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Vaccines
Research progress in this area includes:
Developing a vaccine or vaccines that are safe and effective in preventing HIV infection in exposed individuals is a major public health priority in the national and international effort to combat this pandemic. HIV disease continues to have a major impact on public health worldwide, and its spread is projected to worsen through the year 2000 and beyond. It is estimated that up to 10,000 people become infected with HIV daily of which 90 percent are in the developing world. If current trends persist, the rate of new infections will remain relatively stable in Europe and North America but will expand and devastate parts of Latin America, Africa, and Asia.
In the United States alone, more than 550,000 persons have developed AIDS and as many as 800,000 are believed to be infected with HIV-1. A recent report by the CDC indicates that during 1994 and 1995, State, local, and territorial health departments reported about 80,000 new cases of AIDS each year among persons in the United States. In addition, it is estimated that there are 40,000 to 60,000 new infections occurring each year in the United States.
Finding effective means to control the human, social, and economic costs of HIV/AIDS represents one of the highest public health priorities. While behavioral interventions remain a critical component in preventing the spread of HIV, prevention activities alone will not be sufficient to contain the epidemic, and vaccines may be the only cost-effective way to prevent HIV infection. Therefore, an affordable, safe, and effective vaccine is urgently needed that is also easily delivered and acceptable to various populations at risk. To address these obstacles and facilitate HIV vaccine development, the NIH supports a broad program encompassing basic, preclinical, and clinical vaccine research on candidate vaccine products. In parallel, NIH supports research on risk factors and other preventive interventions that will form an essential foundation for vaccine trials, in collaboration with other Federal agencies, local communities, industry, and international organizations.
The goal of preventive vaccines is to slow and eventually end the HIV pandemic, and to protect the individual from HIV infection and/or disease. Protective efficacy against HIV infection can be measured by a range of clinical and virological end points. Desirable goals of vaccination are to induce immune responses that quickly clear or reduce incoming virus and infected cells, and if established, to control viral replication and maintain a low viral load, thereby preventing disease progression and transmission. It may be unrealistic to expect an HIV vaccine to completely prevent HIV infection. Optimally, the vaccine-induced immune response would be capable of clearing virus and virus-infected cells before widespread dissemination occurs. Thus, limited replication might occur at the site of entry, but disseminated infection would be prevented.
Control of viral replication, even if the virus is disseminated, could maintain a low viral load, thereby preventing secondary spread of the virus to others. Vaccine-induced diminution in viral load also might be correlated with prevention or delay in disease progression; a correlation between low virus load and long-term nonprogression has recently been observed in both animal studies and epidemiologic investigations. Efficacy of vaccines in preventing established infection can be determined relatively early in the conduct of a vaccine trial by viral culture or polymerase chain reaction (PCR). However, assessment of long-term control of viral replication, immunosuppression, and disease progression, which may be critical for assessing efficacy, will make the conduct of efficacy trials more complex. This will be particularly true in populations with access to the most effective multiple-drug therapeutic regimens.
Vaccine efficacy may also be influenced by the dose of infecting virus and by the site or route of exposure. For example, a vaccine may protect against a low dose of virus at a mucosal site but not protect against a large inoculum acquired intravenously. Alternatively, a vaccine may protect against exposure to virus intravenously, but not protect against secondary spread of HIV infection from a mucosal site. Vaccine strategies therefore may need to be tailored for route of HIV exposure and may require combination approaches to optimize protection from frequent and/or multiple routes of exposure, especially in individuals whose immune status might be compromised by other factors.
Various strategies for stimulating a protective immune response against HIV infection are being explored through basic research, animal models, and clinical trials. There are many inherent uncertainties, not only in the identification of the immune responses required for protection against HIV infection or disease but also in the vaccine designs and strategies needed to induce such protective responses. Thus, multiple conceptual and practical approaches to development of candidate vaccines are being pursued at the preclinical level, with prioritization into small Phase I trials and additional selection and prioritization of candidates for further clinical study. The conducting of many small trials and the opportunity to return to the laboratory and refine those candidates that prove less than optimally immunogenic permits rapid incorporation of vaccine improvements. Vaccines also may serve as immunomodulators to improve immune function and diminish disease progression in HIV-infected individuals and may potentially prevent transmission from mother to fetus or from one infected adult to another.
