COVID-19 vaccine booster benefits ‘outweigh risks’ among immunocompromised
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Immunocompromised individuals have several justifiable concerns surrounding COVID-19. One of those concerns is that a two-dose vaccine schedule may not produce a sufficient antibody response to protect them from the virus.
But hope may be on the horizon. On July 12, Israel’s Ministry of Health began offering a third dose of the Pfizer vaccine to severely immunocompromised adults. This was quickly succeeded by the CDC’s recommendation for a third dose among those who were unable to produce the proper antibody response following the administration of the initial vaccine series.
Source: Cedars Sinai.
While statements from the FDA committee alleviated some of the confusion surrounding current qualifications for a booster dose (individuals aged 65 years and older, 18 through 64 years at high risk and 18 through 64 years with frequent institutional or occupational high-risk exposure) and voted against blanket recommendations, the difference between a third vaccine dose and a booster dose remains obscure to many.
Data of any kind surrounding a three-dose COVID-19 vaccine regimen are limited. As experts begin to investigate the feasibility and utility of a third dose, there are a handful of points to consider.
One is that there has been some evidence showing that being immunocompromised hinders the efficacy of SARS-CoV-2 messenger RNA (mRNA) vaccines, even after the second dose. Another is the question of whether a third dose would, in fact, elevate a previously insufficient antibody response.
Further, the type of immunosuppressive drugs a patient is receiving may play a role in antibody response, though many researchers have stated the benefits of a third dose generally outweigh the risks.
“Protection after two doses of mRNA vaccines is not as robust in certain immune compromised individuals, hence the recent CDC recommendation that these patients receive a third vaccine dose. There are also many kinds of ‘immune-compromising conditions,’ including active cancer treatment, receipt of solid organ transplantation, advanced HIV and treatment with medications that modify the immune system. Immune responses to vaccines may differ even across these immune compromised groups,” Gil Y. Melmed, MD, MS, professor of medicine and director of clinical trials and inflammatory bowel disease at Cedars-Sinai, told Healio Gastroenterology. “While immune responses to vaccination against COVID-19 may be lower in some of these populations, vaccines still provide at least some protection from infection.”
Finally, the misinformation and stigma around why a third dose is needed in certain scenarios is cause for mental health concern. How clinicians advise patients about the vaccine — and the need for an extra shot in general — is of utmost importance.
As clinicians who deal with immunocompromised patients wrestle with these questions, an early clinical trial may point the way toward a three-dose COVID-19 vaccine schedule.
First of Many Studies
In their observational study published in JAMA, Brian J. Boyarsky, MD, PhD, general surgery resident at Johns Hopkins University School of Medicine in Baltimore, and colleagues assessed antibody responses to mRNA COVID-19 vaccines in a cohort of 658 transplant recipients. Eligible participants had completed the vaccine series between Dec. 16, 2020, and March 13, and were followed through April 13.
Results showed that just 15% of participants produced a measurable antibody response after the first and second doses. Moreover, 46% demonstrated no antibody response after the first or second doses, whereas 39% had no antibody response after the first dose but showed some antibody response after the second.
“We have seen lots of small articles like this at this point,” Kevin L. Winthrop, MD, MPH, director of the Center for Infectious Disease Studies at Oregon Health & Science University, told Healio Gastroenterology. “There is no question that certain subgroups of immunocompromised patients have decreased responses. However, it is not yet clear if this is clinically meaningful. For those that mount no measurable humoral response, I think it is likely they are less protected.”
Cassandra Calabrese, DO, director of the Rheumatology-Infectious Disease Clinic and training program at the Cleveland Clinic, also believes that a third dose is likely in the cards for immunocompromised populations. However, more questions than answers remain.
“This paper has demonstrated that the second dose is still not 100% effective,” she said.
At the Advisory Committee on Immunization Practices July 2021 meeting, Sara Oliver, MD, MSPH, epidemic intelligence service officer at the CDC, presented evidence comparing the third mRNA COVID-19 vaccine dose among immunosuppressed people with a seropositive response. Among solid organ transplant recipients and patients on hemodialysis who had no detectable antibody response to the initial mRNA vaccine series, 33% to 50% developed an antibody response following an additional vaccine dose. Further, among smaller studies the reactogenicity of the third dose was similar to prior doses.
