Despite recent advances in antiviral therapy, there is no cure for AIDS or HIV infection. Drug therapy, although promising, remains problematic because of side effects, compliance, and expense. In addition, availability of such drugs is limited in developing countries where it is estimated that 90% of HIV infections will occur by the year 2000. For these reasons, the search continues for safe and effective vaccines to prevent HIV infection and AIDS world-wide. The AIDS Vaccine Evaluation Group (AVEG) is conducting phase I and II studies of candidate HIV-1 vaccines.

Vaccines to prevent infectious diseases have been one of the great success stories of modern medicine. However, HIV infection challenges researchers with several unique issues that limit the traditional approaches for developing vaccines. One significant stumbling block in the understanding of HIV in general, and vaccines in particular, has been the lack of appropriate animal models. In addition, we do not know the "correlates of immunity," that is, which components of the immune system are necessary for protection from natural infection.

The use of whole, inactivated virus vaccines, such as inactivated polio virus vaccine, or attenuated live virus vaccines, such as oral polio vaccine, appears too dangerous, given the various problems that have plagued the development of such vaccines in the past. The "Cutter incident" in which inadequate inactivation of the polio vaccine resulted in actual clinical polio is one concern in the manufacture of inactivated whole virus vaccines with HIV-1. Similarly, the recent studies in which attenuated live virus vaccination of SIV (Simian Immunodeficiency Virus) produced clinical infection in infant monkeys have been a sobering influence on the development of attenuated live virus HIV-1 vaccines. There is also considerable liability in growing large volumes of infectious HIV-1, especially with known laboratory acquired cases. For these reasons, most HIV-1 vaccine development has concentrated on subunit vaccines. This allows for excellent safety as only portions of the HIV-1 virus are utilized. Thus, there is no risk of infection from the vaccine product.

The difficulty with the subunit vaccine approach, however, has been the ability to produce optimal immunity. HIV-1 can be transmitted by HIV-1 infected cells and by cell-free virus (1,2). It is thought that both of these modes of transmission will need to be addressed for a vaccine to be effective, although it is not known exactly which components of the immune system are necessary for protection from natural infection. In order to prevent infection, most authorities feel a vaccine regimen must be able to elicit effector T-cell responses to eliminate virally infected cells, while also producing antibody responses to neutralize cell-free virus (3-7). Early vaccine trials have looked at recombinant subunit protein immunogens, such as the HIV-1 envelope rgp120, which have induced envelope-specific neutralizing antibodies (8-12). These immunogens, however, have rarely elicited a CD8+, class-I restricted cytotoxic T-lymphocyte (CTL) response (13-16). Other phase I HIV-1 vaccine studies have demonstrated that live recombinant vaccines can elicit class-I restricted CTL responses to HIV envelope in selected individuals (17-19). Unfortunately, antibody and cellular proliferative responses to these recombinant virus vaccines alone were poor (17, 20-24). However, immunization regimens that employ both live recombinant virus and subunit protein have, in some individuals, elicited both envelope specific CD8+ CTL and neutralizing antibody to the HIV-1 envelope (19, 22-24).

One of the first vaccination regimens to demonstrate such promising results involved a live recombinant vector based on vaccinia virus, the vaccine used to eradicate smallpox. This vector expressed HIV-1 envelope gp160 antigen and was used in association with a gp160 subunit protein. After vaccinia-naive volunteers were given two injections of the vaccinia gp160 recombinant virus, they were boosted with the recombinant gp160 subunit (25, 26). Of the twelve vaccinia-naive volunteers who received this regimen, 75% developed HIV-1 specific neutralizing antibody. Both cell fusion inhibition activity and CD4 binding-domain-blocking antibody were noted in 42% of the volunteers, while CD8+ CTL was noted in 45% of the vaccinees (26-29). Of note, the immune response to vaccinia was noted to be so great that revaccination with the vector did not achieve boosting. Even persons with distant infections did not achieve an adequate immune response. Thus, vaccinia vectors seemed to be useful only for vaccinia naive persons. Lastly, although no serious adverse reactions to vaccinia virus recombinants have been observed, there was some concern about safety and the possibility of transmission of vaccinia virus to close contacts (30-32). Specifically, there was concern that administration of vaccinia to an HIV-positive person might lead to disseminated vaccinia. While this is not an issue in the clinical trial setting, it very well might be an issue in the general clinical use of such a vaccine.

