Long-term effect of pneumococcal conjugate vaccines on invasive pneumococcal disease incidence among people of all ages from national, active, laboratory-based surveillance in South Africa, 2005-19: a cohort observational study.

BACKGROUND: In South Africa, 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2009 and 13-valent PCV (PCV13) was introduced in 2011, both in a two plus one schedule. We evaluated the ongoing effects of PCV on the prevention of invasive pneumococcal disease (IPD) over 15 years of sustained surveillance in South Africa before the COVID-19 pandemic. METHODS: We conducted national, active, laboratory-based surveillance for IPD among all ages in South Africa, including isolate serotyping and susceptibility testing. We fitted linear regression models with vaccine covariates to imputed IPD case counts each year by serotype and age to compare expected and actual IPD cases in 2019, which was the main outcome. Vaccine effects were set to zero to identify expected incidence after the introduction of PCV7 and PCV13. FINDINGS: From Jan 1, 2005, to Dec 31, 2019, surveillance identified 52 957 IPD cases. Among the 50 705 individuals with age data available, 9398 (18·5%) were infants aged younger than 2 years. Compared with expected case numbers (no vaccination) predicted using all available data, overall IPD rates among children younger than 2 years declined by 76·0% (percentage risk difference; 95% CI -79·0 to -72·8%) in 2019; notably, PCV7 and additional PCV13 serotype IPD rates declined by 95·5% (-97·0 to -93·4%) and 93·8% (-96·2 to-90·5%), respectively, whereas non-vaccine serotypes (NVTs) did not change significantly. Among adults aged 25-44 years, overall IPD declined by 50·4% (-54·2 to -46·3%), and PCV7 and additional PCV13 serotype IPD rates declined by 86·1% (-88·7 to -83·1%) and 77·2% (-80·9 to -73·0%), respectively, whereas NVTs increased by 78·5% (56·8 to 103·4%). Individuals aged older than 64 years also benefited from declines in IPD (-30·2%; -41·9 to -16·2%), but NVTs increased (234·9%; 138·1 to 379·4%). INTERPRETATION: We documented sustained direct and indirect benefits of PCV across age groups, and NVT increases in adults older than 24 years. Higher valency PCVs would have the added benefit of preventing this residual disease. FUNDING: National Institute for Communicable Diseases of the National Health Laboratory Service (South Africa) and US Agency for International Development Antimicrobial Resistance Initiative, US Centers for Disease Control and Prevention.

Comparing adults with severe SARS-CoV-2 or influenza infection: South Africa, 2016-2021.

Background: Comparisons of the characteristics of individuals hospitalised with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) or seasonal influenza in low-to middle-income countries with high human immunodeficiency virus (HIV) prevalence are limited. Objectives: Determine the epidemiological differences with those hospitalised with influenza or SARS-CoV-2 infection. Method: We investigated hospitalised individuals ≥18 years of age testing positive for seasonal influenza (2016-2019) or SARS-CoV-2 (2020-2021). We used random effects multivariable logistic regression, controlling for clustering by site, to evaluate differences among adults hospitalised with influenza or SARS-CoV-2 infection. Results: Compared to individuals with influenza, individuals with SARS-CoV-2 infection were more likely to be diabetic (adjusted odds ratio [aOR]: 1.70, 95% confidence interval [CI]: 1.11-2.61) or die in hospital (aOR: 2.57, 95% CI: 1.61-4.12). Additionally, those with SARS-CoV-2 infection were less likely to be living with HIV (not immunosuppressed) (aOR: 0.50, 95% CI: 0.34-0.73) or living with HIV (immunosuppressed) (aOR: 0.27, 95% CI: 0.18-0.39) compared to not living with HIV and less likely to be asthmatic (aOR: 0.21, 95% CI: 0.13-0.33) rather than those living with influenza. Conclusion: Individuals hospitalised with SARS-CoV-2 had different characteristics to individuals hospitalised with influenza before the coronavirus disease 2019 (COVID-19) pandemic. Risk factors should be considered in health management especially as we move into an era of co-circulation of SARS-CoV-2 and influenza pathogens. Contribution: Identifying groups at high risk of severe disease could help to better monitor, prevent and control SARS-CoV-2 or influenza severe disease.

