FUNCTIONS

The aim of this platform is to identify and monitor acute respiratory tract infections (ARI) which may potentially include influenza, RSV and COVID-19. CoughWatchSA is designed to be a long-term surveillance platform for respiratory diseases beyond COIVD-19 and is not similar to the contact-tracing apps released by the National Department of Health. This platform may assist in the early detection of the onset of the influenza season in 2022 and potentially any subsequent waves of COVID-19. Participants in KwaZulu Natal, Western Cape and Gauteng may be linked to a pilot study that will allow for the home-based testing for influenza, RSV and COVID-19. This pilot study is called CoughCheck and will provide laboratory confirmations for suspected cases from CoughWatchSA participants who are eligible. CoughWatchSA will run as a pilot for the remainder of this year and will be officially launched as a complementary surveillance platform to current disease surveillance systems from 2023 onwards.

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The Prospective Household observational cohort study of Influenza, Respiratory Syncytial virus and other respiratory pathogens community burden and Transmission dynamics in South Africa (The PHIRST Study) was a prospective cohort study in a rural and urban site from 2017-2018, with approximately 100 new households enrolled each year and followed up for 10 months. Nasopharyngeal swabs were collected twice-weekly from consenting household members irrespective of symptoms and tested for influenza virus, respiratory syncytial virus (RSV), B. pertussis and S. pneumoniae using a real-time reverse transcription polymerase chain reaction. We collected and tested over 100,000 nasopharyngeal swabs and over 7,000 serum samples. Although the follow-up of the cohort has stopped, we are currently doing serology testing and analysis.

The PHIRST study is a collaboration between the National Institute for Communicable Diseases (NICD), Johannesburg, South Africa; University of Witwatersrand, School of Public Health, Johannesburg, South Africa; United States Centers for Disease Control and Prevention, Atlanta, United States of America (USA); Perinatal HIV Research Unit, Johannesburg, South Africa; MRC/Wits Rural Public Health and Health Transitions Research (Agincourt), Bushbuckridge, South Africa; Medical Research Council (Environment and Health Research Unit), Johannesburg, South Africa and the ISI foundation, Italy.

Primary objectives

1. To estimate the community burden of influenza and RSV, including: (i) the incidence of influenza and RSV infection in the community; (ii) the symptomatic fraction associated with influenza and RSV infection; (iii) the severity associated with symptomatic infections; and (iv) the fraction of individuals with symptomatic infection seeking medical care.
2. To assess the transmission dynamics of influenza and RSV infections in the community, including: (i) the estimation of the household secondary infection risk (SIR), serial interval and length of shedding; (ii) the estimation of transmission of infection between age groups within the household and possibly the community; and (iii) the estimation of the effective reproductive number (Rt) and its variation over time in the community.

Importance

The PHIRST study will improve our understanding of the community burden of influenza, RSV, pertussis, tuberculosis and pneumococcal infection in South Africa. It will also provide data on the carriage prevalence of meningococcus, diphtheria and group A streptococcus. The data generated from this study will also provide important information on the transmission dynamics of influenza, RSV, pertussis and pneumococcus in the community allowing to better strategize interventions (including targeted vaccination strategies) and evaluate their potential impact. 

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PHIRST Protocol 13 July 2018

Contact details

Prof Cheryl Cohen
Tel: 011 386 6593
Email: cherylc@nicd.ac.za

The Prospective Household study of SARS-CoV-2, Influenza, and Respiratory Syncytial virus community burden, Transmission dynamics and viral interaction in South Africa (the PHIRST-C Study) study builds on a previous study, the PHIRST study, that was implemented in 2016-2018 and focused on the community burden and household transmission of influenza, respiratory syncytial virus (RSV), Bordetella pertussis and pneumococcus.

In light of the ongoing corona virus disease 2019 (COVID-19) pandemic, PHIRST-C will be conducted to help us understand the community burden, transmissibility potential and clinical features of illness associated with severe acute respiratory syndrome corona virus 2 (SARS-CoV-2) infection. PHIRST-C is a prospective household cohort study where we follow up 200 households, 100 in a rural community in Mpumalanga Province, and 100 in an urban community in the North West Province. Participants in the study are visited twice-weekly for ten months to collect nasal swabs to test for SARS-CoV-2, influenza, RSV and pertussis; and to collect information on symptoms and healthcare seeking. Results will help us identify how many individuals are infected by SARS-CoV-2, how many of these experience symptoms, seek care, are hospitalised and die.  Blood is collected every two months during this period to look for SARS-CoV-2 antibodies, signalling that someone was infected with the virus and their immune system reacted to that infection. To help us understand the reduction of antibodies in individuals that were infected, we will also be collecting blood every 2 months for an additional 12 months from participants who tested positive for SARS-CoV-2 in the initial follow-up period, helping us understand for how long someone may be immune to the virus after they were infected. 

Overall, PHIRST-C will help us understand who is more at risk for being infected with the virus and becoming severely ill, how long someone may stay infectious, if someone can be re-infected, what proportion of infections occur without any symptoms and to what extent individuals without symptoms can transmit the virus, how SARS-CoV-2 is influenced by other respiratory viruses such as influenza and RSV. We will also examine how age and HIV-infection affect all of the above areas. This information can then in turn be used to inform the design and duration of measures to contain the virus.

Primary objectives

1. To estimate the community burden of SARS-CoV-2, including:
   • the incidence of SARS-CoV-2 infection in the community as determined by polymerase chain reaction (PCR) and serologic assays;
   • the correlation between individuals that seroconverted for SARS-CoV-2 and tested positive by PCR;
   • the incubation period and the symptomatic fraction associated with SARS-CoV-2 infection;
   • the spectrum of severity associated with symptomatic infections;
   • the fraction of individuals with symptomatic infection seeking medical care; and
   • the effect of the interaction of SARS-CoV-2 with influenza and RSV on disease severity.

