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Multicenter Study
. 2022 Jun:80:104042.
doi: 10.1016/j.ebiom.2022.104042. Epub 2022 May 5.

Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy

Maria Pia Sormani  1 , Irene Schiavetti  2 , Matilde Inglese  3 , Luca Carmisciano  2 , Alice Laroni  3 , Caterina Lapucci  3 , Valeria Visconti  4 , Carlo Serrati  5 , Ilaria Gandoglia  6 , Tiziana Tassinari  7 , Germana Perego  8 , Giampaolo Brichetto  9 , Paola Gazzola  10 , Antonio Mannironi  11 , Maria Laura Stromillo  12 , Cinzia Cordioli  13 , Doriana Landi  14 , Marinella Clerico  15 , Elisabetta Signoriello  16 , Eleonora Cocco  17 , Jessica Frau  17 , Maria Teresa Ferrò  18 , Alessia Di Sapio  19 , Livia Pasquali  20 , Monica Ulivelli  21 , Fabiana Marinelli  22 , Matteo Pizzorno  23 , Graziella Callari  24 , Rosa Iodice  25 , Giuseppe Liberatore  26 , Francesca Caleri  27 , Anna Maria Repice  28 , Susanna Cordera  29 , Mario Alberto Battaglia  30 , Marco Salvetti  31 , Diego Franciotta  32 , Antonio Uccelli  3 ; CovaXiMS study group
Collaborators, Affiliations
Multicenter Study

Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies during the Delta and the Omicron waves in Italy

Maria Pia Sormani et al. EBioMedicine. 2022 Jun.

Abstract

Background: In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection in patients with MS (pwMS) under different DMTs and to identify correlates of reduced protection.

Methods: This is a prospective Italian multicenter cohort study, long-term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis) study. 1855 pwMS scheduled for SARS-CoV-2 mRNA vaccination were enrolled and followed up to a mean time of 10 months. The cumulative incidence of breakthrough Covid-19 cases in pwMS was calculated before and after December 2021, to separate the Delta from the Omicron waves and to account for the advent of the third vaccine dose.

Findings: 1705 pwMS received 2 m-RNA vaccine doses, 21/28 days apart. Of them, 1508 (88.5%) had blood assessment 4 weeks after the second vaccine dose and 1154/1266 (92%) received the third dose after a mean interval of 210 days (range 90-342 days) after the second dose. During follow-up, 131 breakthrough Covid-19 infections (33 during the Delta and 98 during the Omicron wave) were observed. The probability to be infected during the Delta wave was associated with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.57, p < 0.001); the protective role of antibodies was preserved over the whole follow up (HR=0.57, 95%CI=0.43-0.75, p < 0.001), with a significant reduction (HR=1.40, 95%CI=1.01-1.94, p=0.04) for the Omicron cases. The third dose significantly reduced the risk of infection (HR=0.44, 95%CI=0.21-0.90,p=0.025) during the Omicron wave.

Interpretation: The risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response.

Funding: Supported by FISM - Fondazione Italiana Sclerosi Multipla - cod. 2021/Special-Multi/001 and financed or co-financed with the '5 per mille' public funding.

Keywords: Breakthrough infections; COVID-19; Disease Modifying Treatments; Multiple Sclerosis.

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Conflict of interest statement

