Moderately to severely immunocompromised Americans who received mRNA vaccines for COVID-19 should receive an additional dose, said the US Centre for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP).
In a unanimous 11-0 vote, the ACIP recommended an additional dose of the Pfizer (ages 12 and up) or Moderna vaccine (ages 18 and up) after a primary series in immunocompromised people, under the conditions of the FDA's emergency use authorisation (EUA).
FDA authorised an additional dose for this population in amendments to the EUAs for the two companies' mRNA vaccines late on Thursday.
This additional dose should be the same type of vaccine as the mRNA primary series, though an alternative mRNA product can be used if there are supply issues. It should also be given at least 28 days after the primary series, CDC staff said in proposed clinical considerations documents.
In addition to solid-organ transplant recipients, CDC staff presented a potential list of other moderate to severe immunocompromising conditions that could qualify for an additional dose under the EUAs:
* Active treatment for solid-tumour and haematologic malignancies
* Receipt of chimeric antigen receptor (CAR) T-cell therapy or stem cell transplant (within two years of transplant or immunosuppression therapy)
* Moderate or severe primary immunodeficiency (e.g., DiGeorge, Wiskott-Aldrich syndromes)
* Advanced or untreated HIV infection
* Active treatment with high-dose corticosteroids (i.e., ≥20 mg prednisone or equivalent per day), alkylating agents, antimetabolites, transplant-related immunosuppressive drugs, cancer chemotherapeutic agents classified as severely immunosuppressive, tumour necrosis factor (TNF) blockers, and other biologic agents that are immunosuppressive or immunomodulatory
Patients will self-attest if they have these conditions, and this will not require "medical sign-off" from any clinician or prescriber, CDC staff said.
ACIP executive secretary Dr Amanda Cohn, of the CDC, said the aim of the EUA was to limit additional doses to individuals considered to have moderate to severe immunocompromising conditions, and that chronic health conditions, such as patients living in long-term care facilities or patients with diabetes or heart conditions, "is not the intent”.
Indeed, the American Medical Association (AMA) stressed that this EUA was for a "limited population”.
"Given that CDC data shows some immunocompromised patients lack the antibodies needed to fight COVID-19 infection, adding an additional dose to the primary series for this population can help protect them from unnecessary hospitalisations and deaths," said AMA president Dr Gerald Harmon.
CDC staff also warned against using serologic testing or cellular immune testing to guide clinical care, noting that no antibody tests are FDA- approved for the purpose of testing post-vaccination antibody levels.
Dr Peter Marks, director of the FDA's Center for Biologics Evaluation and Research, characterised the immunocompromised as a "heterogeneous group" in how they respond to COVID-19 vaccine, and cautioned that this additional dose could be "moderately effective at creating antibody titers".
However, CDC staff noted that these recommendations do not apply to immunocompromised individuals who received Johnson & Johnson as their primary vaccine, "due to insufficient data". MedPage Today noted that CDC and FDA are currently engaged in additional research about this vaccine and expect to report back shortly.
"We had to do what we're doing with the data we had in hand," Marks said, adding that this is a solution for "a large majority of immunocompromised individuals" and the agency hopes to "have a solution for the remainder in the not-too-distant future”.
The Infectious Diseases Society of America (IDSA) applauded the ACIP's decision.
"While data on the use of a third dose of COVID-19 vaccine in immunocompromised patients are limited, there is sufficient evidence supporting its use for specific patient populations," said IDSA president-elect Daniel McQuillen, MD. "IDSA calls for more research to continually inform optimal vaccination strategies for all immunocompromised patients."
In fact, CDC staff made the distinction between a third dose for immunocompromised patients and so-called "booster doses," meaning a dose for fully vaccinated patients when an initial sufficient immune response has waned over time.
For populations including residents of long-term care facilities, adults 65 and older, and healthcare providers, ACIP called for more data.
"Better correlates of immunity are sorely needed," said incoming ACIP chair Dr Grace Lee of Stanford University in California. She said it would be "really helpful to understand the gaps in the data currently existing" and urged a "strong partnership" between manufacturers, FDA, and NIH to "better define what correlates of immunity are".
The fine print: understanding the new policy authorising extra Covid vaccine doses for the immunocompromised
Helen Branswell in Stat News writes that while some people in the US with medical conditions that have compromised their immune systems are now eligible for a third dose of COVID-19 vaccine, the new policy from health officials came together in a hurry. It addresses some questions but leaves a number unanswered, in some cases because there are no data on which to base a decision, she says.
Some experts believe it may also have created a loophole big enough to allow easier access to a third dose for non-immunocompromised people trying to find ways to get one.
