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This phase II trial compares the effect of the GEO-CM04S1 vaccine with the current standard of care vaccine in preventing COVID-19 infections in patients with chronic lymphocytic leukemia (CLL). The GEO-CM04S1 vaccine uses a modified vaccinia virus (MVA) backbone that may be more effective at boosting COVID-19 immunity in patients with poor immune responses. MVA strongly induces T cell expansion (infection fighting blood cells) even in the background of a suppressed immune system, which is the case in the targeted CLL patient population. Using the GEO-CM04S1 vaccine may be more effective at preventing COVID-19 infection in patients diagnosed with CLL.

PRIMARY OBJECTIVE:

I. Estimate the T cell-based immune response rate on day 56 post-injection of synthetic MVA-based SARS-CoV-2 vaccine COH04S1 (GEO-CM04S1) vaccine boost administered at 2.5x10^8 plaque-forming unit (PFU) or standard of care (SOC) vaccine administered as standard of care.

SECONDARY OBJECTIVES:

I. Evaluate the safety of single-dose vaccine boost based on moderate and unacceptable toxicities up to day 28 post-injection for the GEO-CM04S1 and SOC vaccines.

II. Estimate the T cell-based immune response rate at day 112 post-injection of GEO-CM04S1 vaccine at 2.5x10^8 PFU vs SOC severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger ribonucleic acid (mRNA) vaccine administered as COVID-19 vaccine boosters.

III. Select the more promising vaccine to study further as a booster in patients with CLL.

IV. Evaluate SARS-CoV-2 S and N-specific Th1 vs Th2 polarization. V. Estimate the magnitude and durability of T-cell-based immune responses over a 12-month period.

VI. Estimate the levels and durability of SARS-CoV-2-specific IgG in a 12-month period.

VII. Evaluate levels of antibodies neutralizing SARS-CoV-2 in original strain and in variants of concern (VOC) based on the Centers for Disease Control and Prevention (CDC) definition using Spike-pseudotyped lentivirus.

VIII. Evaluate the overall safety profile during follow-up (12 months). IX. Estimate the incidence and severity of COVID-19 infection during follow-up (12 months).

EXPLORATORY OBJECTIVES:

I. Determine the SARS-CoV-2 variant by sequencing virus from polymerase chain reaction (PCR)-confirmed infected participants.

II. Evaluate activated/cycling and memory phenotype markers in SARS-CoV-2 stimulated T cells.

III. Estimate SARS-CoV-2-specfic serum IgA levels measured by enzyme-linked immunoassay (ELISA).

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive GEO-CM04S1 vaccine intramuscularly (IM) on days 0 and 84 on study.

ARM II. Patients receive mRNA vaccine injection IM on days 0 and 84 on study.

Patients undergo blood sample collections throughout the study and are monitored for 1 year.

Inclusion Criteria:

• Documented informed consent of the participant and/or legally authorized representative

• Age: >= 18 years

• Eastern Cooperative Oncology Group (ECOG) =< 1

• Histologically confirmed diagnosis of CLL according to World Health Organization (WHO) classification

• Prior COVID-19 Vaccination (2 or more Pfizer or Moderna) with last injection >= 3 months prior

• Fully recovered from the acute toxic effects (except alopecia) to =< Grade 1 to prior anti-cancer therapy

• White Blood Cells (WBC) >= 1,000/mm^3 (To be performed within 14 days prior to Day 1 of protocol therapy)

• Platelets >= 50,000/mm^3 (To be performed within 14 days prior to Day 1 of protocol therapy)

• Total bilirubin =< 1.5 X upper limit of normal (ULN) (unless has Gilbert's disease) (To be performed within 14 days prior to Day 1 of protocol therapy)

• Aspartate aminotransferase (AST) =< 2.5 x ULN (To be performed within 14 days prior to Day 1 of protocol therapy)

• Alanine transaminase (ALT) =< 2.5 x ULN (To be performed within 14 days prior to Day 1 of protocol therapy)

• Creatinine clearance <1.5 ULN (To be performed within 14 days prior to Day 1 of protocol therapy)

• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test (To be performed within 14 days prior to Day 1 of protocol therapy)

  • If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required

• Agreement by females and males of childbearing potential to use an effective method of birth control or abstain from heterosexual activity for the course of the study through at least 6 weeks after the last vaccine injection

  • Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Exclusion Criteria:

• Known current SARS CoV-2 infection
• Prior Evusheld or other anti-SARS CoV-2 prophylaxis < 2 weeks prior
• Prior hematopoietic cell transplantation (HCT) or chimeric antigen receptor (CAR) T cell therapy within the previous year
• Systemic corticosteroids required for chronic conditions at doses > 0.5mg/kg/day prednisone equivalent within 7 days of enrollment
• Intensive cytotoxic therapies, T-cell depleting therapies, within 30 days of enrollment; however, patients with stable disease on maintenance therapies are allowed (See ConMeds for lists of acceptable and contraindicated therapies)
• Participants who have had a live vaccine =< 30 days prior to administration of any dose of study vaccine or subjects who are =< 2 weeks within administration of inactivated vaccines (e.g., influenza vaccine). Flu shots are allowed > 2 weeks before a study vaccine injection and > 2 weeks post study vaccine injection
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to study agent (e.g., egg allergies)
• Active infection not controlled on appropriate therapy
• History of adverse event with a prior smallpox vaccination
• History of pericarditis or myocarditis
• Any MVA vaccine or poxvirus vaccine in the last 12 months
• Females only: Pregnant or breastfeeding
• Any other condition that would, in the Investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

This trial is observer-blinded because the physical appearance of GEO-CM04S1 and mRNA vaccine may vary. The investigators, treating clinicians, participants, and other study staff, including the nurses involved in soliciting or recording of AEs, will be blinded through the day 112 visit.

The study statisticians, pharmacists, and nurses who administer the vaccine injections will be unblinded. To avoid inadvertent unblinding of the participants at the time of injection, the syringe will be obscured from view by the nurse during injection.