Use of a Live Attenuated Vaccine as an Immune-based Preventive Against COVID-19-associated Sepsis

• ClinicalTrials.gov Identifier: NCT04475081
• Recruitment Status: Not yet recruiting
• First Posted: July 17, 2020
• Last Update Posted: July 20, 2020
• Sponsor: Louisiana State University Health Sciences Center in New Orleans
• Collaborator: Parsemus Foundation
• Information provided by (Responsible Party): Paul Fidel, Louisiana State University Health Sciences Center in New Orleans

Study Description

Brief Summary:

The objective of this randomized clinical trial is to test whether administration of live attenuated MMR vaccine (measles mumps rubella; Merck) to eligible adults at highest risk for contracting COVID-19 (healthcare workers, first responders), can induce non-specific trained innate immune leukocytes that can prevent/dampen pathological inflammation and sepsis associated with COVID-19-infection, if exposed.

Condition or disease	Intervention/treatment	Phase
Sepsis Syndrome	Biological: MMR vaccine	Phase 3

Detailed Description:

Clinical Design. Eligible healthcare workers (HCW) or first responders in the greater New Orleans area (n=60) meeting eligibility criteria will be enrolled into a 12 month study by the Louisiana State University Health Sciences Center Clinical & Translational Research Center (LSUHSC CTRC) clinical staff affiliated with the Louisiana Clinical and Translational Research Science (LA CaTS) Center and blindly randomized to receive the live attenuated M-M-R® II vaccine or placebo (sterile saline) via subcutaneous injection in the arm at a baseline visit following informed consent. Subjects will be recruited from local hospitals and EMS stations throughout the greater New Orleans area by distributing recruitment flyers at the local facilities. The flyers will have contact information for HCWs and EMS first responders to call for more information or to schedule an appointment. Additionally, subjects may be referred to the study by other HCWs or first responders aware of study activities. Subject consenting, interviewing, vaccine administration and biospecimen collection will be performed by the CTRC staff, under full Personal Protective Equipment (PPE) protection. Following informed consent, subjects will be asked to complete the Baseline Demographic & History Questionnaire disclosing their demographic information, employment, medication, vaccination, and medical history. Specifically, the medical history will place emphasis on the presence of diabetes, hypertension, heart disease, and their treatments/medications. Subjects will then have their height, weight, body mass index (BMI), vital signs, and pulse oximetry measured. Subjects will also have their body composition and fat percentage measured using the BOD POD Body Composition Tracking System. Female subjects of childbearing potential will be given a urine-based pregnancy test. Approximately 10cc of blood will be collected along with a nasopharyngeal swab for baseline laboratory analysees (serology, RNA, flow cytometry). When available, a finger prick blood sample will be obtained in addition to the other biospecimens for COVID-19 serological analysis. Those subjects that satisfy the inclusion and exclusion criteria (Eligibility Criteria) will be blindly randomized to receive the live attenuated M-M-R® II vaccine or placebo (sterile saline) via subcutaneous injection. Repeat biosampling will occur on days 14, 30, 60, and at 12 months post-vaccination. At each follow-up, anthropometric measurements, vital signs measurement, and symptom assessment for the presence of symptoms related to COVID-19 infection (fever, headache, myalgia, cough, loss of taste or smell, breathing problems), general well-being (i.e., pain, dental concerns, sleep patterns, general stress level, fatigue), and any changes in medications, medical status, and employment will be collected utilizing the Follow-up Symptom & History Questionnaire. Telephone follow-up calls utilizing the Follow-up Symptom Assessment & History Questionnaire will be made on a monthly basis between the 60-day follow-up visit and the 12-month endpoint visit. Should a subject develop symptoms potentially associated with COVID-19 infection at any point during the 12-month study period, that subject will be seen in the clinic by the Infectious Disease (ID) Co-investigator, and a repeat collection of blood and nasopharyngeal biospecimens will be performed for analysis, and the subject will be asked to complete the Follow-up Symptom & History Questionnaire and get another body composition analysis via BOD POD. Subjects will be asked to report the development of any potential COVID-19 infection-related symptoms or positive COVID-19 infection testing outside of the study, as well as any symptoms potentially related to MMR vaccination. Should a subject become admitted to the hospital related to COVID-19 infection, in-patient information will be obtained via the electronic medical record (EMR) when available.

