Vaccine effectiveness against hospital admission in South African health care workers who received a homologous booster of Ad26.COV2 during an Omicron COVID19 wave: Preliminary Results of the Sisonke 2 Study.

Following the results of the ENSEMBLE 2 study, which demonstrated improved vaccine efficacy of a two-dose regimen of Ad26.COV.2 vaccine given 2 months apart, we expanded the Sisonke study which had provided single dose Ad26.COV.2 vaccine to almost 500 000 health care workers (HCW) in South Africa to include a booster dose of the Ad26.COV.2. Sisonke 2 enrolled 227 310 HCW from the 8 November to the 17 December 2021. Enrolment commenced before the onset of the Omicron driven fourth wave in South Africa affording us an opportunity to evaluate early VE in preventing hospital admissions of a homologous boost of the Ad26.COV.2 vaccine given 6-9 months after the initial vaccination in HCW. We estimated vaccine effectiveness (VE) of the Ad26.COV2.S vaccine booster in 69 092 HCW as compared to unvaccinated individuals enrolled in the same managed care organization using a test negative design. We compared VE against COVID19 admission for omicron during the period 15 November to 20 December 2021. After adjusting for confounders, we observed that VE for hospitalisation increased over time since booster dose, from 63% (95%CI 31-81%); to 84% (95% CI 67-92%) and then 85% (95% CI: 54-95%), 0-13 days, 14-27 days, and 1-2 months post-boost. We provide the first evidence of the effectiveness of a homologous Ad26.COV.2 vaccine boost given 6-9 months after the initial single vaccination series during a period of omicron variant circulation. This data is important given the increased reliance on the Ad26.COV.2 vaccine in Africa.

High Rate of Asymptomatic Carriage Associated with Variant Strain Omicron

The early widespread dissemination of Omicron indicates the urgent need to better understand the transmission dynamics of this variant, including asymptomatic spread among immunocompetent and immunosuppressed populations. In early December 2021, the Ubuntu clinical trial, designed to evaluate efficacy of the mRNA-1273 vaccine (Moderna) among persons living with HIV (PLWH), began enrolling participants. Nasal swabs are routinely obtained at the initial vaccination visit, which requires participants to be clinically well to receive their initial jab. Of the initial 230 participants enrolled between December 2 and December 17, 2021, 71 (31%) were PCR positive for SARS-CoV-2: all of whom were subsequently confirmed by S gene dropout to be Omicron; 48% of the tested samples had cycle threshold (CT) values <25 and 18% less than 20, indicative of high titers of asymptomatic shedding. Asymptomatic carriage rates were similar in SARS-CoV-2 seropositive and seronegative persons (27% respectively). These data are in stark contrast to COVID-19 vaccine studies conducted pre-Omicron, where the SARS-CoV-2 PCR positivity rate at the first vaccination visit ranged from <1%-2.4%, including a cohort of over 1,200 PLWH largely enrolled in South Africa during the Beta outbreak. We also evaluated asymptomatic carriage in a sub study of the Sisonke vaccine trial conducted in South African health care workers, which indicated 2.6% asymptomatic carriage during the Beta and Delta outbreaks and subsequently rose to 16% in both PLWH and PHLWH during the Omicron period. These findings strongly suggest that Omicron has a much higher rate of asymptomatic carriage than other VOC and this high prevalence of asymptomatic infection is likely a major factor in the widespread, rapid dissemination of the variant globally, even among populations with high prior rates of SARS-COV-2 infection.

