Abstract
The immunomodulatory effects of disease-modifying therapies for multiple sclerosis might affect the immune response to vaccines for severe acute respiratory syndrome coronavirus 2. We analyzed the severe acute respiratory syndrome coronavirus 2-specific antibody response and lymphocyte profile before and after Ad26.COV2.S (Johnson & Johnson) vaccination in natalizumab-treated patients with multiple sclerosis. There was a 72-fold increase in mean anti-severe acute respiratory syndrome coronavirus 2 spike immunoglobulin G levels 4 weeks after vaccination and a 137-fold increase after 6 months. Other immune signals were within normal ranges. Natalizumab-treated patients with multiple sclerosis had a robust immune response to Ad26.COV2.S vaccine, and other immune signals were not significantly affected.
Introduction
Coronavirus disease 2019 (COVID-19) is a potentially fatal respiratory illness caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 1 As of July 2023, over 6.95 million people worldwide have lost their lives to COVID-19. 2 Antibodies against the spike glycoprotein are believed to be an important component of immunity to SARS-CoV-2. 3 Vaccines targeting the SARS-CoV-2 spike protein were developed, including messenger RNA (mRNA) vaccines and viral vector-based vaccines. 3 The immunomodulatory effects caused by some disease-modifying therapies (DMTs) used to treat people with multiple sclerosis (MS) have been shown to affect certain vaccines, including those for influenza, rabies, and varicella zoster.3,4 Some MS DMTs (specifically anti-CD20 and sphingosine 1-phosphate receptor modulators) may attenuate the antibody response to mRNA COVID-19 vaccinations, whereas patients receiving other DMTs may have immune responses similar to healthy controls.5–9 Less data are available regarding the immune response from the viral vector SARS-CoV-2 vaccine (Ad26.COV2.S) in MS patients, with limited authorized use declared by the US Food & Drug Administration (FDA) in December 2022. However, data on the Ad26.COV2.S vaccine can still provide useful information on the immune response to this vaccine class.
Natalizumab (TYSABRI®), an α4 integrin antagonist monoclonal antibody, is an efficacious treatment for patients with relapsing forms of MS.10,11 Initial data indicated that natalizumab does not interfere with the production of SARS-CoV-2 spike antibodies.5–7 Here we present quantitative immunological data, lymphocyte profiles, and John Cunningham virus (JCV) index data from stable patients treated with natalizumab before and after administration of the Johnson & Johnson Ad26.COV2.S vaccine.
Methods
Study design and patients
This was an observational, single-center, noninterventional study, collecting data between July–September 2021, with a 6- to 12-month planned follow-up (approved by the Advarra institutional review board). Patients provided written, informed consent prior to enrollment.
Procedures
The Ad26.COV2.S vaccine was administered off-site according to local regulations and availability. Blood samples were collected at the prevaccination (baseline) visit and at 4 weeks (±1 week) and 6 months (6–10 months) postvaccination. Samples were sent to appropriate commercial laboratories for SARS-CoV-2 antibodies analysis: Nucleocapsid antibodies by qualitative immunoassay (Quest Diagnostics or LabCorp) and spike antibodies by semiquantitative immunoassay (Quest Diagnostics or LabCorp). Anti-JCV antibody index was determined using Stratify™ JCV Antibody (with Index) with Reflex to Inhibition Assay (Quest Diagnostics; test code 91665). Standard laboratory testing including electrolytes and liver profile, complete blood count with differential (including hemoglobin, white blood count, and platelets), lymphocyte subset panel, and immunoglobulin panel were conducted.
Prevaccination and postvaccination, paired continuous and binary outcome comparisons were performed using Wilcoxon signed rank test and McNemar's test, respectively.
Results
Patients
Patients (N = 13) had a mean (standard deviation [SD]) age of 49.8 (10.69) years, a mean (SD) disease duration of 14.0 (8.45) years and had been treated with natalizumab for a mean (SD) of 5.5 (4.7) years (Table 1). Additionally, 69.2% of patients used a prior DMT before starting natalizumab, with 66.7% of those patients using only 1 DMT.
Baseline characteristics.
Patients were aged 18–70 years, with multiple sclerosis, on a stable dose of natalizumab for at least 3 months. Patients were excluded if they had a prior SARS-COV-2 infection, had a relapse or new MRI lesion in the last 3 months, had a known allergy or contraindication to vaccine ingredients, had immunosuppressant treatment or any vaccine other than the inactivated influenza vaccine within 4 weeks of the study, were pregnant or anticipated pregnancy or breastfeeding, had an absolute lymphocyte count <0.5 × 109/L, or had concurrent intravenous or subcutaneous immunoglobulin treatment.
DMT: disease-modifying therapy; J&J: Johnson and Johnson; MRI: magnetic resonance imaging; SARS-COV-2: severe acute respiratory syndrome coronavirus 2; MS: multiple sclerosis; JCV: John Cunningham virus.
