Analysis of Immunogenicity, Safety and Efficacy of COVID-19 Vaccines in Immunosuppressed Individuals

The study will evaluate the immunogenicity, safety and efficacy of vaccines against severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) in oncohematological patient population and compare the results with patients without prior oncohematological disease. The study is comprised of retrospective and prospective parts. In retrospective part, biobanked residual biological patient material and data will be used. In prospective part, vaccinated oncohematological patients and vaccinated patients without prior oncohematological disease will be invited to participate in long-term follow-up. The subjects will be invited for blood sample collection every three months from the second vaccine dose administration, i.e. 3 mos., 6 mos., 9 mos. etc. When the study subject receives booster dose, additional blood samples for immunogenicity analyses will be collected up to 14 days before and 4-8 weeks after the booster vaccine dose. The follow-up time points occurring every three months will be counted from the last vaccine's dose. Ten time points in total will be collected and tested for humoral and cellular immunogenicity. For safety analysis patient self-documented systemic events (fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain) occurring up to 7 days following each vaccine dose will be systematized and compared between oncohematological patients and healthy individuals. For efficacy analysis, polymerase chain reaction assay (PCR) confirmed symptomatic disease rates, hospitalization rates and mortality rates will be assessed.

Study Overview

• Status: Recruiting
• Conditions: Hematologic Neoplasms; COVID-19 Vaccines
• Intervention / Treatment: Diagnostic test: S-binding IgG, RBD-binding IgG and N-binding IgG immunoassays and SARS-CoV-2 serum neutralization assay, quantitative serum immunoglobulin tests; Diagnostic test: Assessment of proinflammatory cytokine production and immunophenotypic analysis after stimulation with overlapping S-peptides in peripheral blood mononuclear cells (PBMC); Diagnostic test: Quantitative sequencing for TCR repertoires for SARS-CoV-2-specific antigens

Detailed Description

The study will evaluate the immunogenicity, safety and efficacy of vaccines against SARS-CoV-2 in oncohematological patient population and compare the results with patients without prior oncohematological disease. The study is comprised of retrospective and prospective parts. In retrospective part, biobanked residual biological patient material and data will be used. In prospective part, vaccinated oncohematological patients and vaccinated patients without prior oncohematological disease will be invited to participate in long-term follow-up. The subjects will be invited for blood sample collection every three months from the second vaccine dose administration, i.e. 3 mos., 6 mos., 9 mos. etc. When the study subject receives booster dose, additional blood samples for immunogenicity analyses will be collected up to 14 days before and 4-8 weeks after the booster vaccine dose. The follow-up time points occurring every three months will be counted from the last vaccine's dose. Ten time points in total will be collected and tested for humoral and cellular immunogenicity, detailed below.

The study sample size is based on the number of oncohematological patient population, eligible for vaccination. Our assumed study sample size during the whole study period is up to 2500 adult patients + up to 200 adolescent patients with oncohematological disease and up to 500 adult + up to 70 adolescent patients without prior oncohematological disease. The size of the control group is aimed at achieving sufficient samples for statistical comparison of the groups. All study participants will have received a vaccination schedule specified in each vaccine's Summary of Product Characteristics.

For humoral immunogenicity evaluation blood serums from up to 2500 adult patients + up to 200 adolescent patients with oncohematological disease and up to 500 adult + up to 70 adolescent patients without prior oncohematological disease will be tested at the following time points: 1) up to 10 days before the first vaccine dose, 2) on the day of second vaccine dose, 3) 1 to 3 weeks after second vaccine dose. Further samples will be obtained every 3 months after administration of second vaccine dose. When the study subject receives booster dose, additional blood samples for immunogenicity analyses will be collected up to 14 days before and 4-8 weeks after the booster vaccine dose. The follow-up time points occurring every three months will be counted from the last vaccine's dose. 10 follow-up time points in total. The samples will be used to perform S-binding immunoglobulin G (IgG), receptor-binding domain (RBD)-binding IgG and N-binding IgG immunoassays, SARS-CoV-2 serum neutralization assay against different SARS-CoV-2 variants and quantitative serum immunoglobulin tests.

