Nearly three years after the first cases of COVID-19 began appearing in Wuhan, China, the global health community is pausing today to reflect on the tragic impact of another world-changing virus, HIV, which continues to exact a ghastly toll on humanity.
Since the discovery of the disease in 1981, HIV has claimed an estimated 40.1 million lives worldwide according to the United Nations' program, UNAIDS; in 2021, there were 38.4 million people living with HIV. Between 1.1 and 2 million new infections occur each year.
The Seattle campus of Fred Hutchinson Cancer Center this evening will bathe its core research buildings in red light, the chosen color commemorating World AIDS Day since it was formally established by the United Nations in 1988.
From the earliest days of HIV/AIDS, Fred Hutch virologists, immunologists and epidemiologists have played leading roles in the efforts to understand the virus, test treatments for it, and find ways to prevent it. While worldwide efforts to develop a vaccine for HIV/AIDS have yet to produce one, the work continues.
The Fred Hutch-headquartered HIV Vaccine Trials Network, or HVTN, has recently launched a variety of small, highly focused trials — sometimes called ExMed, or experimental medicine research — each aimed at building incremental progress towards a new generation of vaccine candidates.
Leo Stamatatos, PhD, and colleagues this year started a small clinical trial called HVTN 301 that is a step toward development of the first Fred Hutch-designed HIV vaccine.
The trial will examine how the immune systems of up to 52 volunteers respond to an injected antigen — an immune stimulating protein. The molecule discovered and refined by the Stamatatos group is designed to coax certain white blood cells into making “broadly neutralizing antibodies.” These antibodies are rare immune proteins known to block HIV in ways that the notorious shape-shifting virus cannot evade.
“The first 10 participants completed their immunization without any problems,” Stamatatos said. Although no immunological data has been generated to date, he said he is hopeful that his team will be able to analyze results of the trial in the spring of 2023.
The antigen developed by his group cannot, by itself, cause our immune systems to make these rare, broadly neutralizing antibodies. Instead, his team hopes it will stimulate the volunteers’ B cells — antibody-making factories — to establish a lineage of immune cells that has the potential to do so after a few added evolutionary upgrades. It is a strategy scientists call germline targeting, a stepwise process of forced maturation or evolution.
Stamatatos’ team expects that the B-cell lineage stimulated by the first antigen can be coaxed by two or three subsequent vaccinations, using different antigens, into forms that naturally produce families of these unusual, specialized, broadly neutralizing antibodies.
The relatively brief trial is primarily designed to find out, quickly, if vaccination with the first antigen is safe, and to measure how the body responds to it.
“The ability to use a small trial, where we can be a little more nimble, is going to give us a better opportunity to examine whether a product is performing in the ways scientists desire, and causing the kinds of immune responses thought to be important,” said Gail Broder, MHS, associate director of social and behavioral science and community engagement for HVTN. Broder works with trial sites and their staff to explain the science of clinical trials to potential participants and other stakeholders.
“Smaller trials also allow us to use additional kinds of procedures to really explore the immune responses in depth, in ways that aren’t practical in a larger study,” she said. That would include more invasive procedures like lymph-node biopsies and leukapheresis, in which white blood cells are separated from circulating blood and collected. Such procedures take more time for the participant and carry larger costs to implement, so they are difficult to carry out on a large scale.
In the Stamatatos trial, for example, the researchers are also testing a new way of administering the vaccine, in a series of six smaller doses that gradually grow larger over a two-week period. The total amount of vaccine is the same as would normally be given in a single shot, but this “fractionated dosing” scheme shows potential for stimulating a much more robust immune response. It will not take a massive study to find out if this works, as biostatisticians need detailed immune response data from only a few dozen participants see if the experimental technique has succeeded or failed.
— Fred Hutch virologist Larry Corey, MD
HVTN 302 is another ExMed trial launched in March that has a direct connection to COVID-19. It will test whether the same mRNA technology that was used to deliver genetic instructions for making the SARS-CoV-2 spike protein could be used to deliver, instead, ingredients for making components of three different experimental HIV/AIDS vaccines.
Up to 108 adults who are HIV-negative will be enrolled in the study. The mRNA ingredients of the vaccines will instruct muscle cells near the injection site to produce protein that resemble spikes on HIV, but not the actual virus itself. The hope is that, like the spikes induced by mRNA in COVID-19 vaccines, these HIV spike fragments will stimulate production of HIV antibodies exquisitely tuned to attack the real virus.
“Applying this technology to HIV vaccine research is a defining moment for the field,” said Fred Hutch virologist Larry Corey, MD, in an HVTN Community Compass story marking the launch of the trial.
At the behest of Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases, Corey founded HVTN in 1999 and he remains a co-principal investigator of its Fred Hutch-based leadership and operations center.
“We have been studying various HIV vaccines for decades, and the science continues to progress, especially with the major advancements in the COVID-19 vaccines involving the use of mRNA technology,” Corey said.
