HIV vaccine

An HIV vaccine is a hypothetical vaccine against HIV, the etiological agent of AIDS. As there is no known cure for AIDS, the search for a vaccine has become part of the struggle against the disease.

The urgency of the search for a vaccine against HIV stems from the AIDS-related death toll of over 25 million people since 1981.^[1] Indeed, in 2002, AIDS became the primary cause of mortality due to an infectious agent in Africa (UNAIDS, 2004).

Alternative medical treatments to a vaccine do exist. Highly active antiretroviral therapy (HAART) has been highly beneficial to many HIV-infected individuals since its introduction in 1996 when the protease inhibitor-based HAART initially became available. HAART allows the stabilisation of the patient’s symptoms and viremia, but they do not cure the patient of HIV, nor of the symptoms of AIDS (Martinez-Picardo et al., 2000). And, importantly, HAART does nothing to prevent the spread of HIV through people with undiagnosed HIV infections. Safer sex measures have also proven insufficient to halt the spread of AIDS in the worst affected countries, despite some success in reducing infection rates.

Therefore, a HIV vaccine is generally considered as the most likely, perhaps the only way by which the AIDS pandemic can be halted. However, after over 20 years of research, HIV-1 remains a difficult target for a vaccine.

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Difficulties in developing an HIV vaccine

In 1984, after the confirmation of the etiological agent of AIDS by scientists at the U.S. National Institutes of Health and the Pasteur Institute, the United States Health and Human Services Secretary Margaret Heckler declared that a vaccine would be available within two years (Associated Press, 1984). However, the classical vaccination approaches that have been successful in the control of various viral diseases by priming the adaptive immunity to recognise the viral envelope proteins have failed in the case of HIV-1, as the epitopes of the viral envelope are too variable. Furthermore, the functionally important epitopes of the gp120 protein are masked by glycosylation, trimerisation and receptor-induced conformational changes making it difficult to block with neutralising antibodies. In February 2003, Vaxgen announced that their AIDSVAX vaccine was a failure in North America as there was not a statistically significant reduction of HIV infection within the study population (Francis et al., 2003). In November 2003, it also failed clinical trials in Thailand for the same reason. These vaccines both targeted gp120 and were specific for the geographical regions (Billich et al., 2001).

The ineffectiveness of previously developed vaccines primarily stems from two related factors. First, HIV is highly mutable. Because of the virus' ability to rapidly respond to selective pressures imposed by the immune system, the population of virus in an infected individual typically evolves so that it can evade the two major arms of the adaptive immune system; humoral (antibody-mediated) and systemic (mediated by T cells) immunity. Second, HIV isolates are themselves highly variable. HIV can be categorized into multiple clades and subtypes with a high degree of genetic divergence. Therefore, the immune responses raised by any vaccine need to be broad enough to account for this variability. Any vaccine that lacks this breadth is unlikely to be effective.

The typical animal model for vaccine research is the monkey, often the macaque. The monkeys can be infected with SIV or the chimeric SHIV for research purposes. However, the well-proven route of trying to induce neutralizing antibodies by vaccination has stalled because of the great difficulty in stimulating antibodies that neutralise heterologous primary HIV isolates (Poignard et al., 1999). Some vaccines based on the virus envelope have protected chimpanzees or macaques from homologous virus challenge (Berman et al., 1990), but in clinical trials, individuals who were immunised with similar constructs became infected after later exposure to HIV-1 (Connor et al., 1998).

The human body can defend itself against HIV, as work with monoclonal antibodies (MAb) has proven. That certain individuals can be asymptomatic for decades after infection is encouraging.

Clinical trials to date

17 vaccine candidates are in phase I trials and four in phase I/II. There is only one in phase III (the NIH/Department of Defense’s ALVAC vCP 1521 canary pox vector/AIDSVAX prime-boost vaccine trial now under way in Thailand).

Up to May 2000 over 60 phase I/II trials of candidate vaccines had been conducted worldwide. Most initial approaches focused on the HIV envelope protein. At least thirteen different gp120 and gp160 envelope candidates have been evaluated, in the US predominantly through the AIDS Vaccine Evaluation Group. Most research focused on gp120 rather than gp41/gp160, as the latter are generally more difficult to produce and did not initially offer any clear advantage over gp120 forms. Overall, they have been safe and immunogenic in diverse populations, have induced neutralizing antibody in nearly 100% recipients, but rarely induced CD8+ cytotoxic T lymphocytes (CTL). Mammalian derived envelope preparations have been better inducers of neutralizing antibody than candidates produced in yeast and bacteria. Although the vaccination process involved many repeated "booster" injections, it was very difficult to induce and maintain the high anti-gp120 antibody titers necessary to have any hope of neutralizing an HIV exposure.

The availability of several recombinant canarypox vectors has provided interesting results that may prove to be generalizable to other viral vectors. Increasing the complexity of the canarypox vectors by inclusion of more genes/epitopes has increased the percent of volunteers that have detectable CTL to a greater extent than did increasing the dose of the viral vector. Importantly, CTLs from volunteers were able to kill peripheral blood mononuclear cells infected with primary isolates of HIV, suggesting that induced CTLs could have biological significance. In addition, cells from at least some volunteers were able to kill cells infected with HIV from other clades, though the pattern of recognition was not uniform among volunteers. As canarypox is the first candidate HIV vaccine that has induced cross-clade functional CTL responses,

Other strategies that have progressed to phase I trials in uninfected persons include peptides, lipopeptides, DNA, an attenuated Salmonella vector, lipopeptides, p24, etc. Specifically, candidate vaccines that induce one or more of the following are being sought:

• broadly neutralizing antibody against HIV primary isolates;
• cytotoxic T cell responses in a vast majority of recipients;
• strong mucosal immune responses.

