Encouraging First-in-Human Results for a Promising HIV Vaccine
Posted on by Lawrence Tabak, D.D.S., Ph.D.
In recent years, we’ve witnessed some truly inspiring progress in vaccine development. That includes the mRNA vaccines that were so critical during the COVID-19 pandemic, the first approved vaccine for respiratory syncytial virus (RSV), and a “universal flu vaccine” candidate that could one day help to thwart future outbreaks of more novel influenza viruses.
Inspiring progress also continues to be made toward a safe and effective vaccine for HIV, which still infects about 1.5 million people around the world each year . A prime example is the recent first-in-human trial of an HIV vaccine made in the lab from a unique protein nanoparticle, a molecular construct measuring just a few billionths of a meter.
The results of this early phase clinical study, published recently in the journal Science Translational Medicine  and earlier in Science , showed that the experimental HIV nanoparticle vaccine is safe in people. While this vaccine alone will not offer HIV protection and is intended to be part of an eventual broader, multistep vaccination regimen, the researchers also determined that it elicited a robust immune response in nearly all 36 healthy adult volunteers.
How robust? The results show that the nanoparticle vaccine, known by the lab name eOD-GT8 60-mer, successfully expanded production of a rare type of antibody-producing immune B cell in nearly all recipients.
What makes this rare type of B cell so critical is that it is the cellular precursor of other B cells capable of producing broadly neutralizing antibodies (bnAbs) to protect against diverse HIV variants. Also very good news, the vaccine elicited broad responses from helper T cells. They play a critical supportive role for those essential B cells and their development of the needed broadly neutralizing antibodies.
For decades, researchers have brought a wealth of ideas to bear on developing a safe and effective HIV vaccine. However, crossing the finish line—an FDA-approved vaccine—has proved profoundly difficult.
A major reason is the human immune system is ill equipped to recognize HIV and produce the needed infection-fighting antibodies. And yet the medical literature includes reports of people with HIV who have produced the needed antibodies, showing that our immune system can do it.
But these people remain relatively rare, and the needed robust immunity clocks in only after many years of infection. On top of that, HIV has a habit of mutating rapidly to produce a wide range of identity-altering variants. For a vaccine to work, it most likely will need to induce the production of bnAbs that recognize and defend against not one, but the many different faces of HIV.
To make the uncommon more common became the quest of a research team that includes scientists William Schief, Scripps Research and IAVI Neutralizing Antibody Center, La Jolla, CA; M. Juliana McElrath, Fred Hutchinson Cancer Center, Seattle; and Kristen Cohen, a former member of the McElrath lab now at Moderna, Cambridge, MA. The team, with NIH collaborators and support, has been plotting out a stepwise approach to train the immune system into making the needed bnAbs that recognize many HIV variants.
The critical first step is to prime the immune system to make more of those coveted bnAb-precursor B cells. That’s where the protein nanoparticle known as eOD-GT8 60-mer enters the picture.
This nanoparticle, administered by injection, is designed to mimic a small, highly conserved segment of an HIV protein that allows the virus to bind and infect human cells. In the body, those nanoparticles launch an immune response and then quickly vanish. But because this important protein target for HIV vaccines is so tiny, its signal needed amplification for immune system detection.
To boost the signal, the researchers started with a bacterial protein called lumazine synthase (LumSyn). It forms the scaffold, or structural support, of the self-assembling nanoparticle. Then, they added to the LumSyn scaffold 60 copies of the key HIV protein. This louder HIV signal is tailored to draw out and engage those very specific B cells with the potential to produce bnAbs.
As the first-in-human study showed, the nanoparticle vaccine was safe when administered twice to each participant eight weeks apart. People reported only mild to moderate side effects that went away in a day or two. The vaccine also boosted production of the desired B cells in all but one vaccine recipient (35 of 36). The idea is that this increase in essential B cells sets the stage for the needed additional steps—booster shots that can further coax these cells along toward making HIV protective bnAbs.
