From: 

Progress in HIV Vaccine Development
Thirteenth Meeting of the International Society for Sexually
Transmitted Diseases Research
July 11-14, 1999
Denver, Colorado

Richard P. DiCarlo, MD, Associate Professor of Medicine, Louisiana State University School of Medicine, New Orleans, Louisiana

Introduction

What is the state of HIV vaccine development? At a session devoted to this topic on Tuesday, a number of experts in vaccine research and development presented recent findings in the clinical setting.

The Pipeline: Glycoproteins, Vaccinia, Canarypox

During the past 15 years there has been some progress toward the development of an effective vaccine for the prevention of HIV, but there is still much work to be done.  Candidate vaccines with excellent safety and immunogenicity profiles have been developed. However, the correlates of immune protection are not completely understood, nor is the role of mucosal immunity. While antibody responses and cytotoxic T lymphocyte (CTL) responses to existing candidate vaccines have been studied, we do not fully understand the extent of these responses that will be required for protection.

In a session on Tuesday, Dr. Margaret I. Johnston of the National Institutes of Health reviewed the various vaccines in development.[1] The earliest work on HIV vaccines focused on envelope glycoprotein subunits (such as gp120 and gp160), and this work is ongoing. Beginning in the mid-1990s, increasing attention has been given to  the importance of a good CTL response for vaccine function, and in the late 1990s there has been greater focus on the use of attenuated viruses (such as vaccinia and canarypox) as vectors for antigen delivery. The AIDS Vaccine Evaluation Group (AVEG) has enrolled more than 3000 volunteers in 50 phase I and phase II trials employing these strategies.

Envelope glycoprotein vaccines have proven to be safe and immunogenic. They induce T-helper proliferative responses and neutralizing antibody (NA) responses, although the NA tends to be clade-specific. One potential problem with this approach is that these glycoprotein vaccines do not induce a vigorous CTL response.  (However, it should be kept in mind that this has not been shown to be necessary for vaccine efficacy.) Since monovalent vaccines may stimulate antibodies that can neutralize only a limited number of virus strains, bivalent vaccines that are more broadly reactive have been developed. The first phase III trial of an HIV vaccine using a bivalent recombinant glycoprotein 120, produced by VaxGen, Inc. of San Francisco, began last summer (see below).

Viral vectors that express HIV antigens are appealing because they can induce a good antibody response and they have a greater likelihood of inducing a CTL response. The first one tested was an attenuated vaccinia virus that expressed env, gag, and pol genes. Other vaccinia vectors are under development. Unfortunately, vaccinia vectors pose two potential problems. First, individuals with immunity to vaccinia do not mount good responses to the vector. Second, immunocompromised persons who receive these vaccines have some risk of developing disease from even attenuated vaccinia virus. 

Attenuated canarypox virus avoids both of these problems, and many candidate canarypox vectors have been developed. The virus most extensively studied is vCP-205 (see below). The percentage of persons who develop a CTL response after vaccination with viral vectors is variable. However, when it does develop, the CTL response appears to be both long-lasting and capable of cross-clade killing. A phase I trial with vCP-205 is underway in Uganda and is the first African study using this vector.

Other vaccine strategies are in early trials. Several polyvalent peptide vaccines, two DNA vaccines, and a Salmonella typhi vector expressing gp120 have all been tested on humans in phase I trials. Other candidate vaccines are in preclinical development.  However, Dr. Jack Nunberg and colleagues have developed what may be the most innovative approach to date in mice.[2] He has incubated cells that express the envelope proteins of primary HIV isolates with cells that express CD4 and CCR5 receptors. The culture is fixed at some point during cell fusion, and a so-called fusion-competent protein, which appears only transiently, is thus trapped. When transgenic mice are immunized with this transient protein, they develop an antibody response that can neutralize primary isolates across all clades. This approach is in the very early stages of development.

Research priorities in the future are diverse. Promising vaccine candidates that have gone through phase I and II trials will require evaluation by larger efficacy studies.  Newer candidate vaccines need continued development. Novel approaches to vaccine delivery systems that enhance the mucosal immune response should be investigated.  Finally, assays that measure CTL response should be refined so that we have a better understanding of the correlates of immune protection. Clearly, much has been done toward the development of an HIV vaccine, but serious challenges lie ahead.