2. To assess the transmission dynamics of SARS-CoV-2 infections in the community, including:
   • the estimation of the SARS-CoV-2 household secondary infection risk (SIR), generation time and length of shedding;
   • the estimation of the probability of transmission of SARS-CoV-2 infection between individuals (both symptomatic and asymptomatic/presymptomatic) within the household and potentially the community;
   • the estimation of the SARS-CoV-2 effective reproduction number (Rt) and its variation over time in the community; and
   • the effect of the interaction of SARS-CoV-2 with influenza and RSV on transmission dynamics.

Impact

This study will provide essential information on the natural history of the virus that will impact decisions on optimal strategies for the containment and mitigation of the current and potential future epidemics of SARS-CoV-2 locally, regionally and globally.

PHIRST-C Protocol 16 November 2020

The household transmission study (HTS) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease (COVID-19), is a case-ascertained, prospective, observational household transmission study of household contacts of index cases from two urban communities in the North West Province (Klerksdorp) and the Gauteng Province (Soweto). In order to better understand the transmission dynamics of SARS-CoV-2 in households with HIV-infected and HIV-uninfected COVID-19 index cases, we screen individuals consulting at primary healthcare facilities for respiratory illness or suspected COVID-19 and test them for SARS-CoV-2. If someone tests positive for SARS-CoV-2 and reports to be the first person with respiratory or suspected COVID-19 symptoms in their household, we approach their household for enrolment in the HTS. Following enrolment, nasal swabs are collected from the index cases and their household contacts three times per week for 6 weeks’ post-enrolment to test for SARS-CoV-2, irrespective of presence of symptoms. We also collect serum at enrolment and the end of the follow-up period to test for antibodies to SARS-CoV-2. The HTS started in October 2020 and will continue until August 2021, and will help us understand if compared to HIV-uninfected individuals, HIV-infected individuals shed SARS-CoV-2 for longer, or if there is a difference risk of transmitting the virus to household contact, and to determine the incubation period and the proportion of SARS-CoV-2 individuals that have symptoms.

Primary objectives

1. To determine the time period (range and median) in days that HIV-infected and HIV-uninfected index cases continue to shed SARS-CoV-2 from respiratory specimens after symptoms onset using real-time reverse transcription polymerase chain reaction (rRT-PCR) and viral culture.
2. To determine the temporal variations of SARS-CoV-2 viral-load in respiratory specimens from HIV-infected and HIV-uninfected index cases using reverse transcriptase polymerase chain reaction (rRT-PCR).
3. To determine the secondary infection risk (SIR) in household contacts of HIV-infected and HIV-uninfected index cases.
4. To determine the serial interval (SI) for SARS-CoV-2 transmission from HIV-infected and HIV-uninfected index cases.
5. To determine the antibody response to SARS-CoV-2 early-post infection among HIV-infected and HIV-uninfected index cases.

Impact

This study will provide essential information on the natural history of the virus, also considering how it may differ between HIV-infected and –uninfected individuals. This will impact decisions on optimal strategies for the containment and mitigation of the current and potential future epidemics of SARS-CoV-2 locally, regionally and globally.

Contact information

Dr Sibongile Walaza

Email: sibongilew@nicd.ac.za

The Healthcare Utilisation and Seroprevalence of COVID-19 (HUTS) study is a cross-sectional community survey being conducted in three communities serviced by healthcare facilities where severe respiratory illness (SRI) and influenza-like illness (ILI) surveillance is conducted in South Africa (Mitchell’s Plain, Pietermaritzburg and Klerksdorp) during and after the second wave of SARS-CoV-2 infections in South Africa. The study aims to explore the healthcare seeking behaviour for and cost of respiratory illness during the pandemic and to estimate SARS-CoV-2 community seroprevalence and the COVID-19 knowledge, attitudes and practices (KAP) of the selected communities. The study will complement data from inpatient and outpatient syndromic surveillance conducted in the same target communities to document the clinical spectrum of illness, including the proportion of asymptomatic, mild, severe and fatal cases, both medically and non-medically attended. Serology testing for SARS-CoV-2 is important in order to better quantify the number of COVID-19 cases, including those that may have been asymptomatic or recovered without having been tested. Public health action is guided by the incidence of infection, and therefore understanding the full burden of infection and potentially immunity, is important. Surveillance of antibody seropositivity in the South African population will allow inferences to be made about the extent of infection in the community.

Objectives

In three communities in South Africa, Klerksdorp North West Province, Pietermaritzburg KwaZulu-Natal and Mitchells Plain Western Cape, address the following:

Primary objectives:

1. Characterize healthcare seeking behaviour for respiratory illness during the first wave of the COVID-19 pandemic
2. Determine the proportion of mild and severe respiratory illnesses that were not medically attended during the epidemic period
3. To estimate the household and community economic burden of respiratory illness during the first wave of the epidemic
4. To describe the economic impact of mitigation measures on households during the first wave of the epidemic
5. Describe knowledge, attitudes and practices related to COVID-19 in the community, including prevention
6. Determine the seroprevalence of antibodies to SARS-CoV-2 following the first wave of the pandemic, by age group and HIV-infection status.

Secondary objectives:

1. Provide a more accurate estimate of the burden of COVID-19 in the community by adjusting facility-based surveillance data for healthcare seeking behaviour
2. Assess the sensitivity of sentinel surveillance for COVID-19 at each site
3. Identify risk factors for SARS-CoV-2 infection including age, HIV infection and underlying illnesses
4. To estimate the SARS-CoV-2 infection case-fatality ratio through triangulation with COVID sentinel surveillance and mortality data
5. Determine the seroprevalence of antibodies to other respiratory viruses such as influenza, respiratory syncytial virus and other human coronaviruses

Impact

Understanding community healthcare utilization, KAP and economic burden on households associated with the COVID-19 pandemic is key to guide containment and mitigation measures in local settings and globally. In addition, understanding the disease burden of COVID-19 and groups at increased risk of severe COVID-19 is key to inform mitigation guidelines for ongoing and potential future epidemics.