SARS-CoV-2 correlates of protection from infection against variants of concern.

Serum neutralizing antibodies (nAbs) induced by vaccination have been linked to protection against symptomatic and severe coronavirus disease 2019. However, much less is known about the efficacy of nAbs in preventing the acquisition of infection, especially in the context of natural immunity and against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune-escape variants. Here we conducted mediation analysis to assess serum nAbs induced by prior SARS-CoV-2 infections as potential correlates of protection against Delta and Omicron infections, in rural and urban household cohorts in South Africa. We find that, in the Delta wave, D614G nAbs mediate 37% (95% confidence interval: 34-40%) of the total protection against infection conferred by prior exposure to SARS-CoV-2, and that protection decreases with waning immunity. In contrast, Omicron BA.1 nAbs mediate 11% (95% confidence interval: 9-12%) of the total protection against Omicron BA.1 or BA.2 infections, due to Omicron's neutralization escape. These findings underscore that correlates of protection mediated through nAbs are variant specific, and that boosting of nAbs against circulating variants might restore or confer immune protection lost due to nAb waning and/or immune escape. However, the majority of immune protection against SARS-CoV-2 conferred by natural infection cannot be fully explained by serum nAbs alone. Measuring these and other immune markers including T cell responses, both in the serum and in other compartments such as the nasal mucosa, may be required to comprehensively understand and predict immune protection against SARS-CoV-2.

Estimating averted illnesses from influenza vaccination for children and pregnant women - El Salvador, Panama, and Peru, 2011-2018.

BACKGROUND: Estimating the burden of disease averted by vaccination can assist policymakers to implement, adjust, and communicate the value of vaccination programs. Demonstrating the use of a newly available modeling tool, we estimated the burden of influenza illnesses averted by seasonal influenza vaccination in El Salvador, Panama, and Peru during 2011-2017 among two influenza vaccine target populations: children aged 6-23 months and pregnant women. METHODS: We derived model inputs, including incidence, vaccine coverage, vaccine effectiveness, and multipliers from publicly available country-level influenza surveillance data and cohort studies. We also estimated changes in illnesses averted when countries' vaccine coverage was achieved using four different vaccine deployment strategies. RESULTS: Among children aged 6-23 months, influenza vaccination averted an estimated cumulative 2,161 hospitalizations, 81,907 medically-attended illnesses, and 126,987 overall illnesses during the study period, with a prevented fraction ranging from 0.3 % to 12.5 %. Among pregnant women, influenza vaccination averted an estimated cumulative 173 hospitalizations, 6,122 medically attended illnesses, and 16,412 overall illnesses, with a prevented fraction ranging from 0.2 % to 10.9 %. Compared to an influenza vaccine campaign with equal vaccine distribution during March-June, scenarios in which total cumulative coverage was achieved in March and April consistently resulted in the greatest increase in averted illness (23 %-3,129 % increase among young children and 22 %-3,260 % increase among pregnant women). DISCUSSION: Influenza vaccination campaigns in El Salvador, Panama, and Peru conducted between 2011 and 2018 prevented hundreds to thousands of influenza-associated hospitalizations and illnesses in young children and pregnant women. Existing vaccination programs could prevent additional illnesses, using the same number of vaccines, by achieving the highest possible coverage within the first two months of an influenza vaccine campaign.

Risk Factors for Severe COVID-19 Among Children and Adolescents Enrolled in Acute Respiratory Infection Sentinel Surveillance in South Africa, 2020-2022.

