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This much is clear: Some people in the United States with medical conditions that have compromised their immune systems are now eligible for a third dose of Covid-19 vaccine.

But the new policy from U.S. health officials, announced late last week, 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.

Some experts believe the new policy may also have created a loophole big enough to allow easier access to a third dose for non-immunocompromised people who are trying to find ways to get one.

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“I worry very much that this is going to lead to vaccination chaos,” Michael Osterholm, director of the University of Minnesota’s 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 A study released as a preprint last month, meaning it has not been peer-reviewed, showed that a substantial portion of vaccinated people who ended up in hospital for Covid were immunocompromised.

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Here’s what we know about the new policy, the people it is meant to benefit, the questions it doesn’t answer, and the concerns about how it could be abused.

The semantics of it all

There’s 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 world’s poor are still awaiting initial doses.

This is not that.

The new U.S. 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 isn’t a booster shot, like the jab we’re 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 that 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 ages 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 authorized for people under the age of 18.) Immunocompromised people 18 and older who got two shots of Moderna should get a third shot of Moderna. The Centers for Disease Control and Prevention 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 doesn’t apply to people whose immune systems are mildly impaired by chronic illnesses like diabetes or heart disease. But the Food and Drug Administration’s language about who qualifies isn’t 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 immunocompromise.”

The CDC spells it out in more detail. Those eligible are people who are receiving active cancer treatment for tumors or cancers of the blood; have received an organ transplant and are taking medicine to suppress the immune system; received a stem cell transplant within the last 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 CDC’s Advisory Committee on Immunization Practices on Friday, Patsy Stinchfield, director of the National Association of Pediatric Nurse Practitioners, said her members will now 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 may be taking.

“Immunosuppressive therapies and severe primary immune deficiencies are too broad of terms 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, persons with heart disease. Those kinds of chronic medical conditions are not the intent here,” Amanda Cohn, a CDC 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, they’re 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 need 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 won’t 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 U.S., 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 don’t need a prescription or a letter from their doctor. “It will be a patient’s 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 it’s 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 to 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 can’t craft guidance based on what is likely. It needs evidence. And currently there is none.

At the ACIP meeting, Cohn, who serves as executive secretary of the committee, said few immunocompromised people would have received the J&J vaccine. It wasn’t put into use in this country until early March, and there wasn’t 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 FDA’s 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 haven’t yet been vaccinated to seek out mRNA vaccines, rather than the J&J one, which is manufactured by the company’s Janssen division.

Both are authorized for immunocompromised people, said CDC’s 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.”

The free-for-all

It’s widely known that lots of Americans aren’t waiting for the government to decide whether to authorize 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 don’t want to wait for the government to decide.

The new third dose policy could make it easier to do it, because it’s going to be based on an honor system. Jason Goldman, who represents the American College of Physicians on the ACIP, wondered how this will play out.

“Are people going to game the system, who just want a third dose?” he asked. “I’m already seeing it with patients, after the FDA’s 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 state’s 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 are now gone, said Osterholm, who said he’s heard first-hand from people who tell him “I’m 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.”

This article has been updated to include information on how immunocompromised people can access a third dose of vaccine.

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