As the United States opens the door to broad eligibility to COVID-19 vaccines, questions still loom about long-term efforts to contain the pandemic globally and prepare for viral adaptations. Immunologists at the University of Pennsylvania are working to understand the way people respond to COVID-19 vaccines and the lessons that may provide about how to control the spread of variants around the world. People who have already recovered from COVID-19 are showing signs of robust protection from the coronavirus and its variants after just one dose of the Pfizer or Moderna vaccines, according to a new Penn study published in Science NEWSThe gender vaccine gap More women than men are getting COVID-19 shotsPhilly makes all adults 16 and older eligible for COVID-19 vaccineThe variant is spreading rapidly, sparking debates about the vaccination rollout For people who have never had COVID-19, a full immune response isn't realized until after receiving the second vaccine dose. The small study examines the underlying immunobiology of mRNA vaccines, which give the body instructions to build proteins and induce a protective antibody response. Antibodies provide rapid immunity, but just as importantly, mRNA vaccines encourage the formation of memory B cells. This is what gives the body a long-term blueprint to fight off future changes in the virus. "Antibodies are important and we understand this concept now of antibodies being what protects you," said E. John Wherry, director of the Penn Institute of Immunobiology. "But memory B cells are the actual cells in the immune system that are kind of like precursors. When they get activated, they become the antibody factors. They're kept around as a reserve capacity to help protect you if the antibodies that you have don't work well enough, and also to be the substrate to make new kinds of antibodies in the future. These mRNA vaccines induce a really good memory B cell response." The Penn study looked at mRNA vaccine responses in 44 healthy participants, including 11 who had previously recovered from a COVID-19 infection. All of the participants received either the Pfizer or Moderna vaccine and blood samples were collected for deep immune analyses four times — before and after each vaccine dose. Wherry, the study's senior author, described the different responses between people who had never had COVID-19 and those who had recovered from an infection. Though the vaccines produced high and consistent levels of antibodies in 95% of those who received them, people who were previously infected had a more complete response after just one shot, likely because of the primary response they had to the infection. That primary response doesn't appear to be sufficient on its own for long-term protection without a vaccine, however. People who had a mild or asymptomatic COVID-19 infection in the past may only have low antibody levels, which may not be as effective as the vaccine at neutralizing the variant viruses that have become increasingly prevalent. In part, that's because a past infection may not produce high levels of immunological memory. "What we know from the data that's out there is that people who recover from natural infection have a wide range of immune responses," Wherry said. Vaccination ensures a more thorough and long-lasting response, one that accounts for the natural ability viruses have to undermine the body's creation of memory B cells. This is where the mRNA vaccines make the difference, focusing the body's resources on the spike protein of the virus and its variants. "The spike proteins of viruses do this really important thing in that they allow the virus to fuse with your cell," Wherry said. "To do that, this protein is like a spring-loaded weapon. When it binds, it snaps into a new position, and that new position is actually what's being expressed in the vaccines. That allows your immune response to focus on this key part of the virus that's normally hidden. That's the exact part that's needed to actually protect you."'Everyone has good responses' Notably, the study cohort that did not previously have COVID-19 needed both doses of the mRNA vaccine in order to develop a strong memory B cell response. The people in this "COVID naive" group who had systemic side effects after receiving one dose of the vaccine — including fever, chills, headache and fatigue — all showed slightly stronger serum antibody responses than those who had minimal or no side effects. But it took the second dose in order to get a considerable memory B cell response. The study's findings were consistent in the analysis of antibodies against the D614G mutation of the spike protein and in the South African variant of COVID-19. For those who did not have COVID-19, it took a second dose to get a robust enough immunity level against the mutation and variant, whereas those who recovered from COVID-19 had a strong enough antibody response after one don't know whether we're going to need boosters. I'm glad that we're talking about it. Planning for the worst and hoping for the best is always a good strategy. — E. John Wherry, director of the Penn Institute of Immunobiology "Everyone has good responses to the vaccines. They work to protect people against COVID-19," Wherry said. "But for those who may be worried about side effects, they are not necessarily a bad thing — they may actually be an indicator of an even better immune response. Side effects are pretty common. They're something