BACKGROUND: Identifying children at risk for severe COVID-19 disease from severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may guide future mitigation interventions. Using sentinel surveillance data, we aimed to identify risk factors for SARS-CoV-2-associated hospitalisation among patients aged ≤ 18 years with respiratory illness. METHODS: From April 2020 to March 2022, patients meeting study case definitions were enrolled at four outpatient influenza-like illness (ILI) and five inpatient severe respiratory infection (SRI) surveillance sites and tested for SARS-CoV-2 infection using polymerase chain reaction (PCR). Each ILI clinic shared a catchment area with its corresponding SRI hospital. Potential risk factors for SARS-CoV-2-associated hospitalisation were analysed using multivariable logistic regression by comparing inpatient versus outpatient SARS-CoV-2 cases. RESULTS: Of 4688 participants aged ≤ 18 years, 4556 (97%) with complete PCR and HIV data were included in the analysis. Among patients with ILI and SRI, 92/1145 (8%) and 154/3411 (5%) tested SARS-CoV-2 positive, respectively. Compared to outpatients, hospitalised SARS-CoV-2 cases were associated with age < 6 months ([adjusted odds ratio (aOR) 8.0, 95% confidence interval (CI) 2.7-24.0] versus 1-4 years); underlying medical condition other than HIV [aOR 5.8, 95% CI 2.3-14.6]; laboratory-confirmed Omicron BA.1/BA.2 or Delta variant ([aOR 4.9, 95% CI 1.7-14.2] or [aOR 2.8, 95% CI 1.1-7.3] compared to ancestral SARS-CoV-2); and respiratory syncytial virus coinfection [aOR 6.2, 95% CI 1.0-38.5]. CONCLUSION: Aligning with previous research, we identified age < 6 months or having an underlying condition as risk factors for SARS-CoV-2-associated SRI hospitalisation and demonstrated the potential of sentinel surveillance to monitor COVID-19 in children.

Characteristics of infections with ancestral, Beta and Delta variants of SARS-CoV-2 in the PHIRST-C community cohort study, South Africa, 2020-2021.

BACKGROUND: Data on the characteristics of individuals with mild and asymptomatic infections with different SARS-CoV-2 variants are limited. We therefore compared the characteristics of individuals infected with ancestral, Beta and Delta SARS-CoV-2 variants in South Africa. METHODS: We conducted a prospective cohort study in a rural and an urban site during July 2020-August 2021. Mid-turbinate nasal swabs were collected twice-weekly from household members irrespective of symptoms and tested for SARS-CoV-2 using real-time reverse transcription polymerase chain reaction (rRT-PCR). Differences in demographic and clinical characteristics, shedding and cycle threshold (Ct) value of infection episodes by variant were evaluated using multinomial regression. Overall and age-specific incidence rates of infection were compared by variant. RESULTS: We included 1200 individuals from 222 households and 648 rRT-PCR-confirmed infection episodes (66, 10% ancestral, 260, 40% Beta, 322, 50% Delta). Symptomatic proportion was similar for ancestral (7, 11%), Beta (44, 17%), and Delta (46, 14%) infections (p=0.4). After accounting for previous infection, peak incidence shifted to younger age groups in successive waves (40-59 years ancestral, 19-39 years Beta, 13-18 years Delta). On multivariable analysis, compared to ancestral, Beta infection was more common in individuals aged 5-12 years (vs 19-39)(adjusted odds ratio (aOR) 2.6, 95% confidence interval (CI)1.1-6.6) and PCR cycle threshold (Ct) value <30 (vs >35)(aOR 3.2, 95%CI 1.3-7.9), while Delta was more common in individuals aged <5 (aOR 6.7, 95%CI1.4-31.2) and 5-12 years (aOR 6.6 95%CI2.6-16.7)(vs 19-39) and Ct value <30 (aOR 4.5, 95%CI 1.3-15.5) and 30-35 (aOR 6.0, 95%CI 2.3-15.7)(vs >35). CONCLUSIONS: Consecutive SARS-CoV-2 waves with Beta and Delta variants were associated with a shift to younger individuals. Beta and Delta infections were associated with higher peak viral loads, potentially increasing infectiousness.

