SAFETY and EFFECTIVENESS of the Ad26.COV2.S VACCINE in SOUTH AFRICA

Background: The Sisonke Phase IIIB open-label implementation study vaccinated health care workers (HCWs) with the single dose Ad26.COV2.S vaccine during two phases of the South African Covid-19 epidemic, dominated first by the Beta followed by the Delta variant of concern. Methods: HCWs were vaccinated over 3 months (17 February-17 May 2021). Safety was monitored by self-reporting, facility reporting and linkage to national databases. Vaccine effectiveness (VE) against Covid-19 related hospitalisation, hospitalisation requiring critical or intensive care and death, ascertained 28 days or more post vaccination was assessed up until 17 July 2021. Nested sub-cohorts (A and B) from two national medical schemes were evaluated to assess VE using a matched retrospective cohort design. Results: Over the 3-month period, 477234 HCWs were vaccinated in 122 vaccination sites across South Africa. VE derived from the sub-cohorts comprising 215 813 HCWs was 83% (95% CI 75-89) to prevent Covid-19 deaths, 75% (95% CI 69-82) to prevent hospital admissions requiring critical or intensive care and 67% (95% CI 62-71) to prevent Covid-19 related hospitalisations. The VE was maintained in older HCWs and those with comorbidities including HIV infection. VE remained consistent throughout the Beta and Delta dominant phases of the study. 10279 adverse events were reported and 139 (1.4%) were serious, including two cases of thrombosis with thrombocytopenia syndrome and four cases of Guillain-Barré syndrome who recovered. Conclusion: The single dose Ad26.COV2.S was safe and effective against severe Covid-19 disease and death post-vaccination, and against both Beta and Delta variants providing real-world evidence for its use globally.

POINT-OF-CARE ANTIBODY TESTS for COVID-19: FIELD-BASED PERFORMANCE, SOUTH AFRICA

Background: SARS-CoV2 antibody testing is an important auxillary test especially for retrospective diagnosis or in patients with long COVID-19 or multisystem inflammatory syndrome of childhood. Epidemiological serology studies may also assist public health planning. Access to formal laboratory testing is not universal in many low-and middle-income (LMIC) countries and rapid lateral flow antibody tests are an attractive alternative. Performance of these tests has been inconsistent. A large-scale study was undertaken in South Africa, during the beta and delta waves, to assess the field-based performance of rapid point of care (POC) COVID-19 antibody tests. Methods: Symptomatic, ambulatory persons under investigation (PUIs) aged 18 years and older, presenting for SARS-CoV-2 diagnosis at public health facilities in three provinces, South Africa were enrolled at baseline. All patients completed a questionnaire regarding symptoms. Nasopharyngeal swabs were taken and processed for SARS-CoV-2 PCR testing using a GeneXpert (Cepheid, USA), or manual assay (ThermoFisher TaqPath assay or Seegene Allplex assay) on a real-time platform at routine accredited National Health Laboratory Service laboratories as per routine national protocols. Concomitantly, trained study staff performed three facility-based POC lateral flow antibody tests on a on a fingerstick sample and blood was collected for formal serology. POC tests were selected following a rapid in-laboratory evaluation. Asymptomatic contacts of people with confirmed COVID-19 were recruited into the asymptomatic study arm and rapid tests and PCR were performed. PCR and rapid positive patients and 500 negative controls were followed up at 5-14 days. Antibody tests were compared with formal serology performed on 2 platforms-Euroimmun (Euroimmun, Lubeck) IgA and IgG anti-S antibodies and Abbott Architect IgG test. Results: The sensitivity (S), specificity (Sp), positive (PPV) and negative predictive (NPV) values of tests for PUIs and contacts were calculated (Table 1)∗. Analyses using serology as a reference are forthcoming. Conclusion: Compared with PCR, performance of rapid POC COVID-19 antibody tests was poor with low sensitivity. This may reflect the patient cohort tested as humoral responses typically develop from day 7-14. The tests are unlikely to be useful for acute diagnosis but sensitivity may improve at later timepoints and further follow up data will be analysed by duration of symptom onset, severity of symptoms and wave (beta versus delta).

