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      Negative anti-SARS-CoV-2 S antibody response following Pfizer SARS-CoV-2 vaccination in a patient on ocrelizumab


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          Dear Sirs, Several vaccines for novel Coronavirus (SARS-CoV-2) are now available [1]. In Multiple Sclerosis (MS) patients on anti-CD20 therapy, blunted antibody responses to SARS-CoV-2 infection [2–4] and to some vaccines have been reported [5]. However, there is no data on the immune response to mRNA vaccines against SARS-CoV-2 in patients on anti-CD20 therapies. We present a patient with MS on ocrelizumab, who received the Pfizer mRNA COVID-19 vaccine, and did not seroconvert 27 days after the second vaccine dose as measured by an FDA approved Anti-SARS-CoV-2 S assay. Case presentation A 44-year-old Caucasian male presented 4 years ago with symptomatic myelitis and multifocal demyelinating T2 and T1 Gadolinium contrast enhancing (T1Gd +) lesions throughout the brain and spinal cord. He was diagnosed with Relapsing Remitting MS (RRMS), initiated on semi-annual ocrelizumab therapy and had no evidence of disease activity (NEDA) for 3.5 years. He had been repeatedly tested for the presence of SARS-CoV-2 by RT-PCR through the institutional research program (Fig. 1). He received his first dose of SARS-CoV-2 (Pfizer) vaccine 5 months after ocrelizumab infusion, followed by the second dose 21 days later. There was a moderate post-vaccination systemic reaction with myalgias and fatigue. He received another ocrelizumab infusion 9 days after the second dose of the vaccine (Fig. 1). The decision to receive treatment on schedule was made considering his excellent therapeutic response to date with on-label use of ocrelizumab. On the day of infusion, he had complete depletion of CD19 + and CD20 + but Immunoglobulin G (IgG) level and Absolute Lymphocyte Count (ANC) were normal (Fig. 1). At the time of infusion he tested negative for antibodies to the SARS-CoV-2 nucleoplasmid antigen (Roche Elecsys Anti-SARS-CoV-2), an assay that interrogates for a humoral immune response to SARS-CoV-2 indicating prior infection [6]. This assay does not reflect an immune response from the mRNA vaccines, directed against virus spike but not nucleocapsid protein. Fig. 1 Timeline of patient’s ocrelizumab infusions, vaccination, SARS-CoV-2 test and laboratory results. Patient had serial SARS-CoV-2 PCR tests (negative) through the institutional research program. The red stars indicate negative SARS-CoV-2 PCR tests. Reference range for Anti-SARS-CoV-2 assay (nucleoplasmid) < 1.00 COI, Anti-SARS-CoV-2 spike (S) < 0.8 U/mL, WBC 4.00–10.00 K/uL, Lymphocytes 18.0–41.0%, ALC 0.72–4.10 K/uL, IgG 700–1,600 mg/dL, IgA 70–400 mg/dL, IgM 40–230 mg/dL, CD19 7.0–27.0% lymphocytes, CD20 3.0–20.0% lymphocytes 27 days after the second vaccine dose and 18 days after ocrelizumab infusion, the patient was tested using the Roche Elecsys Anti-SARS-CoV-2 S assay (Fig. 1). This assay is intended for qualitative and semiquantitative detection of antibodies to the SARS-CoV-2 spike (S) protein receptor-binding domain. It is designed to detect adaptive immune response indicating prior infection, and to uniquely detect SARS-Cov-2 anti-S antibodies post mRNA vaccination [7]. Based on the manufacturer’s internal studies in healthy subjects and patients infected with SARS-CoV-2 (positive RT-PCR), the assay is highly specific with a negative predictive value (NPV) of 99.98, while its sensitivity increases from 90.6% 0–7 days after confirmed infection to 96.6% >  = 15 days after positive RT-PCR [8]. The result of this spike antibody assay was negative in our patient indicating no measurable post-vaccination immunity (negative results < 0.40 U/mL). Discussion To our knowledge, this is the first report of SARS-COV-2 vaccine response in a patient with multiple sclerosis on intravenous anti-CD20 therapy. There are cases of negative SARS-CoV-2 IgG assays in MS patients with PCR-confirmed COVID-19 infection on ocrelizumab [2–4]. A recent publication of persistent anti-SARS-CoV-2 IgG antibodies following COVID19 infection in patient on ofatumumab, suggests a detectable humoral response to SARS-CoV-2 [9]. Another investigation indicates that binding titers to spike receptor-binding domain (RBD) protein as assessed on enzyme-linked immunosorbent assay (ELISA) are significantly increased on day 15 post initial 100-μg dose of mRNA-1273 vaccination [10]. Further, unpublished internal validation studies in 24 healthy volunteers for Anti-SARS-CoV-2 S assay at our institution (Dr. Petr Jarolim) suggest positive anti-spike serology after the first dose of mRNA vaccine in all subjects, with some showing titers greater than 250 U/mL (analytical measurement range). The VELOCE trial in RRMS patients showed attenuated but present humoral responses following pneumococcal, influenza and tetanus toxoid vaccinations upon initiation of ocrelizumab [5]. Blunted immunity to hepatitis B vaccine has been observed in patients on rituximab [11, 12]. Ocrelizumab does not affect plasma cells directly and naïve B-cells generally recover significantly faster than memory B-cells [12]. Our patient did not seroconvert when tested 27 days after the second dose of the Pfizer mRNA vaccine. It is likely that antibody response would have been generated after the 1st and the 2nd vaccine doses, 5 months after the prior infusion, despite re-treatment with ocrelizumab on day 9 post-vaccination (Fig. 1). However, it is possible that early re-treatment with ocrelizumab may have further dampened post-vaccination immunity. Our case documents undetectable humoral response after mRNA SARS-CoV-2 vaccination in a B-cell depleted patient and this is potentially concerning. However, the clinical relevance of this result is unclear as it may not indicate a complete absence of an immunity to the wild type SARS-CoV-2 infection [2, 10] In this setting, the formation of antigen-specific cytotoxic anti-viral T cells may help provide some protection. It is not known if the absence of Anti-SARS-CoV-2 S antibodies reflects suboptimal vaccine response and whether delaying anti-CD20 treatments to allow B cell reconstitution before administering COVID-19 mRNA vaccine may be warranted in some patients [2, 9] Larger studies investigating COVID-19 mRNA vaccine response in patients on anti-CD20 treatments are essential to define the optimal “vaccination window.”