Insufficient Immune Response Factors
“Patients take immunosuppressive medication to dampen down their immune system to treat underlying autoimmune disease or to prevent organ rejection after transplantation,” Julie J. Paik, MD, MHS, assistant professor of medicine in the division of rheumatology at The Johns Hopkins University School of Medicine, said in an interview. “Immunosuppressive medication can reduce the immune system’s ability to respond to vaccines or stop the immune system from ramping up after vaccination.”
It is known that patients taking certain immunosuppressive agents — such as methotrexate and rituximab (Rituxan, Genentech) — can have a limited response to pneumonia and influenza vaccines, according to Paik.
“We are now learning that certain immunosuppressive therapies are also hampering the immune response to SARS-CoV-2 vaccination,” she said.
Researchers such as Paik and Caoilfhionn M. Connolly, MD, MSc, a clinical fellow in the division of rheumatology at The Johns Hopkins Hospital, are beginning to see patterns in COVID-19 vaccine responses.
“We have also learned that different types of immunosuppressive therapies limit the immune response to SARS-CoV-2 vaccination more than others,” Connolly said.
Similarly, in IBD, therapies are predominantly immune-based, modifying and sometimes suppressive which has increased patient concern regarding the risk for severe infection outcomes and vaccine response, David T. Rubin, MD, FACG, chief of gastroenterology, hepatology and nutrition and co-director of the Digestive Diseases Center at The University of Chicago, said at the ACG Virtual Grand Rounds 2021.
Overall, information gleaned from studies demonstrated patients with IBD do not experience an increased risk for infection, hospitalization or death; though, these patients are not at a decreased risk either, Rubin added. Comorbidities such as age and weight continue to play a role in immunosuppressed and immunocompetent patients alike.
Recent study data supported initial analyses that, while steroids associated with an increased risk for severe COVID-19 as measured by hospitalization, mechanical ventilation use and death, biologic therapy (ie, anti-tumor necrosis factor) associated with a decreased risk for severe infection and might actually be protective. Rubin noted vaccinated patients taking corticosteroids should be counseled on vaccine efficacy.
In general, antibody response rates following two doses of the mRNA COVID-19 vaccines as labeled by the FDA among patients with IBD have been similar to the general population as seen in the PREVENT-COVID study. However, the CORALE-IBD study demonstrated significant reduction in antibody titers over time suggesting the need for an eventual booster dose.
Booster vs. Third Dose
Distinguishing between the need for a booster shot vs. a third vaccine dose is an important topic to consider as it has caused confusion regarding whether the two are interchangeable or not.
“Third doses of vaccine are intended for immune compromised individuals to bolster immune response in patients who might not have had optimal response after a full regimen of a two-dose vaccine; these are recommended at least 28 days after the second dose,” Melmed said. “Boosters, meanwhile, are intended to bolster vaccine-induced immunity that has lessened over time and is currently relevant for those at increased risk for exposure or complications of the infection beginning 6 months after a second mRNA vaccine dose.”
While the CDC has recommended the third dose based on data showing increased antibody responses to an additional dose among those who did not respond to the two-dose vaccine series (immunocompromised, older individuals, etc.), the booster dose was recommended to combat the emergence of increased contagious virus variants and waning immunity over time.
On the topic of risks vs. benefits of a third vaccine dose, Connolly said, “Potential benefits of a third dose include augmentation of the antibody response, thereby increasing the efficacy of the vaccine. This can extend the immune response and help overcome viral immune-evasion variants.”
Adverse events, ranging from local side effects such as pain, swelling or redness to systemic side effects such as fatigue, myalgia and fever, are the most serious potential drawbacks, according to Connolly. However, she stressed that the safety profile of available vaccine products and series “have been very encouraging.”
“I would point out that the health risks associated with COVID-19 infection among those not receiving full vaccination far outweigh vaccine-related risks,” Melmed added.
Alleviating Patient Concerns
While a third dose seems like a self-evident choice for patients in immunocompromised groups, Paik keeps the discussion grounded in reality.
“We discuss that there is limited data on a third dose in patients on immunosuppression,” she said. “All data currently relates to patients with solid organ transplants on immunosuppression.”
