Gay Men's Health Crisis: Treatment Issues, Volume 7 no. 5 - May, 1993
Mike Barr

Although therapeutic vaccination seems a new concept to many, it is actually a well-known medical technique first introduced a century ago for the treatment of chronic staphylococcal infections, syphilis, and tuberculosis. These early efforts with therapeutic vaccination were only marginally successful; they almost faded from use when antibiotics were introduced in the 1940s. However, therapeutic vaccination today remains the standard of care for babies born to mothers infected with hepatitis B virus and those believed infected with rabies.

There are many theories to explain how an HIV therapeutic vaccine might boost the weakening immune response to HIV and, perhaps, slow the course of disease.[1] However, the exact way a vaccine could help the immune system is still unclear. Furthermore, in cases where therapeutic vaccination does work, like hepatitis B and rabies, the vaccine prevents early infection before the development of a natural immune response. In HIV, therapeutic vaccines would be used after a natural immune response has been elicited and disease is already in progress. Interestingly, therapeutic vaccination is also under investigation for several herpes viruses, another form of chronic viral infection.[2]

Human Studies

The clinical studies of the therapeutic vaccines are summarized on page three. Each therapeutic vaccine is made by a different manufacturing process and includes different parts of HIV, different strains of the virus, and different adjuvants. Some of these differences may be significant. (See Table II, below.) However, at this point in the process, no objectively reviewed information suggests one vaccine product is superior to any other. Claims about the advantages or disadvantages of a particular vaccine or vaccine manufacturing technique come exclusively from its producer. Since studies which will answer these questions have just started, we will publish a detailed article describing the best approach when data emerge. [Editor's Note: See Bulletin of Experimental AIDS Treatments 3/93 for a review of different vaccine manufacturing techniques.]

All studies summarized are phase I/II safety studies. All show that the vaccines are safe and well-tolerated over the course of the study period. One study, though, followed the trial volunteers for over four years and found no evidence of increased viral replication or exacerbated CD4 cell loss.

The therapeutic vaccines induce both humoral and cellular immune responses in the study participants. The humoral arm of the immune system is controlled by B cells and responds to infection by producing antibodies. The vaccines stimulate antibodies to new parts of HIV's envelope, including increased binding antibody in nearly all subjects at titers which usually decreased over time. Neutralizing antibodies were also seen; however, these antibodies were directed at the vaccine itself, not HIV.

The cellular arm of the immune response is controlled by T cells and responds to infection by activating other immune cells to kill diseased or infected cells directly. Components of the cellular arm of the immune system include the familiar CD4 and CD8 cells, as well as natural killer cells, macrophages, and various other monocytes. Cellular responses to the vaccines include improved lymphoproliferative responses, such as delayed hypersensitivity reactions (a skin test of cellular immune response) and T cell proliferation to foreign antigens in nearly all subjects. Increases in cytotoxic T lymphocytes (immune cells which kill viral infected cells) were observed in only a few subjects.

While some studies suggest increases and/or stabilization of CD4 cell counts, these results remain inconclusive and controversial. Some initial reports claimed an observed decrease of HIV in the blood; however, these claims were found to be inaccurate and have been retracted.

The Role of Cellular Immunity

A major problem vaccine researchers face is knowing which aspects of the immune response should be stimulated to improve the course of disease. Recent work by Ronald Desrosiers with an SIV vaccine (Simian Immunodeficiency Virus is a monkey virus similar to HIV which is used as an animal model for human disease) may provide a clue. Desrosiers notes that monkeys immunized with a vaccine which induces high levels of neutralizing antibodies were not protected from infection. However, when the same vaccine was used to induce less robust antibody responses, all animals were protected. "Either the nature of the neutralizing antibodies being elicited is different with the different approaches," Desrosiers concludes, "or the key protective component is something other than neutralizing antibodies." [3, 4]

Accordingly, Gene Shearer of the National Cancer Institute proposes that the same may be true for humans. He notes that HIV-infected individuals continue to produce HIV antibodies, but have a progressive loss of cellular immunity. In the progression towards AIDS, production of interferon-gamma and interleukin-2 (cytokines associated with cellular immunity) falls while production of interleukin-4 (a cytokine associated with humoral immunity) increases.

As evidence to support his theory, Shearer cites cases of seronegative individuals at high risk for HIV infection (such as gay men and injecting drug users) who have been exposed to HIV and demonstrate HIV-specific cellular immunity, but no HIV antibodies. Similarly, cell-mediated immunity specific to HIV has been seen in infants who remain seronegative despite being born to seropositive mothers. "These babies were effectively immunized in utero," Shearer explains.[5]

Shearer suggests these people were infected with "defective" HIV or such a small volume of virus that they became "exposed" without productive infection. Under the right conditions, a certain degree of cellular immunity or protection might be achieved without the production of HIV-specific antibodies. An inoculum of 40 to 80 micrograms, Shearer reasons, is enough to induce strong cellular immunity but a weak or no antibody response. In experiments with macaque monkeys infected rectally with live SIV, Shearer shows that while a high volume of inoculum produced a vigorous antibody response in three out of three monkeys, only one mounted a detectable cell-mediated response to the infection. Perhaps most interesting of all, two monkeys with high antibody levels but little or no cellular immunity have progressed to symptomatic disease. The monkey with strong cellular immunity has not. Seven additional monkeys inoculated with tiny volumes of SIV produced no antibodies and all remain symptom-free more than 75 weeks later.

