How basic biology helps build better vaccines

Vaccines are one of the most impactful public health interventions in human history. Today, a child younger than 10 years old is 40 percent more likely to survive until their next birthday than they would be in a hypothetical scenario in which childhood vaccination did not exist.

Since the 1790s, when Edward Jenner first observed that dairymaids who had been infected with cowpox were protected against smallpox, rigorous research by scientists exploring the basic biology of the immune system has sparked breakthrough after breakthrough, resulting in the development of vaccines for dozens of infectious diseases, from chicken pox to COVID-19.

While those successes are to be celebrated, much work remains. For instance, we still do not know why many potential vaccines fail, why some are effective for a lifetime but others only for a few years, or how one might coax the immune system to better control cancer cells or HIV infection.

Today, immunologists have new ways to address these pressing questions, using advanced analytic and experimental technologies to test and design vaccine components from scratch. They can also directly measure how vaccines affect immune system cells, including B lymphocytes—or B cells—which create antibodies.

We invited three of Rockefeller’s  immunologists—Michel C. Nussenzweig, Marina Caskey, and Gabriel D. Victora—to discuss how research into the intricate details of immune system function can help improve today’s vaccines and unlock the next generation of preventative and therapeutic immunizations.

Nussenzweig is Rockefeller’s Zanvil A. Cohn and Ralph M. Steinman Professor, head of the Laboratory of Molecular Immunology, an investigator at the Howard Hughes Medical Institute, and co-director of the SNF Institute for Global Infectious Disease Research. His work explores the molecular aspects of the immune system’s innate and adaptive responses. Caskey is a professor of clinical investigation in Nussenzweig’s lab, where she develops and evaluates novel therapies for infectious diseases. Victora is the Laurie and Peter Grauer Professor, head of the Laboratory of Lymphocyte Dynamics, and a Howard Hughes Medical Institute investigator. He studies the processes by which the immune system refines its response to infection.

What are your current research interests, and how do they relate to vaccine development?

Gabriel D. Victora: Designing a vaccine or a therapeutic intervention requires fundamental knowledge of all the different parts of the immune system and how they work together. We’re interested in that biology: We investigate in depth how B cells behave and try to find out how to get the best antibodies out of those cells. This serves as a basis for any future clinical exploration by others of how to elicit a particular antibody response. If we can more thoroughly understand the function and evolution of B cells, it will enable the development of vaccines that prompt the immune system to produce the best B cells to fight off infection.

Michel C. Nussenzweig: With chronic infections of viruses such as HIV and hepatitis B, some people have immune systems that are able to control the infection. We are working on understanding how the immune system does that, so the knowledge can be used to craft vaccines to help prevent infection or control it with a single shot, rather than a lifetime of medications.

We continue to do a lot of basic work to understand antibody response to infection in mice, and in humans as well. We study how certain B cells decide to respond to an infection, and, once engaged, what they do in order to develop an optimal response. We hope that knowledge will help create better vaccines for evolving viruses. Right now, vaccines for these types of viruses have to be given every year, such as with the flu and COVID-19. That’s not ideal. If we can understand how and when B cells produce a long-lasting antibody response, we can potentially prompt the immune system to make antibodies that have a more lasting impact.

Marina Caskey: My main focus of research has been HIV, though we now have projects related to hepatitis B as well. One of the big challenges of HIV is that the virus can change itself very rapidly. It modifies its structure over time so that previously existing antibodies can no longer bind to it. This dynamic turns into a competition between the virus and the immune system. Unfortunately, the virus usually wins the race and escapes from the immune system. That’s why there is no current effective vaccine against HIV.

To both treat and potentially prevent HIV with a vaccine, we are exploring the use of broadly neutralizing antibodies (bNAbs). These are antibodies that recognize and attach to many different forms of HIV because they are able to target parts of HIV that need to be conserved. We are working to identify the right combination of bNAbs to use as a therapy to reduce the so-called “reservoir” of HIV infection, so that HIV levels become undetectable in patients. Additionally, if we identify the right antibodies, we can use them as a blueprint to design a vaccine that prompts the immune system to make its own bNAbs.

What are the biggest mysteries you’re trying to solve about the immune system?

