A Study to Assess the Safety and Immunogenicity of a COVID-19 Vaccine Booster in Healthy Adults

A Phase I/IIa, Dose-finding Study to Assess the Safety and Immunogenicity of an Orf Virus-based COVID-19 Vaccine Booster (Prime-2-CoV_Beta) in Healthy Adults

This is an open-label, first-in-human, dose-finding study to evaluate the safety and immunogenicity of a booster vaccination of Prime-2-CoV_Beta in healthy participants.

Study Overview

• Status: Recruiting
• Conditions: COVID-19
• Intervention / Treatment: Biological: Prime-2-CoV_Beta

Detailed Description

Eligible participants will undergo baseline assessments and will receive 1 injection of Prime-2-CoV_Beta at Day 1. Participants will be followed up through 6 months post-booster vaccination. Follow-up visits will be performed at Days 4, 8, 15, 29, and Months 3 and 6, to assess the safety, tolerability, and immunogenicity of Prime-2-CoV_Beta. Additional safety and tolerability data will be assessed 1 day and 2 days after booster vaccination (Days 2 and 3) by telephone. Initially, a total of 60 participants were planned to be vaccinated in 5 cohorts of 12 participants each. Dose ranging of Prime-2-CoV_Beta was planned to be done by dose escalation with doses ranging from 3x104 plaque forming units (PFUs) up to 3x10^7 PFUs.

With protocol Version 7.0, Cohort 6 with 12 participants was added with 6x10^7 PFU. With protocol Version 8.0, 1 additional cohort, Cohort 7 (1.2x10^8 PFU, stratified by previous COVID-19 vaccinations and previous SARS-CoV-2 infections) with 24 participants will be added (total number thus 96 participants).

Procedures for Cohorts 6 and 7 will be the same as for Cohorts 1 - 5, except that for some participants in Cohort 7 ORFV shedding in urine, saliva, blood, and stool will be evaluated.

• Study Type: Interventional
• Enrollment (Estimated): 96
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: University Hospital Tübingen; Phone Number: +49 7071 2987179; Email: ITMPM@med.uni-tuebingen.de

Study Locations

• Germany
  • Baden-Wurttemberg
    • Tübingen, Baden-Wurttemberg, Germany, 72074
      • Recruiting
      • University Hospital Tübingen, Institute of Tropical Medicine
      • Contact: Email: ITMPM@med.uni-tuebingen.de
  • Hamburg
    • Hamburg, Hamburg, Germany, 20359
      • Recruiting
      • Bernhard-Nocht-Institut für Tropenmedizin
      • Contact: Email: ITMPM@med.uni-tuebingen.de

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 55 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion Criteria:

Inclusion criteria

1. Healthy adult men or women aged 18 to 55 years

2. Previous COVID-19 vaccination and previous SARS-CoV-2 infection as follows:

   1. Cohorts 1 to 7a: Full course of vaccination e.g., having received at least 3 doses of a licensed mRNA COVID-19 vaccine or having received at least 2 doses of a licensed mRNA COVID-19 vaccine and a prior SARS-CoV-2 infection, with the last dose of the vaccine being administered ≥ 10 weeks before Day 1 as documented in a respective vaccination certificate
   2. Cohort 7b: No more than 2 doses of any licensed COVID-19 vaccine. Those with fewer COVID-19 vaccinations, preferably none or just one, will be given preference. Non-mRNA COVID-19 vaccines are acceptable. The last vaccine dose must have been given ≥ 10 weeks before Day 1 as documented in a respective vaccination certificate
3. Able to understand the participant information and providing written informed consent
4. Body mass index of 18.5 to 30.0 kg/m² and weight > 50 kg at Screening

5. Women of childbearing potential must:

   1. have a negative pregnancy test at Screening (blood) and at Day 1 (urine)
   2. agree to use, and be able to comply with, highly effective measures of contraception without interruption, from 14 days before Prime-2-CoV_Beta booster vaccination until the end of the study.

