NIAID will not move forward with HIV vaccine trial — What's next step in vaccine research?
Advocates call for renewed commitment to push for vaccine development
Rewind to 2007. A large HIV vaccine clinical trial sponsored by Merck & Co. is shuttered after an interim analysis concluded that the vaccine did not prevent infection. Fast forward to today. The National Institute of Allergy and Infectious Diseases (NIAID) has determined it will not follow through with plans for a large-scale test of a similar experimental AIDS vaccine
The NIAID HIV vaccine study, known as PAVE (Partnership for AIDS Vaccine Evaluation) 100, originally was planned as a large-scale trial of a vaccine strategy termed as a "prime-boost" combination of two vaccines developed through the National Institutes of Health's Vaccine Research Center (VRC). Three DNA immunizations would be administered first, followed by a recombinant adenovirus-vectored boost.
While the NIAID has chosen not to move forward with the larger clinical study, it is calling for proposals for a smaller, more focused study with one specific goal in mind: to determine if the vaccine regimen significantly lowers viral load (the amount of HIV in the blood of vaccinated individuals) who might later become infected with HIV.
"The HIV clinical trial network has been asked to go back to the drawing table to develop a smaller, more focused protocol to determine does the vaccine reduce viral load in volunteers who have the vaccine, then get HIV due to behavior," explains an NIAID spokesperson. "The protocol will be presented to NIAID, which will determine whether to go forward."
Review the history
The Merck trial, known as STEP, was designed to test the MRKAd5 trivalent vaccine. Made with a weakened version of adenovirus Type 5, which was used as a delivery vector, the vaccine included three synthetically produced HIV genes, gag, pol, and nef. Its design was aimed to stimulate production of immune system T cells to kill HIV-infected cells.
Information presented at a special open HIV Vaccine Trials Network (HVTN) scientific meeting in November 2007 and the 15th Conference on Retroviruses and Opportunistic Infections in February 2008 confirms that the investigational HIV vaccine was not effective.1 The vaccine did not prevent HIV infection; it also did not reduce the amount of virus in those study participants who became infected with HIV during the trial.1
According to the STEP results, findings suggest that people who got the vaccine might get infected with HIV more easily if they are exposed to it.2 Researchers saw this trend toward more infections particularly in the group of participants who had pre-existing immunity to adenovirus Type 5, a cold virus that was used as a part of the vaccine.
There were several differences between the Merck MRKAd5 vaccine and the VRC vaccine candidate scheduled for examination in the PAVE 100 trial, points out the AIDS Vaccine Advocacy Coalition, a nonprofit, community- and consumer-based advocacy organization:
- The VRC strategy included three DNA immunizations followed by a single Ad5 boost, whereas Merck's strategy included three immunizations with MRKAd5.
- The kinds of immune responses that people had to the VRC strategy were different compared to MRKAd5.
- The adenovirus used in the VRC strategy was genetically altered in ways that were different from MRKAd5.
- The VRC strategy included the HIV env gene; the MRKAd5 vaccine did not.3
The original PAVE 100 study proposed to test the VRC's HIV vaccine regimen in a trial initially designed to enroll 8,500 volunteers in the United States, South America, the Caribbean, and Eastern and Southern Africa. The study was scheduled to begin U.S. recruitment in October 2007, but it was postponed following the decision to halt immunizations in the STEP HIV vaccine study.
Based on the analyses of the STEP study results, researchers redesigned PAVE 100, reducing it somewhat in its proposed scope. The redesigned study called for testing the VRC vaccine in 2,400 U.S.-based, circumcised men who have sex with men and who lacked pre-existing neutralizing antibodies to Ad5. The study would have tested the vaccine's effect on viral load, provided additional safety information about the product, and examined immune responses to the vaccine and their impact on viral load.
"Based on the available scientific information, NIAID has decided that the VRC vaccine regimen did not warrant a trial of this size and scope and that PAVE 100 will not proceed," the NIAID stated in a July 2008 announcement of its plans.4
What's the next step?
To help overcome challenges faced by those now involved with vaccine research, the International AIDS Vaccine Initiative proposes several interim milestones in its new publication, AIDS Vaccine Blueprint 2008, released in conjunction with the 2008 XVII International AIDS Conference:
- Solve the neutralizing antibody problem. To date, researchers have identified neutralizing antibodies against HIV. They are now trying to figure out how to design immunogens that generate similar antibodies. To speed the discovery of an immunogen that can neutralize a substantial proportion of circulating HIV strains, existing programs that focus on the neutralizing antibody problem should be bolstered.
- Solve the cell mediated immunity (CMI) problem. One lesson from the Merck trial is that inducing effective CMI responses will be more challenging than originally envisioned and might be as challenging as solving the neutralizing antibody problem, states the International AIDS Vaccine Initiative (IAVI). More resources should be devoted to studying the mechanisms behind CMI, which could provide clues for improved vaccine design.
- Trim and improve the pipeline. Current and future AIDS vaccine candidates need to be compared and prioritized in comparison to tested vaccines, says IAVI. Those vaccines that cannot demonstrate superiority should be dropped. To improve the pipeline, IAVI also recommends accelerating the development of replicating vector-based vaccines.
- Sustain the effort. The development of an AIDS vaccine continues to be one the greatest needs of the 21st century and one of science's greatest challenges, IAVI states.5
According to new data released at the 2008 AIDS conference, the number of people worldwide who are newly infected with HIV has fallen from 3 million in 2001 to 2.7 million in 2007; however, the number of people becoming newly infected with the disease each day — 7,500 — remains unacceptably high.6
The quest to develop an AIDS vaccine is at a critical moment, said Seth Berkley, MD, IAVI president and CEO, in a statement accompanying the publication release. "In the wake of the failure of a leading AIDS vaccine candidate nearly a year ago, some have questioned whether we will ever have an AIDS vaccine," he says. "To these skeptics, I say that developing an AIDS vaccine may take more time and innovation than we might have once imagined, but we are confident that science will prevail."
- Robertson M, Mehrotra D, Fitzgerald D, et al. Efficacy results from the STEP Study (Merck V520 Protocol 023/ HVTN 502): A Phase II test-of-concept trial of the MRKAd5 HIV-1 Gag/Pol/Nef trivalent vaccine. Presented at the 15th Conference on Retroviruses and Opportunistic Infections. Boston; February 2008.
- HIV Vaccine Trials Network. Information regarding trials using the MRK Ad5 gag/pol/nef vaccine. Press release. Dec. 21, 2007. Accessed at www.hvtn.org/media/pr/step1207.html.
- AIDS Vaccine Advocacy Coalition. Making sense of the PAVE 100 debate. Fact sheet. Accessed at www.avac.org/pdf/pave_100_brief.pdf.
- National Institute of Allergy and Infectious Diseases. NIAID Will Not Move Forward with the PAVE 100 HIV Vaccine Trial. Press release. July 17, 2008. Accessed at www3.niaid.nih.gov.
- International AIDS Vaccine Initiative. AIDS Vaccine Blueprint 2008. Accessed at www.iavi.org/viewfile.cfm?fid=49229.
- International AIDS Vaccine Initiative. New UNAIDS report reveals global AIDS epidemic slowing. Press release. Accessed at www.iavi.org/viewpage.cfm?aid=11.