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

A Multi-Centre, Randomized, Double Blind, Phase 2b Trial to Evaluate the Safety and Immunogenicity of Janssen Ad26COVS1 (or mRNA (Moderna mRNA-1273 or Pfizer/BNT) and Novavax NVX-CoV2373 COVID-19 Vaccines for Homologous and Heterologous Boosting in Adolescents and Adults Aged 12 to 64 Years With and Without HIV Infection in 3 African Countries Kenya, Democratic Republic of Congo, and Rwanda.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a novel coronavirus that emerged in the human population in Wuhan City, Hubei Province, China in December 2019. As of Jan 2022, there are over 328 million SARS-CoV-2 case worldwide and over 5.54 million deaths as a result of infection with SARS-CoV-2 (COVID-19). According to WHO Situation Report on 17 January 2022, Africa has 7 million confirmed cases with over 160, 804 deaths. The COVID-19 pandemic has caused global suffering, mortality, and severe economic pressures. There is thus a continued urgent global need to develop effective and safe vaccines and drugs to make them available at scale and equitably across all countries including in Africa.

Despite the rapid successes in vaccine development and issuance of WHO Emergency Use Listings (EUL), the WHO SAGE Interim Reports and FDA Emergency Use Authorization (EUA) for COVID-19 vaccine evaluations have reported limitations on safety and efficacy data in certain populations including children and adolescents, pregnant women, and immunocompromised individuals such as those with HIV/AIDS who are at higher risk of severe COVID-19 disease. Africa is especially vulnerable in this respect given the high prevalence of HIV/AIDS in countries such as Kenya where the prevalence is over 20% in some places.

The risk of recurring new waves of COVID-19 cases caused by Variants of Concern (VOC) exacerbates global public health crisis. A weak immune response to either single or two doses of primary vaccination against SARS-CoV-2 has been observed in immunocompromised population. Emerging data from observational studies consistently show waning immunity to primary vaccination for SARS-CoV-2 mutants, and a decline in vaccine effectiveness against SARS-CoV-2 infection and COVID-19 with time since primary vaccinations. These factors have led to consideration of the potential need for, and optimal timing of, booster doses for vaccinated populations. However, vaccine inequality, lack of availability of the same vaccine product used for primary vaccinations and unpredictable vaccine supply remain a challenge in LMIC. Consideration of heterologous COVID-19 vaccine to allow interchangeability (mix and match) use of vaccine products available in LMIC would therefore allow for programmatic flexibility.

Based on a recent systematic review and meta-regression analysis, across the four WHO EUL COVID-19 vaccines with the most data (i.e., BNT162b2, mRNA 1273, Ad26.COV2.S and ChAdOx1-S [recombinant] vaccine), vaccine effectiveness against severe COVID-19 decreased by about 8% (95% confidence interval (CI): 4-15%) over a period of 6 months in all age groups. In adults above 50 years, vaccine effectiveness against severe disease decreased by about 10% (95% CI: 6 - 15%) over the same period. Vaccine effectiveness against symptomatic disease decreased by 32% (95% CI: 11 - 69%) for those above 50 years of age. For some inactivated vaccines (CoronaVac and COVID-19 vaccine BIBP), WHO has already issued the recommendation for the administration of an additional dose to those aged 60 years or older as part of the primary series to make initial immunity more robust.

The FDA issued a EUA for the Janssen Ad26.COV.S1 COVID-19 vaccine for active immunization to prevent COVID-19 caused by SARS-CoV-2 in individuals 18 years of age and older. In September 2021, both the single dose and 2 dose Janssen COVID-19 vaccine regimens demonstrated high efficacy (79% protection (CI, 77%-80%) for COVID-19-related infections and 81 percent (CI, 79%-84%) for COVID-19-related hospitalizations. vs 94% (CI, 58%-100%) protection against symptomatic COVID-19 in the U.S. respectively. Furthermore, the safety profile of the vaccine remained consistent and generally well-tolerated in the 2 regimens. Finally, when a booster of the Janssen COVID-19 vaccine given 6 months after the single shot, antibody levels increased nine-fold one week after the booster and continued to climb to 12-fold higher four weeks after the booster.

On June 14, 2021, Novavax reported the results of its PREVENT-19 pivotal Phase 3 trial of the NVX-CoV2373. The results showed an overall vaccine efficacy of 90.4% (95% CI: 82.9 - 94.6) in the US and Mexico. Sequenced data showed a vaccine efficacy was 93.2% (95% CI: 83.9 - 97.1) against Variants of Concern and Variants of Interest which represented 82% of cases. Studies of NVX-CoV2373 with Matrix-M adjuvant have demonstrated an acceptable safety and reactogenicity profile in adults ≥18 years of age. On December 20, 2021, the WHO issued interim recommendations and authorized under its emergency use listing (EUL) procedure, the NVX-CoV2373 COVID-19 vaccine developed by Novavax and Serum Institute of India.

The pivotal phase 3 registration trial of the Moderna mRNA-1273 COVID-19 vaccine was conducted in the United States of America and involved about 30 000 participants aged 18 years or older with no known history of SARS-CoV-2 infection.

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.