Breakthrough SARS-CoV-2 infections after COVID-19 mRNA vaccination in MS patients on disease modifying therapies
Authors: Sormani Maria Pia , Schiavetti Irene , Inglese Matilde , Carmisciano Luca , Laroni Alice , Lapucci Caterina , Visconti Valeria , Serrati Carlo , Gandoglia Ilaria , Tassinari Tiziana , Perego Germana , Brichetto Giampaolo , Gazzola Paola , Mannironi Antonio , Stromillo Maria Laura , Cordioli Cinzia , Landi Doriana , Clerico Marinella , Signoriello Elisabetta , Frau Jessica , Ferrò Maria Teresa , Sapio Alessia Di , Pasquali Livia , Ulivelli Monica , Marinelli Fabiana , Manzino Marcello , Callari Graziella , Iodice Rosa , Liberatore Giuseppe , Caleri Francesca , Repice Anna Maria , Cordera Susanna , Battaglia Mario Alberto , Salvetti Marco , Franciotta Diego , Uccelli Antonio ,   the CovaXiMS study group
Published: December 2021

Background

Patients with Multiple Sclerosis (pwMS) treated with anti-CD20 or fingolimod showed a reduced humoral response to mRNA-based SARS-CoV-2 vaccines, while the degree of such responses is unimpaired and similar in pwMS treated with other disease modifying therapies (DMTs), or untreated. However, the nature of the SARS-CoV-2 vaccine-induced immune response is based also on cellular immunity and there is emerging evidence that anti-SARS-CoV-2 specific CD4 and CD8 T cell responses can be detected after vaccination also in patients with low antibody levels. In this study we aimed to monitor the risk of breakthrough SARS-CoV-2 infection and to identify correlates of reduced protection in frail vaccinated pwMS on different DMTs.

Methods

We designed a long term clinical follow-up of the CovaXiMS (Covid-19 vaccine in Multiple Sclerosis), a prospective multicenter cohort study enrolling pwMS scheduled for SARS-CoV-2 vaccination with mRNA vaccines and tested for SARS-CoV-2 antibodies before and after the second vaccine dose. These patients were followed with periodic phone calls up to a mean time of 6 months, and all the SARS-CoV-2 breakthrough infections were registered. The impact of DMTs on cumulative incidence of breakthrough Covid-19 cases was presented by Kaplan-Meier curves. A multivariable logistic model was run to assess factors associated to a higher risk of breakthrough infections.

Findings

1705 pwMS (81.6% BNT162b2 and 18.4% mRNA-1273) had a full vaccination cycle (2 vaccine doses, 21/28 days apart). Of them, 1509 (88.5%) had blood assessment 4 weeks after the second vaccine dose. During follow-up, 23 breakthrough Covid-19 infections (cumulative incidence: 1.5%, SE=0.3%) were detected after a mean of 108 days after the second dose (range, 18-230). Of them, 9 were on ocrelizumab, one on rituximab, 4 on fingolimod, 6 on dimethyl-fumarate, one on teriflunomide, and 2 were untreated. Just two cases (a woman on ocrelizumab and a man on teriflunomide) required hospitalization. The probability to be infected was associated only with SARS-CoV-2 antibody levels measured after 4 weeks from the second vaccine dose (HR=0.63, p=0.007); an antibody level of 660 U/mL was calculated as the cutoff for higher risk of infection.

Interpretation

Our data show that the risk of breakthrough SARS-CoV-2 infections is mainly associated with reduced levels of the virus-specific humoral immune response.

Funding

FISM [2021/Special-Multi/001]; the Italian Ministry of Health grant ‘Progetto Z844A 5×1000’. Italian Ministry of Health: Ricerca Corrente to IRCCS Ospedale Policlinico San Martino.