Another ExMed trial, HVTN 303, will enroll up to 70 participants in a series of steps evaluating up to three different vaccine candidates alone or in combination. Launched in August, the trial is a collaboration involving multiple research centers in the HVTN network, including the University of Pittsburgh and Harvard, although no sites for it have been set up in Seattle.
The first of the three vaccines tested is a so-called fusion peptide conjugate, developed by NIAID’s Vaccine Research Center, that used genetic engineering to create pairs of small proteins that normally appear on HIV surfaces. The vaccines are designed to stimulate antibodies that block those proteins. The trial will also evaluate an adjuvant — an immune-boosting component that can enhance the effectiveness of the primary ingredients. Should this first vaccine and adjuvant show promise, volunteers in the study may test them in various combinations and dosages with two other vaccines. The antigens in those vaccines are made of different dummy proteins that mimic molecular features on HIV’s surface.
“The thing I appreciate about these studies is that we don’t typically look at combinations of vaccines in early phase studies,” said Stephaun Wallace, PhD, MS, principal staff scientist at Fred Hutch and director of external relations for HVTN. “The fact that were doing that in these studies speaks to the rapid pace and step-by-step, or iterative, nature of these trials.”
Elsewhere at Fred Hutch, researchers are studying ways to improve the delivery of HIV prevention interventions so people in need can pick a model that best fits their preferences and might also improve their access to care. The field even has a name, “implementation science,” and Fred Hutch researcher Katrina Ortblad, ScD, MPH, is a trained implementation scientist.
Most of her work is focused on finding ways to improve the delivery of HIV pre-exposure prophylaxis, or PrEP, in which people who do not have HIV — but are at risk of acquiring it — take formulations of antiviral drugs that can protect them from HIV infection.
“When we think about HIV, we have really good tools available, but a lot of people aren’t using them,” Ortblad said. “We have interventions that have been proven to work really well in clinical trials conducted in controlled environments; so now we are working to achieve those same effects in real-world settings, by addressing barriers to access and delivery when things are not as tightly controlled.”
During her frequent trips to Kenya, she works with the Kenyan researchers who helped prove the clinical effectiveness of PrEP to find ways improve its acceptance and consistent use. In a pilot project, her team is testing ways to make PrEP — typically obtained from public health clinics — readily and confidentially available from private pharmacies. The team tested this model of delivery at just four pharmacies, then later expanded it to 12.
“With funding from the Bill & Melinda Gates Foundation, we’re planning on a randomized trial to test different variations of this model at 60 pharmacies in Kenya this March. So, we are really scaling it up,” Ortblad said.
Fred Hutch researchers are also involved in studies of one of the most proven tools of HIV prevention — readily available testing followed by immediate enrollment in antiviral treatments — in hopes of expanding its use in Africa.
Fred Hutch biostatistician Deborah Donnell, PhD, who carries out analysis of prevention trials for HVTN’s North Carolina-based sister organization, the HIV Prevention Trials Network, or HPTN, is a co-author of a study that used computer-modelling to assess the potential impact of a “test and treat” strategy were it rolled out in South Africa and Zambia.
The findings of the computer analysis, published recently in The Lancet, were stunning. It was based on projections of findings in a randomized trial of the concept called PopART. The new study projected that if a program of universal, home-based testing and treatment were implemented in 21 communities with a high prevalence of HIV, it could cut the incidence of new HIV infections in half by 2030, compared to the current standard of care.
“We have been observing a slow but steady decrease in HIV incidence in countries in Africa, and that seems likely to be because of the effect of increasing uptake of treatment,” Donnell said. “The study did observe a 20-30% reduction in HIV incidence over the three-year period of the implementation of PopART, so it was great to see the math modeler’s generalize this to the whole population and project it forward to see the potential for such a substantial impact.”
As HIV prevention and treatment options expand, work continues on development of an HIV cure. Fred Hutch researchers are exploring ways of replicating through gene therapy and transplantation the experience of a handful of patients cured of HIV after blood stem cell transplants for leukemia.
While an effective gene therapy is still being developed that can reliably keep HIV at bay — so that a patient no longer needs a lifetime of antiviral medications — Fred Hutch researchers are working to reduce the cost of these approaches and promote efforts to enable development of future therapies in low- and middle-income countries.
Jennifer Adair, PhD, holder of the Fleischauer Family Endowed Chair in Gene Therapy Translation, is a cofounder of the Global Gene Therapy Initiative, a multinational effort to overcome barriers to inclusion in gene therapy studies to treat HIV and other blood disorders such as sickle cell disease.
“Both diseases are prevalent in the same geographic locations and are positioned to be treatable with gene and cell therapy approaches,” Adair said. “Making gene therapy for sickle cell disease available will pave the way for gene and cell therapies to treat HIV once they become available.”
With support from the Bill & Melinda Gates Foundation and others, including funds donated by Adair using her Fleischauer endowment, the global initiative hopes to launch early, Phase 1 gene therapy trials in India and Uganda by 2024.
These broad efforts across Fred Hutch and around the world hold promise that this next year could bring further scientific discoveries and research insights that help reduce the impact of HIV/AIDS.
Sabin Russell is a 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 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. Reach him at firstname.lastname@example.org.
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