The Immune Response of Heterologous Boost Third Dose of mRNA and Protein COVID-19 Vaccine

• ClinicalTrials.gov Identifier: NCT05132855
• Recruitment Status: Active, not recruiting
• First Posted: November 24, 2021
• Last Update Posted: January 19, 2022
• Sponsor: Chang Gung Memorial Hospital
• Collaborator: Medigen Vaccine Biologics Corp.
• Information provided by (Responsible Party): Chang Gung Memorial Hospital

Study Description

Brief Summary:

The severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) specific antibody and neutralizing antibody level induced by adenovirus vector vaccines were lower than mRNA vaccines. Vaccine efficacy of ChAdOx1 nCoV-19 was lower than BNT162b2 and mRNA 1273 in clinical trials. The emergence of highly transmissible and mutant variants of SARS-COV-2 has raised the concern of COVID-19 vaccine effectiveness. The complete vaccination rate is still low in Taiwan. Strict border control measures are imposed by Central Epidemic Command Center. However, the measure of quarantine for flight crew is considered one of the breach of COVID-19 infection control. Despite most of the flight crew has fully vaccinated, several episodes of breakthrough infection occurred among flight crew resulting in domestic infection recently. Low neutralizing antibody was found in a proportion of fully vaccinated flight crew and healthcare workers. A 3rd booster COVID-19 dose is considered for flight crew and healthcare workers. This study is to determine the safety, reactogenicity, and immunogenicity of heterologous 3rd booster of mRNA and protein COVID-19 vaccines.

Condition or disease	Intervention/treatment	Phase
COVID-19; Breakthrough Infection	Biological: BNT162b2; Biological: mRNA-1273; Biological: MVC-COV1901	Phase 1; Phase 2

Detailed Description:

Safety concerns of COVID-19 ChAdOx1 nCoV-19 vaccine have led to a recommendation of heterologous boost with mRNA vaccine in several countries. Initial safety data of heterologous prime-boost with ChAdOx1 nCoV-19 and BNT162b2 vaccines showed well-tolerated. No major differences in reactogenicity were observed between homologous and heterologous vaccination. Immunogenicity of heterologous ChAdOx1 nCoV-19 and BNT162b2 vaccination is better compared with homologous ChAdOx1 nCoV-19 vaccination. Despite the scarcity of safety and immunogenicity of heterologous ChAdOx1 nCoV-19 and mRNA 1273 vaccination, the preliminary reports revealed similar findings. Although both T and B memory cells contribute to the protection, there is evidence that neutralizing serum antibody levels have high correlates of protection for symptomatic SARS-COV-2 infection. The SARS-COV-2 specific antibody and neutralizing antibody level induced by adenovirus vector vaccines were lower than mRNA vaccines. Vaccine efficacy of ChAdOx1 nCoV-19 was lower than BNT162b2 and mRNA 1273 in clinical trials. In the real world, the ChAdOx1 nCoV-19 vaccine appeared less effective than the BNT162b2 and mRNA1273 vaccine in preventing SARS-COV-2 infection. The emergence of highly transmissible and mutant variants of SARS-COV-2 has raised the concern of COVID-19 vaccine effectiveness. The S protein of the widespread SARS-COV-2 delta variant reduced the binding of neutralizing antibodies. Breakthrough infections are increasing worldwide. Vaccine effectiveness decreased significantly after the emergence of the SARS-COV-2 delta variant. Waning immunity is another potential cause of breakthrough infection. Centers for Disease Control of the United States has advocated 3rd booster dose of mRNA vaccine for people at risk of COVID-19 and those who work in high-risk settings including healthcare workers. Israel expanded its 3rd COVID-19 vaccine boost to those aged over 12 years old. The complete vaccination rate is still low in Taiwan. Strict border control measures are imposed by Central Epidemic Command Center. However, the measure of quarantine for flight crew is considered one of the breaches of COVID-19 infection control. Despite most of the flight crew has fully vaccinated, several episodes of breakthrough infection occurred among flight crew resulting in domestic infection recently. Low neutralizing antibody was found in a proportion of fully vaccinated flight crew and healthcare workers. A 3rd booster COVID-19 dose is considered for flight crew and healthcare workers. This study is to determine the safety, reactogenicity, and immunogenicity of heterologous 3rd booster of mRNA and protein COVID-19 vaccines.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 340 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Participant)
• Primary Purpose: Prevention
• Official Title: Safety, Reactogenicity, and Immunogenicity of Heterologous Boost Third Dose of mRNA and Protein COVID-19 Vaccine: a Single-blind and Randomized Study
• Actual Study Start Date: November 30, 2021
• Estimated Primary Completion Date: April 2023
• Estimated Study Completion Date: April 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Booster group 1 (BNT162b2 30ug); The participants in this group will receive BNT162b2 30ug as the booster dose.	Biological: BNT162b2; BNT162b2 is an mRNA vaccine to prevent COVID-19 infection and is approved by the emergency use of authorization (EUA) by the Taiwan FDA.
Experimental: Booster group 2 (mRNA-1273 50ug); The participants in this group will receive mRNA-1273 50ug as the booster dose.	Biological: mRNA-1273; mRNA-1273 is an mRNA vaccine to prevent COVID-19 infection and is approved by the emergency use of authorization (EUA) by the Taiwan FDA.
Experimental: Booster group 3 (mRNA-1273 100ug); The participants in this group will receive mRNA-1273 100ug as the booster dose.	Biological: mRNA-1273; mRNA-1273 is an mRNA vaccine to prevent COVID-19 infection and is approved by the emergency use of authorization (EUA) by the Taiwan FDA.
Experimental: Booster group 4 (MVC-COV1901 15ug); The participants in this group will receive MCV COVID-19 vaccine 15ug as the booster dose.	Biological: MVC-COV1901; MCV COVID-19 vaccine is a protein subunit vaccine containing S2P S-protein which passes the EUA by Taiwan FDA.

