Early High-Titre Convalescent Plasma in Clinically Vulnerable Individuals With Mild COVID-19

Cohort 1: Elderly and high COVID-age population:

Inclusion criteria:

• SARS-CoV-2 RNA detected in a specimen, ≤ 7 days after onset of symptoms

• Symptoms of COVID-19 (so including but not limited to: fever; cough; breathlessness;chest pain; wheeze; sore throat; haemoptysis; runny nose; fatigue; muscle or jointpain; confusion; headache; seizures; nausea; vomiting; diarrhoea; abdominal pain;poor appetite; skin ulcers or rash; ear pain; conjunctivitis; anosmia; bleeding;lymphadenopathy. The attending clinician will determine if symptoms are consistentwith COVID-19.

• Clinical status not requiring admission to hospital for COVID-19 disease and oxygensupport

• Ability to transfuse (per randomisation) within 7 days after onset of symptoms

• Men or women, 70 years or older OR

• under 70 years with significant comorbidities (arterial hypertension, diabetes,obesity, asthma or other chronic pulmonary disease, cardiovascular disease,cerebrovascular disease, chronic kidney disease / dialysis, hemoglobinopathies,liver disease, chronic neurological disease, rheumatoid arthritis, lupus orpsoriasis) resulting in a 'COVID-age' of 70 years or more according to the ALAMArisk calculator https://alama.org.uk/covid-19-medical-risk-assessment/

Exclusion Criteria:

• Age < 18 years (France and Germany only)

• Prior or concurrent treatment for COVID-19 (unless listed as authorized)

• History of COVID-19 disease in the last 90 days prior to enrollment

• Prior anti-SARS-CoV-2 immunization

• Contraindication to receiving CCP including previous history of transfusion-relatedacute lung injury (TRALI) or moderate or severe allergic reaction to bloodcomponents

• Known participant objection to receiving plasma products

• Primary or acquired immune deficiency listed below (see cohort 2)

• Refusal to participate expressed by patient or legally authorised representative

• Pregnancy

Cohort 2: High-risk immunocompromised population

Inclusion criteria:

• SARS-CoV-2 RNA, or positive antigenic test, detected in a specimen, ≤ 7 days afteronset of symptoms

• Symptoms of COVID-19 (so including but not limited to: fever; cough; breathlessness;chest pain; wheeze; sore throat; haemoptysis; runny nose; fatigue; muscle or jointpain; confusion; headache; seizures; nausea; vomiting; diarrhoea; abdominal pain;poor appetite; skin ulcers or rash; ear pain; conjunctivitis; anosmia; bleeding;lymphadenopathy. The attending clinician will determine if symptoms are consistentwith COVID-19.

• Clinical status not requiring admission to hospital for COVID-19 disease and oxygensupport

• Ability to transfuse (per randomisation) within 7 days after onset of symptoms

• Male or female with extremely high risk including: a. Patients with at least one of the following acquired immune deficiencies i. Lymphoid malignancies treated within the last 12 months ii. Lymphoid malignancieswith persistent hypogammaglobulinaemia (IgG < 5g/L) iii. Myeloid malignanciestreated by chemotherapy within the last 12 months iv. Myeloid malignancies treatedby anti-BCL-2 drugs within the last 12 months v. Myeloid malignancies associatedwith prolonged neutropenia (≥ 6 weeks) vi. Solid tumour undergoing treatment withchemotherapy (until 3 months after completion of the last chemotherapy cycle) vii.Allogenic hematopoietic stem cell transplantation within the last 12 months oranytime if on-going treatment for chronic GVHD viii. Organ transplantation ix.Anti-B (CD20/CD19) MoAb and/or mycophenolate mofetil treatment within the last 12months x. Anti-CD19/CD20 CAR-T cell treatment xi. ATG or alemtuzumab treatmentwithin the last 6 months xii. AIDS

OR b. Patients with primary lymphoid immune deficiencies. i. B cell deficiencies (such as Bruton agammaglobulinemia) ii. T cell deficiencies (such as Wiskott Aldrich disease) iii. Combined deficiencies (such as Common variable immunodeficiency).

OR c. Patients without detectable seroconversion ≥ 3 weeks after complete vaccination schedule with an approved vaccine.

Exclusion Criteria:

• Age < 18 years (France and Germany only)

• Prior or concurrent treatment for COVID-19 (dexamethasone, anti-IL-6/IL6R,remdesivir) except for prophylactic administration of anti-SARS-CoV-2 monoclonalantibodies (pre or post exposure) and authorized specific treatment

• History of COVID-19 disease in the last 90 days prior to enrollment

• Contraindication to receiving CCP including previous history of transfusion-relatedacute lung injury (TRALI) or moderate or severe allergic reaction to bloodcomponents

• Known participant objection to receiving plasma products

• Refusal to participate expressed by patient or legally authorised representative

• Pregnancy