This past Thursday, the FDA’s advisory committee on vaccines and similar biological products met to discuss COVID-19 boosters for this fall. They voted in favor of updating the vaccines based on Omicron XBB, a variant lineage that has dominated both in the U.S. and globally this year.
The fall boosters will be monovalent, meaning they’ll only include the XBB strain—unlike our most recent boosters, which were bivalent (including BA.4/BA.5 and the original, Wuhan strain). The FDA has recommended this switch because research suggests monovalent vaccines may be more effective, and because the original coronavirus strain is no longer circulating; we’re mostly seeing XBB right now.
The FDA has not yet decided which exact variant will be used for this fall’s boosters. While experts generally agree that it should be an XBB lineage, the FDA will make a final call on this closer to the fall respiratory virus season. XBB.1.5, XBB.1.9, and XBB.1.16 are all major contenders right now.
This fall’s vaccination campaign is likely to prioritize at-risk populations, including seniors and those with medical conditions that damage their immune systems, similar to the bivalent booster shot rollouts. Ongoing vaccine effectiveness research suggests that these groups benefit most from the protection of an additional booster shot, though people not in these groups obviously benefit as well.
The CDC will make final decisions about which groups will most need the fall boosters, as well as whether some groups may be eligible for more than one of the shots. Children may also become eligible for new boosters; that’ll be up to the CDC as well.
In choosing XBB for the fall boosters, the FDA is standardizing with recommendations from the World Health Organization and European Union, which have also suggested that XBB be the target for the next boosters. Last year, the WHO recommended BA.1, while the U.S. used BA.4/BA.5. Standardizing will be helpful for ongoing data collection, since…
Data problems persist: I’ve written a lot about the U.S.’s disadvantages in tracking vaccine effectiveness, particularly compared to other countries with more standardized health systems. This problem has persisted through all rounds of boosters, including the shots planned for this fall; in fact, it’s even harder now for U.S. agencies to monitor how well the vacines work, as the federal public health emergency’s end led to fewer data collection authorities for the CDC. (Safety monitoring systems will continue, though.)
It’s also worth noting that the boosters this fall will be the first major COVID-19 vaccine rollout following the end of the federal public health emergency. While the Biden administration has devoted some funding for getting vaccines to uninsured Americans, most people will now be getting vaccinated through their health insurance.
This is certain to make the process more complicated and more challenging for many. I’ve already seen stories of people who are eligible for a second bivalent booster having a hard time getting that shot. (See this recent Death Panel episode, for example.) The federal government is doing very little to improve this situation in time for the fall boosters to arrive—and no matter how well XBB vaccines work in theory, they’ll do little in practice if nobody can actually get them.
This week, the FDA made some adjustments to the U.S.’s COVID-19 vaccine guidance in order to standardize all new mRNA shots to bivalent (or Omicron-specific) vaccines, and to allow adults at higher risk to receive additional boosters. The CDC’s vaccine advisory committee and Director Rochelle Walensky both endorsed these changes.
Adults are now considered “up to date” on their COVID-19 vaccines if they have received at least one dose of a bivalent/Omicron-specific vaccine. These are the vaccines manufactured by Pfizer and Moderna that became available last fall.
Any unvaccinated adult should receive one dose of a bivalent vaccine, rather than the former primary series (which was based on the original coronavirus strain). The prior vaccines will essentially go out of use in the U.S.
Seniors (65 or older) and immunocompromised adults may receive an additional bivalent vaccine dose, starting at four months after their prior dose. Recent research has demonstrated that protection from these shots wanes over a couple of months, so there’s a good case for seeking out a new booster if you fall into one of these high-risk categories.
Immunocompromised adults may receive more bivalent doses going forward, in consultation with their doctors. This guidance intends to provide more protection to people who are severely immunocompromised, such as those undergoing cancer treatment.
A new version of the bivalent booster will likely be available in the fall, designed to protect against more recent coronavirus variants. We don’t know much about this yet, but prior FDA and CDC meetings have suggested it will roll out on a similar schedule to the annual flu shot.
These recommendations mostly apply to adults. While the FDA and CDC are also working on simplifying their guidance for children (to similarly prioritize vaccines aligned to current variants), that’s still a more complicated situation right now. See the YLE post for more details.
Another open question, at the moment, is what non-mRNA vaccines may be available, for people who may be allergic to those vaccines or who had severe reactions to earlier doses. Novavax is reportedly working on a bivalent/Omicron-specific option, which people might be able to get this fall. The Johnson & Johnson vaccine is no longer widely used at all.
It makes sense for the FDA and CDC to shift towards bivalent vaccines. Numerous studies have demonstrated that these vaccines perform better against Omicron variants, and this move simplifies the immunization process for everyone involved (doctors, pharmacies, patients, etc.).
However, this shift reveals how poorly the bivalent booster rollout has gone in the U.S. so far. Only 17% of the population has received one, compared to 81% who’s received at least one dose overall, according to the CDC. Even among seniors, only 42% have received a bivalent booster. It would be a massive task for the country to move towards “up-to-date” coverage among all adults.
And the federal government doesn’t appear to be pushing for this in any meaningful way. I’ve already seen several reports on social media of people trying to get an additional booster, and failing—whether because of an insurance issue or because pharmacies have simply stopped offering the shots. This process will only get more challenging when the federal public health emergency ends next month. While the Biden administration has announced funding to cover vaccines for uninsured Americans, that’s just one hurdle among a growing number.
Low uptake of the Omicron-specific boosters does not inspire confidence in the government’s ability to distribute next-gen vaccines. Data from the CDC.
This week, the White House announced that it’s setting up a $5 billion program to support next-generation COVID-19 vaccines and treatments. The program, called Project Next Gen, is essentially a follow-up to Operation Warp Speed (which launched our current COVID-19 vaccines in 2020).
Project Next Gen is a big step toward actually ending the pandemic, not just pretending it’s over. The federal government can support large-scale clinical trials and speed up regulatory approval in a way that no research group or company could. Still, the U.S.’s prior vaccine campaigns don’t inspire confidence that this project will lead to widespread adoption of new shots when they become available.
What are the “next-gen” vaccines under development?
Next-gen COVID-19 vaccines generally fall into two categories: nasal vaccines that would provide better protection against infection, and pan-coronavirus vaccines that would provide better protection against new variants.
