Scientists have been hunting for an effective HIV vaccine since the beginning of the AIDS crisis. For years, many wondered if a single shot offering long-term protection from HIV was even possible. But 2009 marked a turning point in the quest for an HIV vaccine. That year, a Thailand-based trial demonstrated that a vaccine called RV144 was approximately 61% effective within a year, and approximately 31% effective more than three years later.
The RV144 trial breathed new life into the idea that a vaccine could be engineered to harness the body's own antibody response for long-term protection against HIV. A decade later, antibody-based approaches form the cornerstone of HIV vaccine research, and an unprecedented number of HIV vaccine trials are underway.
Now, HIV scientists, researchers, and people with HIV are eagerly awaiting the results of four major HIV vaccine trials that rely on the antibody approach. Those studies are being led by the HIV Vaccine Trials Network (HVTN), a nonprofit organization working in collaboration with the U.S. government, the pharmaceutical industry, and the Bill & Melinda Gates Foundation.
The results of these four trials -- which enrolled 12,600 HIV-negative participants across three different continents -- are expected as early as 2021.
"HIV vaccine research is sort of at the best place it's ever been," said Larry Corey, M.D., principal investigator for HVTN. "We've made some really great technological advancements over the past six or seven years," said Corey, adding, "We're both anxious and excited about what the results will tell us."
These four studies can be broken down into two main approaches: broadly neutralizing antibodies -- which are proteins that directly neutralize the HIV virus -- and other antibodies that are proteins produced by the body's immune response to a viral infection.
Antibodies that Neutralize HIV or Decrease Viral Load
The first two studies employ broadly neutralizing antibodies, which are proteins that directly neutralize the HIV virus. These proteins are not easy to produce. In an adult human, it sometimes takes months, even years, for the body to produce antibodies that can effectively neutralize the HIV virus.
For this reason, it has taken scientists a long time to isolate antibodies from people who are already living with HIV, then clone those antibodies so that they may be given to people who are HIV negative. Another challenge with this approach is that it is difficult to find a one-size-fits-all strategy because there are several different strains of the HIV virus.
"It has been very difficult to develop these broadly neutralizing antibodies," said Corey, because "the virus has so many different strains." Eventually, scientists developed an antibody called VRC01 that they hope will be broadly effective against multiple HIV strains.
Now, thanks in large part to research conducted with the help of HIV-positive volunteers, two large trials of VRC01 are underway that will shed light on the broadly neutralizing antibody approach to HIV vaccination.
Collectively, those two trials are called the AMP study, which stands for "antibody-mediated prevention." The first of these, called HVTN 703/HPTN 081, is studying VRC01 among 1,900 women in Sub-Saharan Africa, and the second, called HVTN 704/HPTN 085, is studying the antibody in 2,700 cisgender men and transgender people who have sex with men in North and South America and in the city of Lausanne, Switzerland. Both trials are being done in collaboration with the HIV Prevention Trials Network.
Full results should be available by September 2020, but preliminary results could be available early next year, according to Mary Marovich, M.D., director of vaccine research at the Division of AIDS at the National Institute of Allergy and Infectious Diseases. Marovich presented an overview of HIV vaccine research in a webinar hosted by AVAC, a global advocacy organization for HIV prevention.
The second approach, inspired by the RV144 Thai trial, involves using vaccines to improve the strength and potency of specific types of proteins produced when the body mounts a response to a viral infection. Although these proteins were long thought to be useless against HIV because they do not directly neutralize the virus, there's now evidence to show they play an important role in decreasing viral load. Can viral load be reduced enough to protect a person from HIV?
There are two major HVTN studies that employ this approach. The first, called HVTN 702, is a Phase 2b/3 trial that includes 5,400 cisgender men and women in South Africa. The specific vaccine used in that trial is called ALVAC + gp120/mf59.
The second of these large trials is called HVTN 705, which is a Phase 2b study of 2,600 cisgender women in Sub-Saharan Africa. That vaccine is called Ad26Mosaic + gp140/alum.
The full trial results for HVTN 702 and HVTN 705 are expected in June 2022, but preliminary results could be available as early as June 2021, according to Marovich.
Within the broadly neutralizing antibody world, scientists are already experimenting with different vaccine combinations. The idea is that two vaccines might provide better coverage than one, explained Corey.
Even as scientists eagerly await the results of these four studies, they continue to advance to newer areas of research and development.
Vaccine Efforts in Early Phases of Study
Meanwhile, there's promising research in animals that is now moving into human trials, said Corey. This includes advances in so-called trimeric structures, which are "envelopes" made of glycoprotein that have the potential to induce antibodies that help protect against HIV.
As well, there's yet another approach called epitope design, which essentially involves targeting the specific binding site where the antibody molecule attaches to the HIV virus.
The third -- and perhaps most complex -- new approach to improving HIV vaccines is called germline binding. The "germline" is a term used to describe the specific cells in our bodies that contain genetic material that's passed on to offspring.
Because humans and HIV have evolved together throughout our long history, HIV-fighting genes "are essentially programmed into our heritage," said Corey. Although infants are born with cells that contain HIV-fighting tools, those cells are deleted early in life.
"If you can get that cell to not be deleted ... and if you can get [a child] to six months old, then you can 'evolve' that child to be the adult you want it to be," said Corey. "There are ways of manipulating the germline to get [beyond] six months, and that's called germline binding."
The flurry of promising new approaches to HIV vaccine research may mean that for future generations, daily antiretroviral medicine could be a thing of the past. Still, there are many challenges ahead in the future of HIV vaccine research. Chiefly, the advent of pre-exposure prophylaxis (PrEP) -- the once-daily HIV prevention pill -- has called into question the ethics of an HIV vaccine trial.
HIV vaccine studies are designed to follow thousands of HIV-negative volunteers over several years, splitting volunteers up into "active" and "placebo" groups to see who contracts HIV and who does not. But if those volunteers start taking PrEP, the protection offered by the antiretroviral would likely obscure the effectiveness of a potential vaccine.
"We're doing this work in an era of ever-increasing PrEP use," said HIV vaccine research advocate and community leader Mark Hubbard, speaking during the AVAC webinar. "PrEP makes [recruitment] harder and harder, and it makes it a little bit more hard to explain how we do that in an ethical way that's respectful to the community."
Despite these challenges, the imminent results of the four major HVTN studies are generating a renewed excitement for HIV vaccine research. Though it's impossible to predict the results of the HVTN studies, HIV researchers are more hopeful than ever that an HIV vaccine is on the horizon.
"The scientific community has worked very assiduously, and we're making progress each year," said Corey. "I think science will get us an HIV vaccine."