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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.

1 Difficulties in developing an HIV vaccine
2 Research achievements
3 Clinical trials to date
4 Economics of vaccine development
5 Controversy
6 References
7 External links

Difficulties in developing an HIV vaccine

In 1984, after the confirmation of the etiological agent of AIDS by Prof. Robert Gallo, 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 individuals 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.

Research achievements

Research supports the contention that a safe and effective vaccine is possible. Vaccines against other diseases where correlates were not known and where there were no ideal animal model have been developed.

Most HIV is transmitted heterosexually, which is known to be less efficient than parenteral exposure. Finally, individuals who become infected with HIV do not succumb to the disease for years even in the absence of anti-retroviral therapy, suggesting that the human immune system is capable of controlling HIV infection partially or temporarily.

Enormous effort has been put into understanding how HIV works; it has produced a number of approaches to vaccination, none of which have been effective. Methods attempted include recombinant proteins, synthetic peptides, recombinant viral vectors, recombinant bacterial vectors, recombinant particles, DNA vaccines to induce production of a specific antigen, and whole-killed and live-attenuated HIV, though these latter two have not progressed into clinical trials in uninfected individuals due to an unfavorable benefit/risk ratio. The role of broadly neutralising antibodies (NAb) is under investigation, although earlier results were discouraging. vaccines are used to investigate the HIV glycoproteins. Attacks on particular parts of the RNA code of the virus have shown some promise, such as those against the nef gene which regulates viral replication.

On November 16, 2004, researchers at the French Institut Pasteur announced that they had been able to induce antibodies to significantly block HIV from infecting human cells, an achievement hailed as an important step towards an HIV vaccine. (365gay.com)

On November 29, 2004, Wei Lu, Jean-Marie Andrieu, and colleagues at the University of Paris in France and Pernambuco Federal University in Recife, Brazil, tested a vaccine on 18 Brazilian patients whose T-cell counts stopped dropping after getting three under-the-skin injections of the tailor-made vaccine. Novel Vaccine Stops HIV

On December 1, 2004, Swedish media announced that a new vaccine will be tested on 40 volunteers. If the new method is successful, vaccinations will be performed in Tanzania next year.

On March 13, 2005, China announced it began human trials for an AIDS vaccine. 49 volunteers between the ages of 18 and 50 would receive the vaccine.

On April 14, 2006, Atlanta 12 uninfected volunteers are to start getting the newly developed HIV vaccine.

The burden of HIV-related disease and transmission in Africa demands that enhanced efforts be made to treat large numbers of infected people with antiretroviral drugs, despite the cost and the emergence of resistant strains, while effective preventative vaccines are developed. Also, access to care and the development of simplified monitoring schemes for positive and negative treatment effects, as well as effective planning on how to obtain and distribute HIV vaccines needs to be addressed. This will be an important step if a large scale phase III HIV-vaccine trial is to be effective (WHO-UNAIDS, 2001), as this may bypass what we saw with antiretroviral therapy, that drugs were initially widely used in only developed countries.

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 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]

The Merck vaccine 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.

Organizers expect that it will take approximately one and a half years to fully enroll volunteers into the study. NIAID and Merck expect the trial be completed in four-and-a-half years, with results anticipated in 2009. More information on enrollment can be found at HVTN's Web site.

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, 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 (CITE).

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 (CITE).

Conducting trials of HIV vaccines in the countries most affected by the epidemic is a challenge,[76] albeit one that has been successfully met in Thailand. When one or more HIV-1 vaccines is identified, the task will be just beginning. The next step will be ensuring access for populations where the need is the greatest. Currently, over 60 million people have become infected with HIV-1 and hundreds of millions are at risk. Many of these individuals have little access to medical care, no access to adult vaccinations and live in countries where the per capita expenditure on health care is a few dollars.

Often, HIV-1 is ill understood and stigmatized. Diagnostic tests or algorithms may need to be altered. Education will be needed to convey not only the value but the anticipated limitations of the vaccines, so that other preventive strategies will be maintained. The role of community organizations in maintaining this balance will be critical (www.avac.org). Regulatory approvals in numerous countries will be required. The issues in the USA are complex.[77] Internationally, there are greater challenges. If a vaccine has not been demonstrated to be universally effective against every HIV-1 subtype, the standard paradigm of approval in one or more industrialized countries followed years or even decades later by acceptance in and distribution to developing countries will not apply. Both the governments of countries affected by HIV-1 and the international regulatory and health authorities must plan ahead for the advent of an HIV-1 vaccine to avoid unnecessary delays.

HIV-1 vaccines might induce antibody responses that would completely prevent HIV-1 infection by strains of virus that are sufficiently well matched to the vaccine. Unfortunately, HIV-1 evolves continuously both within an individual (the source of infection) and within human populations. Therefore, a vaccinated person might be protected initially, but later encounter a virus against which he or she is not immune. Multivalent vaccines or repeated immunization with an updated vaccine may be required for continued protection. Thus, eventually, one might imagine licensure not of a specific HIV-1 vaccine but of a method for producing the vaccine and its updated versions, somewhat analogous to the annual updates of influenza vaccine.

The scientific challenges involved in discovery of a safe and effective vaccine against HIV-1, although daunting, are only the prelude. The task of developing and deploying a vaccine against HIV-1 will be enormous (i.e. gaining licensure and scaling up to produce vaccine for worldwide distribution, developing distribution methods and establishing purchase mechanisms will require an unprecedented co-operative effort by governments, international agencies, philanthropic organizations and the private sector).[78] Recent recognition of the importance of controlling HIV-1 for public health, economic and political stability has been encouraging and there has been substantial growth in academic, government, nonprofit and pharmaceutical industry vaccine research, but the fight is not over. Stopping the march of the pandemic will conserve economic and human resources needed to care for those already infected. Ending the HIV-1 epidemic is critical to allow economic development and promote political stability in the developing world and to reduce loss of life and suffering worldwide.

Controversy

Reginald Finger, M.D., M.P.H., a member of the Advisory Committee on Immunization Practices (ACIP) in the U.S., has stated that the Committee would have to carefully consider an HIV vaccine's effects on sexual activity.

In an interview with Michael Specter of The New Yorker^[2], he said:

"'We would have to look at that closely ... With any vaccine for H.I.V., disinhibition ... would certainly be a factor, and it is something we will have to pay attention to with a great deal of care.'"

Disinhibition is a "medical term for the absence of fear," in this case, fear of sexual activity.

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.

ACIP is an influential 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.

References

^ ^a ^b Joint United Nations Programme on HIV/AIDS (UNAIDS) (December 2005). AIDS epidemic update (PDF). World Health Organization. Retrieved on 2006-01-20.
^ Michael Specter (March 2006). The Bush Administration's war on the laboratory. The New Yorker. Retrieved on 2006-08-20.

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

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