that the drug was designed to do that may just cause initial discomfort. They are telling you that your immune response is working." Wherry said it's important not to get side effects confused with adverse events and use them as a measure of whether COVID-19 vaccines are safe. "There is this claim of side effects and adverse events — side effects being common and on target and OK, adverse events being things that are scary, that are really rare, that are unintended," Wherry said. "For adverse events, we need to study, stop, pause, understand and then adapt. There's a real conflation of those two ideas that I think leads to some lack of confidence." Even the recent pause on the use of the Johnson & Johnson vaccine — which is a traditional "viral vector" vaccine, not an mRNA vaccine — requires a basic examination of risk before mistaking the present caution as grounds for deep distrust. Six women have reported rare and serious blood clots after receiving the single-dose Johnson & Johnson shot. One of them died, while the death of a 21-year-old Ohio man a day after getting vaccinated remains under investigation. "To put the risk of these adverse events in perspective, your chances of dying of COVID, just being an American, are one in 600," Wherry said. "Your chances of having one of these complications of the Johnson & Johnson vaccine are about one in a million. The risk-balance equation here is extremely clear." Building the case that one mRNA vaccine dose may be enough for people who have already had COVID-19 could have ramifications for long-term vaccine distribution strategies. "There may be some settings where we might think about changing policy," Wherry said. "We're going to get to the point of having a lot of the population vaccinated and start to control things, probably before we need to make any policy decisions." Thinking more broadly, the ongoing study in Wherry's lab could influence decisions about how to effectively deploy the vaccine in future hotspots. "To be very clear, this pandemic problem is not going away when the gets to 70% or 80% of people vaccinated. This is a global problem," Wherry said. "We can have Americans vaccinated to a pretty high level, and if we have a pandemic raging in South America or Africa or Asia, it's still going to be a problem here because we're going to have variants driven from other parts of the world that will concern us." Even if enough vaccine supply is developed to meet global needs, the prospect of only using one vaccine dose to safely immunize people with previous infections could make disease control a lot easier. It would mean fewer people have to return for a second dose and tracking progress would become simpler. A versatile, transformative approach One of the more exciting aspects of the study is its findings on strong memory B cell production, which could provide important protection for variants and insights into the development of possible booster shots that are tailored to neutralize them. "We don't know whether we're going to need boosters," Wherry said. "I'm glad that we're talking about it. Planning for the worst and hoping for the best is always a good strategy. These mRNA vaccines induce a really good memory B cell response. As we go to think about boosters that might help with coverage of variants, those memory B cells generated by the vaccine are now our starting point. We don't have to start from square one." The next phase of the study in Wherry's lab will take a larger-scale look at the question of a one- or two-dose regimen in COVID-19-recovered individuals and to see how long the vaccine antibodies last. The lab will also analyze the effect of the vaccine on virus-specific T-cell responses, another facet of the body's protective reaction. Moving forward, Wherry is excited about the potential of mRNA as a tool with wide-ranging applications, both in vaccine science and in the prevention and treatment of other diseases. "They are so easy and quick to make. They're so versatile in what they can do," Wherry said. "I think we've seen a paradigm shift in thinking about infectious disease control, not just in humans but also in animals. The mRNA platform is going to transform the way we do things. In the future, we're going to see this as an inflection point in medicine — not just for vaccines. There are probably other methods that we can think about for mRNA to deliver therapeutics, maybe gene therapy at some point." To get to that point, Wherry said investing in research remains imperative in order to make possible innovations like the COVID-19 vaccines. "We can't overlook fundamental basic science as the foundation that let this happen," Wherry said. "We would not have had a vaccine in a year if there wasn't 20 years of studying what the public would basically think of as esoteric, uninteresting viruses." The study and ongoing research are supported by the National Institutes of Health, the Allen Institute for Immunology, Cancer Research Institute-Mark Foundation Fellowship, Chen Family Research Fund, the Parker Institute for Cancer Immunotherapy, the Penn Center for Research on Coronavirus and Other Emerging Pathogens, the University of Pennsylvania Perelman School of Medicine COVID Fund, the University of Pennsylvania Perelman School of Medicine 21st Century Scholar Fund, and a philanthropic gift from Philadelphia Eagles owner Jeffrey Lurie, 76ers star Joel Embiid and 76ers owners Josh Harris and David Blitzer.