Research Initiative Treatment Action (RITA!); Vol 5, No. 1 January 1999
Dorothy Lewis, PhD
The title of this article, "Vaccine to Prevent AIDS," like the vaccine that it promotes, offers way too much promise. The vaccine, as designed, is highly unlikely to prevent AIDS transmission. Vaccines by their nature must induce an appropriate and sufficient response capable of providing protective immunity. The principle component of this vaccine is intended to induce immune responses against the envelope protein, gp120. Unfortunately, because gp120 is highly mutable—that is to say, it can change in form easily—it may not elicit the necessary response required for its success.
In addition, immune responses to the gp120 protein are primarily directed toward an immunodominant region, the so-called V3 loop. The function of this region is to act as a decoy and therefore antibodies and cell-mediated immunity to this protein are unlikely to deliver the specific protective immunity required to keep a person from contracting HIV upon exposure.
In fact, a recent article in Science shows that immune responses made to determinants exposed during the process of fusion are more likely targets for eliciting the correct immune response. When the envelope protein of the virus (gp120) binds to the surface molecules of the immune cell (CD4) and the process of fusion begins, the virus exposes certain previously hidden parts of itself (antigens) as the viral envelope make the necessary changes to complete fusion with the cell. Early research indicates that targeting these determinants could result in a vaccine with broad neutralization capabilities. (R.A. LaCasse et al., Science 283:357, 1999). These determinants are, perhaps, the more appropriate targets for a protective vaccine. They are more stable and more predictable.
While the results achieved with the gp120 vaccine are hopeful, science cannot yet state with certainty what constitutes protective immunity against HIV. In contrast to the mentioned success of other viral vaccines, designing one to HIV has proven a much more difficult and elusive endeavor. Most of the highly successful preventive viral vaccines are produced by immunization with live attenuated viruses—viruses that have been weakened to the point of being unable to cause disease. Indeed, the two vaccines mentioned in the opposing article—small pox and polio—represent successful but also exceptional viral vaccines. Both are based on live attenuated strains that have been weakened significantly; but it should be noted that despite their attenuation they can still cause problems for immunoincompetent hosts and do result in disease in a few individuals.
The potential threat of a weaken live attenuated vaccine can sometimes be avoided by the creation of a subtype vaccine. Subtype vaccines are produced with genetically engineered proteins, thus eliminating the potential hazards of a live vaccine. Some subtype vaccines have been successful but their usage has limitations as well. The prototype subtype vaccine is that created against Hepatitis B. Hepatitis B is a DNA virus that does not mutate as much as HIV and is controlled by an immunodominant response. This is clearly not the situation presented by HIV.
There is no dispute that vaccines are the most effective way to deal with viral pathogens. The vaccine must, however, be targeted properly and produce sufficient immune response as to eliminate the risk of contracting HIV. Given the nature and design of this vaccine it is highly unlikely that the intended result will occur.
Indeed, the article hints at its potential failure by reiterating warnings about safe sex, emphasizing to potential trial participants that this vaccine may not protect them from acquiring HIV during unprotected sex. One possible positive outcome is that pre-existing immune responses in at-risk people may slow HIV down. That type of outcome might prove to be significant.
Unquestionably, the vaccine cannot cause AIDS and trials using its formulation have proven it safe. There is, however, a more insidious potential danger to the participant. By stimulating the production of antibodies to HIV the participant receiving the vaccine will test positive on an HIV antibody test. Living in a country where testing positive for HIV is still a social and political stigma, despite the efforts of many, the incidental seroconversion of the participant could be a detriment. Will such illusionary test result be used to deny medical coverage, or life insurance coverage? This is only likely to be a problem in this country and not elsewhere given the informed nature of much of our high-risk population.
The article claims that chimpanzees are protected from HIV by this vaccine. While the facts of that claim are not in dispute, it is important to analyze the subliminal message of this statement. This claim of protection assumes that what happens in chimpanzees also happens in humans. HIV in chimpanzees is not pathogenic—that is, HIV does not result in harm or disease in chimpanzees. Hence, the fact that this vaccine prevents infection in chimpanzees is not significant because the chimpanzee is not a relevant infection model for HIV in humans.
This vaccine has been given to many human volunteers, yet the information about the quality of the immune response generated in these human volunteers, especially cell-mediated responses are not reported. Many in the scientific community believe that cell-mediated responses are critical to the control of HIV in humans. This study should offer this efficacy information to enable the volunteer to make a truly informed decision.
It is unlikely this vaccine will be effective at preventing HIV infection. The uncertainty of the efficacy and/or the level of protection offered by this vaccine makes it imperative for trial participants to understand truly the nature of their participation and the inherent social and economic risks of testing positive as a result.
The information gained from the trials in the United States will not be as useful as the information gained from foreign trials, mainly because of the nature of the epidemic in the United States.
If it turns out that the vaccine induces a slowing of the disease process associated with HIV and AIDS, this will prove to be a beneficial result. In the alternative these trials may set up the necessary infrastructure required when a truly preventative vaccine is available. With such an infrastructure in place, many more lives could be saved globally. The medical and research community could react faster once an effective preventative vaccine is available.
The vaccine has a very limited chance of any success. Hidden in its failure may yet exist some political and practical good from the infrastructure it creates.
Sam Avrett, the executive director of the Washington, D.C.-based AIDS Vaccine Advocacy Coalition, said that despite the scientific activity, only slow progress is being made. "We're probably a decade or two away from an effective vaccine that could be distributed throughout the world," Avrett said.
A 1998 report by the National Institutes of Health cautions that finding an effective AIDS vaccine is a tremendous undertaking.
"The only prediction one can make about development of an AIDS vaccine is the same one that can be made for the development of any vaccine - the path will not be straight and much will be learned in the various disciplines of vaccinology in the process," the report said.
From the San Francisco Examiner, December 27, 1998
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Copyright © 1999 - Research Initiative Treatment Action (RITA!). Reproduced with permission. RITA! is published by The Center for AIDS. Contact Thomas Gegeny, MS, ELS, Editor, RITA! for permission to reproduce RITA!. tom@centerforaids.org. http://www.centerforaids.org
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