AIDS Vaccine Development: Challenges and Opportunities
"essential reading" (J. Clin. Invest.)
Caister Academic Press
, Patricia Kahn1
and Ian D. Gust2
1International AIDS Vaccine Initiative, New York and 2University of Melbourne, Australia
xiv + 151
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The HIV/AIDS pandemic is the most devastating global public health crisis since the great plagues of the middle ages, with more than 14,000 new HIV infections and 8000 deaths due to AIDS every day. Although successful vaccines have been developed for the common childhood diseases the development of a vaccine against the AIDS virus is a much greater challenge. More than 20 years after the discovery of the virus the goal of a licensed and globally accessible vaccine is still several years away.
This book reviews the scientific challenges that have impeded the search for an effective AIDS vaccine and discusses current novel research that is accelerating progress. In a series of mini-reviews by the world's leading experts in AIDS vaccine research the book is essential reading for everyone interested in the current progress and future direction of AIDS vaccine development.
"I think that everyone involved in the HIV/AIDS research vaccines should have a copy of this book in his/her library." from Sylva Petrocchi, Policlinico San Matteo, Pavia, Italy.
"As a welcome and indeed valuable addition, "AIDS Vaccine Development" avoids undue intellectual acrobatics, relying instead on an intensely understandable, informative and thought-provoking approach. The volume stands to be an extremely useful acquisition for any library collection wishing to ensure a modern, advanced and readable resource for those interested in AIDS vaccine development." from ASM Microbe.
"a good source of information on the state-of-the-art of HIV vaccine development ... interesting and informative" from Future HIV Ther. 1: 29-33.
"This easy to read book gave me a new appreciation for the enormous problems associated with developing an effective vaccine to HIV. It is unique in that it covers all aspects of the impact of this global problem and the benefit of preventing the disease with vaccines. It takes readers from the global problem of disease through the search for a solution." from Doodys
"This timely book reviews in considerable detail the numerous scientific challenges and problems that have made the search for an effective AIDS vaccine so far unsuccessful. The editors have secured the help of over 40 internationally known experts in AIDS vaccine research and have assembled a 19-chapter volume that is essential reading .... The book contains about 500 scientific references and a wealth of up to date information. It is highly recommended ..." from Archives of Virology (2007) 152: 1045.
"... excellent and readable book ... I recommend it to graduate students and specialists alike." from Microbiology Today (2007).
"... essential reading for a wide variety of audiences interested not only in HIV and AIDS but also in vaccine research, development, and deployment in general." from J. Clin. Invest. (2007) 117: 1736.
Table of contents
Wayne C. Koff and Ian D. Gust
No abstract is available for this chapter, so we present the first paragraph of the introduction. The need for a safe and effective vaccine to prevent AIDS is obvious. Twenty years since HIV was identified as the etiologic cause of AIDS, the WHO-UNAIDS joint program estimates that nearly 40 million people were living with HIV/AIDS and over 3 million died in 2005 alone, and ten new infections occur every minute-the vast majority in the developing world. AIDS is having a dramatic effect on economic activity and life expectancy in many countries, while the pandemic continues its insidious spread: it is estimated that over 100 million more people will become infected in the next two decades if a safe and effective vaccine does not become available.
2. The Global HIV/AIDS Epidemic
Marjorie Opuni, Bernhard Schwartländer, J. Ties Boerma, and Karen Stanecki
Over 65 million people have been infected with HIV since AIDS was first recognized in 1981, and over 25 million of them have died. AIDS is thus the worst epidemic to strike humanity in recorded history. This chapter provides an overview of the HIV and AIDS epidemic by region, highlighting epidemiological trends, the genetic diversity of HIV and differences in the modes of HIV transmission. It then discusses the need for an AIDS vaccine as well as the components of expanded responses to HIV/AIDS and how these can curb the epidemic and its impact.
3. Biology of Early Infection and Impact on Vaccine Design
S. B. Justin Wong and Robert F. Siliciano
Recent studies are providing insights into the early events following exposure to HIV-1, knowledge that is important for the design of preventive vaccines. This chapter summarizes current understanding of these events, with the goal of defining more precisely the "point of no return" after which immune responses cannot eradicate HIV. One key early step is a rapid exponential expansion of the virus population, which occurs as soon as HIV reaches tissue sites with high concentrations of susceptible CD4+ T-cells. Preventing this initial expansion is likely to be critical for achieving sterilizing immunity with vaccines, since once high-level viremia is present, a stable virus reservoir is established in resting memory CD4+ T-cells, which precludes eradication even with potent antiretroviral drugs. For these reasons, vaccine development should focus on preventing HIV from initially accessing crucial tissue sites.