Contact information

Dr. Nicole Wolter

Email: nicolew@nicd.ac.za

The African network for improved diagnostics, epidemiology and management of common infectious agents (ANDEMIA) project is a collaboration between South Africa, Burkina Faso, Côte d’Ivoire, the Democratic Republic of the Congo and is funded by the German Federal Ministry of Education and Research (BMBF) and Research Networks for Health Innovations in Sub‐Saharan Africa. The South African sites are Mapulaneng regional hospital and Matikwana medium district hospital in Mpumalanga and Kalafong hospital in the Gauteng province. The primary goals of the ANDEMIA project are to deliver critical research activities and to build capacities and strengthen collaboration for enhanced detection, control, treatment and prevention of acute respiratory tract (RTI) and gastrointestinal (GI) tract infections and acute febrile disease of unknown cause (AFDUC) in Sub-Saharan Africa in a One Health approach on a regional scale. The primary aim is to establish an integrated sentinel surveillance system, investigate in-depth the pathogens underlying the specific syndromes, examine the link of disease to quality of hospital settings, ecological, environmental and behavioural risk factors and eventually implement improved intervention measures in the target regions, which may serve as a model for other regions.

Objectives

1. To measure the proportion of acute RTI cases amongst total hospitalisations (or cases eligible for hospitalisation) at the sentinel sites
2. To measure the proportion of acute RTI cases amongst total hospitalisations (or cases eligible for hospitalisation) by age category at the sentinel sites
3. To define the aetiology of RTI using improved diagnostics and to test for antibiotic resistance of selected pathogens
4. To describe the epidemiology of these infections, including seasonality, age distribution of patients, risk factors, treatment, treatment outcomes and to test for difference in aetiology and antibiotic resistance between sites.
5. To measure the proportion of deaths amongst acute RTI cases per total number of hospitalisations.

Importance

The research aims at the identification of pathogens underlying common syndromes to guide appropriate interventions, such as adapting guidelines for diagnosis and treatment, encouraging appropriate antibiotic use, implementing rapid diagnostic tests where appropriate, and introducing infection control measures and outbreak management. Our hypothesis is that locally adopted interventions based on integrated surveillance data (integrating clinical and laboratory data) are more effective in improving patient outcomes and disease prevention than vertical disease programmes. Since zoonotic diseases are a major concern, the One Health approach unifying human and animal health, such as aspects of antibiotic use among animals and exposure to zoonotic diseases among humans, will be taken into account. In addition, the data allows exploration of associations between pathogen burden, climate zone and housing density (rural versus urban) in Africa, where there is a paucity of data.

Within Sub-Saharan Africa, the highest risk for infectious disease spread and the greatest need for targeted interventions including outbreak control exist in areas with high population densities and increased population movements but also regions that are less connected to the main public health system and which are characterised by high biodiversity, exhibit ecological alterations and close human-animal contact. Therefore, the network’s main geographical focus will be Burkina Faso, Côte d’Ivoire, the Democratic Republic of the Congo and the Republic of South Africa. Unlike other studies or existing surveillance systems, ANDEMIA will not only focus on easy-access hospital sites, but will additionally target rural regions. ANDEMIA partners have a long history working in such remote African regions, which is a guarantor for the feasibility of the project. As a direct result of the research activities, the network will provide urgently needed epidemiological data on the role of Sub-Saharan Africa as a “reservoir” for various pathogens, including antimicrobial resistant types, both of relevance on a global scale.

Contact details

Andemia Website

Kathleen Subramoney
Tel: 011 386 6392
Email: kathleens@nicd.ac.za

This study is a partnership between NICD, Kenya Medical Research Institute (KEMRI) (Kilifi Wellcome Trust Centre and KEMRI Kisumu), the London School of hygiene and tropical medicine and the University of Antwerp and is supported and funded by PATH. It aims to describe the seasonality of respiratory syncytial virus (RSV), disease burden by age groups in South Africa and Kenya, as well as the cost of RSV-associated hospitalization in South African (from available data) and Kenya (by primary data collection). This data will then be included in a model to compare the cost effectiveness of long acting monoclonal antibodies and maternal vaccination in South and Kenya. 

Objectives

1. Describe the seasonality of RSV disease in South Africa and Kenya (using previously collected data)
2. Estimate the incidence of RSV-associated hospitalizations by month of life among children aged <1 years and in 3-month age bands among those aged 1-<2 years in South Africa and Kenya (using previously collected data)
3. Work with local partners to collect the cost of RSV hospitalizations in Kenya through conducting a costing study at two hospital sites
4. Collaborate with partners to calculate the cost of RSV disease to the government, households and society, by age group and disease severity in South Africa (through analysis of previously unpublished data)
5. Collaborate with partners to quantify the RSV burden which could be potentially prevented through maternal vaccination or infant immunization under different assumptions in South Africa and Kenya

We will document available evidence on the seasonality, burden and cost of RSV-associated influenza-like Illness (ILI), lower respiratory tract infection and mortality (both medically and non-medically attended) in South Africa and Kenya. In addition, we will also describe the direct and indirect cost of RSV-associated respiratory tract infection in South Africa and Kenya. Data will be drawn from the national pneumonia surveillance programme, a costing study completed as part of the national pneumonia surveillance programme and other sources such as statistics South Africa and the demographic health survey. In Kenya similar surveillance programmes will provide data on seasonality and burden, while costing data will be collected during the RSV season 2019-2020. These data will be used to build a cost effectiveness model for maternal vaccines and monoclonal antibodies.