Salk also now believes that cellular responses are critical. He proposes that antibody responses will not protect against HIV; rather, the antibody arm of the immune system needs to be shut off entirely and the cellular portion stimulated in isolation.[6] Salk cites a study of two groups of monkeys immunized with two SIV vaccines.[7] The monkeys immunized with the vaccine which induced the most robust humoral (including neutralizing antibodies) and cellular immune responses developed infection -- as did both of the controls. This, Salk explained, represents an unexpected and paradoxical outcome and raises the question as to whether or not immunization might -- under any circumstances -- induce a protective effect. (He fails to explain, however, why the experiment was not conducted to induce a principally cellular immune response in one group and a predominantly humoral response in the other -- in order to directly compare the utility of each in isolation.) As further evidence, Salk points to a study performed in mice with Leishmaniasis.[8] In that experiment, resistance to disease was associated with cellular immunity and the absence of antibody responsiveness. Also, in work with leprosy patients, resistance to disease is associated with predominance of a cell-mediated immune response while susceptibility to disease is associated with a predominance of an antibody response.

Surrogate Markers

If a consensus has begun to emerge that increased cellular responses are critical to the success of a therapeutic vaccine, there is still no agreement on which cellular responses to measure. As described above, three tests of cellular immunity have been used in therapeutic vaccine studies. However, no data yet exist to support using any one of these measures as markers of efficacy. Margaret Johnston, Acting Deputy Director, Division of AIDS, NIAID commented "The biggest problem with the vaccines is surrogate markers."

Increased cytotoxic T lymphocytes (CTLs) have been observed in a few vaccine study patients. This may be a good sign; Bruce Walker of Harvard University has observed HIV-specific CTLs in four out of five long-term survivors he studied.[9] Walker hopes to characterize further these CTL responses by learning how they might improve prognosis and survival. However, it is technically difficult to measure CTL responses. It is unlikely they will be used widely in the near future.

T cell proliferation to foreign antigens, a measure of the immune system's ability to respond quickly to infection, has also been seen in vaccine study subjects. However, like CTL tests, these tests are difficult to perform and will likely not be used widely. Delayed type hypersensitivity reaction (DTH) measures the immune system's ability to remember previous infection and its response time to infection. Unlike the other tests, DTH is widely available. It is a simple skin test well known to most researchers. A DTH test injects antigens under the skin. Within a few days, the skin becomes indurated (a red, hardened bump) if the immune system has responded to the vaccine. Since the level of induration can be measured (i.e. by measuring how wide the area of hardening is), scientists hope to use the size and length of the DTH reaction to predict ultimate clinical outcome.

Salk and his colleagues have attempted to make the case that improved DTH responses correlate to clinical outcome.[10] Salk reports on a study he began in 1987 with 107 HIV-infected people. The therapeutic vaccine induced both new humoral and cellular immune responses. After six months of follow-up, HIV-infected individuals had significantly improved anti-HIV DTH responses. In a slide presented to several vaccine conferences over the past year, the Salk team grouped responders and non-responders to the vaccine by the strength of their DTH reaction. Among the twelve "responders" there were no deaths, no new opportunistic infections, and only two new cases of Kaposi's sarcoma; while among the twelve "non- responders" four new opportunistic infections, three new cases of Kaposi's sarcoma, and three deaths were observed.

Ostensibly, the responders were the ones who had exhibited the strongest DTH response while non-responders had a weaker DTH reaction. Yet this conclusion was not easy to glean from the bar chart which illustrated the magnitude of DTH responses. Rather, some claim the two groups had different baseline CD4 cell counts. They argue that these baseline differences, not the magnitude of DTH response, account for the difference in outcome.

Conclusion

Small phase I studies of several HIV therapeutic vaccines show that they are safe and induce new cellular and humoral immune responses. No vaccine has conclusively demonstrated a positive effective on CD4 cell levels. No vaccine has demonstrated that it can reduce HIV levels in the body, either. As phase III studies begin, new surrogate markers are needed to measure the treatment effect of the therapeutic vaccines. In particular, research is needed to clarify what role, if any, DTH responses may have in gauging treatment effect.

1. Salk J. Nature 1987; 327:473-76.

2. Straus S, et al. Journal of Infectious Disease 1993; 164:1045-52.

3. Cohen J. Science 1992; 258:1880-1.

4. Daniel M, Kirchhoff F, et al. Science 1992; 258:1938-41.

5. Shearer G. Oral Presentation. 2nd Annual GMHC/CRIA Forum on HIV Vaccines. New York. 11-12 February, 1993.

6. Salk J. Reconceptualization of Requirements For Induction of HIV Immunity By Vaccination. Salk Institute, La Jolla, CA. Presented at VIII International AIDS Conference, Amsterdam. 20 July, 1992.

7. Vaslin B, et al. Abstract PoA 2239. VIII International AIDS Conference, Amsterdam.

8. Bretscher PA, Wei G, Menon JN et al. Science 1992; 257:539-42.

9. Walker B. Oral Presentation. 2nd Annual GMHC/CRIA Forum on HIV Vaccines. February 11-12, 1993.

10. Salk J. Oral Presentation. 5th Annual Meeting of the National

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