV. More than 90 percent of these new infections-approximately 16,000 each day-occurred in developing countries, where antiretroviral therapy is beyond the reach of all but the privileged few. Globally, one in every 100 adults aged 15-49 years is HIV-infected; at least 80 percent of these infections are due to heterosexual transmission. By the end of 1997, an estimated 30.6 million people worldwide were living with HIV/AIDS, a figure projected to reach 40 million by the year 2000.

These grim statistics are powerful reminders of the pressing need for a safe and effective HIV vaccine, as well as for a greater emphasis on other approaches to HIV prevention. Even a partially efficacious vaccine may have an important impact in regions where the epidemic is out of control.

Challenges to Developing an HIV Vaccine

HIV vaccine developers face a number of formidable obstacles, including the geographic variability of HIV subtypes, the lack of a clear understanding of the correlates of protective immunity in HIV infection, the limitations of available animal models of HIV infection, and challenges of inducing mucosal immunity to prevent sexual transmission of HIV.

Reasons for Optimism

Despite these potential impediments, there are many reasons to be optimistic that a useful HIV vaccine can be developed. Perhaps most compelling is the fact that the human immune system can control HIV under certain circumstances. For example, in most individuals with acute HIV infection, the immune system is successful in dramatically down-modulating the burst of viremia seen in the weeks following infection. In addition, a small subset of HIV-infected individuals show little or no immune system deterioration and low levels of viral replication even after 15 or more years of infection in the absence of antiretroviral therapy. Other individuals, including sex workers, have multiple exposures to HIV but remain uninfected. Studies of acute infection, "long-term nonprogressors," and multiply exposed/uninfected people continue to provide clues regarding the immune responses one would want to elicit with a vaccine.

Experimental vaccines have proven protective in animal models of AIDS and, in Phase I and Phase II humans trials, candidate HIV vaccines have been well tolerated and immunogenic. In human studies, cross-clade CD8+ CTL responses to candidate HIV vaccines have been observed, as have antibodies that can neutralize a broad spectrum of HIV subtypes. These findings indicate that the problem of viral diversity and multiple clades may not be insurmountable.

In addition, epidemiological studies indicate that mucosal transmission is relatively inefficient in the absence of other sexually transmitted diseases. This suggests that moderate immune responses at the mucosa may be protective. Finally, recent studies indicate that HIV vaccine efficacy trials among high-risk volunteers are feasible. In this regard, considerable progress has been made in establishing the domestic and international infrastructure for the assessment of HIV vaccines and other prevention efforts.

Increased Resources

To speed the pace of HIV vaccine discovery, many agencies, public and private, have dramatically increased the resources devoted to HIV vaccine research. For example, at the National Institutes of Health (NIH), HIV vaccine funding increased by nearly 80 percent between FY 1995 and the estimated NIH budget for FY 1999. As part of this expanded effort, NIH has awarded numerous grants to foster innovative research on HIV vaccines, and is invigorating and reorganizing its vaccine clinical trials effort. In addition, NIH has established a Vaccine Research Center within the NIH intramural research program to stimulate multidisciplinary research into basic and clinical immunology and virology, and ultimately vaccine design and production.

HIV Vaccine Concepts Under Development

Since the first HIV vaccine trial enrolled volunteers in 1998, at least 40 different vaccine candidates have been studied in clinical trials worldwide, belying the common misperception that few concepts have been examined. HIV vaccine research has progressed from an early focus on HIV surface antigens and the role of antibodies to increased attention to the importance of cytotoxic T cells (CTLs) in HIV immunity. Many novel approaches to elicit anti-HIV antibodies and CTLs are now being pursued:

Subunit vaccines based on viral surface proteins, such as gp120, have the advantage of being safe and simple to prepare. It remains to be seen whether these vaccines will elicit antibodies capable of neutralizing primary HIV isolates. A vaccine candidate based on gp120 from two different HIV clades recently entered Phase III testing in the United States, and a Phase III trial is planned in Thailand.

