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Therapeutic Vaccination: Where Are We Now?

Therapeutic vaccination of HIV-infected individuals remains a compelling and controversial topic. To discuss the progress and setbacks of research into this intervention, as well as its potential clinical usefulness, ACC Executive Editor Matthew O'Rourke interviewed Eric S. Rosenberg, Assistant Professor of Medicine at Harvard Medical School and Massachusetts General Hospital.

Therapeutic vaccination of HIV-infected individuals remains a compelling and controversial topic. To discuss the progress and setbacks of research into this intervention, as well as its potential clinical usefulness, ACC Executive Editor Matthew O'Rourke interviewed Eric S. Rosenberg, Assistant Professor of Medicine at Harvard Medical School and Massachusetts General Hospital.

What are the basic principles and rationale behind therapeutic vaccination?

HIV is unique among chronic viral infections in that it is not well controlled by the host immune system. With Epstein-Barr virus infection, for instance, the virus cannot be eradicated from the body, but immunocompetent individuals are able to control EBV so that it remains latent and is not constantly replicating. With HIV infection, the body does a relatively poor job at controlling viral replication. The major principle underlying immune-based HIV therapies is to induce the immune system -- through either immunization or vaccination -- to do a more effective job at controlling viral replication.

It remains unclear exactly which elements of the immune system need to be stimulated in order to generate an effective response against HIV. There are a couple of schools of thought. The first school says that you need to induce an immune response that closely mirrors what the body does against other viral infections; thus, you need to induce both HIV-specific T-helper-cell and HIV-specific cytotoxic T-cell (CTL) responses, and maybe even HIV-specific neutralizing antibody responses. This is the ideal picture of immune boosting, in which you are able to augment all arms of the immune system. However, we don't know whether or not this ideal scenario is practical, nor whether it is necessary for therapeutic vaccination. So the second school of thought says that there might be ways of bypassing the need for HIV-specific help, such as using adjunctive cytokine stimulation or bypassing the need for CD4 help with stimuli like CD40/CD40 ligand.

HIV-1 Immunogen, or Remune^TM, is the therapeutic vaccine that has been most studied to date. How does this agent work, where is it in clinical development, and what should we make of contradictory data regarding its efficacy?

Remune was developed by Jonas Salk in the late 1980s and is derived from whole inactivated HIV stripped of its envelope proteins and linked with an incomplete Freund adjuvant to further augment immune response. The principle of Remune is to induce HIV-specific T-helper cell responses, which, it is hoped, will in turn augment any existing HIV-specific CTL responses. The history of the scientific evaluation of this vaccine is an unfortunate one, and several issues muddy the water when we look at the clinical-efficacy data. For various reasons, we have no conclusive evidence regarding whether or not Remune works. Kahn and colleagues published data from a randomized, placebo-controlled trial of Remune in 2500 HIV-infected patients enrolled between 1996 and 1997. They were unable to show any clinical benefit from Remune, and the study's Data Safety Monitoring Board had already discontinued the trial for this very reason. The study was designed, and its clinical endpoints of AIDS or death were selected, before we understood how efficacious PI-based combination therapy would be. Most of the enrolled patients in both arms received combination antiretroviral therapy and so had no, or slowed, disease progression. Thus, in the interim analysis, the experts concluded that the vaccine arm couldn't reach either of its clinical endpoints. When a study cannot reach its clinical endpoints, it is labeled a failure. But in this case, the fault lay in the chosen endpoints having become outdated, and not necessarily in the vaccine itself. Combined with recriminations between industry and academic researchers, these problems with study design have hampered the ability of investigators to study further the clinical utility of HIV-1 Immunogen.

I'm part of a research team at Massachusetts General Hospital that a paper in press reporting results of a trial designed to show immunologic benefit with Remune. This small pilot study documents a significant increase in HIV-specific T-helper cell responses with therapeutic vaccination. What we don't know is whether these vaccine-induced HIV-specific responses will translate into any clinical benefit. In a study presented at the 14th World AIDS Conference in Barcelona from a placebo-controlled trial of Remune in 243 chronically infected patients receiving antiretroviral therapy, Fernandez-Cruz and colleagues found that therapeutic vaccination resulted in significant increases in HIV-specific T-helper cell and CTL responses, and reductions in viral load. The possibility of a clinical benefit from Remune needs to be addressed in larger trials. Of note, therapeutic vaccine studies are very expensive, and the likelihood of any given agent working is relatively small, so funding these trials is challenging.

