HIV Vaccine Development: A Progress Report

Dr. Daniel F. Hoth (formerly, Division of AIDS, National Institute of Allergy and Infectious Diseases [NIAID], National Institutes of Health [NIH], Bethesda, Maryland): The worldwide human immunodeficiency virus (HIV) epidemic continues to grow. In the United States, it is estimated that one new HIV infection develops every 9 or 10 minutes [1]. The Centers for Disease Control and Prevention (CDC) estimates that some 1 million HIV infections have developed in the United States. In addition, by the end of 1993, 361 164 cases of the acquired immunodeficiency syndrome (AIDS) and 220 736 AIDS-related deaths had been reported in the United States (CDC Quarterly Surveillance Report hotline, available by calling 404-332-4570). The CDC projects that by the end of 1994 there will be 415 000 to 535 000 cumulative AIDS cases and 320 000 to 385 000 AIDS-related deaths. Even more devastating are projections by the World Health Organization's (WHO) Global Programme on AIDS [2], which estimates that as of 1992, at least 8 to 10 million adults were infected with HIV and about 1 million children were born with it. The WHO conservatively projects that by the year 2000, 30 to 40 million people will develop HIV infection, more than 90% of them in developing countries. Epidemiologists from the Harvard School of Public Health [3] project even higher numbers than those of the WHO, especially for Southeast Asia and Africa. The need for intervention is clear. The public health strategy for preventing and controlling HIV infection depends on changing human behavior to reduce illicit drug injection, needle sharing [4], and the number of unprotected sexual encounters and sexual partners [5]; protecting the blood supply; expanding the diagnosis and treatment of other sexually transmitted diseases [5]; achieving optimal prenatal care for pregnant HIV-infected women; and improving the availability of and compliance with the types of antiviral chemotherapy that reduce seminal viral burden and probably infectiousness [6]. In impoverished developing nations, preventive measures remain largely unavailable, unaffordable, or unpopular [7]. Changes in human sexual behavior are possible but may require intense intervention that may not be practical or affordable in all risk settings [8]. An affordable, available HIV vaccine remains the single most important long-term goal of prevention research [9-11] to supplement expanded education on HIV infection and sexually transmitted diseases, condom marketing, sexually transmitted disease control, prevention and treatment of injection drug use, and development of new barriers to HIV acquisition [12-14]. The human immunodeficiency virus is unlike other viruses that have been successfully prevented by vaccination. Several factors favor control of HIV by vaccination: The virus is limited to a human host with no known animal reservoir; it is not highly infectious; and natural infection generates both antibody and T-cell responses. However, HIV also has many characteristics that make vaccine development difficult: subclinical cases and a carrier state, a long-term infection process, a nonspecific acute clinical disease, significant antigenic variation, viral DNA integration into the host genome, transmission through infected cells, and destruction or alteration of immunoregulatory cell function. For many patients, the first recognizable clinical manifestations of HIV are opportunistic infections that are secondary to immunodeficiency and that may develop years after initial infection. Despite these daunting scientific challenges, significant progress has been made in preclinical and clinical research in the worldwide effort to develop an effective HIV vaccine. We present a brief review for medical readers unfamiliar with HIV vaccinology. Preclinical Vaccine Research Dr. Dani P. Bolognesi (Center for AIDS Research, Duke University, Durham, North Carolina): Contemporary viral vaccines usually work by imitating natural immune responses to pathogens to eventually clear the infection [15]. Most licensed viral vaccines are based on either attenuated forms of the virus or whole inactivated preparations of the agents. A notable exception is the recombinant hepatitis B vaccine, but this also was designed to mimic a natural protective immune response [16]. Because there are no established correlates of protection and no established natural protective immunity to HIV infection, the use of attenuated or whole inactivated virus vaccines is less certain as a strategy. Moreover, these approaches raise obvious safety concerns. Further, HIV presents unprecedented obstacles for vaccine developers because it can be transmitted as a cell-associated virus across mucosal surfaces, it can hide from immune attack by establishing latent infections, and it can escape from existing immunity by generating several antigenic variants. Sequestration of the virus into immunoprivileged sites such as the central nervous