Importance

The burden of RSV is substantial. RSV-associated infection is estimated to have caused 3.2 million episodes of hospitalization for acute lower respiratory infections and 60,000–118,000 deaths among children aged <5 years globally in 2015, most of these occurred in low and middle-income countries. Presently there are no licensed RSV vaccines and the only RSV-specific monoclonal antibody licensed provides short-lived protection and is priced beyond the reach of public health care systems. However new interventions to prevent for RSV infection, specifically hospitalisation with RSV-associated lower respiratory tract infections, are in the pipeline. The data from this project will provide policy makers including national departments of health and international advocacy groups such as GAVI, WHO and the Bill and Melinda Gates Foundation with evidence to inform the cost saving of such interventions. These data can then be used to motivated for the introduction of the interventions in to public health programmes.  In addition, the data on seasonality will help programme managers to design the implementation around the RSV season and so maximise effect and cost of these programmes.

Contact information

Dr Jocelyn Moyes
Email: jocelynm@nicd.ac.za

RADIATES (Rapid Amplification Diagnostic Interventions and Transmission Epidemiology for SARS-CoV-2) Consortium

The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is threatening our social practices, financial security and healthcare systems. South Africa faces unique challenges with respect to managing this pandemic:  a large portion of South Africans live in impoverished and overcrowded communities; and South Africans carry the additional burden of high human immunodeficiency virus (HIV) and tuberculosis (TB) incidence rates. It is not known how SARS-CoV-2 infection will affect HIV-positive or HIV/TB co-infected individuals on treatment, nor how it will affect the nearly 40% of HIV infected individuals who are not on treatment.

Testing is critical for our understanding and implementation of interventions during this pandemic. Therefore, it is imperative that we (1) understand the reproductive number (R0) of SARS-CoV-2 in South Africa, which may differ from other regions of the world due to the unique challenges mentioned above; and (2) develop and implement a rapid, cost effective assay to diagnose infection. We are addressing these research gaps through the following two main aims and specific objectives:

1. Optimisation and evaluation of a reverse transcriptional loop-mediated isothermal amplification (RT-LAMP) diagnostic platform through:

• Optimisation of a robust and cost-effective RT-LAMP assay for use in resource-limited settings
• Evaluation of sensitivity, specificity and usability of RT-LAMP for point of care testing
• Targeted gene sequencing to detect potential mutations within primer/probe binding sites for both RT-LAMP

2. Molecular epidemiological analysis using whole-genome sequencing (WGS) to describe the COVID-19 epidemic in the Western Cape, South Africa

• Phylodynamic analysis used to estimate epidemiological quantities including the current reproduction number, changes in the reproduction number due to public health interventions, epidemic size and transmission patterns between communities with variable income and population density
• Epidemiological models adapted to forecast the impact of rapid POC testing
• Piloting a gene sequencing strategy for the viral spike-encoding gene using the PacBio platform, as a cost-effective surveillance strategy to track evolution of the target for a future vaccine

Together, as the RADIATES Consortium of scientists, clinicians, epidemiologists and bioinformaticians, we hope to dramatically improve testing, surveillance, and understanding of the COVID-19 epidemic in South Africa.

Methods

Optimisation of a robust and cost-effective RT-LAMP assay for use in resource limited settings

We have already optimised a preliminary version of the RT-LAMP for SARS-CoV-2 detection, which allows for the distinction between SARS-CoV-2 positive and negative samples through a simple colour difference. We will optimise reaction conditions for the omission of RNA extraction steps to allow the direct use of patient samples. This includes testing various virus inactivation conditions to maximize recovery of intact RNA. To circumvent the current supply limitations of molecular reagents as well as their associated expense, we will optimise the usage of alternative non-commercial DNA polymerases compatible for RT-LAMP, and produce reagents that will be shared with the network in South Africa. Finally, we will benchmark the detection of multiple RT-LAMP primer sets targeting different regions of the SARS-CoV-2 genome with established rRT-PCR approaches.

Evaluation of sensitivity, specificity and usability of RT-LAMP for point of care testing

We will evaluate the sensitivity and specificity of the RT-LAMP assay on combined nasopharyngeal and oropharyngeal (NP/OP) swab samples collected from symptomatic in- and out-patients through our established influenza-like illness (ILI) and severe acute respiratory illness (SARI) surveillance network. We will initially screen 500 samples for infection with 22 respiratory pathogens, including SARS-CoV-2 and the four common human coronaviruses (huCoV-HKU1, NL63, 229E and OC43), using rRT-PCR. From these, we will select 200 SARS-CoV-2 positive samples, with a range of cycle threshold (Ct) values to estimate sensitivity of the RT-LAMP assay. We will also select 100 SARS-CoV-2 negative samples to evaluate specificity of the RTLAMP assay. Using targeted SARS-CoV-2 gene sequencing will determine whether any false negatives are a direct result of mutations in the primer/probe binding sites. The RT-LAMP will be piloted for diagnosing COVID-19 infection in patients who present with COVID-19 symptoms at hospitals, clinics and mobile community testing sites through two multi-centric initiatives led by the South African Medical Research Council (SAMRC) and the University of Cape Town (UCT). The assay will be used at baseline and its performance will be tested alongside and compared to other diagnostic POC rapid tests and RT-PCR as the gold standard.

Molecular epidemiology and phylodynamics

We will collect a representative random sample of whole genome (WG) sequences from Cape Town by selecting a subset of positive diagnostic samples and controlling for population size and reported infections in each catchment area in the Cape Town Metro District. These sequences will be combined with a random sample of publicly available sequences sampled globally and released on GISAID. Samples will be selected to provide a good representation of multiple time points and will include all publicly available sequences found to have close genetic distance with any sequence in the Cape Town sample. Consensus sequences generated by the project across South Africa will be compared to one another and to the database of global SARS-CoV-2 whole genome sequences available on GISAID (www.gisaid.org). Sequences will be assigned to lineages and sub-lineages as suggested in https://virological.org/t/a-dynamic-nomenclature-proposal-for-sars-cov-2-to-assist-genomic-epidemiology/458. Phylogenetic analyses will be used to determine whether strains circulating in a particular community are the result of a single epidemiological cluster, or the result of multiple importations from other regions/countries. Regular, nationally distributed whole genome sequencing will allow high resolution mapping of the spread of different lineages and sub-lineages across the country, and place this in African and global context. 