Estimating household contact matrices structure from easily collectable metadata.

Contact matrices are a commonly adopted data representation, used to develop compartmental models for epidemic spreading, accounting for the contact heterogeneities across age groups. Their estimation, however, is generally time and effort consuming and model-driven strategies to quantify the contacts are often needed. In this article we focus on household contact matrices, describing the contacts among the members of a family and develop a parametric model to describe them. This model combines demographic and easily quantifiable survey-based data and is tested on high resolution proximity data collected in two sites in South Africa. Given its simplicity and interpretability, we expect our method to be easily applied to other contexts as well and we identify relevant questions that need to be addressed during the data collection procedure.

Rapid Emergence and Evolution of SARS-CoV-2 Variants in Advanced HIV Infection.

Previous studies have linked the evolution of severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genetic variants to persistent infections in people with immunocompromising conditions1-4, but the evolutionary processes underlying these observations are incompletely understood. Here we used high-throughput, single-genome amplification and sequencing (HT-SGS) to obtain up to ~103 SARS-CoV-2 spike gene sequences in each of 184 respiratory samples from 22 people with HIV (PWH) and 25 people without HIV (PWOH). Twelve of 22 PWH had advanced HIV infection, defined by peripheral blood CD4 T cell counts (i.e., CD4 counts) <200 cells/µL. In PWOH and PWH with CD4 counts ≥200 cells/µL, most single-genome spike sequences in each person matched one haplotype that predominated throughout the infection. By contrast, people with advanced HIV showed elevated intra-host spike diversity with a median of 46 haplotypes per person (IQR 14-114). Higher intra-host spike diversity immediately after COVID-19 symptom onset predicted longer SARS-CoV-2 RNA shedding among PWH, and intra-host spike diversity at this timepoint was significantly higher in people with advanced HIV than in PWOH. Composition of spike sequence populations in people with advanced HIV fluctuated rapidly over time, with founder sequences often replaced by groups of new haplotypes. These population-level changes were associated with a high total burden of intra-host mutations and positive selection at functionally important residues. In several cases, delayed emergence of detectable serum binding to spike was associated with positive selection for presumptive antibody-escape mutations. Taken together, our findings show remarkable intra-host genetic diversity of SARS-CoV-2 in advanced HIV infection and suggest that adaptive intra-host SARS-CoV-2 evolution in this setting may contribute to the emergence of new variants of concern (VOCs).

Incidence and transmission of respiratory syncytial virus in urban and rural South Africa, 2017-2018.

Data on respiratory syncytial virus (RSV) incidence and household transmission are limited. To describe RSV incidence and transmission, we conducted a prospective cohort study in rural and urban communities in South Africa over two seasons during 2017-2018. Nasopharyngeal swabs were collected twice-weekly for 10 months annually and tested for RSV using PCR. We tested 81,430 samples from 1,116 participants in 225 households (follow-up 90%). 32% (359/1116) of individuals had ≥1 RSV infection; 10% (37/359) had repeat infection during the same season, 33% (132/396) of infections were symptomatic, and 2% (9/396) sought medical care. Incidence was 47.2 infections/100 person-years and highest in children <5 years (78.3). Symptoms were commonest in individuals aged <12 and ≥65 years. Individuals 1-12 years accounted for 55% (134/242) of index cases. Household cumulative infection risk was 11%. On multivariable analysis, index cases with ≥2 symptoms and shedding duration >10 days were more likely to transmit; household contacts aged 1-4 years vs. ≥65 years were more likely to acquire infection. Within two South African communities, RSV attack rate was high, and most infections asymptomatic. Young children were more likely to introduce RSV into the home, and to be infected. Future studies should examine whether vaccines targeting children aged <12 years could reduce community transmission.

Modeling the impact of COVID-19 nonpharmaceutical interventions on respiratory syncytial virus transmission in South Africa.