4. CTL-Based Vaccines: Evidence for Efficacy in Animal Models and Humans
Jaap Goudsmit, Johannes Antonie Bogaards and Marc Girard
Nearly all candidate AIDS vaccines now in clinical development are designed to stimulate the cellular arm of the immune system, in particular the CD4+ and CD8+ T-cell compartments. Accumulated evidence suggests that these responses will not prevent infection with HIV but may suppress viral replication once infection has occurred, in turn delaying progression to clinical AIDS. In this article we review some of the data from the rhesus macaque/SIV/SHIV model and from natural history studies of HIV-infected people, and discuss how useful CTL-based vaccines are likely to be. Key uncertainties include the longevity of protection by, and the likelihood of viral escape from, HIV-specific CTLs. From the data available we predict that effective suppression of viral load can provide significant clinical and public health benefits, if an even modestly effective CTL-based vaccine is made available as early as possible.
5. What Does A Vaccine Need to Do to Elicit Protective Immunity Against HIV Infection?
Paul Thottingal and Sarah L. Rowland-Jones
The unique challenges of generating an effective vaccine to prevent HIV-1 infection have led immunologists to consider in detail the mechanisms of protective immunity that a successful candidate must elicit. This article reviews our current understanding of protective immunity to HIV-1 infection, based on studies of animal models and of exposed but apparently uninfected people.
6. Antigen Selection and the Design of an AIDS Vaccine
John R. Mascola and Gary J. Nabel
Among the many scientific hurdles and uncertainties facing AIDS vaccine development, we are still learning how to optimize immunogens and vaccination strategies to elicit protective HIV-specific immune responses in humans. Many vaccine prototypes have been studied in pre-clinical and Phase I studies, most based on reasonable assumptions about the need to induce HIV-1 specific CD8 T-cell immunity and/or neutralizing antibodies. This chapter provides an overview of the rationale for the choice of immunogens to include in a candidate vaccine and of strategies to optimize their efficacy.
7. Broadly Neutralizing Antibodies and a Vaccine for HIV
Suganya Selvarajah and Dennis R. Burton
HIV vaccine developers increasingly believe that the best protection against HIV/AIDS will probably require both cellular immunity and antibodies that neutralize a broad range of viral strains. However, designing immunogens that elicit such antibodies has emerged as one of the most challenging problems facing the field. This article reviews these challenges, most of which pertain to the structural features of the HIV envelope (gp120 and gp41). It also describes several strategies being pursued to overcome them by favorably presenting conserved epitopes that have been identified as targets for broadly neutralizing antibodies. However, success will require considerable progress in understanding the structure of Env and its interaction with neutralizing antibodies, in identifying new neutralizing monoclonal antibodies that can fuel this research, and in immunogen design.
8. Vaccines that Induce Cellular Immunity
Britta Wahren and Margaret A. Liu
The ability to induce cell-mediated immunity (CMI) is widely thought to be an important property of any potential AIDS vaccine or immunotherapy. The rationale is based on many observations, including: (1) a demonstrated role for CMI in containing HIV after infection; and (2) the ability of T-cells to target viral epitopes that may be more highly conserved amongst different strains (both intra-clade and cross-clade) than the Env structures that have been evaluated clinically as potential vaccine immunogens. This chapter examines the design issues specific for vaccines intended to induce cellular immunity against HIV/AIDS, discusses characteristics of these approaches (most of which are gene-based) and gives an overview of the different candidates under development.
9. Alternate Routes on the Roadmap to an HIV Vaccine: Importance of Innate and Adaptive Mucosal Immunity
Kenneth L. Rosenthal
HIV is a mucosally transmitted virus that rapidly targets and dramatically depletes activated CD4+ CCR5+ T-cells in mucosal tissues and establishes a major reservoir for viral persistence in gut-associated lymphoid tissues. Several lines of evidence implicate mucosal responses in immune protection against HIV (and SIV), which argues that HIV vaccine development should be re-oriented to emphasize mucosal immunization routes that induce long-term innate and adaptive mucosal responses.
A growing body of knowledge and methods can accelerate progress towards this goal. Recent advances in our understanding of innate immunity have ushered in a new era of studies on vaccine adjuvants that promote mucosal responses when used with a variety of candidate vaccines (including some based on recombinant vectors that target the mucosa) and are proving effective at inducing durable mucosal immunity in mouse models. At the same time, advances in immunogenomics and proteomics are providing opportunities to discover novel genes and molecules involved in vaccine-induced mucosal immunity, while new assays that permit simultaneous measurement of multiple immune responses will greatly facilitate the assessment of mucosal immunity in the context of HIV vaccine trials.
