Gay Men's Health Crisis Treatment Issues, Vol. 5, No. 6 - August 30, 1991
Gabriel Torres, M.D.

BACKGROUND

Vaccines are designed to stimulate the production of antibodies and cellular responses which protect against infection. Antibodies are substances produced by plasma cells (a type of white blood cell) whose function is to recognize certain proteins found on the surface of viruses or bacteria which have entered the body. Antibodies bind to these viral proteins and neutralize them. Such an action can be difficult to achieve with HIV because the original virus is able to change the proteins on its outer coat. Neutralizing antibodies, therefore, may not be enough to stop viral reproduction or the destruction of certain important immune cells. Therefore, another major challenge in HIV vaccines is to trigger a cellular response, or to activate white blood cells (i.e., T-cells, phagocytes, macrophages, and natural killer cells). These cells kill the virus and the ells infected with the virus.

VACCINE APPROACHES

An antibody and cellular response can be achieved in a variety of ways with the use of vaccines. Whole live virus and whole inactivated virus injected into the body may create such a response but also carry the risk of causing HIV infection. The safest vaccine is one produced by technology. A genetically engineered vaccine is referred to as recombinant. Only part of the virus is incorporated into the recombinant vaccine, called a subunit. Researchers have identified specific regions in the HIV virus which trigger an inhibiting immune response. One such region is the focus of a vaccine being tested in both animal and human experiments. It works as follows: A Specific HIV outer- coat protein, pg120, contains a specific region called the V3 loop. The V3 loop does not change and so provides a stable target against which to develop a vaccine. Antibodies directed at the V3 loop bind to HIV, neutralizing the virus, and prevent it from infecting target cells. Unfortunately, during natural infection, neutralizing antibodies alone do not protect the infected person from developing disease, since the structure of HIV is so complex. Other vaccine approaches consist of inserting pieces of the HIV outer envelope into another virus, such as vaccinia (the smallpox virus), in order to trigger an immune response. This type of vaccine is called a recombinant vector vaccine because the live vaccinia virus serves as a vector, or transport vehicle for the HIV protein. Finally, other researchers have used synthetic peptides (small pieces of an HIV-derived protein) to induce an immune response.

ANIMAL EXPERIMENTS

Several animal studies presented in Florence generated considerable controversy. For instance, the simian immunodeficiency virus (SIV) -- the long-considered monkey equivalent of HIV in humans -- was challenged as not being suitable for testing vaccines directed against the V3 loop. One American study found marked differences between HIV and SIV in the way each virus stimulates production of neutralizing antibodies.

Additionally, most SIV experiments introduce the virus by an artificial means, such as an intravenous challenge (the virus is injected directly into the bloodstream). Protection against the virus which is acquired across mucous membranes (through the vagina or anus) has not been achieved in the SIV model. U.S. vaccine expert, Dr. Dani Bolognesi however, defended the SIV model, despite the differences noted above. Bolognesi contends that crude vaccines made from killed whole virus, or from killed infected cells have been successful in preventing infection of SIV in macaque monkeys.

Another focus in florence was the use of monoclonal antibody vaccine, which is highly specific against the V3 loop. A monoclonal antibody is a protein manufactured in the laboratory which targets a single region in HIV. Protection against disease obtained by injecting monoclonal antibodies into an animal or human is referred to as passive immunization. The vaccine, developed by Merck, Sharp and Dohme Corporation, was found to block infection the same strain of HIV used to produce the monoclonal antibody. Three chimpanzee experiments using different types of monoclonal vaccines targeting the V3 loop achieved protective immunity in animals challenged with the virus.

Another study reported that a recombinant gp 160 subunit vaccine, called rgp160, made by Immuno, Inc., protected a chimpanzee from HIV infection for two and a half years. Another chimp, injected with the same vaccine, has remained HIV-negative for three and a half years, the longest period of protection of any HIV vaccine to date. Based on the response of the first chimps studied, a similar vaccine was granted approval by the FDA in November, 1990, for phase I testing in human beings. These trials are currently underway at five AIDS Vaccine Evaluation Units (AVEU) in the United States.