Background: The South African government employed various nonpharmaceutical interventions (NPIs) to reduce the spread of SARS-CoV-2. Surveillance data from South Africa indicates reduced circulation of respiratory syncytial virus (RSV) throughout the 2020-2021 seasons. Here, we use a mechanistic transmission model to project the rebound of RSV in the two subsequent seasons. Methods: We fit an age-structured epidemiological model to hospitalization data from national RSV surveillance in South Africa, allowing for time-varying reduction in RSV transmission during periods of COVID-19 circulation. We apply the model to project the rebound of RSV in the 2022 and 2023 seasons. Results: We projected an early and intense outbreak of RSV in April 2022, with an age shift to older infants (6-23 months old) experiencing a larger portion of severe disease burden than typical. In March 2022, government alerts were issued to prepare the hospital system for this potentially intense outbreak. We then assess the 2022 predictions and project the 2023 season. Model predictions for 2023 indicate that RSV activity has not fully returned to normal, with a projected early and moderately intense wave. We estimate that NPIs reduced RSV transmission between 15% and 50% during periods of COVID-19 circulation. Conclusions: A wide range of NPIs impacted the dynamics of the RSV outbreaks throughout 2020-2023 in regard to timing, magnitude, and age structure, with important implications in a low- and middle-income countries (LMICs) setting where RSV interventions remain limited. More efforts should focus on adapting RSV models to LMIC data to project the impact of upcoming medical interventions for this disease.

Association of HIV Exposure and HIV Infection With In-hospital Mortality Among Hospitalized Infants <1 Year of Age, South Africa, 2016-2018.

We enrolled 1323 hospitalized infants aged <1 year in 2016-2018, and examined the association between HIV status and in-hospital mortality. After controlling for confounders, HIV-exposed uninfected infants did not have an increased risk of mortality, whereas infants living with HIV had 4 times greater risk compared with HIV-uninfected infants.

Transient increased risk of influenza infection following RSV infection in South Africa: findings from the PHIRST study, South Africa, 2016-2018.

BACKGROUND: Large-scale prevention of respiratory syncytial virus (RSV) infection may have ecological consequences for co-circulating pathogens, including influenza. We assessed if and for how long RSV infection alters the risk for subsequent influenza infection. METHODS: We analysed a prospective longitudinal cohort study conducted in South Africa between 2016 and 2018. For participating households, nasopharyngeal samples were taken twice weekly, irrespective of symptoms, across three respiratory virus seasons, and real-time polymerase chain reaction (PCR) was used to identify infection with RSV and/or influenza. We fitted an individual-level hidden Markov transmission model in order to estimate RSV and influenza infection rates and their interdependence. RESULTS: Of a total of 122,113 samples collected, 1265 (1.0%) were positive for influenza and 1002 (0.8%) positive for RSV, with 15 (0.01%) samples from 12 individuals positive for both influenza and RSV. We observed a 2.25-fold higher incidence of co-infection than expected if assuming infections were unrelated. We estimated that infection with influenza is 2.13 (95% CI 0.97-4.69) times more likely when already infected with, and for a week following, RSV infection, adjusted for age. This equates to 1.4% of influenza infections that may be attributable to RSV in this population. Due to the local seasonality (RSV season precedes the influenza season), we were unable to estimate changes in RSV infection risk following influenza infection. CONCLUSIONS: We find no evidence to suggest that RSV was associated with a subsequent reduced risk of influenza infection. Instead, we observed an increased risk for influenza infection for a short period after infection. However, the impact on population-level transmission dynamics of this individual-level synergistic effect was not measurable in this setting.

Knowledge, attitudes, practices and intention to get vaccinated against COVID-19: results from a cross-sectional survey in three peri-urban communities in South Africa.