Tracing the emergence and disappearance of sub-lineages will allow an interpretation of the effectiveness of different non-pharmacological interventions, including social distancing measures, and aid in the investigation and resolution of the clusters that are likely to emerge nationally as these measures are loosened. We will carry out a Bayesian time-scaled phylogenetic analysis making use of known dates of sample collection. By annotating phylogenetic trees with known location of sampling, we will infer the likely time and origin of lineages circulating endogenously in Cape Town. Phylodynamic analysis will be conducted using structured coalescent approaches and realistic epidemiological models. We will develop a susceptible-exposed-infectious-recovered (SEIR) model tailored to COVID-19, which will account for multiple features of its epidemiology and factors that are likely to influence genetic diversity within our random sample. This analysis will build on a phylodynamics pipeline that has been successfully piloted for SARS CoV 2 in multiple locations (http://sarscov2phylodynamics.org). By fitting the SEIR model to Cape Town data, we will estimate the reproduction number, how the reproduction number has varied over time, and the number of infected over time. These time-dependent quantities will be compared to known dates of public health interventions to quantify their likely impact on suppressing the epidemic.

Modelling public health impact of rapid POC testing

Models developed for phylodynamic analysis and fitted to Cape Town data will be modified to include the effects of POC testing and rapid home isolation of detected cases. These effects will be parameterized as an effective reduction in the transmission rate of newly diagnosed people and a reduction in asymptomatic/presymptomatic transmission which may account for nearly half of all transmissions. A range of scenarios will be explored by varying i) availability and frequency of POC testing, ii) proportion of presymptomatic and asymptomatic cases detected, iii) false negative rates which may depend on time since infection and, iv) adherence to home isolation. Because parameters of this model will have already been calibrated to WGS from Cape Town, including epidemic size and reproduction number, the intervention model will provide a range of realistic forecasts for the public health impact of POC testing in this population.

Pilot a gene sequencing strategy for the viral spike gene using the PacBio platform, as a cost-effective surveillance strategy to track evolution of the target for a future vaccine.

PacBio is emerging as a leading platform for studying long viral amplicons. The spike-seq assay will exploit the dramatic increase in depth of the recent PacBio Sequel and Sequel II platforms and use this along with a simple primer barcoding scheme to allow for low cost SARS-CoV-2 spike sequencing. Starting from extracted RNA, we will optimize RT and nested PCR conditions, as well as primer barcoding strategies. PacBio data generated from this assay requires custom processing. We will adapt existing pipelines used for the analysis of barcoded multiplexed HIV amplicons, built atop the Robust Amplicon Denoising algorithm and implemented in the Julia Language. We will release an easy-to-install Julia package and a webserver specifically for this spike-seq assay, completely eliminating the computational burden required for adopting the spike-seq assay. As a proof of principle to demonstrate the importance of such surveillance, we will select spike mutations observed in our spike-seq surveillance and from public datasets, and test whether these mediate escape from neutralizing sera, either from early infections or from vaccinated animals.

Expected deliverables and their impact on the SARS-CoV-2 epidemic in South Africa

Our efforts will help estimate and control SARS-CoV-2 infection and assist with planning prevention interventions to manage health care and this epidemic in South Africa. We believe that this work will be impactful through our analyses to estimate the speed of transmission of SARS-CoV-2, development and implementation of rapid diagnostics for a resource limited country and informing potential viral susceptibility or resistance to future imminent vaccine strategies.

Although the GERMS-SA surveillance programme is housed within the Department of Public Health Surveillance and Response (DPHSR), CRDM collaborates in efforts to do laboratory-based surveillance for five pathogens: Streptococcus pneumoniae, Neisseria meningitidis, Haemophilus influenzae, Group A streptococcus and Group B streptococcus. The surveillance functions on two levels, national and enhanced surveillance. As part of the national surveillance, isolates of laboratory-confirmed invasive disease of the five pathogens are submitted to CRDM for further characterisation, including serotyping/serogrouping and testing for antimicrobial resistance. In addition to this, enhanced surveillance is performed at sentinel sites in all nine South African provinces where additional demographic and clinical data are collected by surveillance officers through patient interview or medial record review.

Importance

The GERMS-SA programme is able to provide strategic information, regarding trends in the pathogens of public health importance e.g. vaccine-preventable diseases to measure the impact of vaccines as in the case with Streptococcus pneumoniae and Haemophilus influenzae type b or plan for future vaccine introductions (Group B streptococcus); epidemic-prone diseases like Neisseria meningitidis and Group A streptococcus to monitor and respond to outbreaks. Data generated through the surveillance programme enable investigators to explore key hypotheses. Strategic surveillance information is channelled to relevant end-users (including the South African Department of Health) to ensure that appropriate public health action follows.

Contact details

Dr Susan Meiring
Tel: 021 404 5302
Email: susan.meiring@nhls.ac.za

The Centre for Respiratory Diseases and Meningitis (CRDM) houses a World Health Organization (WHO)-designated National influenza centre (NIC). This is 1 of 142 NICs in 113 countries that form part of the WHO’s Global Influenza Surveillance and Response System (GISRS). The South African NIC works closely with the stakeholders from the National Department of Health and the WHO Collaborating Centres to monitor the emergence of novel, emerging or resistant influenza virus strains through surveillance activities. The NIC also performs preliminary genotypic and phenotypic characterisation of influenza virus specimens circulating in South Africa and ships representative clinical specimens and isolated viruses to WHO Collaborating Centres for advanced antigenic and genetic analysis.

