FDA Panel Recommends Against Following White House Plan for Booster Doses for All

But it recommended third doses for the elderly and other at-risk groups

FDA Panel Recommends Against Following White House Plan for Booster Doses for All

A U.S. Food and Drug Administration (FDA) committee voted unanimously Friday to recommend booster doses of Pfizer-BioNTech’s COVID-19 vaccine for those over age 65 and those at higher risk of exposure to the virus, including healthcare, frontline and essential workers, under emergency use authorization, but stopped short of recommending boosters for the general population. (Boosters have already been authorized for those with compromised immune systems.)

Pfizer-BioNTech had originally requested that the FDA consider full approval of a booster dose for all people who have been vaccinated with its shot. The 18 members of the committee voted initially 16 to 2 against that move, citing the lack of strong enough data on safety and effectiveness of boosting the general population at this time. The FDA then reworded Pfizer-BioNTech’s original request to include only those at highest risk of COVID-19, which earned a unanimous vote in favor.
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Although the result wasn’t what Pfizer-BioNTech expected, Kathrin Jansen, senior vice president and head of vaccine research and development at Pfizer, said in a statement that “these data, and the larger body of scientific evidence presented at the meeting, underscore our belief that boosters will be a critical tool in the ongoing effort to control the spread of this virus. We thank the committee for their thoughtful review of the data and will work with the FDA following today’s meeting to address the committee’s questions, as we continue to believe in the benefits of a booster dose for a broader population.”

The FDA’s acting commissioner, Janet Woodcock, will take the committee’s recommendation into consideration before making a final decision. If the FDA follows the advice, then the U.S. Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices (ACIP) will review the data and make a recommendation to doctors and health care workers about how the booster will be administered. One important question the ACIP must address, for example, is whether Pfizer-BioNTech’s booster dose should be limited to those who have already received two doses of the companies’ vaccine, since the data reviewed by the FDA committee only included a small subset of those recipients and not people who received the other authorized shots from Moderna and Johnson & Johnson-Janssen.

The committee advised that most of the U.S. population will have to wait to get a booster dose, guidance that directly contradicts the recommendation by U.S. President Joe Biden’s health team, which planned to start widely rolling out boosters on Sept. 20, pending FDA authorization or approval.

The decision heightens the growing tension over the booster question, as public health officials, infectious disease specialists and policy makers disagree about exactly how useful another dose of COVID-19 vaccine can be. The FDA committee members noted that while there is evidence that vaccine-induced immunity wanes over time, giving fully vaccinated people another dose of vaccine will likely have little impact on actually controlling the pandemic in the U.S., since most new cases and severe illnesses are driven by the unvaccinated.

The White House, however, escalated the debate when it announced in August that it supported rolling out a booster dose for the general population beginning Sept. 20, even before the FDA had reviewed the safety and efficacy of doing so. It was a surprising pre-emptive move that the administration said was primarily an attempt to get ahead of the logistics of administering another dose, and to prepare states and local health authorities, but many felt was more driven by political rather than scientific justification.

Over Friday’s day-long meeting, the committee members debated the strength and quality of data showing waning protection among everyone who has been vaccinated so far, and what it means for controlling transmission and spread of COVID-19. The panel members heard from Israeli public health officials, who have the most in depth, although still incomplete, data on waning immunity and the impact of a booster dose, as well as U.S. CDC researchers who understand the dynamics of the U.S. pandemic.

In making its case for a booster, Pfizer-BioNTech acknowledged that about a month after the second of the two doses in the regimen, its vaccine is 96% efficacious in protecting people from symptoms of COVID-19. About two to four months later, that efficacy slips to 90%, and by six months, it drops to 84%—about a 6% decline every two months.

And while Pfizer-BioNTech provided data showing an additional dose of its vaccine could increase levels of neutralizing antibodies against SARS-CoV-2, the virus that causes COVID-19, it did not provide answers to questions about how well that protection could stop transmission of the disease, among other things, to the committee’s satisfaction. The lack of adequate safety data of the third dose among younger people, who are at higher risk of developing rare inflammation of heart tissue, was also among the reasons the committee decided not to recommend the booster at this time for the general population, citing the need for more evidence to support safety, to guide mixing and matching doses, and the impact a booster dose would have on transmission of the virus.

The information on mixing and matching doses is coming shortly from various studies investigating what types of immune reactions people generate if they receive one type of vaccine and get boosted with another; the results have been submitted to a journal but not published yet. Data on the safety could be collected in coming months as more younger get vaccinated and are followed, and scientists in Israel are also studying how a third dose affects transmission of the virus in the population.