The latest finding in Science Translational Medicine looked deeper into the response of helper T cells in the same trial volunteers. Again, the results appear very encouraging. The researchers observed CD4 T cells specific to the HIV protein and to the LumSyn in 84 percent and 93 percent of vaccine recipients. Their analyses also identified key hotspots that the T cells recognized, which is important information for refining future vaccines to elicit helper T cells.
The team reports that they’re now collaborating with Moderna, the developer of one of the two successful mRNA-based COVID-19 vaccines, on an mRNA version of eOD-GT8 60-mer. That’s exciting because mRNA vaccines are much faster and easier to produce and modify, which should now help to move this line of research along at a faster clip.
Indeed, two International AIDS Vaccine Initiative (IAVI)-sponsored clinical trials of the mRNA version are already underway, one in the U.S. and the other in Rwanda and South Africa . It looks like this team and others are now on a promising track toward following the basic science and developing a multistep HIV vaccination regimen that guides the immune response and its stepwise phases in the right directions.
As we look back on more than 40 years of HIV research, it’s heartening to witness the progress that continues toward ending the HIV epidemic. This includes the recent FDA approval of the drug Apretude, the first injectable treatment option for pre-exposure prevention of HIV, and the continued global commitment to produce a safe and effective vaccine.
 Global HIV & AIDS statistics fact sheet. UNAIDS.
 A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Cohen KW, De Rosa SC, Fulp WJ, deCamp AC, Fiore-Gartland A, Laufer DS, Koup RA, McDermott AB, Schief WR, McElrath MJ. Sci Transl Med. 2023 May 24;15(697):eadf3309.
 Vaccination induces HIV broadly neutralizing antibody precursors in humans. Leggat DJ, Cohen KW, Willis JR, Fulp WJ, deCamp AC, Koup RA, Laufer DS, McElrath MJ, McDermott AB, Schief WR. Science. 2022 Dec 2;378(6623):eadd6502.
 IAVI and Moderna launch first-in-Africa clinical trial of mRNA HIV vaccine development program. IAVI. May 18, 2022.
Progress Toward an Eventual HIV Vaccine, NIH Research Matters, Dec. 13, 2022.
NIH Statement on HIV Vaccine Awareness Day 2023, Auchincloss H, Kapogiannis, B. May, 18, 2023.
HIV Vaccine Development (National Institute of Allergy and Infectious Diseases/NIH)
International AIDS Vaccine Initiative (IAVI) (New York, NY)
William Schief (Scripps Research, La Jolla, CA)
Julie McElrath (Fred Hutchinson Cancer Center, Seattle, WA)
McElrath Lab (Fred Hutchinson Cancer Center, Seattle, WA)
NIH Support: National Institute of Allergy and Infectious Diseases
Thank You, Dr. Fauci
Posted on by Lawrence Tabak, D.D.S., Ph.D.
What A Year It Was for Science Advances!
Posted on by Dr. Francis Collins
At the close of every year, editors and writers at the journal Science review the progress that’s been made in all fields of science—from anthropology to zoology—to select the biggest advance of the past 12 months. In most cases, this Breakthrough of the Year is as tough to predict as the Oscar for Best Picture. Not in 2020. In a year filled with a multitude of challenges posed by the emergence of the deadly coronavirus disease 2019 (COVID-2019), the breakthrough was the development of the first vaccines to protect against this pandemic that’s already claimed the lives of more than 360,000 Americans.
In keeping with its annual tradition, Science also selected nine runner-up breakthroughs. This impressive list includes at least three areas that involved efforts supported by NIH: therapeutic applications of gene editing, basic research understanding HIV, and scientists speaking up for diversity. Here’s a quick rundown of all the pioneering advances in biomedical research, both NIH and non-NIH funded:
Shots of Hope. A lot of things happened in 2020 that were unprecedented. At the top of the list was the rapid development of COVID-19 vaccines. Public and private researchers accomplished in 10 months what normally takes about 8 years to produce two vaccines for public use, with more on the way in 2021. In my more than 25 years at NIH, I’ve never encountered such a willingness among researchers to set aside their other concerns and gather around the same table to get the job done fast, safely, and efficiently for the world.