   A highly effective method of contraception or birth control (failure rate less than 1% per year when used consistently and correctly) for this study: combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, transdermal, injectable), progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, implantable), intrauterine device, intrauterine hormone-releasing system, bilateral tubal occlusion, sexual abstinence or vasectomized sexual partner. Abstinence is only acceptable as true abstinence when this is in line with the preferred and usual lifestyle of the participant (abstinent on a long-term and persistent basis). The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant. (Periodic abstinence [e.g., calendar, ovulation, symptothermal, post-ovulation methods and withdrawal] are not acceptable methods of contraception.) Postmenopausal (no menses for at least 1 year without alternative medical cause) or surgically sterile women (tubal ligation, hysterectomy or bilateral oophorectomy) may be enrolled.

6. Male participants must agree not to intend to father a child or to donate sperm starting at Screening, throughout the clinical study. Male participants must also

   1. abstain from sexual intercourse with a female partner (acceptable only if it is the participant's usual form of birth control/lifestyle choice: abstinent on a long-term and persistent basis). The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the participant or
   2. use adequate barrier contraception (male condom) during treatment with the investigational product until the end of the study, and
   3. ensure that, if they have a female partner of childbearing potential, the partner uses a highly effective contraceptive method as outlined in inclusion criterion number 5
   4. use condoms during the entire study if they have a pregnant partner, to avoid exposure of the fetus to the investigational product
7. Willing and able to comply with all study procedures based on the investigator's judgment

Exclusion Criteria:

Previous and concomitant therapy:

1. Receipt of any vaccine (licensed or investigational) from 4 weeks before Prime-2-CoV_Beta booster vaccination or anticipated vaccination during the study until 6 weeks after the Prime-2-CoV_Beta booster vaccination
2. Previous vaccination against COVID-19 with vaccines (licensed or investigational) other than mRNA-based vaccines (licensed or investigational) only applicable for Cohorts 1 to 7a
3. Current or previous treatment with another investigational drug and/or medical device (within 30 days of enrollment or 5 half-lives of that investigational drug)
4. Administration of immunoglobulins or any blood products within 2 months of Prime-2-CoV_Beta booster vaccination

5. Chronic administration of medication associated with impaired immune responsiveness as judged by the investigator (including, but not limited to: immunosuppressive therapy, systemic corticosteroids exceeding 10 mg/day of prednisone equivalent, allergy shots for hypo-sensitization, immunoglobulin, interferon, immunomodulators, cytotoxic drugs, or other similar or toxic drugs) within 2 months before the Prime-2-CoV_Beta booster vaccination (Day 1). Inhaled/nebulized, intra-articular, intrabursal, or topical (skin or eyes) corticosteroids are permitted.

   Previous and concomitant medical condition:

6. Active SARS-CoV-2 infection, confirmed by a commercially available SARS-CoV-2 rapid antigen test at Day 1, or currently on quarantine
7. {deleted}
8. Known history of severe adverse reactions to any vaccine and/or severe allergic reactions to any component of the study vaccine, to any drug, or to any other exposure
9. Known history of angioedema
10. Pregnant or lactating women
11. Any confirmed or suspected immunosuppressive or immunodeficient condition
12. Known history of Guillain-Barré Syndrome
13. Known infection with human immunodeficiency virus, hepatitis C virus or hepatitis B virus
14. Active cancer (malignancy) within 5 years before Day 1 (except for adequately treated non-melanomatous skin carcinoma, at the discretion of the investigator)
15. Moderate or severe illness and/or fever > 38.0 °C within 1 week before Prime-2-CoV_Beta booster vaccination
16. Any clinically significant health problem (medical history and physical examination) or clinically significantly abnormal finding in biochemistry and/or hematology blood tests, urinalysis, or electrocardiogram at Screening according to the investigator's opinion
17. Current or history of cardiovascular disease or structural cardiac disease (including chronic or congenital heart conditions, such as chronic hypertension, coronary heart disease, myocardial infarction and arrhythmias, hypertrophic cardiomyopathy, as well as a history of myocarditis after mRNA vaccinations)
18. History of mRNA vaccination-associated adverse events that were in nature and severity beyond the common AEs expected
19. Current or history of gastrointestinal disease, liver disease, renal disease or endocrine disorders, (including diabetes) and neurological illness (excluding migraine), when judged as clinically significant according to the investigator's opinion
20. Current or history of chronic respiratory diseases, including mild asthma treated by on-demand medication (resolved childhood asthma is allowed)