Vectored vaccines are now in Phase II trials. This approach employs non-HIV viruses (e.g. avian pox viruses) engineered to carry genes encoding one or more HIV epitopes.

Approaches based on a combination of elements, such as a canarypox-vectored product given with a subunit vaccine, are being studied to determine if a robust cellular and humoral response to HIV can be elicited.

Naked DNA vaccines, HIV peptides, and pseudovirions have shown promise in early studies. However, it remains to be seen if these scientifically elegant approaches will have "real world" utility.

Although live-attenuated and whole-killed HIV vaccines have shown promise in non-human primates, their development has been slowed by safety concerns.

Canarypox-vectored Vaccines: Progress and Plans

Recent studies supported by the NIH have examined canarypox vectors encoding multiple HIV gene products, administered both with and without a gp120 subunit vaccine. Early results have been encouraging. Detectable CTL responses have been observed in up to 70 percent of volunteers, and have been seen up to two years following initial vaccination. CTL responses in some patients have cross-clade killing activity. In addition, ADCC responses and HIV-specific CD4+ T cell responses have been observed in approximately 50 percent of participants. These findings have provided the impetus for a Phase II HIV combination vaccine trial known as AVEG 202/HIVNET 014.

A related vector comparison study is ongoing and is evaluating three potential products to determine which vector produces the most robust immune response. An additional trial will assess different HIV subunit vaccines given in conjunction with vectored vaccines.

These studies, as well as additional data that emerge from basic research, will provide the information to determine which products will advance into larger-scale testing.

HIV Vaccine Efficacy Studies

As mentioned above, a Phase III study of a bivalent gp120 vaccine was recently undertaken in the United States by a private company, and an additional Phase III study will be conducted in Thailand. NIH will collaborate with the company in evaluating the immunological responses to the vaccine.

In addition, the NIH has planned "intermediate-sized" trials of promising vaccine candidates to identify products/regimens with plausible efficacy, and eliminate those unlikely to be efficacious. It is anticipated that these trials will provide important information about correlates of immunity, and permit data-driven decisions about the products that should proceed to full-scale efficacy trials.

Conclusion

Most currently available vaccines for other diseases, as well a those in the development pipeline, have resulted from collaborations between partners in the public and private sectors. The successful development of an HIV vaccine will depend on such collaborations to translate basic research findings and technological advances into an HIV vaccine, the "holy grail" of AIDS research. Last year, President Clinton set a national goal of having a useful HIV vaccine within 10 years. With nine years to go, we are well positioned to meet this goal with the extraordinary basic and applied research that is now underway.

Selected References

Corey, L. 12th World AIDS Conference, Geneva, Switzerland, July 2, 1998, abstract 495.

Folkers, GK and Fauci AS. The role of US government agencies in vaccine research and development. Nature Med 1998;4(5 suppl.): 491-494.

Gellin, B (ed.). The Jordan Report: Accelerated Development of Vaccines. Bethesda, Maryland: National Institute of Allergy and Infectious Diseases, 1998.

Haynes, BF, Pantaleo, G and Fauci, AS. Toward an understanding of the correlates of protective immunity to HIV infection. Science 1996;271:324-328.

Heilman CA and Baltimore D. HIV vaccines - where are we going? Nature Med 1998;4(5 suppl.):532-534.

Letvin NL. Progress in the development of an HIV-1 vaccine. Science 1998;280:1875-1880.

Rida, W. et al. Intermediate-size trials for the evaluation of HIV candidates: a workshop summary. J Acquir Immune Defic Syndr Hum Retrovirol 1997;16(3):195-203.

UNAIDS/WHO. Report on the Global HIV/AIDS Epidemic, June 1998.

Weinhold, K. 12th World AIDS Conference, Geneva, Switzerland, July 2, 1998, abstract 494.