Vaccine makers are preparing for a next possible phase of the COVID-19 vaccine rollout: booster doses.
Currently three coronavirus vaccines are authorized for emergency use in the United States -- the two-dose Pfizer/BioNTech vaccine for people 12 and older, the two-dose Moderna vaccine and the single-dose Johnson & Johnson vaccines for everyone 18 and older.
Researchers and health officials suspect that the immunity against COVID-19 these vaccines elicit in the body might wane over time -- possibly after a year or more -- and might not protect as well against coronavirus variants that could emerge and evolve.
A vaccinated person might need a booster dose of vaccine to stay protected against the original coronavirus strain and newly emerging variants -- somewhat similar to how a tetanus booster is recommended every 10 years or different flu vaccines are recommended each year.
"Many people may be familiar with tetanus-toxoid vaccines that are recommended every 10 years -- that's a booster dose. It's reminding our immune system so that if we ever got exposed to that toxin, our immune system would remember it and respond very quickly," Dr. William Moss, professor and executive director of the International Vaccine Access Center at Johns Hopkins Bloomberg School of Public Health, told CNN in May.
In the case of COVID-19 vaccines it remains unknown for how long immune protection lasts, but vaccine developers and health officials know it may not be forever -- and that emerging variants could escape immunity.
"There is a little nuance with COVID-19 vaccines," Moss said.
While typical booster doses use same vaccine someone previously received to remind the immune system about immunity to a pathogen, any future boosters for the COVID-19 shot could use different vaccines altogether.
Currently, "the need for and timing for COVID-19 booster doses have not been established. No additional doses are recommended at this time," the US Centers for Disease Control and Prevention notes on its website.
But Americans should prepare to have a COVID-19 vaccine booster shot within a year, US Surgeon General Dr. Vivek Murthy told CNN's Wolf Blitzer in May, saying "people should be prepared for the fact that we may need a booster within a year."
Despite such predictions, Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, told CNN the bottom line is "we don't know."
"We're preparing for the eventuality that we might need boosters, but I think we've got to be careful not to let the people know that inevitably, x number of months from now, everyone's going to need a booster. That's just not the case," Fauci, chief medical adviser to President Joe Biden, said at a Washington Post Live event. "We may not need it for quite a while."
Scientists at a number of companies that make COVID-19 vaccines have also predicted the need for boosters within a year -- but the scientific community is not in widespread agreement on this.
So far, studies have shown that mRNA vaccines -- those made by Pfizer and Moderna -- maintain more than 90% efficacy six months after getting vaccinated. And scientists say it's likely much longer.
Other studies have looked at antibodies in the lab. While a decline is expected over time, Fauci told the Washington Post in May "the steepness of that slope is unclear right now."
Experts say it is also unclear how these antibody levels correlate with real-world immunity, and to what extent other parts of the immune system -- such as T cells -- could factor into protection.
Whether booster coronavirus vaccine doses are modified or not, missing a booster dose -- if one is recommended in the future -- could leave someone less protected against COVID-19.
"A person who skipped a booster is placing themselves at higher risk of getting infected, and getting disease from the SARS-Coronavirus-2, but I would also expect that they're going to have some partial immunity and so they may be protected against more severe disease," Moss said. SARS-CoV-2 is the virus that causes COVID-19.
"They're just at higher risk of infection and disease than someone who got the booster, but they have more immunity than someone who was never vaccinated."
Scientists are also currently investigating whether it makes a difference if someone gets the same type of vaccine as a booster as the original dose administered.
"This question of mixing and matching certainly is relevant to booster doses," Moss said. "It's also relevant to any two-dose vaccine schedule, and it's also an area of active research."
Researchers in the United Kingdom reported in May that people who got mixed doses of coronavirus vaccines -- receiving a different vaccine type as a second dose than the first dose -- appear to be more likely to experience mild side effects such as fever, chills, fatigue or headache.
But the side effects following mix-and-match vaccinations were short-lived and there were no other safety concerns, the researchers reported in the Lancet medical journal.
Currently, the CDC says, "COVID-19 vaccines are not interchangeable" and there has been no decision either in the US or globally on the need for booster doses yet, let alone which vaccine might be appropriate for any booster.
All three companies that currently have authorized coronavirus vaccines in the United States -- Pfizer, Moderna and Johnson & Johnson -- are investigating the potential use of boosters.
"The data that I see coming, they are supporting the notion that likely there will be a need for a booster somewhere between eight and 12 months," Pfizer CEO Albert Bourla told Axios in May. "But that remains to be seen and I believe in one, two months we will have enough data to speak about it with much higher scientific certainty."
