TREATMENT ISSUES, Volume 6, Number 8 - September, 1992; The Gay Men's Health Crisis Newsletter of Experimental Therapies
Gabriel Torres, M.D.

So far, the three strains of HIV used for vaccine development have been LA1 (IIIB), SF2 and MN. The IIIB strain is the most widely used in candidate vaccine trials, though the MN strain is more prevalent in people in the U.S. Envelope proteins, which are particles from the outer part of the HIV coat, such as gp160 and gp120, comprise the most well-known human HIV vaccines. Inner core HIV proteins which have been widely used in vaccine work are p24 and p27. In addition, whole inactivated virus (WIV), stripped of its envelope, has been used in some vaccine trials.

Candidate vaccines have taken various forms including recombinant (manufactured) HIV proteins, synthetic peptides, whole virus particles and vector vaccines, which use another virus to carry the vaccine into the body. Some new approaches include the use of pseudo-viruses and various adjuvants that are added to assist in the development of an immune response. Phase I trials have demonstrated that most candidate vaccines are well-tolerated and that few side effects result from their administration. Minor side effects include fever, malaise, mild pain and erythema at the injection site. Many of these vaccines have induced humoral responses (antibody activation) including binding antibodies in nearly 100% of immunized subjects followed by a decrease in antibody titers over subsequent weeks, as well as neutralizing antibodies in a majority of cases. In trials of recombinant gp160, cellular responses have also been noted which represent the generation of lymphocytes and T killer cells. When blood from vaccinated patients was injected into laboratory mice, the mice were protected from HIV infection.

THERAPEUTIC VACCINES

Various presentations in Amsterdam focused on the use of vaccines as immunotherapy, which means that they enhance the immune response in HIV-positive people and hopefully prevent disease progression. The only human vaccine which is known to be effective in preventing disease progression is the rabies virus vaccine. It has the expectation of eliciting an immune response that will counteract the effect of the rabies virus prior to the onset of symptoms. Among the hopeful HIV candidate drugs are gp160 and gp 120. Descriptions of each of these therapies follow.

GP 160

Various presenters from different parts of the world presented encouraging data about the use of recombinant gp160. Dr. Christos Tsoukos from Canada presented the results of a small phase I trial using 21 asymptomatic HIV-positive participants with less than 500 T4 cells at entry.[1] Ten patients received 160 ug of gp160 and 11 receive 320 ug of the vaccine injections on days 0, 30, 60, 90 and 180. There was no evidence of toxicity after one year. Ninety percent developed either new or augmented antibody responses to specific gp160 epitopes. These patients have also had significant increases in absolute T4 cell counts (mean increase is 117) and the percentage of T4 cells (mean increase 2%). There were no significant differences in absolute T4 cells between the different dose groups.

Dr. Fred Valentine of New York University presented data on 52 asymptomatic HIV and Hepatitis B virus (HBV) antibody positive patients with T4 cell counts over 400 who received one of four doses of gp160 or recombinant hepatitis B vaccine.[2] Patients receiving gp160 developed substantial lymphocyte responses as well as antibodies directed at gp160. Lymphocytes recovered from immunized patients also released interleukin-2, a virus-killing substance, when stimulated by gp160 in the test tube and directly attacked gp160 envelope proteins. The immune responses demonstrated by the patients in Dr. Valentine's trials occurred only in participants who received the gp160 vaccine and not in those who received the Hepatitis B vaccine, suggesting that they were caused by the vaccine and not by a general response of the immune system related to stimulation with a nonspecific antigen.

Dr. Gary Blick, a community physician from Greenwich, Connecticut, investigated the combination of gp160 and p24 vaccines.[3] Participants were enrolled to receive 320 ug of gp160 vaccine and 640 ug of p24 vaccine on days 0 and 7, and months 1, 2, 4 and 6, and then at three month intervals thereafter for 24-months. Thirty patients were enrolled with different levels of entry T4 counts. There was no evidence of toxicity other than a red inflamed reaction at the injection site. All of those with greater than 200 T4 cells at entry had new or augmented antibody responses against HIV's gp160 protein. Levels of Beta-2 microglobulin, p24 antigens, and p24 antibodies have remained stable. No patient with entry T4 cells between 200 and 500 has developed AIDS or ARC or has died. Mean changes in T4 cell counts ranged from 42-108, but could not be ascribed solely to the vaccine, since patients were also on antiretroviral therapies.

