May 18th is HIV Vaccine Awareness Day, a day to recognize the volunteers, community members, and researchers working to find a safe and effective vaccine to prevent HIV. Such a vaccine, along with existing HIV treatment and prevention strategies, would help achieve the goal of ending the HIV epidemic. The journey to find a viable vaccine to prevent HIV transmission is 4 decades in the making, but recent progress shows that we may be on the cusp of a breakthrough. Yet the same struggles and roadblocks that have prevented a successful vaccine still face scientist and researchers, so we look forward with cautious optimism as a number of companies put forth candidates for clinical trials. Read on below to learn about the challenges and potential breakthroughs in the world of HIV vaccine development that are driving progress and innovation.

The following article was reposted from the Association of American Medical Colleges. You can find the original article here.

The Hunt for an AIDS Vaccine Approaches 40 with Hope and Caution

When researchers discovered the virus that causes AIDS in 1984, then-Health and Human Services (HHS) Secretary Margaret Heckler told a news conference, “We hope to have a vaccine ready for testing in about two years. … Another terrible disease is about to yield to patience, persistence, and outright genius.”

Nearly 40 years later, the world still waits for an AIDS vaccine.

That futility appears particularly striking in the COVID-19 era, when scientists created effective vaccines less than one year after the outbreak of the disease. But the AIDS virus, HIV, has proven especially nimble at dodging the body’s immune defenses, primarily by quickly mutating and camouflaging itself.

“HIV is a wily virus,” says Dagna Laufer, MD, vice president of clinical development at IAVI, a New York-based nonprofit scientific research organization that develops vaccines and antibodies.

However, experiments employing new strategies are moving forward against the disease, which emerged in the United States in 1981. In January, IAVI and Moderna announced the launch of a human trial for several HIV vaccines that use mRNA technology. In March, researchers at Duke University School of Medicine in North Carolina published results from an animal trial for an HIV vaccine that they hope to soon test in people. Meanwhile, Johnson & Johnson is running a trial for an HIV vaccine with several thousand volunteers.

Still, researchers say a vaccine for public use remains years away. Here is a summary of how HIV avoids immune responses spurred by vaccines and how researchers are trying to overcome the impediments.

HIV mutates, hides, and attacks to frustrate immune defenses

“From the very second HIV infects a person, it starts to escape from the immune response,” says David Diemert, MD, clinical director of the GW Vaccine Research Unit at the George Washington University School of Medicine and Health Sciences (GW SMHS), in Washington, D.C., one of four sites for the trial of the IAVI-Moderna vaccines.

The first escape tactic involves rapidly reproducing and mutating. “It makes changes in its genome every time it makes a copy of itself,” says Barbara Taylor, MD, MS, associate professor of infectious diseases at the University of Texas Health Science Center at San Antonio Joe R. and Teresa Lozano Long School of Medicine. “Someone with HIV who’s not on treatment can have hundreds of thousands of slightly different versions of HIV.”

As a result, each time the immune system identifies a form of the virus and attacks it, countless other mutations run free, and the immune system has to go after those as well.

“The immune system is constantly chasing after these mutated viruses” and never catches up with them all, Diemert says.

Making the chase more difficult is that the virus hides by enveloping itself in dense sugar molecules that the body recognizes as part of itself, explains Drew Weissman, MD, PhD, who runs an RNA research lab at Perelman School of Medicine at the University of Pennsylvania (PSOM) in Philadelphia. Antibodies that try to reach the virus through these sugars get rejected, he says, because they are seen as attacking the body itself.

Meanwhile, the virus infects and eventually kills CD4-positive T-cells, a type of white blood cell that is the primary regulator of the person’s immune response to foreign pathogens. The depletion of those T-cells weakens a person’s immune defense.

To top it off, HIV never fades away in someone’s body, as viruses typically do. It inserts genetic copies of itself into the person’s DNA. A preventive vaccine will need to block infection very quickly.

“This virus lives in you forever,” says Laufer at IAVI.

She says these impediments explain why only six HIV vaccines have gone through a phase 3 clinical trial, with none producing strong enough immune responses to make a product for the public.

“There’s never been a vaccine developed for a virus that has so much variability, and for which it is so difficult to raise neutralizing antibodies,” says Dan Barouch, MD, PhD, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center (BIDMC) and at Harvard Medical School.

The latest strategies induce a variety of defenses to attack the swarm of HIV strains

Several current vaccine experiments aim to use a series of inoculations to stimulate the immune system to produce antibodies that can potentially block HIV infection.

