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People with vasculitis may need at least three or four vaccinations for COVID-19 before they start to show an immune response against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, new research has suggested.

In a longitudinal retrospective study, serum antibody neutralization against the Omicron variant of the virus and its descendants was found to be “largely absent” after the first two doses of COVID-19 vaccine had been given to patients. But increasing neutralizing antibody titers were seen after both the third and fourth vaccine boosters had been administered.

Results also showed that the more recently people had been treated with the B-cell–depleting therapy rituximab, the lower the levels of immunogenicity that were achieved, and thus protection against SARS-CoV-2.

“Our results have significant implications for individuals treated with rituximab in the post-Omicron era, highlighting the value of additive boosters in affirming increasing protection in clinically vulnerable populations,” the team behind the work at the University of Cambridge in Cambridge, England, has reported in Science Advances.

Moreover, because the use of rituximab reduced the neutralization of not just wild-type (WT) Omicron but also the Omicron-descendant variants BA.1, BA.2, BA.4, and XBB, this highlights “the urgent need for additional adjunctive strategies to enhance vaccine-induced immunity as well as preferential access for such patients to updated vaccines using spike from now circulating Omicron lineages,” the team added.

Studying Humoral Responses to SARS-CoV-2 Vaccines

Corresponding author Ravindra K. Gupta, BMBCh, MA, MPH, PhD, told Medscape Medical News that studying humoral responses to SARS-CoV-2 vaccines in immunocompromised individuals such as those with vasculitis was important for two main reasons.

“It is really important at individual level for their own health, of course, but also because we know that variants of concern have often evolved and developed within patients and can then spread in wider populations,” he said.

Gupta, who is professor of clinical microbiology at the Cambridge Institute for Therapeutic Immunology & Infectious Disease, Cambridge, England, added: “We believe that the variants of concern that we're having to deal with right now, including Omicron, have come from such [immunocompromised] individuals.”

Omicron “was a big shift,” Gupta noted. “It had a lot of new mutations on it, so it was almost like a new strain of the virus,” he said. Few studies have looked at the longitudinal immunogenicity proffered by COVID vaccines in the post-Omicron era, particularly in those with vasculitis who are often treated with immunosuppressive drugs, including rituximab.

Two-Pronged Study Approach

For the study, a population of immunocompromised individuals diagnosed with vasculitis who had been treated with rituximab in the past 5 years was identified. Just over half (58%) had received adenovirus-based AZD1222/ChAdOx1 nCoV-19 (AstraZeneca-Oxford; AZN) and 37% BNT162b2 (Pfizer-BioNTech; mRNA) as their primary vaccines. Patients with antineutrophil cytoplasmic antibody–associated vasculitis comprised the majority of those who received rituximab (83%) compared with less than half of those who did not take rituximab (48%).

A two-pronged approach was taken with the researchers first measuring neutralizing antibody titers before and 30 days after four successive COVID vaccinations in a group of 32 individuals with available samples. They then performed a cross-sectional, case-control study in 95 individuals to look at neutralizing antibody titers and antibody-dependent cell-mediated cytotoxicity (ADCC) in individuals who had (n = 64) and had not (n = 31) been treated with rituximab in the past 5 years and had samples available after their third and fourth COVID vaccinations.

The first analysis was done to see how people were responding to vaccination over time. “That told us that there was a problem with the first two doses and that we got some response after doses three and four, but the response was uniformly quite poor against the new variants of concern,” Gupta said.

A human embryonic kidney cell model had been used to determine individuals’ neutralizing antibody titers in response to WT, BA.1, BA.2, BA.4, and XBB pseudotyped viruses. After the first and second COVID vaccinations, the geometric mean titer (GMT) against each variant barely increased from a baseline of 40.0. The greatest increases in GMT was seen with the WT virus, at 43.7, 90.7, 256.3, and 394.2, after the first, second, third and fourth doses, respectively. The lowest increases in GMT were seen with the XBB variant, with respective values of 40.0, 40.8, 45.7, and 53.9.

Incremental Benefit Offers Some ‘Reassurance’

Vasculitis specialist Rona Smith, MA, MB BChir, MD, who was one of the authors of the paper, told Medscape Medical News separately that the results showed there was “an incremental benefit of having COVID vaccinations,” which “offers a little bit of reassurance” that there can be an immune response in people with vasculitis.

Although results of the cross-sectional study showed that there was a significant dampening effect of rituximab treatment on the immune response, “I don't think it's an isolated effect in our [vasculitis] patients,” Smith suggested, adding the results were “probably still relevant to patients who receive routine dosing of rituximab for other conditions.”

Neutralizing antibody titers were consistently lower among individuals who had been treated with rituximab vs those who had not, with treatment in the past 18 months found to significantly impair immunogenicity.

The ADCC response was better preserved than the neutralizing antibody response, Gupta said, although it was still significantly lower in the rituximab-treated than in the non-rituximab–treated patients.

When to Vaccinate in Vasculitis?

Regarding when to give vaccines to people with vasculitis, Smith said: “Current recommendations are that patients should receive any vaccines that they're offered routinely, whether that be COVID vaccines, flu vaccines, pneumococcal vaccines.”

As for the timing of those vaccinations, she observed that the current thinking was that vaccinations should “ideally be at least 1 month before a rituximab treatment, and ideally 3-4 [months] after their last dose. However, as many patients are on a 6-month dosing cycle, it can be difficult for some of them to find a suitable time window to have the COVID vaccine when it is offered.”

Additional precautions, such as wearing masks in crowded places and avoiding visits to acutely unwell friends or relatives, may still be prudent, Smith acknowledged, but he was clear that people should not be locking themselves away as they did during the COVID-19 pandemic.

When advising patients, “our general recommendation is that it is better to have a vaccine than not, but we can't guarantee how well you will respond to it, but some response is better than none,” Smith said.

The study was independently supported. Gupta had no relevant financial relationships to disclose. Smith was a co-author of the paper and has received research grant funding from Union Therapeutics, GlaxoSmithKline/Vir Biotechnology, Addenbrooke’s Charitable Trust, and Vasculitis UK. Another co-author reported receiving research grants from CSL Vifor, Roche, and GlaxoSmithKline and advisory board, consultancy, and lecture fees from Roche and CSL Vifor.

Sara Freeman is a freelance medical reporter based in London, England. She has written for Medscape Medical News and other specialist medical news outlets for many years and has a particular interest in providing news coverage and other reportage from medical conferences.