Federal regulators are closing in on approvals next month to begin widely distributing and administering COVID-19 vaccine booster shots.
The large-scale effort will be a reinforcement of protection among vaccinated Americans at a time when transmission of the delta variant continues to rise throughout the U.S. population, including breakthrough infections among those already immunized.
Growing research has shown that the effectiveness of the mRNA vaccines from Pfizer and Moderna wanes incrementally as time passes from the initial two doses. Vaccinated people still maintain significant protection against serious disease and death — far more so than those who are unvaccinated — but their roles in the transmission and evolution of the virus continue to be a serious concern among epidemiologists and policymakers.
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Over the past year, Penn Medicine scientists have been studying the immune responses of a small group of people that includes some who received COVID-19 vaccinations without a previous infection and others who were naturally infected with the coronavirus. Some of those who were naturally infected also later received a series of two vaccine doses, giving the Penn Medicine team a better understanding of their immunity as a result of both the natural infection and their subsequent response to each dose of the vaccine.
Among the early findings from that research, first published in April, researchers concluded that the people who never had a natural COVID-19 infection needed both mRNA vaccine doses in order to have robust immune responses. People with a previous natural infection got a significant boost in their immune responses after receiving just one vaccine dose, but didn't see significant additional benefit after the second dose.
How these findings play into questions people have about boosters and what to do collectively during the next stages of the pandemic have increasingly preoccupied the Penn Medicine team.
"This is a really complicated topic and we're obviously thinking about it constantly," said E. John Wherry, director of the Penn Institute of Immunology and lead researcher in the ongoing study.
In several countries — Israel, Germany, France and Italy — policies have shifted to providing just one vaccine dose to people who have had a previous COVID-19 infection. At the same time, among vaccinated people without a past infection, much of Europe and China are now moving in the direction of boosters, much like the U.S.
Israel already has administered COVID-19 booster shots to more than 1.5 million residents, touting promising signs of their effectiveness, particularly among the elderly. Both Pfizer and Moderna also have pointed to strong results from initial data on booster shots, and Johnson & Johnson has done the same for its adenovirus-based vaccine booster. Germany, Hungary and the Dominican Republic have begun administering booster shots in selected, at-risk populations as well.
Wherry's team at Penn has closely examined the intricate details of the body's immune response to a natural coronavirus infection and vaccination, accounting for multiple known variants. His lab studies not just the production of antibodies, which provide rapid immunity and diminish over time, but also the long-term blueprint for protection that people get from memory B cells and T cells, which inhibit viral replication and literally attack and kill invading cells. All of these components work together as a system and "talk" to each other.
I think the general public perception is that vaccines provide sterilizing immunity — in the very strictest sense, if you're vaccinated, then the virus can never get in your body, never exist in you, in your nose, or replicate at all. That you'll have armor on and no virus gets in. That's simply not a practical reality. What vaccines do — all vaccines — is they prevent disease." — E. John Wherry, director of Penn's Institute of Immunology
T cells: A backline defense
The latest research from Wherry's lab offers a stronger understanding of the role of T cells, a diverse collection of immune cells that are difficult to measure but no less important than antibodies in potentially limiting the severity of COVID-19. Though most licensed vaccines use antibodies as a benchmark to measure effectiveness, T cells are vital to the full immunological picture because they target different parts of the virus.
"One of the key differences between antibody responses and T cells is that the antibodies for this virus are targeting parts of the virus that seem to be mutating or evolving — delta, the South African variant, lambda, some of these others we're starting to hear about," Wherry said. "T cells generally target other parts of the proteins that are not mutating as much."
Since T cells target more conserved regions of the virus, they should be more resilient to changes in the virus and should be a strong indicator of how well vaccines set people up for long-term protection. If antibodies are waning in the general population and the much-discussed spike protein they target adapts, the question is whether T cells will be a dependable backline defense and if booster shots can keep antibody levels in a comfortable range.
"We felt like it was very important to create a slightly more holistic view of the mRNA vaccine-induced immune responses, knowing that T cells were going to be really important for control of infectious disease," Wherry said. "One of the benefits of looking at T cells here is that we're fairly confident that if they do provide some protection — the data is still relatively limited — they're going to be targeting parts of the virus that are not changing as we go from delta to the next variant."
