Nearly 16 years ago, leading AIDS researchers were so skeptical about an experimental HIV vaccine trial just started in Thailand that they publicly criticized a U.S. government decision to fund it. But the trial involving 16,000 volunteers was carried out anyway.
When it was completed in 2009, the results were startling. The controversial vaccine showed a modest effectiveness of 31% — a surprise because it was the first time any HIV vaccine was found to work at all. Nothing better has been achieved since.
Now, the same vaccine tested so long ago in Thailand has delivered another surprise.
In a small study, known as HVTN 097 and led by the HIV Vaccine Trials Network, an international collaborative headquartered at Fred Hutchinson Cancer Research Center, researchers found that the old vaccine formulation — designed to block HIV strains found in Thailand — stirred up an even stronger immune response among volunteers in South Africa, where a different strain of HIV predominates.
That strain, a subtype known as clade C, is responsible for the infections in half of the 38 million people living with HIV in the world today. It is the dominant strain in southern Africa, India and China — where the need for an effective HIV vaccine is most pressing. Yet the results of this latest study — based on immune responses of the 73 volunteers who received it — suggest the Thai vaccine might have worked just as well, if not better, for people living in South Africa.
“This breaks open the thought pattern that each region of the world needs a separate type of HIV vaccine based upon their circulating strains,” said Dr. Larry Corey, Fred Hutch president and director emeritus and principal investigator for HVTN. He is senior author of the paper describing the results of the study, which were published today in the journal Science Translational Medicine.
The research only shows how the South African participants’ immune systems reacted to the Thai vaccine — there was no attempt to see whether the vaccine reduced the rate of HIV infection among them.
And to be sure, the 31% effectiveness found in 2009 for the Thai formulation is well below what is needed for a successful HIV vaccine. Most childhood vaccines, for example, protect 85% to 95% of those who receive them. A vaccine that protects fewer than one in three recipients could give a false sense of protection.
Nevertheless, the surprising performance of the Thai vaccine in 2009 led researchers to look for ways to improve it. In 2016 they launched HVTN 702, a large-scale trial in South Africa of a new and possibly better vaccine based on the one originally used in Thailand. It contains specific components from clade C viruses and several other modifications, all designed with South Africa in mind.
HVTN 702 is fully underway, with 5,407 participants, but results will not be analyzed until the trial is completed in late 2022. At a minimum, researchers hope this improved version of the Thai vaccine will show a 50% reduction in HIV infections over a two-year period.
The big HVTN 702 study is led by Dr. Glenda Gray, co-principal investigator of HVTN and president and chief executive of the South African Medical Research Council.
“If you want to make a dent in the HIV epidemic, you have to attack it in the areas of the world where clade C circulates,” she said in a telephone interview from Cape Town.
She is also lead author of the paper published today. In that small study, which tested the 2009 Thai vaccine formula more recently in South Africa, researchers had at their disposal analytical tests that simply were not available when the original Thai trial started. These newer tests are helping vaccine scientists determine what changes in the immune system may show up in patients who are protected from HIV by a given vaccine. These so-called “correlates of immunity” can serve as flags to guide designers of future vaccines toward more effective formulations.
Surprisingly, by several measures, the South African group showed a higher level of potentially protective responses to the old Thai vaccine than did the group in Thailand.
Gray said that she did not expect the immune systems of the South African participants to respond so vigorously.
Just why they did so, no one knows for sure.
Among the factors that might play a role are race, nutrition and environmental exposures to different diseases, Gray said. Another may be the different composition of the gut microbiome — the community of bacteria and viruses that naturally inhabit the colon, where studies show microorganisms interact with our immune systems and can affect responses to vaccines.
In the newly released study, researchers also looked at how antibodies, protective proteins stirred up by the vaccine, might trigger an increase in blood cells that can destroy HIV-infected cells — a phenomenon little understood at the time of the big Thai trial. When blood tests of South African participants in the recent small trial were compared with those of stored samples from Thais in the 2009 study, the level of this “antibody-dependent” protection was higher among the South African group.
Because the big new trial in South Africa, HVTN 702, uses a different version of the Thai vaccine than the one evaluated a decade ago, the surprising findings of the small study published this week cannot be used to predict the outcome of the larger trial in 2022.
The redesigned Thai vaccine, now tailored for South Africa’s clade C strain, said Gray, “may give us a completely different immune response, which may be better, the same or worse.”
Regardless of how the big trial of the redesigned Thai vaccine turns out three years from now, Gray said the newly released findings will provide researchers with a useful tool to evaluate HVTN 702 and learn from it, no matter the outcome.
“The world of science changes rapidly, so we always have to put our best foot forward,” she said. “Only time will tell whether it was correct or not.”
The HVTN 097 trial was funded by the National Institutes of Health through the National Institute of Allergy and Infectious Diseases.
Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs.
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