MCN: So far, the field does not know enough to design vaccines against some truly important pathogens, such as HIV and norovirus, plus we do not have a universal flu vaccine that protects against all strains of influenza. Many of these pathogens are adroit at evading typical immune responses. For example, pathogens that evolve rapidly, like flu or HIV, change bits and pieces on the outside of the viral particle that the immune system would normally recognize. Finding and targeting viral elements that cannot change is part of what we do.

“By studying and understanding a pathogen’s tricks, we can learn to design vaccines to overcome them.”

Several years ago, our lab identified two broadly neutralizing antibodies that target those conserved viral elements on HIV in the blood of people whose bodies have successfully combated HIV without the help of drugs. Now, in collaboration with Marina, we have been testing those antibodies in clinical trials. Last March, we showed that participants who received a treatment with these two bNAbs just once had undetectable levels of virus for up to 20 weeks. By studying and understanding a pathogen’s tricks, we can learn to design vaccines to overcome them.

GDV: Currently, if you get a measles vaccine, you are protected forever, but if you get any type of protein or mRNA vaccine, the protection lasts only a certain amount of time and antibody levels decline after that. We don’t know what makes a response last forever, and that’s essentially a B cell biology question. What is the biology of these B cells that last forever?

We study tiny clusters of cells in the lymph nodes called germinal centers, in which B cells multiply and mutate—a form of high-speed evolution—to produce antibodies with the highest affinity for an invading pathogen. By understanding how B cells control rounds of mutation and proliferation, we can better understand how an immune response matures over time, changing again and again until it reaches an ideal response, with B cells that are long-lasting.

For example, we recently used imaging techniques to spot bursts of single B cells dividing rapidly and taking over a germinal center. We found that when these B cells are proliferating, they skip the cell cycle phase in which mutation takes place, suggesting that they are safeguarding successful mutations and avoiding deleterious mutations. Principles like these shed light on exactly what the immune system is doing to produce effective antibodies. That knowledge can help researchers design vaccines that prompt the immune system in the right way to produce the most effective antibodies against an infection.

There are additional areas of medicine in which B cells play a role that is important but not entirely understood. In allergies, why is it that some people’s B cells make an antibody called IgE that generates severe allergic responses? In autoimmunity, why is it that some people’s B cells attack their own organism instead of attacking foreign pathogens? If we can understand how and why B cells are reacting in these abnormal ways, perhaps we can guide those reactions, preventing them from producing antibodies that generate severe allergy and autoimmune reactions.

How can basic research help address current challenges in vaccine development?

MCN: There are two ways we can do better in vaccine development. One way is to find rare individuals who avoid or suppress infection naturally and study them to find out how they are doing it and try to replicate it. In the case of COVID-19, for example, we collected blood from volunteers who had recovered from infection. Most of the samples had a weak antibody response to the virus, but we identified three distinct antibodies that could potently neutralize the virus. Cloning those antibodies in the lab is one way to work backwards to learn how to make those antibodies for other people.

Another approach is to do the fundamental research on how immunity and immune responses develop in order to understand the whole process well enough to be able to design therapies and vaccines based on underlying principles. We recently discovered that B cells can store advantageous mutations, to produce antibodies with a stronger affinity to a pathogen, by cloning themselves instead of continuing to mutate. In this way, they strategically produce the most effective antibodies. If we understand the system well enough, perhaps we can engineer vaccines to produce the same response.

GDV: In order to make vaccines better, we need to know the underlying biology of what happens when a person receives many doses of vaccines, such as five doses of the COVID-19 vaccine. Say you get three doses of a vaccine against the original strain, then one dose against a different strain, and then another dose against another different strain. How does the immune system react when it is exposed to a series of immunogens? Does it max out at some point?

“Booster vaccines might work best if we wait until a virus strain is sufficiently divergent from the original strain.”

To understand that biology, we’ve been exploring a phenomenon called “original antigenic sin.” This occurs when the immune system reacts most strongly to the first viral strain it encounters, and then responses to later variants are blunted. That’s very important in flu immunizations, where we keep getting updated vaccines over and over.

We developed a molecular fate-mapping approach in which we tracked antibodies from different B cell cohorts in mice. We discovered that if a booster shot contains an antigen that is sufficiently different from the original antigen, then the immune system will reset and produce antibodies from new B cell populations, not the old B cells. If the same rules apply to humans, booster vaccines might work best if we wait until a virus strain is sufficiently divergent from the original strain.