To address these safety issues, alternative viral vectors have been studied. Researchers have looked for viruses that can infect mammalian cells and cause them to produce foreign proteins, while also accommodating a large amount of foreign DNA in their genome. Canarypox, an avian pox virus vector, met these criteria, as well as being stable at room temperatures and inexpensive to produce. In addition, canarypox has the added benefit of being host-range restricted. This means that it goes through an abortive cycle of replication without producing infectious virus in mammalian cells. Canarypox virus has been utilized in clinical trials as a rabies vaccine, a measles vaccine, a Japanese encephalitis vaccine, and now as vaccines containing various HIV-1 genes (33-37). Safety data for these ALVAC vaccines has been excellent with promising immunogenicity data. Higher doses of canarypox virus have not caused any adverse effects in a wide variety of animals, including those that are profoundly immunosuppressed. This suggests that canarypox recombinants are not likely to disseminate and cause progressive disease in human recipients or be transmitted to unvaccinated contacts. One of the first studies to look at a canarypox vector as a potential HIV vaccine involved the ALVAC gp160MN recombinant (ALVAC vCP125) which expressed the envelope and transmembrane portion (gp160) from the MN strain of HIV-1. As in all of the AVEG (AIDS Vaccine Evaluation Group) trials to be discussed, this was a phase I, randomized, placebo-controlled, double-blinded, multicenter study involving healthy HIV-1 uninfected volunteers at lower risk for HIV-1 infection. This ALVAC vCP125 recombinant was directly compared to the ALVAC rabies vaccine to help ensure blinding of the study and to serve as a control for detection of non-specific pox virus-related activity in CTL assays. This trial looked at several different variables, including two doses of the ALVAC gp160MN (106 and 107 TCID50)* and various schedules of immunization (0, 1 or 2, 6 or 9 , and 12 months). It compared vaccinia-immune to vaccinia-naive volunteers to determine if immunity conferred by prior immunization interfered with the immune response to the canarypox gp160 recombinant. Also, two prime/boost immunization sequences compared the ALVAC recombinant alone to boosting with the subunit vaccine HIV-1 SF-2 rgp120 at the last two immunizations of the trial. Results of the trial demonstrated that of the 131 volunteers who were enrolled, HIV-1 MN and SF-2 neutralizing antibodies were elicited most frequently by priming with the ALVAC vCP125 followed by boosting with the rgp120 (38). At the lower dose of ALVAC vCP125 (106 TCID50), three of the fifteen volunteers tested positive for anti-HIV-1 envelope specific CTL (39). Several volunteers receiving the higher 107 TCID50 dose also tested positive for CD8+ CTL against the HIV-1 envelope-both with and without subunit boost. French vaccine trials being conducted at about the same time had even more impressive immunogenicity data. Of the twenty volunteers who received the ALVAC vCP125 vector followed by boosts with the subunit protein gp160 MN/LAI, neutralizing antibody was found in 90%, while CD8+ CTL activity was induced in 40% (40, 41). * Tissue Culture Infectious Dose

Hoping to improve on this initially promising data, a more complex canarypox recombinant vaccine was constructed in order to stimulate a more vigorous immune response. ALVAC vCP205 consists of a complex antigen containing HIV-1 gp120 (strain MN) attached to the transmembrane portion of HIV-1 gp41 (strain LAI), as well as the HIV-1 LAI genes encoding for the gag and protease proteins. This is thought to be particularly relevant given the apparent importance of gag-specific CTL which appear to predominate in HIV-infected persons and in several children born to HIV-infected mothers who were subsequently shown to be HIV negative (42). Not only does this construct provide for more antigenic material, but it also allows for its unique presentation as pseudovirions. These virus-like particles are released by cells that are infected in vitro with the ALVAC vCP205, allowing for the expression of conformational epitopes of the envelope protein in a more "natural" way. An initial French study involved 25 volunteers who received ALVAC vCP205 at a dose of 105.8 TCID50 at 0, 1, 3, and 6 months or at 0 and 1 months boosted with a peptide at 3 and 6 months. Results demonstrated that vCP205 alone is able to induce binding antibody to gp160 MN/LAI and to a V3 MN peptide as well as lymphoproliferation one month after the third injection (43).

