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AIDS Vaccine Research

2002 Edition, February 22, 2002

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Active, Most Current

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ISBN: 978-0-8247-0645-6
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Product Details:

  • Revision: 2002 Edition, February 22, 2002
  • Published Date: February 22, 2002
  • Status: Active, Most Current
  • Document Language: English
  • Published By: CRC Press (CRC)
  • Page Count: 357
  • ANSI Approved: No
  • DoD Adopted: No

Description / Abstract:

Preface

There is perhaps no greater need in medical science at the inception of the 21st century than the development of a preventive vaccine against HIV (see Chapter 1, by Gary Nabel). It seems paradoxical that a human pathogen that medical science knows more about than virtually any other causative agent remains without a solution (Chapter 2, by Oren Cohen and Anthony Fauci, provides insight into this statement). Yet, we can draw from many analogies. We may understand everything about a mountain but not be able to reach its summit until there is a new technological advance. Is that the current situation with AIDS? Do we have the essential information and multiple tempting pathways but no sure compass to reach the top? Or is a major piece of information missing? There is no way for us to give an honest answer. It is possible that a partially—or even completely— successful preventive vaccine against HIV will be developed within the next five years, but it is also possible that this will never be achieved. However, reality is likely to lie somewhere between these two extreme predictions. Our best estimate is that we will have a partially effective vaccine before this decade ends.

There has been some debate about what a vaccine must accomplish. Some have argued that a vaccine must be able to completely prevent HIV infection (‘‘sterilizing immunity''). Others, however, have argued that we can strive for a more limited and realistic goal: a vaccine that prevents disease but not infection. Indeed, this is the view of several of the authors of this book. Since sterilizing immunity seems out of reach, infection without disease would appear to be an acceptable alternative. However, this concession may be premature. We do not think there has been sufficient time or enough studies to justify giving up on the greater challenge of full prevention. Furthermore, one can never be sure that any infection will not ultimately lead to disease, and it would require decades of follow-up to obtain that information. Meanwhile, the premature belief that a vaccine has been effective may lead to increased risky behavior, and consequently greater incidence of infection. Of course, the opposite is also true: a vaccine that is not completely protective but reduces the amount of virus should help reduce transmissibility and ameliorate disease progression. The problem is in knowing which of the two scenarios will prevail.

What, then, are the major obstacles to the development of a preventive vaccine? They include at least the following:

1. The fact that HIV is a retrovirus, which upon infection rapidly integrates its DNA form into the host cell's chromosomal DNA, leading to persistent infection for the life of that cell and all its progeny. Thus, controlling the infection requires not only prevention of further virus spread but also destruction of the infected cells.

2. The lack of a small, readily available animal model. The only useful animal models currently involve primates infected with a simian virus (SIV) or chimeric virus (SHIV), rather than HIV-1. These primate model systems are not readily accessible to all investigators, and the results take a long time to generate.

3. The genetic variability of HIV means that an effective vaccine must be broadly active to prevent the emergence of resistant viruses (see Chapter 3, by Vladimir Lukashov, Jaap Goudsmit, and William Paxton).

4. The virus can destroy the immune system and render it ineffective.

5. HIV can co-opt the very same immune activation pathways required for successful vaccination for its own replication once infection is established.

6. There is a dearth of large companies dedicated to this pursuit, owing to the difficulty of the problem, the need for a prolonged research programs, and potential financial risk.

If we were able to achieve an early vigorous immune response that leads to virtual sterilizing immunity, obstacles 1, 4, and 5 would be irrelevant. Similarly, viral resistance would not be an issue, especially if appropriate epitope enhancement is possible (see Chapter 6, by Jay Berzofsky, Jeffrey Ahlers, and Igor Belyakov). Therefore, the only significant scientific problem left is the availability of a good animal model. We do not subscribe to the argument that because SIV is not HIV the monkey model is irrelevant. Rather, SIV—and better yet, SHIV— infection of rhesus macaques seems to be quite applicable (Chapter 11, by David Pauza and Marianne Wallace). Indeed, greater availability of this model system to scientists could be the single most important factor facilitating vaccine development. If applications of successful basic science at academic centers would not be hampered by logistical difficulties such as the need for scale-up in vaccine production, FDA approval, available target populations, and funding for population trials, then interest from the pharmaceutical industry would certainly follow. Some of these latter issues are being tackled by the International AIDS Vaccine Initiative (IAVI) (see Chapter 12, by Seth Berkley). There is no doubt that IAVI will make a great impact on HIV vaccine research and development, complementing other strategic programs at the academic centers and the National Institutes of Health.

We come to the real crux of the issue: how to develop a sufficiently early and vigorous response to HIV infection to achieve marked, if not complete, HIV suppression. This concept is the focus of most HIV vaccine research today. Mucosal immunity mediated by cytotoxic T cells is considered a key component of an effective vaccine and is generally achieved by using DNA vaccines encoding several HIV proteins. This may be done by direct inoculation of naked DNA or by using other recombinant viruses or vectors (Chapter 7, by Harriet Robinson). Alternatively, ‘‘crippled'' forms of HIV itself may be used when pseudotyped with genes encoding envelope-like proteins from other viruses (Chapter 8, by June Kan-Mitchell and Flossie Wong-Staal). The current (and readily mutable) strategy at the Institute of Human Virology (IHV) is the combination of: 1) a carrier of HIV genes that facilitates mucosal immunity against HIV using modified Salmonella or Shigella (Chapter 9, by George Lewis, Tarek Shata, and David Hone); 2) tat toxoid, i.e., a modified, biologically inactive Tat delivered as a protein or as a gene in a bacterial carrier—tat is an important extracellular toxin that facilitates HIV spread and suppresses the immune response to HIV (Chapter 11, by David Pauza and Marianne Wallace); and 3) a gp120-CD4 chimeric protein for eliciting high serum levels of broadly neutralizing antibodies as evidenced by studies by Anthony DeVico of the Institute of Human Virology in primate, rodent, and ungulate studies.

What we are missing is a sure way to produce an almost immediate anti- HIV response. One way to achieve this would be to markedly enhance production of the anti-HIV β-chemokines because they are made within a few hours of lymphocyte activation until neutralizing antibodies (weeks) and killer T cells (days) are available to finish the task. Alternatively, we may learn how to make a vaccine that maintains a sufficiently high level of potent antibodies and CTLs so that exposure to HIV at any time will not lead to infection. We do not yet know how to achieve either of these goals. Regarding innate immunity, however, work by Thomas Lehner and his colleagues (Chapter 10) has led to the revelation that certain heat-shock proteins stimulate β-chemokine production, and that this correlates with protection in the SIV/monkey model. Although this is not practical for an HIV preventive vaccine, it is an interesting beginning.

No preface to a book on HIV vaccine development is complete without mentioning the remarkable progress made over the last five years or so in our understanding and appreciation of the cellular immune response to HIV and its impotant role in any HIV vaccine. This book includes two chapters by leaders in the field (Chapter 4, by Toma´sˇ Hanke and Andrew McMichael, and Chapter 5, by Guislaine Carcelain, Lucile Mollet, and Brigitte Autran).

None of us can predict when a truly successful HIV preventive vaccine will be developed. What we can predict is that this book is a timely telling of where the field stands and should provide the reader with a clear perspective on the challenges to the biomedical research community.