• Home
  • HIV/AIDS News
  • NIAID HIV/AIDS Vaccine Research and Development Strategy and Opportunity

NIAID HIV/AIDS Vaccine Research and Development Strategy and Opportunity

Date: November 30, 1995
Source: National Institutes of Health (NIH)
Author: National Institute of Allergy and Infectious Diseases (NIAID)

The identification of a safe and effective vaccine against the Human Immunodeficiency Virus (HIV) is of the highest priority to U.S. and worldwide efforts to control the epidemic. The National Institute of Allergy and Infectious Diseases (NIAID) has the lead responsibility at the National Institutes of Health (NIH) in the area of HIV vaccine research and development. In executing this mandate, the Institute has developed a comprehensive scientific research agenda implemented through and integrated program of fundamental and empiric research. The purpose of this paper is to describe the Institute's vision of the optimal strategic approach, including the spectrum of current scientific opportunity, which must be pursued to ensure success.
Shortly after the discovery of HIV as the cause of AIDS over 10 years ago, it became apparent that the development of a safe and effective vaccine would pose unprecedented challenges. Many believed that the abilities of the virus to rapidly mutate, to evade strong humoral and cellular immune responses in the course of natural infection, and to produce a silent latent infection in lymphocytes and macrophages precluded the possibility of successful vaccination. As understanding of HIV pathogenesis has grown, additional scientific and logistical challenges have emerged. No clear correlate of immune protection has been identified, either in animal models where vaccine protection has been achieved or in studies of human cohorts at risk of infection. Because individuals at high risk for HIV infection are typically exposed many times over a period of years to multiple genetic variants of virus, it seems likely that successful vaccination will require a substantially longer and broader immune response than has been demonstrated in most animal models to date. The theoretical possibilities of vaccine-mediated enhancement or of misguided increases in risk-taking behavior among vaccine trial participants raise unusual degrees of concern. A number of social and ethical factors suggest that efficacy trials will be very difficult. Market forces do not foster a desirable level of private sector activity in vaccine research and development.
Despite these challenges, several factors contribute to a more optimistic outlook for HIV vaccine research and development today and set the stage for a number of important scientific opportunities.
Vaccine-induced protection is possible. In 1989 a whole-killed SIV vaccine was shown to protect macaques from SIV infection, a finding which stimulated considerable enthusiasm for HIV vaccine research. Several years later, this result was largely discounted due to the presence of xenoantigens in the vaccine and challenge virus. More recent research with genetically and biologically attenuated strains of SIV, however, has demonstrated that long-lasting, broad protection from a highly virulent primate lentivirus can be achieved. Furthermore, vaccines that protect against several animal retroviruses have been licensed for veterinary use.
The immune system may be capable of complete control of HIV infection. It is now well established that the initial immune response of the vast majority of infected individuals results in long-term but partial control of the disease. Animal model research has demonstrated that transient infection with highly pathogenic strains of SIV can occur in vaccinated animals. Evidence is also accumulating to suggest that transient infection may occur in some unvaccinated humans. Researchers are now investigating adults who have been repeatedly exposed to HIV but are not infected, as well as children born to HIV infected mothers who either remain uninfected or who are infected and subsequently appear to clear HIV. The goal of this research is to identify immune and other host factors and viral factors that can clear an incipient infection.
Mucosal transmission is relatively inefficient. Reported rates of transmission of HIV across human mucosal surfaces have ranged between and 0.001 and 0.03. Reproducible transmission of SIV across rectal mucosa in monkeys occurs only with amounts of virus at least 1,000-fold higher than that required for intravenous transmission.
Candidate HIV vaccines have proven safe and immunogenic. NIAID initiated the first clinical trial of an HIV candidate vaccine in collaboration with MicroGeneSys, demonstrating interest and commitment on the part of government and the private sector to pursue vaccine research and development. To date, about 20 different candidates have been tested in human trials involving over 2,000 uninfected adult volunteers. Based on over 2,000 person years of follow-up in NIAID-supported trials, all candidate vaccines tested appear to be free of serious harmful side-effects. Concerns about vaccine-induced harmful immune responses have not been realized. Strong cellular and humoral immune responses, with memory, have been induced. More detailed summaries of these responses can be found elsewhere.