Dr. Robert Redfield from the Walter Reed Army Institute of Research in Rockville, Maryland presented data concerning 30 patients who had received recombinant gp160 in the original trial of the vaccine [See Treatment Issues, Vol 5, No 6].[4] Dr. Redfield reported that after increasing the vaccination schedule from three to six injections, 29 of the 30 patients mounted an immune response. Perhaps most significantly, by using polymerase chain reaction (PCR), he was able to demonstrate reductions in viral load 18 to 24 months after vaccination. Toxicities remain limited to local reactions.

A large multicenter, placebo-controlled trial is underway to assess the efficacy of this vaccine in HIV-positive participants with more than 400 T4 cells. In a poster presentation, Redfield and colleagues reported an increase in the absolute number and percentage of T4 cells in the majority of patients vaccinated with gp160.[5] In a controlled study comparing AZT to placebo among gp160 recipients, the researchers were able to demonstrate that the T4 cell elevations were not related to AZT.

A poster presentation by a Stanford group headed by Dr. Smriti Kundu showed that gp160 injections were able to induce a type of lymphocyte cell able to kill HIV-infected cells. Another Stanford researcher, Dr. David Katzsenstein reported on the use of a skin test, namely a gp160 protein injected under the skin directly after six gp160 injections.[6] This test is used to detect whether the gp160 vaccine is working to boost the immune response, as measured by cytotoxic T-lymphocyte activity and lymphocyte proliferation. Forty-eight hours after the injection, swelling around the site of injection correlates with a positive response to the vaccine. The skin test will be used to monitor patients in vaccine trials.

GP 120

Dr. Deborah Birx of Walter Reed Army Hospital, in cooperation with researchers from Genentech, Inc., demonstrated that in 45 asymptomatic HIV-positive patients, recombinant IIIB gp120 is well-tolerated.[7] The vaccine induced new cellular and humoral responses to HIV. Responses were dose-related and the only toxicities reported were mild headaches in 9 out of 45 participants and one case of increased liver enzymes.

PREVENTIVE VACCINES

Various investigators reported on initial results of candidate vaccines used in HIV-negative individuals to prevent HIV infection. Dr. Hoth projects that a candidate vaccine with a 60% efficacy made available in 1988 to 1 million persons at risk of infection, could prevent 145,000 infections. On the other hand, if we wait for a vaccine to be 90% effective, which would take until 2004, only 87,000 infections of the same would be prevented. This analysis suggests that candidate vaccines should be made widely available as early as possible, despite the possibility of not being maximally effective.

IIIB RGP 120/HIV-1

Vaccine Investigators from the federally-funded AIDS Vaccine Clinical Trials Network also reported on the safety and immunogenicity of the rgp 120 described above.[8] This vaccine given with an alum adjuvant had been shown to elicit type-specific neutralizing antibodies in chimpanzees and protect them from when HIV is intravenously introduced into the body. Two years later, the chimpanzees still have no sign of HIV infection.

In a double-blind, dose-escalation phase I trial, 25 HIV-negative volunteers at low risk for HIV infection were randomized to receive either 100 or 300 mcg of the vaccine or the alum adjuvant (a vehicle that helps the body have a bigger immune response to the vaccine) injection at 0, 4 and 32 weeks. Few side effects were reported. They included pain and redness at the injection site, malaise, headache, nausea, and one case of elevation in liver enzymes. Antibody responses directed against he V3 loop (a specific inner region of HIV) and blocking antibodies against T4 were elicited in those receiving the 300 mg dose. Nine of ten developed neutralizing antibodies at the highest titer seen with a IIIB envelope vaccine. In addition, a lymphocyte-inducing response was elicited in nine of ten participants receiving the higher dose.