Nasal vaccines basically deliver immunity with a spray into the nose, rather than a shot in the arm. This type of vaccine already exists for other common viruses, like the flu. They’re easier to receive for people wary of needles, but they also have a big advantage for the immune system: these vaccines boost immunity in the nose, mouth, and upper respiratory tract, which are the main places where the coronavirus typically infects people. With a nasal vaccine’s help, the immune system is better poised to fight off the virus at infection, rather than fighting off severe symptoms after someone is already infected.
Pan-coronavirus vaccines, meanwhile, address the variant challenge. Our current COVID-19 vaccines are designed around the virus’ spike protein, a component on the outside of the virus that helps it break into human cells. But the spike protein is the primary area where the coronavirus mutates; the spike proteins of XBB.1.5.1 or XBB.1.16 are very different from that of the original virus. New pan-virus vaccine candidates are designed around different aspects of the virus that don’t mutate as much, and therefore would remain more protective against new variants.
For more details on why these vaccine options are important and which candidates are now in the pipeline, I recommend reading this Substack post by Eric Topol, the prominent COVID-19 commentator and director of the Scripps Translational Research Institute. Topol has been calling on the Biden administration to support next-generation vaccines for a long time; he’s written extensively on this subject.
Why is a federal program important to advance these vaccines?
Operation Warp Speed was a monumental achievement, probably the most successful aspect of the U.S.’s response to COVID-19. The federal government provided significant funding to pharmaceutical companies, while also assisting with clinical trial development and facilitating collaboration between companies and the FDA. And the first mRNA vaccines were delivered within one year of the pandemic starting.
Project Next Gen will provide a similar boost to the companies working on next-gen vaccines. It’s not going to operate at the same scale as Operation Warp Speed; it received $5 billion in funding, compared to Warp Speed’s $18 billion. Still, that’s a huge chunk of money for companies, and other types of federal support that will be crucial for quickly starting up large clinical trials.
The White House is currently assessing pharmaceutical companies that it may partner with on this initiative, according to reporting by the Washington Post. There’s no clear timeline for Project Next Gen yet, as the government will need to work with specific companies and the FDA to plan trials, but it’ll certainly be much faster than these vaccines would get to people otherwise.
What are the challenges facing Project Next Gen?
While this initiative is great news, its implementation will face a lot of challenges—especially after the new vaccines become available. The federal government’s rhetoric around COVID-19, combined with our now-mostly-dismantled infrastructure for responding to the disease, will present major barriers to getting people vaccinated.
For example, it’s obviously very ironic that the Project Next Gen announcement came in the same week as Biden signed a bill ending one of the federal COVID-19 emergencies. And the timing isn’t just coincidental: the White House and HHS are actually using the emergency’s end to fund this project, moving in money that was previously devoted to COVID-19 testing and other preventative measures.
The administration is basically telling people: “COVID-19 is over, but uh, we might need you to get a new vaccine or two next year so that you don’t die from it.” It’s hard to blame people for not getting the second part of the message.
We’re already seeing this with the Omicron boosters: only 17% of the U.S. population has received one, according to CDC data. Lack of awareness about those vaccines and the many barriers that now exist to get the shots contributed to that low number. Even if Project Next Gen delivers the most effective COVID-19 vaccines possible, a lot more investment would be necessary to actually get them to people.
Second Omicron boosters for high-risk adults: The FDA and CDC are planning to authorize a second round of bivalent, Omicron-specific vaccines for high-risk adults, the Washington Post reported this week. This decision will apply to Americans over age 65 and those who have compromised immune systems, with these groups becoming eligible four months after their initial bivalent boosters. It’s unclear exactly when the decision will become official; the FDA and CDC will make authorizations sometime “in the next few weeks,” according to WaPo.
HHS announces (underwhelming) Long COVID progress: This week marks one year since Biden issued a presidential memo kicking off a “whole-of-government response” to Long COVID. The Department of Health and Human Services (HHS) commemorated the occasion with a fact sheet sharing the federal government’s progress so far. Unfortunately, that progress has been fairly minor, mostly consisting of reports and guidance that largely summarize existing government programs or build on existing systems (such as Veterans Affairs hospitals). Many of the Long COVID programs that Biden previously proposed have not received funding from Congress; meanwhile, the National Institutes of Health’s RECOVER initiative, the one program that has been funded, has faced a lot of criticism.
RECOVER PIs recommend action on treatment: Speaking of RECOVER: this week, a group of scientists leading research hubs within the national study called for federal funding that would support treatment. The principal investigators (PIs) of these hubs have developed expertise in Long COVID through recruiting and studying patients, leading them to identify gaps in available medical care for long-haulers. To respond, the PIs recommend that Congress allocate $37.5 million to support Long COVID medical care at the RECOVER research sites. Their proposed budget includes patient outreach, telehealth support, educating healthcare workers on Long COVID, and more.
Ventilation improvements in K-12 schools: The CDC released a new study this week in its Morbidity and Mortality Weekly Report, sharing results of a survey (conducted last fall) including about 8,400 school districts representing 62% of public school students in the U.S. Research company MCH Strategic Data asked the districts about how they’d improved ventilation in their school buildings, along with other COVID-19 safety measures. About half of the districts reported “maintaining continuous airflow in classrooms,” one-third reported HVAC improvements, 28% reported using HEPA filters, and 8% reported using UV disinfectants. The results indicate that many districts have a long way to go in upgrading their indoor air quality.
Flu vs. COVID-19 mortality risk: Ziyad Al-Aly and his colleagues at the VA healthcare system in St. Louis have published another paper analyzing COVID-19 through the VA’s electronic health records. This study, published in JAMA Network, describes the mortality risk of COVID-19 compared to seasonal flu for patients hospitalized during the 2022-2023 winter season. The researchers evaluated about 9,000 COVID-19 patients and 2,400 flu patients, finding that risk of death for COVID-19 patients in the 30 days following hospitalization was about 1.6 times as high as the risk of death for flu patients. Despite great advances in vaccines and treatments, COVID-19 remains more dangerous than other seasonal viruses, the study suggests.
Biobot launches mpox dashboard: This week, leading wastewater surveillance company Biobot Analytics launched a new dashboard displaying its mpox (formerly monkeypox) monitoring. Biobot tests for mpox at hundreds of sewage sites across the U.S., largely through its partnership with the CDC, and will continue this monitoring through at least summer 2023. The new dashboard shows mpox detections nationally over time and monitoring sites by state; it also includes some information on how mpox surveillance differs from COVID-19 surveillance.
