Randomised trial optimising COVID-19 vaccination in patients with chronic health conditions and a poor response to standard vaccination

INTERVENTION: For the main study randomised comparison, patients will randomised using a minimisation program (developed by the CRCTU) in a 1:1 ratio. Patients will be randomised to receive: Arm 1: Pfizer SARS‐CoV2 Vaccine Arm 2: Moderna SARS‐CoV2 Vaccine For the sub‐study randomised comparison, patients will be randomised using a minimisation program in a 1:1:1 ratio. Patients will be randomised to receive: Arm 1: Pfizer SARS‐CoV2 Vaccine Arm 2: Moderna SARS‐CoV2 Vaccine Arm 3: Novavax SARS‐CoV2 Vaccine The dose of Pfizer vaccine is 30 µg contained in 0.3 ml of the diluted vaccine given intramuscularly. The dose of Moderna vaccine is 0.5 ml, containing 100 micrograms of messenger RNA (mRNA), given intramuscularly. The dose of Novovax vaccine is 5 µg recombinant spike protein with 50 µg Matrix‐M1 adjuvant (0.5 ml). A dose of 5 µg recombinant spike protein with 50 µg Matrix‐M1 adjuvant (0.5 ml) will be given intramuscularly. Where possible participants will be followed up in accordance with standard clinical practice for the relevant disease cohort and data will be collected retrospectively from clinic records 3 months after re‐boost vaccination. Where participants do not attend for a routine clinic visit, data may be collected following an additional telephone follow‐up call. CONDITION: Patients with 1) solid cancer; 2) lymphoid malignancies; 3) immune‐mediated rheumatic diseases; 4) end stage kidney disease; 5) liver disease; 6) inflammatory bowel disease on immune suppressive therapy; 7) haematopoietic stem cell transplant; and 8) primary immunodeficiency who have received two doses of SARS‐CoV‐2 vaccine but have proven inadequate response to the SARS‐CoV‐2 vaccine ; Infections and Infestations ; COVID‐19 (SARS‐CoV‐2 infection) PRIMARY OUTCOME: ; 1. Anti‐spike SARS‐CoV‐2 antibody and T cell responses to SARS‐CoV‐2 peptides following Pfizer and Moderna re‐boost vaccinations will be measured before the re‐boost vaccination was given and will be compared with those achieved at day 21 post dose:; 1.1. Anti‐spike SARS‐CoV‐2 antibodies following re‐boost vaccination will be measured using the Roche platforms by the Public Health England (PHE) Laboratories at Porton Down. The Roche assays will measure the presence and amount of serum antibodies to both the spike (S) and the nucleocapsid (N) antigens of SARS‐CoV‐2. This assay will enable the discrimination of antibody responses to SARS‐CoV‐2 that results from vaccination and/or SARS‐CoV‐2 infection.; 1.2. T cell responses to SARS‐CoV‐2 peptides following re‐boost vaccination will be measured using the Oxford Immunotec modified T‐spot discovery SARS‐CoV‐2 assay. This IFN? ELISpot assay will provide insights into the participants’ reactivity to SARS‐CoV‐2 s1, s2, nucleocapsid and membrane peptides.; SECONDARY OUTCOME: ; 1. In a sub‐set of participants with lymphoid malignancies, measure the change in vaccine‐specific immunogenicity in response to vaccination (as defined for the primary outcome) with Pfizer, Moderna or Novavax vaccines.; 2. In all patient groups, we will assess the capacity of re‐boost vaccine‐induced SARS‐CoV‐2 antibodies to neutralise/block SARS‐CoV‐2 infection using IgG (pseudo)neutralisation assays (CE marked Menarini Diagnostics surrogate neutralisation assay) and measured in samples collected before the re‐boost vaccination was given and compared with those achieved at day 21 post‐dose.; INCLUSION CRITERIA: 1. Aged =18 years 2. Have an inadequate response to two doses of SARS‐CoV‐2 vaccine measured at least 14 days after receipt of the second vaccine, defined by SARS‐CoV‐2 spike antibody response. An inadequate response is defined as: 2.1. Antibody non‐response: SARS‐CoV‐2 anti‐spike antibodies below the level of detection using the PHE Roche platform [or equivalent] =8 AU/ml, or 2.2. Antibody low‐response: SARS‐CoV‐2 anti‐spike antibodies >8 and <400 AU/mL using the Roche platform [or equivalent]) 2.3. There is no agreed international/WHO cut off for titres of AU following vaccination and serologic assessment. As such, the low responder status for OCTAVE‐DUO eligibility is by definition arbitrary. We have examined the serology levels obtained in the OCTAVE study, compared with PITCH (health care workers without vulnerable conditions) and elected to choose a titre that equ