Evaluating the Immune Response to COVID19 Vaccination in Immunodeficient Patients

The purpose of this study is to understand the immune response to coronavirus disease-19 (COVID-19) vaccination in patients on B-cell depleting therapies (BCDT) over time, which in the future may help to inform clinical decision making in this patient population.

Study Overview

• Status: Active, not recruiting
• Conditions: Multiple Sclerosis; Autoimmune Blistering Disease; B-Cell Deficiency
• Intervention / Treatment: Biological: COVID19 vaccine

Detailed Description

This will be a prospective, observational cohort study consisting of individuals with autoimmune diseases who are undergoing treatment with anti-CD20 medications at the time they receive a vaccine against COVID-19. Control groups will include healthy individuals, individuals with autoimmune diseases on other immunomodulators, and individuals with autoimmune diseases not on immunotherapy.

Participants will undergo serial blood draws and saliva collections at prespecified time points surrounding vaccination. A subset of agreeable participants will undergo skin biopsy within days of the first vaccination, with the option to repeat skin biopsy after the second vaccination. Additional blood, saliva and skin biopsy specimens may be obtained after booster vaccinations or after known COVID19 infections .

Specimens collected will be used for studies aimed at (1) understanding the pathobiology of neurologic/inflammatory/immune diseases and the immunologic response to COVID-19 vaccination, (2) identifying how and why treatments used for neurologic/immune diseases may impact the effectiveness of vaccination, and (3) identifying dermatologic manifestations of the immunologic response to the COVID-19 mRNA vaccine.

The investigators are investigating both the production of antibodies against the virus over time and deeply interrogating the T-cell response to vaccination using methods that measure T-cell reactivity to the COVID-19 virus, including single cell RNA sequencing.

• Study Type: Observational
• Enrollment (Estimated): 400

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • New Haven, Connecticut, United States, 06520
      • Yale University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: Yes

• Sampling Method: Non-Probability Sample

Study Population

There will be four groups of participants overall:

• Patients with autoimmune neurologic/autoimmune blistering disease (AIBD) who are on B-cell depleting therapy (anti-CD20 monoclonal antibodies)
• Patients with autoimmune neurologic/AIBD who are on other types of immunomodulators
• Patients with autoimmune neurologic/AIBD who are untreated
• Healthy controls

Description

Subjects with neurologic/immunologic condition:

• at least 18 years of age
• Known diagnosis of autoimmune neurologic disease (e.g. multiple sclerosis (MS), neuromyelitis optica, myelin oligodendrocyte glycoprotein (MOG) -associated disorder) or autoimmune blistering disease (AIBD).

• EITHER:

  • Treated with an anti-CD20 (rituximab, ocrelizumab) medications for >6 months at the time of vaccination (B-cell depletion therapy, BCDT)
  • On no immunomodulatory therapy for their autoimmune condition for >6 months at the time of vaccination
  • Treated with a non-BCDT immunotherapy
• No relapse of neurologic/immunologic disease for >6 months prior to the time of enrollment
• Subject is eligible and willing to receive COVID-19 vaccination in accordance with local and national guidelines, or subject intends to receive booster COVID-19 vaccination in accordance with recommendations from their primary medical team.
• No active skin condition (e.g. open sores) preventing blood draw

Healthy Controls:

• at least 18 years of age
• No evidence of neurological/immunologic disease/illness/condition
• Subject is eligible and willing to receive COVID-19 vaccination in accordance with local and national guidelines, or subject intends to receive booster COVID-19 vaccination in accordance with recommendations from their primary medical team.
• No active skin condition (e.g. open sores) preventing blood draw/skin biopsy

Exclusion Criteria:

• Use of high dose steroids for treatment of neurologic/immunologic disease within 1 month of COVID-19 vaccination
• Anti-CD20 B-cell depleting therapy infused within 2 weeks of first study visit
• Inability to comply with the requirements of the protocol, in the opinion of the primary investigator

Study Plan

How is the study designed?

