Women & HIV

From a Failed Vaccine, New Insights Into Fighting HIV

Scientists are sifting the data to see what elements of RV144 inoculation worked.

A new study offers insight into why an HIV vaccine failed to protect most people who received it, but it also points to promising new targets for future vaccine efforts.

Scientists believe an HIV vaccine, designed to prevent infection with the virus that causes AIDS, is still several years away. Tests of experimental vaccines have largely been failures so far.

Nevertheless, the prospect of a vaccine remains tantalizing because it could make a major dent in the spread of HIV and AIDS around the world.

The new research "gives us a handle on how the immune system deals with the virus and is affected by a vaccine," said study lead author Dr. Barton Haynes, director at the Duke Human Vaccine Institute at Duke University in Durham, N.C. "It gives us clues and a firm direction to look into."

The study is based on work by more than 100 scientists from 25 institutions, and appears in the April 5 issue of the New England Journal of Medicine.

Haynes and his colleagues examined the results of a 2009 study of an HIV vaccine in Thailand. In a trial involving more than 16,000 people, the vaccine appeared to cut the risk of infection by only 31 percent. That was still considered a major advance over previous vaccines that didn't work at all, Haynes noted.

The vaccine, called RV144, wasn't ready for prime time because it didn't protect enough people, Haynes said. "You want to get it above 50 percent," he said, and some scientists believe the rate should be even higher than that.

Despite the vaccine's failure, the authors of the new study were able to use the data to learn more about how the immune system deals with HIV and how the vaccine changes the "big picture" of the body's response to the virus.

The new research is an "exhaustive molecular analysis," said Dr. Lindsey Baden, an associate professor of medicine in the infectious disease division at Brigham and Women's Hospital in Boston who co-wrote a commentary accompanying the study.

Haynes said one surprising finding is about an antibody -- a soldier of the immune system -- that helps protect against influenza infection. Ironically, the antibody appears to be able to mitigate the effect of otherwise protective antibodies, he said.

Another finding was that higher levels of antibodies that home in on a particular region of HIV's outer shell, called V1V2, were associated with lower rates of infection with the virus.

This and other information in the study may help researchers come up with theories about where to go next with vaccine development, Baden said. Among other things, it can reveal parts of the immune system that can be most useful in battling the transmission of HIV.

Vaccines are available to fight other kinds of viruses, such as measles and influenza. HIV is unique, however, because it inserts its genetic material into the body's cells.

"When a person gets infected with HIV, that genetic material goes underground," Haynes said. "It's invisible to the body's immune system."

Another challenge is that the virus mutates, becoming a moving target.

"It changes so rapidly in the person who gets infected that even when the immune system does try to control it, in most people the immune system is always playing catch up," Haynes said.

More information

There's more on HIV/AIDS at the U.S. National Library of Medicine .

Possible Clues Found to Why HIV Vaccine Showed Modest Protection

Analysis by NIH-Supported Scientists May Help Identify Requirements for HIV Vaccine

Insights into how the first vaccine ever reported to modestly prevent HIV infection in people might have worked were published online today in the New England Journal of Medicine. Scientists have found that among adults who received the experimental HIV vaccine during the landmark RV144 clinical trial, those who produced relatively high levels of a specific antibody after vaccination were less likely to get infected with the virus than those who did not. The National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, co-funded the research.

“This analysis has produced some intriguing hints about what types of human immune responses a preventive HIV vaccine may need to induce,” said NIAID Director Anthony S. Fauci, M.D. “With further exploration, this new knowledge may bring us a step closer to developing a broadly protective HIV vaccine.”

In the RV144 clinical trial, which involved more than 16,000 adult volunteers in Thailand, the group that received the vaccine had a 31 percent lower chance of becoming infected with HIV than the group that received a placebo. Since the study results were reported in 2009, a consortium of more than 100 scientists from 25 institutions has been searching for molecular clues to explain why the vaccine showed a modest protective effect.

The new report describes the researchers’ analyses of blood samples taken from a representative subset of study participants: 41 who were vaccinated and later became infected with HIV and 205 vaccinated participants who remained uninfected. The participants who made relatively high levels of one antibody to HIV were significantly less likely to become infected than those who did not. This particular binding antibody attaches to a part of the outer coat of the virus called the first and second variable regions, or V1V2, which may play an important role in HIV infection of human cells. The antibody belongs to a family called immunoglobulin G, or IgG.

Vaccinated study participants who had relatively high levels of a different type of HIV binding antibody, however, appeared to have less protection from the virus than vaccinated participants who had low levels of this protein. The antibody attaches to a part of the virus’s outer coat called the first constant region, or C1, and belongs to a family called immunoglobulin A, or IgA. The study team hypothesizes that the C1 IgA antibody either was associated with less benefit from HIV vaccination or directly reduced the benefit of vaccination.

“The remarkable international collaboration to understand the RV144 study results has generated important hypotheses for scientists to investigate,” said Barton F. Haynes, M.D., the leader of the new analysis and the director of the NIAID-funded Center for HIV/AIDS Vaccine Immunology based at Duke University in Durham, N.C.

Researchers plan to further evaluate the new findings in studies to be conducted in non-human primates using the RV144 vaccine regimen and other vaccines. Scientists must conduct more tests to determine whether high levels of V1V2 antibodies directly caused the modest protective effect seen in the RV144 study or simply were linked to other, still unidentified factors responsible for the trial’s encouraging outcome. Such testing also will determine whether the V1V2 antibody response is merely a marker of HIV exposure or decreased susceptibility to HIV infection.

The study authors note that different vaccine candidates may protect against HIV in different ways. Therefore, more research is needed to understand whether these new findings will be relevant to other types of HIV vaccines or to similar vaccines tested against HIV strains from other regions or against different routes of exposure to the virus, according to the authors.

The RV144 laboratory research was initiated and coordinated by the U.S. Military HIV Research Program at the Walter Reed Army Institute of Research. The U.S. Army Medical Research and Materiel Command and the Bill and Melinda Gates Foundation co-funded the research along with NIAID. NIH/NIAID provided funding through grant number U19 AI067854-07 and through HIV Vaccine Research Interagency Agreement number Y1-AI-2642.