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          Durability of Responses after SARS-CoV-2 mRNA-1273 Vaccination

          To The Editor: We recently reported the results of a phase 1 trial of a messenger RNA vaccine, mRNA-1273, to prevent infection with SARS-CoV-2; those interim results covered a period of 57 days after the first vaccination. 1,2 Here, we describe immunogenicity data 119 days after the first vaccination (90 days after the second vaccination) in 34 healthy adult participants in the same trial who received two injections of vaccine at a dose of 100 μg. The injections were received 28 days apart. The recipients were stratified according to age (18 to 55 years, 56 to 70 years, or ≥71 years), and the assays used have been described previously. 1,2 At the 100-μg dose, mRNA-1273 produced high levels of binding and neutralizing antibodies that declined slightly over time, as expected, but they remained elevated in all participants 3 months after the booster vaccination. Binding antibody responses to the spike receptor–binding domain were assessed by enzyme-linked immunosorbent assay. At the day 119 time point, the geometric mean titer (GMT) was 235,228 (95% confidence interval [CI], 177,236 to 312,195) in participants 18 to 55 years of age, 151,761 (95% CI, 88,571 to 260,033) in those 56 to 70 years of age, and 157,946 (95% CI, 94,345 to 264,420) in those 71 years of age or older (Figure 1). Serum neutralizing antibodies continued to be detected in all the participants at day 119. On a pseudovirus neutralization assay, the 50% inhibitory dilution (ID50) GMT was 182 (95% CI, 112 to 296) in participants who were between the ages of 18 and 55 years, 167 (95% CI, 88 to 318) in those between the ages of 56 and 70 years, and 109 (95% CI, 68 to 175) in those 71 years of age or older. On the live-virus focus reduction neutralization test mNeonGreen assay, the ID50 GMT was 775 (95% CI, 560 to 1071), 685 (95% CI, 436 to 1077), and 552 (95% CI, 321 to 947) in the same three groups, respectively. On the live-virus plaque-reduction neutralization testing assay, the 80% inhibitory dilution GMT was similarly elevated at 430 (95% CI, 277 to 667), 269 (95% CI, 134 to 542), and 165 (95% CI, 82 to 332) in the same three groups, respectively (Figure 1). At day 119, the binding and neutralizing GMTs exceeded the median GMTs in a panel of 41 controls who were convalescing from Covid-19, with a median of 34 days since diagnosis (range, 23 to 54). 2 No serious adverse events were noted in the trial, no prespecified trial-halting rules were met, and no new adverse events that were considered by the investigators to be related to the vaccine occurred after day 57. Although correlates of protection against SARS-CoV-2 infection in humans are not yet established, these results show that despite a slight expected decline in titers of binding and neutralizing antibodies, mRNA-1273 has the potential to provide durable humoral immunity. Natural infection produces variable antibody longevity 3,4 and may induce robust memory B-cell responses despite low plasma neutralizing activity. 4,5 Although the memory cellular response to mRNA-1273 is not yet defined, this vaccine elicited primary CD4 type 1 helper T responses 43 days after the first vaccination, 2 and studies of vaccine-induced B cells are ongoing. Longitudinal vaccine responses are critically important, and a follow-up analysis to assess safety and immunogenicity in the participants for a period of 13 months is ongoing. Our findings provide support for the use of a 100-μg dose of mRNA-1273 in an ongoing phase 3 trial, which has recently shown a 94.5% efficacy rate in an interim analysis.
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            Effect of ocrelizumab on vaccine responses in patients with multiple sclerosis: The VELOCE study.

