Ad26.COV2.S as a Heterologous Booster in Adults After Single- or Two-Dose of Inactivated COVID-19 Vaccine

This study aims to address evidence gaps regarding the safety, reactogenicity and immune responses of a heterologous boost of a single dose of Ad26.COV2.S (half or full dose) at pre-specified time intervals in recipients who are documented to have received either 1-dose or 2-doses (primary series completion) of inactivated COVID-19 vaccines, Sinovac and/or Sinopharm.

This is a prospective, multi-center, observer-blind Phase 1/2 adaptive study to assess the safety, reactogenicity, and immunogenicity of a booster dose of Ad26.COV2.S in adults ≥ 18 years of age in Study Part A and Part B. A total of 690 participants will be recruited. If the optional Group (A4) is feasible and enrolled, the total recruitment will be 800 participants. Priority enrolment is given to Groups A1 and A2, followed by Groups A3 and B1. Enrolment of groups are open-label allocation and assessor-masked.

The Study is divided into 2 Parts: Part A and B.

Study Part A is a prospective, multi-center, assessor-masked Phase 1/2 study to assess a booster dose (3rd dose) of Ad26.COV2.S as an IM injection in the deltoid muscle in adults who have completed the two-dose homologous primary series of inactivated vaccine of Sinovac or Sinopharm, 21 to 35 days apart and who meet eligibility criteria. Participants will receive either the full-dose (5x10\^10 vp) or half-dose (2.5x10\^10 vp) of the study product, and at early (45-75 days) or later (90-240 days) time interval and followed from Visit 1 (V1) to Visit 7 (V7) at 336 days.

A total of 580 adult volunteers aged 18 years or older, who have verified vaccination cards with documented completion of homologous primary vaccination series with either two doses of Adsorbed COVID-19 (inactivated) Sinovac (SV) or Sinopharm (SP) vaccine, against original and novel variants of SARS-CoV-2 will be enrolled. A 20% dropout rate is assumed. Enrolment is increased to 360 (300+20% dropout) for the safety assessment, to detect common adverse events with an event rate of 1%.

Part B is a prospective, multi-center, open-label, assessor-masked Phase 1/2 heterologous prime-boost study to assess the Ad26.COV2.S (full dose) as the 2nd vaccination in subjects who are documented to all have received the 1st dose of Sinovac or all received the 1st dose of Sinopharm COVID-19 vaccine, with an interval of 28 days or more, followed from Visit 1 (V1) to Visit 7 (V7) at 336 days.

Together with the Sponsor, the PIs will decide on the feasibility of enrolment of participants who all have already received 1 dose of Sinopharm or who all have received 1dose of Sinovac, based on current public health policy and vaccine coverage.

For safety assessment:

Adverse events (AEs) will be systematically collected at all clinic visits. Solicited AEs will be assessed in all subjects immediately (30 minutes) after each injection. Subjects (or with necessary supports) will record solicited AEs daily in the Diary Card for the seven days following injection. If a solicited AE is ongoing at a 7-day post-injection follow-up visit (Visit 2), or occurs after 7 days post-injection, the event will be recorded as AE and continued to be followed as per AE monitoring requirements.

Adverse events and special reporting situations, whether serious or non-serious, that are related to study procedures or that are related to non-investigational sponsor products will be reported from the time a signed and dated informed consent form (ICF) is obtained until the end of the study/early withdrawal. All other unsolicited AEs will be reported from the time of vaccination until completion of the participant's last study-related procedure. All AESIs, SAEs, and AEs leading to discontinuation from the study (regardless of the causal relationship) are to be reported from the moment of vaccination until completion of the participant's last study related procedure.

For immunological assessment:

Primary objectives

1. To assess the IgG immune response against the Spike protein of SARS-CoV-2, measured by ELISA and compared with baseline (pre-boost titer) at Days 28, 84, 168 and 336 following either half dose (2.5x10\^10 virus particles (vp)) or full dose (5x10\^10 vp) of Ad26.COV2.S vaccination at pre-specified time intervals in adults who have already received either one-dose or two-doses of an inactivated COVID-19 vaccine.
2. To assess a subset for functional (neutralizing) humoral immune responses elicited by each of the regimens as measured by pseudovirus neutralization assay, IgG at baseline, Days 28, 84, 168 and 336 following Ad26.COV2.S vaccination.

Secondary objective

1. To assess a subset for functional (neutralizing) humoral immune responses elicited by each of the regimens as measured by microneutralization neutralization assay, IgG at baseline, Days 28, 84, 168 and 336 following Ad26.COV2.S vaccination.