Number of groups / cohorts

4

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Healthy control; Healthy controls Participants will receive COVID19 vaccination according to standard of care (any FDA approved vaccine). They will donate serial biospecimens before and after vaccination according to the study design.	Biological: COVID19 vaccine; All participants receive one or more FDA-authorized COVID19 vaccinations according to standard of care and current medical recommendations. The intervention is not specifically administered as part of the study.
Disease control; Disease controls (individuals with a qualifying autoimmune condition, but not treated with any immunomodulator). Participants will receive COVID19 vaccination according to standard of care (any FDA approved vaccine). They will donate serial biospecimens before and after vaccination according to the study design.	Biological: COVID19 vaccine; All participants receive one or more FDA-authorized COVID19 vaccinations according to standard of care and current medical recommendations. The intervention is not specifically administered as part of the study.
B-cell depleted; Individuals with autoimmune disease (multiple sclerosis or autoimmune blistering disease) who are treated with B-cell depleting anti-CD20 monoclonal antibodies. Participants will receive COVID19 vaccination according to standard of care (any FDA approved vaccine). They will donate serial biospecimens before and after vaccination according to the study design.	Biological: COVID19 vaccine; All participants receive one or more FDA-authorized COVID19 vaccinations according to standard of care and current medical recommendations. The intervention is not specifically administered as part of the study.
Other immunomodulator; Individuals with autoimmune disease (multiple sclerosis or autoimmune blistering disease) who are treated with a non-CD20 monoclonal antibody immunomodulator to treat their disease. Participants will receive COVID19 vaccination according to standard of care (any FDA approved vaccine). They will donate serial biospecimens before and after vaccination according to the study design.	Biological: COVID19 vaccine; All participants receive one or more FDA-authorized COVID19 vaccinations according to standard of care and current medical recommendations. The intervention is not specifically administered as part of the study.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in coronavirus disease 19 (COVID19) antibody titers over time	COVID 19 spike and neutralizing antibody titers will be monitored serially	Baseline, 2 weeks post vaccine 1, pre-vaccine 2, 1 week post vaccine 2, 6 months post vaccine 2; pre- and 2 week post any additional vaccines
Change in severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) specific T-cell activation over time	Flow cytometry characterizing immunophenotype of SARS-CoV2 specific T cells	Baseline, 2 weeks post vaccine 1, pre-vaccine 2, 1 week post vaccine 2, 6 months post vaccine 2; pre- and 2 week post any additional vaccines

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Skin biopsy analysis	Histologic and immunologic characterization of skin biopsy specimens, comparing vaccinated to unvaccinated arm, at one or more timepoints post-vaccination	7 days post vaccine 1; 7 days post vaccine 2; 4 days post booster (all timepoints optional)
Measurement of COVID19 antibodies in saliva	Descriptive assessment of whether COVID antibodies can be detected in saliva at any time point	Baseline, 2 weeks post vaccine 1, pre-vaccine 2, 1 week post vaccine 2, 6 months post vaccine 2; pre- and 2 week post any additional vaccines
Immune analysis	Deep immunologic assessment (flow cytometry, single cell RNA sequencing) of blood specimens; descriptive analysis at each timepoint with comparisons over time will be performed.	Baseline, 2 weeks post vaccine 1, pre-vaccine 2, 1 week post vaccine 2, 6 months post vaccine 2; pre- and 2 week post any additional vaccines
Changes in patient reported outcomes: COVID history	Subjective reports of vaccination-associated symptoms and COVID risk factors (COVID-19 survey)	Baseline, 2 weeks post vaccine 1, pre-vaccine 2, 1 week post vaccine 2, 6 months post vaccine 2; pre- and 2 week post any additional vaccines
Change in patient reported outcomes: patient reported disability steps	Subjects will complete Patient Derived Disability Step score	Baseline, 2 weeks post vaccine 1, pre-vaccine 2, 1 week post vaccine 2, 6 months post vaccine 2; pre- and 2 week post any additional vaccines
Change in patient reported outcomes: overall symptoms	SymptoMS screening questionnaire	Baseline, 2 weeks post vaccine 1, pre-vaccine 2, 1 week post vaccine 2, 6 months post vaccine 2; pre- and 2 week post any additional vaccines

Collaborators and Investigators

• Sponsor: Yale University
• Collaborators: National Institute of Allergy and Infectious Diseases (NIAID); Robert Leet and Clara Guthrie Patterson Trust
• Investigators: Principal Investigator: Erin Longbrake, Yale University

Study record dates

Study Major Dates

• Study Start (Actual): February 10, 2021
• Primary Completion (Estimated): May 31, 2024
• Study Completion (Estimated): June 30, 2024

Study Registration Dates

• First Submitted: March 15, 2022
• First Submitted That Met QC Criteria: March 16, 2022
• First Posted (Actual): March 18, 2022

Study Record Updates

• Last Update Posted (Actual): February 16, 2024
• Last Update Submitted That Met QC Criteria: February 13, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Nervous System Diseases; Immune System Diseases; Demyelinating Autoimmune Diseases, CNS; Autoimmune Diseases of the Nervous System; Demyelinating Diseases; Autoimmune Diseases; Multiple Sclerosis; Immunologic Deficiency Syndromes
• Other Study ID Numbers: 2000029889; 2U19AI089992-11 (U.S. NIH Grant/Contract); 2U19AI089992-06A1 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: Sequencing data will be made publicly available upon publication of the study. Other study related data will be made available upon request and presentation of an appropriate research plan by qualified researchers

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No