Efficacy trials among high-risk volunteers appear feasible. Data from studies conducted in both the U.S. and in developing countries indicate that cohorts of people at high risk of HIV transmission through sexual or needle sharing behavior can be recruited and retained in follow-up. Furthermore, data from an anonymous survey of participants in a phase II preventive vaccine study indicate that, in the aggregate, volunteers do not increase their risk behavior and understand key aspects of trial design.
The ideal HIV vaccine will be safe, produce no serious side effects, and protect against chronic infection and/or disease upon subsequent exposure to all virus subtypes. This protection will be sustainable throughout the period of potential exposure to HIV, regardless of the route of exposure. In the long term, the vaccine will be inexpensive to manufacture and easy to store and administer anywhere in the world, including developing countries. It must be noted that a less-than-ideal vaccine could have a substantial positive public health impact. Furthermore, it is very likely that progress toward the ultimate goal will occur in incremental steps in which vital lessons are learned from less-than-ideal vaccines.
NIAID's strategy to identify a safe and effective HIV vaccine contains four elements:
o Maintain a program of scientific inquiry that integrates fundamental research and empiric development to advance a broad front of critical knowledge and a variety of vaccine designs through laboratory, animal, and human research.
o Develop more and better-defined partnerships between NIAID and industry sponsors of vaccine development.
o Identify scientific opportunities that will accelerate HIV vaccine research and development and determine resource requirements to fully exploit them.
o Strengthen linkages with communities and other public or private organizations working in the field.
There are many opinions on the best approach to identifying a safe and effective vaccine. At one extreme are those who favor basic research and the accumulation of much more fundamental knowledge before proceeding to large clinical trials. At the other are those who favor a more empiric approach of traditional vaccinology, arguing that products must be quickly evaluated in human efficacy trials to obtain the best information of how to improve vaccine designs. These points of view frame a much larger continuum of relevant scientific activity that is neither purely "fundamental" nor "empiric", and that contributes to the advancement of both approaches.
NIAID believe that success in identifying a safe and effective HIV vaccine will require progress across this continuum. Its program is, therefore, designed to capitalize on the most important and promising scientific opportunities regardless of their place in the fundamental-empiric spectrum. Priorities for allocating resources are based on this comprehensive view and implemented through flexible mechanisms that provide for the integration of fundamental research and empiric development. Acknowledging the limitations of the terminology, fundamental research will generate the knowledge needed to design and study promising vaccine concepts, and empiric development will characterize the clinical usefulness of those concepts and generate new insights of fundamental knowledge. NIAID's current program and its specific priorities and plans are described in detail in the NIAID HIV/AIDS Research Agenda.
Toward the fundamental end of the spectrum, NIAID's program is aimed at improving our understanding of HIV and related retroviruses and of immune responses to those viruses. In keeping with its traditional role, the Institute supports research to address a broad array of very basic questions about HIV pathogenesis, the host immune response to HIV, and the mechanisms by which HIV infection persists. In addition, NIAID supports more applied, obstacle-oriented research to identify the correlates of immune protection; develop animal models that more closely mimic HIV transmission, infection, and disease; evaluate novel antigen presentation methods, including new adjuvants; improve understanding of the behavioral determinants of risk taking behavior and factors that correlate with willingness to participate in vaccine trials. NIAID relies predominantly, although not exclusively, on investigator-initiated grants to advance knowledge across this broad front of fundamental research. In toto, this knowledge forms the basis of most public and private sector efforts to identify promising vaccine designs.
Given the urgent need for a safe and effective HIV vaccine, the past successes of empiric vaccine development for other infectious diseases, and limited private sector involvement in the field, NIAID also supports considerable activity of a more empiric nature. This effort is intended to ensure that a number of promising vaccine designs are pursued in parallel. NIAID believes that this is important for two reasons. First, fundamental knowledge regarding optimal presentation of HIV antigens to the human immune system is presently insufficient to predict which approach will be successful. Second, most of the successful vaccines against viral diseases in current use are based on the whole-killed or the attenuated virus concept. Furthermore, the most successful design in the SIV-macaque model (the model most closely resembling HIV disease in humans) has been live-attenuated SIV. The potential use of whole-killed or live-attenuated HIV in humans, however, raises complex technological and safety concerns. Advances in biotechnology have made it feasible to design less problematic, novel vaccine prototypes, including recombinant proteins, viral and bacterial vectors, virus-like particle, synthetic peptides, and nucleic acid immunogens. These, as well as the more classical vaccine designs, are in NIAID-supported preclinical, animal model, and human trials. These studies are also designed to maximize the potential contribution to fundamental research.