Primary outcome measures will be peripheral blood monocytic MDSCs (M-MDSC) and/or granulocytic MDSCs (G-MDSC) determined by flow cytometry from whole blood samples. Specifically, documented increases in the MDSCs per subject from baseline through 30-60 days post-vaccination is expected in the MMR group compared to placebo group. Measles antibody are also expected to increase in the MMR group and will serve as a control for the MMR vaccination. Stationary levels of MDSCs and measles antibodies are expected in the MMR group over the 12-month period.

The investigators will perform the COVID-19 RNA testing at baseline, 14, 30, and 60 days post-vaccination, and at any point over the 12-month period that symptoms arise. All patients that are COVID-19+ at baseline or become COVID-19+ through the study will be included for secondary outcome analyses. The Secondary outcome measures will be COVID-19 antibodies (seropositive) as evidence of infection, sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level) over the 12-month period post-vaccination. In-patient information will be obtained through the EMR when available. Out-patient information will be obtained via self-reporting utilizing the Follow-up Symptom & History Questionnaire.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 60 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: MMR vaccine vs placebo
• Masking: Single (Participant)
• Masking Description: Randomized by study nurse
• Primary Purpose: Prevention
• Official Title: Use of a Live Attenuated Vaccine Repurposed as an Innate Immune-based Preventive Against COVID-19-associated Sepsis/Inflammation
• Estimated Study Start Date: August 17, 2020
• Estimated Primary Completion Date: October 31, 2021
• Estimated Study Completion Date: December 1, 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: MMR vaccination; Subjects will be randomized to receive the MMR Vaccine subcutaneously	Biological: MMR vaccine; Merck MMR-II vaccine
Placebo Comparator: Placebo control; Subjects will be randomized to receive sterile saline given subcutaneously	Biological: MMR vaccine; Merck MMR-II vaccine

Outcome Measures

Primary Outcome Measures :

1. Induction of myeloid-derived suppressor cells (MDSCs) [ Time Frame: 14 days post-vaccination ]
   peripheral blood monocytic MDSCs (M-MDSC) and/or granulocytic MDSCs (G-MDSC) determined by flow cytometry from whole blood samples as percentage/fold increase over baseline
2. Induction of MDSCs [ Time Frame: 30 days post vaccination ]
   peripheral blood monocytic MDSCs (M-MDSC) and/or granulocytic MDSCs (G-MDSC) determined by flow cytometry from whole blood samples as percentage/fold increase over baseline
3. Induction of MDSCs [ Time Frame: 60 days post vaccination ]
   peripheral blood monocytic MDSCs (M-MDSC) and/or granulocytic MDSCs (G-MDSC) determined by flow cytometry from whole blood samples as percentage/fold increase over baseline
4. Induction of MDSCs [ Time Frame: 12 months post vaccination ]
   peripheral blood monocytic MDSCs (M-MDSC) and/or granulocytic MDSCs (G-MDSC) determined by flow cytometry from whole blood samples as percentage/fold increase over baseline

Secondary Outcome Measures :

1. COVID-19 infection positive [ Time Frame: 14 days post-vaccination ]
   COVID-19 antibodies (seropositive) or COVID-19 RNA+ as evidence of infection
2. COVID-19 infection positive [ Time Frame: 30 days post-vaccination ]
   COVID-19 antibodies (seropositive) or COVID-19 RNA+ as evidence of infection
3. COVID-19 infection positive [ Time Frame: 60 days post-vaccination ]
   COVID-19 antibodies (seropositive) or COVID-19 RNA+ as evidence of infection
4. COVID-19 infection positive [ Time Frame: 12 months post-vaccination ]
   COVID-19 antibodies (seropositive) or COVID-19 RNA+ as evidence of infection
5. Health questionnaire [ Time Frame: 14 days post-vaccination ]
   Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)
6. Health questionnaire [ Time Frame: 30 days post-vaccination ]
   Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)
7. Health questionnaire [ Time Frame: 60 days post-vaccination ]
   Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)
8. Health questionnaire [ Time Frame: 3 months post-vaccination ]
   Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)
9. Health questionnaire [ Time Frame: 4 months post-vaccination ]
   Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)
10. Health questionnaire [ Time Frame: 5 months post-vaccination ]
    Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)
11. Health questionnaire [ Time Frame: 6 months post-vaccination ]
    Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)
12. Health questionnaire [ Time Frame: 7 months post-vaccination ]
    Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)
13. Health questionnaire [ Time Frame: 8 months post-vaccination ]
    Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)
14. Health questionnaire [ Time Frame: 9 months post-vaccination ]
    Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)
15. Health questionnaire [ Time Frame: 10 months post-vaccination ]
    Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)
16. Health questionnaire [ Time Frame: 11 months post-vaccination ]
    Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)
17. Health questionnaire [ Time Frame: 12 months post-vaccination ]
    Sepsis/lung inflammation, ICU/ventilator usage, in-patient health related co-morbidities and self-reporting mental status (such as general fatigue/stress level)