            The phase IIIb A Study to Evaluate the Effects of Ocrelizumab on Immune Responses in Participants With Relapsing Forms of Multiple Sclerosis (VELOCE) study (NCT02545868) assessed responses to selected vaccines in ocrelizumab (OCR)-treated patients with relapsing multiple sclerosis.
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              Is Open Access

              Vaccines for COVID‐19

              Summary Since the emergence of COVID‐19, caused by the SARS‐CoV‐2 virus at the end of 2019, there has been an explosion of vaccine development. By 24 September 2020, a staggering number of vaccines (more than 200) had started preclinical development, of which 43 had entered clinical trials, including some approaches that have not previously been licensed for human vaccines. Vaccines have been widely considered as part of the exit strategy to enable the return to previous patterns of working, schooling and socializing. Importantly, to effectively control the COVID‐19 pandemic, production needs to be scaled‐up from a small number of preclinical doses to enough filled vials to immunize the world’s population, which requires close engagement with manufacturers and regulators. It will require a global effort to control the virus, necessitating equitable access for all countries to effective vaccines. This review explores the immune responses required to protect against SARS‐CoV‐2 and the potential for vaccine‐induced immunopathology. We describe the profile of the different platforms and the advantages and disadvantages of each approach. The review also addresses the critical steps between promising preclinical leads and manufacturing at scale. The issues faced during this pandemic and the platforms being developed to address it will be invaluable for future outbreak control. Nine months after the outbreak began we are at a point where preclinical and early clinical data are being generated for the vaccines; an overview of this important area will help our understanding of the next phases.

                Author and article information

                J Neurol
                J Neurol
                Journal of Neurology
                Springer Berlin Heidelberg (Berlin/Heidelberg )
                27 February 2021
                : 1-3
                [1 ]Department of Neurology, Brigham and Women’s Hospital, Harvard Medical School, Boston, MA USA
                [2 ]GRID grid.65499.37, ISNI 0000 0001 2106 9910, Department of Medical Oncology, , Dana-Farber Cancer Institute and Harvard Medical School, ; Boston, MA USA
                [3 ]Department of Pathology, Brigham and Women’s Hospital, and Harvard Medical School, Boston, MA USA
                Author information
                © Springer-Verlag GmbH, DE part of Springer Nature 2021

                This article is made available via the PMC Open Access Subset for unrestricted research re-use and secondary analysis in any form or by any means with acknowledgement of the original source. These permissions are granted for the duration of the World Health Organization (WHO) declaration of COVID-19 as a global pandemic.

                : 5 February 2021
                : 9 February 2021
                : 10 February 2021
                Letter to the Editors



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