Importance

We submit results on the advanced antigenic and genetic analysis to WHO Collaborating Centres and these data form the basis for WHO recommendations on the composition of the Northern and Southern Hemisphere influenza vaccine each year. We also serve as a technical resource on influenza-related matters to the National Department of Health.

Contact details

Website

Dr Nicole Wolter 
Email: nicolew@nicd.ac.za

National syndromic surveillance for pneumonia is a prospective, syndromic, hospital-based sentinel surveillance programme that was initiated in 2009. The surveillance programme was first implemented in 3 of South Africa’s 9 provinces: Gauteng (Chris Hani Baragwanath Hospital), KwaZulu-Natal (Edendale Hospital), Mpumalunga (Mapulaneng and Matikwana Hospitals) and was expanded to North West (Klerksdorp-Tshepong Hospital Complex) in 2010 and Western Cape (Red Cross Children’s Hospital (RCCH) and Mitchell’s Plain Hospital) in 2015. In 2014 Rahima Moosa Mother and Child Hospital and Helen Joseph Hospital replaced Chris Hani Baragwanath Hospital as the Gauteng sites. Dedicated staff screen all medical admissions from Monday to Friday and enrol patients into the programme if they meet the clinical case definition of acute or chronic respiratory illness. Collected specimens are tested for influenza, respiratory syncytial virus (RSV) as well as Bordetella pertussis.

Pneumonia is a leading cause of hospitalisation and death in children and adults in South Africa, and this programme provides policy makers, clinicians and the general medical community with regular updates on seasonality, trends and the burden of pathogens associated with pneumonia, providing strategic information to support planning and monitoring of pneumonia prevention and control activities. RSV is the commonest cause of hospitalised pneumonia among children. Data on the burden, risk groups and seasonality will be important to guide decision making around the implementation of maternal vaccines and/or long acting monoclonal antibodies under development for the prevention of disease in infants. Pertussis has increased in South Africa following the change to use of the acellular pertussis vaccine in the expanded programme on immunisation since 2009. The pneumonia surveillance programme provides systematic data on burden of disease risk groups and outbreaks and will be useful to monitor the impact of interventions such as maternal vaccination should they be implemented. The programme provides data on the timing and annual seriousness of the influenza season as well as data on burden and risk groups for severe influenza. In addition, this surveillance programme increases the capacity for surveillance and diagnosis of respiratory pathogens in South Africa and it provides the influenza virological data to the World Health Organization (WHO) that informs the southern hemisphere influenza vaccine development annually.

Surveillance for outpatient influenza-like illness

Influenza-like illness (ILI) is a non-specific respiratory illness characterised by fever and cough which is used to capture trends of influenza and respiratory syncytial virus (RSV) over time. The systematic influenza-like illness surveillance programme was established in 2012. It is currently active at public health clinics serviced by hospitals included in the National Pneumonia Surveillance Programme. The clinics include Edendale Gateway Clinic in KwaZulu-Natal, Jouberton Clinic in North West Province and Mitchell’s Plain clinic and Eastridge Clinic in Western Cape Province. This enables us to make comparisons between severe and mild illness in the same populations as our pneumonia surveillance populations. Patients presenting at these sites are enrolled prospectively. Dedicated staff screen and enrol patients meeting the ILI and suspected pertussis case definitions. 

Influenza, RSV and pertussis cause a large burden of mild illness which may be associated with substantial cost and absenteeism. National syndromic surveillance for pneumonia in South Africa captures the burden of severe illness, but misses less severe illness that does not require hospitalisation. In order to best understand the full burden of respiratory disease in South Africa, we conduct surveillance and measure the burden of mild, outpatient disease as well as more severe, inpatient disease. By comparing mild to severe disease, the contribution of viruses and pertussis bacteria to these syndromes is better described. In describing risk factors like underlying conditions (including HIV status) associated with disease the understanding of disease severity and possible factors contributing to severe disease can be better understood. These data allow policymakers to prioritise influenza, RSV and pertussis in relation to other conditions in South Africa. As vaccination is expensive, additional information of risk factors associated with severe disease may assist with targeted vaccination programmes. This surveillance programme also allows us to monitor local pertussis disease rates to better understand seasonality and periodicity of pertussis in South Africa, which is especially important with the global resurgence that is being observed for pertussis.

Contact details

Dr Sibongile Walaza
Tel: 011 386 6410
Email: sibongilew@nicd.ac.za

The RSV Global Online Mortality Database, abbreviated as RSV GOLD, is the first global registry for children younger than 5 years dying with RSV infection. The aim is to identify clinical and socioeconomic characteristics of children dying from RSV infections to identify important risk factors for child mortality due to RSV and to ultimately combat RSV-associated childhood mortality. Data is extracted year from the existing national syndromic surveillance and submitted. There are 51 countries participating and the project is funded by the Bill and Melinda Gates Foundation.

Importance

Globally, approximately 33.1 million episodes of RSV- associated lower respiratory tract infection occur each year, about 10% of these will be hospitalised and nearly 200 000 will die.  An improved understanding of risk factors for RSV-associated mortality will help recognize the potential impact of the various types of vaccines that are under development. Providing policy makers with this data will assist in establishment of a vaccine policy for RSV. Ultimately, the goal of this project is to combat RSV-associated childhood mortality.

Contact details

RSV Gold Website

Dr Jocelyn Moyes
Tel: jocelynm@nicd.ac.za

The Centre for Respiratory Diseases and Meningitis (CRDM) also provides a special diagnostic service to clinicians for pathogens which are not tested for routinely in other National Health Laboratory Service and private laboratories, or when clusters of severe respiratory disease or meningitis are identified throughout the country. Tests offered include avian influenza, seasonal influenza and RSV subtyping, B. pertussis, C. diphtheriae, group A streptococcus, group B streptococcus, Legionella spp, Middle East Respiratory Syndrome Corona Virus (MERS-CoV) as well as panels for community- and hospital-acquired pneumonia, atypical pneumonia, neonatal sepsis, and bacterial and viral meningitis. Requests for diagnostics are to be discussed with the laboratory (contact details below) and should be accompanied by the submission form that can be found HERE.