Exploratory Objectives

1. To characterize PCR-confirmed COVID-19 breakthrough infections following booster vaccination by assessing anti-S and anti-N IgG.
2. To characterize cellular immune responses including Th1/Th2.
3. To consider statistical tests of noninferiority in comparing the different study arms.
4. To assess Adenovirus 26 neutralizing antibodies at baseline if feasible.

Study duration: Subjects will be followed for approximately 336 days following Ad26.COV2.S vaccination. The total study period will be 18 months, including 12-month follow-up period.

The Clinical Data Management System, including eCRFs, statistical analysis and data archival are under the responsibility of the center of excellence for Biomedical and Public Health Informatics (BIOPHICS), the center of data management for clinical research at the Faculty of Tropical Medicine, Mahidol University.

Based on the final protocol of the study, a comprehensive set of CRFs/eCRFs will be prepared to capture all the relevant data required for analysis and reporting.

Information about COVID-19 disease, correlates of immunity, safety, and local epidemiology and public health context regarding the new SARS-CoV-2 virus are rapidly evolving during the pandemic. Therefore, it is critical to recognize that the approach outlined in this document may be adapted as new data, expert consensus and public health policies evolve.

Eligibility Criteria:
Inclusion Criteria:

Potential participants must meet all inclusion criteria to be enrolled and participate in the study, as follows:

1. Adult male or female aged 18 years or more on the day of signing the ICF, confirmed by identification cards.
2. Verified, documentation of past COVID-19 vaccination i. Study Part A: having completed the 2-dose homologous primary regimen (21 to 35 days apart) of inactivated COVID-19 vaccine of either Sinovac-Sinovac OR Sinopharm-Sinopharm ii. Study Part B: having received one dose of inactivated COVID-19 vaccine of either Sinovac or Sinopharm with the appropriate interval period
3. Women of childbearing potential who are test negative with a highly sensitive urine pregnancy test at Visit 1, prior to study vaccine administration.
4. Subject has provided written informed consent prior to performance of any study-specific procedures and is willing and has means to be contacted and to contact the investigator during the study.
5. In the investigator's clinical judgment, the participant is in good health, or has stable and well-controlled medical conditions.
6. Participant agrees to not donate bone marrow, blood, and blood products from the study vaccine administration until 3 months after receiving the study vaccine.

Exclusion Criteria:

Potential participants who meet any of the following exclusion criteria will be excluded from enrolment and participation in the study:

1. The participant has a clinically significant acute illness (this does not include minor illnesses such as diarrhea or mild upper respiratory tract infection), or is a patient under investigation (PUI) or has a body temperature ≥38.0ºC (100.4°F) within 24 hours prior to the planned study vaccination. Assignment may be made at a later date is permitted at the discretion of the investigator. Please notify the Sponsor (or medical monitor) of this decision.
2. Contraindication to Ad26.COV2.S according to labelling of the product. For example, if the participant has a known or suspected allergy or history of anaphylaxis or other serious adverse reactions to vaccines or their excipients (including specifically the excipients of the study vaccine;refer to the IB (IB Edition 5 Ad26.COV2.S 2021 and its addenda).
3. Pregnant or planning to become pregnant within 3 months after study vaccine administration
4. Participant has a history or current condition as follows

   1. Known documented history of COVID-19 infection prior to enrollment
   2. Any confirmed or suspected immunosuppressive or immunodeficient state.
   3. Heparin-induced thrombocytopenia or thrombosis in combination with thrombocytopenia.
   4. Acute polyneuropathy (e.g. Guillain-Barré syndrome).
   5. Capillary leak syndrome
   6. Contraindication to IM injections and blood draws e.g., bleeding disorders.
   7. An underlying clinically significant acute or chronic medical condition or physical examination findings for which, in the opinion of the investigator, participation would not be in the best interest of the participant (e.g., compromise the well being) or that could prevent, limit, or confound the protocol-specified assessments.
   8. Major psychiatric illness which in the investigator's opinion would compromise the participant's safety or compliance with the study procedures.
5. If the participant received or plans to receive:

   1. Licensed live attenuated vaccines - within 28 days before or after planned administration of study vaccine.
   2. Other licensed (not live) vaccines - within 14 days before or after planned administration of study vaccine.
   3. Treatment with immunoglobulins (Ig) in the 3 months or exogenous blood products (autologous blood transfusions are not exclusionary) in the 4 months before the planned administration of the study vaccine or has any plans to receive such treatment during the study.
6. If the participant cannot communicate reliably with the investigator, or, in the opinion of the investigator, is unlikely to adhere to the requirements of the study or is unlikely to complete the full course of vaccination and observation.
7. Employee of the study center directly involved with the proposed study or with study investigators.