It’s also pretty amazing that the first two conditionally approved vaccines from Pfizer and Moderna were found to be more than 90 percent effective at protecting people from infection with SARS-CoV-2, the coronavirus that causes COVID-19. Both are innovative messenger RNA (mRNA) vaccines, a new approach to vaccination.
For this type of vaccine, the centerpiece is a small, non-infectious snippet of mRNA that encodes the instructions to make the spike protein that crowns the outer surface of SARS-CoV-2. When the mRNA is injected into a shoulder muscle, cells there will follow the encoded instructions and temporarily make copies of this signature viral protein. As the immune system detects these copies, it spurs the production of antibodies and helps the body remember how to fend off SARS-CoV-2 should the real thing be encountered.
It also can’t be understated that both mRNA vaccines—one developed by Pfizer and the other by Moderna in conjunction with NIH’s National Institute of Allergy and Infectious Diseases—were rigorously evaluated in clinical trials. Detailed data were posted online and discussed in all-day meetings of an FDA Advisory Committee, open to the public. In fact, given the high stakes, the level of review probably was more scientifically rigorous than ever.
First CRISPR Cures: One of the most promising areas of research now underway involves gene editing. These tools, still relatively new, hold the potential to fix gene misspellings—and potentially cure—a wide range of genetic diseases that were once to be out of reach. Much of the research focus has centered on CRISPR/Cas9. This highly precise gene-editing system relies on guide RNA molecules to direct a scissor-like Cas9 enzyme to just the right spot in the genome to cut out or correct a disease-causing misspelling.
In late 2020, a team of researchers in the United States and Europe succeeded for the first time in using CRISPR to treat 10 people with sickle cell disease and transfusion-dependent beta thalassemia. As published in the New England Journal of Medicine, several months after this non-heritable treatment, all patients no longer needed frequent blood transfusions and are living pain free .
The researchers tested a one-time treatment in which they removed bone marrow from each patient, modified the blood-forming hematopoietic stem cells outside the body using CRISPR, and then reinfused them into the body. To prepare for receiving the corrected cells, patients were given toxic bone marrow ablation therapy, in order to make room for the corrected cells. The result: the modified stem cells were reprogrammed to switch back to making ample amounts of a healthy form of hemoglobin that their bodies produced in the womb. While the treatment is still risky, complex, and prohibitively expensive, this work is an impressive start for more breakthroughs to come using gene editing technologies. NIH, including its Somatic Cell Genome Editing program, continues to push the technology to accelerate progress and make gene editing cures for many disorders simpler and less toxic.
Scientists Speak Up for Diversity: The year 2020 will be remembered not only for COVID-19, but also for the very public and inescapable evidence of the persistence of racial discrimination in the United States. Triggered by the killing of George Floyd and other similar events, Americans were forced to come to grips with the fact that our society does not provide equal opportunity and justice for all. And that applies to the scientific community as well.
Science thrives in safe, diverse, and inclusive research environments. It suffers when racism and bigotry find a home to stifle diversity—and community for all—in the sciences. For the nation’s leading science institutions, there is a place and a calling to encourage diversity in the scientific workplace and provide the resources to let it flourish to everyone’s benefit.
For those of us at NIH, last year’s peaceful protests and hashtags were noticed and taken to heart. That’s one of the many reasons why we will continue to strengthen our commitment to building a culturally diverse, inclusive workplace. For example, we have established the NIH Equity Committee. It allows for the systematic tracking and evaluation of diversity and inclusion metrics for the intramural research program for each NIH institute and center. There is also the recently founded Distinguished Scholars Program, which aims to increase the diversity of tenure track investigators at NIH. Recently, NIH also announced that it will provide support to institutions to recruit diverse groups or “cohorts” of early-stage research faculty and prepare them to thrive as NIH-funded researchers.