You alluded to controversies between academic researchers and manufacturers over the publication of the article by Kahn. Do these controversies persist? Are they important in how HIV physicians should evaluate Remune?

Many of the academic researchers felt that the manufacturer was trying too hard to spin the results to put the vaccine in a favorable light. In addition, the large pharmaceutical company that partnered with the biotech firm that developed Remune has been purchased a couple of times, and the eventual parent company decided that, given the level of controversy surrounding this agent, studying it was no longer a worthwhile investment. Taken together, these developments have helped lead to a situation in which, to this day, we have no idea whether this 17-year-old vaccine belongs in our therapeutic armamentarium. People have very strong feelings either for or, more commonly, against Remune, and these feelings have gotten in the way of evaluating this agent objectively.

Other than Remune, what therapeutic vaccines are in the pipeline, and how do their mechanisms of action differ?

Most therapeutic vaccines being investigated are DNA-based, and most of these are being studied first as preventive rather than as therapeutic vaccines; however, therapeutic uses for these agents are being discovered. In fact, although Remune is by far the furthest along in clinical development of any therapeutic vaccine, the proof-of-principle for therapeutic vaccination came recently from 2 studies of DNA-based preventive vaccines.

In the first, Amara and colleagues at Emory University immunized rhesus monkeys with a DNA prime followed by a recombinant modified vaccinia Ankara booster, both of which contained multiple HIV proteins. The monkeys were then challenged with a virulent strain of SIV. The DNA vaccine did not prevent SIV infection in any of the monkeys; however, the immunized animals did extremely well at controlling SIV infection compared with nonimmunized controls. These researchers are now planning to study this vaccine in both HIV-negative (as a preventive agent) and HIV-positive individuals (as a therapeutic agent).

In the second study, Barouch and colleagues at Beth Israel Deaconess Hospital and Harvard Medical School immunized rhesus monkeys with a DNA-based vaccine expressing SIV Gag and HIV Env genes and boosted by a plasmid that stimulated interleukin-2 (IL-2) production. The results were very similar to those in the Emory study. All of the monkeys became infected when challenged with SIV. However, all of the vaccinated monkeys were able to control viral replication, whereas all of the monkeys who received placebo demonstrated progressive disease.

In both of these studies, DNA vaccination augmented CTL and CD4-cell responses against SIV. The usual caveats about preliminary animal studies apply, but these results raise the hope for developing a therapeutic vaccine for humans. In a follow-up to the study by Barouch, however, the virus managed to escape the vaccine-induced immune response in one of the immunized monkeys. A pessimist would view this as bad news indeed, because this case of viral escape suggests that even if we develop a therapeutic vaccine that works, the virus is extremely smart and might be able to outwit the resulting immune response.

Another area of research is dendritic-cell vaccines. These vaccines are designed to retrain the host immune system to fight HIV by loading up a patient's dendritic cells -- which are the best antigen presenters, or coaches, of the immune system -- with known HIV epitopes in vitro, then reintroducing these cells into the host. Bhardwaj and colleagues have successfully created dendritic-cell flu vaccines using influenza epitopes. Several groups of researchers, including our own, are now investigating dendritic-cell vaccines as immunotherapy for HIV-infected individuals. We don't yet have any data, but this is the latest area of therapeutic vaccine research.

How might therapeutic vaccination be used with structured treatment interruptions or other immune-boosting strategies or therapies?

We were studying the use of Remune in 40 chronically infected individuals with good responses to antiretroviral therapy and viral loads less than 50 copies/mL for several months. We were planning to initiate structured treatment interruptions with these patients, on the principle that if we augmented T-helper-cell responses by therapeutic vaccination and then augmented CTL responses by exposing patients to their own autologous virus during a treatment interruption, the CTL responses would be maintained by the presence of the augmented T-helper-cell responses. We had just started immunizing patients when the parent pharmaceutical company decided to discontinue all Remune studies.

In all likelihood, for Remune to work, it will have to be used as an adjuvant with other immune-boosting strategies, such as structured treatment interruption, or other immune-boosting agents, such as IL-2. For DNA-based vaccines, we don't know whether this will be necessary; hopefully it won't be. I'm currently working with Barouch's team, however, on a study using a promising DNA vaccine in patients identified and treated during acute HIV infection to determine the safety and immunogenicity of this agent.