Nationwide, fewer people are getting lab-based COVID-19 tests now than at any time since the start of the pandemic. Chart via the CDC.
When the public health emergency ends this spring, COVID-19 testing is going to move further in two separate directions: rapid, at-home tests at the individual level, and wastewater testing at the community level.
That was my main takeaway from an online event last Tuesday, hosted by Arizona State University and the State and Territory Alliance for Testing. This event discussed the future of COVID-19 testing following the public health emergency, with speakers including regulatory experts, health officials from state agencies, and executives from diagnostic companies.
“The purpose of testing has shifted” from earlier in the pandemic, said Dr. Thomas Tsai, the White House’s COVID-19 testing coordinator, in opening remarks at the event. Public health agencies previously used tests to monitor COVID-19 in their communities and direct contact-tracing efforts; now, individual tests are mostly used for diagnosing people, and the resulting data are widely considered to be a major undercount of true cases.
While the speakers largely agreed about the continued value of rapid, at-home tests (for diagnosing people) and wastewater surveillance (for tracking COVID-19), they saw a lot of challenges ahead for both technologies. Here are some challenges that stuck out to me.
Challenges for rapid, at-home tests:
The public health emergency’s end won’t have an immediate impact on which COVID-19 tests are available, health policy researcher Christina Silcox from Duke University explained at the event. But, in the coming months, the FDA is likely to also end its emergency use authorization for COVID-19 diagnostics. As a result, companies that currently have tests authorized under this emergency will need to apply for full approval. Relatively few rapid tests are currently approved in this way, so the change could lead to fewer choices for people buying tests.
At the same time, it will become harder for many Americans to access rapid tests. After the federal emergency ends, private insurance companies will no longer be required to cover rapid tests. Some insurance providers might still do this (especially if large employers encourage it), said Amy Kelbik from McDermott+Consulting, but it will no longer be a universal option. At the same time, Medicare will stop covering rapid tests; Medicaid coverage will continue through fall 2024.
In light of these federal changes, state health officials at the ASU event talked about a need for continued funding to support rapid test distribution from state and local agencies. “Testing will continue to inform behavior, but will become drastically less available,” said Heather Drummond, testing and vaccine program leader at the Washington State Department of Health. Washington has led a free test distribution program, but it’s slated to end with the conclusion of the federal health emergency, Drummond said; she’d like to see services like this continue for the people who most need free tests.
Drummond and other health officials also discussed the challenges of educating people about how to interpret their test results, as COVID-19 guidance becomes less widely available. The vast majority of rapid, at-home test results are not reported to public health agencies—and, based on the event’s speakers, this isn’t a problem health agencies are particularly interested in devoting resources to solving right now. But as rapid tests become the default for diagnosing COVID-19, continued outreach will be needed on how to use them.
Also, as I’ve written before, some PCR testing infrastructure should still be maintained, for cases when someone needs a more definitive test result or wants documentation in case of long-term symptoms. PCR test access will likely get even worse after the federal health emergency ends, though, as insurance plans will also stop covering (or cover fewer costs for) these tests.
Challenges for wastewater surveillance:
Overall, wastewater surveillance is the best source for community-level COVID-19 data, speakers at the ASU event agreed. Official case numbers represent significant undercounts of true infections, and hospitalizations (while more reliable) are a delayed indicator. Wastewater data are unbiased, real-time, population-level—and the technology can be expanded to other common viruses and health threats, health officials pointed out at the event.
But wastewater surveillance is still very uneven across the U.S. It’s clear just from looking at the CDC’s map that some states have devoted resources to detailed wastewater testing infrastructure, with a testing site in every county—while others just have a handful of sites. Funding uncertainty likely plays a role here; speakers at the event expressed some confusion about the availability of CDC funds for long-term wastewater programs.
The CDC’s wastewater surveillance system has also faced challenges with standardizing data from different testing programs. And, at state and local agencies, health officials are still figuring out how to act on wastewater data. Agencies with more robust surveillance programs (such as Massachusetts, which had two officials speak at the ASU summit) may be able to provide success stories for other agencies that aren’t as far along.
Broader testing challenges:
For diagnostic company leaders who spoke at the event, one major topic was regulatory challenges. Andrew Kobylinski, CEO and co-founder of Primary.Health, said that the FDA’s test requirements prioritize highly accurate tests, even though less sensitive (but easier to use) tests might be more useful in a public health context.
Future COVID-19 tests—and tests for other common diseases—may need a new paradigm of regulatory requirements that focus more on public health use. At the same time, health agencies and diagnostic companies could do more to collect data on how well different test options are actually working. While it’s hard to track at-home tests on a large scale, more targeted studies could help show which tests work best in specific scenarios (such as testing after an exposure to COVID-19, or testing to leave isolation).
Company representatives also talked about financial challenges for developing new tests, particularly as interest in COVID-19 dies down and as recession worries grow this year. While a lot of biotech companies dove into COVID-19 over the last three years, they haven’t always received significant returns on their investments. For example, Lucira, the company behind the first flu-and-COVID-19 at-home test to receive authorization, recently filed for bankruptcy and blamed the long FDA authorization process.
Mara Aspinall, the ASU event’s moderator and a diagnostic expert herself, ended the event by asking speakers whether COVID-19 has led to lasting changes in this industry. The answer was a resounding, “yes!” But bringing lessons from COVID-19 to other diseases and health threats will require a lot of changes—to regulatory processes, funding sources, data collection practices, and more.
FDA authorizes joint COVID/flu rapid test, but there’s a catch: Late last week, the FDA issued emergency use authorization to the U.S.’s first at-home, rapid test capable of detecting both COVID-19 and the flu. This could be a really useful tool for people experiencing respiratory symptoms, since COVID-19 and flu can appear so similar. But you might not be seeing this test on pharmacy shelves anytime soon: Lucira Health, the test’s manufacturer, just declared bankruptcy. And the company actually blamed FDA authorization delays for contributing to its financial situation, as it had produced supplies anticipating a fall/winter sale of tests. Brittany Trang at STAT News reported on the situation; read her story for more details.