Eligibility Criteria

• Ages Eligible for Study: 18 Years to 70 Years (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

• 18-70 years of age
• Employed as a HCW (hospital, outpatient clinic, private office or 1st responder (EMS) in the greater New Orleans region
• Able to provide a signed and dated informed consent
• Able to provide pre-randomized blood specimen

Exclusion Criteria:

• Any known MMR vaccine contraindication
• Fever
• Weakened resistance toward infections due to a disease in/of the immune system
• Individuals receiving medical treatment that affects the immune response or other immunosuppressive therapy in the last year (see excluded medications).
• Individuals with a congenital cellular immunodeficiency
• Individuals with a malignancy involving bone marrow or lymphoid systems
• Individuals with any serious underlying illness (such as malignancy). People with cardiovascular disease, hypertension, diabetes, and/or chronic respiratory disease are eligible if not immunocompromised (at the discretion of the ID Co-investigator)
• Individuals with known or suspected HIV infection, even if asymptomatic or has normal immune function. (Due to the risk of disseminated MMR infection)
• Individuals with an active skin disease such as eczema, dermatitis or psoriasis at or near the site of vaccination. A different site can be chosen if necessary
• Pregnant or women who think they may test positive for pregnancy in this next month following MMR vaccine administration.
• Individuals who have received a MMR or another live vaccine (i.e., Zostavax, nasal flu vaccine) within the last year
• Individuals with known anaphylactic reaction to any of the ingredients present in the MMR vaccine
• Individuals previously testing positive for SARS-CoV-2 or documented seropositive for SARS-CoV-2 antibodies prior to enrollment in this study

Contacts and Locations

Contacts

Contact: Paul L Fidel, PhD; 985-869-3445; pfidel@lsuhsc.edu

Contact: Mary Meyaski, RN; 504-421-3241; mmeyas@lsuhsc.edu

Sponsors and Collaborators

Louisiana State University Health Sciences Center in New Orleans

Parsemus Foundation

Investigators

• Principal Investigator: Paul L Fidel, PhD; Louisiana State University Health Sciences Center - New Orleans

More Information

Publications:

Fidel PL Jr, Noverr MC. Could an Unrelated Live Attenuated Vaccine Serve as a Preventive Measure To Dampen Septic Inflammation Associated with COVID-19 Infection? mBio. 2020 Jun 19;11(3). pii: e00907-20. doi: 10.1128/mBio.00907-20.

• Responsible Party: Paul Fidel, Professor and Associate Dean, Louisiana State University Health Sciences Center in New Orleans
• ClinicalTrials.gov Identifier: NCT04475081
• Other Study ID Numbers: PF-1214
• First Posted: July 17, 2020
• Last Update Posted: July 20, 2020
• Last Verified: July 2020

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: We plan to share de-identified participant data to other researchers at their request and with justification. Primary and secondary outcome measures will be shared
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR); Analytic Code
• Time Frame: 2 years
• Access Criteria: If fully justified for additional research purposes

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No
• Product Manufactured in and Exported from the U.S.: No

Keywords provided by Paul Fidel, Louisiana State University Health Sciences Center in New Orleans:

MMR vaccine; COVID-19; Sepsis; trained innate immunity; myeloid-derived suppressor cells; inflammation

Additional relevant MeSH terms:

Sepsis; Toxemia; Systemic Inflammatory Response Syndrome; Infection; Inflammation; Pathologic Processes; Shock