What is the clinical efficacy and safety of SARS-CoV-2 adjuvanted recombinant protein vaccine (monovalent) consisting of a stabilized prefusion trimer of the SARS-CoV-2 S protein in prevention of symptomatic COVID-19 infection?

Study Setting National Institute of Infectious Diseases The National Hospital Sri Lanka Colombo North Teaching Hospital

This will be a Phase III, randomized, modified double-blind, placebo-controlled, multi-stage, multi-center, multi-country study to assess the efficacy, safety, and immunogenicity of two CoV2 preS dTM-AS03 vaccines (monovalent and bivalent) in adults 18 years of age and older with 2 stages. Participants will be screened for eligibility criteria at the time of inclusion and then randomized to either the investigational vaccine or placebo in a 1:1 ratio in each stage as shown below.

1. In Stage 1, the AS03 adjuvanted monovalent vaccine with the prefusion S protein from the prototype (D614) variant will be evaluated against a placebo control.
2. In Stage 2, the AS03 adjuvanted bivalent vaccine with the prefusion S protein from the prototype and South African variant (D614 + B.1.351) will be assessed against a placebo control.

This study will first be initiated globally including Sri Lanka with stage 01, where participants will be randomized in a 1:1 ratio to receive 2 injections 21 days apart of either CoV2 preS dTM-AS03 (D614) or Placebo. The availability of the bivalent vaccine for Stage 2 is scheduled for September 2021 while the monovalent vaccine (Stage 1) is scheduled to start in May 2021. It is expected to complete recruitment of Stage 1 by the middle of August 2021 and therefore do not anticipate any significant overlap in enrollment between the two stages.

In stage 01, total of 8000 participants will be randomized, out of which 6400 will be SARS-CoV-2 naïves and 1600 will be SARS-CoV-2 non naïves. In stage 02, total of 10, 715 participants will be randomized, out of which 8572 will be SARS-CoV-2 naïves and 2143 will be SARS-CoV-2 non naïves.

Randomization will be stratified by age groups (18-59 years of age and 60 years of age and older), baseline SARS-CoV-2 rapid serodiagnostic test positivity, and site. Participants will be randomized using an Interactive Response Technology (IRT).

Study interventions

Investigational medicinal product 1 (Stage 1): CoV2 preS dTM-AS03 (D614) • Form: Solution and emulsion for injection • Composition: prefusion S delta TM COVID-19 antigen D614 strain (10 ?g) and AS03 adjuvant that is an oil-in-water emulsion containing squalene (10.69 milligrams), DL-?- tocopherol (11.86 milligrams) and polysorbate 80 (4.86 milligrams) • Route of administration: Intramuscular (IM) • Frequency: 2 injections administered 21 days apart.

Investigational medicinal product 2 (Stage 2): CoV2 preS dTM-AS03 (D614 + B.1.351) • Form: Solution and emulsion for injection • Composition: prefusion S delta TM COVID-19 antigen D614 + B.1.351 (5 ?g D614 antigen +5 ?g B.1.351 antigen) and AS03 adjuvant that is an oil-in-water emulsion containing squalene (10.69 milligrams), DL-?-tocopherol (11.86 milligrams) and polysorbate 80 (4.86 milligrams) • Route of administration: Intramuscular (IM) • Frequency: 2 injections administered 21 days apart.

Placebo • Form- Liquid • Composition- 0.9% normal saline • Route of administration: Intramuscular (IM) • Frequency: 2 injections administered 21 days apart.

All participants will receive two injections (via intramuscular administration) given 21 days apart, followed by a 12-month safety follow up. Participants will be contacted once a week over the entire duration of the study to inquire about the development of symptoms of COVID-19-like-illness and to remind participants to contact study staff if they experience any symptoms of COVID-19-like illness. Study duration for each participant would be 365 days post-last injection (ie, approximately 386 days total).

Blinding Participants, outcome assessors, investigators, laboratory personnel, sponsor, study staff, those administering the study intervention will remain blinded throughout the study. Those preparing the study interventions will be unblinded.

1. Aged 18 years or older on the day of inclusion (Both male and female)
2. For persons living with HIV, stable HIV infection determined by participant currently on antiretrovirals with CD4 count > 200/mm3
3. Subjects who have had SARS-CoV-2 rapid sero-diagnostic test performed at the time of enrollment to detect presence of SARS-CoV-2 antibodies. Both sero positive and negative subjects will be enrolled however with restriction in sero-positive numbers as a target number of sero-negative subjects need to be enrolled.
4. Does not intend to receive an authorized/approved COVID-19 vaccine despite encouragement by the Investigator to receive the authorized vaccine available to them at the time of enrollment.
5. A female participant is eligible to participate if she is not pregnant or breastfeeding and one of the following conditions applies: o Is of non-childbearing potential. To be considered of non-childbearing potential, a female must be post-menopausal for at least 1 year or surgically sterile. OR o Is of childbearing potential and agrees to use an effective contraceptive method or abstinence from at least 4 weeks prior to the first study intervention administration until at least 12 weeks after the second study intervention administration.

A participant of childbearing potential must have a negative highly sensitive pregnancy test (urine or serum as required by local regulation) within 25 hours before any dose of study intervention. 6. Informed consent form has been signed and dated. 7. Able to attend all visits and to comply with all study procedures 8. Covered by health insurance, only if required by local, regional, or national regulations

1. Known systemic hypersensitivity to any of the vaccine components, or history of a life-threatening reaction to a vaccine containing any of the same substances
2. Dementia or any other cognitive condition at a stage that could interfere with following the study procedures based on Investigator’s judgment.
3. Self-reported thrombocytopenia, contraindicating intramuscular (IM) vaccination based on Investigator’s judgment.
4. Bleeding disorder, or receipt of anticoagulants in the past 21 days preceding inclusion, contraindicating IM vaccination based on Investigator’s judgment.
5. Unstable acute or chronic illness that in the opinion of the Investigator or designee poses additional risk as a result of participation or that could interfere with the study procedures.
6. Moderate or severe acute illness/infection (according to investigator judgment) on the day of vaccination or febrile illness (temperature ? 38.0°C [? 100.4°F]). A prospective participant should not be included in the study until the condition has resolved or the febrile event has subsided.
7. Receipt of any vaccine in the 30 days preceding or on the day of the first study vaccination or planned receipt of any vaccine between the first study vaccination and in the 30 days following the second study vaccination except for influenza vaccination, which may be received at any time in relation to study intervention.
8. Prior administration of a coronavirus vaccine (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2], SARS-CoV, Middle East Respiratory Syndrome [MERSCoV])
9. Receipt of solid-organ or bone marrow transplants in the past 180 days
10. Receipt of anti-cancer chemotherapy in the last 90 days
11. Participation at the time of study enrollment (or in the 30 days preceding the first study vaccination) or planned participation during the present study period in another clinical study investigating a vaccine, drug, medical device, or medical procedure.
12. Deprived of freedom by an administrative or court order, or in an emergency setting, or hospitalized involuntarily
13. Identified as an Investigator or employee of the Investigator or study center with direct involvement in the proposed study, or identified as an immediate family member (ie, parent, spouse, natural or adopted child) of the Investigator or employee with direct involvement in the proposed study