Ten lessons drawn from the groundbreaking Sisonke study – a multicentre, open-label, single-arm phase 3B vaccine implementation study of healthcare workers (HCW) in South Africa, with prospective surveillance for two years. The primary endpoint is the rate of severe COVID 19, including hospitalisations and deaths.
The study enrolled and vaccinated participants nationally at potential vaccination roll-out sites between 17 February and 26 May 2021. After May 2021, additional HCWs were vaccinated as part of a sub-study at selected clinical research sites.
The study authors discuss 10 lessons learnt to strengthen national and global vaccination strategies, which were published online by The South African Medical Journal.
Sisonke phase 3B open-label study: Lessons learnt for national and global vaccination scale-up during epidemics
A E Goga, L-G Bekker, N Garrett, S Takuva, I Sanne, J Odhiambo, F Mayat, L Fairall, Z Brey, L Bamford, G Tanna, G Gray.
Published online in SA Medical Journal
Consistently advocate for vaccination to reduce public hesitancy
During the study period there were reports of vaccine hesitancy in the mainstream and media relating to adverse events. We realised a key advocacy message was that severe adverse reactions to vaccination are rare and can be managed, but severe COVID 19 is life threatening. In the Sisonke study, such questions were largely addressed through clear messaging and peer education using webinars, posters/leaflets, social media engagements and interviews on local, national and international news outlets.
It was important for the Sisonke investigators and team to respond to queries arising from potential participants or stakeholders, and to dispel myths and misunderstandings regarding vaccines. Communicating risks became more complex when the rare blood-clotting condition was first reported. Sisonke messaging explained that headaches during the first three days could be managed with reassurance, but needed to be taken more seriously if severe, with an onset between four and 20 days after vaccination or associated with blurred vision, weakness or difficulty speaking.
It is, however, important to communicate the risk of these events alongside the risks of COVID 19, so people can make informed choices.
An electronic vaccination data system is critical
Paper forms were used to document vaccinations at some sites, often resulting in delays in EVDS data capture. An EVDS is important for real-time documentation of vaccinations and tracking of district, provincial and national progress. It also facilitates scheduling and real-time communication with vaccinees, recording their characteristics, ensuring standardisation of implementation and data quality. Critically, Sisonke enabled the National Department of Health (NDoH) to test the implementation of the EVDS. The electronic system should ensure everyone is linked with an occupation and workplace. Busy vaccination centres should use EVDS scheduling to avoid over-crowding, and employ queue marshals to monitor vaccinees abide by their EVDS appointment time and assist with social distancing.
Facilitate access to a choice of vaccination sites, like religious and community centres, schools, shopping malls and drive-through centres on weekdays and weekends
The limited number of vaccination sites meant long queues and HCWs had to wait, sometimes for ~three hours, for vaccines. A key lesson was vaccination sites should be easily accessible, using community centres, religious centres/halls, schools, shopping malls and drive-through centres, with parking space for the 15 minutes of observation. Partnering with local religious and community leaders is essential.
Let digitally literate people help elderly and marginalised people register for vaccination
During the Sisonke study, registration for vaccination occurred mainly through a web-based portal. We learnt that registration should be allowed through various portals and systems, including WhatsApp and short message service (SMS), and that digitally literate people should help elderly and marginalised people to register for vaccination so that the digital divide does not exclude anyone. The opening of vaccination sites to walk-ins during the final week demonstrated that many HCWs had not refreshed their details or had missed SMS notifications. This emphasised the importance of allowing walk-ins during vaccine roll-outs to maximise uptake.
Develop clear “how to” guides for vaccine storage, pharmacy staff and vaccinators
Nurses have prepared and administered vaccines for decades, but there has not been a recent vaccination campaign of this scale and complexity during a pandemic. COVID 19 vaccines are provided as small-volume injections. Ensuring the volume is correctly drawn up is critical. Cold-chain management also needs monitoring and accountability. The Ad26.COV2.S and Pfizer-BioNTech vaccines have varying reconstitution and storage requirements. Pfizer must be reconstituted by injecting saline into the vial, neither can be shaken, needles cannot be changed between drawing up a dose and injecting it, and microdrops remaining in the needle nib increase wastage and risk sub-optimal dosing.
The reconstituted vaccine must be stored between 2°C and 25°C and used within six hours of dilution. Consequently, close communication is needed between staff who reconstitute vaccine and staff who manage the vaccine queues, to prevent vaccine wastage. The Sisonke protocol team realised the need for detailed resources on how to draw up each dose. Study training provided quality assurance, and a 3-step volume verification process was instituted to ensure every dose counted. Furthermore, each dose was quality checked before leaving the pharmacy, and there was little wastage (<1%)
Allocating this process to dedicated trained teams and expanding their capacity optimised efficiency at vaccination centres and should be continued during large-scale vaccination rollout. Many of the processes and tools developed for Sisonke have already been adapted and are being used in the national COVID-19 vaccination programme.
