Coronavirus disease (COVID-19) technical guidance: The Unity Studies: Early Investigation Protocols

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The Unity Studies: WHO Sero-epidemiological Investigations Protocols

Unity Studies is a global sero-epidemiological standardization initiative, which aims at increasing the evidence-based knowledge for action.

WHO, in collaboration with technical partners, has developed several standardized eneric epidemiological investigation protocols branded as UNITY studies. These studies aim to support national public health and social measures, promote the international comparability of research and address gaps in current knowledge regarding the COVID-19 pandemic.

The emergence of a new virus means that our understanding of the transmission patterns, immunity, severity, clinical features, and risk factors for infection is still limited. The WHO UNITY Studies can be adapted to local settings and implemented rapidly to collect robust data on key epidemiological parameters to understand, respond and control the COVID-19 pandemic.

Unity Studies logo

The UNITY Studies promote standardized epidemiological, molecular and serological methods to facilitate international comparisons so that both countries and the global community can collectively address knowledge gaps and inform an evidence-based COVID-19 response.

Finally, UNITY Studies enable countries, regardless of their resource setting, to conduct local investigations and are thus an invaluable tool for research equity.

The widespread interest in the UNITY Studies underlines their value. More than 100 countries have signalled their intention to implement one or more UNITY protocols and studies are underway in over half.

The following publication provides a detailed description of the UNITY Studies initiative and its global utilization during the COVID-19 pandemic: http://doi.org/10.1111/irv.12915. The results of an external evaluation which assessed the utility of the initiative to countries in responding to the pandemic and how it fulfilled its key objectives can be found here: https://www.researchsquare.com/article/rs-1789741/v1.

The results of this initiative, which were used to inform regional and global evidence-based recommendations and action, can be found in the following systematic reviews and meta-analyses:

 

Join or ask!

For more information or questions on the Unity global initiative, contact us:

[email protected]

Unity Studies network sites

The global network of Unity Studies network sites ensures response readiness for rapid evaluation of any novel respiratory viruses of pandemic potential and respiratory transmitted pathogens (for example influenza, coronaviruses etc.). Chosen sites are primed to conduct country-specific standardized, pre-planned and pre-approved investigations using the Unity Studies template protocols.

Governance

Unity Studies network sites will be governed by the terms of reference (ToR) provided below. The ToR provides a description of the duties of the network sites, criteria for site selection and a description of the benefits of participating in the network. It also details how interested institutions/entities can join this global effort.

List and access to individual protocols

1 -  Population-based age-stratified seroepidemiological investigation protocol for COVID-19 infection

-  Access the protocol
-  Acknowledgements

This protocol is a population-based, age-stratified prospective study for assessing SARS-CoV-2 infection. It is intended to provide key epidemiological and serologic characteristics of SARS-CoV-2 in the general population. This includes the extent of infection in the general population and age-specific infection cumulative incidence, as determined by seropositivity, and the fraction of asymptomatic or subclinical infection.

For more information, please contact: [email protected].

 

2 -  Measuring COVID-19 vaccines effectiveness

Cohort study to measure COVID-19 vaccine effectiveness among health workers 

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This document outlines the methods of a prospective cohort study to evaluate the effectiveness of the COVID-19 vaccine in the health workers (HWs), with a focus on hospital-based HWs. HWs should be enrolled ideally prior to or simultaneous with the implementation of the COVID-19 vaccination campaign.

For more information, please contact: [email protected].

COVID-19 vaccine effectiveness against severe acute respiratory infections (SARI) hospitalisations (test-negative case-control design)

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This guidance document proposes enhanced data collection within existing SARI surveillance systems. This document describes how existing hospital-based surveillance systems for SARI can be adapted to collect data to inform estimates of vaccine effectiveness against COVID-19 in persons of all ages. It outlines in details methods for collecting and analysing data on vaccinated and unvaccinated patients based on a case control “test negative design” (TND).

For more information, please contact: [email protected].

COVID-19 vaccine effectiveness estimation using the screening method 

This guidance document proposes technical advice to primarily measure overall COVID-19 vaccine effectiveness against laboratory-confirmed symptomatic SARS-CoV-2 infection (COVID-19) in the vaccine-eligible population using the screening method (or case coverage or case cohort design).

