STD Quarterly: World’s first large-scale HIV vaccine trial doesn’t indicate protection for overall population

Scientists won’t give up on their hunt for effective vaccine

The news is in from the world’s first large-scale trial of a HIV vaccine, and it isn’t good: The vaccine failed to achieve a statistically significant reduction of HIV infection within its study population as a whole.

While scientists are debating the analysis of findings from the AIDSVAX B/B vaccine trial, they do agree on one thing: the search must go on to find an effective HIV vaccine. Worldwide, an estimated 5 million people were newly infected with HIV in 2001.1

"AIDSVAX was important because it demonstrated for the first time that we are able to conduct a scientifically sound Phase III trial on a global basis," observes Lawrence Corey, MD, principal investigator of the Seattle-based HIV Vaccine Trials Network (HVTN), a partnership of research scientists, clinical trial sites, and community representatives working with industry and governments in the global HIV vaccine search. "The next step is to continue pressing forward with Phase I and II trials so that scientists can identify the best vaccine candidates to take to Phase III."

In the landmark first trial, 3,330 volunteers received the AIDSVAX B/B vaccine, and 1,679 received a placebo. According to the initial results, the percentage of volunteers who received AIDSVAX and became infected with HIV is statistically equal to the percentage of volunteers who received the placebo and became infected with HIV, meaning that the vaccine is not protective for the overall population.

However, the study did show a statistically significant reduction of HIV infection in certain vaccinated groups, claims VaxGen of Brisbane, CA, the developer of the AIDSVAX vaccine. The results are the first to be reported from the company’s three-year, multinational, randomized, double-blind, placebo-controlled Phase III trials of AIDSVAX.

Initial results from the trial, which tested the AIDSVAX B/B vaccine, yielded the following preliminary findings:

  • The reduction of infection among the entire sample of volunteers, including all racial groups, was 3.8% (p-value = 0.76; n = 5,009).
  • There were 67% fewer HIV infections among ethnic minorities, other than Hispanic individuals, who received vaccine compared to placebo recipients (p-value <0.01; n = 498).
  • There were 78% fewer HIV infections among black volunteers who received vaccine compared to placebo recipients (p-value <0.02; n = 314).

Some scientists question whether the analysis of the AIDSVAX subgroup findings can be statistically significant due to the low numbers of participants within the subgroups. What is the company’s next move?

"VaxGen’s next steps are to finish our analyses by merging our clinical and laboratory data in an effort to find a biological explanation for the efficacy we saw in some subgroups," says company spokesman Jim Key. At press time, a more detailed analysis of the data was set to be presented at the Keystone Symposia on HIV, scheduled for March 29 to April 4 in Banff, Alberta.

Thailand results next

The AIDSVAX vaccine is composed of a recombinant form of the protein (gp120) on the surface of HIV and is produced in mammalian cell culture. The vaccine contains noninfectious, genetically engineered proteins (rgp120) that mimic proteins on the surface of two strains of HIV subtype B. Subtype B is prevalent in North America, Europe, Australia, Japan, and Puerto Rico.

The AIDSVAX B/B trial, conducted in the United States, Canada, Puerto Rico, and the Netherlands, included 5,108 men who have sex with men and 309 at-risk women, all of whom tested HIV-negative when they joined the trial. Three shots, spaced three months apart, were given initially, followed by booster shots every six months. All volunteers were counseled to practice safer sex and not to count on protection from the vaccine.

VaxGen’s Phase III trial in Thailand is testing a formulation of AIDSVAX designed to protect against HIV subtypes B and E, which is prevalent in Southeast and East Asia and the Central African Republic. The trial is to be completed soon, says Key. The company will announce the results of that trial in the second half of 2003, he notes. Unlike the AIDSVAX B/B trial, which tested the vaccine against sexual transmission of the virus, the trial in Thailand is examining the vaccine’s effectiveness against infection acquired by injection drug use. (CTU will report the results of the Thailand trial when the study is completed.)

VaxGen scientists are in the early stage of developing a vaccine against HIV subtype C, prevalent in Sub-Saharan Africa, India, and China. The company is committed to developing increasingly effective formulations of AIDSVAX that target all HIV subtypes.

New approaches in wings

Look to the future for important news on vaccine research. The Bethesda, MD-based National Institute of Allergy and Infectious Diseases (NIAID) is aiding in the development of more than 20 vaccine candidates to prevent HIV infection. Some vaccines are in the early stages of preclinical evaluation, while others are near testing in human subjects. Several new types of HIV vaccines are under investigation, with ongoing trials of adenovirus and canarypox vectors as well as DNA-based vaccines.

Six to eight new clinical trials will move these products forward in safety evaluations in the next 12-18 months, according to the HVTN, which is funded by NIAID. Additional research is being conducted in NIAID’s Dale and Betty Bumpers Vaccine Research Center in Bethesda.

Clinical tests began in November 2002 of a novel vaccine directed at the three most globally important HIV subtypes, or clades. The vaccine, developed by scientists at the NIAID’s research center, incorporates HIV genetic material from clades A, B and C, which cause nearly 90% of all HIV infections around the world. It is the first multigene, multiclade HIV vaccine to enter human trials, according to the NIAID.2

The vaccine includes parts of four HIV genes; three of these vaccine components are modified versions of HIV genes called gag, pol, and nef taken from clade B, the subtype that predominates in Europe and North America. The fourth vaccine component is derived from an HIV gene, env. According to NIAID scientists, the env gene codes for a protein on the outer coat of the virus that allows it to recognize and attach to human cells. The vaccine represents the first attempt to combine modified env from clades A and C, which are the most common in Africa, as well as from clade B. A single vaccine combining multiple env components from different HIV subtypes could be effective in many places in the world, states the NIAID.

Another Phase I trial includes an experimental vaccine developed by the Yerkes National Primate Research Center of the Atlanta-based Emory University, the university’s Vaccine Center, and the Bethesda-based NIAID Laboratory of Viral Diseases.3 The vaccine strategy includes two inoculations of a DNA vaccine that primes the immune system to recognize HIV, and a subsequent booster vaccine based on a recombinant poxvirus. Neither of the components incorporates the actual virus; instead, the vaccine produces the three major proteins expressed by HIV. Scientists believe the vaccine induces the immune system to respond to the distinguishing features of HIV so the system will respond to the actual virus should it appear.

"The HIV Vaccine Trials Network has four Phase I and II trials under way now, with four more beginning shortly," Corey remarks. "Trials like these are essential to finding an effective, global HIV vaccine."

References

1. HIV Vaccine Leadership Group Core. Results of VaxGen’s Phase III AIDSVAX B/B Trial. Questions And Answers. Seattle: HIV Vaccine Trials Network; January 2003. Accessed at www.hvtn.org/pressroom/press_releases.sht?id=27.

2. Oplinger A. New HIV Vaccine Holds Promise of Global Effectiveness. Bethesda, MD: National Institute of Allergy and Infectious Diseases; Nov. 13, 2002.

3. Korschun H. AIDS Vaccine Developed at Emory and the NIH Moves to Clinical Trials. Atlanta: Emory University; Jan. 23, 2003.