Additional doses can help rev up the immune systems of vulnerable people
Millions of people who got Moderna’s or Johnson & Johnson’s COVID-19 vaccines will soon be lining up for another dose.
On October 20, the U.S. Food and Drug Administration authorized a third dose of Moderna’s mRNA vaccine for select groups. The groups include people age 65 and older as well as 18- to 64-year-olds who have underlying conditions that put them at higher risk for severe disease, or who live or work in conditions that put them at high risk of exposure or complications from falling ill. The agency also authorized a second dose of the J&J one-shot vaccine for everyone who got that jab. And FDA said the additional shots could come from any of the authorized or approved vaccines in a mix-and-match strategy.
On October 21, an advisory panel for the U.S. Centers for Disease Control and Prevention also gave the thumbs up for boosters for people in those groups. Soon after, CDC director Rochelle Walensky gave the official OK, paving the way for Moderna and J&J shot recipients to join the millions more who received Pfizer’s COVID-19 vaccine and became eligible for boosters in September (SN: 9/21/21).
These shots may be especially important for older people whose immune systems have weakened with age, and for those with medical conditions that put them at higher risk of serious complications of the disease. While the vaccines greatly reduce the chance of being hospitalized and dying, there are some chinks in the armor that still leave millions of such people vulnerable to the disease. Fully vaccinated people can get COVID-19 and die from it, though at much lower rates than unvaccinated people.
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Colin Powell, a former chairman of the U.S. Joint Chiefs of Staff and secretary of state, died October 18 of complications of COVID-19 even though he was fully vaccinated, his family said in a statement posted on Facebook. Powell, 84, had multiple myeloma, a blood cancer that erodes immune defenses against infections. Booster shots may help rev up the immune systems of such vulnerable people, perhaps providing enough protection to stave off the disease’s worst complications.
Even for healthy people, the vaccines’ effectiveness appears to be dipping. For instance, people in a clinical trial who got Moderna’s vaccine from August through December 2020 had a 36 percent to 40 percent higher chance of a breakthrough infection than those vaccinated in January through April this year, Jacqueline Miller, therapeutic area head for infectious diseases at Moderna, said at a meeting of the FDA advisory panel considering Moderna’s booster. That panel endorsed both the Moderna and J&J booster during meetings held October 14 and 15.
Still, experts emphasize that getting shots to unvaccinated people, not boosters to the vaccinated, will make the biggest difference in controlling the pandemic. “People who are in the ICU aren’t there because they haven’t gotten a third dose; they haven’t gotten any dose,” Paul Offit, director of vaccine education at the Children’s Hospital of Philadelphia, said at the October 14 advisory panel meeting. What’s more, he added, it may not be reasonable to expect the vaccines to prevent infections and mild illnesses. “That is a high bar to which we hold no other vaccines.”
Here are answers to five common questions about booster shots.
Is Moderna’s jab really becoming less effective over time?
Like the Pfizer vaccine, Moderna’s mRNA vaccine is holding strong against hospitalizations and deaths from COVID-19.
Preventing such severe complications of COVID-19 is the vaccines’s most important role, Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, said at the October 14 meeting. But when evaluating the value of a booster shot, officials should also take into account complications such as blood clots or long COVID that might result from mild to moderate disease, he said.
Moderna’s shot was still 95.8 percent effective at preventing hospitalizations and 97.9 percent effective at preventing deaths, researchers reported September 4 in a preprint in the Lancet. But efficacy against any COVID symptoms was only about 88 percent, while its effectiveness against asymptomatic infection was 72.7 percent, the researchers found. That’s a decline from about 96 percent effectiveness against symptomatic disease and around 90 percent effectiveness against asymptomatic infections among health care workers vaccinated from December 28, 2020, through May 19, 2021, researchers reported September 22 in the New England Journal of Medicine.
Concerns about waning immunity prompted the FDA panel to give the thumbs-up for vulnerable groups to get a third dose of the vaccine.