Importance

By providing diagnostic testing to clinicians, we can assist in finding the correct course of treatment for patients and also to identify clusters of cases which may need investigation.

Contact details

Dr Nicole Wolter
Tel: 011 555 0352
Email: nicolew@nicd.ac.za

Dr Mignon du Plessis
Tel: 011 555 0387
Email: mignond@nicd.ac.za

Dr Jinal Bhiman
Tel: 011 386 6390
Email: jinalb@nicd.ac.za

Influenza-like illness (ILI) is a non-specific respiratory illness characterised by fever and cough which is used to capture trends of influenza and respiratory syncytial virus (RSV) over time. The systematic influenza-like illness surveillance programme was established in 2012. It is currently active at public health clinics serviced by hospitals included in the National Pneumonia Surveillance Programme. The clinics include Edendale Gateway Clinic in KwaZulu-Natal, Jouberton Clinic in North West Province and Mitchell’s Plain clinic and Eastridge Clinic in Western Cape Province. This enables us to make comparisons between severe and mild illness in the same populations as our pneumonia surveillance populations. Patients presenting at these sites are enrolled prospectively. Dedicated staff screen and enrol patients meeting the ILI and suspected pertussis case definitions. 

Influenza, RSV and pertussis cause a large burden of mild illness which may be associated with substantial cost and absenteeism. National syndromic surveillance for pneumonia in South Africa captures the burden of severe illness, but misses less severe illness that does not require hospitalisation. In order to best understand the full burden of respiratory disease in South Africa, we conduct surveillance and measure the burden of mild, outpatient disease as well as more severe, inpatient disease. By comparing mild to severe disease, the contribution of viruses and pertussis bacteria to these syndromes is better described. In describing risk factors like underlying conditions (including HIV status) associated with disease the understanding of disease severity and possible factors contributing to severe disease can be better understood. These data allow policymakers to prioritise influenza, RSV and pertussis in relation to other conditions in South Africa. As vaccination is expensive, additional information of risk factors associated with severe disease may assist with targeted vaccination programmes. This surveillance programme also allows us to monitor local pertussis disease rates to better understand seasonality and periodicity of pertussis in South Africa, which is especially important with the global resurgence that is being observed for pertussis.

Contact details

Dr Sibongile Walaza
Tel: 011 386 6410
Email: sibongilew@nicd.ac.za

We performed an unmatched case-control study nested within the national syndromic surveillance for pneumonia in South Africa, which is a prospective syndromic hospital-based sentinel surveillance programme. The study was conducted in three of the nine provinces of South Africa at hospitals and the associated primary healthcare (PHC) facilities.

All infants admitted at a study hospital with any acute medical illness irrespective of duration and symptoms were eligible for enrolment. Each site also enrolled 3 controls, irrespective of HIV status, each week from patients presenting to the associated PHC clinics without any symptoms of any medical illness within 14 days of enrolment. At enrolment, both cases and controls had a nasopharygeal aspirate and a nasopharygeal swab taken for the identification of influenza, RSV, pertussis and other respiratory pathogens using a multipathogen RT PCR. In addition, whole blood was taken for identification of respiratory bacterial pathogens and paired serum (from first and follow-up visits) were tested for influenza, RSV and pertussis antibodies. Enrolment of new patients  and follow-up was completed in December 2018 and we are currently performing serology testing and analysing the data.

Objectives

1. Assess the burden of disease associated with influenza and other respiratory pathogens among hospitalised infants aged <1 year presenting with any medical illness, irrespective of duration of symptoms, over a 3-year period from 2017-2019 in South Africa
2. Estimate the attributable fraction of influenza and other respiratory pathogens as measured through PCR and for serology overall and in HIV-exposed and –unexposed infants separately
3. Describe the burden of disease associated with influenza and other respiratory pathogens among hospitalised infants aged <1 year in HIV-exposed and –unexposed infants
4. Compare the detection of influenza virus, RSV and pertussis by PCR from respiratory specimens collected at enrolment versus results from the testing of acute and convalescent serum samples for antibodies against these respiratory pathogens
5. Describe risk factors (socioeconomic, maternal and infant) associated with any hospitalisation and hospitalisation testing positive for influenza, RSV and pertussis in infants presenting with a medical illness irrespective of symptom duration

Importance

Pneumonia is one of the leading causes of hospitalisations and death among infants aged <1 year. Influenza, respiratory syncytial virus (RSV), pertussis and other respiratory pathogens contribute significantly to pneumonia hospitalisations. It is important to quantify the disease burden for specific pathogens accurately in order to guide policy for prevention and interventions such as vaccination. Although there are some published data on the burden of hospitalised pneumonia due to respiratory pathogens among South African infants, these data have two important limitations when used to guide policy. Firstly, available data are restricted to infants with a respiratory presentation. However, infants may have an atypical clinical presentation; therefore, disease burden estimates which include only respiratory symptoms may underestimate the true burden. The second limitation of existing disease burden studies is the fact that they rely on confirmation of the presence of infection by PCR only. Including serologic evaluation has been shown to increase disease burden estimates in infants as infants may test negative using molecular diagnostics for several reasons. It is essential that studies of disease burden include controls without disease because carriage of these respiratory organisms in the absence of disease can occur.

Contact details

Dr Nicole Wolter
Tel: 011 555 0352
Email: nicolew@nicd.ac.za

Dr Sibongile Walaza
Tel: 011 386 6410
Email: sibongilew@nicd.ac.za

The Viral Watch programme is an active, prospective sentinel surveillance programme where participating clinicians (mostly private practitioners) submit specimens from outpatients with influenza-like illness to CRDM for testing of influenza, respiratory syncytial virus and pertussis. Currently, the programme is operational in 8 of the 9 South African provinces. The main aim of the programme is to describe influenza epidemiology in South Africa, to provide influenza strains for global vaccine strain selection and to provide annual estimates of influenza vaccine effectiveness.