For cellular immunogenicity evaluation PBMC samples from up to 100 oncohematological patients and 20 healthy individuals will be tested at the following time points: 1) up to 10 days before the first vaccine dose and 2) 1 to 3 weeks after second vaccine dose. Further samples will be obtained every 3 months after administration of second vaccine dose. When the study subject receives booster dose, additional blood samples for immunogenicity analyses will be collected up to 14 days before and 4-8 weeks after the booster vaccine dose. The follow-up time points occurring every three months will be counted from the last vaccine's dose. Ten follow-up time points in total. Cellular immunogenicity will be evaluated in oncohematological patients, who may have a weak humoral response to vaccines. The following groups of oncohematological patients will be included: 1) 20 to 40 recent recipients of allogeneic stem cell transplantation (allo-SCT), meeting these requirements: 2-8 months after allo-SCT; cluster of differentiation 3 (CD3) positive cell count >0.1*109/L; patients with mild chronic graft-versus-host disease (GvHD) and/or receiving <0.5mg/kg prednisolone (or equivalent); patients with <2nd grade acute GvHD; >3 months after anti-CD20 therapy; postgraft immunosuppression with calcineurin inhibitors is allowed; 2) 20 to 40 patients after recent administration of proteasome inhibitors (0-30 days after treatment), who received at least one full cycle of treatment and achieved a satisfactory and stable disease response, allowing a safe temporary treatment discontinuation for immunization against COVID-19; 3) 20 to 40 patients after a recent anti-CD20 administration (0-180 days after treatment), who received at least one full cycle of treatment and achieved satisfactory and stable disease response, allowing a safe temporary treatment discontinuation for immunization against COVID-19. Other specific patient groups will be enrolled in the cellular immunogenicity part, as the primary analysis results show which specific subpopulations lack humoral immune response. PBMC samples from individuals without prior diagnosis of oncohematological disease will be selected randomly. The samples will be used for assessment of proinflammatory cytokine (interferon-gamma (IFN-gamma), interleukin-2 (IL-2) and IL-4) production and immunophenotypic analysis (CD45, CD3, CD4, CD8, CD16, CD56, CD14, CD19) after stimulation with overlapping S-peptides in PBMC.

Cellular immunogenicity will be evaluated by performing quantitative sequencing for T-cell receptor (TCR) repertoires for SARS-CoV-2-specific antigens using immunoSEQ technology (Adaptive Biotechnologies Inc., 1165 Eastlake Ave E, Seattle, Washington 98109, United States).

For safety analysis patient self-documented systemic events (fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain) occurring up to 7 days following each vaccine dose will be systematized and compared between oncohematological patients and healthy individuals.

For efficacy analysis, PCR confirmed symptomatic disease rates, hospitalization rates and mortality rates will be assessed. In case of detected breakthrough infection, additional biological samples will be obtained as soon as possible to evaluate humoral and cellular immunity at the time of infection and repeated until PCR-negativity is achieved.

• Study Type: Observational
• Enrollment (Anticipated): 3270

Contacts and Locations

• Study Contact: Name: Kazimieras Maneikis, MD; Phone Number: +37068862381; Email: kazimieras.maneikis@santa.lt
• Study Contact Backup: Name: Karolis Šablauskas, MD; Phone Number: +37068862381; Email: karolis.sablauskas@santa.lt

Study Locations

• Lithuania
  • Vilnius, Lithuania, LT-08661
    • Recruiting
    • Vilnius University hospital Santaros klinikos
    • Contact: Kazimieras Maneikis, MD; Phone Number: +37068862381; Email: kazimieras.maneikis@santa.lt
    • Contact: Karolis Šablauskas, MD; Phone Number: +37068862381; Email: karolis.sablauskas@santa.lt
    • Principal Investigator: Kazimieras Maneikis, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 10 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

• Sampling Method: Non-Probability Sample

Study Population

Patients with haematological malignancies compared to healthy control group.

Description

Inclusion criteria for oncohematological patients

1. >/= 12 years of age.
2. Prior diagnosis of oncohematological disease.
3. The patient has signed an informed consent form.
4. The patient was vaccinated with SARS-CoV-2 vaccine.

Inclusion criteria for healthy individuals

1. >/= 12 years of age.
2. Patients without prior diagnosis of oncohematological disease.
3. The patient has signed an informed consent form.
4. The patient was vaccinated with SARS-CoV-2 vaccine.

Exclusion criteria No exclusion criteria will be applied.