Introduction: South Africa has the largest number of confirmed cases of COVID-19 in Africa. Data to inform public health strategies to mitigate the spread of new variants and severity of disease is needed, including information on knowledge, attitudes and practices (KAP) regarding COVID-19, factors associated with intention to get vaccinated, and viewpoints on reliable sources of data. Methods: we investigated these topics as part of the COVID-19 healthcare utilization and seroprevalence (HUTS) cross-sectional survey in three communities in South Africa: Mitchell´s Plain (Western Cape Province), Pietermaritzburg (KwaZulu-Natal Province) and Klerksdorp (North West Province) during and after the second wave of COVID-19 prior to vaccine availability. Results: primary caregivers from 5799 households participated in the study, 41.1% from Pietermaritzburg, 34.2% from Klerksdorp and 24.7% from Mitchells Plain. Two-thirds and 94.7% of respondents had correct knowledge on the cause and spread of COVID-19, respectively. Knowledge measures were significantly associated with age less than 65 years, the highest level of education and site (Mitchells Plain). Desired preventive behaviors were associated with higher socio-economic status. While 64.7% of people intended to get vaccinated, those over 64 years of age were more likely to intend to vaccinate (aOR: 1.25, 95% CI: 1.06-1.47). Vaccine intention related to protection of self (58.4%) and family (40.0%). The most trusted source of COVID-19 information was television (59.3%) followed by radio (20.0%). Conclusion: these data can be used to design targeted public health campaigns for the current COVID-19 and future epidemics, ensuring that socio-economic constraints and preference for trusted information are considered.

Estimating the time-varying reproduction number for COVID-19 in South Africa during the first four waves using multiple measures of incidence for public and private sectors across four waves.

OBJECTIVES: The aim of this study was to quantify transmission trends in South Africa during the first four waves of the COVID-19 pandemic using estimates of the time-varying reproduction number (R) and to compare the robustness of R estimates based on three different data sources, and using data from public and private sector service providers. METHODS: R was estimated from March 2020 through April 2022, nationally and by province, based on time series of rt-PCR-confirmed cases, hospitalisations, and hospital-associated deaths, using a method that models daily incidence as a weighted sum of past incidence, as implemented in the R package EpiEstim. R was also estimated separately using public and private sector data. RESULTS: Nationally, the maximum case-based R following the introduction of lockdown measures was 1.55 (CI: 1.43-1.66), 1.56 (CI: 1.47-1.64), 1.46 (CI: 1.38-1.53) and 3.33 (CI: 2.84-3.97) during the first (Wuhan-Hu), second (Beta), third (Delta), and fourth (Omicron) waves, respectively. Estimates based on the three data sources (cases, hospitalisations, deaths) were generally similar during the first three waves, but higher during the fourth wave for case-based estimates. Public and private sector R estimates were generally similar except during the initial lockdowns and in case-based estimates during the fourth wave. CONCLUSION: Agreement between R estimates using different data sources during the first three waves suggests that data from any of these sources could be used in the early stages of a future pandemic. The high R estimates for Omicron relative to earlier waves are interesting given a high level of exposure pre-Omicron. The agreement between public and private sector R estimates highlights that clients of the public and private sectors did not experience two separate epidemics, except perhaps to a limited extent during the strictest lockdowns in the first wave.

Healthcare utilization during the first two waves of the COVID-19 epidemic in South Africa: A cross-sectional household survey.

