Editor’s note: Although best known as a cancer research center, Fred Hutch also is a hub of HIV research. This is one of a series leading up to World AIDS Day on the breadth of our work, from investigating HIV at a molecular level to searching for a cure to running the world’s largest HIV vaccine clinical trial network.
The HIV Vaccine Trials Network — headquartered at Fred Hutchinson Cancer Research Center — is having a banner year.
Last month in South Africa, the HVTN launched a clinical trial called the Imbokodo Study to test an experimental vaccine regimen designed to protect against HIV subtypes around the world. Over the coming months, the Imbokodo study will roll out in four other southern African countries.
The latest study joins three other large HVTN vaccine or vaccine-related clinical trials already underway around the globe.
“We are in the midst of an unprecedented time in HIV vaccine research — we have four concurrent efficacy trials underway, which will collectively enroll 12,200 volunteers in the search for an HIV vaccine over the next few years,” said HVTN founder and leader Dr. Larry Corey in a statement prepared for World AIDS Day. “With the support of our funders and research partners, we are doing all that we can to honor loved ones taken from us too soon and drive the progress that will secure a future without HIV.”
The number of clinical trials in the field at the same time is a testament to the expertise that the HVTN — the largest global network developing HIV/AIDS vaccines — has developed in running large and complicated vaccine studies.
It also reflects the explosion of new knowledge about HIV that scientists have uncovered in the struggle to develop a vaccine against a particularly challenging virus.
The regimen in the Imbokodo Study — called a mosaic vaccine — is a new concept for HIV vaccines. The experimental vaccine contains a medley, or mosaic, of genes from various HIV subtypes responsible for infections in different parts of the world. (The genetic pieces are made in the lab and cannot cause HIV.)
The goal of the Imbokodo study is to prompt a broad immune response that would be effective against any variety of the virus anywhere in the world.
Imbokodo is sponsored by Janssen Pharmaceutical Companies, a research division of Johnson & Johnson, with additional funding from the Bill & Melinda Gates Foundation and the National Institute of Allergy and Infectious Diseases, or NIAID (part of the U.S. National Institutes of Health). Also involved in the study are researchers from Beth Israel Deaconess Medical Center, the Ragon Institute of MGH, MIT and Harvard and the U.S. Military HIV Research Program.
NIAID funded preclinical and early-phase clinical work on the mosaic vaccine, which was developed in the laboratory of Dr. Dan H. Barouch of Beth Israel Deaconess Medical Center. Dr. Bette Korber of Los Alamos National Laboratory led the computational analysis behind the mosaic genetic sequences incorporated in the vaccine.
With the mosaic design, “what we’re aiming for is a global vaccine,” said Janssen’s Dr. Frank Tomaka, one of the study co-chairs, at an HVTN meeting in Seattle in October. “HIV preventive vaccines are difficult because the immune responses that may protect against one subtype may not work against another. Our goal is to produce one vaccine that can be shipped everywhere and can be efficacious everywhere.”
Scientists have made enormous progress against HIV since the virus roared onto the world stage in 1981, attacking its victims’ immune systems and leaving them to die of AIDS-related infections and cancers. The introduction of combination antiretroviral therapy in the mid-1990s turned what had been a death sentence into a chronic, manageable disease, at least for those who have access to and can tolerate the drugs.
Later studies found that treatment equals prevention: Keeping the virus durably suppressed through treatment can halt transmission to others. Those without HIV can protect themselves from infection by taking an antiretroviral pill, a strategy known as pre-exposure prophylaxis, or PrEP.
But although HIV treatment is universally hailed as one of the great medical breakthroughs of modern history, it has not ended the pandemic. Only about half of the 37 million people living with HIV worldwide are on therapy. Many can’t afford it, don’t have access to it or don’t even know they’re infected. Almost 2 million new HIV infections still occur globally each year.
Vaccines have long been the surest path to ending or containing infectious diseases. Corey, who had earlier chaired the AIDS Clinical Trials Group to test therapies for HIV, organized the HVTN in 2000. It is headquartered at Fred Hutch and funded by NIAID. The original network included nine clinical research sites nationwide. Today, it has more than 30 sites on five continents.