NIAID believes that private-public sector partnership and a vigorous level of industrial activity are pivotal to progress in this field. The Institute is, therefore, placing considerable effort on strengthening ties between the two sectors. A number of the Institute's activities, which are intended to serve the general scientific community, have particular relevance to needs of the private sector. The cornerstone, of course, is NIAID's commitment to and support of fundamental research, which leads to information that will diminish, or at least clarify, the scientific risks involved in HIV vaccine development, and facilitate the design of prototype vaccines. Second, NIAID develops and provides viral challenge stocks, important reagents, and access to animal models for evaluating novel designs and delivery methods (including adjuvants) to the scientific community. Third, in collaboration with the World Health Organization and United Nations AIDS Program (WHO/UNAIDS) and other international organizations, NIAID has established a global, basic, and clinical research network that includes specimen repositories, viral characterization laboratories, and multidisciplinary clinical research sites. Fourth, NIAID has established vital links with various communities of potential trial participants by involving representatives in all phases of trial design, implementation, and analysis. Fifth, the Institute has implemented research to address questions related to behavior, attitudes, counseling, informed consent, recruitment, and retention, all of which will play a key role in the ultimate success of efficacy trials and in building productive research-community partnerships. Sixth, NIAID-funded researchers and staff have developed alternative designs for efficacy trials that will expedite "proof of concept" efficacy trials to identify vaccine designs that have promising level of efficacy.
Industry-NIAID development plans
In order to implement its overall strategy of evaluating a variety of possible vaccine designs, NIAID must establish collaborative partnerships with private sector sponsors that have vaccine products in development. These partnerships must, in turn, also contribute to industry's goals by facilitating progress toward product licensure. Recognizing industry's need for precise planning in the face of this field's substantial scientific and economic uncertainty, NIAID has recently begun formulating joint development plans with its partners. These plans, negotiated between industry sponsors and NIAID, are specifically intended to encourage private sector collaboration with the Institute. They outline the laboratory, animal model, and human research and development path that will lead to a clinical trial designed to determine whether the specific vaccine design affords protection form HIV. They define each partner's responsibilities in areas where private sector and NIAID interests and priorities coincide. (Ideally, activities directed specifically toward licensure will be carried out with substantial private sector support, while NIAID resources will be directed toward test-of-concept and related fundamental research. These plans will not, of course, preclude other research independently supported by the company.)
The plans will contain the concept-specific milestones, options, and decision-making criteria to be applied at each major decision point. These milestones and criteria will be individualized, based on the general considerations outlined in the next section, the specific vaccine design in question, and the best available scientific information at the time they are determined. They will, of course, be evaluated and assessed by the partnership on an ongoing basis for their continued validity and usefulness. The plan, with its milestones and criteria, implies a commitment of resources and energy on the part of the collaborators to proceed accordingly, barring new important scientific information, opportunities, or unforeseen business/fiscal consideration on the part of either partner.
General Considerations on Developmental Milestones and Criteria - NIAID Perspective
Earlier attempts to define and utilize generic decision-making criteria applicable to all potential vaccine designs and circumstances proved extremely frustrating to investigators, vaccine manufacturers, and NIAID. The following discussion, therefore, outlines general principles of NIAID's current approach to the negotiation of the more specific criteria to be contained in these development plans.
ANIMAL MODELS: While animal model evaluations may provide an indication of clinical efficacy of a candidate vaccine, there is currently no ideal model of HIV disease in animals and, thus, no ideal standard animal model experiment. The specific animal model experiments and the criteria of safety and efficacy needed to advance a given candidate at various stages of its development will, therefore, require careful consideration, planning, and agreement. They should, however, be based on consideration of the likely mechanism(s) of action, safety and immunogenicity data from earlier studies, and other relevant considerations. Specific details in this regard will be an important component of each prospectively negotiated development plan.