Outcome Measures

Primary Outcome Measures :

1. The immune response after heterologous boost third dose of COVID-19 vaccines after homologous prime-boost AZD1222 vaccination [ Time Frame: Day 28 after third dose boost ]
   Immunogenicity studies include SARS-CoV-2 anti-spike IgG, the 50% neutralizing antibody titer (NT50) and IFN - secreting T cells specific to whole spike protein.
2. The immune response after heterologous boost third dose of COVID-19 vaccines after homologous prime-boost AZD1222 vaccination [ Time Frame: Day 180 after third dose boost ]
   Immunogenicity studies include SARS-CoV-2 anti-spike IgG, the 50% neutralizing antibody titer (NT50) and IFN - secreting T cells specific to whole spike protein.
3. The immune response after heterologous boost third dose of COVID-19 vaccines after homologous prime-boost AZD1222 vaccination [ Time Frame: Day 360 after third dose boost ]
   Immunogenicity studies include SARS-CoV-2 anti-spike IgG, the 50% neutralizing antibody titer (NT50) and IFN - secreting T cells specific to whole spike protein.

Secondary Outcome Measures :

1. The safety of heterologous boost third dose of COVID-19 vaccines [ Time Frame: From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 12 months ]
   Evaluation of the safety profile included Solicited local adverse events (AEs), solicited systemic AEs, AE of special interest (AESI), and serious adverse events (SAEs)

Eligibility Criteria

• Ages Eligible for Study: 20 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Criteria

Inclusion Criteria:

1. Participant is willing to give written informed consent for participation in the trial.
2. Participants should receive 2 doses of the AZD1222. Evidence of this will be gathered from medical history and/or medical records including the COVID-19 vaccine registration yellow card.