COVID-19 surveillance stressed out essential workers: For a new report, the nonprofit Data & Society interviewed 50 essential workers from meatpacking and food processing, warehousing, manufacturing, and grocery retail industries about their experiences with COVID-19 surveillance efforts, like temperature checks and proximity monitoring. Overall, workers found that these surveillance measures added time and stress to the job but did not actually provide information about COVID-19 spread in their workplaces. (Companies often cited privacy concerns as a reason not to share when someone got sick, according to the report.) The report shows how health data often doesn’t make it back to the people most impacted by its collection.
Vaccinations vs. Long COVID meta-analysis: A new paper published this week in the BMJ examines how COVID-19 vaccination impacts Long COVID risk. The researchers (at Bond University in Australia) performed a meta-analysis, compiling results from 16 prior studies. While the studies overall showed that vaccination can decrease risk of getting Long COVID after an infection (and may reduce symptoms for patients already sick with Long COVID), the studies were too different in their methodologies to actually allow for “any meaningful meta-analysis,” the authors noted. To better study this question, more rigorous clinical trials are needed, the researchers wrote.
Tracking Long COVID with insurance data: Another notable Long COVID paper, published this week in JAMA Health Forum: researchers at the insurance company Elevance Health compared health outcomes for about 13,000 people with post-COVID symptoms compared to 27,000 who did not have symptoms. The researchers found that, in the one year following acute COVID-19, Long COVID patients had higher risks for several health outcomes, including strokes, heart failure, asthma, and COPD; people in the post-COVID cohort were also more likely to die in that year-long period. I expect insurance databases like the one used in this paper may become more common Long COVID data sources. Also, see Eric Topol’s Substack for commentary.
FDA committee recommends RSV vaccine applications: Finally, a bit of good news on the “other respiratory viruses” front: the FDA’s vaccine advisory committee has recommended the agency move forward with two applications for RSV vaccines. Major pharmaceutical companies Pfizer and GlaxoSmithKline (GSK) have been working on RSV vaccine options; while early data appear promising, clinical trials on both vaccines have found potentially concerning safety signals. The trial populations have been relatively small, making these signals difficult to interpret right now but worthy of additional study. As usual, Katelyn Jetelina at Your Local Epidemiologist has provided a great summary of the FDA advisory committee meeting.
The FDA recommends that the U.S. shifts to annual COVID-19 vaccines, with a variety of data sources feeding into decision-making. Screenshot from the VRBPAC meeting on January 26, 2023.
On Thursday, the FDA’s Vaccines and Related Biological Products Advisory Committee (or VRBPAC) met to discuss the future of COVID-19 vaccines. While the committee readily agreed that our current, Omicron-specific shots are working well and should be used more broadly, it had a hard time answering other questions about future vaccine regimens—largely due to a lack of good data.
Now, the lack of good U.S. data on vaccine effectiveness is not a new problem. I personally have been writing about thissince fall 2021, to the point that I feel like a broken record for bringing it up again. To summarize: the U.S. has a fractured health system in which every state tracks vaccinations differently, with a lot of local public health departments and private companies in the mix, too. As a result, it’s challenging for researchers to determine exactly who is getting COVID-19 after vaccination and how the virus is impacting them.
This lack of detailed vaccine effectiveness data was a problem in fall 2021, when federal officials decided on an initial round of booster shots. And it’s still a problem in winter 2023, as the same officials attempt to plot out a future in which COVID-19 is another disease that we deal with on an annual basis.
But this week’s VRBPAC meeting revealed some other areas of data that are also lacking as we try to answer questions about future vaccines. Here’s my summary of five primary data gaps that came up at the meeting, and some suggestions for potential solutions.
Detailed vaccine effectiveness data
The biggest data gap, of course, is our lack of answers to the question: Who is getting sick with COVID-19 after vaccination? And related questions: How sick did they get? Which variants did they get sick with? What preexisting conditions or comorbidities did they have?
Our lack of standardized medical data in the U.S. makes it tough to answer these questions at the population level. Analyzing variants is particularly tricky, given that variant surveillance in the U.S. tends to be entirely anonymized—with no connections between the genomic sequencing of random PCR tests and the health outcomes (or vaccination statuses) of those patients. And analyzing preexisting conditions can be crucial as officials try to decide which groups of people need extra boosters, but these conditions often are not collected in standard databases or linked to COVID-19 records.
As a result, U.S. officials tend to rely on other countries with more comprehensive, standardized data systems for information on how well the vaccines work. We also have to rely on the pharmaceutical companies producing these vaccines, which often don’t openly share their data—they tend to present clinical trial results in press releases, over peer-reviewed studies. Companies also tend to do trials that align better with their own financial interests, rather than looking at the full scope of vaccine effectiveness.
Even in this week’s VRBPAC meeting, scientists from Moderna presented results from a clinical trial—conducted in the U.K.—that tested the company’s bivalent boosters against the original (non-Omicron) boosters.
Better tracking of variants
The primary reason why our COVID-19 vaccines require updates in the first place is the coronavirus’ continued evolution. Every new lineage of Omicron that rises to prevalence is either a bit better at spreading quickly, a bit better at evading immunity from prior infection or vaccination, or both. To successfully tweak our vaccines in the future, scientists will need to know which variants are out there and how dangerous they are.
Right now, variant tracking largely relies on PCR testing, as researchers randomly select some swab samples to sequence. But with fewer and fewer people getting PCR tests, the sample pool is dwindling. As a result, to stay ahead of new variants, the U.S. needs to diversify its surveillance options. That will likely include more variant sequencing from wastewater (as a population-level COVID-19 sample), more sequencing at hospitals and healthcare centers, and more travel surveillance focused on international variant patterns.
Variant surveillance will also need to inform how suited U.S.-developed COVID-19 vaccines are for the rest of the world. Right now, the pharmaceutical companies that have produced the most effective vaccines (i.e. Pfizer and Moderna) are American—so American regulators are essentially dictating vaccine policy for the world, even though their priority is the U.S. FDA official Jerry Weir said as much at the meeting. U.S. hegemony over COVID-19 vaccines will continue to be a complex, fraught topic going forward.
Tracking different types of immunity
At the VRBPAC meeting, Moderna, Pfizer, and Novavax all presented data on how well their vaccines work against currently-dominant coronavirus variants. While they included some clinical data (case rates, hospitalization rates), the presentations mostly focused on one metric: antibody titers. To calculate if a vaccine works against a certain variant, the easiest strategy is measuring the antibodies produced after a vaccinated blood sample is exposed to that variant.