PHASE I: Phase I testing provides a first opportunity to explore the normal volunteer's immune response to HIV antigens presented in the particular vaccine design. In general, NIAID is most interested in working with partners to initiate phase I studies of promising examples (candidates) of vaccine designs that have not previously been evaluated. There should be a plausible scientific rationale supported by basic and preclinical research, as well as evidence that the vaccine candidate is safe in small animals and, usually, nonhuman primates. (NIAID maintains limited resources to assist in generating these data.)
PHASE II: Phase II trials, which enroll a larger number of individuals (including some with a history of high-risk behavior) will provide additional information of safety and immunogenicity in persons similar to those who will be entered into efficacy trials and who, presumably, would use the licensed vaccine. The development plan will outline the specific criteria of immunogenicity and safety, which must be met in phase I trials in order to proceed into phase II.
DETERMINATION OF EFFICACY: The decision to proceed to a clinical trial of efficacy determination is a major one. The development plan will define specific criteria of efficacy and safety data from phase II and animal model experiments that must be met in order to proceed to further studies of efficacy. These criteria will be design-specific and will have been developed by the partnership in the course of earlier studies on the basis of the accumulated experience with the particular candidate. The criteria and modifications to them will be as objective and as specific as possible, may specify various contingencies depending on outcome, and will be agreeable to the partnership.
The development plan will also describe the scientific and logistical plans for potential efficacy trial(s), including the degree of certainty with which efficacy would be measured. The proposed trial(s) may provide a relatively precise measure of efficacy or, alternatively, may be designed to estimate the vaccine's effect within a broader range (e.g., a so-called intermediate or test-of-concept trial). While the latter approach may not necessarily lead to licensure of a specific vaccine product, it may be appropriate for the accumulation of preliminary data about the usefulness of the vaccine design and its worthiness for additional development. Furthermore, the fundamental knowledge gained from such trials will be important in making incremental progress toward the ultimate goal. The development plan may also specify several contingency options, depending on the outcome of phase II trials.
NIAID believes that HIV vaccine research and development should be specifically identified as the highest AIDS-related biomedical research priority of the NIH for the following reasons:
The worldwide need to develop an effective HIV vaccine is more urgent than ever. There are approximately 20 million individuals infected with HIV and 4.5 million AIDS cases worldwide. The African epidemic has cost over $30 billion and the United Nations estimates that AIDS will reduce Africa's overall labor force by as much as 25 percent by the year 2010. At the current rate, the impact on the world wide economy is estimated to reach $514 billion by the year 2000, and, in a worst case scenario, will rob the world of 1.4 percent of its gross product.
Identification of a safe and effective HIV vaccine will result in both financial and health benefits to the people of the U.S. It costs approximately $119,000 to care for each HIV-infected individual over his or her lifetime. The disease has already cost $75 billion, with $3 to $6 billion being spent on new HIV infections each year. Costs to life and health insurance industries were nearly %1.6 billion in 1994; claims since 1986 total an estimated $904 billion. Furthermore, it has been estimated that AIDS will have cost the U.S. economy $81 to $107 billion by the year 2000.
It is in the long range health interests of the U.S. to take a worldwide perspective on the need for an effective HIV vaccine. The dynamics of the epidemic in several developing countries provide opportunities to expedite progress in HIV vaccine research and development. The knowledge gained from such studies will benefit the entire world. Furthermore, new strains of HIV have now been documented.
Market forces do not currently foster an adequate level of private sector activity in empiric research; an increased commitment by the NIH may help boost investor confidence. Empiric research and development have traditionally been left to the private sector, which generally produces the products and contributes development expertise. In the case of HIV vaccines, however, the market forces that drive private sector investment decisions are not favorable. At the present time, private sector activity is skewed heavily toward smaller, less well-capitalized biotechnology companies that have insufficient resources to accomplish their goals. Most of the larger pharmaceutical companies are concentrating their efforts on potentially less risky and/or more profitable pursuits. Many companies involved in HIV vaccine research and development have either terminated their programs or cut back on their investment over the past 2 to 3 years. One international company with considerable experience in vaccine research and development maintains one of the world's largest and most active HIV vaccine programs with only substantial foreign government support.
There are a number of scientific opportunities beyond the limit of current resources that, if pursued, would significantly accelerate progress toward an HIV vaccine.