 

3 - The First Few X (FFX) cases and contact investigation protocol for COVID-19 infection

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-  Acknowledgements

The following protocol has been designed to investigate the First Few X number of cases and their close contacts (FFX). Using a standardized protocol such as the protocol provided here, epidemiological exposure data and biological samples can be systematically collected and shared rapidly in a format that can be easily aggregated, tabulated and analysed across many different settings globally. FFX is the primary investigation protocol to be initiated upon identification of the initial laboratory-confirmed cases of COVID-19 in a country.

For more information, please contact: [email protected].

 

4 -  Household transmission investigation protocol for COVID-19 infection

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- Acknowledgements

The household transmission investigation is a case-ascertained prospective study of all identified household contacts of a laboratory confirmed COVID-19 infection. It is intended to provide rapid and early information on the clinical, epidemiological and virological characteristics of COVID-19. 

 

5 -  Assessment of risk factors for COVID-19 in health workers:

Protocol for a prospective study of a cohort of HW 

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This protocol has been designed to investigate the extent of SARS-CoV-2 infection and risk factors for infection among health care workers. Follow-up and testing of respiratory specimens and serum of health care workers within a facility in which a confirmed case of COVID-19 is receiving care can provide useful information on transmissibility and routes of transmission and are important for limiting amplification events in health care facilities.

For more information, please contact:  [email protected].

 

Protocol for a case-control study

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Aiming at assessing risk factors for COVID-19 in health workers, the current protocol consists of a nested case-control study of health workers involved in the care of any confirmed COVID-19 cases. The study is based upon the use of incidence density sampling. The study is to be initiated as soon as a case of SARS-CoV-2 infection is confirmed among health workers in a health care setting. Health workers with confirmed COVID-19 will be recruited as cases. Health workers exposed to COVID-19 patients in the same setting but without infection will be recruited as controls with a target of at least 2–4 controls for every case.

For countries or health care facilities willing and able to participate, WHO is proposing to conduct an international multi-centre case-control study.

For more information, please contact: [email protected]. Upon request, WHO will provide a Go.Data template for data collection to local investigators.

 

6- Schools and other educational institutions transmission investigation protocol for coronavirus disease 2019 (COVID-19)

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The overall aim of this protocol is to gain an understanding of the transmission dynamics of COVID-19 infection among cases and contacts within schools and other educational institutions.

For more information, please contact: [email protected].

 

7 - A prospective cohort study investigating maternal, pregnancy and neonatal outcomes for women and neonates infected with SARS-CoV-2

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The purpose of this study is to determine if SARS-CoV-2 infection during pregnancy increases the risk of adverse pregnancy, perinatal, neonatal, and postpartum outcomes; and describe pregnancy, perinatal, neonatal and postpartum outcomes among women who have received at least one dose of a COVID-19 vaccine during pregnancy. Additionally, the study will characterize the clinical spectrum of COVID-19 in pregnant women; determine the probability of detecting SARS-CoV-2 RNA in pregnancy-related fluids (i.e. amniotic fluid), breast milk and tissues; follow clinical outcomes of women and their neonates up to 6 weeks after childbirth; and assess COVID-19 vaccine uptake among pregnant women in the study, along with symptoms and events following vaccination.

For more information, please contact: [email protected]

 

8 - Surface sampling of coronavirus SARS-CoV-2: A practical “how to” protocol for health care and public health professionals

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The role of environmental contamination in transmission of SARS-CoV-2 is currently not clear. This protocol has been designed to determine (viable) virus presence and persistence on fomites in various locations where a patient infected with SARS-CoV-2 is currently receiving care or being isolated, and to understand how this may relate to COVID-19 transmission events in these settings. It is therefore important that it is done as part of a comprehensive outbreak investigation and that information obtained by environmental studies is combined with the results of epidemiological, laboratory and sequence data from COVID-19 patient investigations.

For more information, please contact:  [email protected].

 

 

Summary of protocols available for country use and adaptation:

Protocol and question to be answered / population under investigation: Objectives

Measuring COVID-19 vaccines effectiveness (VE)

Cohort study to measure COVID-19 vaccine effectiveness among health workers

Question/population:
Health workers in participating hospitals, eligible for vaccination, with no contraindication to receive COVID-19 vaccine

 

Primary objectives:

  • To measure product-specific COVID-19 vaccine effectiveness (VE) amongst hospital health workers eligible for vaccination against all laboratory-confirmed SARS-CoV-2 infection

Secondary objectives (depending on sample size)