In an earlier study, it had appeared as if Pfizer’s vaccine effectiveness was slipping against the coronavirus, particularly the delta variant, while Moderna’s vaccine was maintaining its protection levels, researchers reported September 17 in Morbidity and Mortality Weekly Report. Some researchers speculate that the difference could stem from the Moderna vaccine having much higher doses — 100 micrograms of mRNA per dose compared with Pfizer’s 30 micrograms — that could produce higher levels of antibodies that would take longer to dip.
But the result might also have been an artifact of geography, says David Dowdy, an infectious diseases epidemiologist at the Johns Hopkins Bloomberg School of Public Health. During the study period, delta was surging in the South where more people got the Pfizer vaccine than the Moderna vaccine. Moderna’s vaccine has been most widely used in the Midwest, where delta wasn’t as bad at the time of the study, he says.
“People want to believe that the main driver of vaccine effectiveness is the immune response,” Dowdy says. “It certainly matters, but it’s also important how much you’re getting exposed to this virus.… The more exposure people see, the less effective these vaccines are going to appear to be.”
Over time, naturally waning immunity and the rise of more infectious coronavirus variants along with social factors, such as relaxed masking and social distancing regulations, will also bite into the Moderna vaccine’s effectiveness, he says. “The same forces that are causing lower immunity over time for Pfizer are also acting on Moderna.”
The antibodies sparked by Moderna’s vaccine certainly wane in the eight months after the first dose, researchers reported October 15 in the New England Journal of Medicine. Those declining antibody levels hint that people may be becoming more susceptible to infection. But, so far, it’s still difficult to directly link antibody levels in the blood to how well people are protected against COVID-19.
And antibodies aren’t the only tool our immune systems have to fight off disease. Immune cells called T cells, which can coordinate the immune response to an infection or kill off infected cells, appear to remain in the body at stable levels at least eight months after vaccination. So even if vaccinated people get infected, the immune system can quickly rally the troops and protect people from severe disease.
What about Johnson & Johnson’s shot — is it becoming less effective?
Clinical trial data suggest that the effectiveness of the J&J shot, made by the company’s pharmaceutical division Janssen, isn’t waning overall, company representatives said at the October 15 advisory panel meeting. Compared with the mRNA vaccines, antibody levels after a J&J shot increase over time rather than decrease, researchers reported in the New England Journal of Medicine study. What’s more, the amount of T cells remains steady over a period of eight months.
While immune defenses prompted by the vaccine are steadfast, the coronavirus has found ways to evade protection from vaccine antibodies. When it was authorized in February, the J&J vaccine was about 85 percent effective at preventing hospitalizations, and about 66 percent effective at preventing moderate to severe disease (SN: 2/27/21). But the rise of viral variants has changed that.
In countries where the delta variant is dominant, like the United States, the shot is still more than 70 percent effective at preventing COVID-19 symptoms. That number dips to around 50 percent in South America, where there are coronavirus variants that can evade parts of the immune system, including gamma, lambda and mu.
What’s more, some real-world data hint that the shot might not be as effective as clinical trials suggest, the FDA’s Marks noted at the meeting. Starting about a month after a dose of the vaccine, the single shot was 68 percent effective at preventing hospitalization, researchers reported in the Sept. 17 Morbidity and Mortality Weekly Report. The study included adults who were hospitalized for COVID-19 at some point from March 11, 2021 through August 15, 2021.
Crucially, regardless of whether or not immunity wanes over time, the protection that the one shot offers against severe disease or against milder infections is not equal to the mRNA vaccines, said Amanda Cohn, a chief medical officer for vaccines policy at the CDC. But a booster dose can help, which is why the FDA panel voted to make boosters available to everyone who got that shot. A second dose given two months after the first can boost protection to even higher levels, on par with Moderna’s and Pfizer’s mRNA jabs. In a U.S.-based clinical trial, the J&J booster dose had 94 percent efficacy at preventing COVID-19 symptoms. Global efficacy is lower, at 75 percent.