Canarypox + rgp120

Dr. Robert Belshe of the St. Louis University School of Medicine reported on the recently completed, multicenter, phase II trial of vCP-205.[3] This trial was designed to provide expanded safety and immunogenicity data of the vector alone and combined with recombinant glycoprotein 120 (rgp120). These parameters were evaluated in HIV-1-seronegative volunteers recruited from both low- and high-risk groups. The study was also designed to assess volunteer behavior and the extent to which behavioral issues influence the feasibility of conducting expanded efficacy trials.

Volunteers received either the vector plus rgp120, the vector plus saline, or placebo plus saline at 0,1,3, and 6 months. Safety and immunogenicity evaluations were done after each dose. Risk assessment, counseling, and HIV testing were conducted every 3 months. Over 400 volunteers were enrolled. The vaccine was extremely well-tolerated. Binding antibodies developed in over 90% of the volunteers who received the vaccine, but the NA response was best in those who received the vector plus rgp120. (In contrast, other studies have demonstrated that significantly higher NA titers are achieved when volunteers receive the vector alone initially and later receive a booster dose of rgp120.) At any point in time, approximately 30% of vaccinated volunteers demonstrated a CTL response. If assessed repeatedly over 2 years, approximately 60% show evidence of a CTL response at some point. 

The behavioral data suggest that larger efficacy trials are feasible. Most volunteers felt that participation in the trial had a positive impact on their lives. Some experienced a negative impact on personal relationships as a result of participation in the trial, but very few experienced other problems (including problems with insurance companies).  Overall, there was a net decrease in risk behavior among study participants. This suggests that volunteers understood the nature of the study and did not have a false sense of security, an issue of concern for the testing of candidate vaccines in high-risk populations.

Although there were some incident HIV infections in both the vaccine and placebo volunteers, the trial was not designed to evaluate efficacy. In summary, the results suggest that vCP205 with rgp120 boost is a plausible candidate for efficacy trials.

Phase III Efficacy Trials of Bivalent rgp120 AIDSVAX[tm] B/E
and B/B Vaccines in Uninfected Injecting Drug Users (Thailand)
and Men Who Have Sex With Men (North America) - A Progress
Report - Donald P. Francis, VaxGen, Inc.

The only phase III efficacy trials of an HIV vaccine to date have begun within the past 13 months. One is being conducted in North America and Europe, the other in Thailand; both are evaluating a bivalent rgp120. There are considerable data to suggest that gp120 may be the appropriate antigen for a vaccine. It is the major surface protein, and it mediates virus attachment to both CD4 and chemokine receptors. Most NA in HIV-infected individuals is directed toward gp120, and antibody to rgp120 can neutralize HIV in vitro. Immunization with rgp120 has protected chimpanzees from infection with homologous and heterologous strains of HIV-1. Finally, recombinant glycoprotein vaccines have been effective for other sexually transmitted viral infections, such as hepatitis B virus. Dr. Donald P. Francis of VagGen, Inc. provided a progress report on the trials of this promising bivalent glycoprotein vaccine.[4]

There has been some question about whether recombinant envelope glycoprotein will elicit an immune response that is sufficient to offer protection. One concern has been the relative lack of a CTL response, although the extent to which this is necessary for protection is unknown. An additional concern has been the breadth of the antibody response. This problem appears to have been resolved with the development of a bivalent vaccine. Antibodies elicited after receipt of monovalent rgp120 were not capable of neutralizing many virus strains. These "breakthrough" strains were analyzed, and rgp120 from a second strain was added to the vaccine. The viruses used for the North American vaccine are MN and GNE8. Both are clade B viruses, but they employ different chemokine receptors (one is syncytial-forming and one is non-syncytial-forming), and they differ at several key epitopes on gp120. Antibodies induced by this bivalent vaccine are more broadly reactive and are capable of neutralizing primary HIV isolates.

Data from phase I studies of rgp120 indicated that it is safe and highly immunogenic.  No serious adverse events were reported. In addition, the rate of false positive HIV-1 ELISA tests in vaccinated subjects appeared to be quite low (<5%). Subjects who test falsely positive on screening tests can easily be distinguished from infected
individuals by Western blot assay. The safety and immunogenicity data suggested that this was a reasonable candidate for further study. The question of whether NA alone will be sufficient for protection can only be answered through the conduct of carefully designed efficacy trials.