10. HIV Subtypes, Antigenic Diversity, and Vaccine Design
Bette T. Korber, Catherine C. Miller, and Thomas K. Leitner
The variation of HIV-1 on the individual level, between individuals, and between different subtypes is considered a major obstacle in HIV-1 vaccine design. HIV-1 subtypes, or clades, are clearly distinguishable genetic classifications of HIV. Recombination is an inherent aspect of HIV evolution, and inter-subtype recombinant forms are frequently found in regions of the world where multiple forms are co-circulating. Vaccine reagents, to be useful, must elicit immune responses that are cross-reactive in the context of this complex backdrop of diverse strains. There are no clear and general genotype-serotype relationships between sequences and neutralizing antibodies. T-lymphocyte responses to HIV cover the spectrum from subtype-specific, to diminished but detectable inter-clade responses, to broadly cross-reactive. While the relative merits of developing HIV-1 subtype-specific vaccines for different proteins are as yet unresolved, given the polyclonal and host specific nature of the immune response, regional subtype appropriate vaccines may be helpful for maximizing the set of potential cross-reactive responses between vaccine strains and the circulating population. Different strategies for vaccine design that attempt to contend with diversity are discussed.
11. The HIV Vaccine Pipeline
Since the first human trial of an HIV candidate vaccine was conducted in 1987, the HIV vaccine pipeline has experienced an important evolution. The first wave of candidate vaccines, based on the concept that neutralizing antibodies were capable of conferring protection against HIV/AIDS, lead to the development of the first generation of envelope vaccines, mostly based on gp120. The second wave was guided by the paradigm that cytotoxic T-cells (CTL) were responsible for protection, and candidate vaccines were developed based on live recombinant viral vectors and naked DNA. The third wave is just starting, with the recognition that a highly effective preventive vaccine may have to induce both broadly reactive antibodies capable of neutralizing primary isolates of HIV, as well as long lasting cross-reactive CTL. Different candidate vaccines and combinations are now in the pre-clinical pipeline, and some of them are already moving to clinical trials.
Novel approaches, such as the use of structural biology, or a more careful consideration of HLA-escape epitopes, promise a new era of more rational vaccine design. With the availability of larger numbers of candidate vaccines, a more systematic approach to expand and explore the pipeline is needed. This requires the standardization of reagents, techniques and criteria to move candidate vaccines through the pipeline in a comparative fashion, including immunogenicity assays and animal protection experiments. It is also increasingly recognized that carefully designed efficacy trials (Phase IIb or Phase III) are essential for the identification of immune correlates of protection, information that would accelerate the future development or improvement of HIV vaccines.
12. Clinical Site Development and Preparation for AIDS Vaccine Efficacy Trials in Developing Countries
Patricia E. Fast, Jean-Louis Excler, Mitchell Warren and Nzeera Ketter
Experience over the past decade shows that high-quality AIDS prevention trials can be successfully conducted in resource-poor settings. For example, Thailand successfully conducted the world's second AIDS vaccine trial, and in 2003 launched another one, while a smaller (proof-of-concept) efficacy study is ongoing in non-industrialized countries, In addition, nearly a dozen developing countries have cumulatively helped carry out over 20 Phase I and II studies. However, preparation for clinical trials in research-poor settings requires significant investment in infrastructure, equipment, training and health care for local communities. It also entails creating an "enabling environment" by building political support and partnerships with community organizations, engaging the media to reach out to the community-at-large, and (in some countries) clarifying regulatory pathways. Most of all, trials require a committed team of effective local scientists and staff and (particularly in the initial phases) experienced clinical trials professionals. More capacity for clinical trials of HIV vaccines and other prevention methods is still needed in resource-poor settings hit hard by the AIDS epidemic. The time to build this capacity is now.
13. Issues in the Design of HIV Vaccine Efficacy Trials
Steven G. Self
This chapter discusses several issues in the design of HIV vaccine efficacy trials. It first describes how primary objectives are formulated for Phase IIB and Phase III studies and how they are used to determine the numbers of volunteers needed for these designs. The discussion then turns to primary efficacy endpoints, and to why and how they differ from those typically used in efficacy trials for other vaccines. Two possible designs for "nested" studies to examine immunologic correlates of protection against HIV/AIDS are described, along with some potential pitfalls in interpreting them. The chapter concludes with some guidelines for planning analyses of subgroups within trial cohorts and for determining the proportion of volunteers to allocate to vaccine versus placebo groups.