Basic and applied research
Advances in a number of areas of fundamental research could greatly facilitate the design and evaluation of potential HIV vaccines. In particular, research on correlates of immune protection, animal models, mucosal immunity, and HIV diversity are of the highest priority. The following summarizes a more detailed accounting of the key research needs and gaps described in the NIAID HIV/AIDS Research Agenda.
CORRELATES. There are currently several lines of research that could help identify the correlates of immune protection. Reports of adults and infants who have been exposed to HIV but are not infected have suggested that some individuals may be relatively resistant to HIV infection and/or have the capacity to clear the virus during the early stage of infection. A better system to identify and thoroughly evaluate exposed/uninfected individuals is needed. Recent reports of individuals in the earliest/acute stage of HIV infection have helped elucidate immune mechanisms that may play a role in the initial control of HIV infection. Most of these individuals have been identified because they experienced an acute viral syndrome. Methods to identify additional individuals in the acute stage, including those who do not experience symptoms, are needed. This should include the development of improved assays for viral detection and seroconversion, more frequent screening of individuals at high risk for infection, and referral of newly infected individuals to laboratories and clinics that can evaluate them and determine the impact of early therapeutic intervention. In addition, elucidating important host factors, particularly immune responses that predict outcome, would greatly facilitate the conduct of vaccine efficacy trials.
ANIMAL MODELS. Animal model research and the development of better animal models are two major areas of scientific opportunity. Additional work in animal models could expedite understanding of the correlates of immune protection. There is a pressing need for animal models that more accurately reflect human HIV disease and routes of exposure, particularly mucosal exposure, in order to improve the relevance of preclinical vaccine evaluation. Recent exciting data on pathogenic chimeric SHIV in monkeys and a report of HIV disease in a chimpanzee suggest that improved models can be developed. In addition, development of methods to obtain twin macaques could lead to extremely valuable experiments that define the immune correlates of protection from SIV infection/disease. Increased evaluation of promising vaccine candidates in standardized, comparative studies will facilitate advances in fundamental knowledge, as well as the selection of the most promising candidates for further study.
MUCOSAL IMMUNITY. While most vaccine concepts have focused on induction of systemic immune responses, candidate vaccines capable of inducing mucosal responses are being explored in several laboratories. Additional research on the role of mucosal immunity in the control of HIV infection and methods to induce mucosal immunity are needed.
HIV DIVERSITY. The genetic diversity of HIV is now well described and several laboratories are maintaining active surveillance in this country and in selected populations in other countries. Additional molecular characterization of HIV around the world would lead to a better understanding of the extent of genetic diversity. Equally important is accelerating research on the immunologic significance of this genetic diversity and the characterization of HIV serotypes. Research to identify common neutralizing antibodies and CTL epitopes should facilitate design of vaccines with broad protective ability. This can best be accomplished through improvement of humoral and cellular assays. In particular, improvements in standardization and quantification of CTL assays would facilitate study of the impact of genetic diversity on CTL activity.
Vaccine concept evaluation
There are also important opportunities to help ensure that innovative HIV vaccine approaches are pursued in preclinical and clinical evaluation in adequate number and in a timely manner.
The NIAID's AIDS Vaccine Evaluation Group is a comprehensive phase I/II clinical trials network. Most of what we know about existing vaccine candidates has come from work done by this group of outstanding investigators. The group's overall productivity and contributions to the field would be greatly augmented by the addition of a contract laboratory for performance of some routine immunologic and virologic assays needed to meet the milestones and time lines called for in the collaborative development plans. This would permit existing core and mucosal immunology laboratory investigators to expand research on innovative assays that require a centralized but creative academic research laboratory, and to devote greater attention to research dissecting human immune responses elicited by various vaccine approaches.
NIAID's Strategic Programs for Innovative Research on AIDS Treatment offers a model for innovative bench to clinic, multidisciplinary collaborations, which should be implemented to advance creative vaccine approaches. In these programs, groups of investigators would pursue iterative laboratory, animal model, and early clinical research on a particular novel vaccine design.
It is difficult for academic investigators to obtain funding for certain animal model, immunology, and toxicology studies needed to move a vaccine design from concept to early clinical product. Supplemental support for such work would help elicit greater private sector interest in and sponsorship of novel vaccine designs. Other important opportunities are discussed in the earlier section on animal models.