“As far as I’m concerned, it was always going to be necessary for J&J recipients to get a second shot,” said James Hildreth, an immunologist and president and CEO of Meharry Medical College in Nashville. A single dose of the vaccine might be used in some situations, he said, such as to top up the immune responses of people who previously had COVID-19 (SN: 8/19/21).
Will the side effects after a booster dose be worse?
In clinical trials, side effects of a Moderna booster were no worse than, and sometimes milder than, the effects seen after the second shot. Arm pain, some redness and swelling were worse for some participants, but those effects were short-lived. Most of the other side effects, including fever, chills, headaches and nausea were reported by fewer participants and were milder than after the second shot. Similarly, recipients of a second dose of J&J’s shot reported side effects on par with or milder than the reaction to the first shot.
There were no reports in the companies’ clinical trials of myocarditis, inflammation of the heart muscle, that is an uncommon, but potentially serious side effect of all three vaccines, particularly in young men (SN: 6/23/21). Such heart problems have been more prevalent with the mRNA vaccines. But the studies contain too few people to uncover rare side effects.
Some real-world data from Israel’s experience with the Pfizer booster suggests that the rate of myocarditis after a booster may be lower than after the second shot, said Sharon Alroy-Preis, Israel’s director of Public Health Services. A study of more than 5 million Israelis found that about 40 out of every million vaccinated males develop myocarditis, especially after the second shot, researchers reported October 6 in the New England Journal of Medicine. But only 17 of the more than 2.5 million people ages 16 to 59 who got a booster developed myocarditis or pericarditis, inflammation of the sac surrounding the heart, Israeli officials said.
The lower rate of the complication after a booster shot may be because the third dose came months after the first two, giving the immune system time to adjust and not overreact to another shot of vaccine, Alroy-Preis said.
Some studies found that the Moderna vaccine carried a slightly higher risk of the heart problems than Pfizer’s does. Other studies didn’t show discrepancies. In the United States, the highest rate reported for the inflammatory conditions was 39 cases per million doses of mRNA vaccine given to 18- to 24-year-old males, the CDC’s Kathleen Dooling said October 21 during a presentation at the advisory panel meeting.
Worries over the heart complications had prompted several members of the FDA advisory committee to withhold support for giving booster shots to people younger than 65. But others on that panel had pointed out that the risk of young people developing heart inflammation from COVID-19 are much greater than the risk of the vaccine causing the side effect.
The J&J vaccine has other risks, including a blood clots accompanied by reduced platelet counts. That condition, called thrombosis with thrombocytopenia, happens most often in females ages 30 to 39, with about 10 cases for every million J&J doses given, Dooling said. As of October 13, 47 cases of the rare clotting disorder have occurred out of the 15.3 million doses given. Of those 47 cases, five were fatal.
J&J’s vaccine also has a risk of a rare neurological disorder called Guillain Barré syndrome. Through July 24, 130 cases of the disorder have been reported after getting a J&J shot. The condition is most often seen in males ages 50 to 64. In that group, the condition was reported at a rate of 16 cases per million J&J doses.
Blood clots are also common among people with COVID-19, and Guillain Barré syndrome is a possible complication of the disease as well.
Should I stick with the same vaccine brand that I got before?
The FDA gave the green light to allow people to get any of the three authorized vaccines as a booster. That decision gives health officials the flexibility to administer different shots, if necessary, the Washington Post reported October 19.
Some people are already getting boosters from a different manufacturer than the source of their original vaccination, says Julie Swann, a health systems and pandemic modeler at North Carolina State University in Raleigh. “With Pfizer, you can go off-label since it is fully approved” by the FDA, she says. But vaccine providers probably need to wait for an official nod to mix and match with the Moderna and J&J vaccines, which are still under emergency use authorization.