The first dose of Pfizer's coronavirus vaccine in the United States was administered on December 14, 2020 -- five months ago. As time goes on, if people received their second dose of vaccine eight months ago, "they may need a third one," Bourla said. "This could be coming sooner than later, I believe from September, October. But this is something, again, that the data need to confirm."
Moderna is currently conducting booster shot trials too.
The fight against the coronavirus pandemic is expected to continue through next year due to the emergence of variants, Dr. Stephen Hoge, president of Moderna, said during an earnings call in early May.
"We think this is just the beginning," Hoge said. "Therefore, we're committed as a company to make as many updates to the vaccine, to add as many variants as we think are necessary, to ensure that when people receive a booster, it provides the broadest immune protection against the widest range of variants."
Johnson & Johnson is also looking into the potential for boosters.
"We have ongoing and planned trials that will aid our assessment of the need for, and timing of, booster doses of our vaccine," according to an emailed statement Johnson & Johnson sent to CNN in May.
Johnson & Johnson's coronavirus vaccine, along with Pfizer's, Moderna's, and four others, are being tested as seasonal boosters in a study called Cov-Boost being conducted by the UK's National Institute for Health Research and the University of Southhampton.
The biotechnology company Novavax has developed a coronavirus vaccine that its chief executive officer Stanley Erck believes could be used as a booster shot for people who have already been vaccinated. The company plans to apply for emergency use authorization of its vaccine in the United States in the third quarter of 2021.
"In the US, I think it will be the booster for everyone, particularly if we get it out late in the third quarter," Erck told CNN in May. "It's going to be time to start boosting -- whether it's six months or at a year point."
The decision to use COVID-19 boosters is expected to involve two agencies -- the US Food and Drug Administration and the CDC -- and the regulatory process to get the shots into arms could vary depending on whether the booster is the same vaccine that was originally used or is a modified version.
"So, if it's the same vaccine, my understanding is that what would have to happen is that the CDC would have to recommend an additional dose with details around when that should occur," Moss said.
If it's a modified vaccine, "this is where things get interesting and I don't think we quite know," he said, but added that the regulatory process could be similar to what happens with flu vaccines each year.
"Technically, whenever a vaccine like that is modified, it's often considered a new vaccine and has to go through the whole process again. But there is a precedent, obviously, with influenza virus vaccines, not to do that," Moss said. "So, the influenza vaccine each year doesn't have to go through a large Phase 3 trial."
That's because the vaccine technology stays the same, and the only change is the flu virus itself that the vaccine targets to elicit immunity to a specific flu virus strain that's circulating.
CDC's Advisory Committee on Immunization Practices will discuss the question of boosters Wednesday.
"At this time, available information suggests that the FDA-authorized vaccines remain effective in protecting the American public against currently circulating strains of SARS-CoV-2. However, if there is an emergence of SARS-CoV-2 variant(s) in the U.S. that are moderately or fully resistant to the antibody response elicited by the current generation of COVID-19 vaccines, it may be necessary to tailor the vaccines to the variant(s)," an FDA spokesperson told CNN in May.
The FDA updated its guidance for vaccine developers in February, noting that manufacturers should "generate the data to support authorization" of a modified vaccine.
"Further discussions will be necessary to decide whether in the future, modified COVID-19 vaccines may be authorized without the need for clinical studies," according to the guidance. But overall, vaccine developers are "encouraged" to perform exploratory studies on modified vaccines to boost immune responses.
Some research suggests that people who are immune compromised could benefit from booster doses of vaccine.
For instance, organ transplant recipients might not have an adequate response to coronavirus vaccines because they take drugs to suppress their immune systems. That helps reduce the risk of the body rejecting new organs but may also limit responses to vaccines.
A third dose of coronavirus vaccine could help boost antibody levels among some organ transplant recipients who have not had robust responses to the standard vaccination schedules, according to a study published in the journal Annals of Internal Medicine in June.
Among patients in the study who had no measurable antibodies after receiving two doses of vaccine, one-third of them saw a rise in antibodies after a third dose -- and among those with low antibody levels after two doses, all of them saw an increase after a third dose.
When it comes to coronavirus vaccines, "we don't really have a good sense of what level you need for protective immunity," Dr. Dorry Segev, an author of the study and founder of the Epidemiology Research Group in Organ Transplantation at Johns Hopkins University, told CNN. "We don't know if you need the same off-the-charts level of antibodies that people with normal immune systems have."
But for transplant patients, after a two-dose full vaccine series, "the overwhelming majority have either no antibodies or low antibodies," Segev said.
When pharmaceutical companies tested coronavirus vaccines in clinical trials last year, they specifically excluded people who were taking immunosuppressive drugs due to potential risks.
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