Clinical research like this has been preliminary and conditional throughout the pandemic, always based on developing information and extrapolation of data with large populations in mind. It has successfully demonstrated the power of the COVID-19 vaccines and pointed us to a safer world, but the research remains a stepwise work in progress — sometimes marked by contradictions. Wherry knows the public is exhausted.
"The clarity of our public health messaging has been — to be kind, I'll say it has been poor," Wherry said. "To be unkind, I'd say it has been part of the problem. We've just not been able to give consistent, simple messages. And scientists like me are part of the problem. It's very hard for you to get us to say, 'It always works this way and it never works that way,' because that's just not how science works."
The current push toward booster shots in the U.S. comes in the context of a resurgence in infections driven by the highly contagious delta variant, whose behavior is tricky to decipher against the backdrop of vaccination. About 62% of the U.S. population has received at least one COVID-19 vaccine dose and just over 53% of the population is fully vaccinated, making the past few months particularly muddy to interpret.
Delta is spreading not only among a large population of unvaccinated people, but also among a growing number of vaccinated people. That's to be expected, even at the highest rates of vaccine effectiveness, but it also has led to a crisis of confidence and the return of restrictions in many parts of the country.
"If you vaccinate 100 million people, you're going to have five million get infected just because those are the statistics of how well the vaccine works in a large population," Wherry said. "As your denominator of vaccinated people increases, you're going to see way more vaccinated people who are actually infected."
For this reason, Wherry believes the conversation about booster shots needs to be put in better perspective.
"The first thing we need to try to get straight, among all of us, is what the expectations for a booster would be in the general population," Wherry said. "The data out there is very mixed. We now have epidemiological data about an increased rate of infections in vaccinated people. But I think we're conflating a couple of things in our expectation of vaccines."
For one, Wherry said the public needs to internalize what getting vaccinated is immediately meant to accomplish.
"I think the general public perception is that vaccines provide sterilizing immunity — in the very strictest sense, if you're vaccinated, then the virus can never get in your body, never exist in you, in your nose, or replicate at all. That you'll have armor on and no virus gets in," Wherry said. "That's simply not a practical reality. What vaccines do — all vaccines — is they prevent disease. They don't necessarily prevent any infection. We have to be careful about expecting that a booster vaccination is going to drive infections to absolute zero in our vaccinated populations."
Weighing the need for boosters
This is the crux of the debate about breakthrough infections of COVID-19. There is concern among scientists that proclaiming the need for a third dose wrongly implies the vaccines aren't working, while others believe the third dose will help us stay ahead of the curve.
The Centers for Disease Control and Prevention's unnerving study on a July outbreak of infections among vaccinated people in Provincetown, Massachusetts has stoked fears about the delta variant's ability to get past vaccines. That study found 74% of people infected in the outbreak already were vaccinated, leading to widespread misinterpretation that has fueled anti-vaccine sentiments based on a poor understanding of the outbreak's implications and complete context.
Similar findings on breakthrough infections in Israel and in nursing homes, where the effectiveness of vaccines has been shown to decline over time — and with delta, in particular — also can be used to support misguided takeaways about the "experimental" nature of the vaccines. (Meanwhile, truly experimental treatments, like the anti-parasitic medication ivermectin, are held up by vaccine skeptics as preferable alternatives despite the dangers of improper administration).
The data on how much a booster actually boosts immunity in healthy, normal people simply doesn't exist — at least not in the public sphere. We don't really know how much benefit the booster will give us for limiting infection. — E. John Wherry, director of Penn's Institute of Immunology
The evidence about breakthrough infections points more to the benefits of vaccination than any signs they're not doing their job.
"What we are seeing in all of these cases is that the people who do get infected — and I hate the term breakthrough infection — they're not getting really sick," Wherry said. "There are very few vaccinated people ending up in the hospital, almost none dying. Your likelihood of dying from COVID-19 if you're vaccinated is one in a million. If you're not vaccinated, it's one in 50. That's what vaccines do — and that effect seems to be reasonably durable."
As Wherry sees it, the term "breakthrough infection" carries a connotation that badly misses the mark.
"Words matter. They have implications," he said. "'Breakthrough' sort of implies that you've broken something, or something has failed. Most of the time, these 'breakthrough' infections are really mild. You're not getting very sick. You're not ending up in the hospital. You're not dying. The vast majority of these examples show you that the vaccine is working."
In the Provincetown outbreak, for example, none of the several hundred vaccinated people who were infected died and only a few were hospitalized. The minority of unvaccinated people infected in the outbreak didn't fare as well.