Basic research on HIV and the immune system provides crucial information required for the development of vaccine candidates. These efforts, however, are complicated by many unique aspects of HIV infection including an unprecedented degree of antigenic variation. Recent findings indicate that there are at least two major groups of HIV-1 (M and O), with each exhibiting several major genotypic subtypes (clades). To date, virus from one clade (B) predominates in the United States. However, there is extensive variation within a single clade and even in a single individual. This variation is likely to affect recognition by and escape from humoral and cellular immune responses. Vaccines capable of eliciting an immune response to a broad spectrum of antigenic specificities or to highly conserved epitopes will thus be required to protect against HIV infection.
The NIAID-sponsored HIV variation project is investigating the rate and magnitude of both genetic and antigenic variation in HIV and related retroviruses. The findings from this project will help determine the impact of such variation on strategies for developing potential AIDS vaccines.
The nature of the immune response needed to protect against HIV infection or to ameliorate established infection is poorly understood because much still needs to be learned about immune responses, in general, and those relevant to protection from viruses with the potential to establish latency in infected cells, in particular. In this context, a great deal of new information will be necessary if one is to create vaccines that will be effective against a virus such as HIV that replicates within cells, specifically targets and destroys cells of the immune system, and can spread by cell-to-cell transmission. This includes knowledge concerning (1) the factors that regulate the induction of cytotoxic T cells that destroy virally infected cells of various types, (2) the factors that determine whether effector immune responses that occur to key antigens are amplified rather than tolerized or deleted responses, (3) the factors that establish immunologic memory responses to antigens of interest so that protection is persistent, (4) the identity, source, regulation, and mechanism of action of cytokines that affect, directly or indirectly, viral replication and persistence, (5) the signaling events that result in productive T cell activation or interfere with responsiveness, (6) the role of antibodies in reducing virus load and/or controlling the spread of infection, (7) the mechanisms by which antibodies function to neutralize HIV and related viruses, and (8) the role of antibody-dependent killing of infected cells.
Currently, NIH researchers are pursuing a multipronged approach for the development of HIV vaccines. These include traditional approaches such as the incorporation of killed viruses in known adjuvants and the development of attenuated viruses. There are serious concerns about the safety of these approaches that remain unresolved, but studies in animal models on killed and attenuated virus vaccines may help to reveal the correlates of immune protection and the requirements for an effective vaccine. However, the unique problems posed by HIV suggest a need for increased efforts to design novel approaches. Several being pursued include the use of synthetic viral peptides, recombinant proteins, and virus-like particles. In addition, live recombinant vectors, vaccines composed of virus genome incorporated into the genomes of highly immunogenic but non-disease-producing carrier viruses such as vaccinia and avipox, are being studied. Other vaccines under evaluation exhibit efficient delivery of antigens to selected compartments of the immune system, such as the mucosal area, where specialized immune responses particularly relevant to preventing entry of HIV are needed.
One area of emphasis is the design of synthetic vaccine candidates capable of inducing both cellular and humoral immunity. This involves identifying peptide segments of the HIV glycoprotein envelope and internal proteins, such as gag and reverse transcriptase (RT), that induce immune-targeted helper T cells and cytotoxic T lymphocyte (CTLs). Another approach is the development of genetically engineered, noninfectious HIV mutants that lack the viral RNA genome or are crippled in such a way that the virus is unable to infect yet contains a full complement of HIV antigenic proteins, which can assemble as virus-like particles, against which a protective response can be generated. The latter vaccine candidates can be produced in genetically engineered cell lines.
One promising new approach to eliciting cell-mediated and humoral immune responses utilizes the direct injection of "naked" DNA encoding HIV antigens into muscle or other accessible tissues. Animals injected with DNA construct for the HIV envelope (env) gene produced CTLs and humoral responses specific for the HIV envelope and produced antibodies that neutralized certain infectious HIV isolates in vitro. All these studies need to be expanded to include a far wider group of molecular, bacterial, and viral vectors and to include strategies that address the problems of intracellular HIV and viral latency.
The NIH, through its intramural programs, has developed a novel approach for the prevention of a representative AIDS-related OI in the form of a candidate vaccine for cryptococcal meningitis. Investigators at the NICHD and the NIAID have conducted a Phase I trial with a cryptococcal glycoconjugate vaccine. This could serve as a prototype for a vaccine approach to AIDS-related OIs caused by eukaryotic pathogens.
