A Vaccine Booster (GEO-CM04S1) for the Prevention of COVID-19 in Patients With Chronic Lymphocytic Leukemia

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.

Eligibility Criteria:
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)