HUMAN EXPERIMENTS

The results of some early safety trials in humans with various recombinant vaccines were presented in Florence. There is much hope that these trials will pave the way for large-scale efficacy trials within the next three years. A study from Vanderbilt University reported on a phase I trial using two recombinant vaccines in ten uninfected volunteers. The first vaccine was genetically engineered and was produced by inserting the gp160 gene into a vaccinia virus. It was produced by Bristol-Myers Squibb. A booster vaccine, consisting of a subunit of purified gp160 (VaxSyn), made by MicroGene Sys Inc., was then given to the same ten volunteers 11 to 27 months after the initial vaccinia-derived vaccine was administered. After they received the booster, the vaccinated volunteers developed immune responses, including neutralizing antibodies, determined to be strong enough to protect them against HIV infection.

Another researcher who has used the vaccinia virus vaccine in humans is Dr. Daniel Zagury of the Pierre and Marie Curie University in France. He was ordered by his government, however, to stop testing the vaccine after three AIDS patients receiving the vaccine on a compassionate basis, died. Their deaths were due to improper inactivation of the vaccinia virus.

In Florence, Dr. Zagury also presented data on a new vaccine therapy which may have restored immune function in six other AIDS patients. This vaccine -- a combination of alpha-interferon, HIV proteins, and an inactivated HIV pseudo-virus -- has been referred to as a vaccine "cocktail." Zagury reported marked clinical improvement in the six AIDS patients treated with the vaccine cocktail, including increases in T4 cell counts to near normal values. A press release from the conference news office was highly critical of the presentation, and called Zagury an "enfant terrible" and his vaccine cocktail, "the dubious concoction of a witch."

GP 160 VACCINE (VAXSYN)

A more rigorous and widely-publicized vaccine trial was reported in the New England Journal of Medicine just a week before the conference. The trial tested recombinant gp160 (VaxSyn), produced by genetic engineering by MicroGeneSys, Inc. in Connecticut. The trial was conducted at the Walter Reed Army Institute of Research, Rockville, Maryland. Thirty HIV positive volunteers who had asymptomatic infection and T4 cell counts over 400 were injected with the vaccine, given either as three or six injections over 4-6 months. In 19 of the 30 participants (63%) both antibody and cellular immunity to HIV proteins increased in response to the vaccine.

After ten months of follow-up, the mean T4 cell counts had not decreased in the 19 subjects who responded to the vaccine. Counts decreased by 7.3% in the 11 patients who did not respond. The best responses in the trial were seen in those subjects who received six injections and those who had over 600 T4 upon entry of the trial. There was no increase in HIV replication or viral activity in any of the subjects as a consequence of vaccination. This study, though very promising, must be interpreted cautiously since it is still unclear whether T cell responses to gp160 and neutralizing antibodies will translate into clinical benefits for patients with HIV. A larger placebo-controlled phase II trial involving 140 subjects is fully enrolled at the Walter Reed Research Center. The first analysis of the data should be available in early 1992.

CONCLUSION

Significant progress has been made in the design and testing of vaccines that have the potential for protecting both HIV- uninfected and HIV-infected persons. Because of he large variability in HIV strains and because of the ability of the virus to mutate, vaccines directed at conserved regions, such as the V3 loop, have the greatest potential for success. The potential for vaccines to serve as immunotherapies in persons already infected seems to be real. The years to come await much larger efficacy trials to determine if the preliminary results of phase I trials will be reproduced in large populations of persons at risk for HIV or with asymptomatic infection. The World Health Organization and the vaccine researchers will be convening to decide on the specific populations to have used in the large vaccine trials. Unfortunately, the potential for significant benefit from a vaccine in persons with advanced diseases is very low.

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