AI Disentangles Protein Folding: Proteins, which are the workhorses of the cell, are made up of long, interconnected strings of amino acids that fold into a wide variety of 3D shapes. Understanding the precise shape of a protein facilitates efforts to figure out its function, its potential role in a disease, and even how to target it with therapies. To gain such understanding, researchers often try to predict a protein’s precise 3D chemical structure using basic principles of physics—including quantum mechanics. But while nature does this in real time zillions of times a day, computational approaches have not been able to do this—until now.
Of the roughly 170,000 proteins mapped so far, most have had their structures deciphered using powerful imaging techniques such as x-ray crystallography and cryo–electron microscopy (cryo-EM). But researchers estimate that there are at least 200 million proteins in nature, and, as amazing as these imaging techniques are, they are laborious, and it can take many months or years to solve 3D structure of a single protein. So, a breakthrough certainly was needed!
In 2020, researchers with the company Deep Mind, London, developed an artificial intelligence (AI) program that rapidly predicts most protein structures as accurately as x-ray crystallography and cryo-EM can map them . The AI program, called AlphaFold, predicts a protein’s structure by computationally modeling the amino acid interactions that govern its 3D shape.
Getting there wasn’t easy. While a complete de novo calculation of protein structure still seemed out of reach, investigators reasoned that they could kick start the modeling if known structures were provided as a training set to the AI program. Utilizing a computer network built around 128 machine learning processors, the AlphaFold system was created by first focusing on the 170,000 proteins with known structures in a reiterative process called deep learning. The process, which is inspired by the way neural networks in the human brain process information, enables computers to look for patterns in large collections of data. In this case, AlphaFold learned to predict the underlying physical structure of a protein within a matter of days. This breakthrough has the potential to accelerate the fields of structural biology and protein research, fueling progress throughout the sciences.
How Elite Controllers Keep HIV at Bay: The term “elite controller” might make some people think of video game whizzes. But here, it refers to the less than 1 percent of people living with human immunodeficiency virus (HIV) who’ve somehow stayed healthy for years without taking antiretroviral drugs. In 2020, a team of NIH-supported researchers figured out why this is so.
In a study of 64 elite controllers, published in the journal Nature, the team discovered a link between their good health and where the virus has inserted itself in their genomes . When a cell transcribes a gene where HIV has settled, this so-called “provirus,” can produce more virus to infect other cells. But if it settles in a part of a chromosome that rarely gets transcribed, sometimes called a gene desert, the provirus is stuck with no way to replicate. Although this discovery won’t cure HIV/AIDS, it points to a new direction for developing better treatment strategies.
In closing, 2020 presented more than its share of personal and social challenges. Among those challenges was a flood of misinformation about COVID-19 that confused and divided many communities and even families. That’s why the editors and writers at Science singled out “a second pandemic of misinformation” as its Breakdown of the Year. This divisiveness should concern all of us greatly, as COVID-19 cases continue to soar around the country and our healthcare gets stretched to the breaking point. I hope and pray that we will all find a way to come together, both in science and in society, as we move forward in 2021.
 CRISPR-Cas9 gene editing for sickle cell disease and β-thalassemia. Frangoul H et al. N Engl J Med. 2020 Dec 5.
 ‘The game has changed.’ AI triumphs at protein folding. Service RF. Science. 04 Dec 2020.
 Distinct viral reservoirs in individuals with spontaneous control of HIV-1. Jiang C et al. Nature. 2020 Sep;585(7824):261-267.
COVID-19 Research (NIH)
2020 Science Breakthrough of the Year (American Association for the Advancement of Science, Washington, D.C)