“I worry this is going to lead to vaccination chaos,” Michael Osterholm, director of the University of Minnesotaʼs Center for Infectious Diseases Research and Policy, told STAT.
Why the policy to begin with? Studies have shown that some people who are moderately to severely immunocompromised do not get much, if any protection, from the regular vaccine regimens. A study released as a preprint last month, meaning it has not been peer-reviewed, showed that a substantial portion of vaccinated people who ended up in hospital for COVID, were immunocompromised.
Hereʼs what we know about the new policy, the people it is meant to benefit, the questions it doesnʼt answer, and the concerns about how it could be abused.
The semantics of it all
Thereʼs a heated international debate going on right now about booster shots, which some vaccine makers insist will soon be needed, some rich countries are considering, and the World Health Organization opposes because most of the worldʼs poor are still awaiting initial doses.
This is not that. The new US policy says in effect: some immunocompromised people need three shots of vaccine instead of two when they are first vaccinated against COVID. For them, this isnʼt a booster shot, like the jab weʼre supposed to get every 10 years to refresh our immunity against tetanus. The third shot here is part of their primary series of COVID vaccinations.
Even the WHO agrees this is important. When Director-General Tedros Adhanom Ghebreyesus called for a moratorium on the administration of booster shots earlier this month, the agency was at pains to make clear it felt immunocompromised people should be exempted, because they need a third shot to get adequate protection.
The who of it all
For starters, this policy change only applies to immunocompromised people who were vaccinated with one of the messenger RNA vaccines — in other words the Pfizer-BioNTech or Moderna jabs. It is not applicable to the Johnson and Johnson vaccine. (More on that later.)
Only immunocompromised people aged 12 and older are eligible for a third dose — for any doses, actually. Immunocompromised people 12 and up who started with Pfizer should get a third shot of the Pfizer vaccine. (The Pfizer vaccine is the only one authorised for people under 18.) Immunocompromised people 18 and older who got two shots of Moderna should get a third shot of Moderna. The CDC says if the matching vaccine is not available, a dose of the other mRNA vaccine will do.
The policy is not meant to apply to all people who are considered immunocompromised. For example, it doesnʼt apply to people whose immune systems are mildly impaired by chronic illnesses like diabetes or heart disease. But the FDAʼs language about who qualifies isnʼt terribly clear.
The policy, the agency says, covers people who had a solid organ transplant or who have been diagnosed with conditions that are “considered to have an equivalent level of immunocompromised”.
The CDC spells it out in more detail. Those eligible are people who are receiving active cancer treatment for tumours or cancers of the blood; have received an organ transplant and are taking medicine to suppress the immune system; received stem cell transplant within the past two years or are taking medicine to suppress the immune system; were born with or developed moderate or severe primary immunodeficiency, such as DiGeorge syndrome or Wiskott-Aldrich syndrome; have advanced or untreated HIV infection; or are on active treatment with high-dose corticosteroids or other drugs that may suppress their immune responses.
At a meeting of the CDCʼs Advisory Committee on Immunization Practices on Friday, Patsy Stinchfield, director of the National Association of Pediatric Nurse Practitioners, said her members would start searching through electronic records trying to find people who qualify. But she asked for more help, appealing for precise guidance like diagnostic codes and specific drugs these people might be taking.
“The terms immunosuppressive therapies and severe primary immune deficiencies are too broad to be useful,” she said. One of the ways CDC tried to identify who was eligible was by spelling out who was not.
“The intent of this is to limit this to individuals who are considered … to be moderate or severe, and so, for instance, would not include long-term care facility residents or persons with diabetes or with heart disease. Those kinds of chronic medical conditions are not the intent here,” the CDC’s Amanda Cohn, who is a vaccines expert, told the committee.
The why of it all
As mentioned above, studies have shown some people who are immunocompromised respond poorly — or not at all — to the standard regimen of COVID vaccines. They are more likely to be a breakthrough case, developing COVID even if they are fully vaccinated. If they catch it, theyʼre more likely to develop severe COVID, more likely to transmit it to other people, and more likely to have prolonged infections, meaning they provide the SARS-CoV-2 virus opportunities to mutate in ways that increase the risk dangerous variants will emerge.
Several small studies have shown that immunocompromised people who got a third dose of vaccine had better antibody responses than those who only got two. But Keipp Talbot, a Vanderbilt University vaccine expert who is on the vaccine advisory committee, which goes by the acronym ACIP, warned that doctors needed to be clear with their immunocompromised patients that they still need to take other precautions to avoid COVID. A third dose will make then safer, Talbot said, but it wonʼt make them safe. They still have weaker responses to the vaccine than people whose immune systems are intact.