Leverage instant messaging platforms, likw WhatsApp, for quick communication among staff at vaccination centres
Given the nature of COVID 19, information changed regularly. Providing factual information to vaccination sites is key to enhance efficiency and allay concerns. We realised the need to distribute a wide range of tools from job aids, checklists, press statements and posters through WhatsApp groups to keep vaccination staff updated. These groups enabled principal investigators to rapidly implement changes and redistribute vaccine doses to avoid wastage, and allowed investigators and vaccination centre staff to support each other during long days and weeks.
Safety ‒ health assessments at vaccination sites and transparency regarding adverse events
Although severe allergic reactions to COVID 19 vaccines are rare, we realised real-time rapid health assessments are needed at vaccination centres to identify people at risk of severe reactions. These assessments are important to identify those with a history of severe allergic reactions/anaphylaxis, who need to be administered medication before vaccination under medical supervision at specialised centres. Those with a history of allergy have to be identified and observed for 30 rather than 15 minutes. In the Sisonke study, the rate of reported non-serious and serious adverse events with vaccination was low, with most reported events being manifestations of mild-to-moderate reactogenicity (81%), while thromboembolic events occurred mainly in those with risk factors for thromboembolism.
Education and communication regarding these adverse events are needed early, frequently and honestly, and should juxtapose the benefits v. vaccination risks. Too often, risks were communicated separately from the benefits of vaccination, generating fear and confusion, particularly of the risk of thrombosis with thrombocytopenia syndrome related to vaccine administration. The study team realised that weighing risks against benefits is contextual. While the USA had the luxury of being at a far-advanced stage of their roll-out, with 37% of their population vaccinated by 13 April 2021 when the FDA recommended a pause, the proportion of the population vaccinated in SA was 0.5% (just <300,000), with a third wave rapidly approaching.
Reciprocal licensure and safety arrangements must be considered against the contextual risk of suspending vaccination programmes because of rare events, despite limited access to vaccine options.
For example, reports indicated that France and Poland did not suspend their use of Ad26.COV2.S while safety data were under review, providing an important precedent for determining policy based on vaccination coverage and community transmission. As with movement restrictions, decisions informed by local data are advisable.
Provide real-time, responsive support to vaccinees after vaccination
Adverse event reporting systems that are easily accessible, easy to use and data free are needed to maximise adverse event reporting and follow-up. In the Sisonke study, adverse event reporting included text message-based electronic reporting, 24/7 toll-free call centres, website links, health facility-based reporting, and encouragement of spontaneous case reporting. The study team established an effective safety monitoring system based on both active (when the team follows up directly with vaccinees) and passive (when vaccinees are asked to report sideeffects to the team) reporting. A national roll-out should include an active national vaccine adverse event surveillance system and a safety desk operating 24/7 which is responsive to vaccinees’ concerns.
Develop efficient systems to monitor and investigate COVID-19 breakthrough infections and deaths
During and after vaccination, monitoring and investigating breakthrough infections (BTIs) and deaths are critical to understand the emergence of new variants. We realised the need for a national BTI consortium that unites teams from the National Institute for Communicable Diseases, the National Health Laboratory Service, the SAMRC Burden of Disease Research Unit, epidemiologists and private laboratories to ensure complete documentation of disease, hospitalisations and deaths, and viral genetic information.
Furthermore, the Sisonke study showed that each severe BTI and death needed investigation and review by a team of experts to confirm the occurrence and establish temporality (in relation to vaccination or COVID 19). For any national rollout, similar systems are needed, and should be led by key national stakeholders and experts.
Flexibility and teamwork are essential in vaccination centres, across national, provincial and district levels and between public and private sites
Sisonke’s mandate was to reach as many HCWs as possible within three months with the research-allocated 500,000 doses of the Ad26. COV2.S vaccine imported for this purpose. This outreach was achieved through a public-private partnership in many sites, with the private sector either serving as vaccination centres or providing staff as vaccinators, pharmacists or syringe fillers. Nothing was off limits for vaccination centre staff, who engaged with health department teams, carried fridges, oversaw meticulous preparation of doses and consent processes and managed side-effects and reporting.
The Sisonke study team and collaborators made history by moving from the ENSEMBLE phase 3 trial results to the large-scale phase 3B study in <2 months. It is an example of what is possible when political will, science, hard work, partnership, and a strong desire to act come together to serve public health.
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