With the world facing the latest in a seemingly endless stream of coronavirus variants and with bullish talk from manufacturers about a need for even more vaccine shots you wouldnt be alone if you were wondering: Are Covid boosters always going to be a fixture in our future?

The simple truth is that, at this point, theres no definitive answer to that question.

But virologists, immunologists, and vaccinologists have opinions that are anchored in an understanding of how the immune system works and in emerging data on how Covid vaccines engage with this complicated enterprise that has evolved to help humans fend off disease threats.

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STAT asked a number of these experts whether they think we face a future of endless Covid boosting. In the main, their answers were more reassuring than we expected.

Some said they think three doses of vaccine may protect many people for some time against the worst of Covids potential ravages. Many said they think the benefit of the third shot, given after a six-month interval, will turbocharge immune responses.

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Interestingly, a number said they think that even if we end up needing more boosters down the line, the messenger RNA vaccines the Pfizer and Moderna vaccines that have been the cornerstone of the U.S. vaccine effort to date may not be the vaccines we use for that purpose. Vaccines that cause fewer side effects may be needed if public health authorities want to persuade people to get regular or even sporadic boosters.

Here are some observations and informed theories from nine leading experts in this field.

Ali Ellebedy, an associate professor of pathology and immunology at Washington University School of Medicine in St. Louis, studies what happens in the lymph nodes and bone marrow of people who have been vaccinated against Covid-19. Hes been amazed at how long the first two doses of mRNA vaccine act on the immune system; half a year after the second shot, the response is still maturing. He wouldnt have predicted that, Ellebedy admitted.

There is an ongoing reaction in our lymph nodes thats going for six months. And that reaction, we are showing, that it is actually enhancing the potency of the antibodies, he said. Even before the third dose.

The maturation of the immune response which would be accelerated by a third dose, given after a longer interval brings big benefits. The antibodies we make improve in quality through a process called affinity maturation. They become more capable of recognizing their viral target, even if that target has made changes to its appearance, in the way variants have done.

If you wait six months or more between a priming and boost, what you see is not just a boosting of the immunity that you got from the first vaccine, but you see a broadening of the immune response so that it recognizes other viruses or other variants. Your immune response becomes much more cross-protective, said David Topham, an immunologist at the University of Rochester Medical Center and director of the New York Influenza Center of Excellence.

Florian Krammer, a professor of vaccinology at the Icahn School of Medicine at Mount Sinai Hospital in New York, had been reluctant to get a booster shot, figuring he had solid protection from the two doses of Pfizer he received earlier this year. Better to allocate scarce doses to low-income countries that have had limited access to date to vaccine, he thought.

The emergence of the highly mutated Omicron variant has changed his thinking on the advisability of giving booster shots. But Krammer is not sure what the long-term impact of the third dose will be. We see that you get your booster and you get up to two times, three times the [antibody] level that you had after the second dose. But the question is: How long does it last? How far will it fall? Will the set point be the same? he asked.

Even with booster doses there might be breakthrough infections at some point, said Krammer. And I think the real goal is to get so much immunity in the population that the virus is annoying but not problematic.

Barney Graham has long thought that a delayed third dose would be needed to complete a Covid vaccine series.

An immunologist who was deputy director of the National Institutes of Healths Vaccine Research Center until his retirement at the end of August, Graham led the NIH team that worked on the prototype of the Covid spike protein that many vaccine manufacturers used in their vaccines.

The antibodies induced by delayed third doses will be of higher quality, generating a broader immune response that can more reliably recognize even mutated viruses, such as new variants, he said.

Once you give the [antibody-producing] B cells a chance to mature and then boost them later that type of response tends to make immunity across all these different variants more similar, he said.

Graham also believes as we go forward, our immunity against SARS-CoV-2 may be naturally topped up by occasional exposures to the virus; thats called anamnestic boosting. Neutralizing antibodies will probably decline after the third dose, as they did after the second, so we may get infected by SARS-2 from time to time. But the other facets of the immune response will kick in to stop the virus from descending into the lungs, where it can do serious damage.

So I think that the whole question about durability of immunity is going to have to be determined by three years from now, are people still getting sick or are they relatively well-protected against severe disease regardless of whatever their antibody level is in serum. Because that may wane, but you still have a lot of memory B cells that can rapidly respond, Graham said.

Anthony Fauci, Grahams former boss, agreed, though he didnt rule out the possibility of another booster down the road.

What I think could ultimately happen is that by a prime, second, and then a third boost and who knows, maybe a fourth boost, you get a level of protection that would sort of transform all of this to overwhelmingly an asymptomatic or mildly symptomatic infection. So that it starts to drift much, much more towards the common cold coronaviruses, said Fauci, director of the National Institute of Allergy and Infectious Disease.

Marion Pepper and her laboratory at the University of Washington have been working to come up with real world evidence on how well the immunity weve been acquiring protects against SARS-2. They have been following a cohort of people who were vaccinated or who were infected and in some cases were both infected and then vaccinated. Among those vaccinated, some have received two shots; some have received a third. It is an observational study; they did not randomly assign the people they are following to these groups.

Pepper said from what her group is seeing, she expects boosters to give an important window of enhanced protection. But she doesnt think there is limitless benefit from boosting again and again, using the same vaccine strain. She and her team saw, for instance, that people who had been infected, vaccinated, and then boosted did not get much additional benefit from the third dose of vaccine.I think there is a misconception that the immune system can constantly be repetitively elevated such that you dont go back to that same starting point, she said. And in some people, maybe if they didnt have a good first immune response, it will enhance their cell numbers. But for the large majority you end up hitting a set point of memory that doesnt just keep getting bigger every single time you get the same boost.