Instead of preventing disease, some vaccines are used to treat diseases. What work are you conducting in therapeutic vaccines?

MCN: In therapeutic cancer vaccines, we’ve only recently been able to sequence cancers and learn enough about them to possibly produce something tailored to an individual. And the mRNA platform needed to produce a therapeutic cancer vaccine fast enough is only recently available. We’re at the very, very beginning of that whole process.

We do know immune manipulations, such as PD-1 and CTL4 immunotherapies, are game changers in therapy. You can think of them as global vaccinations, as ways of enhancing immune responses. That’s what a vaccine does, just in a specific way.

For HIV, we’re learning about how the immune system can help control the infection. Understanding that will be an essential part of trying to create a vaccine that can be therapeutic. But before we can do that, we need to understand what people who actually control HIV really do in order to control it. This is something that is just evolving now.

MC: We are currently finishing a couple studies with broadly neutralizing antibodies as a treatment. In a study of people with HIV, we combined the antibodies with another drug that enhances immune system activity. We want to see if the antibodies can keep the virus suppressed, even without standard antiretroviral therapy, and to see if this combination of antibodies plus an immune-stimulating drug can enhance a person’s own immune response. The hope is that even once the antibody washes out, the immune system can continue to suppress the virus on its own. If we are successful, our approach could put the possibility of a functional cure for HIV back on the table: a finite course of combination treatments inducing durable remission, in place of lifelong antiretroviral therapy.

GDV: I’m very interested in how the immune system is involved in diseases such as cancer, autoimmune disease, and neurodegeneration. In these conditions, B cells appear to be present and involved, but no one yet understands what role these cells are playing. What is it that B cells do in cancer—why are they so present inside some tumors and not others? And do B cells play a pivotal or secondary role in these conditions, including multiple sclerosis, where the best current drugs are treatments that target B cells? These kinds of questions are still wide open, and revealing the underlying mechanisms of B cells in these conditions could lead us to potentially stunning breakthroughs in vaccine development.

B cells may also help lead toward treatments as we continue to study the role of the immune system in the gastrointestinal tract. With my colleague Daniel Mucida and his team here at Rockefeller, we identified how specific gut cells communicate with T cells, triggering them to either attack or ignore antigens from food and pathogens. Next, we want to know what B cells are doing in the gut. Understanding the logic of the gut immune system will help us better understand, and potentially treat, conditions like inflammatory bowel disease and colitis.

When you look to the future of vaccines, what areas of vaccine development are you excited about?

MC: Historically, the majority of vaccines have been developed empirically, by means of observation, without much knowledge about how a protein structurally interacts with the immune system. Now, new technologies allow vaccines to be rationally designed, with a specific purpose, to induce a specific immune response. This is still very new; we are just in the beginning of this type of vaccine design.

“New technologies allow vaccines to be rationally designed, with a specific purpose, to induce a specific immune response.”

For infections like the flu, mRNA vaccines are a good platform because modifications can be done very quickly. But they are not a solution for everything because the immune response that mRNA induces may not be adequate for every type of pathogen. There is still more to be learned about mRNA vaccines and how to best apply them.

GDV: Today’s vaccines are based on rigorous scientific testing supported by a deep understanding of the immune system. The vaccines that have already been designed with the knowledge we have are amazing, and if we get answers to the questions we’re asking now, we could do phenomenal things in the future.

Right now, we know how to give an organism an antigen and let the organism’s immune system target whatever part of the antigen it wants. If that spontaneous targeting works out, we have a vaccine. If it doesn’t, as in the case of HIV, we don’t. In the future, we can be better at guiding the immune system to target the conserved part of a virus, rather than a random location.

To do that, an active area of research for the field has been germline-targeting vaccines, designed to guide B cells to produce specific, potent antibodies that bind to a conserved site on a pathogen. In this case, it’s not so much about the formulation of the vaccine, whether it’s RNA, DNA, or protein. Instead,  the focus is on engineering the antigen we’re going to expose the immune system to, so that it elicits the exact response we want: B cells that produce antibodies targeting a specific, conserved place on a pathogen.

It will be much harder to make a germline-targeting vaccine if we don’t understand how antibodies work and what kind of cells make them. The more we understand the basic rules of how the complex, intricate immune system works, the better we will be at devising interventions. That’s the value and beauty of basic science.