UTILITY of COVID-19 POINT-OF-CARE ANTIGEN TESTS in LOW-MIDDLE INCOME SETTINGS

Background: Access to SARS-CoV-2 polymerase chain reaction (PCR) testing is a bottleneck globally, especially in low-and middle-income countries (LMICs). Reliable point-of-care (POC) diagnostics for coronavirus disease 2019 (COVID-19) are cheaper and easier to scale-up than PCR especially in LMICs, and will facilitate interruption of transmission. We report the field-based effectiveness of rapid point-of-care (POC) antigen COVID-19 tests during the beta and delta waves, in South Africa. Methods: We enrolled symptomatic, ambulatory persons under investigation (PUIs) aged 18 years and older, presenting for SARS-CoV-2 diagnosis at public health facilities in three provinces, South Africa. All patients completed a questionnaire regarding symptoms. Nasopharyngeal swabs were taken and processed for SARS-CoV-2 PCR testing using either GeneXpert (Cepheid, USA), or with a manual assay (ThermoFisher TaqPath assay or Seegene Allplex assay) on a real-time PCR platform at routine, accredited National Health Laboratory Service laboratories, as per routine national protocols. Concomitantly, trained study staff performed three facility-based POC antigen tests on a nasal/nasopharyngeal swab, as recommended by the manufacturer. Asymptomatic contacts of people with confirmed COVID-19 were recruited into the asymptomatic study arm and rapid tests and PCR were performed. The sensitivity (S), specificity (Sp), positive (PPV) and negative predictive (NPV) values of tests for PUIs and contacts were calculated using PCR as the reference standard. Results: Between Oct 2020-2021 1816 participants were enrolled;472 (26%) tested PCR or rapid test positive;235 positives (49.8%) and 532 negatives were followed up at 5-14 days;574 asymptomatic contacts were enrolled, of which 21 (3.7%) were PCR positive. Performance of the three antigen tests are shown in Table 1∗. Conclusion: In a real world setting, during the beta and delta waves, compared with PCR the sensitivity of rapid antigen tests ranged from 35-68%. This may reflect low viral loads at diagnosis. Further work will compare antigen test performance in patients with high versus lower cycle threshold (Ct) values. Meanwhile, PCR testing capacity needs urgent scale-up in LMICs and improved POC diagnostics are needed to facilitate COVID-19 diagnosis in LMICs.

SYMPTOM DURATION in COVID-19 CONVALESCENT PATIENTS: REGIONAL & CLINICAL ASSOCIATIONS

Background: Post-Acute Sequelae of SARS-CoV-2 (PASC) is characterized by persistent symptoms negatively impacting quality of life several weeks after SARS-CoV-2 diagnosis. Proposed risk factors include older age, female sex, comorbidities, and severe COVID-19, including hospitalization and oxygen requirement. Yet, associations of these factors with prolonged symptoms remain poorly understood globally. Methods: The global, observational cohort study HVTN 405/HPTN 1901 characterizes the clinical and immunologic course in the first year after SARS-CoV-2 infection among adults. The cohort was categorized by infection severity (asymptomatic;symptomatic with no oxygen requirement [NOR];non-invasive oxygen requirement [NIOR];or invasive oxygen requirement [IOR]). A regression model was applied to estimate geometric mean ratios (GMR) for duration and odds ratios (OR) for persistence of symptoms. Results: 759 participants from Peru (25.2%), USA (26.0%), Republic of South Africa (RSA, 37.7%), and non-RSA Sub-Saharan Africa (11.2%) were enrolled a median of 51 (IQR 35-66) days post-diagnosis, from May 2020 to Mar 2021. 53.8% were female, 69.8% were <55yo (median 44yo, IQR 33-58) and identified as non-Hispanic Black (42.7%), Hispanic (27.9%) or non-Hispanic White (15.8%). Comorbidities included obesity (42.8%), hypertension (24%), diabetes (14%), HIV infection (11.6%) and lung disease (7.5%). 76.2% were symptomatic (NOR 47.4%;NIOR 22.9%;and IOR 5.8%). Among symptomatic participants, median acute COVID-19 duration was 20 days (IQR 11-35);43.3% had ≥1 persistent symptom after COVID-19 resolution (39.8% NOR;49.1 % NIOR+IOR;p=0.037);16.8% reported ≥1 symptom >42 days (14.0% NOR;21.6% NIOR+IOR;p=0.025). Symptom duration was not associated with age or sex assigned at birth but was associated with disease severity (GMR 2.09;95%CI 1.5-2.91, p<0.001 for NIOR vs NOR;not significant for IOR vs NIOR), lung disease (GMR 2.43;95%CI 1.42-4.16, p=0.001), and global region (p<0.05, see Figure 1). Prolonged viral shedding was associated with persistent diarrhea (OR 6.59;95%CI 1.65-26.86;p=0.008). Conclusion: A recovery course consistent with PASC was significantly associated with infection severity, lung disease, and region. Regional differences in symptom profiles and duration may be influenced by viral diversity, genetic, or cultural factors and likely reflect disparities in healthcare access and interventions. Better understanding PASC associations may improve clinical assessment and management globally.