Here in the United States, an ongoing AVEG trial is evaluating ALVAC vCP205 in two different immunization schedules (0, 1, 3, 6, 9, and 12 months or 0, 1, 6, 9, and 12 months), while also comparing immune responses in vaccinia-naive and in vaccinia-immune subjects. The safety and immunogenicity of ALVAC vCP205 is being compared to that of the ALVAC rabies glycoprotein (ALVAC RG), as well as evaluating the immunogenicity of ALVAC vCP205 with and without prior administration of ALVAC RG. This is being done in an attempt to evaluate whether repeated doses of canarypox influence the subsequent immune response. In addition, this trial has added HIV envelope booster immunizations with SF-2 rgp120 at months 9 and 12. Preliminary results at this time show that CD8+ CTL responses to HIV proteins appear to be present in about 50% of vaccinees. Boosting with gp120 generates neutralizing antibody response in nearly 100% of subjects.

A follow-up study that is further evaluating ALVAC vCP205 is currently finishing enrollment. In this trial, a higher titered preparation of vCP205 will be used as well as a variety of regimens in which the envelope subunit SF-2 rgp120 is used in combination with vCP205. The goal is to elicit consistent CTL responses for almost all vaccinees. One unique regimen administers both vaccines simultaneously at different sites in an attempt to induce a rapid and potent cellular response as well as a strong humoral response to HIV envelope proteins. Another unique aspect to this trial is the addition of individuals at higher risk for HIV infection. This is to begin a pilot evaluation of CTL responses between higher and lower risk subjects as a prelude to a larger phase II trial. Preliminary data from the trial will be forthcoming over the next year. Another equally complex canarypox recombinant vaccine, ALVAC vCP300, is currently being evaluated for safety and immunogenicity. This recombinant vector contains the same genes as vCP205, including the HIV-1 envelope gp 120 (strain MN) linked to the transmembrane portion of HIV-1 gp41 (strain LAI), as well as the gag and protease genes from strain LAI. In addition, this construct contains portions of the pol and nef genes that encode for CTL epitopes. Once again this experimental vaccine is being compared to the ALVAC rabies glycoprotein in a variety of vaccination regimens, both with and without subunit boosts of gp120. Thus, the combination vaccine approach has matured in the last year and seems to be the leading design for further clinical trials.

One issue that has emerged in the last five years is the safety of these subunit products. Recently Keefer, et al. reviewed the safety of these canarypox vector vaccines and the other candidate HIV-1 vaccines used in the AVEG trials (44). To date these phase I trials have included over 2000 participants. Local and occasional systemic reactions are the only toxicities that have been clearly attributable to the candidate vaccines. These reactions appear to be related to the adjuvant preparations contained in the vaccines and seem to be of a self-limited nature. This review looked at several different concerns that have been raised previously in the scientific community. For example, it is known that the HIV-1 envelope not only contains components that suppress a variety of immune functions, but that it also contains certain areas of homology with host regulatory and structural proteins that may lead to autoimmunity. Clinical monitoring and serial T-lymphocyte measurements have provided no evidence of important adverse immunologic effects. Possible autoimmune phenomena have been limited to three vaccinees. Two volunteers experienced arthralgias which responded to a short course of oral corticosteroids, and one volunteer was diagnosed with a mixed connective tissue disease five years after receiving one vaccination during an AVEG trial. Of note, this volunteer had experienced livedo reticularis, a lace-like rash associated with certain rheumatologic conditions, prior to entry in the AVEG trial. The oncogenic potential of candidate HIV-1 vaccines was another issue that has been discussed, given the incidence of various neoplasms in the HIV-1 infected population. No statistically significant increase in malignancies has been seen when the AVEG volunteers have been compared to a population-based SEER data base which estimates the frequency of cancer in the general population. There also was no statistical difference when comparisons were made between the vaccine and placebo groups or between the various vaccine preparations. Thus, the conclusion of the investigators and the Data Safety Monitoring Board for the HIV-vaccine trials is that there appears to be no substantive increased risk of autoimmune disease from any of the candidate HIV-1 vaccines yet tested.