While this is the easiest strategy, it’s far from the only way to examine how well a vaccine works. Members of the VRBPAC committee frequently asked the pharmaceutical companies for those other metrics: T cells, B cells, and more ways of measuring the immune system’s response to COVID-19. But the companies had little response to these questions. Even FDA and NIH officials at the meeting admitted that they still didn’t have a good understanding of how, exactly, our current vaccines impact our immune systems, beyond generating antibodies.
To better evaluate future vaccines, scientists will need to get better at measuring other aspects of our immune responses. That includes future mRNA vaccines as well as next-generation vaccines in the works right now, such as nasal vaccines (recently authorized in China and India) and vaccines designed to protect against all variants (currently in development at Duke University and other institutions).
I also think it’s worth noting that, as Katelyn Jetelina writes in her coverage of the VRBPAC meeting at Your Local Epidemiologist, the FDA could require pharmaceutical companies to study the immune system more holistically when they submit further vaccine updates for authorization. “The FDA could require sponsors to do detailed investigations, e.g. assessing lymph nodes, bone marrow, and breakthroughs,” she writes. “This would help us understand immunity better, so we can make better recommendations. It’s not clear why they aren’t pushing for this.”
Improving vaccine safety tracking
Two years after the first COVID-19 vaccines were authorized, we now know that the vaccines are overwhelmingly safe and effective. Most people have mild side effects following their shots, like sore arms and fatigue, but the benefits of getting vaccinated far outweigh the risks. However, some discussion at the VRBPAC meeting indicated that federal agencies could do a better job of tracking rare (yet important) serious side effects.
For example, a safety presentation from the Kaiser Permanente Vaccine Study Center suggested that there might be a small increase in stroke risk for older adults who get vaccinated. The risk has only appeared in one vaccine safety database so far and appears to be minimal, per the FDA, but it’s still worth closer examination.
In addition, as Helen Branswell and Matthew Herper discuss in the STAT News liveblog, the VRBPAC meeting didn’t present much new data about vaccine safety risks for children, such as myocarditis among boys and young men. Plus, we have limited data so far on whether vaccination may contribute to autoimmune conditions or Long COVID-like symptoms, a problem that has shown up in some studies and anecdotal reports.
If public health officials are going to continue encouraging Americans to get COVID-19 shots once a year (or more), they will need to thoroughly address concerns about these potential side effects. This is particularly true for young children, a group that’s been vaccinated at fairly low numbers so far.
Navigating COVID-19’s interactions with other vaccines
At the VRBPAC meeting, FDA officials suggested a potential future in which most Americans get one COVID-19 vaccine per year, on a similar timeline to the annual flu shot. Variant strains might be selected in the spring or summer, with vaccines developed and produced in time for a fall vaccination campaign. Some at-risk groups (older adults, people with compromised immune systems, etc.) might get two doses each year.
To make this possible, the VRBPAC committee members suggested that we’ll need to track how COVID-19 vaccines intersect with other vaccines. For example, if an older adult receives their flu shot and COVID-19 shot in the same doctor’s visit, does that dampen how well one or the other vaccine works? Does it increase the risks of severe side effects? We don’t know, at this point.
Another major area of future study will be how COVID-19 vaccines may fit into regular, childhood immunization schedules for young kids. Similarly to the COVID-19 plus flu question, scientists will need to track any potential interactions between COVID-19 shots and other regular shots—along with answering questions about how many shots are needed, timing between shots, and more.
One day, I’m sure, we will have a regular COVID-19 vaccination schedule in the U.S. that runs parallel to our flu vaccination schedule. But it will take time, discussions, and a lot more data to get there.
This week, the FDA and CDC authorized new booster shots from both Pfizer and Moderna that are tweaked to specifically target Omicron BA.4 and BA.5. The vaccines will start becoming available at pharmacies and doctors’ offices across the country in the coming days.
Much of the media coverage of these new boosters has focused on the fact that they’re the first COVID-19 vaccines derived from a newer variant, as opposed to the original Wuhan strain. BA.5 and BA.4.6, a sublineage of BA.4, are causing almost all COVID-19 cases in the country right now; some experts hope that a booster campaign targeted to these versions of the coronavirus will lead to actual decreases in transmission, not just severe disease.
While this is an important milestone, I’d like to focus on a couple of reasons these shots are notable from a data perspective. First, the Omicron boosters are the first COVID-19 vaccines authorized in the U.S. without data from human trials. During vaccine development, companies typically start with lab studies, then test the vaccine in animal models, then in humans. Because the BA.4/BA.5 shots were designed so recently, Pfizer and Moderna haven’t had time to test them in humans yet.
From a safety and efficacy perspective, this lack of data isn’t a huge concern because the new vaccines are very close to BA.1 versions that have been tested in humans. As Katelyn Jetelina explained in a Your Local Epidemiologist post about the new vaccines:
Literally the difference of a few amino acids—like a few letter edits on a Word document. We aren’t changing the number of words in the paper (like dosage of RNA), or the content of the paper, or the platform (like Word to Excel). Because of the minimal change, we are confident that BA.1 bivalent safety data will accurately reflect BA.5 safety.
Another important piece of context here is that flu vaccines—which are updated each year to reflect currently circulating versions of the virus—are typically not tested in humans before they’re rolled out in annual flu campaigns. So, the new COVID-19 shots are following an existing process; future vaccine adjustments for new variants going forward will likely happen in a similar way.
Second, the Omicron boosters are the first COVID-19 vaccines authorized in the U.S. before they’ve been tested in other countries. For previous booster campaigns, effectiveness data from countries with better-organized health systems that started using new rounds of shots before we did (such as the U.K. and Israel) have been key for U.S. regulators making authorization decisions.
But the BA.4/BA.5 boosters haven’t been rolled out anywhere else yet. Several other countries (the E.U., the U.K., Canada, Switzerland, Australia) have authorized Omicron BA.1 boosters—those that have gone through more clinical testing. The U.S. is the first to try the BA.4/BA.5 option. It will be interesting to see whether there are significant differences in how these countries’ fall booster campaigns mitigate potential surges.