  • To measure COVID-19 VE:
    • against symptomatic laboratory-conformed COVID-19 infection
    • against asymptomatic laboratory-confirmed COVID-19 infection
    • against severe laboratory-confirmed COVID-19 infection
    • by time since vaccination
    • by different age groups
    • by different high-risk comorbidities
    • previous SARS-CoV-2 infection
    • by HW occupation and/or ward
    • patient-facing vs. non-patient-facing HWs
    • in individuals who have been partially vaccinated (one dose for most COVID-19 vaccines) compared to those who are fully vaccinated (two doses for most COVID-19 vaccines)

Measuring COVID-19 vaccines effectiveness (VE)

Protocol for a case-control study

Question/ population:
severe acute respiratory infections (SARI) hospitalisations associated with laboratory-confirmed SARS-CoV-2

 

 

Primary objective:

  • To measure overall COVID-19 vaccine effectiveness (CVE) against laboratory-confirmed SARS-CoV-2 in hospitalised SARI patients belonging to the target group(s) for COVID-19 vaccination.

Secondary objectives:

  • To estimate overall and product-specific CVE against laboratory-confirmed SARS-CoV-2 requiring hospitalisation among SARI patients in vaccination target groups by:
    • age group
    • sex
    • risk group (e.g. specific chronic conditions)
    • time since vaccination
    • in persons who have received one dose of vaccine compared to those who have received two doses
    • specific SARS-CoV-2 genetic variant(s)
  • To estimate CVE for more severe outcomes (e.g. ICU admission, or in-hospital mortality)
  • To identify potential factors that may modify CVE: chronic medical conditions, influenza vaccination, living in a long-term care facility (LTCFs), receiving statins or other long-term medication (depending on availability of these data in the participating country), and higher risk of exposure to SARS-CoV-2.
Protocol:
Population-based age-stratified seroepidemiological investigation protocol for COVID-19 infection
 
Question/ population:
Virus infection in the general population 
  		Primary objectives:
  • To measure the seroprevalence of antibodies to COVID-19 in the general population by sex and age group, in order to ascertain the cumulative population immunity; and
  • To estimate the fraction of asymptomatic, pre-symptomatic or subclinical infections in the population and by sex and age group.
Secondary objectives, such as, but not limited to:
  • To determine risk factors for infection by comparing the exposures of infected and non-infected individuals;
  • To contribute to determine the case fatality ratio; and
  • To contribute to an improved understanding of antibody kinetics following COVID-19 infection.
Protocol:
The First Few COVID-19 X cases and contacts transmission investigation protocol (FFX)
 
Question/ population:
Cases and close contacts in the general population or can be restricted to semi-close settings (like households, health care settings, schools).

The primary objectives are to provide descriptions or estimates of :

  • clinical presentation of COVID-19 infection and course of associated disease;
  • secondary infection rate (SIR) and secondary clinical attack rate of COVID-19 infection among close contacts (overall, and by key factors such as setting, age and sex, for various end-points);
  • serial interval of COVID-19 infection;
  • symptomatic proportion of COVID-19 cases (through contact tracing and laboratory testing); and identification of possible routes of transmission.
  • identification of possible routes of transmission

The secondary objectives are to support the estimation of:

  • the basic reproduction number (R0) of COVID-19 virus;
  • the incubation period of COVID-19; and
  • the preliminary COVID-19 infection and disease-severity ratios (for example, case‑hospitalization ratio [CHR] and case-fatality ratio [CFR]).


Protocol:
Household transmission of COVID-19 investigation protocol (HH)
 
Question/ population: Cases and close contacts in household setting

Primary objectives:

  • To better understand the extent of transmission within a household by estimating the secondary infection rate for household contacts at an individual level, and factors associated with any variation in the secondary infection risk.
  • To characterize secondary cases including the range of clinical presentation, risk factors for infection, and the extent and fraction of asymptomatic infections
  • To characterize serologic response following confirmed COVID-19 infection
Assessment of COVID-19 risk factors among Health Workers (HW)
 
 
 
 

Protocol:
Prospective study of a cohort of health workers)
 
Question/ population:
All health workers in a health care setting in which patient(s) with a laboratory-confirmed COVID-19 infection are receiving care

 

 

 

 

 

 

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Protocol: 
Protocol for a case-control study
 
Question/ population:
Health workers exposed to COVID-19 patients 
 

Primary objectives:

  • To better understand the extent of human-to-human transmission among health workers by estimating the secondary infection rate[1] for health worker contacts at the individual level.
  • To characterize the range of clinical presentations of infection and the risk factors for infection among health workers.
  • To evaluate the effectiveness of infection prevention and control measures among health workers.
  • To evaluate the effectiveness of infection prevention and control programmes at health facility and national level.

