Treatment Issues, Volume 12, Number 10 - October 1998
Luis Santiago

The primary objective of the study is to determine if this vaccine protects individuals from HIV infection. According to study researchers, the size of the cohort (5,000) plus the 2:1 ratio selected between vaccine and placebo recipients, will allow them to determine if the vaccine achieves even moderate levels of efficacy. As a secondary objective, the study will investigate whether the vaccine has any impact on HIV viral load on those participants that get infected despite vaccination. Beyond the potential efficacy effect of the vaccine, the VaxGen phase III trial is also being closely watched as a demonstration of industry's capability to successfully conduct these large trials in the U.S. and Asia.

The Product Being Tested

The candidate vaccine being tested in the U.S. is called Bivalent AIDSVAX B/B vaccine. It is made of recombinant versions of the HIV surface protein gp120 produced by genetically engineered bacteria. It is called bivalent because recombinant gp120 (rgp120) has been derived from two different strains of the HIV subtype B, by far the most common HIV subtype circulating in the U.S. The two B subtype strains used are the MN and the GNE8. The product to be tested in Thailand is called Bivalent AIDSVAX B/E. It includes rgp120 derived from a subtype B strain (MN), and also from a subtype E strain (A244). E is the most common subtype in that country.

The original VaxGen product, which has been administered in clinical studies to more than 1,100 people, consisted of rgp120 from only one strain (MN or IIIB) of the virus. This "monovalent" vaccine was shown to be safe, causing only minor adverse reactions, such as pain and inflammation at the injection site, common with many vaccines. Of these 1,100 people, about 600 were HIV-negative individuals enrolled in phase I and phase II studies of this product as a preventive vaccine. The rest were HIV-positive individuals who participated in the therapeutic studies of this vaccine.

Studies have demonstrated that this vaccine protects chimpanzees from infection with HIV. Because chimpanzees can get infected with HIV but almost never develop AIDS, they are not considered an ideal "animal model" for testing a human HIV vaccine. Nevertheless, there was a clear difference in these studies between vaccinated and unvaccinated chimpanzees: While all the unvaccinated animals got infected when challenged with HIV, all the vaccinated chimps, two in one study and three in the other, were protected. (In the first study, the chimps were challenged using the same HIV strain - IIIB - that was the basis for the vaccine with which they were vaccinated. In the second study, the vaccine strain - MN - differed from the challenge strain, SF2.)

Human phase II studies showed that most participants developed neutralizing antibody responses against viruses of the same strain the vaccine was made from, or other closely related lab-adapted viruses. Both MN and IIIB are considered lab-adapted viruses because they are grown in laboratory cell lines. The vaccine-induced antibodies, however, were not able to neutralize "primary isolates" of HIV, that is, virus obtained from infected people. A total of 11 high-risk participants in the phase II rgp120 MN studies got infected with HIV despite being vaccinated - nine in the U.S. and two in Thailand. Breakthrough infections such as these are expected in these initial trials, and they must be carefully interpreted since these studies were not designed to demonstrate efficacy.

In a panel held during the 12th World AIDS Conference last summer in Geneva, Switzerland, VaxGen researcher Phillip Berman presented his company's scientific strategy for the development of their vaccine. Regarding the 11 breakthrough HIV infections on the rgp120 MN studies, they attribute four of them (three in the U.S. and one in Thailand) to an incomplete immunization schedule. Of the remaining seven, five were infections with a virus of a different subtype (Thailand), or a different strain (U.S.). Their conclusion is that, although their product seems to achieve some level of protection, it could be improved by adding another type of rgp120, one that is structurally similar to the most common HIV subtypes and strains in a particular country or region. This is exactly what the new "bivalent" products are. In this model, referred to as the "sieve" strategy, every successive efficacy trial will look at the HIV strains that caused the breakthrough infections, create a recombinant version of its gp120, and add it to the vaccine. In the end, a variety of polyvalent vaccines may be created.

Ready or Not...

Other researchers and community advocates question this conclusion, mainly because the number of cases on which the analysis is based is very small and the phase II studies were not designed for this type of analysis. "You can't say, on the one hand, that the breakthrough infections don't tell us anything about vaccine efficacy, and then use these same data to suggest the vaccine works against some strains and not others," says International AIDS Vaccine Initiative's (IAVI) Newsletter editor and community vaccine advocate David Gold.

