If you’re confused about coronavirus vaccination, you’re not alone. Blame the confusion on the coronavirus itself.

With SARS-CoV-2 mutations – particularly the mutations that give rise to the wildly contagious omicron variant – have come scientific studies that have fed into changing vaccination guidance. Let’s cut through the noise and make sense of COVID-19 vaccinations and boosters, starting with those who are immunocompromised or have a weakened immune system.

First, to be clear, “immunocompromised” does not apply to those whose immune systems are undergoing inevitable age-based decline. Dr. Thomas Campbell, a University of Colorado School of Medicine and UCHealth virologist and infectious disease specialist, says there’s a sliding scale to immune-system deficiency.

“It’s a continuum. On one hand, there are people who are severely immunocompromised – those with recent bone-marrow or heart or lung transplants,” Campbell said. At the other end, there are changes in the immune system associated with age.

The U.S. Centers for Disease Control and Prevention’s definition of “immunocompromised” with respect to the coronavirus is for now strict. It includes those with immune systems pharmaceutically throttled after organ transplants, those in active cancer treatment, stem-cell transplant patients, those with immunodeficiency syndromes or advanced HIV infections, or patients on high-dose corticosteroids or other immune-suppressing drugs. Such patients have been especially vulnerable to severe disease and death since the beginning of the pandemic.

What does the CDC say about vaccinations and boosters?

For those immunocompromised and older than 12, the CDC guidance with respect to the Moderna and Pfizer vaccines that more than 90% of the Colorado population has received is as follows:

• The primary vaccine series – that is, what is now considered a basic level of vaccination – is three shots from Moderna (ages 18+) and Pfizer (ages 5+). The third shot comes four weeks after the second.
• On Feb. 11, the CDC shortened the waiting time between the third shot and the fourth-shot booster to three months. (Those ages 5 to 11 don’t get the fourth shot.)
• Note that, if the first two vaccine doses were Moderna, the third dose should also be Moderna (same story with Pfizer). The fourth shot – the booster, can be either Pfizer or Moderna.
• In the case of Moderna, the third-shot dosage should be the standard primary-series dosage of 100 micrograms of mRNA – not the lower 50-microgram dose of the Moderna booster. (The Pfizer vaccine’s 30-microgram doses are uniform anyway.)

This last point is subtle, says Dr. Mindy Lam, a CU School of Medicine and UCHealth internal medicine physician.

“Among patients who go to outside pharmacies for vaccination, there’s some confusion about that third dose,” Lam said. “I write it down and ask them to tell their pharmacy that it’s a third full dose and not a booster.”

For those who are immunocompromised but got the single-dose Johnson & Johnson vaccine, the CDC recommends a dose of mRNA vaccine 28 days after the J&J dose and then an mRNA booster dose at least two months after the mRNA  dose (learn more detail about J&J guidelines).

Dr. Tomer Mark, a CU School of Medicine and UCHealth blood cancer specialist, says vaccination is particularly important for his immunocompromised patients.

“I’m absolutely encouraging my patients to get third and fourth doses,” he said. “I think everybody agrees that immunocompromised patients do not have the same vaccine response as people with intact immune systems do, and even if they’ve had natural COVID-19 infections, they don’t produce antibodies the same way.”

Lam says anecdotal evidence backs emerging data that immunocompromised patients who get a fourth dose fare better should a breakthrough infection occur.

“I think we’re seeing that people who have gotten boosted have less severe illness that’s more short-lived,” she said.

As well, Mark says, immunocompromised patients who take weeks or months to clear COVID-19 can incubate new coronavirus variants. Odds are that’s what happened with the omicron variant, which has 30 mutations on its spike protein alone.

“If these patients are infected, they can carry live virus for a long time and give it the opportunity to mutate,” Mark said.

Campbell adds that immunocompromised patients can also receive an antibody combination, Evusheld, to provide a protective boost beyond that of the four-shot vaccine regimen. The AstraZeneca infusion received U.S. Food and Drug Administration emergency-use authorization as a coronavirus pre-exposure prophylaxis in December 2021, and UCHealth has good supply of the drug.

Clear your confusion and get a boost

For the majority who enjoy healthy immune systems, the CDC’s guidance is simpler. Assuming an mRNA vaccine, those 12 and older should get the two-dose primary series and then a booster. The booster can be different than that of the primary series and should come five months after the second dose. Those initially vaccinated with the single-dose J&J vaccine should get a single mRNA booster two months after the J&J dose, for a total of two doses to be up to date.

Limited vaccine supplies early in the pandemic led to recommendations that vaccination lag a coronavirus infection by 90 days (natural immunity, the logic went, would be at least partially protective during that time). That has changed, Campbell says, and the CDC recommends, for the safety of others, only that you don’t get boosted while you’re still contagious.

“I’d say wait a minimum of 10 days after the onset of covid symptoms,” he said. “Natural immunity will give you protection from that infection, so there’s no reason to rush out and get the booster.”

As to whether those with age-related immune-system decline will be at some point be getting a fourth shot as is happening in Israel, Campbell says nobody knows yet. As the coronavirus becomes endemic, public health officials and policymakers must weigh the emergence of new coronavirus variants and the severity of the disease they cause, vaccine effectiveness over time, and other factors, he says. Among those factors are that vaccines “are not the only tool in our box,” Campbell says: Monoclonal antibodies and new antiviral therapies, if administered early in the course of COVID-19 infection, can sharply reduce disease duration and severity among the immunocompromised and the rest of us.

“So my advice to people at high risk is, if you’ve contracted COVID, don’t hesitate to contact your doctor and get a treatment that will prevent you from getting hospitalized,” he said.

And, he adds, if you aren’t among the roughly half of eligible Colorado residents who have gotten their third- or fourth-dose booster shot, now is the time.