system or certain lymphoid organs also appears to be an important feature of pathogenesis [17]. Attenuated and whole inactivated vaccine products, along with many recombinant DNA, protein, and peptide approaches, have been studied in various animal models of HIV infection, including HIV itself and related viruses such as simian immunodeficiency virus or feline immunodeficiency virus. The results present a complex picture. Some studies with attenuated and whole virus vaccines have shown promise in simian immunodeficiency virus and feline immunodeficiency virus models, whereas recombinant approaches have been far less effective. However, when studied in the chimpanzee model of HIV infection, recombinant subunit vaccines involving parts of the HIV envelope have effectively protected animals from infection, whereas whole inactivated virus preparations were ineffective [18]. Although more direct comparisons of each of the vaccine strategies should bring this picture into sharper focus, there are several possible reasons for the disparate results. The most important of these are differences among the animal models. Infection with feline immunodeficiency virus and simian immunodeficiency virus leads to disease in cats or monkeys, respectively, whereas HIV infection of chimpanzees does not. This difference may be due, at least in part, to the vigor with which the infection is established and thereby the potency of the vaccine required for protection. It would appear that human HIV infection associated with a long disease-free interval may represent a middle ground between the rapid disease induced by some feline immunodeficiency virus and simian immunodeficiency virus strains and the indolent HIV infection of chimpanzees. It has been suggested that infection of monkeys with simian immunodeficiency virus strains that induce a slower onset of disease may be more relevant than any model now widely used in HIV research. It is interesting to note that recombinant approaches have proved effective in at least one experiment that used the slower simian immunodeficiency virus model [19]. The reasons for the failure of whole inactivated virus vaccine to protect chimpanzees (attenuated vaccines have not been widely tested) are not entirely clear [20]. One possible explanation relates to the role of human cellular antigens associated with killed virus preparations used for vaccination and virus challenge stocks. Studies have recently shown that such antigens play a major role in protection [21]. Similar antigens may play a lesser role in chimpanzee models, but this has not been tested directly [22]. When a short-term model for simian immunodeficiency virus infection and disease is used, the attenuated virus vaccine has provided the most impressive protection [23]. Previous infection (about 2 years earlier) with a genetically modified virus that replicates poorly in monkeys and does not cause disease allowed animals to resist challenge with a relatively large dose of highly pathogenic simian immunodeficiency virus [23]. It should be possible to take full advantage of this model to derive insights on correlates of protection. Because this approach involves infection with a retrovirus, studies should include potential nonimmune correlates, such as production of inhibitory cytokines or other factors as well as the phenomenon of in vivo viral interference, to achieve the broadest scope in a search for protection correlates. Vaccine manufacturers have relied on two general factors in selecting candidates for development: safety considerations and results in chimpanzees who received candidate vaccines that were based on HIV itself. Consequently, manufacturers have largely shied away from inactivated or live attenuated vaccines and have relied on studies in chimpanzees in which vaccines based on various configurations of the HIV envelope could protect against infection. These were feasibility studies only, however, and did not examine the duration and breadth of protection or the efficacy of vaccines against various modes of virus transmission. Several features of the HIV envelope are considered potentially troublesome. Studies in vitro indicate that the native envelope can induce T-cell anergy and even death by apoptosis if certain conditions are met [24, 25]. Regions of molecular mimicry with normal-cell surface antigens, notably major histocompatibility complex (MHC) gene products, could induce autoantibodies [26]. Such properties suggest that the HIV envelope might be immunosuppressive and possibly pathogenic. Fortunately, considerable experience with more than 1600 persons not infected with HIV who received envelope-based vaccines has not shown evidence of immunosuppression. Nonetheless, the appearance of autoantibodies, antibodies that might enhance infection, or more subtle T-cell defects should continually be carefully monitored in vaccine trials. The absence of guiding principles for immune correlates of protection notwithstanding, challenges that