Exclusion Criteria:

The participant may not enter the trial if ANY of the following apply:

1. Fever or evidence of upper respiratory tract infections
2. Confirmed COVID-19 cases (PCR-confirmed infection or detectable anti-nucleocapsid protein IgG)
3. History of anaphylaxis, severe allergic disease, or reactions likely to be exacerbated by any component of study vaccines (e.g. hypersensitivity to the active substance or any of the listed ingredients of any study vaccine).
4. Malignancy requiring receipt of immunosuppressive chemotherapy or radiotherapy for treatment of solid organ cancer/hematological malignancy within the 6 months prior to enrollment.
5. Bleeding disorder (e.g. factor deficiency, coagulopathy or platelet disorder), or prior history of significant bleeding or bruising following intramuscular injections or venipuncture.
6. Has received vaccines other than COVID-19 vaccine within one month
7. Pregnancy or willingness/intention to become pregnant within 3 months post booster vaccine
8. Aged < 20 years or unable to sign the informed consent
9. Any other significant disease, disorder, or finding which may significantly increase the risk to the volunteer because of participation in the study, affect the ability of the volunteer to participate in the study, or impair interpretation of the study data or insufficient level of language to undertake all study requirements in the opinion of the Investigators.

Contacts and Locations

Locations

Taiwan

Chang Gung Memorial Hospital

Taoyuan city, Taiwan, 333

Sponsors and Collaborators

Chang Gung Memorial Hospital

Medigen Vaccine Biologics Corp.

Investigators

• Principal Investigator: Cheng-Hsun Chiu, MD, PhD; Chang Gung Memorial Hospital

More Information

Publications:

Hillus D, Schwarz T, Tober-Lau P, Vanshylla K, Hastor H, Thibeault C, Jentzsch S, Helbig ET, Lippert LJ, Tscheak P, Schmidt ML, Riege J, Solarek A, von Kalle C, Dang-Heine C, Gruell H, Kopankiewicz P, Suttorp N, Drosten C, Bias H, Seybold J; EICOV/COVIM Study Group, Klein F, Kurth F, Corman VM, Sander LE. Safety, reactogenicity, and immunogenicity of homologous and heterologous prime-boost immunisation with ChAdOx1 nCoV-19 and BNT162b2: a prospective cohort study. Lancet Respir Med. 2021 Nov;9(11):1255-1265. doi: 10.1016/S2213-2600(21)00357-X. Epub 2021 Aug 13.

Liu X, Shaw RH, Stuart ASV, Greenland M, Aley PK, Andrews NJ, Cameron JC, Charlton S, Clutterbuck EA, Collins AM, Dinesh T, England A, Faust SN, Ferreira DM, Finn A, Green CA, Hallis B, Heath PT, Hill H, Lambe T, Lazarus R, Libri V, Long F, Mujadidi YF, Plested EL, Provstgaard-Morys S, Ramasamy MN, Ramsay M, Read RC, Robinson H, Singh N, Turner DPJ, Turner PJ, Walker LL, White R, Nguyen-Van-Tam JS, Snape MD; Com-COV Study Group. Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial. Lancet. 2021 Sep 4;398(10303):856-869. doi: 10.1016/S0140-6736(21)01694-9. Epub 2021 Aug 6.

Normark J, Vikström L, Gwon YD, Persson IL, Edin A, Björsell T, Dernstedt A, Christ W, Tevell S, Evander M, Klingström J, Ahlm C, Forsell M. Heterologous ChAdOx1 nCoV-19 and mRNA-1273 Vaccination. N Engl J Med. 2021 Sep 9;385(11):1049-1051. doi: 10.1056/NEJMc2110716. Epub 2021 Jul 14.

• Responsible Party: Chang Gung Memorial Hospital
• ClinicalTrials.gov Identifier: NCT05132855
• Other Study ID Numbers: 202101767A3
• First Posted: November 24, 2021
• Last Update Posted: January 19, 2022
• Last Verified: November 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

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

Keywords provided by Chang Gung Memorial Hospital:

COVID-19; Breakthrough infection; Heterologous vaccine booster; mRNA vaccine; Protein subunit vaccine

Additional relevant MeSH terms:

COVID-19; Infections; Respiratory Tract Infections; Pneumonia, Viral; Pneumonia; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases