https://ojs.wpro.who.int/ 1WPSAR Vol 13, No 1, 2022 | doi: 10.5365/wpsar.2022.13.1.873 Perspective S tudies of the first few “X” (FFX) – formerly known as “First Few 100” – cases involve rapid collection of data and specimens from the cases of a novel pathogen or emerging variants and their close contacts. Collection of standardized high-quality clinical, epidemiological, virological and serological data in FFX studies can provide insight into transmission dynamics, severity, risk factors for severe disease and the clinical spectrum of disease. These data can be used in risk assessment and modelling studies, to forecast potential impact and guide preparedness planning and public health interventions. Independent studies of coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have provided insights into key transmissibility and severity parameters.1 Although these studies are valuable in contributing to the growing body of scientific evidence on COVID-19 epidemiology, there is need for a greater number of harmonized studies (e.g. FFX studies) that can be rapidly implemented in early epidemic phases.2 In early January 2020, the World Health Organization (WHO) adapted and added to existing pandemic influ- enza and Middle East respiratory syndrome coronavirus (MERS-CoV) protocols for COVID-19 and rebranded them as UNITY studies – a global sero-epidemiological stand- ardization initiative. UNITY protocols aim to increase evidence-based knowledge for action, and are an invalu- able tool for improving equity by providing harmonized and fit-for-purpose protocols for all income and resource settings.3 UNITY studies allow for timely comparison and aggregate analysis of data across countries and regions, to contextualize data to different settings and offer a depth of understanding that is not readily available using other platforms. WHO solicited interest in implementing these protocols during the COVID-19 pandemic from partners to address knowledge gaps and inform public health response measures.4 Despite being in an unprecedented pandemic, many countries were able to leverage existing infrastructure to implement UNITY studies. Insights from participating countries are centrally reported to WHO headquarters and regional offices, and include contribu- tions from 98 WHO Member States (including Australia, Mongolia, the Philippines and Singapore in the Western Pacific Region).4,5 More in-depth understanding of the epidemiology of COVID-19 gained through such studies can be used to inform adaptive and ongoing control strategies. For example, in early 2020, a study aligned with FFX and UNITY conducted in China showed that most second- ary cases were probably infected around the time of symptom onset of the primary cases.6 This highlighted the need for household infection control measures, given that immediate intervention by local health authorities following symptom onset of the primary case is difficult to achieve. Data from another aligned study conducted in the United Kingdom of Great Britain and Northern Ireland a The University of Melbourne, Melbourne, Victoria, Australia. b Victorian Infectious Diseases Reference Laboratory, Peter Doherty Institute for Infection and Immunity, Melbourne, Victoria, Australia. c Hunter New England Local Health District, Population Health, Wallsend, New South Wales, Australia. d Menzies School of Health Research, Charles Darwin University, Darwin, Northern Territory, Australia. e College of Medicine and Dentistry, James Cook University, Cairns, Queensland, Australia. f Hunter New England Local Health District, Population Health, Tamworth, New South Wales, Australia. g World Health Organization Regional Office for the Western Pacific, Manila, Philippines. h World Health Organization, Geneva, Switzerland. i Peter Doherty Institute for Infection and Immunity at the University of Melbourne and the Royal Melbourne Hospital, Melbourne, Victoria, Australia. j Murdoch Children’s Research Institute, Melbourne, Victoria, Australia. Published: 24 March 2022 doi: 10.5365/wpsar.2022.13.1.873 The ongoing value of first few X studies for COVID-19 in the Western Pacific Region Adrian J Marcato,a James E Fielding,b Kristy Crooks,c,d Peter D Massey,e,f Linh-Vi Le,g Isabel Bergerih and Jodie McVernona,i,j Correspondence to Jodie McVernon (email: j.mcvernon@unimelb.edu.au) WPSAR Vol 13, No 1, 2022 | doi: 10.5365/wpsar.2022.13.1.873 https://ojs.wpro.who.int/2 Marcato et alFFX studies for COVID-19 linguistically diverse communities