Clinical trial NCT04475081: Use of a Live Attenuated Vaccine as an Immune-based Preventive Against COVID-19-associated Sepsis
Official title: Use of a Live Attenuated Vaccine Repurposed as an Innate Immune-based Preventive Against COVID-19-associated Sepsis/Inflammation
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sepsis Syndrome
Keywords: MMR vaccine
COVID-19
Sepsis
trained innate immunity
myeloid-derived suppressor cells
inflammation
Lead sponsor: Louisiana State University Health Sciences Center in New Orleans
Sponsor class: OTHER
Collaborators: name: Parsemus Foundation
First posted: 2020-07-17
Enrollment: 50
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: MMR vaccine vs placebo
Primary purpose: PREVENTION

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.

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 analyses (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 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, 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.

Eligibility 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

Primary outcomes:
measure: Induction of MDSCs
timeFrame: 30 days post vaccination
measure: Induction of MDSCs
timeFrame: 60 days post vaccination
measure: Induction of MDSCs
timeFrame: 12 months post vaccination
Secondary outcomes:
measure: COVID-19 Infection Positive
timeFrame: 30 days post-vaccination
measure: COVID-19 Infection Positive
timeFrame: 60 days post-vaccination
measure: COVID-19 Infection Positive
timeFrame: 12 months post-vaccination
measure: Health Questionnaire
timeFrame: 14 days post-vaccination
measure: Health Questionnaire
timeFrame: 30 days post-vaccination
measure: Health Questionnaire
timeFrame: 60 days post-vaccination
measure: Health Questionnaire
timeFrame: 3 months post-vaccination
measure: Health Questionnaire
timeFrame: 4 months post-vaccination
measure: Health Questionnaire
timeFrame: 5 months post-vaccination
measure: Health Questionnaire
timeFrame: 6 months post-vaccination
measure: Health Questionnaire
timeFrame: 7 months post-vaccination
measure: Health Questionnaire
timeFrame: 8 months post-vaccination
measure: Health Questionnaire
timeFrame: 9 months post-vaccination
measure: Health Questionnaire
timeFrame: 10 months post-vaccination
measure: Health Questionnaire
timeFrame: 11 months post-vaccination
measure: Health Questionnaire
timeFrame: 12 months post-vaccination
Other outcomes:
Locations:
city: New Orleans
country: United States
facility: Clinical and Translational Research Center
state: Louisiana
Study officials:
affiliation: Louisiana State University Health Sciences Center - New Orleans
name: Paul L Fidel, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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):e00907-20. doi: 10.1128/mBio.00907-20.