Pfizer-BioNTech maintains that protection from its vaccine remains high enough to shield people from severe illness and in most cases, hospitalization and death; most vaccinated people who get infected experience mild disease. But there are worrying signs that with the Delta variant, the more transmissible variant that is now the dominant virus behind new infections, even that trend is changing. In Israel, more vaccinated people getting breakthrough infections are also getting more severe disease. Pfizer scientists say that the data suggest not that Delta is finding ways to escape the vaccine defenses, but that the protection from the vaccine is weakening.

That’s why the company asked the FDA for a booster dose—to restore some of that initial vaccine protection. The company presented data from 23 people in the original phase 1 study of the vaccine who received a booster dose six to eight months after the second dose, as well as 306 people who were originally receiving placebo but, after the vaccine received emergency use authorization in December, switched to get two doses of vaccine. Because they got their two shots later, they received their booster dose later as well, about three to four months after their second dose. By comparing the two groups, Pfizer-BioNTech scientists could determine how much immunity waned, and how a booster dose affected that dwindling immunity.

The data showed that overall, after the first dose of the two-dose regimen, levels of antibodies that can neutralize SARS-CoV-2 remain low, which is why the company and the FDA initially recommended a second dose, three weeks later, when the vaccine was first authorized in Dec. 2020. The first dose helped to prime the immune system and educate immune cells to recognize the COVID-19 virus, while the second dose activated those cells more robustly.

In its latest analyses provided to the FDA, however, the company said that even though levels of antibodies didn’t jump after the first dose, people were still protected against COVID-19 disease; when they compared disease symptoms among people who received only one dose and those who remained unvaccinated, the partially vaccinated enjoyed fewer symptoms after about a week. It turns out that immunity continues to build with each successive dose. Their data also showed that boosting this protection again can be done with another dose of the existing vaccine, even if Delta is causing more infections. The increased levels of antibodies generated by this dose were high enough to neutralize even Delta, as well as other variants including Beta and Gamma.

That’s especially reassuring, Pfizer’s Dr. William Gruber senior vice president of vaccine clinical research and development said, since data from Israel suggest a worrying trend of increasing numbers of not just breakthrough infections but more severe disease and hospitalizations among people vaccinated with two doses who get infected. The committee also heard from Dr. Sharon Alroy-Preis, director of public health services at the Ministry of Health in Israel and Ron Milo, professor at the Weizmann Institute, who presented the data on breakthrough infections and explained the reason why Israeli health authorities decided to authorize a booster dose for all vaccinated people in the country. They showed encouraging data, although early, that since booster doses were recommended on July 30, the reproductive number, or number of people a single infected person can go on to infect, has dropped in the country to below 1.0, which is the public health goal.

“The booster improved protection against COVID-19 10-fold against confirmed infection…and helped Israel to dampen severe cases in its fourth wave,” Alroy-Preis told the committee.

Since Israel began its mass vaccination campaign several months ahead of most countries, and achieved a high rate of coverage relatively quickly, Gruber said that the trends reported in Israel suggest that “we may see an increase in severe disease among those vaccinated early in the U.S. campaign. If so, then the time for a booster dose is now. After a booster dose we are seeing a robust immune response that equals or greatly exceeds the response we see after the second dose. The response continues to mature and inspires optimism for a high level of protection against current and future variants after the third dose.”

Immunologically, what’s happening is that with each successive dose of the vaccine, the immune system is getting smarter and producing a more comprehensive array of antibodies and other virus-fighting cells; the immune memory from previous doses builds each time, so both the quantity and the quality of immune responses is better by the third dose. Pfizer’s data shows that a month after the booster dose, levels of neutralizing antibodies are five to seven times higher than levels a month after the second dose.

And there is an immunological reason for that, says says Dr. Otto Yang, professor of medicine and infectious disease at University of California Los Angeles, who is not part of the FDA advisory committee. “Antibodies undergo a process called somatic hypermutation, and mutate to become more efficient with longer exposure to a target,” he says. “So additional boosters give you both a renewed quantity of antibodies after the original target but also better activity against variants.” Studies seem to support this idea—people who have been infected naturally with COVID-19, for example, and recovered, seem to generated stronger immune responses after getting vaccinated than people who haven’t had the disease. And transplant patients with weaker immune systems who have received a booster dose of Pfizer-BioNTech also show stronger responses after the third dose than after the second one.

Taken together, Pfizer-BioNTech maintained the data, as well as the continuing threat of Delta and potentially other new variants, warrant a booster.

