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      Randomised trials of COVID-19 vaccines in Africa - charting the path forward

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          Abstract

          Vaccines have played a critical role in controlling disease outbreaks, hence the proliferation of the development and testing of multiple vaccine candidates during the COVID-19 pandemic. Randomised trials are gold standards for evaluating the safety and efficacy of pharmaceutical interventions such as COVID-19 vaccines. However, contextual differences may attenuate effects of COVID-19 vaccines. Thus, the need to conduct COVID-19 vaccine trials in all settings, including in Africa. We conducted a cross-sectional analysis of planned, ongoing, and completed COVID-19 vaccine trials in Africa. We searched the South African National Clinical Trials Register, Pan African Clinical Trials Registry, and International Clinical Trials Registry Platform (ICTRP) on 12 January and 30 April 2022; and complemented this with a search of ClinicalTrials.gov on 17 May 2022. We screened the search output and included randomised trials with at least one recruitment site in Africa. We identified only 108 eligible trials: 90 (83%) evaluating candidate COVID-19 vaccines, 11 (10%) assessing if existing vaccines could prevent SARS-CoV-2 infection, and 7 (7%) evaluating interventions for improving COVID-19 vaccination coverage. South Africa had the highest number of trials at 58 (54%). Beyond South Africa, countries with more than 10 trial sites include Kenya, Ghana, Egypt, Uganda, and Zimbabwe. Among the trials, 14 (13%) do not have principal investigators based in Africa, 39 (30%) are funded by industry, and 91 (84%) are funded by institutions based outside the host country. COVID-19 vaccine trials with recruitment sites in Africa represented only 7% of the 1453 COVID-19 vaccine trials in the ICTRP. The paucity of COVID-19 vaccine trials conducted on the African continent is a cause for concern. This has implications for the role that Africa may play in future pandemics. SIGNIFICANCE: • There are generally very few vaccine trials conducted in Africa, relative to the rest of the world. • The limited vaccine trials in Africa could be attributed to limited expertise and resources, both human and material, as well as lack of perceived market. • It is reassuring that many COVID-19 vaccines are planned, being conducted, or have been conducted in multiple African countries; but there is a need for more African public sector funding for vaccine trials on the continent.

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          Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

          Abstract Background Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and the resulting coronavirus disease 2019 (Covid-19) have afflicted tens of millions of people in a worldwide pandemic. Safe and effective vaccines are needed urgently. Methods In an ongoing multinational, placebo-controlled, observer-blinded, pivotal efficacy trial, we randomly assigned persons 16 years of age or older in a 1:1 ratio to receive two doses, 21 days apart, of either placebo or the BNT162b2 vaccine candidate (30 μg per dose). BNT162b2 is a lipid nanoparticle–formulated, nucleoside-modified RNA vaccine that encodes a prefusion stabilized, membrane-anchored SARS-CoV-2 full-length spike protein. The primary end points were efficacy of the vaccine against laboratory-confirmed Covid-19 and safety. Results A total of 43,548 participants underwent randomization, of whom 43,448 received injections: 21,720 with BNT162b2 and 21,728 with placebo. There were 8 cases of Covid-19 with onset at least 7 days after the second dose among participants assigned to receive BNT162b2 and 162 cases among those assigned to placebo; BNT162b2 was 95% effective in preventing Covid-19 (95% credible interval, 90.3 to 97.6). Similar vaccine efficacy (generally 90 to 100%) was observed across subgroups defined by age, sex, race, ethnicity, baseline body-mass index, and the presence of coexisting conditions. Among 10 cases of severe Covid-19 with onset after the first dose, 9 occurred in placebo recipients and 1 in a BNT162b2 recipient. The safety profile of BNT162b2 was characterized by short-term, mild-to-moderate pain at the injection site, fatigue, and headache. The incidence of serious adverse events was low and was similar in the vaccine and placebo groups. Conclusions A two-dose regimen of BNT162b2 conferred 95% protection against Covid-19 in persons 16 years of age or older. Safety over a median of 2 months was similar to that of other viral vaccines. (Funded by BioNTech and Pfizer; ClinicalTrials.gov number, NCT04368728.)
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            Safety and Efficacy of Single-Dose Ad26.COV2.S Vaccine against Covid-19