Rapid rise in paediatric COVID-19 hospitalisations during the early stages of the Omicron wave, Tshwane District, South Africa

BackgroundSouth Africa reported a notable increase in COVID-19 cases from mid-November 2021 onwards, starting in Tshwane District, linked to rapid community spread of the Omicron variant. This coincided with a rapid rise in paediatric COVID-19-associated hospitalisations. MethodsWe synthesized data from five sources to describe the impact of Omicron on clinical manifestations and outcomes of hospitalized children ([≤]19 years) with positive SARS-CoV-2 tests in Tshwane District from 31 October to 11 December 2021, including: 1) COVID-19 line lists; 2) collated SARS-CoV-2 testing data; 3) SARS-CoV-2 genomic sequencing data; 4) COVID-19 hospitalisation surveillance; and 5) clinical data of public sector paediatric ([≤]13 years) COVID-19 hospitalisations. FindingsDuring the six-week period 6,287 paediatric ([≤]19 years) COVID-19 cases were recorded in Tshwane District, of these 462 (7.2%) were hospitalized in 42 hospitals (18% of overall admissions). The number of paediatric cases was higher than in the prior 3 waves, uncharacteristically preceding adult hospitalisations. Of the 75 viral specimens sequenced from the district, 99% were Omicron. Detailed clinical information obtained from 139 of 183 (76%) admitted children ([≤]13 years; including all public sector hospitalisations) indicated that young children (0-4 years) were most affected (62%). Symptoms included fever (47%), cough (40%), vomiting (24%), difficulty breathing (23%), diarrhoea (20%) and convulsions (20%). Length of hospital stay was short (mean 3.2 days), and in 44% COVID-19 was the primary diagnosis. Most children received standard ward care (92%), with 31 (25%) receiving oxygen therapy. Seven children (6%) were ventilated; four children died, all related to complex underlying co-pathologies. All children and majority of parents for whom data were available were unvaccinated. InterpretationRapid increases in paediatric COVID-19 cases and hospitalisations mirror high community transmission of SARS-CoV-2 (Omicron variant) in Tshwane District, South Africa. Continued monitoring is needed to understand the long-term impact of the Omicron variant on children. Research in contextO_ST_ABSEvidence before the studyC_ST_ABSThe announcement of the new Omicron (B.1.1.529) variant of the SARS-CoV-2 virus was made on 24 November 2021. Clinical characteristics, and disease profiles of children with COVID-19 before the arrival of Omicron have been described in the literature. Added value of the studyThis study describes the rapid rise in paediatric COVID-19-associated hospitalisations in Tshwane District in the Gauteng Province of South Africa - one of the first known epicentres of the new Omicron variant of the SARS-CoV-2 virus. The clinical picture as well as the steep increase in paediatric positivity rates and hospitalizations are described in detail from the perspective of a large South African health district, providing a broad overview on how the Omicron variant affects the paediatric population. Implication of all available evidenceThis study describes the clinical picture and outcomes in children in the current wave of SARS-CoV-2 Omicron variant infections by incorporating data from 42 hospitals at all levels of care in a large district within the South African health system. This provides novel paediatric data to assist global preparation for the impact of the Omicron variant in the paediatric setting.

Breakthrough Covid-19 infections during periods of circulating Beta, Delta and Omicron variants of concern, among health care workers in the Sisonke Ad26.COV2.S vaccine trial, South Africa