Healthcare utilization surveys contextualize facility-based surveillance data for burden estimates. We describe healthcare utilization in the catchment areas for sentinel site healthcare facilities during the first year of the COVID-19 pandemic. We conducted a cross-sectional healthcare utilization survey in households in three communities from three provinces (KwaZulu-Natal, Western Cape and North West). Field workers administered structured questionnaires electronically with the household members reporting influenza-like illness (ILI) in the past 30 days or severe respiratory illness (SRI) since March 2020. Multivariable logistic regression was used to identify factors associated with healthcare utilization among individuals that reported illness. From November 2020 through April 2021, we enrolled 5804 households and 23,003 individuals. Any respiratory illness was reported by 1.6% of individuals; 0.7% reported ILI only, 0.8% reported SRI only, and 0.1% reported both ILI and SRI. Any form of medical care was sought by 40.8% (95% CI 32.9% - 49.6%) and 71.3% (95% CI 63.2% - 78.6%) of individuals with ILI and SRI, respectively. On multivariable analysis, respiratory illness was more likely to be medically attended for individuals at the Pietermaritzburg site (aOR 3.2, 95% CI 1.1-9.5, compared to Klerksdorp), that were underweight (aOR 11.5, 95% CI 1.5-90.2, compared to normal weight), with underlying illness (aOR 3.2, 95%CI 1.2-8.5), that experienced severe illness (aOR 4.8, 95% CI 1.6-14.3) and those with symptom duration of ≥10 days (aOR 7.9, 95% CI 2.1-30.2, compared to <5 days). Less than half of ILI episodes and only 71% of SRI episodes were medically attended during the first two COVID-19 waves in South Africa. Facility-based data may underestimate disease burden during the COVID-19 pandemic.

Association of close-range contact patterns with SARS-CoV-2: a household transmission study.

Background: Households are an important location for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission, especially during periods when travel and work was restricted to essential services. We aimed to assess the association of close-range contact patterns with SARS-CoV-2 transmission. Methods: We deployed proximity sensors for two weeks to measure face-to-face interactions between household members after SARS-CoV-2 was identified in the household, in South Africa, 2020-2021. We calculated the duration, frequency, and average duration of close-range proximity events with SARS-CoV-2 index cases. We assessed the association of contact parameters with SARS-CoV-2 transmission using mixed effects logistic regression accounting for index and household member characteristics. Results: We included 340 individuals (88 SARS-CoV-2 index cases and 252 household members). On multivariable analysis, factors associated with SARS-CoV-2 acquisition were index cases with minimum Ct value <30 (aOR 16.8 95% CI 3.1-93.1) vs >35, and female contacts (aOR 2.5 95% CI 1.3-5.0). No contact parameters were associated with acquisition (aOR 1.0-1.1) for any of the duration, frequency, cumulative time in contact, or average duration parameters. Conclusions: We did not find an association between close-range proximity events and SARS-CoV-2 household transmission. Our findings may be due to study limitations, that droplet-mediated transmission during close-proximity contacts plays a smaller role than airborne transmission of SARS-CoV-2 in the household, or due to high contact rates in households. Funding: Wellcome Trust (Grant number 221003/Z/20/Z) in collaboration with the Foreign, Commonwealth, and Development Office, United Kingdom.

The attributable fraction of respiratory syncytial virus among patients of different ages with influenza-like illness and severe acute respiratory illness in a high HIV prevalence setting, South Africa, 2012-2016.

OBJECTIVES: The detection of respiratory syncytial virus (RSV) in upper airway samples does not necessarily infer causality of illness. We aimed to calculate the attributable fraction (AF) of RSV in clinical syndromes across age groups. METHODS: Using unconditional logistic regression models, we estimated the AF of RSV-associated influenza-like illness (ILI) and severe acute respiratory illness (SARI) cases by comparing RSV detection prevalence among ILI and SARI cases to those of healthy controls in South Africa, 2012-2016. The analysis, stratified by HIV serostatus, was conducted in the age categories <1, 1-4, 5-24, 25-44, 45-64, and ≥65 years. RESULTS: We included 12,048 individuals: 2687 controls, 5449 ILI cases, and 5449 SARI cases. RSV-AFs for ILI were significant in <1, 1-4, 5-and 24, 25-44-year age groups: 84.9% (95% confidence interval [CI] 69.3-92.6%), 74.6% (95% CI 53.6-86.0%), 60.8% (95% CI 21.4-80.5%) and 64.1% (95% CI 14.9-84.9%), respectively. Similarly, significant RSV-AFs for SARI were 95.3% (95% CI 91.1-97.5) and 83.4% (95% CI 70.9-90.5) in the <1 and 1-4-year age groups respectively. In HIV-infected persons, RSV was significantly associated with ILI cases vs controls in individuals aged 5-44 years. CONCLUSION: High RSV-AFs in young children confirm RSV detection is associated with severe respiratory illness in South African children, specifically infants. These estimates will assist with refining burden estimates and cost-effectiveness models.