Do the links between research into therapeutic vaccines and research into a preventive vaccines remain close? Do any of the same issues of genetic diversity and cross-clade protection apply?

I'll start with your second question. The extent of the challenge posed to the development of immune-based therapies or vaccines by the genetic diversity of HIV remains unknown, but recent documented cases of superinfection suggest that it could be significant. Our group just published a paper in Nature in which we describe a particular case in our cohort of individuals who underwent structured treatment interruptions after being diagnosed and treated during acute infection. During this patient's first interruption, he did reasonably well, but he met our criteria to restart therapy. Coming off therapy a second time, he showed a real broadening of his immune responses, and stayed off therapy for approximately 300 days, with excellent virologic control. Then, almost overnight, his viral load shot up. He went back on therapy, then interrupted it for a third time, and did poorly.

We thought that, similar to the monkey in the follow-up paper by Barouch, this patient's virus had somehow outwitted his immune response. However, when we sequenced his viral isolates, we found that he had become infected with a new virus during his second treatment interruption. Thus, we have documented the second known case of HIV superinfection. While the case recently published in the New England Journal of Medicine concerned superinfection with a new clade of HIV, in our patient both viruses were clade B. Thus, his second virus was genetically very similar to his first virus, but the patient's immune response was not able to protect against its introduction. Even if you aren't pessimistic about the opportunities for vaccine development, this case sounds alarm bells. After all, the goal for both therapeutic and preventive vaccines is to develop an agent that will offer protection against all HIV clades. In this case, an excellent immune response against HIV wasn't even able to protect against a distinct virus from the same clade.

As for the connection between the 2 fields of vaccine research, I think it remains close; there is still a lot of hope that a therapeutic vaccine will be developed out of our attempts to make a preventive one, as well as a lot of hope that one day we will finally know enough about the immunobiology of HIV to create an effective preventive vaccine.

— Eric S. Rosenberg, MD

Dr. Rosenberg is Associate Editor of ACC.

Published in Journal Watch HIV/AIDS Clinical Care January 1, 2003

FURTHER READING

Altfeld M et al. HIV-1 superinfection despite broad CD8+ T-cell responses containing replication of the primary virus. Nature 2002 Nov 28 ; 220:434-9.

Amara RR et al. Control of a mucosal challenge and prevention of AIDS by a multiprotein DNA/MVA vaccine. Science 2002 Apr 6 ; 292:69-74.

Barouch DH et al. Control of viremia and prevention of clinical AIDS in rhesus monkeys by cytokine-augmented DNA vaccination. Science 2000 Oct 20 ; 290:486-92.

• Original article (Subscription may be required)
• Medline abstract (Free)

Barouch DH et al. Eventual AIDS vaccine failure in a rhesus monkey by viral escape from cytotoxic T lymphocytes. Nature 2002 Jan 17 ; 415:335-9.

• Medline abstract (Free)

Bhardwaj N et al. Influenza virus-infected dendritic cells stimulate strong proliferative and cytolytic responses from human CD8+ T cells. J Clin Invest 1994 Aug; 94:797-807.

Fernandez-Cruz E et al. Three-year evaluation of a therapeutic vaccine (HIV-1 Immunogen) administered with antiretrovirals versus antiretroviral therapy alone in patients with HIV chronic infection. 14th World AIDS Conference, July 7-12, 2002, Barcelona . Abstract ThOrA1482.

Goulder PJ and Walker BD. . HIV-1 superinfection -- A word of caution. N Engl J Med 2002 Sep 5; 347:756-8.

Jost S et al. A patient with HIV-1 superinfection. N Engl J Med 2002 Sep 5 ; 347:731-6.

• Original article (Subscription may be required)
• Medline abstract (Free)

Kahn JO et al. Evaluation of HIV-1 Immunogen, an immunologic modifier, administered to patients infected with HIV having 300 to 549 x 106/L CD4 cell counts. JAMA 2000 Nov 1 ; 284:2193-202.

• Original article (Subscription may be required)
• Medline abstract (Free)

Letvin NL et al. Prospects for vaccine protection against HIV-1 infection and AIDS. Annu Rev Immunol 2002; 20:73-99.

• Medline abstract (Free)