Background and justification: On 31 December 2019, the World Health Organization (WHO)
was alerted to a cluster of pneumonia cases of unknown etiology in patients in Wuhan
City, Hubei Province of China, which, one week later, was attributed to a novel
coronavirus (severe acute respiratory syndrome coronavirus 2: SARS-CoV-2). Given its
rapid spread globally, WHO declared that the outbreak of SARS-CoV-2 met pandemic criteria
on 11th March 2020. By mid-April 2020 more than 2.5 million cases and more than 170,000
deaths have been laboratory-confirmed in 210 countries and territories.

Influenza virus is responsible for elevated morbidity and mortality globally every year.
In South Africa annual seasonal influenza epidemics occur during the winter months
(May-October, with peak transmission in June-July) and result in an estimated 19 million
symptomatic infections, 128,000 severe cases and 11,000 deaths on average every year.

Human respiratory syncytial virus (RSV) is the commonest cause of childhood acute lower
respiratory tract infection, especially among infants <3 months of age. In South Africa
RSV circulates throughout the year with peak transmission occurring usually during
February-April. Nonetheless, from systematic virologic surveillance data delayed RSV
transmission is expected to occur in South Africa in 2020. This has the potential to
result in concomitant SARS-CoV-2, influenza and RSV peak transmission in the country.

HIV incidence remains high in South Africa. Similarly, rates of pulmonary tuberculosis
(PTB), with concomitant damage to lung tissue, remain persistently high despite concerted
national efforts. HIV and PTB infections have been associated with an increased risk of
severe illness (i.e., hospitalization and death) following infection with common
respiratory pathogens, including influenza and RSV, even among individuals on
antiretroviral therapy.

Understanding the community burden, transmissibility potential and clinical features of
illness associated with SARS-CoV-2 infection is critical to inform the design and
duration of containment and mitigation measures, both locally and globally. An accurate
estimation of risk factors for community transmission, acquisition and duration of
infectiousness is crucial to inform guidance for public health measures to limit
transmission as well as models for epidemic forecasting for this and potential future
epidemics. Moreover, factors specific to South and sub-Saharan Africa (SSA) such as HIV,
tuberculosis, high proportion of the population who are children, malnutrition, and
limited healthcare resources have the potential to impact both the transmission dynamics,
progression and prognosis of SARS-CoV-2 disease; as well as the burden on the healthcare
system and society.

Whereas knowledge has been gained on the transmissibility and clinical features of
SARS-CoV-2 since its emergence several key questions related to the natural history of
the virus remain poorly answered, notably in African context. In particular, the
community attack rate by age, the role of children in community and household
transmission, the asymptomatic infected fraction, the role of asymptomatic individuals in
transmission, the interaction of SARS-CoV-2 with other common respiratory pathogens such
as influenza and RSV, the risk of reinfection with SARS-CoV-2 and the correlation between
PCR-confirmed infection and serologic response among others, remain poorly understood.
Critically, the effect of HIV infection on transmission and disease severity associated
with SARS-CoV-2 infection is unknown. South Africa has an HIV prevalence of approximately
15% in the general population, representing over 7 million people of whom over 5 million
are taking antiretroviral therapy.

Aim: In urban and rural South African environments, the study aims to characterize the
community burden (including the clinical features) and transmissibility of SARS-CoV-2
within the context of a functional antibody response. In addition, the effect of the
interaction of SARS-CoV-2 with influenza virus and RSV on disease severity and
transmission dynamics will be assessed. This will be undertaken from an early stage
throughout the epidemic in South Africa.

Primary objectives:

1. To estimate the community burden of SARS-CoV-2, including:

1.1 the incidence of SARS-CoV-2 infection in the community as determined by
polymerase chain reaction (PCR) and serologic assays; 1.2 the correlation between
individuals that seroconverted for SARS-CoV-2 and tested positive by PCR; 1.3 the
incubation period and the symptomatic fraction associated with SARS-CoV-2 infection;
1.4 the spectrum of severity associated with symptomatic infections; 1.5 the
fraction of individuals with symptomatic infection seeking medical care; and 1.6 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:

2.1 the estimation of the SARS-CoV-2 household secondary infection risk (SIR), generation
time and length of shedding; 2.2 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; 2.3 the
estimation of the SARS-CoV-2 effective reproduction number (Rt) and its variation over
time in the community; and 2.4 the effect of the interaction of SARS-CoV-2 with influenza
and RSV on transmission dynamics.

Methods: A household-level prospective cohort study will be conducted in one rural and
one urban community located in Mpumalanga Province (the Agincourt demographic
surveillance site) and North West Province (Klerksdorp), respectively. The study will be
conducted for 14 months of intensive follow up (July 2020 to August 2021) with a
post-intensive follow-up continuing for a further 16 months (until December 2022).

Two hundred households; 100 per site with expected average number of household members of
5 resulting in 1,000 study participants of all ages; will be randomly selected from a
list of 327 households that participated and successfully completed a 10-months follow-up
period in a study similar to that currently proposed, but directed at community burden
and transmission dynamics of influenza, respiratory syncytial virus and other respiratory
pathogens (the PHIRST study conducted during 2016-2018 in the same two communities). The
approached households will be re-assessed for study eligibility (i.e., a minimum of 3
household members and at least 80% of household members consenting to participate). The
households in the 2016-2018 PHIRST study were identified by randomly selected
geo-coordinates within the two communities. Baseline characteristics for this cohort are
already available and will be re-ascertained after obtaining consent. Consenting
household members that have entered the household since termination of the 2016-2018
PHIRST study will be also enrolled. Each household and household member will be
enumerated and the HIV infection status and the level of immunosuppression of
HIV-infected individuals will be assessed (if unknown) in consenting individuals.

Each household member will be followed twice per week during the intense follow-up period
(12 months) of the study. During this period upper respiratory tract samples will be
collected irrespective of presence of symptoms and data on key symptoms, healthcare
seeking, hospitalization and death will be captured at each follow up visit on a REDCap
tablet-based real-time database. Respiratory samples will be tested by reverse
transcriptase real-time polymerase chain reaction (rRT-PCR) for SARS-CoV-2, influenza and
RSV, and selected samples will be cultured and sequenced. An infection risk questionnaire
will be administered to all study participants at enrollment and every month thereafter.
Sera will be collected at enrollment and every 2 months during the 12-month intense
follow-up period from all participants. In addition, sera will be collected every 2
months for a further 6 months following the 12-month intense follow-up period from study
participants that tested positive for SARS-CoV-2 by rRT-PCR on respiratory specimens at
14, 16 and 18 months and from all study participants at 18 months. Sera will be tested
for the presence of SARS-CoV-2, influenza and RSV antibodies. Wearable proximity sensors
will be deployed for 8-12 days in each household over the 6-month intense follow-up
period.

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.