            Background The Ad26.COV2.S vaccine is a recombinant, replication-incompetent human adenovirus type 26 vector encoding full-length severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein in a prefusion-stabilized conformation. Methods In an international, randomized, double-blind, placebo-controlled, phase 3 trial, we randomly assigned adult participants in a 1:1 ratio to receive a single dose of Ad26.COV2.S (5×10 10 viral particles) or placebo. The primary end points were vaccine efficacy against moderate to severe–critical coronavirus disease 2019 (Covid-19) with an onset at least 14 days and at least 28 days after administration among participants in the per-protocol population who had tested negative for SARS-CoV-2. Safety was also assessed. Results The per-protocol population included 19,630 SARS-CoV-2–negative participants who received Ad26.COV2.S and 19,691 who received placebo. Ad26.COV2.S protected against moderate to severe–critical Covid-19 with onset at least 14 days after administration (116 cases in the vaccine group vs. 348 in the placebo group; efficacy, 66.9%; adjusted 95% confidence interval [CI], 59.0 to 73.4) and at least 28 days after administration (66 vs. 193 cases; efficacy, 66.1%; adjusted 95% CI, 55.0 to 74.8). Vaccine efficacy was higher against severe–critical Covid-19 (76.7% [adjusted 95% CI, 54.6 to 89.1] for onset at ≥14 days and 85.4% [adjusted 95% CI, 54.2 to 96.9] for onset at ≥28 days). Despite 86 of 91 cases (94.5%) in South Africa with sequenced virus having the 20H/501Y.V2 variant, vaccine efficacy was 52.0% and 64.0% against moderate to severe–critical Covid-19 with onset at least 14 days and at least 28 days after administration, respectively, and efficacy against severe–critical Covid-19 was 73.1% and 81.7%, respectively. Reactogenicity was higher with Ad26.COV2.S than with placebo but was generally mild to moderate and transient. The incidence of serious adverse events was balanced between the two groups. Three deaths occurred in the vaccine group (none were Covid-19–related), and 16 in the placebo group (5 were Covid-19–related). Conclusions A single dose of Ad26.COV2.S protected against symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection and was effective against severe–critical disease, including hospitalization and death. Safety appeared to be similar to that in other phase 3 trials of Covid-19 vaccines. (Funded by Janssen Research and Development and others; ENSEMBLE ClinicalTrials.gov number, NCT04505722 .)
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              Safety and efficacy of an rAd26 and rAd5 vector-based heterologous prime-boost COVID-19 vaccine: an interim analysis of a randomised controlled phase 3 trial in Russia

              Background A heterologous recombinant adenovirus (rAd)-based vaccine, Gam-COVID-Vac (Sputnik V), showed a good safety profile and induced strong humoral and cellular immune responses in participants in phase 1/2 clinical trials. Here, we report preliminary results on the efficacy and safety of Gam-COVID-Vac from the interim analysis of this phase 3 trial. Methods We did a randomised, double-blind, placebo-controlled, phase 3 trial at 25 hospitals and polyclinics in Moscow, Russia. We included participants aged at least 18 years, with negative SARS-CoV-2 PCR and IgG and IgM tests, no infectious diseases in the 14 days before enrolment, and no other vaccinations in the 30 days before enrolment. Participants were randomly assigned (3:1) to receive vaccine or placebo, with stratification by age group. Investigators, participants, and all study staff were masked to group assignment. The vaccine was administered (0·5 mL/dose) intramuscularly in a prime-boost regimen: a 21-day interval between the first dose (rAd26) and the second dose (rAd5), both vectors carrying the gene for the full-length SARS-CoV-2 glycoprotein S. The primary outcome was the proportion of participants with PCR-confirmed COVID-19 from day 21 after receiving the first dose. All analyses excluded participants with protocol violations: the primary outcome was assessed in participants who had received two doses of vaccine or placebo, serious adverse events were assessed in all participants who had received at least one dose at the time of database lock, and rare adverse events were assessed in all participants who had received two doses and for whom all available data were verified in the case report form at the time of database lock. The trial is registered at ClinicalTrials.gov (NCT04530396). Findings Between Sept 7 and Nov 24, 2020, 21 977 adults were randomly assigned to the vaccine group (n=16 501) or the placebo group (n=5476). 19 866 received two doses of vaccine or placebo and were included in the primary outcome analysis. From 21 days after the first dose of vaccine (the day of dose 2), 16 (0·1%) of 14 964 participants in the vaccine group and 62 (1·3%) of 4902 in the placebo group were confirmed to have COVID-19; vaccine efficacy was 91·6% (95% CI 85·6–95·2). Most reported adverse events were grade 1 (7485 [94·0%] of 7966 total events). 45 (0·3%) of 16 427 participants in the vaccine group and 23 (0·4%) of 5435 participants in the placebo group had serious adverse events; none were considered associated with vaccination, with confirmation from the independent data monitoring committee. Four deaths were reported during the study (three [<0·1%] of 16 427 participants in the vaccine group and one [<0·1%] of 5435 participants in the placebo group), none of which were considered related to the vaccine. Interpretation This interim analysis of the phase 3 trial of Gam-COVID-Vac showed 91·6% efficacy against COVID-19 and was well tolerated in a large cohort. Funding Moscow City Health Department, Russian Direct Investment Fund, Sberbank, and RUSAL.
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                Author and article information

                Journal
                sajs
                South African Journal of Science
                S. Afr. j. sci.
                Academy of Science of South Africa (Pretoria, Gauteng, South Africa )
                0038-2353
                1996-7489
                June 2022
                : 118
                : 5-6
                : 1-4
                Affiliations
                [01] Cape Town orgnameSouth African Medical Research Council South Africa
                [04] Cape Town orgnameSouth African Medical Research Council South Africa
                [03] Pretoria orgnameUniversity of Pretoria orgdiv1Department of Paediatrics and Child Health South Africa
                [02] Durban orgnameSouth African Medical Research Council orgdiv1HIV and Other Infectious Diseases Research Unit South Africa
                Article
                S0038-23532022000300007 S0038-2353(22)11800500007
                10.17159/sajs.2022/13224
                094401f7-7811-4b3b-9ec8-cf8ca3508d2c

                This work is licensed under a Creative Commons Attribution 4.0 International License.

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                Categories
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                prospective registration,COVID-19 vaccines,Africa,pandemic,clinical trials

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