Breakthrough COVID Studies Lend Support to Use of New Boosters in Immunosuppressed Patients

Tara Haelle

October 04, 2022

People with immune-mediated inflammatory diseases who are taking immunosuppressants don't mount as strong of an immune defense against the Omicron variant as they did against the original SARS-CoV-2 wild-type virus, according to two studies published in Annals of the Rheumatic Diseases. One of the studies further showed that vaccinated individuals taking immunosuppressants have poorer cross-neutralizing responses to Omicron than do healthy vaccinated individuals, even after three doses of the COVID-19 mRNA vaccines.

"We carefully suggest that if Omicron-specific vaccination can be administered, it may be an effective way to reduce the risk of breakthrough infections in patients with autoimmune rheumatic disease," Sang Tae Choi, MD, PhD, of the University College of Medicine in Seoul, Korea, and one of the authors of the study on cross-neutralizing protection, told Medscape Medical News. "However, further research is needed on Omicron-specific vaccine effectiveness in patients with immune dysfunctions. We believe that these study results can be of great benefit in determining the strategy of vaccination in the future."

The earlier study, published in July, examined the ability of COVID-19 vaccines to induce cross-reactive antibody responses against Omicron infections in patients with autoimmune rheumatic diseases (ARDs). The observational study involved 149 patients with ARDs and 94 healthcare workers as controls, all of whom provided blood samples a median 15 weeks after their second COVID vaccine dose or a median 8 weeks after their third dose. A little more than two thirds of the patients (68.5%) had received a third mRNA vaccine dose. None of the participants previously had COVID-19.

The researchers compared the rate of breakthrough infections with the Omicron variant to the neutralizing responses in patients' blood, specifically the cross-neutralizing antibody responses because the original mRNA vaccines targeted a different variant than Omicron. Breakthrough infections were assessed by survey questions.

"Our findings suggested that neither primary series vaccinations nor booster doses are sufficient to induce Omicron-neutralizing responses above the threshold in patients with ARDs, although responses were noticeably increased following the third dose of an mRNA vaccine," write Woo-Joong Kim, of the Chung-Ang University College of Medicine in Seoul, Korea, and his colleagues. "This impairment of cross-neutralization responses across most of our patients contrasts starkly with a potent elicitation of the Omicron-neutralizing responses after the third vaccination in healthy recipients."

The average neutralizing responses against the original SARS-CoV-2 strain were similar in both groups: 76% in patients with ARDs and 72% in healthcare workers after the second dose. The mean response after a third dose was 97% in healthcare workers and 88% in patients.

The average cross-neutralizing response against the Omicron variant was far lower, particularly in those with rheumatic disease: only 11.5%, which rose to 27% after the third dose. Only 39% of the patient sera showed neutralization of Omicron, even after the third dose. Meanwhile, the mean cross-neutralizing response in healthcare workers was 18% after the second dose and 50% after the third.

When the researchers compared seropositivity rates against the original virus to neutralizing responses against Omicron, the association between these was stronger in healthcare workers than in those with ARDs. In fact, among patients with ARDs who seroconverted, only 41% showed any response against Omicron. Among all the patients, most of those who didn't respond to Omicron (93.5%) had initially seroconverted.

The researchers also looked at the ability to neutralize Omicron on the basis of disease in those who received three doses of the vaccine. About half of those with lupus (52%) showed any neutralization against Omicron compared with 25% of those with rheumatoid arthritis, 37.5% of those with ankylosing spondylitis, 33% of those with Behçet snydrome, and all of those with adult-onset Still's disease.

The rate of breakthrough infections was lower in patients (19%) than in healthcare workers (33%). A similar pattern was seen in the more recent study, published on September 5. Researchers used data from a prospective cohort study in the Netherlands to examine incidence and severity of Omicron breakthrough infections in patients with immune-mediated inflammatory diseases. The researchers compared infection rates and severity among 1593 vaccinated patients with inflammatory disease who were taking immunosuppressants and 579 vaccinated controls (418 patients with inflammatory disease not on immunosuppressants and 161 healthy controls).

