Sisonke: reaching several goals together

Research infrastructure and expertise from decades of HIV and tuberculosis research enabled several COVID-19 vaccine trials to be conducted in South Africa. The ChAdOx1 nCoV-19 vaccine procured by the South African Government did not protect against infection with the beta (B.1.351) variant of concern¹ in a phase 1/2 trial and was therefore abandoned in early 2021.² A single dose of the Ad26.COV2.S vaccine had been shown to be effective against the beta variant of SARS-CoV-2 by the ENSEMBLE trial,³ but as of early 2021 it was not yet authorised by the national regulator. Thus, South Africa found itself without a licensed and available SARS-CoV-2 vaccine.⁴

The Sisonke (“We are together” in isiXhosa) open-label, phase 3b, implementation study, which is reported in The Lancet by Linda-Gail Bekker and colleagues,⁵ stepped in. Offering the single-dose Ad26.COV2.S vaccine (Johnson & Johnson) to volunteer health-care workers, the Sisonke study not only yielded important real-life vaccine effectiveness data but also enabled South Africa to start vaccinating an important risk group.⁶

In the Sisonke study,⁵ 122 vaccination sites recruited 477 102 health-care workers, of whom 75% were female, including 39 383 individuals known to have HIV. Recruitment spanned mid-February to mid-May, 2021, a period during which the delta (B.1.617.2) variant of concern replaced the beta variant and drove South Africa's third COVID-19 epidemiological wave.⁷ Overall, vaccine effectiveness from 4 weeks after vaccination was 83% (95% CI 75–89) to prevent COVID-19-related death, 75% (69–82) to prevent COVID-19-related hospitalisation requiring critical or intensive care, and 67% (62–71) to prevent COVID-19-related hospitalisation. Importantly, vaccine effectiveness was reduced but maintained in participants older than 50 years and those with self-reported HIV infection and other comorbidities, and throughout the periods dominated by both the beta and delta variants.

The Sisonke study's strength is that it provided real-world evidence in a highly exposed population with a substantial proportion of HIV-infected individuals. Furthermore, it enabled health-care workers, who have a high risk of infection and are an essential workforce, especially during pandemic waves, to be vaccinated ahead of the national programme.

The pandemic has substantially affected the education of future health professionals because teaching had to be done online and in-clinic training was halted. Additionally, health services focused on COVID-19 care, with all elective and non-emergency care de-escalated.

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Participation in the Sisonke trial put minimal additional demands on participants, but yielded important data on vaccine effectiveness and safety in real life, including groups who are under-represented in most vaccine trials. It employed South Africa's then newly launched national electronic vaccination data system, which was then also used for the governmental vaccine roll-out programme.

The broad definition of health-care worker used in the Sisonke study, including students and auxiliary staff not exposed to patients, did not allow prioritisation according to risk category.8, 9

Although the single-dose Ad26.COV2.S vaccine was effective against severe COVID-19 caused both by beta and delta variants of SARS-CoV-2, the short follow-up period reported here did not allow assessment of the duration of protection, nor did the reported study period include the emergence of the omicron (B.1.1.529) variant of concern in South Africa from November, 2021.¹⁰ Breakthrough infections with omicron in Sisonke participants have been published in the meantime in a preprint publication.¹¹ As per the interim recommendations of WHO's Strategic Advisory Group of Experts on Immunization, a single dose of Ad26.COV.2 does not provide long-lasting reliable immunity.¹¹ Through Sisonke2, a follow-on trial of Sisonke, over 230 000 participants of the first Sisonke trial received a second Ad26.COV.2 dose, which was ideally timed to assess its effectiveness against the omicron variant, and has been reported in another preprint publication.¹²

Some health-care workers who did not enrol in the Sisonke study might have chosen to access the BNT162b2 (Pfizer–BioNTech) vaccine through the national roll-out programme, and those not enrolling for Sisonke2 might have opted to wait for heterologous booster doses with perceived higher efficacy. However, a substantial proportion of health-care workers in South Africa, as elsewhere, remain unvaccinated.

Open-label implementation studies allow for improved monitoring of adverse events and vaccine effectiveness compared with typical postmarketing surveillance. This type of investigation is particularly valuable when groups with unique characteristics are targeted. We believe the Sisonke study was exemplary.

TF volunteered to participate in the Sisonke trials and WP volunteered to participate in the ENSEMBLE trial. TF as Vice-Dean of Clinical Services and Social Impact of the Faculty of Medicine and Health Sciences of the University of Stellenbosch, is responsible for the partnership between the health authority and the faculty in terms of teaching and clinical training. Additionally, she was responsible for the organisational component of vaccine roll-out in the faculty. WP is a member of the South African Ministerial Advisory Committee on COVID-19 vaccines.