21. Current or history of alcohol and/or drug abuse within the last 6 months before Day 1

    Previous and concomitant clinical study experience

22. Current participation in another study or previous enrollment in this clinical study

    Other exclusion criteria

23. Investigator or employee of the study group or sponsor with direct involvement in the proposed study or relatives of the research staff with direct involvement in the proposed study
24. Prolonged exposure to sheep or goats (e.g., shepherds, sheep farmer)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

7

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort 1; Prime-2-CoV_Beta, dose: 30 000 PFUs	Biological: Prime-2-CoV_Beta; 1 intramuscular injection (1.0 mL each) into the deltoid muscle on Day 1
Experimental: Cohort 2; Prime-2-CoV_Beta, dose: 300 000 PFUs	Biological: Prime-2-CoV_Beta; 1 intramuscular injection (1.0 mL each) into the deltoid muscle on Day 1
Experimental: Cohort 3; Prime-2-CoV_Beta, dose: 3 000 000 PFUs	Biological: Prime-2-CoV_Beta; 1 intramuscular injection (1.0 mL each) into the deltoid muscle on Day 1
Experimental: Cohort 4; Prime-2-CoV_Beta, dose: 150 000 000 PFUs	Biological: Prime-2-CoV_Beta; 1 intramuscular injection (1.0 mL each) into the deltoid muscle on Day 1
Experimental: Cohort 5; Prime-2-CoV_Beta, dose: 30 000 000 PFUs	Biological: Prime-2-CoV_Beta; 1 intramuscular injection (1.0 mL each) into the deltoid muscle on Day 1
Experimental: Cohort 6; Prime-2-CoV_Beta, dose: 60 000 000 PFUs	Biological: Prime-2-CoV_Beta; 1 intramuscular injection (1.0 mL each) into the deltoid muscle on Day 1
Experimental: Cohort 7; Prime-2-CoV_Beta, dose: 1 200 000 000 PFUs	Biological: Prime-2-CoV_Beta; 1 intramuscular injection (1.0 mL each) into the deltoid muscle on Day 1