"For the unvaccinated, a lot of them were hospitalized, and many of them were way more sick," Wherry said. "While that outbreak was labeled as evidence of breakthrough infections, I would say that it's really good evidence of the vaccines working. Vaccines prevented people from dying."
What's not fully clear about vaccinated people who become infected is how much of a role they're playing in viral transmission and mutation, especially relative to the more evident role played by the unvaccinated population. Research suggests that pre-symptomatic and asymptomatic spread are more common with the delta variant, and that vaccinated people who become infected can have elevated viral loads not seen in previous variants, even if they are at low risk for serious disease.
This uncertainty simultaneously explains why some unvaccinated people have become more emboldened in their stances against it and why those who champion the effectiveness of vaccines want boosters to further enhance protection collectively.
Wherry is fully in favor of booster shots for immunocompromised people, who have shown very good responses to them in limited studies. He also believes they could be valuable for the elderly, since vaccines have not worked as well among this group.
"The data on how much a booster actually boosts immunity in healthy, normal people simply doesn't exist — at least not in the public sphere," Wherry said. "We don't really know how much benefit the booster will give us for limiting infection. There's a little bit of data emerging from Israel, but not enough to really dig into it and understand what's happening."
As it has throughout the pandemic, emerging data can create a complicated picture.
With the delta variant specifically, there is some limited but striking data from Israel that shows a previous natural infection is actually more protective against the variant than two vaccine doses in a person who has never been infected. The researchers behind this study qualified it with a strong caveat: intentionally seeking out a natural COVID-19 infection is foolhardy, since there is a potentially very high cost to the body of achieving natural immunity, up to and including death.
While research may point to the power of the body's natural immune response to a COVID-19 infection, the most far-flung vaccine detractors have falsely peddled the idea that the delta variant surge is a consequence of vaccinations. On its face, this notion is ridiculous, since the delta variant existed last year before vaccines were authorized, yet it illustrates the frightening misinformation war underway at a critical point in the pandemic.
Together with other mounting evidence, Wherry's latest research solidifies the view that even one vaccine dose boosts the immunity of people who had a previous COVID-19 infection, making their already strong responses more robust and durable. People who had an especially mild infection, but who remain unvaccinated, may have a higher level of vulnerability as their antibodies diminish and the virus evolves beyond delta.
The biggest hurdle? Transmission among unvaccinated people
What this says about the direction of U.S. policy goes back to Wherry's point about messaging. Boosters may prove to be helpful, but they're not going to address the biggest problem the country still faces.
"For the general public, my opinion is the jury is still out on boosters. I don't think there's any harm in an individual person getting a third dose," Wherry said. "But I kind of think what we're doing is trying to throw a whole lot of water on a few smoking embers that are in front of us while there is a giant forest fire behind us — all the unvaccinated people spreading COVID-19."
Even as other countries have adopted a one-dose policy for people with a past infection, Wherry still thinks it's best for now that unvaccinated people get both doses. There may be a point in time when the unvaccinated population is small enough in the U.S. that recommending one dose becomes a possibility, but the risk of mixed messaging is still too high at this stage and could undermine the safest approach to vaccination both individually and at large.
"The analogy is the same reason why a doctor advises you to take your full course of antibiotics even when you start feeling better," Wherry said. "If you don't, what happens is the few bacteria that didn't get killed by the antibiotics end up acquiring mutations and resistance to those antibiotics — and then they grow out. The same thing happens if antibody levels are low. You can actually select out escape variants. We don't really know that here for SARS-CoV-2, but that's a theoretical concern that a lot of us have suggested we need to be aware of going forward."
On a global scale, the implications of boosters may be even more important. The World Health Organization already has expressed misgivings about using limited vaccine supplies on third doses when much of the world is struggling to vaccinate large populations at all.
Many who resist getting vaccinated tend to point to this issue and adopt a defeatist outlook about how the virus will continue unchecked due to global spread for years to come. Wherry insists this always has been a form of dead-end logic and a deflection from the core problem of vaccine refusal — a raging fire that even boosters will have trouble containing.
"This is a global problem. Not a local one," he said. "We need to be good partners around the world, or we're going to face this problem for longer than we want to — and that's been challenging for scientific and political reasons. But you have to take a methodical approach to this. We can't help distribute and implement vaccine policies around the world if we can't even put one foot in front of the other at home."