IMMUNO RGP 160

Investigators from the AIDS Vaccine Evaluation Group presented the results an Immuno rgp 160 phase I safety study using 60 HIV-negative volunteers. Immuno rgp 160 is different from other gp160 vaccines because it is produced in mammal cells rather than insect cells, and is coated with a sugar-like substances. This version therefore more closely resembles the gp160 protein made by natural HIV. Volunteers received 12.5 or 50 mcgs of Immuno rgp 160 or an adjuvant control by injections given at 0,1, 6 and 12 months. After three injections, more than 90% of the volunteers had developed antibodies which bind rgp160 and lymphocyte-inducing responses. In the extension studies with this vaccine doses of 200 mcgs will be used to see if the vaccine induces neutralizing antibodies.

GP120 VACCINE

Dr. James Kahn from the University of San Francisco presented the initial results of a phase I study using a recombinant gp120 vaccine developed by Chiron Corporation.[9] The vaccine was made using recombinant gp120 from the SF2 strain of HIV, taken from the ovary cell of a Chinese hamster. It is fully glycosylated (coated with sugar molecules) as well, therefore mimicking the native conformation of an HIV surface protein, and it can bind to the CD4 receptor of HIV. In the study 42 HIV-negative participants received gp120 and an adjuvant oil emulsion (MF59) alone or with increasing doses of a potent immunomodulator called muramyl tripeptide (MTP-PE). All volunteers who received the three injections of gp120 and MTP-PE developed neutralizing antibodies, and two thirds developed cross-neutralizing antibodies directed against another HIV strain called MN. Volunteers who received gp120/MF59 had no serious side effects; those who received MTP-PE had more adverse effects including muscle aches, headache and fever. Another vaccine being developed by Chiron Corporation is the Env 2-3 antigen, a recombinant gp120 from the SF2 strain of HIV which is produced in yeast. In an initial trial of 62 subjects, 75% developed neutralizing antibodies to HIV's SF2. Trials are planned combining this vaccine with the MF59 adjuvant and MTP-PE.

SALK THEORY

Dr. Jonas Salk, the developer of the polio vaccine, introduced a new vaccine theory at the Amsterdam international conference which generated much controversy. He postulates that two types of immune responses account for containment of HIV infection: the first is the cellular response called the "TH1 response"' and the second is a humoral response, called the "TH2 response" and characterized by the production of antibodies. Dr. Salk suggests that an effective vaccine should arrest the immune system so that only the TH1 response occurs, but not the TH2 response. This theory supported the work of Dr. Gene Shearer of the NIH who reported HIV-specific cellular responses in HIV-negative repeated exposure through high-risk individuals who have remained free of HIV infection (as measured by PCR) despite high risk behaviors. Dr. Salk suggests that minuscule amounts of the virus may be able to elicit cellular responses without eliciting antibodies. This theory was challenged at the conference by other vaccine researchers such as Robert Redfield and Emilio Emini, who feel that both antibody and cellular responses are important in preventing initial infection because they can neutralize virus much quicker than memory cells.

CONCLUSION

The debate and the research move vaccine progress forward, making it perhaps one of the most exciting areas of HIV medical science. Unfortunately, trials of therapeutic vaccines presently enrolling human participants, are difficult to access. It is essential for pharmaceutical companies and government research officials to work together to expand access to these therapies. An expanded access program on a true parallel track with clinical trials would be ideal. Treatment Issues will continue to report on all HIV vaccine research as it unfolds.

FOOTNOTE --------

1. Int'l Conf on AIDS. Abst.# Tu.B. 0560, Amsterdam, July 1992.

2. Int'l Conf on AIDS. Abst.# Tu.B. 0561, Amsterdam, July 1992.

3. Int'l Conf on AIDS. Abst.# Tu.B. 0562, Amsterdam, July 1992.

4. Int'l Conf on AIDS. Abst.# Tu.B. 0563, Amsterdam, July 1992.

5. Int'l Conf on AIDS. Abst.# Po.B. 3040, Amsterdam, July 1992.

6. Int'l Conf on AIDS. Abst.# Po.A. 2192, Amsterdam, July 1992.

7. Int'l Conf on AIDS. Abst.# Tu.B. 0564, Amsterdam, July 1992.

8. Int'l Conf on AIDS. Abst.# Mo.B. 0026, Amsterdam, July 1992.

9. Int'l Conf on AIDS. Abst.# Mo.B. 0025, Amsterdam, July 1992.

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