Evaluating Safety and Immune Response of Janssen, Moderna, Pfizer/BNT, and Novavax COVID-19 Vaccines for Same and Mixed Boosters in Adolescents and Adults Aged 12-64 With and Without HIV in Kenya, DRC, and Rwanda

Inclusion criteria

• 1. Adolescent male or female aged ≥ 12 to 17 years at screening and adult male or female aged ≥ 18 to 64 years at screening (inclusive).
• 2. Written informed consent (and assent if adolescent), after review of the consent form and having adequate opportunity to discuss the study with an investigator or a qualified designee. For participants who cannot read or write, the consent must be witnessed by a literate third party not involved in study conduct.
• 3. Comply with study procedures, including potential home visits for COVID-19 follow-up.
• 4. Has completed a primary homologous vaccination series at least 3 months prior to enrollment. Vaccinations allowed include:
• a) mRNA (Moderna mRNA-1273 or Pfizer/BNT) - primary series is 2 doses
• b) Adenovector 26 (Janssen Ad26COVS1) - primary series is 1 dose;
• c) Inactivated whole virus (Sinopharm-BIBP or Sinovac) - primary series is 2 doses;
• 5. Female participants of childbearing potential (defined as any female who has experienced menarche and who is NOT surgically sterile [i.e, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy] or postmenopausal [defined as amenorrhea at least 12 consecutive months or documented plasma follicle-stimulating hormone level ≥40 mIU/mL]) must agree to consistently use an effective method of contraception from enrolment and agree to continue adequate contraception until 12 weeks after vaccination:
• a. Condoms (male or female)
• b. Diaphragm with spermicide
• c. Cervical cap with spermicide
• d. Intrauterine device
• e. Oral or patch contraceptives
• f. Hormonal Contraceptives implants or injection e.g., Norplant®, Depo-Provera®.
• g. Abstinence, as a form of contraception, is acceptable if in line with the participant's lifestyle.

NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. These procedures and laboratory test results must be confirmed by physical examination, by participant recall of specific date and hospital/facility of procedure, or by medical documentation of said procedure.

• 6. Medically stable at screening, as determined by the investigator (based on review of health status, vital signs, medical history, and targeted physical examination). Acceptable Vital signs as determined by the Principal Investigator or designee.
• 7. Receiving highly active antiretroviral therapy (HAART) and using the same regimen the past 8 weeks before screening. Changes in antiretroviral dosage within 8 weeks prior to entering the study are permitted. In addition, the exchange of pharmacological formulation (e.g., the conventional formulation for combination formulations) is allowed. If regimen has changed then the participant can be reconsidered for inclusion once the 8 weeks has passed.
• 8. An HIV-1 viral load < 1000 copies/mL and/or CD4 Count ≥ 200 cells/mm3 within 3 months before randomization. May be taken during screening or utilize medical testing from clinic.
• 9. Documentation of HIV positivity by HIV rapid test or assay as per the Ministry of Health guidelines in the respective countries.

Each HIV (-) participant must meet all the following criteria to be enrolled in this study:

• 1. Male or female aged ≥ 18 to 64 years at screening, inclusive.
• 2. Willing and able to give informed consent prior to study enrolment and comply with study procedures, including potential home visits for COVID-19 follow-up.
• 3. Has completed a primary homologous vaccination series at least 3 months prior to enrollment. Vaccinations allowed include:
• a. mRNA (Moderna mRNA-1273 or Pfizer/BNT) - primary series is 2 doses
• b. Adenovector 26 (Janssen Ad26COVS1) - primary series is 1 dose;
• c. Inactivated whole virus (Sinopharm-BIBP or Sinovac) - primary series is 2 doses;
• 4. Female participants of childbearing potential (defined as any female who has experienced menarche and who is NOT surgically sterile [i.e, hysterectomy, bilateral tubal ligation, or bilateral oophorectomy] or postmenopausal [defined as amenorrhea at least 12 consecutive months or documented plasma follicle-stimulating hormone level ≥40 mIU/mL]) must agree to abstain from enrolment and through 3 months after the last vaccination OR agree to consistently use an effective method of contraception from enrolment and through 3 months after the last vaccination:
• a. Condoms (male or female)
• b. Diaphragm with spermicide
• c. Cervical cap with spermicide
• d. Intrauterine device
• e. Oral or patch contraceptives
• f. Hormonal Contraceptives implants or injection e.g., Norplant®, Depo-Provera®.
• g. Abstinence, as a form of contraception, is acceptable if in line with the participant's lifestyle.

NOTE: Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. These procedures and laboratory test results must be confirmed by physical examination, by participant recall of specific date and hospital/facility of procedure, or by medical documentation of said procedure.

• 5. Medically stable at screening, as determined by the investigator (based on review of health status, vital signs, medical history, and targeted physical examination). Acceptable vital signs by PI.
• 6. Documentation of negative HIV rapid test (or assay) as per the Ministry of Health guidelines in the respective countries.

