SPOTLIGHT
Capsules from Keystone

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SPECIAL FEATURE
A Living History of AIDS Vaccine Research

PRIMER
Understanding the Transmitted Virus: What are researchers learning about the enemy that a preventive AIDS vaccine would need to block—the virus that is transmitted and establishes infection?

SPOTLIGHT

Capsules from Keystone

A lot of snow fell the week of March 22-27 in Keystone, Colorado, which was accompanied by a flurry of updates from researchers who gathered for the joint Keystone Symposia on “HIV Immunobiology: From Infection to Immune Control” and “Prevention of HIV/AIDS.”

This year’s meeting marked the 25th anniversary of Keystone Symposia’s first HIV/AIDS meeting, which was held in 1984, three years after the first HIV infections were described. The speakers at the conference’s opening session left no doubt that 28 years later, there is still much to do to address the AIDS pandemic. “We probably got rid of the iceberg, but under the water there is a mass of ice, and that’s the current AIDS epidemic,” said Didier Trono, of the Ecole Polytechnique Federale de Lausanne, in his introductory address. Nobel laureate Francoise Barre-Sinoussi from the Institut Pasteur said recent developments in the AIDS vaccine field illustrate the need for new directions in research. “We have to come back to basic science,” she said.

If the plethora of findings presented at this year’s conference is any indication, researchers are already heeding her call. A broad collection of updates, ranging from studies of vaccine candidates in animal models to ongoing analysis of clinical trial results, should all serve to inform the development of future vaccine candidates.

Susan Buchbinder, the principal investigator of the STEP trial, provided another update on this now notorious Phase IIb test-of-concept trial of Merck’s adenovirus serotype 5 (Ad5)-based vaccine candidate, MRKAd5. Receipt of MRKAd5 was associated with enhanced susceptibility to HIV infection among some individuals, specifically uncircumcised men who have sex with men (MSM) who had pre-existing immunity to the Ad5 virus used to deliver fragments of HIV to the immune system. In its naturally circulating form, Ad5 is a cause of the common cold, but MRKAd5 cannot cause HIV or Ad5 infections.

At Keystone, Buchbinder described efforts to address some of the possible theories for the apparent increased risk of HIV infection among this group of vaccinated volunteers.

One finding of interest was that volunteers in the STEP trial who received an inactive placebo instead of MRKAd5, and who had the highest levels of pre-existing immunity to the Ad5 vector, actually had the lowest risk of HIV infection of all the volunteers in the trial. This observation led to the proposal that perhaps some unknown factor renders individuals with high Ad5 immunity less susceptible to HIV infection. But based on several analyses, Buchbinder said this association did not seem to be true.

Another factor under consideration was whether volunteers who received MRKAd5 were at an increased risk of HIV infection because they were infected with herpes simplex virus (HSV)-2, another sexually transmitted virus. Infection with HSV-2 was associated with a roughly two-fold increased risk of HIV infection among all STEP participants, but it did not explain the enhanced risk of infection among only vaccine recipients.

Buchbinder then unveiled new data from the extended follow-up of STEP participants, from October 2007 to January 2009, the period after the volunteers were informed whether they had received MRKAd5 or placebo (a process known as unblinding). Researchers were initially concerned that once the study was unblinded, volunteers would alter their behaviors and therefore the data collected would no longer be reliable. Buchbinder said that while there was a slight drop in high-risk sexual activity soon after the trial was unblinded, it quickly returned to the level that was previously observed during the trial.

The rate of HIV infection among MSM remained high, with 48 new infections occurring during this period—26 among those who received the vaccine candidate and 22 among placebo recipients. Buchbinder showed that the increased risk of HIV infection among vaccine recipients seems to be disappearing over time. However, Buchbinder emphasized that while this finding may offer some reassurance that the effect is time-limited, the results must be interpreted cautiously because of the small numbers of volunteers in these groups. Buchbinder also reported that 12 additional infections have occurred among women volunteers (only one had occurred when the first trial results were announced) and these were divided evenly between MRKAd5 and placebo recipients.

Dennis Burton, a professor at Scripps Research Institute, presented results of an effort by IAVI and the neutralizing antibody consortium (NAC), which he leads, to identify new broadly neutralizing antibodies (see VAX February 2007 Primer on Understanding Neutralizing Antibodies). As part of its research study, known as protocol G, IAVI is collecting samples from individuals who have been HIV infected for at least three years. Researchers then screen the samples in the laboratory against an assortment of viruses and isolate antibodies from them. They then screen the antibodies to see if they can neutralize a broad variety of HIV variants in the lab.

So far, two antibodies have neutralized HIV particularly well, even compared to the four previously identified broadly neutralizing antibodies. “There is great interest in these antibodies,” Burton said. Further analysis will show precisely how these antibodies successfully neutralize HIV and may provide additional targets for vaccine candidates.

Dan Barouch, an associate professor of medicine at Beth Israel Deaconess Medical Center, reported results from a study in rhesus macaques testing a combination of a DNA and an adenovirus vector-based vaccine candidate.

Barouch’s adenovirus vaccine candidate, referred to as Ad5HVR48, is almost entirely composed of Ad5, except one of its proteins was replaced with the corresponding protein from another strain of adenovirus (Ad48), which is much less prevalent worldwide than Ad5.

The study involved 30 rhesus macaques, evenly divided into five groups, each receiving a different vaccination regimen. All animals were then injected with a high dose of simian immunodeficiency virus (SIV), the monkey equivalent of HIV. Immediately after being exposed to SIV, T-cell responses were much higher in the animals that received the DNA prime/Ad5HVR48 boost compared to those that received only Ad5HVR48. But Barouch was surprised to find that the final outcome was actually different. The animals that received only Ad5HVR48, had on average much lower levels of virus circulating in their blood than those that received the combination regimen.

After 500 days, four of 12 animals in the DNA/Ad5HVR48 groups were alive, compared to 10 of 12 in the Ad5HVR48-only groups and one of six monkeys that received a placebo injection.

The combination regimen tested by Barouch is similar to the DNA/Ad5 vaccine candidates developed at the Vaccine Research Center (VRC) that are slated to undergo testing in a 1,200-person Phase II trial called HVTN 505. This trial, a smaller version of the originally proposed Phase IIb test-of-concept trial known as PAVE 100, is currently under review by the US Food and Drug Administration. Scott Hammer, the principle investigator of the trial, stressed that these results could not be directly extrapolated to the VRC’s DNA/Ad5 prime-boost regimen. There are several differences between the vaccine candidates, and other monkey studies with the VRC’s prime-boost regimen have provided different results than this study by Barouch and colleagues.

This article was adapted from an article written by Andreas von Bubnoff and Richard Jefferys in the March-April 2009 issue of IAVI Report.

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