Sormani MP received consulting fees from Roche, Biogen, Merck, Novartis, Sanofi, Celgene, Immunic, Geneuro, GSK, Medday; received payment or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Roche, Biogen Merck, Novartis, Sanofi, Celgene; participated on a Data Safety Monitoring Board or Advisory Board for Roche, Sanofi, Novartis, Merck. Uccelli A received grants (to his Institution) from FISM, Biogen, Roche, Alexion, Merck Serono; participated on a Data Safety Monitoring Board or Advisory Board (to his Institution) for BD, Biogen, Iqvia, Sanofi, Roche, Alexion, Bristol Myers Squibb. Ulivelli M received consulting fees from Biogen, Novartis, Serono. Caleri F received honoraria for lectures or presentation from Biogen, Merck, Teva, Novartis, Sanofi-Genzyme, Roche; received support for attending meeting and travel grant from Biogen, Merck, Teva, Novartis, Sanofi-Genzyme, Roche; received honoraria for participation on Advisory Boards from Biogen, Merck, Teva, Novartis, Sanofi-Genzyme, Roche. Cordioli C received grants or contracts from Roche, Novartis, Merck Serono, Biogen, Celgene; received consulting fees from Biogen. Inglese M received grants or contracts from FISM, INAIL, European Union. Laroni A received grants or contracts from Italian Ministry of University, Ministry of Health; received consulting fees from Merck, Biogen, Roche, Novartis, Bristol-Myers Squibb Pharma EEIG; received honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from Mercks, Biogen, Roche, Novartis, Bristol-Myers Squibb Pharma EEIG. Salvetti M received grants or contracts from Biogen, Merck, Novartis; received payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Biogen, Merck, Novartis, Roche, Sanofi. Landi D received consulting fees from Merck Serono, Celgene, Bristol Myers Squibb, Roche, Novartis, TEVA; received payments or honoraria for lectures, presentations, speakers’ bureaus, manuscript writing or educational events from Merck Serono, Celgene, Bristol Myers Squibb, Biogen, Roche, Novartis, Sanofi Genzyme, Mylan; received support for attending meetings and/or travel from Merck Serono, Biogen, Roche, Sanofi Genzyme, Novartis, Mylan; participated on Data Safety Monitoring Board or Advisory Board for Merck Serono, Celgene Bristol Myers Squibb, Biogen, Roche, Sanofi Genzyme. Mannironi A, Pasquali L, Ferrò MT, Liberatore G, Brichetto G, Serrati C, Marinelli F, Carmisciano L, Clerico M, Di Sapio, A, Tassinari T, Visconti V, Perego G, Pizzorno M, Callari G, Cocco E, Frau J, Gazzola P, Repice AM, Schiavetti I, Signoriello E, Stromillo ML, Cordera S, Franciotta D, Iodice R, Lapucci C, Battaglia MA, Gandoglia I have nothing to disclose.

Figures

Fig 1
Figure 1
A schematic view of the events in the observation period. The first part of the study was pre-panned with blood samples taken after the second vaccine dose and a clinical follow up, up to the third vaccine dose, a Covid infection or the last follow up date, whichever came first (Delta wave period, yellow box). During the conduction of the study a third vaccine dose was recommended for patients with MS (starting since November 2021). The Omicron wave (blue box) arrived in Italy at mid-December.
Fig 2
Figure 2
Cumulative probability of breakthrough infection in the two periods. The yellow box reports infections during the Delta wave, the blue box infections during the Omicron wave.
Fig 3
Figure 3
Kaplan Meier survival curves displaying the cumulative probability of a breakthrough infection during the Delta wave (March 4 to December 15, 2021) (panel a), and during the Omicron wave (December 15, 2021, to March 25, 2022) (panel b) in groups defined by patients treated by anti-CD20 drugs (ocrelizumab or rituximab), by fingolimod and other therapies. P-values according to the log-rank test.
Fig 4
Figure 4
ROC curve reporting sensitivity and specificity of antibody levels after the second vaccination dose to identify a higher risk of breakthrough infection.
Fig 5
Figure 5
Covid-19 cases (red dots) and severe Covid-19 cases (hospitalized) (yellow stars) according to disease modifying therapy and antibody level. The red dotted line represents the antibody level cut-off better discriminating patients at risk of breakthrough infection (627 BAU/mL).
Fig 6
Figure 6
Kaplan Meier survival curves displaying the cumulative probability of a breakthrough infection in pwMS who received vs those who did not receive a third vaccine dose (landmark analysis, see text for details).
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