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Although 2 doses of some COVID-19 vaccines offer protection, immunocompromised people may need extra measures for higher effectiveness. Fly View Productions/Getty Images
  • A new study shows that people with suppressed immune systems do not have enough protection from the standard two-dose regimen of COVID-19 vaccines.
  • The data suggests that vaccine effectiveness against COVID-19 illness and hospitalization may be lower among immunocompromised people.
  • The rate of effectiveness also varies considerably among different patient subgroups, with organ transplant recipients having lower protection.
  • The study supports current CDC guidance saying those who are moderate to severely immunocompromised should receive a third dose of mRNA vaccines.

There are many studies about the effectiveness of COVID-19 vaccines in people with healthy immune systems, but research on people with various immune-suppressing conditions is still limited.

Now, new research is helping break down how protected people can be if they’re vaccinated — even if they’re immunocompromised.

A new study, published last month in the CDC’s Morbidity and Mortality Weekly Report, found that people with compromised immune systems were likely to show reduced immune responses to COVID-19 vaccines, and two doses did not offer as much protection as they did for adults with healthy immune systems.

But they were still more protected than if they had not been vaccinated at all.

The research collected data from nine U.S. states via the VISION Network and analyzed 89,000 COVID-19-related hospitalizations between January and September 2021.

Scientists found that 2 doses of the mRNA vaccines were 77 percent effective against hospitalizations in immunocompromised individuals, regardless of age. In comparison, this figure was 90 percent for people with healthy immune systems (called immunocompetent in the CDC study).

The findings show evidence that immunocompromised adults were less protected from severe disease.

Stefan Siebert, PhD, professor of inflammation medicine and rheumatology at the University of Glasgow, said the results were in line with expectations.

“The main conclusion is that the [immunocompromised] weren’t quite as protected [against COVID-19], according to the way they defined vaccine efficacy,” he told Healthline. “But what they found is that the vaccines worked, but not quite as well for immunocompromised.”

He said it was reassuring that the number of vaccinated people who tested positive for SARS-CoV-2 was low. It was around 3.8 percent for vaccinated people, whether they were immunocompromised or not.

The study supported CDC guidance, which says two doses are not enough for people with suppressed immune systems.

Dr. David Hirschwerk, an infectious disease specialist at Northwell Health in New York, said the study was one of many reports that reiterate the importance for immunocompromised patients to receive a third dose of the COVID-19 mRNA vaccines.

“The vaccines are safe and effective overall after two doses, but particularly for those with compromised immune systems, the value of a third dose amplifies the benefit greatly,” he said.

Being immunocompromised means a person has a medical condition or is undergoing treatment that suppresses the normal functioning of their immune system.

There are two types of immunosuppression. People may have primary immunodeficiencies from birth or secondary immunodeficiencies, which happen later in life. HIV, diabetes, and leukemia are in the latter category.

Medical treatment like chemotherapy and oral steroids can also cause someone to develop a suppressed immune system. People with rheumatic and inflammatory conditions like arthritis, lupus, or Crohn’s disease who take drugs that suppress their immune system, cancer patients, or organ transplant patients are considered within this group.

These conditions or drugs may affect the performance of B-cells and T-cells, which are the building blocks of our immune response.

Hence, immunocompromised people might fail to mount a robust response to COVID-19 vaccines.

This means that people with suppressed immune systems won’t produce the necessary amount or type of antibodies to fight off SARS-CoV-2. Such people are more likely to fall sicker with COVID-19, be hospitalized, and have fatal outcomes from the disease.

“These patients are [not only] at an increased risk of COVID-19 because of their condition, [but] because of the immune suppression, they can’t quite mount that immune response needed for full protection either,” Siebert said.

The researchers discovered that the vaccines’ effectiveness was lower among certain immunocompromised subgroups, namely solid organ and stem cell transplant recipients.

The study said they likely experienced an attenuated immune response, lowering their protection to 59 percent.

Meanwhile, among all the immunocompromised subgroups analyzed, vaccine effectiveness was highest at 81 percent for people with rheumatic or inflammatory disorders.

The rate was 74 percent for blood cancer patients.

Certain drugs, like steroids or B-cell inhibitors, for example, can negatively affect patients’ immune responses to vaccination.

Siebert said the type or frequency of medication these patients take could also affect their protection level.

The CDC study echoes previous findings from other trials and highlights the need for further treatment or preventive measures in immunocompromised groups.

A study conducted by King’s College London found that almost 3 out of 5 blood cancer patients failed to mount an immune response against SARS-CoV-2 after receiving two doses of the Pfizer vaccine.

People with solid tumors also had a less robust response to vaccination compared with healthy individuals.

Antibody production also seems to be impaired in immunocompromised people.

A study showed that only 25 percent of kidney transplant patients had detectable antibodies against SARS-CoV-2 after two doses of the COVID-19 vaccines.

Antibody titers, even if detected in the blood, are also likely to be lower in the immunocompromised.