The Viral Watch programme was started by the then National Institute for Virology in Johannesburg, South Africa, in 1984. At that time, 12 sites in the central, high-lying Gauteng province were enrolled. Between 1984 and 2004, the total number of sites ranged between 10 and 19. In 2005, amid fears of an impending pandemic, the programme was actively expanded to include new sites in all areas of the country. From 2004 to 2008, the number of participating sites increased from 15 to 170, and by 2008 there were sites in all 9 South African provinces. Practitioners who expressed an interest in the programme during academic events, conferences, and continuing medical education meetings or other forums, as well as practitioners who were referred by colleagues joined the programme. Criteria considered in the selection of health care practitioners included the presence of a motivated clinician, geographic representativeness, a large and diverse patient base, differing patient demographics and socioeconomic conditions, and inclusion of paediatric patients.

Objectives

Influenza and respiratory viruses

1. To determine the prevalence, seasonality and geographical distribution of influenza and respiratory syncytial virus (RSV).
2. To characterise annual circulating influenza strains to guide vaccine strain selection for the Southern Hemisphere influenza vaccine, identify drift from the annual vaccine and identify antiviral drug resistance
3. To generate annual estimates of influenza vaccine effectiveness for South Africa

Emerging respiratory viruses

1. To develop capacity for identification of and sampling from individuals with suspected infection caused by avian influenza viruses or other emerging respiratory viruses capable of causing outbreaks or pandemic from sentinel sites
2. To maintain a national network of clinicians, hospitals and public health clinics for communicable disease monitoring and response

Importance

The Viral Watch programme includes a relatively large proportion of patients accessing care in the private sector in South Africa, which puts it apart from the national syndromic surveillance for pneumonia and influenza-like illness surveillance (in public clinics) programmes. This is important for several reasons. Firstly, the relatively high influenza vaccine coverage allows for annual estimation of influenza vaccine effectiveness which would not be possible with public sector data only. Lastly, emerging infections may be introduced or first identified in travellers who may be more likely to access care in the private sector or travel through the ports of entry. Viral Watch has the flexibility to include important sites such as at ports of entry or areas where contact occurs at the animal-human interface, to facilitate detection of emerging pathogens.

Data from this surveillance programme enable us to track trends in the seasonality and geographic distribution of influenza and RSV. The Viral Watch programme is an important contributor to the establishment of an early warning and monitoring system for emergence of future pandemic viruses in the country. Influenza epidemiological and virological data generated through the program for South Africa contribute to a better understanding of the dynamics of influenza worldwide and in Africa in particular. Specifically data from the viral watch is used to determine the timing of the influenza season as well as the transmissibility each year. It also assists in identifying seed viruses for the production of seasonal influenza vaccines to be used in the southern hemisphere, particularly South Africa.

Contact details

Dr Sibongile Walaza
Tel: 011 386 6410
Email: sibongilew@nicd.ac.za

In collaboration with the World Health Organization (WHO) and 21 additional countries, we perform surveillance for RSV in children younger than 2 years using the Global Influenza Surveillance and Response System (GISRS). Data is extracted from the existing national syndromic surveillance and submitted to GISRS on a monthly basis. In addition, we house 1 of 4 WHO Respiratory Syncytial Virus Reference Laboratories (RSV RL) globally.

Objectives

1. Establish the feasibility of RSV surveillance built on the GISRS platform for future global expansion
2. Evaluate the performance of the case definition for surveillance of RSV in different age groups among those aged <2 years
3. Ascertain RSV seasonality patterns in different countries and geographical regions
4. Improve knowledge of the RSV-associated hospitalisation burden
5. Determine age and at-risk groups among those aged <2 years, for severe RSV disease
6. Build evidence that would enable countries to make informed policy decisions around introduction of RSV preventive products such as vaccines and monoclonal antibodies
7. To provide technical guidance on the virological component of RSV surveillance to WHO RSV pilot laboratories.

Importance

Globally, approximately 33.1 million episodes of RSV- associated lower respiratory tract infection (LRTI) occur each year, about 10% of these will hospitalised and nearly 200 000 will die. In South Africa, RSV- associated LRTI accounts for 3262 (per 100 000) hospitalisation annually. With new prevention technologies on the horizon (vaccines and longer acting monocloncal antibodies) estimating burden of RSV-associated LRTI is important to support the introduction of these technologies.

Contact details

Websites:
RSV laboratory testing

Dr Jocelyn Moyes
Email: jocelynm@nicd.ac.za

Dr Nicole Wolter 
Email: nicolew@nicd.ac.za

The Centre for Respiratory Diseases and Meningitis serves as a regional reference laboratory (RRL) for the WHO Regional Office (WHO/AFRO), Immunization and Vaccines Development Cluster, which is part of the WHO/AFRO VP-IBD surveillance network. Cerebrospinal fluid samples are submitted from 12 Southern and East African countries for molecular detection and serotyping/grouping of S. pneumoniae, H. influenzae and N. meningitidis. Isolates from culture-positive cases are submitted for phenotypic confirmation. Data are reported back to submitting countries and WHO AFRO. Training and site assessments are provided to improve surveillance capacity in these 12 countries.

Importance

Through the VP-IBD network, we contribute to the surveillance objectives of WHO by documenting the presence of disease, identifying circulating serotypes, and measuring serotype distribution. With the use of polymerase chain reaction in the testing of samples, case detection can be increased. In the post-vaccine introduction period, the laboratory network generates data and collaboration networks to assess disease trends over time and monitor changes in circulating strains/serotypes in different countries and regions.

Contact details

Website

Mrs Linda de Gouveia
Tel: 011 555 0327
Email: lindad@nicd.ac.za