The North American trial is ongoing at 60 sites. This study is focusing on sexual transmission of HIV, and MSM comprise the majority of the study population (although some high-risk women have also been enrolled). Five thousand subjects will be enrolled, randomized to receive vaccine or placebo in a 2:1 ratio, and followed for 3 years (more than 3500 have been enrolled to date). A second study is ongoing in Thailand. The vaccine used in this study contains rgp120 from the MN strain along with that from a clade E strain.

If a Vaccine is Effective, What's Next?

Dr. William L. Heyward of the CDC addressed the difficult problems posed by a successful phase III clinical trial demonstrating reasonable efficacy in the prevention of HIV infection.[5] As he stated, we will be better off if we begin to address these questions now, so that effective vaccination programs can be implemented as soon as possible. 

Degree of Efficacy

One of the first issues that will need to be addressed is the level of efficacy required for approval. This decision is likely to be made on a country-by-country basis. In areas of relatively low HIV prevalence, a vaccine with relatively high efficacy will be necessary in order to have a beneficial impact. In high-prevalence areas, a vaccine with relatively low efficacy may still have an enormous impact on control of the epidemic. Since it is unlikely that we will have a vaccine that approaches 100% efficacy, vaccines will have to be administered in the context of broader education and counseling programs that can enhance their effectiveness.

Follow-up

Phase IV studies with tens of thousands of enrollees will be required to better understand the safety, acceptability, and effectiveness of these vaccines in clinical settings. The CDC will need to conduct surveillance studies to assess breakthrough infections, epidemics, and adverse events. Molecular epidemiologic studies to investigate potentially new virus subtypes will also be necessary.

Complete Programs

Guidelines for vaccine use will have to be developed. Vaccines cannot be expected to replace counseling and risk-reduction programs. Implementation of vaccine programs will require support. Since the most at-risk persons tend to be in marginalized populations, trust in the vaccine and in government agencies will have to be established. This will require mass outreach and education campaigns. Finally, in order to successfully vaccinate high-risk persons of limited means, government agencies will need both financial and technical assistance.

Use Outside of Tested Region

One additional dilemma of great concern involves the decision to implement vaccine programs in geographic regions where the vaccine has not been tested. If a type-specific vaccine is found to be efficacious in North America, should we proceed to implementation programs in areas of great need (such as sub-Saharan Africa) as quickly as possible, or will we need to conduct additional phase III trials with other type-specific vaccines first? These questions are complex and raise scientific, ethical, and financial concerns. We would do well to begin addressing these issues now.
 

References

1.Johnston MI: Overview: What is in the pipeline? (Symposium VI: Progress in HIV Vaccine Development) Thirteenth Meeting of the International Society for Sexually Transmitted Diseases Research, July 11-14, 1999, Denver, Colorado. 

2.LaCasse RA, Follis KE, Trahey M, et al: Fusion-competent vaccines: broad neutralization of primary isolates of HIV. Science 283(5400):357-62, 1999 Jan 15. 

3.Belshe R: Phase II safety and immunogenicity trial of live recombinant canarypox ALVAC-HIV (vCP205) and HIV-1 SF-2 rgp120 in HIV-1 uninfected adult volunteers. (Symposium VI: Progress in HIV Vaccine Development) Thirteenth Meeting of the International Society for Sexually Transmitted Diseases Research, July 11-14, 1999, Denver, Colorado. 

4.Francis DP: Phase III efficacy trials of bivalent rgp120 AIDSVAX B/E and B/B vaccines in uninfected injecting drug users (Thailand) and men who have sex with men (North America): A progress report. (Symposium VI: Progress in HIV Vaccine Development) Thirteenth Meeting of the International Society for Sexually Transmitted Diseases Research, July 11-14, 1999, Denver, Colorado. 

5.Heyward WL: What do we do when a vaccine is proven to prevent HIV?  (Symposium VI: Progress in HIV Vaccine Development) Thirteenth Meeting of the International Society for Sexually Transmitted Diseases Research, July 11-14, 1999, Denver, Colorado. 

[Medscape, 1999. © 1999 Medscape, Inc.]