The FDA, however, countered that existing protection, especially against more severe disease, remains sufficient, and that the data don’t show that the decline in immunity necessarily puts people at risk. In addition, the FDA review noted that Pfizer-BioNTech’s study doesn’t provide the strongest type of data to support efficacy of a booster dose at this time. Dr. Joohee Lee, medical officer in the clinical review branch at the FDA, summarized the companies’ booster study and noted that it “was not designed to assess the relative vaccine efficacy of the crossover group vs. the original [vaccine] group and the post hoc analysis is exploratory in nature.” She also noted that because people in the studies knew they were all receiving the vaccine, they could have biased the results.

Members of the panel also raised concerns about the strength of evidence supporting a booster dose at this time, at least for the general population, noting the relatively small number of people in the Pfizer-BioNTech study and the short period of follow up especially for younger people. “It feels like there is a lot of data circulating that would be helpful to our discussion but is not available at this moment because it will be presented soon, so at this moment it is difficult to make a decision on [general] booster doses today,” said Dr. Steven Pergam, medical director at Seattle Cancer Care Alliance.

From a public health point of view, however, those concerns may seem semantic, and the committee’s recommendation will likely continue to divide experts in the field. While it’s true that the current two-dose vaccine does protect well against severe disease, any COVID-19 disease continues to strain the already struggling health care system. And any disease, especially with Delta, which transmits far more easily among people than earlier variants of the virus, could be dangerous to public health.

“It’s not just about serious illness and death, but about people getting infected and spreading the virus,” says Yang. “If people can get breakthrough infections, even if they don’t get sick they can spread the virus. And that’s a problem for society, especially when a large percentage of people are not vaccinated. And even mild infection can cause significant health problems in people, from clotting to heart attacks, strokes, and long COVID. So not getting infected is clearly a benefit.”

The committee members noted that because the recommendation is under EUA, it could be revised as more data come in to support the need to broaden the groups eligible for a booster dose. For now, they say, the focus should be on continuing to reach people who haven’t been vaccinated at all; that will likely have the biggest impact on slowing the spread of the virus and ultimately getting the COVID-19 pandemic under control.

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Some Vaping Companies Are Turning to Synthetic Nicotine to Outsmart the FDA

Troy Johnston swears he wanted to play by the rules. Johnston, who owns the Texas-based vaping company VaporSalon, tried to follow the U.S. Food and Drug Administration’s (FDA) guidelines for selling e-cigarette products, which required all manufacturers to file paperwork known as premarket tobacco product applications (PMTAs) by Sept. 9, 2020. In these applications, companies…

Some Vaping Companies Are Turning to Synthetic Nicotine to Outsmart the FDA

Troy Johnston swears he wanted to play by the rules.

Johnston, who owns the Texas-based vaping company VaporSalon, tried to follow the U.S. Food and Drug Administration’s (FDA) guidelines for selling e-cigarette products, which required all manufacturers to file paperwork known as premarket tobacco product applications (PMTAs) by Sept. 9, 2020. In these applications, companies were tasked with proving that their products were, on balance, good for U.S. public health—namely by giving adult smokers a less-dangerous alternative than traditional cigarettes.

As required, Johnston filed applications for all 47,000 nicotine e-liquids his company sells, an undertaking that he says cost his business thousands of dollars and countless hours of work. But he wanted a back-up plan, just in case the FDA’s decision didn’t go his way. So in August, he looked into purchasing synthetic nicotine—a product that some in the vaping industry argue the FDA doesn’t have the power to regulate as it does other e-liquids, since it is not derived from tobacco.
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When the agency rejected the vast majority of VaporSalon’s PMTAs on Aug. 26, Johnston was ready. “VaporSalon is switching to TOBACCO FREE NICOTINE,” he posted from VaporSalon’s Facebook page that day, adding that “the main purpose” was to skirt FDA regulations. “We never wanted to switch to [synthetic nicotine], but the FDA forced us to make that decision as we have so many adults relying on us” for alternatives to cigarettes, Johnston wrote in an email to TIME.

Johnston may have been unusually candid in his post, but he’s not alone in searching for a savior in synthetic nicotine. The FDA has so far rejected PMTA paperwork for more than 5 million e-cigarette products, many of them flavored vaping liquids. Faced with the choice of removing their products from the market entirely or working in a regulatory gray area, some of those manufacturers are embracing uncertainty and pivoting to synthetic nicotine.

Tony Abboud, executive director of the Vapor Technology Association, a trade group for the e-cigarette industry, says there are plenty of non-regulatory reasons a company might want to use synthetic nicotine—its purity, for example, or freedom from traditional tobacco, with all its baggage and sordid history. But he concedes that the FDA authorization process has forced some hands. “The process has been so convoluted and so opaque that, without question, it’s driven companies in this direction,” he says.