Some strains of HIV-1 can infect chimpanzees, thereby establishing an animal model to evaluate vaccines and infection with HIV-1. However, a limitation of the model has been that infections with most isolates have not been accompanied by disease. After incubation periods exceeding 7 years, several chimpanzees recently have shown signs of immune suppression and AIDS. HIV-1 from the affected animals may have become adapted to chimpanzee cells and developed a higher pathogenic potential.
In studies utilizing the HIV/chimpanzee model, native or recombinant HIV Env proteins and virus vectors carrying HIV protein genes have induced both cellular and humoral immunity. In addition, studies of Env product vaccine candidates as well as more complex HIV vaccine strategies have shown efficacy in preventing HIV infection in chimpanzees. Hyperimmune anti-HIV immunoglobulin (HIVIG) and monoclonal antibodies to Env protein have also been evaluated for safety and potential to prevent HIV infection in chimpanzees under experimental conditions. Chimpanzees with persistent HIV infection have been exposed to other HIV isolates from the same or different clades in an attempt to learn whether immune responses that were not capable of clearing the initial infection were, nonetheless, capable of combating a new strain. Thus, infected chimps may provide a valuable resource for studying cross-reactive immune responses. The NIH supports chimpanzee colonies and programs that evaluate vaccine candidates and products for passive immunity in this animal model. The importance of using virus challenge stocks and routes of exposure that more closely approximate naturally occurring HIV strains has been appreciated, and new stocks are in development both for strains found in the United States and elsewhere.
Major developments have resulted from studies using the simian immunodeficiency virus (SIV). The importance of this model rests with both the genetic relatedness of SIV to HIV and the AIDS-like syndromes that develop in several species of infected macaques. These disease end points, which are not demonstrable in the chimpanzee model, are very important for vaccine development. Different SIV isolates provide virus/host interactions that exhibit different degrees of virulence reflecting the spectrum of HIV infections that occurs in humans. More importantly, in addition to sterilizing immunity to prevent infection, macaque models permit investigation of vaccine effects that may be more realistic goals for initial human vaccines -- protection against disease and vaccine modulation of viral replication. Experimental vaccines analogous to those being developed for clinical trials as well as several other approaches are being evaluated in this model. At the current time, the SIV/macaque model represents the most complete animal model for the comparative evaluation of AIDS vaccine candidates and adjuvants.
To date, approaches based on live attenuated virus have exhibited the greatest degree of efficacy and provide opportunities for defining correlates of immune protection. Concerns for safety, particularly in infants, must be resolved before progress can be made with this vaccine approach. However, studies of attenuated AIDS vaccines in animal models may provide constructs with improved safety for development of live vector vaccines or virus-like particles, i.e., genetically "killed" vaccine approaches.
Chimeric viruses (SHIV) made by replacing the envelope gene (and other selected genes) of SIV with any of a variety of HIV-1 envelope genes show increased promise for vaccine evaluation in macaques. SHIV viruses infect and persist in macaques, and recent constructs have induced CD4 cell depletion, AIDS, and death. Vaccines containing HIV envelope components, that are intended for human use, can now be tested for immunogenicity and efficacy in macaques in a disease model. SHIV constructs that infect efficiently via the mucosal route and incorporate genes for envelope protein from non-clade B HIV are being developed to evaluate vaccine-induced protection against divergent HIV isolates.
The pig-tailed macaque, Macaca nemestrina, which is susceptible to infection with selected stocks of HIV-1 and HIV-2, and baboons, which can be infected with some isolates of HIV-2, continue to be studied. HIV-2 stocks have been developed that induce AIDS-like disease in M. nemestrina and baboons.
Other animal models currently being used for vaccine development and evaluation include the severe combined immunodeficiency (SCID) mouse model. Human immune system tissues have been successfully transplanted into SCID mice to create a system for testing vaccine candidates or components of the human immune response to HIV vaccines.
Feline immunodeficiency virus (FIV) isolates that are pathogenic for cats now exist, and a vaginal transmission model recently has been developed. Its convenience and relatively low cost might make it an attractive model for analysis of biomedical agents to block transmission, such as microbicides. Vaccine experiments with cross strain protection have been performed in this model and its relevance as an animal disease make this an attractive model for further vaccine studies.
Equine infectious anemia virus (EIAV) may provide a unique model to investigate the relevance of vaccine-induced enhancement of lentivirus disease as well as escape from protective immunity.