The when of it all
The third dose should be given 28 days or more after the second dose in the COVID jab series. Timing of the third dose will need to vary from case to case depending on the care an immunocompromised person is receiving, Kathleen Dooling, a CDC vaccine expert, told the committee.
Moderately and severely immunocompromised people were near the front of the vaccine rollout in the US, meaning many if not most would be several months out from their second jab at this point. So they could seek their third shot immediately.
The how of it all
From the sounds of the ACIP discussion, it is expected this will be a patient-instigated process. Health providers who treat eligible people will surely be advising them to seek out a third dose of an mRNA vaccine, as Stinchfield of the National Association of Pediatric Nurse Practitioners suggested. But many immunocompromised people may not need those prompts.
The plan is that they should not have to jump through hoops to get a third dose. They donʼt need a prescription or a letter from their doctor. “It will be a patientʼs attestation,” Cohn said. Nor will they need to take a test to see whether they need an additional shot. There are no FDA-approved antibody tests for use after vaccination, Dooling told the committee. And itʼs not yet established what a protected immune system looks like — what kinds and levels of antibodies are enough to fend off COVID infection.
So even though there are a lot of antibody tests, “interpretation of such would be very difficult and not particularly useful in a population recommendation”, Dooling said.
The what-about-J&J of it all
A small proportion of vaccinated Americans got the one-dose Johnson and Johnson vaccine — only about 13.5 million compared with nearly 64 million who are fully vaccinated with the Moderna vaccine and nearly 90 million vaccinated with the Pfizer-BioNTech jab.
The fact that the J&J vaccine is one dose rather than two would make you wonder whether immunocompromised people who got that vaccine are in greater need of an additional dose than people in similar straits who got two doses of mRNA vaccine.
Seems likely, right? Problem is, the FDA canʼt craft guidance based on what is likely. It needs evidence. And currently there is none. At the ACIP meeting, Cohn said few immunocompromised people would have received the J&J vaccine. It wasnʼt put into use in this country until early March, and there wasnʼt much of it available initially. Many immunocompromised people would have been vaccinated by the time the J&J vaccine became broadly available.
Peter Marks, head of the FDAʼs Center for Biologics Evaluation and Research, said at the ACIP meeting that the agency is working to come up with an answer about whether J&J vaccine recipients who are immunocompromised would benefit from another dose of vaccine. It hopes to have answers soon.
In the meantime, if there are immunocompromised people who received the one-dose vaccine, they are in regulatory limbo. Additionally, there was no decision taken to advise immunocompromised people, who havenʼt yet been vaccinated, to seek out mRNA vaccines, rather than the J&J one, which is manufactured by the companyʼs Janssen division.
Both are authorised for immunocompromised people, said the CDCʼs Dooling, who suggested “it will probably warrant a discussion between patient and vaccinator, whether the one dose of Janssen versus an initial primary series followed by an additional dose of an mRNA vaccine is the right choice.”
Itʼs widely known that lots of Americans arenʼt waiting for the government to decide whether to authorise booster doses for everyone who has been vaccinated. The CDC is aware that at least 1.1 million people have managed to get themselves another dose, ABC News reported recently.
Some of them are immunocompromised people, said ACIP member Camille Kotton, director of an organ transplant clinic at Massachusetts General Hospital. She knows because they tell her. “Because they are educated and savvy, they have gone out and figured out how to get themselves additional doses of vaccine.”
But some of them are not immunocompromised. They are just people who hear the debate about boosters, watch the spread of the highly transmissible Delta virus, and donʼt want to wait for the government to decide.
The new third dose policy could make it easier to do it, because itʼs going to be based on an honour system. Jason Goldman, who represents the American College of Physicians on the ACIP, wondered how this would play out.
“Are people going to game the system, who just want a third dose?” he asked. “Iʼm already seeing it with patients, after the FDAʼs announcement, calling my office, wanting me to give them a letter to justify that they need a third dose when they are not immunocompromised.”
Up until now there have been some guard rails around extra doses, Osterholm said. Insurance companies might refuse to cover the administration fee or a stateʼs COVID vaccine registry might tell a vaccinator not to give an additional dose, if people were seeking an extra dose in the state where they got their other doses.
The guard rails have now gone, said Osterholm, who said he has heard first-hand from people who tell him “Iʼm just going to go get it.”
He said he “can only imagine how many more people” will seek a third dose now, adding: “I could easily see several million people wanting to get that additional dose.”
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