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

2

Cohorts and Interventions

Group / Cohort	Intervention / Treatment
Oncohematological patient group; Patients with prior diagnosis of oncohematological disease vaccinated with SARS-CoV-2 vaccine.	Diagnostic test: S-binding IgG, RBD-binding IgG and N-binding IgG immunoassays and SARS-CoV-2 serum neutralization assay, quantitative serum immunoglobulin tests; S-binding IgG, RBD-binding IgG and N-binding IgG immunoassays and SARS-CoV-2 serum neutralization assay, quantitative serum immunoglobulin tests.; Diagnostic test: Assessment of proinflammatory cytokine production and immunophenotypic analysis after stimulation with overlapping S-peptides in peripheral blood mononuclear cells (PBMC); Quantitative evaluation of proinflammatory cytokine (IFN-gamma, IL-2 and IL-4) production after stimulation with overlapping S-peptides in peripheral blood mononuclear cells and immunophenotypic analysis (CD45, CD3, CD4, CD8, CD16, CD56, CD14, CD19); Diagnostic test: Quantitative sequencing for TCR repertoires for SARS-CoV-2-specific antigens; Quantitative sequencing for TCR repertoires for SARS-CoV-2-specific antigens
Healthy control group; Subjects without prior diagnosis of oncohematological disease vaccinated with SARS-CoV-2 vaccine.	Diagnostic test: S-binding IgG, RBD-binding IgG and N-binding IgG immunoassays and SARS-CoV-2 serum neutralization assay, quantitative serum immunoglobulin tests; S-binding IgG, RBD-binding IgG and N-binding IgG immunoassays and SARS-CoV-2 serum neutralization assay, quantitative serum immunoglobulin tests.; Diagnostic test: Assessment of proinflammatory cytokine production and immunophenotypic analysis after stimulation with overlapping S-peptides in peripheral blood mononuclear cells (PBMC); Quantitative evaluation of proinflammatory cytokine (IFN-gamma, IL-2 and IL-4) production after stimulation with overlapping S-peptides in peripheral blood mononuclear cells and immunophenotypic analysis (CD45, CD3, CD4, CD8, CD16, CD56, CD14, CD19); Diagnostic test: Quantitative sequencing for TCR repertoires for SARS-CoV-2-specific antigens; Quantitative sequencing for TCR repertoires for SARS-CoV-2-specific antigens

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Humoral immune response elicited by COVID-19 vaccines	SARS-CoV-2 antibody level in response to COVID-19 vaccines	7 to 21 days after the second vaccine dose

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cellular immune response elicited by COVID-19 vaccines	Evaluation of T-cell phenotype and cytokine production after stimulation with overlapping S-peptides in peripheral blood mononuclear cells using flow cytometry in response to COVID-19 vaccines; Quantitative sequencing for TCR repertoires for SARS-CoV-2-specific antigens	7 to 21 days after the second vaccine dose
Safety of COVID-19 vaccines	Number of systemic events (fever, fatigue, headache, chills, vomiting, diarrhea, new or worsened muscle pain, and new or worsened joint pain)	up to 7 days after each vaccine dose administration
Efficacy of COVID-19 vaccines	Evaluation of COVID-19 incidence	starting 7 days after the completion of vaccination schedule and up to 100 weeks

Collaborators and Investigators

• Sponsor: Vilnius University

Publications and helpful links

General Publications

• Maneikis K, Šablauskas K, Ringelevičiūtė U, Vaitekėnaitė V, Čekauskienė R, Kryžauskaitė L, Naumovas D, Banys V, Pečeliūnas V, Beinortas T, Griškevičius L. Immunogenicity of the BNT162b2 COVID-19 mRNA vaccine and early clinical outcomes in patients with haematological malignancies in Lithuania: a national prospective cohort study. Lancet Haematol. 2021 Aug;8(8):e583-e592. doi: 10.1016/S2352-3026(21)00169-1. Epub 2021 Jul 2.

Study record dates

Study Major Dates

• Study Start (Actual): March 24, 2021
• Primary Completion (Anticipated): March 1, 2024
• Study Completion (Anticipated): March 1, 2024

Study Registration Dates

• First Submitted: April 20, 2021
• First Submitted That Met QC Criteria: May 2, 2021
• First Posted (Actual): May 4, 2021

Study Record Updates

• Last Update Posted (Actual): January 14, 2022
• Last Update Submitted That Met QC Criteria: December 27, 2021
• Last Verified: December 1, 2021

More Information

Terms related to this study

• Keywords: Immunogenicity; Hematologic Neoplasms; COVID-19 Vaccines
• Additional Relevant MeSH Terms: Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Virus Diseases; Infections; Respiratory Tract Infections; Respiratory Tract Diseases; Neoplasms; Pneumonia, Viral; Pneumonia; Lung Diseases; Neoplasms by Site; Hematologic Diseases; COVID-19; Hematologic Neoplasms; Physiological Effects of Drugs; Immunologic Factors; Antibodies; Immunoglobulins; Immunoglobulins, Intravenous
• Other Study ID Numbers: OH-VACC-IMMUN

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No
• IPD Plan Description: No individual data will be shared

Drug and device information, study documents

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