The NIAID has established HIV Vaccine Working Groups, including representatives drawn from intramural scientists at the NIH, NIH-sponsored extramural scientists, and community constituency groups, to assist in the scientific coordination and planning of NIAID efforts in focused areas of vaccine design and correlates of immunity. The National Cooperative Vaccine Development Groups (NCVDG), comprising eight awardee groups, has been established by NIAID for the discovery and development of vaccine candidates. Research teams comprising scientists from industry, academia, and government collaborate to develop and test novel experimental HIV vaccine concepts in laboratory and animal models.
Several new adjuvants such as immune-stimulating complexes (ISCOMs), muramyl tripeptide, Quil A or QS 21, liposomes, and MF59 have been studied in macaques for their ability to stimulate humoral and cellular responses as well as to provide protection against virus challenge with candidate vaccines. These as well as other adjuvants have now been studied in human clinical trials with HIV envelope vaccines. Novel approaches to induce effective, durable immune responses are still needed. Use of cytokines (delivered either as proteins, as DNA, or in vectors) to modify and channel immune responses is an extremely active area of research in both mice and macaques.
Collaborative Mucosal Immunity Groups (CMIGs) have initiated studies focused on induction and assessment of regional mucosal immune responses to HIV in human subjects as well as functional antibodies to prevent transmission in primate models. Studies in this area remain critical for prevention of infection in the worldwide pandemic.
Industrial partners will play an essential role in development of HIV vaccines and other biomedical interventions to prevent infection. Factors that affect the participation and collaboration of industrial partners need to be addressed. These include not only economic, legal, and regulatory issues but also scientific ones. Vaccines need to prevent HIV infection, not only in the United States but worldwide. Collaborations must be established to provide relevant clinical isolates and information for the preparation and testing of such vaccines. Moreover, to facilitate the development of safe and efficacious vaccines, mechanisms should be adopted to promote further utilization of information generated from relevant animal models. Presently, few vaccine developers are pursuing the SIV/macaque models partly because of the need to develop unique reagents and methodologies and the extensive resources required. Collaborative programs among industrial, governmental, and academic agencies are needed to evaluate the comparative efficacy of parallel vaccine approaches against HIV and related retroviral models.
The AIDS Clinical Trials Group ACTG 076 has demonstrated that transmission of HIV from mother to infant can be significantly reduced by use of a zidovudine (ZDV) regimen given to HIV-infected pregnant women and their newborn infants. However, the complex ACTG 076 regimen is not useful to most of the developing world, where the largest proportion of HIV infection among women and children exists. An ideal regimen would be given once or only for a limited period of time, easily administered, nontoxic to mother and child, inexpensive, and have potential to prevent postpartum transmission via colostrum or breast milk.
The mechanism of the ZDV effect is not known, but initial studies indicate that ZDV therapy was associated with only a modest decrease in maternal RNA copy number, and that reduction in RNA level by ZDV explained only part of the observed treatment effect. Other studies have suggested that the presence of autologous or broadly reactive neutralizing antibody in HIV-infected women may be associated with lower rates of HIV transmission to their infants. An active immune response of newborn infants to HIV has also been suggested to be effective in averting perinatal transmission by studies reporting detection of HIV-specific cellular immune responses in some uninfected infants born to HIV-infected women. Additionally, several investigators have reported the rare occurrence of apparent clearance of HIV infection in perinatally exposed infants.
Thus, vaccines capable of stimulating the mother's and/or infant's immune response or passive immunity therapies may be capable of reducing perinatal transmission. Like Hepatitis B, the use of active, passive, or active/passive strategies to reduce transmission has the highest potential for reducing mother-to-child transmission in developing countries.
Preclinical studies on perinatal transmission and immune interventions were funded through an RFA in FY 1995. Clinical studies targeted toward developing active or passive immunization strategies to prevent perinatal HIV transmission are being conducted at 49 Pediatric ACTG sites funded by NIAID and NICHD and four NIAID-funded AIDS Vaccine Evaluation Group (AVEG) sites and at international sites through grant and contract (HIVNET) support. HIVIG product and trials support for the passive immunity studies has also been provided through NHLBI.
To date the NIAID-supported AIDS Vaccine Evaluation Group (AVEG) has conducted or initiated 25 Phase I and II trials with 16 different candidates.