And third, these boosters are likely to be the last COVID-19 vaccines authorized while they’re still covered by federal funding.Recent announcements from officials like Ashish Jha have suggested that, in 2023, the government will stop buying vaccine supplies in large quantities to distribute for free. Instead, COVID-19 vaccines will start to be privately-purchased, health insurance-mediated products like other vaccines.
While some local governments and large health institutions will likely still organize free vaccine distributions for future rounds of shots, the lack of federal supplies will be a major shift. It will make COVID-19 vaccination harder to access, especially among people without health insurance—likely leading to even lower uptake. We need to make this last free booster campaign count.
Going forward, here are a few questions I’ll be tracking as these boosters get rolled out:
How will public health agencies track the effectiveness of these new vaccines? We’ll want to see how the BA.4/BA.5 shots compare to prior boosters at preventing infections, hospitalizations, and deaths. Data on breakthrough cases is already pretty limited in the U.S., so we may have to rely on specific local health departments and health systems that have better infrastructure for this.
What additional boosters might be needed in the future? As we examine how well these Omicron-specific boosters work, we will need to keep track of the potential need for more shots. Will immunocompromised people or older adults need second rounds of Omicron shots, for example?
What new variants will come on the scene? Also impacting the potential need for further vaccine shots: the arrival of new variants, either continued Omicron mutations or something else entirely. Wastewater surveillance may be particularly helpful for variant tracking as PCR testing continues to be less available.
How will the privatization of vaccines impact tracking? If COVID-19 vaccines are no longer purchased and distributed by the federal government after 2022, will this impact the CDC’s ability to track vaccinations? We’re already seeing more vaccine distribution at private pharmacies and doctors’ offices as opposed to publicly-run clinics; I wonder how this trend may continue.
For more information on the new boosters, check out:
Last fall, I wrote—both in the COVID-19 Data Dispatchand for FiveThirtyEight—that the U.S. did not have the data we needed to make informed decisions about booster shots. Several months later, we still don’t have the data we need, as questions about a potential BA.2 wave and other future variants abound. Discussions at a recent FDA advisory committee meeting made these data gaps clear.
Our country has a fractured public health system: every state health department has its own data systems for COVID-19 cases, vaccinations, and other metrics, and these data systems are often very difficult to link up with each other. This can make it difficult to answer questions about vaccine effectiveness, especially when you want to get specific about different age groups, preexisting conditions, or variants.
To quote from my November FiveThirtyEight story:
In the U.S., vaccine research is far more complicated. Rather than one singular, standardized system housing health care data, 50 different states have their own systems, along with hundreds of local health departments and thousands of hospitals. “In the U.S., everything is incredibly fragmented,” said Zoë McLaren, a health economist at the University of Maryland Baltimore County. “And so you get a very fragmented view of what’s going on in the country.”
For example, a database on who’s tested positive in a particular city might not be connected to a database that would reveal which of those patients was vaccinated. And that database, in turn, is probably not connected to health records showing which patients have a history of diabetes, heart disease or other conditions that make people more vulnerable to COVID-19.
Each database has its own data fields and definitions, making it difficult for researchers to integrate records from different sources. Even basic demographics such as age, sex, race and ethnicity may be logged differently from one database to the next, or they may simply be missing. The Centers for Disease Control and Prevention, for instance, is missing race and ethnicity information for 35 percent of COVID-19 cases as of Nov. 7.*
*As of April 9, the CDC is still missing race and ethnicity information for 35% of COVID-19 cases.
This past Wednesday, the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC) met to discuss the future of COVID-19 booster shots. Notably, this committee didn’t actually need to vote on anything, since the FDA and CDC had already authorized a second round of boosters for Americans over age 50 and immunocompromised people the week before.
When asked why the FDA hadn’t waited to hear from its advisory committee before making this authorization decision, vaccine regulator Peter Marks said that the agency had relied on data from the U.K. and Israel to demonstrate the need for more boosters—combined with concerns about a potential BA.2 wave. The FDA relied on data from the U.K. and Israel when making its booster decision in the fall, too; these countries, with centralized health systems and better-organized data, are much more equipped to track vaccine effectiveness than we are.
With that authorization of second boosters for certain groups already a done deal, the VRBPAC meeting this past Wednesday focused more on the information we need to make future booster decisions. Should we expect annual COVID-19 shots, like we do for the flu? What about shots that are designed to combat specific variants? A lot of this is up in the air right now, the meeting discussion indicated.
Also up in the air: will the FDA ever host a virtual VRBPAC meeting without intensive technical difficulties? The meeting had to pause for more than half an hour to sort out a livestream issue.
we can pull together extraordinary vaccines in under a year we can cook up oral antivirals that slash hospitalization and death rates by 90% we can manufacture great masks, and detect viral infections with 15-minute tests
we cannot get VRBPAC livestreams to work
— Katherine J. Wu, Ph.D. (@KatherineJWu) April 6, 2022
Here are some vaccine data questions that came up on Wednesday, drawing from my own notes on the meeting and the STAT News liveblog:
How much does protection from a booster shot wane over time? We know that booster shots increase an individual’s protection from a coronavirus infection, symptoms, hospitalization, and other severe outcomes; CDC data presented during the VRBPAC meeting showed that, during the Omicron surge, Americans who were boosted were much more protected than those with fewer doses. But we don’t have a great sense of how long these different types of protection last.
How much does booster shot protection wane for different age groups? Waning immunity has been a bigger problem among seniors and immunocompromised people, leading to the FDA’s decision on fourth doses for these groups. But what about other age groups? What about people with other conditions that make them vulnerable to COVID-19, like diabetes or kidney disease? This is less clear.
To what degree is waning immunity caused by new variants as opposed to fewer antibodies over time? This has been a big question during the Delta and Omicron surges, and it can be hard to answer because of all the confounding variables involved. In the U.S., it’s difficult to link up vaccine data and case data; tacking on metrics like which variant someone was infected with or how long ago they were vaccinated often isn’t possible—or if it is possible, it’s very complicated. (The U.K. does a better job of this.)
Where will the next variant of concern come from, and how much will it differ from past variants? Computational biologist Trevor Bedford gave a presentation to VRBPAC that attempted to answer this question. The short answer is, it’s hard to predict how often we’ll see new events like Omicron’s emergence, in which a new variant comes in that is extremely different from the variants that preceded it. Bedford’s analysis suggests that we could see “Omicron-like” events anywhere from every 1.5 years to every 10.5 years, and we should be prepared for anything on that spectrum. The coronavirus has evolved quite quickly in the last two years, Bedford said, and will likely continue to do so; though he expects some version of Omicron will be the main variant we’re dealing with for a while.