IAVI-Moderna: The vaccines in this trial train certain types of B-cells (which are white blood cells) as part of a strategy to produce a wide variety of antibodies against common forms of the virus, explains Taylor at the Long School of Medicine. To do this, the vaccine delivers immunogens (a substance that elicits an immune response) that induce the B-cells to start the process of developing antibodies called bnAbs (broadly neutralizing antibodies).

The trial will involve 56 volunteers at four sites, IAVI reports. It is a phase 1 trial, which focuses largely on safety and determining dosage levels.

A critical element is how the vaccines are delivered. The initial inoculation will be followed by several boosters, which differ from typical boosters (such as those against COVID-19) in that they are not a repeat of the same substance, Taylor says. Instead, each booster contains a different mix of immunogens to guide the B-cells to make more bnAbs against more versions of the virus.

“The idea is to get a diverse set of antibodies in people” before HIV tries to infect them, says Jeffrey Bethony, PhD, professor in the GW Vaccine Research Unit at George Washington University and a researcher on the trial of the IAVI-Moderna vaccines at that site.

Duke and PSOM: A similar approach was taken in a study involving mice that was published this month in Cell Reports by researchers at PSOM and Duke University School of Medicine. The vaccine activated B-cells in the mice to develop bnAbs, and also activated T-cells to help amplify the response and make higher levels of antibodies.

“You need this stronger ‘helper cell’ response to make broadly neutralizing antibodies,” says Weissman of PSOM, a co-author on the study.

“The vaccines are doing similar things — trying to induce broadly neutralizing antibodies,” he notes about the IAVI-Moderna and the mouse studies. “They’re looking at different routes to get there.”

Researchers expect to soon test the vaccine in monkeys, then humans, Weissman says.

Johnson & Johnson: An ongoing clinical trial, run by Johnson & Johnson, also seeks to induce a broad antibody response with multiple inoculations. Over the course of a year each person gets four doses of slightly different vaccines, each of which delivers immunogens and proteins to initiate immune responses to common HIV strains.

This is a phase 3 trial, which is designed to study efficacy and adverse reactions. The trial is part of the Mosaicoproject, which focuses on men who have sex with men and on transgender people, with trials carried out at sites in North America, South America, and Europe.

mRNA improves the creation and delivery of vaccines

The vaccines used in the IAVI-Moderna and in the mouse studies use mRNA technology. That technology significantly shortens the time it takes to make a new version of a vaccine.

Traditionally, vaccines are made from a bacteria or virus, or parts of them (such as proteins or sugars). These have to be grown, often in chicken eggs. Flu vaccines, for example, take five or six months to create.

The mRNA technology creates vaccines differently. mRNA is a molecule that delivers instructions to cells to build specific proteins. mRNA tells a cell to make a protein that’s used by a specific virus, and the appearance of that protein sets off an immune response that builds the body’s ability to fend off the actual virus if it ever invades. Scientists have likened the process to changing a computer code to respond to new conditions.

“It’s really easy to make mRNA, so you can quickly make new vaccines that are targeting different proteins [in the virus] or different parts of the virus very quickly,” says Diemert, the lead investigator of the IAVI-Moderna trial at GW SMHS.

Laufer, from IAVI, expects that new versions of these HIV vaccines can be made “in weeks, or maybe a couple of months.”

Another advantage, Weissman says, is that “mRNA is a good delivery system.” He explains that in the trial with mice, mRNA induced a B-cell response and a T-cell “helper” response “that drove more potent B-cell antibody responses.”

Some scientists caution that mRNA cannot solve fundamental challenges of immunogen development.

“The fundamental problem in the HIV vaccine field is not a delivery problem. It’s an immunization problem,” says Barouch at BIDMC. “We don’t have an immunogen that works. mRNA is not going to solve that problem. It will allow the field to try more things more quickly.”

Hope is tempered by caution learned from history

HIV vaccine researchers are understandably reluctant to predict when a vaccine might prove effective enough to market. They recall former HHS Sectary Heckler’s prediction in 1984 that the disease was “about to yield” to scientific progress.

Actually, vaccine trials did start about three years later. But Heckler’s optimism that those trials would succeed was based on what scientists had experienced with other diseases. In 2006, Heckler told Frontline, “We did not know that the replication of the virus would be so difficult” to contain.

Barouch echoes the views of others when he says, “We will not have an HIV vaccine for a substantial period of time.”

Asked to define that time, Barouch says, “I can’t be more specific. There’s not a clear trajectory. It’s not like we have to do these 10 steps. A clinically proven vaccine is still a long way off.”

Diemert at GW SMHS sums up the prevailing perspective of those working on current vaccine experiments: “I am cautiously optimistic.”