A decade ago — in the fall of 2007 — HIV vaccine researchers got a reminder of just how challenging it would be to develop a vaccine against a rapidly mutating virus that attacks the very immune system designed to fight it. A major HVTN clinical trial had to be halted when it was found that the experimental vaccine neither prevented HIV infection nor reduced the amount of virus in the blood among vaccine recipients who became infected with HIV. In some cases, it could make the recipient more susceptible to the virus.
The trial was the biggest in the field at the time, and the vaccine being tested had been considered the best hope. With new resolve, scientists went back to the drawing board to investigate different vaccine strategies.
The Imbokodo Study “grew out of failure,” Corey said. “Science learns from the past to rebuild the future.”
Even as they were working on new approaches, HIV vaccine researchers in 2009 got unexpected good news: A candidate vaccine regimen being tested in Thailand became the first to show modest protection, reducing the risk of contracting HIV by about 31 percent. Although not enough protection to warrant licensing, the so-called Thai vaccine regimen revitalized the field, showing for the first time that a protective vaccine against HIV was possible.
One of the other large HIV vaccine clinical trials now underway is testing a new version of that vaccine regimen modified to be longer lasting and effective against the predominant HIV subtype in South Africa, which has the largest HIV epidemic in the world. Called HVTN 702, this study got underway in November 2016 and is enrolling 5,400 HIV-negative South African men and women. Results are expected by late 2020. If it provides at least 50 percent protection, it could become the first licensed vaccine regimen against HIV.
Two other large vaccine-related clinical trials underway, known as the AMP studies, take a distinctly different approach. Launched in April 2016, they are investigating whether a certain immune protein known as a broadly neutralizing antibody, delivered by intravenous infusion, provides protection against all strains of HIV.
Conducted in parallel, one AMP study is enrolling 1,500 women in southern Africa and the other is enrolling 2,700 men and transgender people who have sex with men in the United States, Brazil, Peru and Switzerland. Results are expected by 2020. AMP will not lead directly to a licensed product, but information gleaned from the results could help scientists reverse-engineer a potent vaccine to elicit such antibodies or lead to new preventive and treatment options.
The Imbokodo Study, also known as HVTN 705/HPX2008, will enroll 2,600 HIV-negative women between 18 and 35 years old in South Africa, Malawi, Mozambique, Zambia and Zimbabwe. Half of the women will receive the vaccine regimen and half a placebo, given four times over a year. Full enrollment is expected to take about 15 months, with results expected in 2021.
Each participant in the new study will be followed for two years after the last injection appointment. If the vaccine is effective, follow-up will be extended by a third year to see how long protection lasts. All participants will be counseled on the best ways to prevent HIV and all will be referred for treatment if they do become infected.
As in all vaccine candidates that make it to large clinical trials, the mosaic vaccine regimen first showed protection in animal studies and then was tested for safety in smaller human trials dubbed the Approach and Traverse studies. Researchers selected the name Imbokodo — which means “the rock” in Zulu — to follow the mountain-climbing theme but also as a salute to the strength of the 2,600 women who will enroll in the clinical trial.
In 1956, 20,000 South African women marched to protest apartheid, a historic moment celebrated in a freedom song.
“Wathint’ abafazi, wathint’ imbokodo!” the marchers sang. “You strike the women, you strike the rock.”
“In other words, don’t fight with us,” said Dr. Glenda Gray, president of the South African Medical Research Council. A co-leader of the HVTN and head of its African programs, Gray is chair of both the Imbokodo Study and HVTN 702, the South Africa vaccine trial.
For many reasons, HIV has hit women in sub-Saharan Africa particularly hard. Globally, women make up half of the 36.7 million people living with HIV, and 80 percent of infected women live in sub-Saharan Africa.
Young women ages 15 to 24 are at particular risk and are two to eight times more likely to be infected than their male peers, often through sex with an older male partner, said Dr. Kathryn Mngadi, a physician-scientist and HVTN researcher at the CAPRISA eThekwini research clinic in Durban, South Africa, and a co-chair of the Imbokodo Study.
“Deep down inside," Mngadi said at the recent HVTN meeting, "I and my co-chairs and the huge team that stands behind us are hoping we will be able to say to HIV: ‘If you strike a woman, you strike a rock.’”
Mary Engel is a former staff writer at Fred Hutchinson Cancer Center. Previously, she covered medicine and health policy for the Los Angeles Times, where she was part of a team that won a Pulitzer Prize for Public Service. She was also a fellow at the Knight Science Journalism Program at MIT. Follow her on Twitter @Engel140.