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) exacerbate 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. Efficacy was evaluated for those subjects who received the second dose 21-42 days after the first dose. Vaccine efficacy (VE) was estimated as 94.1% (95% confidence interval (CI) 89.3–96.8%). In the phase 3 trial, the safety data supported a favorable safety profile. Reactogenicity symptoms, defined as solicited local injection site or systemic reactions during the seven days after vaccination, were frequent, mostly mild to moderate and short-lived after dosing for both adult age groups. The vaccine’s AE profile did not suggest any specific safety concerns (WHO SAGE, 2021). The US CDC and FDA recommend that adolescents age 12 to 17 years old can receive a 3^rd primary series at least 4 weeks after the 2^nd dose and 4^th booster shot at least 2 months after their last dose (CDC 2022).

The phase 2/3 pivotal registration trial of the BNT162b2 (Pfizer-BioNTech) vaccine was conducted at sites in six countries (Argentina, Brazil, Germany, South Africa, Turkey and the USA) and involved about 43 000 participants aged 16 to 85 years. The estimated vaccine efficacy (VE) was 94.6% (95% credibility interval (CI) 89.9–97.3%). Reactogenicity and adverse events associated with the vaccine were generally milder and less frequent in the older group (≥55 years of age) than the younger group (18–55 years of age) and tended to increase after the second dose. Reactogenicity was mostly mild to moderate and short-lived for both adult age groups (WHO SAGE, 2021). The WHO SAGE approved BNT162b2 (Pfizer-BioNTech) vaccines for children aged 6 months and older, having met the necessary criteria for safety and efficacy for administration (WHO SAGE, 2022). On 5^th January 2022, the US CDC endorsed the Advisory Committee on Immunization Practices’ (ACIP) recommendation to expand eligibility of booster doses to those 12 to 15 years old. CDC recommended that adolescents age 12 to 17 years old should receive a booster shot 5 months after their initial Pfizer-BioNTech vaccination series. ACIP reviewed the available safety data following the administration of over 25 million vaccine doses in adolescents; COVID-19 vaccines are safe and effective (CDC 2022).

The FDA and WHO have both recommended continued evaluation of vaccine effectiveness following issuance of a EUA and/or licensure which is critical to address the existing uncertainties, with high urgency to understand homologous and heterologous boosting, both for improved coverage of variants of concern and due to limitations of global vaccine availability. The VIBRI Consortium proposes to carry out a Multi-Centre Phase 2b RCT to evaluate the Safety and Immunogenicity of the Janssen Ad26COVS1 and, the Novavax NVX-CoV2373 and mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccines used as homologous and heterologous boost strategies among HIV positive adolescents and adults with a small control arm of HIV (-) participants. The trial will enroll up to 300 HIV (+) adolescents 12 to 17 years and about 1,650 adults aged 18 to 64 years (of which 1350 will be HIV (+) and 300 HIV (-), who have completed a primary series with a homologous vaccine series based on any one vaccine platform of a) mRNA (Moderna or Pfizer), b) adenovirus 26 (J&J) or c) inactivated (Sinopharm or Sinovac).  These three have been the main vaccine platforms introduced across the three participating countries (Kenya, Democratic Republic of Congo and Rwanda) as of the current protocol. Participants must have completed the primary series at least 3 months prior to enrollment.  In Stage 1, the booster vaccines will be evaluated in adult participants 18-64 years while in Stage 2, the booster vaccines will be assessed in adolescents 12-17 years of age.

Given the difference in vaccine rollout between countries, the timing of enrollment within each country is expected to stagger.  All adult participants will be randomized 1:1 within their primary vaccine platform to receive either a single dose of Janssen Ad26COVS1 vaccine or Novavax NVX-CoV2373 COVID-19 vaccine between 5 and 7 months from completion of their primary series for adult participants and ≥5-12. All adolescent participants will be randomized 1:1 within their primary vaccine platform to receive either a single dose of Novavax NVX-CoV2373 COVID-19 vaccine or an mRNA (Moderna mRNA-1273 or Pfizer/BNT) vaccine ≥5 months after the primary series for adolescent participants. The booster vaccination interval for adolescents is consistent with new guidances guidance from the US CDC/FDA and is reflective of real-world settings  implementation of country MOH COVID-19 vaccination programs.  Due to the uncertainty of vaccine supply and to allow for adequate capture of participants, the pre-booster vaccination enrollment period may vary anywhere from -85 days to 0 days till the time of boost (Day 0).