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of participants with treatment-emergent adverse events (TEAEs) and serious adverse events (SAEs) throughout the study	All safety data will be summarized descriptively overall and by cohort. TEAEs will be summarized by descriptive statistics using contingency tables (counts of events, number and proportion of participants with events) and presented by system organ class and preferred term, as well as by severity.	Day 1 (vaccination day) to month 6 (end of study visit, ±14 days)
Proportion of participants with solicited local adverse events (first 7 days after Prime-2-CoV_Beta booster vaccination): pain at injection site, redness, induration, and swelling.	Solicited local adverse events will be summarized by descriptive statistics using contingency tables (counts of events, number and proportion of participants with events).	Day 1 (vaccination day) to day 8 (Visit 3; ±1 day)
Proportion of participants with solicited systemic adverse events (first 7 days after Prime-2-CoV_Beta booster vaccination): fever, fatigue, headache, chills, vomiting, nausea, diarrhea, new or worsened muscle pain, new or worsened joint pain.	Solicited systemic adverse events will be summarized by descriptive statistics using contingency tables (counts of events, number and proportion of participants with events).	Day 1 (vaccination day) to day 8 (Visit 3; ±1 day)
Proportion of participants with unsolicited treatment-emergent adverse events throughout the study	All unsolicited adverse events which occur after the first administration of investigational product are defined as treatment-emergent adverse events. Treatment-emergent adverse events will be summarized by descriptive statistics using contingency tables (counts of events, number and proportion of participants with events) and presented by system organ class and preferred term, as well as by severity.	Day 1 (vaccination day) to month 6 (end of study visit, ±14 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Level of neutralizing antibody titers versus SARS CoV-2 (Wuhan wild type) at each post-booster vaccination assessment	Immunogenicity endpoints will be descriptively analyzed by cohort and visit. Separate analyses will be done for the different parameters, e.g., different antibodies evaluated with different serological immunogenicity assays.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
Geometric mean fold rise (GMFR) of neutralizing antibodies (versus Wuhan wild type) from Baseline to each post-booster vaccination assessment	The fold change from Baseline will be computed for each participant. The fold rise is calculated as the ratio of the post- vs pre-vaccination titer value. The fold change from Baseline will be summarized using descriptive statistics by cohort and visit. Additionally, the GMFR with 95% CI will be presented.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
IgG antibody titer versus SARS-CoV-2 receptor-binding protein	Immunogenicity endpoints will be descriptively analyzed by cohort and visit. Separate analyses will be done for the different parameters, e.g., different antibodies evaluated with different serological immunogenicity assays.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
Geometric mean titers (GMT) of receptor-binding protein-specific IgG antibodies	Immunogenicity endpoints will be descriptively analyzed by cohort and visit. Separate analyses will be done for the different parameters, e.g., different antibodies evaluated with different serological immunogenicity assays.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
Geometric mean fold rise of receptor-binding protein-specific IgG antibodies from Baseline	The fold change from Baseline will be computed for each participant. The fold rise is calculated as the ratio of the post- vs pre-vaccination titer value. The fold change from Baseline will be summarized using descriptive statistics by cohort and visit. Additionally, the geometric mean fold rise with 95% confidence interval will be presented.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
Proportion of participants with adverse events of special interest throughout the study	Adverse events of special interest will be summarized by descriptive statistics using contingency tables (counts of events,number and proportion of participants with events) and presented by system organ class and preferred term, as well as by severity. The frequency (% of participants) of adverse events of special interest throughout the study will be tabulated.	Day 1 (vaccination day) to day 8 (Visit 3; ±1 day)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
IgG antibody titer versus SARS-CoV-2 S1 protein	Immunogenicity endpoints will be descriptively analyzed by cohort and visit. Separate analyses will be done for the different parameters, e.g., different antibodies evaluated with different serological immunogenicity assays.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
Geometric mean titers of IgG S1-specific antibodies	Absolute values of serological immunogenicity assays as described will be presented using descriptive summary statistics by cohort and visit. Additionally, Geometric mean titers with 95% confidence interval (CI) will be provided. For each cohort, serological immunogenicity assays will be presented graphically displaying Geometric mean titers with 95% CIs at all visits.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
Geometric mean fold rise of IgG S1-specific antibodies from Baseline	The fold change from Baseline will be computed for each participant. The fold rise is calculated as the ratio of the post- vs pre-vaccination titer value. The fold change from Baseline will be summarized using descriptive statistics by cohort and visit. Additionally, the geometric mean fold rise with 95% CI will be presented.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
IgG antibody titer versus SARS-CoV-2 N-protein	Immunogenicity endpoints will be descriptively analyzed by cohort and visit. Separate analyses will be done for the different parameters, e.g., different antibodies evaluated with different serological immunogenicity assays.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
Geometric mean titers of N-specific IgG antibodies	Absolute values of serological immunogenicity assays as described will be presented using descriptive summary statistics by cohort and visit. Additionally, geometric mean titers with 95% confidence interval (CI) will be provided. For each cohort, serological immunogenicity assays will be presented graphically displaying geometric mean titers with 95% CIs at all visits.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
Geometric mean fold rise of N-specific IgG antibodies from Baseline	The fold change from Baseline will be computed for each participant. The fold rise is calculated as the ratio of the post- vs pre-vaccination titer value. The fold change from Baseline will be summarized using descriptive statistics by cohort and visit. Additionally, the geometric mean fold rise with 95% confidence intervals will be presented.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
Level of neutralizing antibody titers versus the variant of concern SARS-CoV-2_Beta, SARS-CoV-2_Delta and SARS-CoV-2_Omicron at each post-booster vaccination assessment	Immunogenicity endpoints will be descriptively analyzed by cohort and visit. Separate analyses will be done for the different parameters, e.g., different antibodies evaluated with different serological immunogenicity assays.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
Geometric mean fold rise of neutralizing antibodies from Baseline to each post-booster vaccination assessment	The fold change from Baseline will be computed for each participant. The fold rise is calculated as the ratio of the post- vs pre-vaccination titer value. The fold change from Baseline will be summarized using descriptive statistics by cohort and visit. Additionally, the geometric mean fold rise with 95% confidence intervals will be presented.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 3 (±14 days), month 6 (end of study visit, ±14 days)
Percentage of cytokine producing S and N protein-specific T-cells compared to Baseline	Analyses based on S- and N-specific antibodies will be performed as described for receptor-binding protein specific antibodies.	Day 1 (vaccination day), day 8 (±1 day), day 15 (±2 days), day 29 (±1 day), month 6 (end of study visit, ±14 days)
Additional assays to measure the immune response to Prime-2-CoV_Beta and the immune response to the Orf virus vector backbone	Orf virus-specific antibodies will be summarized descriptively as described for virus-specific antibodies.	Day 1 (vaccination day), day 15 (±2 days), day 29 (±1 day), month 6 (end of study visit, ±14 days)
Additional assays to measure ORF virus (ORFV) shedding in urine, saliva, blood, and stool	ORFV shedding will be assessed with quantitative polymerase chain reaction to allow detection of genome copies of ORFV.	Day 1 (vaccination day), day 2, day 4, day 8 (±1 day)

