Breakthrough COVID-19 infection in people with MS after SARS-CoV-2 vaccination: Should we still be concerned?

The COVID-19 outbreak is the first significant pandemic of the 21st century, causing global mortality and important public health consequences. Over the past 3 years, COVID-19 has dominated and influenced medical research, raising important concerns in patients affected by immune-mediated diseases or receiving immunosuppressant medication, like people with multiple sclerosis (PwMS). Just after the start of the pandemic in 2020, and prior to the availability of SARS-CoV-2 vaccinations, large international registries were set up to evaluate COVID-19 severity and outcomes in PwMS. What was discovered was that not the disease itself but the use of anti-CD20 monoclonal antibodies in PwMS has shown to increase the risk of a severe course including death after SARS-CoV-2 infection in PwMS. ¹ COVID-19 vaccination was recommended in all persons with MS (PwMS), including those treated with disease-modifying therapies, but the effectiveness of vaccination in terms of prevention of (severe) COVID-19 remains uncertain in some patient categories. After the introduction of various vaccinations in 2020/2021, an abundance of data emerged regarding SARS-CoV-2 immunity in PwMS.^2,3 Various studies showed severely impaired humoral responses in patients on anti-CD20 therapies and sphingosine-1 phosphate (S1P) receptor modulators.^4–6 These findings have led to special precautions including additional vaccinations and alterations of treatment dosing and/or frequency in PwMS on these therapies. But to what extent are these patients prone to severe COVID-19 breakthrough after vaccination? And are our additional measures to increase the immunological responses to vaccination justified? To answer these questions, it is of great importance to explore not only the immunological effect of vaccinations but also the clinical consequences to assess whether we still need to be concerned at this stage of the pandemic.

In this current issue of Multiple Sclerosis Journal, two separate research groups report on COVID-19 breakthrough after SARS-CoV-2 vaccination in PwMS. Wood et al. ⁷ evaluated COVID-19 infections in vaccinated PwMS participating in a previous seroprevalence study in the United Kingdom (involving five MS centers located in Cardiff, Newport, Nottingham, London, and Swansea). ⁸ In their longitudinal multicentre study, 647 PwMS were recruited, including 172 patients treated with ocrelizumab and 38 with fingolimod. In this cohort, 173 (27%) experienced at least one documented COVID-19 infection. Seronegativity was associated with an increased odds of COVID-19 breakthrough only after the second vaccination dose (odds ratio (OR) = 2.35; 95% confidence interval (CI) = 1.34–4.12), but not after the third dose (OR = 1.05; 95% CI = 0.57–1.91), p = 0.88). Furthermore, a twofold excess risk of COVID-19 in PwMS who remained seronegative after the first dose of vaccination against COVID-19 was found. However, 96% (119 out of 124) of all COVID-19 infections were mild, while only 4% were severe, requiring hospitalization and/or oxygenation (no fatal cases reported). Four out of five severe infections occurred between the second and third vaccination and one after the third vaccination. All severe infections occurred in patients who were seronegative following their last vaccination (four on ocrelizumab and one on alemtuzumab).

Another cohort of COVID-19 vaccine-breakthrough infections in this current issue is described by Klineova et al. ⁹ In this second prospective multicenter cohort study, PwMS and several autoimmune neuro-inflammatory disorders (neuromyelitis optica spectrum disorder (NMOSD), myelin oligodendrocyte glycoprotein–associated disease (MOGAD), neurosarcoidosis, or auto-immune encephalitis) were enrolled in five MS centers in the United States (New York City and surrounding vicinity). Treating neurologists inquired about COVID-19 infections during clinical contacts, recording timing, and severity after vaccination in relation to the type of disease-modifying therapy (DMT) used both at the time of vaccination and infection. Instead of relating the serostatus to the risk of breakthrough infections, Klineova et al. aimed to analyze the severity (hospitalization status) of COVID-19 breakthrough infections. Their cohort consisted of 211 patients with breakthrough infections, including 194 PwMS, 11 with NMOSD, and 6 with other autoimmune diseases (i.e. MOGAD). Of the 211 patients infected, 4 (1.9%) were asymptomatic and 22 (10.4%) required hospitalization (with two fatal outcomes). Interestingly, Klineova et al. divided the breakthrough infections requiring hospitalization in a pre-Omicron and during Omicron group. Before Omicron, 7/45 (15.5%) cases needed hospitalization (including one death), while during Omicron 15/166 (9%) patients required hospitalization (including one death). Of the 22 infections that led to hospitalization, 17 (77%) were treated with anti-CD20 therapies, 2 (9%) with S1P modulator treatment, 1 (5%) with teriflunomide, and 2 (9%) were untreated. The three infections that led to critical illness or death all occurred in the setting of anti-CD20 treatment.

The cohorts described in this issue are valuable because we need to assess the risk of severe COVID-19 outcomes in patients who are unable to achieve a good immunological response after vaccinations. Both cohorts add that although breakthrough COVID-19 infection occurs frequently, the number of severe COVID-19 cases is low. Furthermore, these cohorts show that most cases of severe COVID-19 occur in patients on anti-CD20 therapies. Therefore, especially in the presence of other risk factors (high age, comorbidity, and a known status of seronegativity after vaccination), we and our patients should be alert to avoid and treat SARS-CoV-2 (re)infections.

Logically, the focus of these cohorts and many related studies lie on patients treated with anti-CD20 monoclonal antibodies as these therapies have been proven to increase the risk of severe COVID-19 outcomes. For patients on S1P modulators, the data are less abundant. Interestingly, the affected immunological response of these patients does not only include humoral immunity (as is the case in patients on anti-CD20 therapies) but cellular immunity is also severely impaired. However, patients on S1P modulators do not seem to have an increased risk of severe courses of COVID-19, which has not yet been fully explained. Data on breakthrough COVID-19 in these patients are still scarce; therefore, extra data would be valuable.

Finally, it remains important to interpret data in the current era of the pandemic. The Omicron variants have proven to be highly contagious but only rarely result in severe diseases, also in PwMS. ¹⁰ Fortunately, important data regarding the risk factors for severe breakthrough SARS-CoV-2 infections in PwMS have now enriched our knowledge so we know when and in which patients we should keep our vigilance.