A recent study of patients on immunosuppressive therapy for chronic inflammatory diseases found that these people had significantly lower titers compared with healthy controls.

But Siebert pointed out that a third dose won’t be a cure-all.

“I think there will be some people, because of their condition or their treatments, no matter how many doses you give them, they will not be able to mount that sort of immune response, or [reach] that level of protection,” he said.

He added that although the study can’t definitively say whether the third primary dose is the right strategy for all immunocompromised populations, it does say that they need something more.

But a newer analysis by the CDC has quantified the benefits of a third dose for the immunosuppressed.

The study found that a third primary dose not only reduced the risk of hospitalization in people with weak immune systems, but it also increased vaccine effectiveness from 69 percent to 88 percent.

A third primary dose versus a booster

Booster doses of COVID-19 vaccines are half the dose of what’s originally administered, while a third primary dose is a full dose that aims to get immunocompromised individuals on the same level of protection as those who aren’t immunocompromised.

For example, the booster dose of the Pfizer-BioNTech vaccine is 30 micrograms (µg), while the Moderna is 50 µg — both half of their respective full doses.

“Immunocompromised individuals need the third (primary) dose, which is different from the ‘booster’ that other people are getting now,” said Dr. Margaret A. Liu, chair of the board of the International Society for Vaccines, professor of microbiology and immunology at the University of California, San Francisco, and a foreign adjunct professor at the Karolinska Institute in Stockholm, Sweden.

“The third primary dose is needed to get [the immunocompromised] to the same level as the [immunocompetent], and boosters to keep you at that same level,” Siebert added. “Boosters will keep them there once [protection] starts wearing down.”

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Some doctors may advise their immunocompromised patients to take a break from their medication a few weeks before or after their dose to aid the body in mounting an immune response.

But there’s no consensus or evidence showing the benefits of this or the correct timing.

“There isn’t evidence on [how to] balance disease and protection. We are sort of making decisions and gathering evidence and trying to act in real-time,” Siebert said.

He explained that a lot of these drugs have long half-lives, meaning they still may be in the blood or body 2 weeks after pausing.

“So, the rationale for stopping the drug that’s going to be around for 5 weeks for 2 weeks doesn’t make a lot of sense,” he said.

For some people, a pause of even a week can cause a flare-up, leading to more problems.

“I’ve had some people who have not had a flare for 20 years, so they might be more willing to reduce [or stop their current medication], whereas I’ve had some people whose disease is really active still and hard to control, and even a [week’s break] for them could be a disaster,” Siebert said.

He stressed the importance of individual decision-making and acting on a case-by-case basis.

“The reason there isn’t consensus is that one of the things that have consistently come out [of research] is that having active disease increases your risk of [more severe COVID-19],” he said.

“[If you stop,] not only do you flare up, which seems to be bad in itself, but also you’re more likely to get steroids and other rescue treatments,” he added, highlighting the complexity of the decision.

Liu also reiterated that studies so far have not specifically been able to show any particular protocol to follow with regard to medication before or after vaccination, “except for the main point that [these] patients need a third dose.”

Some drugs may hinder COVID-19 vaccination effectiveness

Siebert said the current U.S. guidelines suggest stopping the chemotherapy drug methotrexate, for example, 2 weeks before vaccination. This is largely based on data from influenza, which showed that a few weeks’ break prior to vaccination aided the immune response.

The British Society for Rheumatology, on the other hand, recommends that patients continue using their regular medication.

“If you are on a regular weekly drug or daily drug, the general feeling is don’t stop it. There are always exceptions. But try and avoid steroids around the time of your vaccine.”
— Dr. Stefan Siebert

Although the study comprised a more limited cohort, and the median age of patients was over 65 years old, Hirschwerk said there’s “ample data that speaks to the value of a third dose in younger immunosuppressed patients — particularly those receiving B-cell inhibiting drugs.”

Siebert advised immunocompromised people to limit the time they spend in indoor settings and crowded places as much as possible.

“The data for indoors, and a lack of ventilation, is still massive,” he said. “I’m not as worried about my patients when they are [outdoors] in the open or in smaller groups.”

On the topic of vaccines, he recommended those immunocompromised to get their third primary vaccine dose unless there’s a medical reason not to have it.

“Then expect to get a booster 6 months after that,” he said. “Try to have common sense in an area with a high prevalence of COVID-19. The safety of social distancing [and] wearing masks are still going to be key,” he said.

He added that the vaccination status of the people around you will also be a factor in ensuring you’re protected.

Liu agreed.

“They should be in consultation with their doctor to get the third dose if they already haven’t. They should be careful about their exposures, i.e., particularly with [unvaccinated] people. If they are gathering with people, it still would be best to be outside if possible, and people in their group could test themselves, since even immunized people can get infected and can shed virus when asymptomatic.”
— Dr. Margaret A. Liu

“It is all about minimizing risk while trying to still live life,” Liu said. “Masks and social distancing are still important.”