Virus World

Scientists are examining the role of T cells, which are likely crucial for long-term protection against SARS-CoV-2. When COVID-19 began spreading like wildfire in the Northeast United States this spring, critical care doctor Nuala Meyer could barely believe what she was seeing. “The number of patients who were presenting with critical illness all at the same time was staggering,” remembers Meyer, a professor of medicine at the Hospital of the University of Pennsylvania. But it wasn’t just that these patients were really sick—it was that they were sick in a startling variety of ways. Some had cardiac issues. Others had blood clots in their legs. Then there were those who developed pneumonia and related respiratory problems. Organ failure affected some. The list went on and on. When Meyer and colleagues profiled the ways in which hospitalized patients’ bodies had tried to combat the virus, they found a variety of different immune responses. T and B cells were highly activated in some but not others, for instance. Their work joins a swath of recent publications aiming to decipher the role of these crucial cells in fending off SARS-CoV-2. To understand how vaccines and long-term immunity function, scientists say, they’ll need to uncover how T and B cells fight this most challenging of infections. In pursuit of this goal, Meyer and her colleagues examined immune responses in a sample of 125 patients. Their findings were published in Science July 15.

The researchers found that some patients had very unbalanced immune cell activity and that this imbalance could manifest in multiple ways. For instance, some produced lots of CD4+ T cells—helper cells that assist other parts of the immune system to block or destroy the virus—but very few CD8+ T “killer” cells, which destroy infected cells in the body. Meanwhile, some patients generated lots of B cells, which churn out antibodies, but not in concert with the two main types of T cell. Getting these cells to work together is important, explains coauthor Michael Betts, an immunologist at the Penn Institute for Immunology, because it helps fight infection on several fronts at once. Some T cells, for instance, help B cells to produce antibodies—it’s a joint effort. In some patients studied by the group, there was a worrying lack of T and B cells in general. Severely ill patients, notably, experienced “the spectrum” of responses, says Betts—from hardly any T and B cell activation to excessive amounts. He says it’s still not clear what drives severe illness in many patients. Scientists also don’t yet know precisely what kind of T and B cell response occurs in patients who have mild or no symptoms....

A collaborative team of scientists has made a successful proof-of-principle demonstration of an advanced HIV vaccine strategy--an approach that may also work in protecting people from an array of other deadly infectious diseases. The team, led by scientists at Scripps Research, also included the Ragon Institute of Massachusetts General Hospital, MIT and Harvard University; the La Jolla Institute for Immunology; and IAVI, a scientific research organization focused on HIV and other global health challenges. Their research appears in Science. The new vaccine strategy centers on stimulating the immune system to produce broadly neutralizing antibodies (bnAbs) against HIV. These special antibodies are capable of neutralizing many different strains of the fast-mutating virus by binding to important yet difficult-to-access regions of the virus surface that don't vary much from strain to strain.

The new vaccine strategy centers on stimulating the immune system to produce broadly neutralizing antibodies (bnAbs) against HIV. These special antibodies are capable of neutralizing many different strains of the fast-mutating virus by binding to important yet difficult-to-access regions of the virus surface that don't vary much from strain to strain. A vaccine that elicits such antibodies could save many millions of lives and billions of dollars--and ultimately, may help eliminate HIV as a significant public health problem. Based on a concept called "germline targeting," this novel strategy could potentially provide protection against the millions of different strains of the virus circulating globally. Achieving this goal has so far been elusive; no HIV vaccine candidate has ever been shown to induce a protective bnAb response in humans.

"I believe that we need a germline-targeting strategy to develop an effective vaccine against HIV, and the same type of strategy may be helpful for making vaccines against many other difficult pathogens," says the study's co-senior author William Schief, PhD, a professor in the Department of Immunology and Microbiology at Scripps Research. "Here, with a great collaborative effort among multiple labs, we've shown the feasibility of a general germline-targeting approach."  This study drew scientists from diverse backgrounds and areas of expertise: co-senior authors are Scripps Research's Schief, Facundo Batista, PhD, chief scientific officer at the Ragon Institute, and Shane Crotty, PhD, a professor in the Vaccine Discovery Division at La Jolla Institute for Immunology.