The burden of RSV-associated illness in children aged < 5 years, South Africa, 2011 to 2016.

BACKGROUND: Vaccines and monoclonal antibodies to protect the very young infant against the respiratory syncytial virus (RSV)-associated illness are effective for limited time periods. We aimed to estimate age-specific burden to guide implementation strategies and cost-effectiveness analyses. METHODS: We combined case-based surveillance and ecological data to generate a national estimate of the burden of RSV-associated acute respiratory illness (ARI) and severe acute respiratory illness (SARI) in South African children aged < 5 years (2011-2016), including adjustment for attributable fraction. We estimated the RSV burden by month of life in the < 1-year age group, by 3-month intervals until 2 years, and then 12 monthly intervals to < 5 years for medically and non-medically attended illness. RESULTS: We estimated a mean annual total (medically and non-medically attended) of 264,112 (95% confidence interval (CI) 134,357-437,187) cases of RSV-associated ARI and 96,220 (95% CI 66,470-132,844) cases of RSV-associated SARI (4.7% and 1.7% of the population aged < 5 years, respectively). RSV-associated ARI incidence was highest in 2-month-old infants (18,361/100,000 population, 95% CI 9336-28,466). The highest incidence of RSV-associated SARI was in the < 1-month age group 14,674/100,000 (95% CI 11,175-19,645). RSV-associated deaths were highest in the first and second month of life (110.8 (95% CI 74.8-144.5) and 111.3 (86.0-135.8), respectively). CONCLUSIONS: Due to the high burden of RSV-associated illness, specifically SARI cases in young infants, maternal vaccination and monoclonal antibody products delivered at birth could prevent significant RSV-associated disease burden.

The economic burden of RSV-associated illness in children aged < 5 years, South Africa 2011-2016.

BACKGROUND: Data on the economic burden of RSV-associated illness will inform decisions on the programmatic implementation of maternal vaccines and monoclonal antibodies. We estimated the cost of RSV-associated illness in fine age bands to allow more accurate cost-effectiveness models to account for a limited duration of protection conferred by short- or long-acting interventions. METHODS: We conducted a costing study at sentinel sites across South Africa to estimate out-of-pocket and indirect costs for RSV-associated mild and severe illness. We collected facility-specific costs for staffing, equipment, services, diagnostic tests, and treatment. Using case-based data we calculated a patient day equivalent (PDE) for RSV-associated hospitalizations or clinic visits; the PDE was multiplied by the number of days of care to provide a case cost to the healthcare system. We estimated the costs in 3-month age intervals in children aged < 1 year and as a single group for children aged 1-4 years. We then applied our data to a modified version of the World Health Organization tool for estimating the mean annual national cost burden, including medically and non-medically attended RSV-associated illness. RESULTS: The estimated mean annual cost of RSV-associated illness in children aged < 5 years was US dollars ($)137,204,393, of which 76% ($111,742,713) were healthcare system incurred, 6% ($8,881,612) were out-of-pocket expenses and 13% ($28,225,.801) were indirect costs. Thirty-three percent ($45,652,677/$137,204,393) of the total cost in children aged < 5 years was in the < 3-month age group, of which 52% ($71,654,002/$137,204,393) were healthcare system incurred. The costs of non-medically attended cases increased with age from $3,307,218 in the < 3-month age group to $8,603,377 in the 9-11-month age group. CONCLUSIONS: Among children < 5 years of age with RSV in South Africa, the highest cost burden was in the youngest infants; therefore, interventions against RSV targeting this age group are important to reduce the health and cost burden of RSV-associated illness.