Covid-19 Living Data

Trial ISRCTN73765130 ; EudraCT 2021-002175-19
Publication Munro APS, Lancet Infect Dis, 2022
Dates: 2022-01-11 to 2022-01-25
Funding: Public/non profit (National Institute for Health Research (NIHR) and the Vaccine Task Force. ChAdOx1 nCoV-19, BNT162b2, and mRNA-1273 used in this study were supplied by the UK Health Security Agency)
Conflict of interest: Yes

Methods
	RCT
	Location : Multicenter / UK Follow-up duration (months): 1.7
	ChAdOx1 primary series + BNT162b2 boost + BNT162b2 2nd boost (n =44) ChAdOx1 primary series + BNT162b2 boost + half-dose mRNA-1273 2nd boost (n = 44) BNT162b2 primary series + BNT162b2 boost + BNT162b2 2nd boost (n = 39) BNT162b2 primary series + BNT162b2 boost + half-dose mRNA-1273 2nd boost (n = 39)
Inclusion criteria	Willing and able to give written informed consent Male or Female aged 30 years or above in good health as determined by a trial clinician may have well controlled or mild-moderate comorbidity Female participants of childbearing potential must be willing to ensure that they or their partner use effective contraception from 1 month prior to first immunisation continuously until 3 months after boost immunisation In the Investigator’s opinion, is able and willing to comply with all trial requirements Willing to allow their General Practitioner and consultant, if appropriate, to be notified of participation in the trial Willing to allow investigators to discuss the volunteer’s medical history with their General Practitioner and access all medical records when relevant to study procedures Agreement to refrain from blood donation during the study Received priming dose of COVID-19 vaccination in December 2020, January or February 2021 and is at least 84 days post second vaccination.
Exclusion criteria	Receipt of any vaccine (licensed or investigational) other than the study intervention within 30 days before and after each study vaccination (one week for licensed seasonal influenza vaccine or pneumococcal vaccine) Prior or planned receipt of any other investigational or licensed vaccine or product likely to impact on interpretation of the trial data (e.g. adenovirus vectored vaccines, any coronavirus vaccines) Participants who are pregnant at enrolment or planning to become pregnant during the first 3 months following vaccination Administration of immunoglobulins and/or any blood products within the three months preceding the planned administration of the vaccines Any confirmed or suspected immunosuppressive or immunodeficient state asplenia recurrent severe infections and use of immunosuppressant medication within the past 6 months, except topical steroids or short-term oral steroids (course lasting ≤14 days) History of 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 SmPC-listed ingredients of the Pfizer vaccine) Any history of anaphylaxis Current diagnosis of or treatment for cancer (except basal cell carcinoma of the skin and cervical carcinoma in situ) Bleeding disorder (e.g. factor deficiency, coagulopathy or platelet disorder), or prior history of significant bleeding or bruising following IM injections or venepuncture Continuous use of anticoagulants, such as coumarins and related anticoagulants (i.e. warfarin) or novel oral anticoagulants (i.e. apixaban, rivaroxaban, dabigatran and edoxaban) History of cerebral venous sinus thrombosis, antiphospholipid syndrome or heparin induced thrombocytopenia and thrombosis (HITT or HIT type 2) Suspected or known current alcohol or drug dependency 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 Severe and/or uncontrolled cardiovascular disease, respiratory disease, gastrointestinal disease, liver disease, renal disease, endocrine disorder and neurological illness (mild/moderate well controlled comorbidities are allowed) History of active or previous auto-immune neurological disorders (e.g. multiple sclerosis, Guillain-Barre syndrome, transverse myelitis). Bell’s palsy will not be an exclusion criterion Significant renal or hepatic impairment Scheduled elective surgery during the trial Participant with life expectancy of less than 6 months Participants who have participated in another research trial involving an investigational product in the past 12 weeks. This does not exclude participants in trials of AZD1222 (ChAdOx1 nCOV-19) who were originally recipients of placebo and who received AZD1222 (ChAdOx1 nCOV-19) or BNT162b2 as part of the “national schedule” with AZD1222 (ChAdOx1 nCOV-19) or BNT162b2 dose 1 from mid-Dec 2020 through end February 2021 and then AZD1222 (ChAdOx1 nCOV-19) or BNT162b2 second dose 12 twelve weeks later (this is allowed by the COV001 and COV002 protocols) Insufficient level of English language to undertake all study requirements in opinion of the Investigators except where translation has been able to be provided and is available.
Interventions
	Intervention 1 IM 3mcg dose of BNT162b2, 6 months after ChAdOx1 primary schedule and BNT162b2 booster 1 IM dose of 50 mcg mRNA-1273 (half dose), 6 months after ChAdOx1 primary schedule and BNT162b2 booster 1 IM 3mcg dose of BNT162b2, 6 months after BNT162b2 primary schedule and BNT162b2 booster
	Control 1 IM dose of 50 mcg mRNA-1273 (half dose), 6 months after BNT162b2 primary schedule and BNT162b2 booster
Participants
	Randomized 166 participants
	Characteristics of participants Type of participants: Healthy adults N=166 80 males Children: 0 Pregnant women: 0 Immunocompromized patients: 0 Mean age: Age range: NR
	Description of participants Healthy adults aged 30 years or over, including elderly and those with well controlled or mild-moderate comorbidity, who had received a 2-dose primary schedule of either BNT162b2 or ChAdOx1 and a BNT162b2 booster at 18 centers in the UK
Primary outcome
	In the register 1. Immunology measured using serum Anti Spike protein IgG levels at 28 days [this outcome was changed to 14 days in the prospective protocol amendment for the fourth dose sub-study]; 2. Safety/Reactogenicity measured using the following from participant records: Incidence and details of solicited adverse events between 0 and 7 days, Incidence and details of unsolicited adverse events between 0 and 28 days, Incidence and details of Serious Adverse Events (SAEs) and Adverse Events of Special Interest (AESIs) throughout the study
	In the report 1. Anti-spike protein IgG antibody titres at 14 days; 2. cellular immune responses; 3. solicited local and systemic adverse events within 7 days of the fourth dose, unsolicited adverse events within 28 days of the fourth dose, medically attended adverse events up to 3 months following the fourth dose, adverse events of special interest, and serious adverse events. Serious adverse events and adverse events of special interest throughout the study.
Documents available	Protocol Yes. In English Statistical plan Yes Data-sharing stated: Yes, When the study is completed Data accessibility: Individual participant data will be made available when the study is complete upon reasonable requests made to the corresponding author ( s.faust@soton.ac.uk ); data can be shared through secure online platforms after proposals are approved. All the sequence datasets used in the T-cell analysis are available in the public GISAID database (https://www.gisaid.org).
Risk of bias Overall The overall risk of bias reported in the table corresponds to the highest risk of bias for the outcomes assessed for the systematic review	Some concerns
General comment	In addition to the published article, the trial registries, protocol, statistical analysis plan and supplementary appendices were used in data extraction and assessment of risk of bias. The article reports early results from a fourth booster sub-study. Follow up for longer term results continues. The primary outcomes in the article reflect those in the prospective protocol amendment relating to this fourth booster sub-study. The trial (n = 166) did not have any pre-specified target sample size, but enrolled those who had received a BNT162b2 booster after either BNT162b2 or mRNA-1273 primary schedules in a previous stage of the overall study.