BackgroundWe report breakthrough infections (BTIs) during periods of circulating Beta, Delta and Omicron variants of concern, among health care workers (HCW) participating in the Sisonke phase 3B Ad26.COV2.S vaccine trial (ClinicalTrials.gov number, NCT04838795). Data were gathered between 17 February and 15 December 2021. Duration of each period in this study was 89 days for Beta, 180 days or Delta and 30 days for Omicron. ResultsA total of 40 538 BTIs were observed, with 609 during Beta, 22 279 during Delta and 17 650 during Omicron. By 15 December, daily infections during Omicron were three times that seen during the peak observed during Delta. However, unlike the Delta period, with Omicron there was a clear and early de-coupling of hospitalisation from cases as a percentage of the Delta peak curves. Omicron significantly infected a greater proportion of HCW in the 18-30 year age-group, compared with the 55+ age group. There were 1 914 BTI-related hospitalisations - 77, 1 429 and 408 in the Beta (89 days), Delta (180 days) and Omicron (30 days) periods, respectively. During Omicron, 91% hospitalized HCWs required general ward care, 6% high care and 3% intensive care, compared with 89% general ward care, 4% high care and 7% intensive care, during Delta and 78% general care, 7% high care and 16% intensive care during Beta (p<0.001). During Beta and Beta 43% of hospitalized HCW needed supplementary oxygen and 7-8% needed ventilation, compared with 16% and 0.2% respectively during the Omicron period (p<0.001). Median length of hospitalization was significantly lower with Omicron compared with Beta and Delta (3 days compared with 5-6 days, p<0.001). ConclusionsWe illustrate more BTIs but reassuringly less severe Covid-19 with Omicron. Re-infections and Omicron-driven primary infections were likely driven by high population SARS-CoV-2 seroprevalence, waning vaccine effectiveness over time, increased Omicron infectivity, Omicron immune evasion or a combination of these and need further investigation. Follow-up of this cohort will continue and reports will be updated, as time and infections accrue.

Safety of the single-dose Ad26.CoV2.S vaccine among healthcare workers in the phase 3b Sisonke study in South Africa

BackgroundThe Sisonke open-label phase 3b implementation study aimed to assess the safety and effectiveness of the Janssen Ad26.CoV2.S vaccine among health care workers (HCWs) in South Africa. Here, we present the safety data. MethodsWe monitored adverse events (AEs) at vaccination sites, through self-reporting triggered by text messages after vaccination, health care provider reports and by active case finding. The frequency and incidence rate of non-serious and serious AEs were evaluated from day of first vaccination (17 February 2021) until 28 days after the final vaccination (15 June 2021). COVID-19 breakthrough infections, hospitalisations and deaths were ascertained via linkage of the electronic vaccination register with existing national databases. FindingsOf 477,234 participants, 10,279 (2.2%) reported AEs, of which 139 (1.4%) were serious. Women reported more AEs than men (2.3% vs. 1.6%). AE reports decreased with increasing age (3.2% for 18-30, 2.1% for 31-45, 1.8% for 46-55 and 1.5% in >55-year-olds). Participants with previous COVID-19 infection reported slightly more AEs (2.6% vs. 2.1%). The commonest reactogenicity events were headache and body aches, followed by injection site pain and fever, and most occurred within 48 hours of vaccination. Two cases of Thrombosis with Thrombocytopenia Syndrome and four cases of Guillain-Barre Syndrome were reported post-vaccination. Serious AEs and AEs of special interest including vascular and nervous system events, immune system disorders and deaths occurred at lower than the expected population rates. InterpretationThe single-dose Ad26.CoV2.S vaccine had an acceptable safety profile supporting the continued use of this vaccine in our setting. FundingFunding was provided by the National Treasury of South Africa, the National Department of Health, Solidarity Response Fund NPC, The Michael & Susan Dell Foundation, The Elma Vaccines and Immunization Foundation - Grant number 21-V0001, and the Bill & Melinda Gates Foundation - grant number INV-030342.

Prior infection with SARS-CoV-2 boosts and broadens Ad26.COV2.S immunogenicity in a variant dependent manner

The Johnson and Johnson Ad26.COV2.S single dose vaccine represents an attractive option for COVID-19 vaccination in resource limited countries. We examined the effect of prior infection with different SARS-CoV-2 variants on Ad26.COV2.S immunogenicity. We compared participants who were SARS-CoV-2 naive with those either infected with the ancestral D614G virus, or infected in the second wave when Beta predominated. Prior infection significantly boosted spike binding antibodies, antibody-dependent cellular cytotoxicity and neutralizing antibodies against D614G, Beta and Delta, however neutralization cross-reactivity varied by wave. Robust CD4 and CD8 T cell responses were induced after vaccination, regardless of prior infection. T cell recognition of variants was largely preserved, apart from some reduction in CD8 recognition of Delta. Thus, Ad26.COV2.S vaccination following infection may result in enhanced protection against COVID-19. The impact of the infecting variant on neutralization breadth after vaccination has implications for the design of second-generation vaccines based on variants of concern.