She suggested vaccinating with another strain of the virus something like the Omicron version, for example might draw new immune cells into the fray and broaden the scope of the protection the vaccine offers. There are, however, many weighty factors to consider in making a decision to change the Covid vaccine.

Other experts have concerns about whether were as far along as Graham and some others hope. Paul Bieniasz, head of the laboratory of retrovirology at Rockefeller University, said the work he and his team have done suggests there is still room to top up immunity in vaccinated people and unfortunately plenty of unvaccinated people who still need protection.Bieniasz had thought, like some of the others cited here, that with booster doses people would start to get the upper hand on the virus. But the emergence of Omicron has shaken his faith that our immune systems are going to take the lead in what he called a genetic arms race.

I was much more confident a couple of weeks ago that the antibodies would have the edge in being able to outstrip the evolutionary capacity of SARS-CoV-2. But I dont think thats completely clear now, he said.

Topham too thinks viral evolution may dictate whether we have future dates with booster shots.

If next week we see the emergence of a variant that can escape the current vaccine, then yes, were going to have to get another shot of an improved vaccine as soon as they can make it, he said.

People likely wont agree to take mRNA vaccines indefinitely

The Pfizer-BioNTech and Moderna vaccines have been game-changers in this pandemic, proving that new vaccines can be designed, tested, and mass-produced within a hitherto unthinkable time. The first syringes containing the Pfizer vaccine began to slide into arms in the United Kingdom and the U.S. about 11 months to the day from when a Chinese scientist posted the genetic sequence of the SARS-CoV-2 virus on internationally accessible databases.

The vaccines are extraordinarily protective. Theyre also reactogenic; they can come with a real kick. Some people experience no side effects of note while others have only a sore arm. But a significant portion of people experience headache, fatigue, and malaise; others spike fevers, experience muscle aches, and are wracked with chills. And of course, there is an elevated rate of myocarditis and pericarditis inflammation of heart muscle or tissue around the heart, respectively in some males in their teens and early 20s who get vaccinated with these shots.

In the throes of the pandemic, people have seen these vaccines as the best hedge against a potentially fatal encounter with Covid-19. But as our immunity against the new virus rises, experts like Ellebedy dont think folks will be willing to put up with potentially feeling lousy for a day or two after getting a booster.

People in a pandemic can accept things, but I think if youre talking about a regular vaccine thats not really needed because of a pandemic, Im not sure if people would be more accepting of that, he said.

John Wherry, director of the Institute for Immunology at the University of Pennsylvania, agreed. I dont think were going to see just a yearly wild-type spike mRNA vaccine every year ad infinitum, he said, suggesting people will likely be drawn to other types of vaccines as boosters down the road, if we need them.

Currently in the U.S. the only other vaccine option is the one manufactured by Johnson and Johnson, which has not been a popular draw. Less than 4% of vaccine doses administered in the country have been J&Js vaccine. But it is conceivable other vaccines with fewer side effects will become available here.

Novavax and the partnership of Sanofi and GSK are both producing recombinant protein vaccines that are thought to be highly promising. Novavax, which has struggled to produce vaccine at commercial scale, has been given an emergency use authorization by Indonesia and other countries are expected to follow suit. Novavax has filed with regulatory authorities in Canada and the European Union, among others, and has said it expects to file for an EUA from the Food and Drug Administration. The Sanofi-GSK vaccine is still in Phase 3 testing.

Recombinant protein vaccines are generally not as reactogenic as mRNA vaccines.

If you get two vaccines and both work and one you know makes you feel sick for a day, and the other one doesnt, you know who wins, right? Krammer said of the prospects for another type of vaccine to make inroads in the U.S. booster shot market.Akiko Iwasaki, an immunologist at Yale University, thinks we will likely need vaccines that are administered differently if we want to prevent Covid infections. She and colleagues last week published a paper in Science on pre-clinical study of an intranasally administered vaccine. Early data from Israel is showing that the third dose, even though it provides a very effective protection, it also does wane, Iwasaki said. So its not like the third dose will fix antibody response forever. Thats kind of hard to ask any vaccine to do that.Developing a vaccine that aims to arm the mucosal tissues of the upper respiratory tract with immune protection would stop SARS-2 at its point of entry, not after it is rampaging through our cells. Its really like putting the guard outside the door as opposed to inside the door, she said.

The early estimates of the efficacy of the mRNA vaccines to prevent infections in the 95% range created unrealistic expectations about what Covid vaccines would be able to do over the long-term in blocking all infections. As months pass from vaccination, weve seen declines in neutralizing antibody levels and an increase in breakthrough infections among the vaccinated a phenomenon that seems to be accelerating with the spread of the Omicron variant.

But make no mistake. The vaccines are working. In the vaccinated, hospitalizations and deaths triggered by Covid infections have plummeted. Those are the performance metrics we need to be keeping our eyes on, said Wherry.

We are currently hyper-aware hyper-aware of infections. And the reaction to these infections in at least vaccinated people is disproportionate with their consequences right now, he told STAT. To me, its the wrong mindset.

Wherry said he knows people who have been vaccinated and have later become infected. Im walking the dogs and they complain to me, Great vaccine. And I just turn and say When did you have Covid? And they said Two days ago.

His response? Really? Yeah, its a great vaccine.

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Will we always need Covid-19 boosters? Experts have theories - STAT - STAT