There might be other reasons why this vaccine did not work for these individuals. It is possible that the concentration of neutralizing antibodies was not enough to prevent HIV from establishing a foothold. It could also be that the vaccine version of gp120 is too "different" from the real protein gp120 at the surface of the virus. Other researchers argue that more work should be done with these types of vaccines before they are tested for efficacy in large numbers of people. Some of this work would involve modifying the structure of the vaccine and the way it is presented to the immune system in order to achieve a more significant antibody response.1 Others believe an HIV vaccine will only be truly effective if it stimulates a different kind of immune response, know as cellular or CTL response, something the VaxGen vaccine does not do. Unfortunately, products that generate these type of responses are not ready yet for phase III trials (see below).

Nevertheless, VaxGen has its own solid arguments for the study, especially the data showing this vaccine is safe, that it protected chimpanzees from HIV infection and that it generates strong anti-HIV antibody responses. According to VaxGen, data from the phase II studies of its new bivalent vaccine show that antibodies are being generated in most participants against both the GNE8 and the MN strains and that this supports moving ahead to efficacy studies. The general opinion among community vaccine advocates, including David Gold and Sam Avrett from the AIDS Vaccine Advocacy Coalition (AVAC), is that on the whole the trial is a step forward, and may give a clear answer to the question of whether or not AIDSVAX is efficacious. Moreover, VaxGen deserves credit for launching the study with private, not public, financing.

Reaching the High-Risk Individuals

One concern that has been raised about the study is related to its ability to recruit high-risk participants. The current inclusion criteria are: (1) HIV-negative men that have had anal intercourse within the past 12 months. Those in a continuous monogamous sexual relationship of 12 months or more with the same HIV-negative partner will be excluded; (2) HIV-negative women with a current sexual relationship with an HIV-positive male partner, or more than one male sexual partner and one or more STDs (sexually transmitted disease) in the last 12 months. (Criteria for women are currently undergoing change.) Injection-drug users (current or past), pregnant women and recipients of any previous HIV vaccine are excluded from the U.S. trial. The sample size selected for the study assumes a 1.5% yearly incidence of new infection, a rate based on the cohorts of men who have sex with men (MSM) identified and studied by the HIV Network for Prevention Trials (HIVNET).

Not all the sites involved in this study have the same level of expertise regarding the recruitment and follow-up of high-risk individuals. A cohort with a slightly lower incidence might make the results of the trial inconclusive, or it may require increasing the number of participants, thus adding to the cost of the study.

Risk Reduction Counseling

One of the dilemmas associated with the study of preventive HIV vaccines is the ethical requirement to provide participants, most of whom are individuals who engage in high-risk behavior, with effective counseling on the need and the ways to reduce the risk of getting infected. Good counseling practices, which have been developed over the last decade, can function as well as a "partially effective" vaccine. In a recent meeting in New York, VaxGen's John Jermano and Phillip Berman presented their plan to community advocates and research staff from sites considering joining the study. One of the most serious concerns raised was the lack of a formal counseling protocol to be followed by all sites. Sites are being instructed to follow the Centers for Disease Control (CDC) counseling guidelines, which are considered by VaxGen to be the community "standard." Advocates and researchers argued for a more formal approach, especially since many of the sites have no experience counseling high-risk individuals. The lack of a consistent counseling protocol that can be monitored and measured, including all pertinent counseling material, puts the study on shaky ethical ground.

Participants' Informed Consent

Another issue that has been brought up by some community advocates is the need to inform participants about the controversy surrounding large-scale human testing of this particular product. A study by the University of California San Francisco presented at the Geneva Conference interviewed 90 individuals from communities likely to be targeted for HIV vaccine studies.2 This group included African Americans, gay men and intravenous drug users from Durham, NC, San Francisco and Philadelphia, respectively. These potential participants clearly expressed that they want "to know the history of the vaccine, why it is being tested, and what its problems have been in the past." VaxGen's study's informed consent clearly states that it is not known whether this vaccine will provide protection against HIV infection. This is, however, a standard statement for all vaccine efficacy trials. Part of the history of this vaccine is the decision made by the National Institute of Allergy and Infectious Diseases (NIAID) four years ago not to go ahead with efficacy studies of the original monovalent product. Some community advocates believe that, at minimum, this fact should be included in the informed consent document.