Significant progress has been made in the evaluation of vaccine candidates developed by manufacturers. For example, all vaccine candidates tested to date in Phase I trials have been shown to be safe and well tolerated. Phase I trials involving HIV-seronegative individuals have shown that (1) the majority of vaccines induce binding antibodies; (2) moderate titers of neutralizing antibody directed toward homologous and heterologous laboratory strains of HIV-1 are produced; (3) neutralization of virus in assays employing standard PHA-stimulated blasts has not been detected; and (4) the duration of the neutralizing response in some trials has been maintained for up to 2 years in up to 50 percent of the individuals in the trial. In addition, recent studies testing a recombinant poxvirus vaccines, including vaccinia-gp160, canarypox-gp160, and canarypox-env, gag, protease, with or without a subsequent recombinant gp120 subunit booster vaccine have been shown to induce strong CD8+ CTL responses in a proportion of the volunteers; those boosted with recombinant envelope proteins also make neutralizing antibody. More complex vaccinia and canarypox vectors incorporating portions of pol and nef are now under study. Several peptide vaccine candidates are under study, including mixtures of envelope peptides, a gag-lipopeptide designed to induce CD8+ CTL, hybrid peptides including both T- and B-cell epitopes. In addition, particulate vaccines are of interest, and the first of these, Ty-p24 virus-like particles, is being tested parenterally with and without adjuvant and with mucosal administration. Additional studies are planned with other vaccine candidates for mucosal administration.
The NIH has performed a Phase II trial with gp120 vaccine candidates that enrolled uninfected at-risk individuals. The study demonstrated that antibody responses did not differ between higher and lower risk populations, and associated studies found that most participants understood the elements of the trial and did not systematically alter their risk behavior as a result of participation in the trial. A second Phase II trial is planned to further explore the combination of recombinant canarypox and envelope subunit boosting.
Research required to prepare for clinical evaluations of potential vaccine candidates in efficacy trials is being performed in several domestic and international areas with populations at risk of HIV infection. As candidate vaccines become ready for efficacy trials, it will be important to have identified populations who remain at risk for HIV infection after counseling and risk-reduction measures have been implemented and who are willing to participate in the trials. Characterizing the circulating viral strains and risk factors, learning how to effectively reduce risk behaviors, and gaining the support of the communities (and, as applicable, governments) will take considerable time and effort. In preparation for implementation of efficacy trials, investigators participating in the HIV Vaccine Efficacy Trials Network (HIVNET) are determining the incidence of HIV in populations such as injection drug users, gay/bisexual men, and individuals attending sexually transmitted disease clinics, in the United States and several international sites, who may participate in future vaccine trials. In addition, risk behavior and the impact of risk reduction efforts are being assessed. Investigators are obtaining virus from individuals who recently seroconverted to ensure that vaccines genetically match virus strains now circulating. Close collaboration has been established and continues between the HIVNET and the Fogarty International Center AIDS International Training and Research Program (AITRP) to train local investigators and develop necessary laboratory skills and infrastructure for international vaccine efficacy trials and trials of other interventions. These trials provide opportunities for fundamental research to increase our understanding of HIV transmission and disease progression.
The NIH also plans to study innovative strategies for prevention or reduction of sexual and perinatal HIV transmission through the domestic and international epidemiologic and vaccine preparedness cohorts already in place. Using this infrastructure, NIAID-supported investigators are studying prevention strategies, such as STD diagnosis and treatment to reduce susceptibility to and transmission between sexual partners, targeted chemical and mechanical barrier methods, behavioral interventions, methods for reducing perinatal exposure to maternal HIV-infected blood and secretions, and simple relatively inexpensive pharmacologic or immunologic interventions to reduce mother-to-child transmission of HIV.
The NIH supports a program to develop and standardize immunologic laboratory assessments of AIDS vaccines in primates. In addition, NIH supports an AIDS vaccine reagent project for clinical analysis and preclinical vaccine development.
NIAID supports the AIDS Research Reagent and Reference Program, which provides an extensive repository of materials useful in basic and applied research for vaccine development.
For more information on Vaccines HIV/AIDS-related research at the NIH, contact:
Bonnie Mathieson, Ph.D.
Office of AIDS Research, NIH
Building 31, Room 4C06
Bethesda, MD 20892
(301) 496-3677 TELEPHONE
(301) 496-4843 FAX
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