The germline-targeting approach is meant to launch the production of a desired bnAb by stimulating the right antibody-producing cells. Antibodies are produced by immune cells called B cells, which start out in a "naïve" or "germline" state.  A large repertoire of these germline B cells circulates in the blood and other tissues. In a viral infection--or after immunization with a vaccine that mimics an infecting virus--some germline B cells will bind at least weakly to structures on the surface of the virus. That will stimulate the cells to begin a weeks-long maturation process, in which the antibodies continuously improve in their ability to bind to the surface, thereby neutralizing the virus.  The germline-targeting strategy for an HIV vaccine aims to stimulate the small number of germline B cells that are capable of maturing into cells that make bnAbs. Researchers suspect that other attempts to create an HIV vaccine that elicits bnAbs have failed because they haven't stimulated a sufficient number of these "bnAb precursor" germline B cells. Schief and colleagues previously demonstrated a germline-targeting strategy for one special case: a bnAb that grabs hold of HIV in an unusual way. The new approach is more powerful because it works for antibodies that grip their targets via a much more common mechanism. Furthermore, analyses performed in the study indicate that the approach can likely also be applied to vaccines for many other difficult pathogens such as influenza, dengue virus, Zika virus, hepatitis C and malaria.

To demonstrate the feasibility of their strategy, Schief and Jon Steichen, PhD, a study co-first author and senior scientist in the Schief lab, started by choosing a known HIV bnAb called BG18 as the test case. Informed by structural studies of BG18 bound to its target on the virus--including structures determined for this study in the lab of Andrew Ward, PhD, professor of Integrative Structural and Computational Biology at Scripps Research, and published structures from the lab of Pamela Bjorkman, PhD, at Caltech--Steichen and Schief identified key features of this antibody's HIV-gripping ability.  Next, they searched a large database of human antibody genes in order to find B cells making antibodies that naturally share BG18's key features. Then they used a sophisticated strategy to select and evolve a set of virus-mimicking proteins that could potentially activate multiple BG18-like B cells. These proteins would eventually serve as "immunogens" to stimulate BG18-like B cells in human vaccination.

"As the repertoire of B cells differs from person to person, and in the same person over time, we believe that you need to target more than a few of these cells to have a reasonable chance of activating one of them in any given vaccine recipient," Steichen says.  In the lab of Shane Crotty at the La Jolla Institute for Immunology, tests of blood samples from HIV-negative human donors confirmed that the team's immunogens bound well to normal circulating B cells that have the desired BG18-like features.....

Published in Science (October 31, 2019):

https://doi.org/10.1126/science.aax4380

Every year, we're reminded to return to the pharmacy for a flu shot. Why can't we have a flu vaccine that offers long-term protection, like those for measles or polio? That's because the influenza virus continuously evolves, so the immune response we build up one year might not work the next year—or even on the version of the flu you catch the same year. As a result, the virus remains dangerous: last year, it caused more than 60,000 deaths in the United States alone. New findings, published in Cell, reveal why making a general-purpose vaccine that guards against all versions of the flu is so hard: Instead of improving its memory of the previous version of virus, the immune system develops its response to the new virus variant from scratch, mostly using immune cells that have no memory of the virus. "If we can figure out how to help the immune system to keep building on what it has already learned, we could develop better vaccines for highly evolving viruses like the flu, or HIV, or Hepatitis C," says Gabriel D. Victora, assistant professor at Rockefeller.

Blocked memory

Victora and his team explored the behavior of immune cells in mice after a first and second exposure to a flu vaccine. Specifically, they looked at B cells, white blood cells that release antibodies. Antibodies are proteins that respond to invaders such as viruses by attacking them or tagging them for attack by other cells. During an infection or immunization, B cells enter so-called germinal centers in the lymph nodes, where they mutate many times until they evolve to target the new invader. "A germinal center is like a boot camp," says Victora. "They go in very bad, they come out very good, releasing better antibodies that bind more tightly to their targets." Those very good B cells are the immune system's cellular memory and can release antibodies that latch on to one part of the virus. Ideally, these B cells would return to the germinal centers the next time the body is faced with a virus or vaccine, and evolve even more sophisticated antibodies to target the slightly different version of the virus even better, ultimately becoming able to produce the so-called broadly neutralizing antibodies that the virus can't escape from. And that's what researchers need in order to make a universal vaccine. 

"The idea is you would keep calling memory cells back into germinal centers by repeated vaccination," Victora says, "in order to make them evolve several times until they become the super B cells that you need to give you a universal flu vaccine or an HIV vaccine." But instead of seeing the B cells return, the researchers found something different. They genetically marked the mice's germinal centers with fluorescent colors during the first vaccination so they could track the behavior of their descendants during the second vaccination. To their surprise, more than 90 percent of the B cells that entered the germinal centers on the second vaccination were uncolored—a sign that they were newcomers. A genetic analysis also revealed these cells hadn't gone through the mutation process that germinal center B cells typically undergo, further suggesting they were present in that site for the first time. The boot camp veterans, however, were mostly absent. Out of the hundreds of types of B cells that entered the germinal centers on the first vaccination, only a few made it back the second time, despite many of them being able to bind to the virus. It appears that coming back a second time is reserved only for a chosen few B cells....

Published in Cell (December 19, 2019):

https://doi.org/10.1016/j.cell.2019.11.032