Other Vaccines in the Pipeline

Among other HIV vaccine candidates, Pasteur-Merieux Connaught's ALVAC-HIV is closest to human efficacy trials. The vaccine consists of a collection of HIV genes packed into the canarypox virus, which infects but does not cause disease in humans. Phase II studies of this vaccine have shown it can induce cellular responses in 40% to 60% of vaccinees, although these responses are not long-lasting. This vaccine is then combined with a "booster," which can be rgp120 or rgp160, to induce the other arm of the immune system, antibody production. Combining both sets of immune responses, the cellular and the humoral (antibodies), may create a more complete immune response that targets HIV-infected cells and free virus, increasing the potential for successful immunization.

In fact, this vaccine was almost ready to move to efficacy studies, but the company decided not to go ahead with the current version or construct, which is called vCP205. It is currently developing newer constructs that might induce stronger and more diverse cellular responses. Phase I studies of some of these constructs have started in France and the United States. Efficacy studies are not planned until at least the year 2000.

A phase I study of the original vCP205 product is due to start in Uganda this year, making it the first HIV vaccine to be tested in Africa. The objective of the Ugandan study is to evaluate the nature of the CTL immune responses generated by the vaccine. Most HIV-positive Ugandans are infected with HIV subtypes A and D, while the product being tested only includes genes encoding for subtype B core proteins. But there are data from vaccinated individuals suggesting CTL immune responses against HIV subtypes A, E and C are being induced in some participants by the subtype B-based vaccine. Pasteur-Merieux Connaught is also developing a new generation of canarypox constructs based on HIV subtypes found in Uganda and elsewhere in Africa.3

The Big Picture

There is no question that preventive HIV vaccines are getting more attention than ever. Recent speeches by Anthony Fauci, Director of NIAID, and Neal Nathanson, Director of the Office of AIDS Research (OAR), emphasized the need for increased research on vaccines. Major policy organizations, such as the American Foundation for AIDS Research and AIDS Action Council, claim that HIV vaccines are part of their advocacy agenda. More concretely, National Institutes of Health (NIH) spending for preventive vaccine research rose in the projected FY 1999 budget to about 10% of the NIH AIDS research budget. Officials from the NIH Division of AIDS reiterated at a recent meeting of their AIDS Research Advisory Committee (ARAC) that discovery and development of HIV vaccines and other prevention interventions are among the highest priorities of the NIH AIDS research program.

Still, these increased efforts face daunting challenges. One of these is the unwillingness of large pharmaceutical companies to invest in HIV vaccine development. Pasteur-Merieux Connaught's HIV vaccine development program stands alone as the only comprehensive program of its kind among these large corporations. Merck is devoting increasing resources to its DNA-based vaccine research (see chart on page 4). Wyeth-Lederle is collaborating with Apollon on DNA vaccine development. But other traditional vaccine manufacturers such as SmithKline Beecham have an extremely limited involvement in the development of vaccines for HIV. Several potentially viable HIV vaccine candidates have been languishing in preclinical and phase I limbo due to lack of industry enthusiasm. It remains to be seen what will be NIH's success in advancing newer vaccine concepts, and what they can do to boost industry development of HIV vaccines.

At the 1999 Keystone Conference, progress will be reported on NIH's 1997 Innovation Grants. These OAR funds were channeled to support basic immunology research and vaccine concept development. The results of this research may alter industry's perception of the scientific uncertainty of developing vaccines against HIV, which they claim is a major hurdle for investment. While it is true that we still lack basic knowledge on how to induce protection from HIV, there is plenty of evidence suggesting that it can be achieved.

Footnotes:

1. Burton DR and Moore JP. Nature Medicine Vaccine Supplement, May 1998; 4(5):495-8.

2. UCSF Press Release, Geneva, Switzerland, July 1, 1998.

3. IAVI Report. April-June 1998; 3(2):1, 7.

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