What will the seasonality of COVID-19 be? The global public health system has a well-established process for developing new flu vaccines, based on monitoring circulating flu strains in the lead-up to flu seasons in different parts of the world. Eventually, we will likely get to a similar place with COVID-19 (if annual vaccines become necessary! also an open question at the moment). But right now, the waxing and waning of surges caused by new variants and human behavior makes it difficult to identify the actual seasonality of COVID-19.
At what point do we say the vaccine isn’t working well enough? This question was asked by VRBPAC committee member Cody Meissner of Tufts University, during the discussion portion of the meeting. So far, the most common way to measure COVID-19 vaccine effectiveness in the lab is by testing antibodies generated by a vaccine against different forms of the coronavirus. But these studies don’t account for other parts of the immune system, like T cells, that garner more long-term protection than antibodies. We need a unified method for measuring vaccine effectiveness that takes different parts of the immune system into account, along with real-world data.
How might vaccine safety change over time? This question was brought up by Hayley Ganz of Stanford, another VRBPAC committee member. The CDC does have an extensive system for monitoring vaccine safety; data from that system should be readily available to the experts making booster shot decisions.
Today, I presented to @US_FDA VRBPAC with an overview of SARS-CoV-2 evolution up to this point and a brief perspective for what to expect going forward. Slides are here: https://t.co/QnzOctVCSN and my slot in the full recording is viewable here: https://t.co/n5rlgOvtEg. 1/13
Another thing I’m wondering about right now, personally, is how the U.S.’s shifting focus away from case data might make all of this more complicated. As public health agencies scale down case investigations and contact tracing—and more people test positive on at-home, rapid tests that are never reported to these agencies—we’re losing track of how many Americans are actually getting COVID-19. And breakthrough cases, which are more likely to be mild or asymptomatic, might also be more likely to go unreported.
So, how does the U.S. public health system study vaccine effectiveness in a comprehensive way if we simply aren’t logging many of our cases? Programs such as randomized surveillance testing and cohort studies might help, but outside of a few articles and Twitter conversations, I’m not seeing much discussion of these solutions.
Finally: a few friends and relatives over age 50 have asked me about when (or whether) to get another booster shot, given all of the uncertainties I laid out above. If you’re in the same position, here are a couple of resources that might help:
This week, the FDA’s vaccine advisory committee had a two-day meeting to discuss booster shots for Moderna’s and Johnson & Johnson’s COVID-19 vaccines. From the outside, these meetings may have appeared fairly straightforward: the committee voted unanimously to recommend booster shots for both vaccines.
But in fact, the discussions on both days were wide-reaching and full of questions, touching on the many continued gaps in our knowledge about the need for additional vaccine doses. The FDA committee continues to make decisions based on rather limited data, as do other top U.S. officials. Case in point: on Thursday, the committee was asked to consider data from Israel’s booster shot campaign—which is utilizing Pfizer vaccines—as evidence for Moderna boosters in the U.S.
In the Moderna vote on Thursday afternoon, committee member Dr. Patrick Moore, a virologist at the University of Pittsburgh, said that he voted “on gut feeling rather than really truly serious data.” The comment exemplified how much we still don’t know regarding the need for boosters, thanks in large part to the CDC’s failure to comprehensively track breakthrough cases in the U.S.
Um. Am I the only person who is seriously bothered to hear a VRBPAC committee member say he voted "on gut feeling rather than really truly serious data"?
Still, there are a few major facts that we have learned since the FDA and CDC discussions on Pfizer boosters that took place a couple of weeks ago. Here’s my summary of what we’ve learned—and what we still don’t know.
What we’ve learned since the Pfizer discussion:
Israel’s booster rollout continues to align with falling case numbers. On Thursday, representatives from the Israeli national health agency presented data on their booster shot rollout—which, again, is using Pfizer vaccines. The vast majority of seniors in Israel have now received a third dose, and over 50% of other age groups have as well. According to the Israeli scientists, this booster rollout both decreased the risk of severe COVID-19 disease for older adults and helped to curb the country’s Delta-induced case wave, causing even unvaccinated adults to have a decreased risk of COVID-19.
In Israel, severe cases among both vaccinated and unvaccinated adults decreased after the country provided third Pfizer doses to its residents. Screenshot taken from Thursday’s VRBPAC meeting.
You can read more about Israel’s booster campaign in this paper, published in the New England Journal of Medicine in early October. It’s worth noting, however, that Delta is known to spur both case increases and decreases in cycles that can be somewhat unpredictable—and may not be exactly linked to vaccination. So, I personally take the Israeli claims that boosters stopped their case wave with a grain of salt.
Spain and Italy have finished this wave and Israel is almost done; the UK and Germany are on the rise, and the US is headed down. Delta isn't correlated with % vaccinated. Israel argues it is boosters, but causality is not assignable. The rise and fall of COVID is complex. pic.twitter.com/UVwcoFJIuP
Decreased vaccine effectiveness against infection may be tied more to Delta and behavioral factors than “waning antibodies.” This week, the New York State Department of Health (DOH) announced results from a large study of vaccine effectiveness which is, from what I’ve seen, the first of its kind in the U.S. The New York DOH used state databases on COVID-19 vaccinations, tests, and hospitalizations to examine vaccine effectiveness against both infection and hospitalization in summer 2021, when Delta spread rapidly through the state.
They found that vaccine effectiveness against infection did decline over the summer. But the declines occurred similarly for all age groups, vaccine types, and vaccine timing (i.e. which month the New Yorkers in the study received their vaccines)—suggesting that the decline in effectiveness was not tied to waning immune system protection. Rather, the effectiveness decline correlated well with Delta’s rise in the state. It also correlated with reduced safety behaviors, like the lifting of New York’s indoor mask mandate and the reopening of various businesses.
Vaccine effectiveness against hospitalization declined for older adults, but remained at very high levels for New Yorkers under age 65, the study found. Here’s what lead author Dr. Eli Rosenberg said in a statement:
The findings of our study support the need for boosters in older people in particular, and we encourage them to seek out a booster shot from their health care provider, pharmacy or mass vaccination site. We saw limited evidence of decline in effectiveness against severe disease for people ages 18 to 64 years old. While we did observe early declines in effectiveness against infections for this age group, this appears to have leveled off when the Delta variant became the predominant strain in New York. Together, this suggests that ongoing waning protection may be less of a current concern for adults younger than 65 years.