Finally, concern about volunteers becoming HIV-1 infected during the vaccine trials has been addressed. A total of 20 participants (less than 1%) over the eight-year period have become infected with HIV. All of these individuals engaged in high risk behavior that put them at risk of acquiring HIV, despite the counselling provided to them during the course of the trial. This included persons who were at both lower and higher risk, as determined by sexual questionnaires, for acquiring HIV prior to the trials. To date, the clinical course of the HIV infection does not appear to be different from that observed in natural history studies.

In addition to the possible medical side-effects of the HIV-1 vaccines, consideration has been given to the psychological and social aspects of volunteers testing HIV-positive. Many volunteers, especially those who have received the gp160 subunit vaccines, have developed antibodies that cause them to test positive on ELISA/western blot assays, when they are actually seronegative. Interestingly, only 10-15% of those receiving gp120 vaccines test positive in these assays. With the increasing numbers of vaccinees in the trials, the FDA has now recognized HIV vaccination as a potential cause of a positive HIV serology. In more recent trials, western blots or other assays can be utilized to distinguish vaccination from infection because the ALVAC constructs, ALVAC vCP205 and vCP300, have deletions in part of the sequences of the envelope transmembrane region, gp41. HIV-1 infected persons demonstrate antibodies directed against the particular gp41 sequences deleted in the ALVAC constructs, whereas vaccinated voluteers do not. New gp41 ELISA assays have been developed specifically for this purpose.

In summary, the HIV-1 vaccine field has progressed greatly in the last five years. All candidate vaccines have shown superb safety profiles. Induction of humoral antibodies by subunit envelope proteins has been achieved, while recombinant vector-based vaccines have induced detectable CTL responses. Combination regimens can elicit both responses in most individuals. One challenge still to be addressed is the strain specificity of the antibody responses. In general, it has been difficult to neutralize or kill wild-type HIV-1 as compared to laboratory-adapted HIV-1 strains. Moreover, the vaccines and vaccine regimens have tended to be monovalent. Whether protection to heterologous challenge will occur is unclear. It may require a clinical trial to answer these issues. Many authorities feel that if we are to make progress in defining what standards a vaccine regimen must meet in order to interrupt HIV-1 transmission, we must study such transmission directly. Thus, a well-designed proof-of-concept vaccine efficacy trial is the next apparent step in HIV-1 vaccine development. In these authors' opinions, the safety of the current products, their current immunogenicity, and the continued spread of HIV-1, despite the best educational efforts, indicate that such a clinical trial is warranted.

Matthew Meldorf was Staff Physician at the AIDS Vaccine Evaluation Unit from 1996-1997. He is currently a Clinical Instructor at the Greater Baltimore Medical Center.

Lawrence Corey is a Co-Principal Investigator of the AIDS Vaccine Evaluation Unit, and Head of Infectious Disease at the Fred Hutchinson Cancer Research Center. HIV; Advances in Resistance & Therapy 1997; 7(1): 24-28. Reprinted courtesy of Cliggott Communications, c 1997.

Volunteers are encouraged to participate. Volunteers must be:

* HIV negative

* healthy

*18-60 years of age

* living in the area for the next 18-24 months

For more information, please call 667-2300. http: weber.u.washington.edu/~vaccine/

Studies enrolling, Summer 1997 014C to evaluate the safety and immunogenicity of the Therion recombinant vaccinia-HIV-1IIIB env/gag/pol vaccine (TBC-3B) and MN rgp120/HIV-1 in alum. Volunteers in 014C must never have been vaccinated for smallpox. 031 to study safety and immunogenicity of Apollon HIV-1 gag/pol DNA vaccine (APL-400-047) Vaccine will be given either intramuscularly by needle and syringe or by Biojector 2000r Needle-free Jet Injection SystemT 202 to study further safety and immunogenicity of live recombinant canarypox (ALVAC-HIV vCP205) with or without HIV-1 SF-2 rgp120 This is the second phase II study done by the AVEG.

We are also conducting a study of people who have been exposed to HIV but who remain uninfected. Individuals who fit this profile should also call 667-2300.

References

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These articles were provided by the Seattle Treatment Education Project - Copyright (c) 1997 - Seattle Treatment Education Project. Noncommercial reproduction encouraged. Distributed by AEGIS - http://www.aegis.com

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