Preliminary Efficacy of the NVX-CoV2373 Covid-19 Vaccine Against the B.1.351 Variant

BackgroundThe emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants threatens progress toward control of the Covid-19 pandemic. Evaluation of Covid-19 vaccine efficacy against SARS-CoV-2 variants is urgently needed to inform vaccine development and use. MethodsIn this phase 2a/b, multicenter, randomized, observer-blinded, placebo-controlled trial in South Africa, healthy human immunodeficiency virus (HIV)-negative adults (18 to 84 years) or medically stable people living with HIV (PLWH) (18 to 84 years) were randomized in a 1:1 ratio to receive two doses, administered 21 days apart, of either NVX-CoV2373 nanoparticle vaccine (5 {micro}g recombinant spike protein with 50 {micro}g Matrix-M1 adjuvant) or placebo. The primary endpoints were safety and vaccine efficacy [≥]7 days following the second dose against laboratory-confirmed symptomatic Covid-19 in previously SARS-CoV-2 uninfected participants. ResultsA total of 4387 participants were randomized and dosed at least once, 2199 with NVX-CoV2373 and 2188 with placebo. Approximately 30% of participants were seropositive at baseline. Among 2684 baseline seronegative participants (94% HIV-negative; 6% PLWH), there were 15 and 29 predominantly mild to moderate Covid-19 cases in NVX-CoV2373 and placebo recipients, respectively; vaccine efficacy was 49.4% (95% confidence interval [CI]: 6.1 to 72.8). Efficacy in HIV-negative participants was 60.1% (95% CI: 19.9 to 80.1), and did not differ by baseline serostatus. Of the primary endpoint cases with available whole genome sequencing, 38 (92.7%) of 41 were the B.1.351 variant. Post-hoc vaccine efficacy against B.1.351 was 51.0% (95% CI: - 0.6 to 76.2) in HIV-negative participants. Among placebo recipients, the incidence of symptomatic Covid-19 was similar in baseline seronegative vs baseline seropositive participants during the first 2 months of follow-up (5.3% vs 5.2%). Preliminary local and systemic reactogenicity were primarily mild to moderate and transient, and higher with NVX-CoV2373; serious adverse events were rare in both groups. ConclusionsThe NVX-CoV2373 vaccine was efficacious in preventing Covid-19, which was predominantly mild to moderate and due to the B.1.351 variant, while evidence of prior infection with the presumptive original SARS-CoV-2 did not confer protection against probable B.1.351 disease. (Funded by Novavax, The Bill and Melinda Gates Foundation, and the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number, NCT04533399)

Implications of the new WHO guidelines on HIV and infant feeding for child survival in South Africa

The World Health Organization released revised principles and recommendations for HIV and infant feeding in November 2009. The recommendations are based on programmatic evidence and research studies that have accumulated over the past few years within African countries. This document urges national or subnational health authorities to decide whether health services should mainly counsel and support HIV-infected mothers to breastfeed and receive antiretroviral interventions; or to avoid all breastfeeding; based on estimations of which strategy is likely to give infants in those communities the greatest chance of HIV-free survival. South Africa has recently revised its clinical guidelines for prevention of mother-to-child HIV transmission; adopting many of the recommendations in the November 2009 World Health Organization's rapid advice on use of antiretroviral drugs for treating pregnant women and preventing HIV infection in infants. However; one aspect of the new South African guidelines gives cause for concern: the continued provision of free formula milk to HIV-infected women through public health facilities. This paper presents the latest evidence regarding mortality and morbidity associated with feeding practices in the context of HIV and suggests a modification of current policy to prioritize child survival for all South African children