Sisonke phase 3B open-label study: Lessons learnt for national and global vaccination scale-up during epidemics

Sisonke is a multicentre, open-label, single-arm phase 3B vaccine implementation study of healthcare workers (HCWs) in South Africa, with prospective surveillance for 2 years. The primary endpoint is the rate of severe COVID-19, including hospitalisations and deaths. The Sisonke 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. We discuss 10 lessons learnt to strengthen national and global vaccination strategies: (i) consistently advocate for vaccination to reduce public hesitancy;(ii) an electronic vaccination data system (EVDS) is critical;(iii) facilitate access to a choice of vaccination sites, such as religious and community centres, schools, shopping malls and drive-through centres;(iv) let digitally literate people help elderly and marginalised people to register for vaccination;(v) develop clear 'how to' guides for vaccine storage, pharmacy staff and vaccinators;(vi) leverage instant messaging platforms, such as WhatsApp, for quick communication among staff at vaccination centres;(vii) safety is paramount - rapid health assessments are needed at vaccination centres to identify people at high risk of serious adverse events, including anaphylaxis or thrombosis with thrombocytopenia syndrome. Be transparent about adverse events and contextualise vaccination benefits, while acknowledging the small risks;(viii) provide real-time, responsive support to vaccinees post vaccination and implement an accessible national vaccine adverse events surveillance system;(ix) develop efficient systems to monitor and investigate COVID-19 breakthrough infections;and (x) flexibility and teamwork are essential in vaccination centres across national, provincial and district levels and between public and private sectors.

Sisonke phase 3B open-label study: Lessons learnt for national and global vaccination scale-up during epidemics.

Sisonke is a multicentre, open-label, single-arm phase 3B vaccine implementation study of healthcare workers (HCWs) in South Africa, with prospective surveillance for 2 years. The primary endpoint is the rate of severe COVID­19, including hospitalisations and deaths. The  Sisonke 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. We discuss 10 lessons learnt to strengthen national and global vaccination strategies:(i) consistently advocate for vaccination to reduce public hesitancy; (ii) an electronic vaccination data system (EVDS) is critical; (iii) facilitate access to a choice of vaccination sites, such as religious and community centres, schools, shopping malls and drive-through centres; (iv) let digitally literate people help elderly and marginalised people to register for vaccination; (v) develop clear 'how to' guides for vaccine storage, pharmacy staff and vaccinators; (vi) leverage instant messaging platforms, such as WhatsApp, for quick communication among staff at vaccination centres; (vii) safety is paramount - rapid health assessments are needed at vaccination centres to identify people at high risk of serious adverse events, including anaphylaxis or thrombosis with thrombocytopenia syndrome. Be transparent about adverse events and contextualise vaccination benefits, while acknowledging the small risks; (viii) provide real-time, responsive support to vaccinees post vaccination and implement an accessible national vaccine adverse events surveillance system; (ix) develop efficient systems to monitor and investigate COVID­19 breakthrough infections; and (x) flexibility and teamwork are essential in vaccination centres across national, provincial and district levels and between public and private sectors.