Secondary objectives such as, but not limited to:

  • To determine the serological response of health workers with symptomatic and possibly asymptomatic COVID-19 infection;
  • To characterize the duration and severity of COVID-19-associated disease among health workers.

 

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The primary objective of this case-control study among health workers is:
  • to characterize and assess the risk factors for SARS-CoV-2 infection in health workers exposed to COVID-19 patients.
The secondary objectives of the study are:
  • to evaluate the effectiveness of current COVID-19 IPC measures among health workers;
  • to describe the range of clinical presentation for SARS-CoV-2 infection in health workers, including disease duration and outcome; and
  • to determine serological responses in health workers with confirmed SARS-CoV-2 infection following exposure to COVID-19 patients, and in those exposed to COVID-19 patients but without SARS-CoV-2 infection.

 

Protocol:
Schools and other educational institutions transmission investigation protocol for COVID-19
 
Question/ population:
Students and staff of schools and other educational institutions with a laboratory confirmed case of COVID-19
 
 

The overall aim is to gain an understanding of the transmission dynamics of COVID-19 infection among cases and contacts within schools and other educational institutions.
Primary objectives are:

  • to estimate infection rates for overall and secondary COVID-19 infections in this context
  • to estimate the secondary clinical attack rate of COVID-19 in this setting
  • to estimate the fraction of asymptomatic COVID-19 infections within schools and other educational institutions
  • to describe the epidemiological and clinical characteristics of primary and secondary cases of COVID-19
  • to identify potential risk/protective factors associated with the COVID-19 infection risk.

Secondary objectives are:

  • to estimate the incubation period of COVID-19 and the duration of infectiousness and of detectable shedding;
  • to estimate the serial interval of COVID-19 infection in this setting;
  • to estimate the reproduction numbers: R0 and R of COVID-19 in this setting; and
    to characterize the serological response following confirmed COVID-19 infection

Protocol:
A prospective cohort study investigating maternal, pregnancy and neonatal outcomes for women and neonates infected with SARS-CoV-2

 
Question/ population:
pregnant or recently pregnant women (and their neonates), both infected with SARS-CoV-2 (exposed) and not infected with SARS-CoV-2 during pregnancy (unexposed).

 

 

Primary objectives:

  1. To analyze if SARS-CoV-2 infection in pregnant women increases the risk of adverse outcomes (as per outcomes 1-4 above) as compared to pregnant women who are not infected with SARS-CoV-2.
  2. To estimate the risk of mother-to-child-transmission of SARS-CoV-2 virus during pregnancy, intrapartum, postpartum (including during breastfeeding) among mother-neonate pairs with confirmed SARS-CoV-2 infection in pregnancy
  3. To describe viral presence and persistence in amniotic fluid, placenta, cord blood, fetus, neonate as well as in breast milk and other bodily fluids (urine, feces, vaginal fluids)
  4. To characterize the clinical course and disease spectrum of COVID-19 during pregnancy

Secondary objectives:

  1. Estimate the cumulative incidence of asymptomatic, subclinical, and clinically apparent SARS-CoV-2 infection during pregnancy, as assessed by seroconversion or a positive RT-PCR test during and following pregnancy.
  2. Measure the frequency of detectable RNA for SARS-CoV-2 by RT-PCR and IgG/IgM antibodies in neonates born to women infected with SARS-CoV-2 during pregnancy.
  3. Characterize the signs, symptoms, and disease course of neonates who have SARS-CoV-2 infection following childbirth from a pregnant woman infected with SARS-CoV-2

Optional secondary objective:

To determine if disease severity and disease characteristics of COVID-19 are different in pregnant women compared to non-pregnant women of reproductive age. 


    Protocol:

    Surface sampling of SARS-CoV-2: A practical “how to” protocol for health care and public health professionals


     
    Question/ population:
    For environmental surfaces

    Primary objectives:

    • To assess the extent and persistence of surface contamination of SARS-CoV-2; and
    • To identify environmental surfaces and fomites that may play a role in onward transmission of COVID-19.


    Secondary objectives such as, but not limited to:

    To characterize of the sequence diversity of SARS-CoV-2 in environmental samples, as capacity and resources permit. 
    For more information, please contact:  [email protected]

     

     

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