Finally, evaluation of vaccines to prevent perinatal transmission and pediatric AIDS offers opportunities to expedite the study of some promising approaches in humans and to develop more practical and cost-effective alternatives to zidovudine. To facilitate this research, NIAID has proposed the establishment of an international pediatric prevention trials network, which will require additional resources to implement.
Other opportunities
It would be desirable to attract more talented researchers, particularly immunologists, to the field of HIV vaccine research and development. Funding levels have not permitted the award of all high quality grant applications. Some more empiric vaccine research has been regarded as "too applied" within the current NIH system of peer review.
These problems would be helped by additional resources. Even within existing resources, however, progress could be made if HIV vaccine research and development were explicitly identified as the NIH's highest AIDS research priority. This would facilitate: 1) funding of more "pilot" or short-term/high risk projects under a variety of administrative mechanisms of grant and contract supplementation; 2) use of set-aside funds targeted towards awarding high priority and high quality investigator-initiated grants submitted in response to a broad vaccine-related program announcement; 3) changes in the emphasis of the NIH peer review system to place greater weight on programmatic relevance and applied research and development.
Finally, rapid mobilization of resources in response to pressing scientific need, implementation of new or expanded programs, facilitation of collaboration between researchers and across international borders, and provision of assistance, reagents, and other resources, could be greatly enhanced. This would best be accomplished through a master contractor that has science management expertise and the ability to quickly fund essential research under the direction of NIAID staff and as recommended by NIAID advisors.
Success in carrying out the research needed to reach the ultimate goal will require a partnership between scientists and the communities of individuals who are asked to participate in this research. Efforts are already underway to strengthen linkages with domestic and foreign communities of individuals at increased risk of infection and are described in some detail in the NIAID HIV/AIDS Research Agenda.
The likelihood of success will be increased by close coordination of NIH with private and public sector organizations that share its interest in HIV vaccine research and development. Both for-profit and non-profit organizations bring their own unique resources and skills to the overall endeavor. Like all public agencies, the NIH must (and should) operate under regulations and policies mandating peer review and competitive procurement. It is, as a matter of course, answerable to diverse constituencies that have conflicting visions of priorities and the government's role. Privately funded organizations, on the other hand, have fewer checks on spending, more sharply focused missions, and smaller and less diverse constituencies. They are, by definition and design, able to move more quickly, assume similar levels of risk more easily, and address certain pressing needs more rapidly. However, they lack the level, breadth, and stability of government/NIH resources. A more closely integrated effort, capitalizing upon the strengths of private and public efforts, could provide synergistic, complementary mechanisms of support and increase efficiency, productivity, and incentives for private sector investment in HIV vaccine development. The NIAID intends to devote considerable energy strengthening collaborative interactions with other public and private organizations (e.g., the Department of Defense, the Agence Nationale de Reserches sur le SIDA, Medial Research Council, UNAIDS {United Nations AIDS Program), International AIDS Vaccine Initiative (Rockefeller Institute), the Sabin Foundation).
Finally, NIAID proposes changes in its mechanisms for obtaining independent advice and guidance. We believe that this effort should involve a small group of widely respected and committed individuals with extensive relevant laboratory and field experience. They will meet regularly and will provide detailed guidance concerning NIAID's efforts, with special focus on those activities aimed at the empiric components of the Institute's program. The group will also have a key role in coordination beyond NIAID, where most efforts are directed to more empiric activities. This group will work with and/or through various other working groups of actively involved scientists and community representatives focused on more specific areas of basic or clinical research, such as the existing Vaccine Design Focus Group, the Correlates of Human Immune Protection Focus Group, the AIDS Vaccine Evaluation Group and HIV Advisory Allergy and Infectious Diseases Council, and the AIDS Research Advisory Committee (ARAC) will continue to provide broad program oversight and advice, including review of concepts for new vaccine initiatives.
The challenges confronting the identification of safe and effective HIV vaccine are enormous. The NIAID believes that the optimal strategy to achieving this goal involves four components: 1) maintenance of a program of scientific inquiry that advances a broad front of critical knowledge and a variety of vaccine designs through laboratory, animal and human research, which integrates fundamental research and empiric development; 2) encouragement of pharmaceutical/biotechnology industry collaboration; 3) identification of scientific opportunities and the resources required to exploit them; and 4) strengthening of relationships with other public and private organizations and communities at risk.