On December 13 2004, a large phase II clinical trial of a novel HIV vaccine began enrolling volunteers at sites in North America, South America, the Caribbean and Australia. The organizers were seeking 3,000 participants. The trial was co-funded by the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), and the pharmaceutical company Merck & Co. Inc. Merck developed the experimental vaccine called V520 to stimulate HIV-specific cellular immunity, which prompts the body to produce T cells that kill HIV-infected cells. In previous smaller trials, this vaccine was found to be safe and to induce cellular immune responses against HIV in more than half of volunteers.^[1]

V520 contains a weakened adenovirus that serves as a carrier for three subtype B HIV genes. Subtype B is the most prevalent HIV subtype in the regions of the study sites. Adenoviruses are among the main causes of upper respiratory tract ailments such as the common cold. Because the vaccine contains only three HIV genes housed in a weakened adenovirus, study participants cannot become infected with HIV or get a respiratory infection from the vaccine. It was announced in September 2007 that the trial for V520 would be discontinued after it determined that the vaccination was ineffective. [1] Additionally, it appears that V520 may have made recipients more receptive to infection by HIV-1. ^[2]

Organizers expected results in 2009, however in September 2007 declared the vaccine a failure. [2]

Novel approaches, including modified vaccinia Ankara (MVA), adeno-associated virus, Venezuelan Equine Encephalitis (VEE) replicons, and codon-optimized DNA have proven to be strong inducers of CTL in macaque models, and have provided at least partial protection in some models. Most of these approaches are in, or will soon enter, clinical studies.

Economics of vaccine development

A June 2005 study estimates that $682 million is spent on AIDS vaccine research annually.[3]

Economic issues with developing an AIDS vaccine include the need for advance purchase commitment (or advance market commitments) because after an AIDS vaccine has been developed, governments and NGOs may be able to bid the price down to marginal cost.[4]

Controversy

Some conservatives, such as Reginald Finger, M.D., M.P.H., a member of the Advisory Committee on Immunization Practices (ACIP) in the U.S., have stated that the Committee would have to carefully consider an HIV vaccine's effects on sexual activity. ACIP is a government committee linked to the Centers for Disease Control. ACIP is charged with advising the President on prevention of vaccine-related diseases. Dr. Finger's term expired in June, 2006.

Similar controversy has arisen in response to the recent introduction of the HPV vaccine, which prevents infection with certain strains of human papillomavirus, another sexually transmitted disease.

See also

• Subunit HIV vaccine

References

1. ^ ^{a b} Joint United Nations Programme on HIV/AIDS (UNAIDS) (December 2005). AIDS epidemic update (PDF). World Health Organization. Retrieved on 2006-01-20.
2. ^ Timberg, Craig. "AIDS vaccine may have raised risk of infection", The Washington Post, 2007-10-25. Retrieved on 2007-11-12. 

• Berman, P. W., Gregory, T. J., Riddle, L., Nakamura, G. R., Champe, M. A., Porter, J. P., Wurm, F. M., Hershberg, R. D., Cobb, E. K. and Eichberg, J. W. (1990) Protection of chimpanzees from infection by HIV-1 after vaccination with recombinant glycoprotein gp120 but not gp160. Nature 345, 622-625
• Connor, R. I., Korber, B. T., Graham, B. S., Hahn, B. H., Ho, D. D., Walker, B. D., Neumann, A. U., Vermund, S. H., Mestecky, J., Jackson, S., Fenamore, E., Cao, Y., Gao, F., Kalams, S., Kunstman, K. J., McDonald, D., McWilliams, N., Trkola, A., Moore, J. P. and Wolinsky, S. M. (1998) Immunological and virological analyses of persons infected by human immunodeficiency virus type 1 while participating in trials of recombinant gp120 subunit vaccines. J. Virol. 72, 1552-1576
• McCutchan, F. E. (2000b) Understanding the genetic diversity of HIV-1. AIDS 14, S31-S44
• Peeters, M. and Sharp, P. M. (2000) Genetic diversity of HIV-1: the moving target. AIDS 14, S129-S140
• Poignard, P., Sabbe, R., Picchio, G. R., Wang, M., Gulizia, R. J., Katinger, H., Parren, P. W., Mosier, D. E. and Burton, D. R. (1999) Neutralizing antibodies have limited effects on the control of established HIV-1 infection in vivo. Immunity 10, 431-438
• Romano, L., Venturi, G., Giomi, S., Pippi, L., Valensin, P. E. and Zazzi, M. (2002) Development and significance of resistance to protease inhibitors in HIV-1 infected adults under triple-drug therapy in clinical practice. J. Med. Virol.' 66, 143-150
• Specter, Michael. Political Science: The Bush Administration's war on the laboratory. The New Yorker. March 13 2006.
• UNAIDS (2004) Report on the global AIDS epidemic, July 2004

• Vaccines for Development
• Be the Generation - Information on HIV Vaccine Clinical Research in 20 American Cities
• Australian recruiter for HIV treatment studies
• Aids Vaccine Integrated Project (European Union research programme)
• AIDS.gov - The U.S. Federal Domestic HIV/AIDS Resource
• HIVtest.org - Find an HIV testing site near you
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