Immune response
Data availability varied between prevaccination, 4 weeks postvaccination, and 6 months postvaccination (Table 2). At baseline, 2 out of 13 patients were positive for anti-SARS-CoV-2 nucleocapsid antibodies. By week 4 postvaccination, 2 additional patients tested positive for the nucleocapsid protein. All patients tested positive for anti-spike antibodies. Overall, there was a 72-fold increase in mean anti-spike antibodies in response to the Ad26.COV2.S vaccine at 4 weeks (N = 13, p = 0.0015). By 6 months, there was a 137-fold increase in mean anti-spike antibodies (n = 11, p = 0.033). Similar results were seen when patients with a positive anti-SARS-CoV-2 nucleocapsid antibody result were excluded from this analysis (Table 2). Other immune signals at all timepoints were within normal limits, with no significant changes observed from prevaccination to postvaccination. Of the 5 patients with a negative JCV serostatus at baseline, 2 seroconverted at 6 months. These 2 patients were older (54 and 61 years) and JCV index was low (0.23 and 0.47). Among patients with pre- and postvaccination JCV index values, there was no appreciable change in anti-JCV index values from baseline to 4 weeks (n = 5) or to 6 months (n = 7), except for one (0.43 to 1.51 at 6 months).
Prevaccination and postvaccination immune response results.
*Statistically significant change (p < .05) determined by Wilcoxon signed-rank test.
The sensitivity analysis excluded patients with a positive anti-SARS-CoV-2 nucleocapsid antibody assay test result.
Patients did not have a test for JCV at that time point.
ABS: absolute; CD: cluster of differentiation; COVID-19: coronavirus disease 2019; Ig: immunoglobulin; NK: natural killer; RBC: red blood cell; WBC: white blood cell; SARS-CoV-2: severe acute respiratory syndrome coronavirus 2; JCV: John Cunningham virus.
Discussion
The COVID-19 pandemic had a profound impact on global health amongst vulnerable patient populations. While significant strides were made in understanding the SARS-CoV-2 virus and developing vaccines, the effects of the pandemic are long-lasting. As the world adapts to living with COVID-19 as an endemic infection, it becomes crucial to continue characterizing the immune response to vaccination, particularly among MS patients.
To date, limited reports exist that address the effect of natalizumab treatment on the immune response to viral vector vaccines. To fill this gap, this study looked specifically at the Ad26.COV2.S vaccine response in MS patients treated with natalizumab. Natalizumab-treated patients immunized with the Ad26.COV2.S vaccine displayed a 72-fold increase in anti-spike antibodies after 4 weeks and a 137-fold increase after 6 months, indicating that natalizumab-treated patients have a robust humoral immune response to this vaccine. The data presented here is consistent with reports indicating that natalizumab does not interfere with an immune response from SARS-CoV-2 mRNA vaccines in general, as measured by anti-spike immunoglobulin G (IgG) antibody titers.5–9
Though the detection of the B-cell-mediated humoral response that produces anti-spike IgG antibodies is often used to indicate vaccine-induced immune response, several other immune cell types could be affected by vaccination. The results of lymphocyte and immunoglobulin profiling over the 6-month analysis indicated that all cell types were within normal range.12,13 Additionally, the Ad26.COV2.S vaccine did not appreciably alter anti-JCV antibody index, which is important in this cohort of patients due to the risk of natalizumab-associated progressive multifocal leukoencephalopathy.
Limitations of this study include the small sample size (n = 13) and the lack of a healthy control group, which limit statistical analyses. However, this study does provide healthcare practitioners with additional quantitative data on the immune response to Ad26.COV2.S vaccination in MS patients who are treated with natalizumab. These natalizumab-treated patients had a robust immune response to Ad26.COV2.S vaccine, and vaccination did not impact other important immune signals. The positive humoral response from this viral vector-based vaccine is reassuring for patients interested in alternatives to mRNA vaccines and relevant for multiple diseases.
Footnotes
Acknowledgments
All named authors meet the International Committee of Medical Journal Editors criteria for authorship for this manuscript and take responsibility for the integrity of the work. The authors were assisted in preparing the manuscript by Luke Ward, PhD, and John Watson, PhD, of Ashfield MedComms (Middletown, CT, USA), an Inizio Company. Celia Nelson of Ashfield MedComms copyedited and styled the manuscript per journal requirements. Biogen provided funding for writing support. The authors provided final approval of all content and were responsible for the decision to submit it for publication.
Contribution statement
MG contributed to the study design, investigation, supervision, analysis, writing-review, and editing. MZ contributed to the investigation, analysis, writing-review, and editing. BB contributed to the investigation, analysis, writing-review, and editing. MB contributed to the investigation, analysis, writing-review, and editing. OK contributed to the study design, supervision, analysis, writing-review, and editing. HL contributed to the analysis, writing-review, and editing. ZS contributed to the analysis, writing-review, and editing. NS contributed to the study design, analysis, writing-review, and editing. JPM contributed to the analysis, writing-review, and editing. RLA contributed to the study design, supervision, analysis, writing-review, and editing.
Declaration of competing interests
MG has received speaker/consultant fees from Acorda, Amgen, Biogen, EMD Serono, Medtronic, Novartis, Sanofi Genzyme, Saol Therapeutics, and Teva Pharmaceuticals. MZ has received speaker/consultant fees from Biogen, Novartis, BMS, Horizon Therapeutics, Genentech, EMD Serono, and Sanofi. BB has received speaker/consultant fees from Biogen and BMS. MB has received speaker/consultant fees from Genzyme and Biogen. OK reports nothing to disclose. HL, ZS, NS, JPM, and RLA are employees of and may own stock and/or stock options in Biogen.
Data sharing statement
Requests from qualified investigators for anonymized data should be addressed to the corresponding author.
Funding
The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by Biogen, which provided funding for these analyses. Biogen also funded medical writing support in the development of this manuscript. Biogen reviewed and provided feedback on the manuscript to the authors. The authors had full editorial control and provided final approval of all content.