14. Lessons from the AIDSVAX B/B' Vaccine Efficacy Trial
Susan P. Buchbinder and Jonathan D. Fuchs
We have much to learn from the North American Phase III trial of VaxGen's AIDSVAX B/B' vaccine, even though the vaccine proved to have no overall efficacy in preventing HIV-1 infection. The trial was statistically well-powered to provide clear answers on its primary and secondary endpoints, and met its goals in recruiting and retaining volunteers over the three-year study. Unfortunately, premature release of data suggesting vaccine efficacy in certain racial subgroups of the study population (based on statistically unadjusted analyses) caused considerable confusion in the field and the general public. It also highlighted the importance for future trials of selecting the most important subgroup analyses in advance and ensuring that the study has adequate statistical power to resolve them clearly. And it spotlighted the need to enroll volunteers reflecting the diversity of at-risk populations, and to utilize broad biostatistical expertise before releasing results to the media.
15. The Thai VaxGen Trial: What Have We learned?
One year after VaxGen launched its Phase III vaccine trial in 5,000 North Americans and Europeans at risk for sexual transmission of HIV (Chapter 14), a second trial began in 2,500 intravenous drug users in Thailand. In November 2003, analysis of final results from the Thai trial showed clearly that the gp120-based AIDSVAX vaccine had no efficacy in this population, in agreement with results from the first Phase III study. Despite these disappointing findings, the trial yielded invaluable information about conducting large-scale studies in IDU populations-something many researchers thought could not be done-and offers compelling insights into the conduct of future efficacy trials in developing countries.
16. Regulatory Issues for AIDS Vaccine Development
The development and licensure of a successful HIV vaccine involves meeting various regulatory requirements that were put in place to protect individuals from unsafe or ineffective pharmaceutical products. Regulatory agencies such as the U.S. Food and Drug Administration (FDA), the European Agency for the Evaluation of Medicinal Products (EMEA) and the South African Medicines Control Council must approve vaccine products before they are tested in clinical trials or licensed for general use. Approval is based on a scientific assessment of risks and benefits, and involves a review of manufacturing, preclinical and clinical information. In this article I discuss possible ways to expedite regulatory approval at all stages of development and to involve regulatory agencies in the development process-important steps in reducing the time it will take until an effective HIV vaccine can become widely available.
17. Vaccine Scale-Up and Manufacturing
Donald F. Gerson, Bhawani Mukherjee and Rattan Banerjee
It is not true that if you make a small machine that works, and then make a larger one in exactly the same way with the same materials, that it will also work. (Feynman, 1994). In vaccine development, the laboratory process for producing a test antigen during the discovery phase cannot be used to make vaccines at large manufacturing scale. Rather, detailed experimentation is needed to ensure that the product can be made reproducibly-not 3 times but 3 billion times over a span of many years.
Vaccine manufacture and licensure are facility, equipment and process-dependent; in other words, the process defines the product. Creating a robust, reproducible manufacturing process is therefore key to licensure and to ensuring a long-term supply of high-quality vaccine. This article describes the complexities of scaling up vaccine production from the laboratory to the factory, reviews the technologies needed to manufacture different categories of AIDS vaccine candidates, and discusses various models for financing manufacture in ways that promote vaccine access in the world's poorest regions.
18. Global Access to Vaccines: Deployment, Use and Acceptance
Jon Kim Andrus and Ciro A. de Quadros
Rapid introduction of a safe and effective HIV vaccine will be critical for curbing the global HIV epidemic and the massive number of deaths from AIDS. The slow "trickle-down" process by which new vaccines from developed countries have historically been introduced into developing nations must be circumvented once an effective HIV vaccine is licensed. This article examines some of the obstacles that impede widespread access to vaccines, and then draws upon the lessons learned to formulate a set of recommendations for achieving rapid global access to a future AIDS vaccine.
19. The Potential Public Health Impact of Imperfect HIV-1 Vaccines
Roy Anderson and Stanley Plotkin
The many biological uncertainties regarding vaccination against HIV make it likely that the first available vaccines will be only partly effective. The most likely scenario is that these vaccines may not prevent the establishment of infection, but instead might work by reducing viral load and transmission to sexual partners. Mathematical models indicate that such partially effective vaccines will be valuable only if protection is long-lasting and risk behaviour amongst vaccinees does not increase greatly. Therefore, once efficacy is demonstrated in a controlled trial, long- term follow-up will be necessary to determine vaccine effectiveness. Another issue is the effect of vaccination on viral load if vaccinees become infected, with current data suggesting that decreasing viral load would delay the onset of disease and greatly reduce transmission. Despite some caveats, suboptimal vaccines that give persistent sterile immunity or that slow disease progression and diminish transmission could have major public health benefits if properly used, particularly in mass vaccination campaigns.
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(EAN: 9781904455110 9781913652326 Subjects: [virology] [microbiology] [medical microbiology] )