I was surprised that this study didn’t come up in the FDA advisory committee meetings this week, and will be curious to see if it’s cited in future booster shot discussions. The study does align, however, with the committee’s decision against recommending booster shots for all adults over age 18 who received Moderna vaccines.
Johnson & Johnson vaccine recipients appear to need boosters more than mRNA vaccine recipients. On Friday, presentations from both J&J representatives and FDA scientists made a clear case for giving J&J vaccine recipients a second dose of this adenovirus vaccine. In one 30,000-patient study, patients who received a second J&J shot two months after their first shot saw their vaccine efficacy (against symptomatic infection) rise from 74% to 94%.
Interestingly, unlike the Pfizer and Moderna vaccines, a J&J shot’s ability to protect against coronavirus infection appears relatively stable over time. However, a booster shot can make this vaccine more effective—especially against variants. Despite arguments from J&J representatives that their vaccine’s second dose should come six months after the first dose, the FDA advisory committee voted to recommend second J&J shots just two months after the first dose, for all adults over age 18.
It’s worth noting that this vaccine regimen might effectively change J&J’s product from a one-shot vaccine to a two-shot vaccine. STAT’s Helen Branswell and Matthew Herper go into the situation more in their liveblog.
Mixing and matching vaccines is a strong strategy for boosting immunity, especially if one of the vaccines involved uses mRNA technology. This week, the National Institutes of Health (NIH) released a highly anticipated study (posted as a preprint) on mix-and-match vaccine regimens. The NIH researchers essentially tested every possible booster combination among the three vaccines that have been authorized in the U.S. Before and after vaccination, the researchers took blood samples and tested for antibodies that would protect against the coronavirus.
In short, the NIH study found that all three vaccines—Pfizer, Moderna, and J&J—will provide a clear antibody boost to people who have received any other vaccine. But the mRNA vaccines (Pfizer and Moderna) provide bigger benefits, both in the form of higher baseline antibody levels (after two shots) and a higher boost. The best combination was a J&J vaccine initially, followed by a Moderna booster, Dr. Katelyn Jetelina notes in a Your Local Epidemiologist summary of the study.
Every vaccine provided a “boost” of protective antibodies to recipients of every other vaccine. Figure from the NIH preprint. mrna-1273 refers to the Moderna vaccine, Ad26.COV2.S refers to the J&J vaccine, and BNT162b2 refers to the Pfizer vaccine.
The booster regimens also appeared to be safe, with limited side effects. But this was a relatively small study, including about 450 people. In their discussion on Friday afternoon, the FDA advisory committee members said that they would be very likely to authorize mix-and-match vaccine regimens after seeing more safety data.
Moderna and J&J boosters appear to be safe, with similar side effects to second shots. Safety data from Moderna’s and J&J’s clinical trials of their booster shots, along with data from the NIH mix-and-match study, indicate that the additional doses cause similar side effects to first and second doses. After a booster, most recipients had a sore arm, fatigue, and other relatively minor side effects.
And here’s what we still don’t know:
Which medical conditions, occupations, and other settings confer higher breakthrough case risk? I wrote about this issue in detail in September. The U.S. continues to have little-to-no data on breakthrough case risk by specific population group, whether that’s groups of people with a specific medical condition or occupation. This data gap persists, even though U.S. researchers have some avenues for breakthrough risk analysis at their disposal (see: this post from last week).
This lack of data came up in FDA advisory committee discussions on Thursday. An FDA representative was unable to cite any evidence that people in specific occupational settings are at a higher risk for breakthrough cases.
Question from Cody Meisner again about data that shows people in certain occupational settings more vulnerbale to severe covid?
Are there any rare vaccine side effects that may occur after breakthrough doses? When I covered the FDA advisory committee meeting on Pfizer boosters, I noted that Pfizer’s clinical trial of these shots included just 306 participants—providing the committee members with very limited data on rare adverse events, like myocarditis. Well, Moderna’s clinical trial of its booster shots was even smaller: just 171 people. J&J had a larger clinical trial, including over 9,000 people.
These trials and the NIH mix-and-match study indicated that booster shots cause similar side effects to first and second shots, as I noted above. But few clinical trials are large enough to catch very rare (yet more serious) side effects like myocarditis and blood clots. (In J&J’s case, blood clots occur roughly twice for every million doses administered.) Federal officials will carefully watch for any side effects that show up when the U.S.’s booster rollout begins for Moderna and J&J.
How do antibody levels correlate to protection against COVID-19, and what other aspects of the immune system are involved? The NIH mix-and-match study focused on measuring antibody levels in vaccine recipients’ blood, as did other booster shot trials. While it may sound impressive to say, for example, “J&J recipients had a 76-fold increase in neutralizing antibodies after receiving a Moderna booster,” we don’t actually know how this corresponds to protection against COVID-19 infection, severe disease, and death.
Some experts—including a couple of those on the FDA advisory committee—have said that discussions focusing on antibodies distract from other types of immunity, like the memory cells that retain information about a virus long after antibody levels have fallen. More research is needed to tie various immune system measurements to real-world protection against the coronavirus.
What needs to happen at the FDA for mix-and-match vaccination to be authorized? One challenge now facing the FDA is, the federal agency has clear evidence that mix-and-match vaccine regimens are effective—but it does not have a traditional regulatory pathway to follow in authorizing these regimens. Typically, a company applies for FDA authorization of its specific product. And right now, no vaccine company wants to apply for authorization of a regimen that would involve people getting a different product from the one that brings this company profit.
So, how will the FDA move forward? There are a couple of options, like the CDC approving mix-and-match boosters directly. See this article for more info.
Finally: I can’t end this post without acknowledging that, as we discuss booster shots in the U.S., millions of people in low-income countries have yet to even receive their first doses. Many countries in Africa have under 1% of their populations vaccinated, according to the Bloomberg tracker. While the Biden administration has pledged to donate doses abroad, boosters take up airtime in expert discussions and in the media—including in this publication. Boosters distract from discussions of what it will take to vaccinate the world, which is our true way out of the pandemic.
COVID-19 Data Dispatch 