and workers who were unable to work from home have been disproportionately infected.9,10 Existing FFX study populations can be expanded into longitudinal cohorts with extended follow-up to address questions regarding persistence of immunity following both natural and vaccine-induced immunity, and its effectiveness in preventing infection and disease upon re-exposure. These data will be critical in informing future control measures, particularly with the emergence of new variants and the commencement of vaccination campaigns. For maximum utility, countries should exercise or pilot these studies in advance of future outbreaks – for example, at the beginning of influenza seasons – to facilitate timely implementation during emergencies. Piloting will allow countries to consider data collection and management, laboratory testing and capacity, ethics and governance approvals, identify a suitable workforce and develop workflows in advance of outbreaks, to ensure that they are effective. Piloting should also consider developing scalable, feasible and culturally appropriate methods for collect- ing data and specimens, to improve equity and health outcomes for the vulnerable and those at greater risk of disease. These methods should be developed with communities for communities.11 Historical evidence shows that previous pandemics have disproportionately impacted First Nations peoples.12–15 Adapting FFX and UNITY studies within a First Nations context can lead to a deeper understanding of the experience of families, explore household transmission in different types of households and improve understanding of how studies can be operationalized to inform culturally appropriate and safe disease control strategies. FFX studies and the broader suite of UNITY stud- ies remain incredibly useful in the current regional and global context, and they could provide ongoing robust and comparable evidence of COVID-19 epidemiology in low- and middle-income countries as the pandemic evolves. Investing in UNITY studies, readiness and preparedness planning will better support the ongoing COVID-19 re- sponse and help to ensure research equity and improve capacity to respond rapidly to future emerging pathogens. (United Kingdom) established a sensitive and specific symptom profile of COVID-19, including the reporting of anosmia in patients. This symptom was later added to the United Kingdom’s COVID-19 symptom list.7 There is also continuing uncertainty about the role of children in spreading COVID-19 and the extent of true asymptomatic and pre-symptomatic transmission. Although the spread appears to be influenced by social settings and household structures, public health interventions (e.g. test, trace and isolate; spontaneous and imposed behavioural and distancing measures and mobility restrictions; communi- cation campaigns; and varying degrees of community en- gagement and cohesion in response) have led to differing rates of transmission within and between countries. FFX studies can provide opportunities to explore transmis- sion dynamics and severity during all epidemic phases, provided that contacts of cases can still be traced. FFX and other UNITY studies are well placed to provide information on SARS-CoV-2 variants such as alpha, beta and delta, which are marked by different biological characteristics to those previously observed in epidemiological studies.8 Pooling of data from FFX stud- ies may help us to understand how SARS-CoV-2 could behave in the Western Pacific, particularly in settings that have not yet experienced uncontrolled epidemics and in populations with low vaccination coverage or low levels of natural immunity. Areas with limited resources to conduct intensive surveillance studies would benefit from globally standardized data collection and analysis to assist with more nuanced planning for future outbreaks. FFX studies provide a platform to compare epidemi- ology between waves and jurisdictions and can be used to inform targeted and context-specific public health interventions. For example, Australia and Singapore – countries in the Western Pacific – experienced subsequent waves of epidemic activity that exhibited different epide- miological patterns to earlier waves. The first wave in Australia predominantly featured cases acquired overseas or their close contacts, whereas the second wave was amplified in aged-care and health-care setting outbreaks that led to community transmission.9 Singapore’s initial epidemic was characterized by outbreaks in migrant workers residing in dormitories, with low-level commu- nity transmission. In late 2021, Singapore experienced an epidemic wave of the delta variant with widespread com- munity transmission.10 In both settings, culturally and WPSAR Vol 13, No 1, 2022 | doi: 10.5365/wpsar.2022.13.1.873https://ojs.wpro.who.int/ 3 FFX studies for COVID-19Marcato et al 5. Pung R, Park M, Cook AR, Lee VJ. Age-related risk of house- hold transmission of COVID-19 in Singapore. Influenza Other Respir Viruses. 