Exclusion criteria

• 1. Use of a heterologous COVID-19 primary series at the platform level (mRNA, Adenovector and inactivated vaccine).
• 2. Use of an extended primary vaccination series or prior booster with any SARS-COV2 vaccine.
• 3. Any subject with prior Adverse Events of Special Interest Relevant to COVID-19 (see table 6).
• 4. Unstable or Severe Chronic disease inclusive of:
• a. Hypertension (elevated blood pressure [SBP>180mmHg or DBP>110mmHg]). Note that participants can be retested once after resting or return on another day for retesting. Participants may also have anti-hypertensive medication adjusted and may be reassessed after at least 2 weeks.
• b. Congestive heart failure (CHF) stage 3 or greater or diagnosed cardiovascular disease that is not controlled using medication in the past 6 months.
• c. Chronic obstructive pulmonary disease (COPD) with a history of an acute exacerbations repeated in the past 2 years. Note: If participant has been stable the last 6 months and are not Gold stage 3 or greater, they may be included.
• d. Asthma stage 4 and/or unstable cases with asthma therapy adjustments in the past that 2 months.
• e. Type 1 or any type 2 diabetes (adult onset) of severe grade by history/medical review or with an HbA1c > 8.5 in the last 6 months.
• f. Chronic kidney disease requiring dialysis or GFR <30 (may use associated creatinine based on age and gender).
• g. Chronic hepatic disease with evidence of hepatic compromise by history/medical review. Includes known Hepatitis B or C.
• h. Chronic or serious neurological diseases (e.g. cerebrovascular disease (including transient ischemic attacks), autoimmune disorders, neurologic deterioration (including dementia), Guillain Barre syndrome).
• i. Any ongoing, symptomatic acute illness requiring medical or surgical care or chronic illness of severe grade or that is not stable over the past 6 months (at the discretion of the investigator).
• j. HIV Stage III/IV
• 5. Cognitive impairment - congenital or acquired
• 6. A child in care i.e., a child who is in the custody, care or guardianship of a director or a director of adoption.
• 7. Participation in research involving an investigational product (drug/biologic/device) within 30 days prior to first study vaccination and planned participation during this study. Exception is if participant in a follow up safety phase and the investigation product has been given > 6 months previously.
• 8. Prior receipt of an Ebola vaccine i.e., Ad26.ZEBOV/MVA-BN-Filo vaccines.
• 9. Received any other vaccine within 4 weeks prior to first study vaccination or planned vaccination within 4 weeks after study vaccination (including mass vaccination campaigns). Participants may be revaluated after the window has passed.
• 10. Any autoimmune or immunodeficiency disease/condition (iatrogenic or congenital), excluding HIV. Note: Stable endocrine disorders that have a confirmed autoimmune etiology (e.g., thyroid, pancreatic), including stable diabetes are allowed.
• 11. Chronic administration (>14 continuous days) of immunosuppressant, systemic glucocorticosteroids, or other immune-modifying drugs within 60 days prior to first study vaccination, excluding HAART. Note: An immunosuppressant dose of glucocorticoid is defined as a systemic dose ≥ 10 mg of prednisone per day or equivalent. The use of topical, inhaled, and nasal glucocorticoids will be permitted.
• 12. Received immunoglobulin, blood-derived products, or other immunosuppressant drugs within 90 days prior to first study vaccination, excluding HAART.
• 13. Known disturbance of coagulation (iatrogenic or congenital). Note: The use of low-dose aspirin (≤ 325 mg/day) as prophylaxis is acceptable in dosages consistent with local standards of care, but the use of other platelet aggregation inhibitors, thrombin inhibitors, Factor Xa inhibitors, or warfarin derivatives is exclusionary, regardless of bleeding history, because these imply treatment or prophylaxis of known cardiac or vascular disease.
• 14. Any disease or disorder that would indicate a life expectancy less than 3 years such as active cancer.
• 15. Any known allergies to products contained in the investigational product or latex allergy or any history of anaphylaxis in relation to any previous vaccination.
• 16. Women who are breastfeeding or who are pregnant at the time of screening or plan to become pregnant within the first 12 months of the study.
• 17. A serious adverse event that occurs between screening and randomization. Subjects will not be allowed to be randomized.
• 18. History of alcohol abuse or drug addiction within 2 years prior to the first study vaccination.
• 19. Any condition (other than HIV) that, in the opinion of the investigator, would pose a health risk to the participant if enrolled (including neurologic or psychiatric conditions deemed likely to impair the quality of safety reporting).
• 20. Study team member or first-degree relative of any study team member (inclusive of sponsor, and site personnel involved in the study).

Temporary exclusions:

• 21. Acute respiratory and/or non-respiratory illness or documented temperature of > 38°C in the past 24 hours. Note: Participant may be re-evaluated after symptoms have resolved for at least 3 days.
• 22. Positive RT-PCR SARS-CoV-2 test during screening or at time of randomization. Subject must be SARS-COV-2 symptom free and have a negative test prior to randomization.
• 23. Documented severe SARS-CoV-2 infection in the last 3 months. May be rescreened when this period has passed.