One in five patients with inflammatory disease (21%) were taking immunosuppressants that substantially impair antibodies, such as anti-CD20 therapy, S1P modulators, or mycophenolate mofetil combination therapy, and 48% of these patients seroconverted after primary vaccination compared with 96% of patients taking other immunosuppressants and 98% of controls.

Breakthrough infection rates were similar between the control group (31%) and those taking immunosuppressants (30%). Only three participants had severe disease requiring hospitalization: one control and two patients taking immunosuppressants.

"In both studies, the controls had similar or higher rates of breakthrough infections, compared with the immunosuppressed," noted Alfred Kim, MD, an assistant professor of medicine at Washington University, St Louis, Missouri, but he added, "one has to consider differences in mitigation strategies, such as masking, that may explain these findings." That is, patients taking immunosuppressants may be taking fewer risks in the community or have fewer potential exposures, especially in the Korean study, wherein the controls were healthcare workers.

A greater disparity in infections occurred when considering seroconversion rates. Breakthrough incidence was 38% among those taking immunosuppressants who did not seroconvert, compared with 29% among those who did. A similar trend was seen in breakthrough incidence between those taking strongly antibody-impairing immunosuppressants (36% breakthrough rate) and those taking other immunosuppressants (28%).

Among those taking immunosuppressants who seroconverted, a primary series of vaccination reduced the risk of a breakthrough infection by 29%. Protection became more robust with a booster or prior infection, both of which reduced breakthrough infection risk by 39% in those taking immunosuppressants who seroconverted.

"We demonstrate in patients with immune-mediated inflammatory diseases on immunosuppressants that additional vaccinations are associated with decreased risk of SARS-CoV-2 Omicron breakthrough infections," wrote Eileen W. Stalman, MD, PhD, of Amsterdam UMC in the Netherlands, and her colleagues.

Though neither study broke down immune response or breakthrough infection based on individual medications, Kim said that previous research allows one to extrapolate "that prior culprits of poor vaccine responses [such as B-cell depleting drugs, mycophenolate, and TNF [tumor necrosis factor] inhibitors will continue to bear the greatest burden in breakthrough infection, including Omicron."

Overall, he found the data from both studies relatively consistent with one another.

"Those on immunosuppression, particularly mechanisms that have been established as risk factors for poor vaccine responses, are at risk of breakthrough infection during the era of Omicron," Kim said.

The earlier study from Korea also found that "the median time between the third-dose vaccination and the date of confirmed breakthrough infection in patients with ARDs was significantly shorter compared with that in health care workers" at just 93 days in patients vs 122 days in healthcare workers. They postulated that this population's limited neutralization of Omicron explained this short-lived protection.

Most of the patients with breakthrough infections (74%) in that study showed no neutralization against Omicron, including the only two hospitalized patients, both of whom had strong responses against the original SARS-CoV-2 strain. The significant decline over time of neutralization against Omicron suggested "the potential for a substantial loss of the protection from breakthrough infection," the authors write.

"The third dose of an mRNA vaccine could improve the cross-neutralization of the SARS-CoV-2 Omicron variant in patients with autoimmune rheumatic disease [although] more than half of the patients failed to generate Omicron-neutralizing antibodies," Tae Choi told Medscape Medical News. "Our study sheds light on the relative deficiency of the Omicron-specific neutralizing responses in patients with autoimmune rheumatic disease and their anticipated vulnerability to breakthrough infection."

The message for clinicians, Kim said, is to "continue to urge our patients to maintain additional and boosting doses per guidance, use pre-exposure prophylaxis such as Evusheld, and continue other mitigation strategies as they have done."

The Dutch study was funded by The Netherlands Organization for Health Research and Development; the Korean study used no external funding.

The authors of the Korean study had no disclosures. The Dutch study's authors reported a wide range of disclosures involving more than a dozen pharmaceutical companies but not including Pfizer or Moderna. Dr Kim's industry disclosures include Alexion, ANI, AstraZeneca, Aurinia, Exagen, Foghorn Therapeutics, GlaxoSmithKline, Kypha, and Pfizer .

Ann Rheum Dis. Published online July 25, 2022. Full text

Ann Rheum Dis. Published online September 5, 2022. Full text

Tara Haelle is a health/science journalist based in Dallas. Follow her at @tarahaelle

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