2021;15(2):206–8. doi:10.1111/irv.12809 pmid:32990399 6. Wu J, Huang Y, Tu C, Bi C, Chen Z, Luo L, et al. Household transmission of SARS-CoV-2, Zhuhai, China, 2020. Clin In- fect Dis. 2020;71(16):2099–108. doi:10.1093/cid/ciaa557 pmid:32392331 7. Boddington NL, Charlett A, Elgohari S, Byers C, Coughlan L, Vilaplana TG, et al. Epidemiological and clinical characteristics of early COVID-19 cases, United Kingdom of Great Britain and Northern Ireland. Bull World Health Organ. 2021;99(3):178–89. doi:10.2471/BLT.20.265603 pmid:33716340 8. Tracking SARS-CoV-2 variants. Geneva: World Health Organization; 2021. Available from: https://www.who.int/en/activities/tracking- SARS-CoV-2-variants/, accessed 12 October 2021. 9. COVID-19 National Incident Room Surveillance Team. COVID-19, Australia: Epidemiology Report 23 (Fortnightly reporting period ending 16 August 2020). Commun Dis Intell (2018), 2020;44. doi:10.33321/cdi.2020.44.70 pmid:32847492 10. COVID-19 situation report. Singapore: Ministry of Health; 2021. Available from: https://covidsitrep.moh.gov.sg/, accessed 26 Octo- ber 2021. 11. Crooks K, Massey PD, Taylor K, Miller A, Campbell S, Andrews R, et al. Planning for and responding to pandemic influenza emergen- cies: it’s time to listen to, prioritize and privilege Aboriginal perspec- tives. Western Pac Surveill Response J. 2018;9(5 Suppl 1):5−7. doi:10.5365/wpsar.2018.9.5.005 pmid:31832246 12. Flint SM, Davis JS, Su JY, Oliver-Landry EP, Rogers BA, Goldstein A, et al. Disproportionate impact of pandemic (H1N1) 2009 influenza on Indigenous people in the Top End of Australia’s Northern Territory. Med J Aust. 2010;192(10):617–22. doi:10.5694/j.1326-5377.2010. tb03654.x pmid:20477746 13. Boggild AK, Yuan L, Low DE, McGeer AJ. The impact of influenza on the Canadian First Nations. Can J Public Health. 2011;102(5):345– 8. doi:10.1007/BF03404174 pmid:22032099 14. Verrall A, Norton K, Rooker S, Dee S, Olsen L, Tan CE, et al. Hos- pitalizations for pandemic (H1N1) 2009 among Maori and Pacific Islanders, New Zealand. Emerg Infect Dis. 2010;16(1):100–2. doi:10.3201/eid1601.090994 pmid:20031050 15. Centers for Disease Control and Prevention (CDC). Deaths related to 2009 pandemic influenza A (H1N1) among American Indian/ Alaska Natives - 12 states, 2009. MMWR Morb Mortal Wkly Rep. 2009;58(48):1341–4. pmid:20010508 Pandemic-ready, flexible systems are paramount to sup- port an equitable, proportionate and informed emergency public health response. Conflicts of interest All authors declare no conflicts of interest. Ethics statement Ethics approval was not required for this perspective piece. Funding All work was undertaken as part of the authors’ regular employment. References 1. Global research on coronavirus disease (COVID-19). Geneva: World Health Organization; 2021. Available from: https://www.who.int/ emergencies/diseases/novel-coronavirus-2019/global-research-on- novel-coronavirus-2019-ncov, accessed 12 October 2021. 2. Van Kerkhove MD, Broberg E, Engelhardt OG, Wood J, Nicoll A; CONSISE steering committee. The consortium for the standardiza- tion of influenza seroepidemiology (CONSISE): a global partnership to standardize influenza seroepidemiology and develop influenza investigation protocols to inform public health policy. Influenza Other Respir Viruses. 2013;7(3):231–4. doi:10.1111/irv.12068 pmid:23280042 3. Coronavirus disease (COVID-19) technical guidance: The Unity Studies: Early Investigation Protocols. Geneva: World Health Organ- ization; 2021. Available from: https://www.who.int/emergencies/ diseases/novel-coronavirus-2019/technical-guidance/early-investi- gations, accessed 19 February 2021. 4. Bergeri I, Lewis HC, Subissi L, Nardone A, Valenciano M, Cheng B, et al. Early epidemiological investigations: World Health Organi- zation UNITY protocols provide a standardized and timely inter- national investigation framework during the COVID-19 pandemic. Influenza Other Respir Viruses. 2022;16(1):7–13. doi:10.1111/ irv.12915 pmid:34611986