Read more: How Juul Hooked Kids and Ignited a Public Health Crisis

The FDA has had the power to regulate tobacco products since 2009, when then-President Barack Obama signed into law the Family Smoking Prevention and Tobacco Control Act. That law defines a tobacco product as “any product made or derived from tobacco that is intended for human consumption.”

Under a literal reading, synthetic nicotine falls outside that definition, since it is lab-made and not derived from tobacco. Some e-cigarette companies are using that largely unlitigated loophole as a lifeline.

The Germany-based nicotine wholesaler Contraf-Nicotex-Tobacco GmbH primarily sells tobacco-derived product. But Torsten Siemann, the firm’s managing director, says in recent months there’s been a noticeable increase in interest, particularly from U.S. companies. “There are quite some companies who want to try to avoid [the FDA’s review process],” Siemann says, adding that his company supports synthetic nicotine regulation and would stop sales “as soon as this starts to be an illegal market.”

Whether using synthetic nicotine actually places companies outside the FDA’s grasp is up for debate. An FDA spokesperson, in an email, said only that the agency is “aware of a number of electronic nicotine delivery systems (ENDS) claiming to contain only synthetic nicotine (not nicotine sourced from tobacco). We are considering how best to address such products.” On its website, the FDA says it will handle synthetic nicotine regulation on “a case-by-case basis.”

The issue is “definitely gray,” says Marc Scheineson, a partner at the Washington, D.C. law firm Alston & Bird and a former FDA associate commissioner. For example: while the FDA may not have the authority to regulate synthetic nicotine as a tobacco product, it may be able to regulate it as a drug, he says, since the agency could argue that synthetic nicotine alters the structure and function of the body, one of the definitions the FDA uses to designate something a drug. Congress could also choose to amend the definition of a tobacco product to include non-tobacco-derived nicotine, if it saw fit.

In 2010, a Washington, D.C. circuit court ruled that e-cigarettes that use tobacco-derived nicotine must be regulated as tobacco products, not drugs. But that decision specified that the FDA could regulate other nicotine products—such as patches and gums marketed for smoking cessation—as drugs. That seems to clear a path for regulating synthetic nicotine as a drug, says Dennis Henigan, vice president of legal and regulatory affairs at the anti-smoking Campaign for Tobacco-Free Kids (CTFK).

“We think that’s crystal clear,” Henigan says. “FDA, on the drug side, has the authority to enforce the law against [synthetic nicotine products] right now.”

CTFK, along with six other health groups, argued as much in a Sept. 2 letter to the FDA, noting that some companies were already using synthetic nicotine to circumvent FDA processes. Many of those companies had previously manufactured tobacco-based nicotine products, but were not granted marketing authorization because they could not prove their flavored liquids were beneficial enough to adult smokers to outweigh their risks of appealing to underage users—and now, those manufacturers can make the same flavored juices using synthetic nicotine.

“Continued agency inaction on synthetic nicotine e-cigarette products will undermine the regulatory system established by Congress, both for drugs and for tobacco products,” CTFK and its partners wrote. “And continued inaction will allow the manufacture, sale, and widespread availability of flavored products—exactly the products that caused the current epidemic of youth e-cigarette usage and nicotine addiction—to flourish.”

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This isn’t the first time public-health groups have argued that the FDA needs to crack down on synthetic nicotine. CTFK first wrote to the FDA about it in 2018, in response to marketing by the synthetic nicotine supplier Next Generation Labs. (Next Generation Labs did not respond to TIME’s request for comment.) The same year, several public-health-focused attorneys argued in a Boston College Law Review article that the FDA was leaving open a loophole that companies could “exploit it in order to evade regulation” and “can, and should, address this problem by regulating synthetic nicotine products as drugs.”

Neither missive did much. In March of this year, the Wall Street Journal reported that Puff Bar—which makes a popular line of disposable, flavored e-cigarettes—was using synthetic nicotine to avoid agency regulation, sparking another letter to the FDA from CTFK and other health groups.

Abboud, from the Vapor Technology Association, says he fears that if the FDA regulates synthetic nicotine as a drug, many e-cigarette companies will go out of business, potentially handing the market back to traditional cigarette companies. “The drug [approval] pathways are even more cumbersome, even more time-consuming, and more expensive than any other [regulatory] pathway,” he says.

That may be true. But Henigan, from CTFK, says it’s unacceptable for companies to simply sell products as they see fit. “These companies are proceeding under the assumption that they’re simply unregulated,” he says. “That’s a dangerous situation.”

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