Collaborators and Investigators

• Sponsor: University Hospital Tuebingen
• Collaborators: FGK Clinical Research GmbH; VisMederi srl; Staburo GmbH; Viedoc Technologies AB
• Investigators: Principal Investigator: Meral Esen, Dr., University Hospital Tübingen, Institute of Tropical Medicine

Publications and helpful links

General Publications

• Esen M, Fischer-Herr J, Gabor JJ, Gaile JM, Fleischmann WA, Smeenk GW, de Moraes RA, Belard S, Calle CL, Woldearegai TG, Egger-Adam D, Haug V, Metz C, Reguzova A, Loffler MW, Balode B, Matthies LC, Ramharter M, Amann R, Kremsner PG. First-in-Human Phase I Trial to Assess the Safety and Immunogenicity of an Orf Virus-Based COVID-19 Vaccine Booster. Vaccines (Basel). 2024 Nov 18;12(11):1288. doi: 10.3390/vaccines12111288.

Study record dates

Study Major Dates

• Study Start (Actual): June 24, 2022
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2026

Study Registration Dates

• First Submitted: May 24, 2022
• First Submitted That Met QC Criteria: May 24, 2022
• First Posted (Actual): May 25, 2022

Study Record Updates

• Last Update Posted (Actual): April 7, 2026
• Last Update Submitted That Met QC Criteria: March 31, 2026
• Last Verified: March 1, 2026

More Information

Terms related to this study

• Keywords: SARS-CoV-2; vaccine; COVID-19; Orf virus
• Additional Relevant MeSH Terms: Respiratory Tract Infections; Infections; RNA Virus Infections; Virus Diseases; Respiratory Tract Diseases; Lung Diseases; Pneumonia, Viral; Pneumonia; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; COVID-19; PRIME-2-CoV_Beta COVID-19 vaccine
• Other Study ID Numbers: PRiME2_21_1; 2024-511266-36-00 (Ctis); WHO UTN Number (Other Identifier: U1111-1303-8564)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• 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