Among patients with IBD specifically, most have responded to the initial vaccine series; Freddy Caldera, DO, MS, of the division of gastroenterology and hepatology at the University of Wisconsin School of Medicine and Public Health, told Healio Gastroenterology it is important to ensure patients are clear on additional vaccine dose recommendations.
“If you have IBD and you’re told to get an extra dose, you’re perceiving that you are not immune and that the vaccine doesn’t work, which is not what studies are showing,” Caldera said. “What I am telling my patients is the initial studies show the vast majority of people mount an antibody response; the CDC recommendation is based on this evidence and you qualify for an extra dose now which, in a way, could be an early booster.”
Caldera noted there is no harm in an extra dose, but there is harm in panic caused by improper explanation.
“We’ve seen a lot of mental health issues where people then perceive that they’re not protected and that they’re thinking, ‘Okay, do I have to social distance again? Do I have to do everything else again?’” Caldera added. “I just want to make sure that it’s clear to the providers when they’re recommending an extra dose, or they’re saying, ‘This is what the Crohn’s and Colitis Foundation wants,’ what it’s based in, because a good percentage of people don’t know why.”
According to Calabrese, while some patients are waiting for data to emerge regarding the safety of additional dosing, it is imperative to keep an eye on the big picture.
“The important message here is that immunocompromised persons need to maintain caution, especially now with the spread of the delta variant,” she said. “We are seeing breakthrough infections even in immunocompetent vaccinated persons.”
It is for this reason that the ethical debate about a third dose in the immunocompromised vs. any dose in the immunocompetent is so critical. There are no easy answers. That said, Connolly stressed that striking the right balance is essential to achieving the overall goal of eliminating COVID-19.
“Our focus should be on talking with everyone who is unvaccinated,” Caldera concluded. “The problem is not delta; the problem is going to be what happens after delta if we keep having this. It’s not even about vaccinating the U.S.; it’s about vaccinating the world.”
- References:
- American College of Gastroenterology: Special COVID-19 vaccine update. https://webfiles.gi.org/links/virtgrandround/ACG_COVID-19_Vaccine_Update.pdf. Accessed: Sept. 24, 2021.
- Botwin GJ, et al. Am J Gastroenterol. 2021;doi:10.14309/ajg.0000000000001342.
- Boyarsky BJ, et al. JAMA. 2021; doi:10.1001/jama.2021.7489.
- Data and clinical considerations for additional doses in immunocompromised people. www.cdc.gov/vaccines/acip/meetings/downloads/slides-2021-07/07-COVID-Oliver-508.pdf. Accessed: Sept. 24, 2021.
- Derikx LAAP, et al. J Crohns Colitis. 2021;doi:10.1093/ecco-jcc/jjaa215.
- FDA authorized booster dose of Pfizer-BioNTech COVID-19 vaccine for certain populations. www.fda.gov/news-events/press-announcements/fda-authorizes-booster-dose-pfizer-biontech-covid-19-vaccine-certain-populations. Accessed: Sept. 24, 2021.
- Interim clinical considerations for use of covid-19 vaccines currently approved or authorized in the United States. www.cdc.gov/vaccines/covid-19/clinical-considerations/covid-19-vaccines-us.html#considerations-covid19-vax-immunocopromised. Accessed: November 02, 2021.
- Kamar N, et al. N Engl J Med. 2021;doi:10.1056/NEJMc2108861.
- Kappelman et al. Gastroenterology. 2021;doi:10.1053/j.gastro.2021.06.016.
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- Longlune N, et al. Nephrol Dial Transplant. 2021;doi:10.1093/ndt/gfab193.
- Maxime E, et al. medRxiv. 2021;doi:10.1101/2021.07.02.21259913.
- Melmed GY, et al. Ann Intern Med. 2021;doi:10.7326/M21-2483.
- Parekh R, et al. Dig Dis Sci. 2021;doi:10.1007/s10620-021-07104-0.
- Pozdnyakova V, et al. Gastroenterology. 2021;doi:10.1053/j.gastro.2021.08.014.
- Werbel WA, et al. Ann Intern Med. 2021;doi:10.7326/L21-0282.
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