Preliminary clinical trial data suggest that mixing and matching different vaccines is just as good, or better, than receiving the same vaccine for all doses. That trial, led by the U.S. National Institute of Allergy and Infectious Diseases, is analyzing the immune responses of more than 450 vaccinated people who originally received either two doses of Pfizer’s or Moderna’s shot or one dose of J&J’s (SN: 6/11/21). The researchers divided the participants into one of nine groups. Some groups received another dose of the same jab — like, for example, a third dose of Pfizer’s vaccine. Other participants got a shot from a different developer — such as two doses of Pfizer’s vaccine followed by J&J’s.
Getting an additional dose of any kind boosted antibody levels across the board, researchers reported October 13 at medRxiv.org. When people received the same shot as before, antibodies that stop the virus from infecting cells increased compared to before the booster dose. But for some groups, a mixed regimen gave a bigger antibody boost than sticking with the original brand. That was particularly true for people who had originally received J&J’s shot, which triggers the body to produce fewer antibodies than mRNA vaccines.
Those results mirror a recent mix-and-match trial of Pfizer’s vaccine with one from AstraZeneca, which is similar to the J&J shot. The AstraZeneca vaccine is used in many countries around the world, but is not authorized in the United States. In that study, people who got an AstraZeneca jab made higher levels of antibodies if their follow-up dose came from Pfizer. Pfizer recipients made more antibodies when sticking with a second mRNA dose than from switching to AstraZeneca, researchers reported August 6 in Lancet. That study didn’t measure T cells or other types of immunity, though.
The results are promising, but there’s still lots to learn, Kirsten Lyke, a vaccinologist at the University of Maryland School of Medicine in Baltimore who is involved with the NIAID study, said at the October 15 meeting. She and her colleagues plan to look at T cells, too, not just antibodies. What’s more, it’s possible that some combinations of the vaccines might spark immunity that lasts longer than others. For now, though, it’s impossible to say whether one regimen might be better than another. Lyke and her team are following participants for at least a year to find out.
Some of the CDC advisory panel members said at the October 21 meeting that they would encourage people who got J&J’s jab to strongly consider getting an mRNA vaccine as their second shot. But people should be mindful of the risk of myocarditis for some people, panelists cautioned.
Are people going to need more booster shots in the future?
No one knows. But that question was on the mind of many FDA panelists.
Michael Kurilla, an immunologist at the National Institutes of Health’s National Center for Advancing Translational Sciences in Bethesda, Md., noted that the rationale for mRNA boosters is that antibody levels in the blood are waning and over time vaccinated people become susceptible to infection. At the meeting, Kurilla wanted to know if there is any evidence to suggest that a booster dose might provide longer-lived protection than the first two doses.
That’s the “1-million-dollar question that I don’t have the answer to,” Israel’s Alroy-Preis responded.
Alroy-Preis attended the October 14 meeting to provide an update on whether boosters for Pfizer’s mRNA jab were helping control the virus in Israel. Officials there began rolling out the shots to older people at the end of July and to all eligible age groups at the end of August. So far, booster shots are curbing severe cases of the disease, as well as infections, in all age groups shortly after the shot is administered, Alroy-Preis and colleagues reported in a preliminary study posted October 7 at medRxiv.org.
It’s possible that the months between the original shots and the booster might help immunity last longer. But it’s still unknown when is the best time for people to receive each shot.
Data presented at the meeting from Moderna’s clinical trial, for instance, suggest that a third shot gives people with lower antibody levels a larger boost than people who still have lots of antibodies in their blood. Most people with fewer coronavirus-attacking antibodies had been vaccinated earlier, in 2020, a sign that it’s better to wait longer between doses.
The shots also protect people from disease even when researchers can’t detect antibodies in the body, Kurilla said. That means other parts of the immune system, like T cells, are helping out. But it’s still far from clear whether mRNA vaccines will offer long-term immunity. And if they don’t, it could be either because protection from these types of vaccines simply isn’t long-lived or because people aren’t getting doses at the right time.
For now, the question is what do we want the boosters to do, Kurilla noted. The jabs don’t appear to stop infection itself for very long, but are good against severe disease. “We can’t look at this as boost people every six months,” Kurilla said. Experts, however, seem to be more open to the idea of an annual shot, like for the flu.