A framework for measuring timeliness in the outbreak response path: lessons learned from the Middle East respiratory syndrome (MERS) epidemic, September 2012 to January 2019

Background Epidemics are a constant threat in the 21st century, particularly disease outbreaks following spillover of an animal virus to humans. Timeliness, a key metric in epidemic response, can be examined to identify critical steps and delays in public health action. Aim To examine timeliness, we analysed the response to the Middle East respiratory syndrome (MERS) epidemic, with a focus on the international and One Health response efforts. Methods We performed a historical review of the MERS epidemic between September 2012 and January 2019 in three steps: (i) the construction of a timeline identifying critical events in the global response, (ii) the performance of a critical path analysis to define outbreak milestones and (iii) a time gap analysis to measure timeliness in the execution of these milestones. Results We proposed 14 MERS-specific milestones at different phases of the epidemic, assessing timeliness of the public health response as well as at the animal–human interface, where we identified the most significant delays. Conclusions When comparing timeliness across three coronavirus epidemics, i.e. MERS (2012), SARS (2002) and COVID-19 (2019), we identified clear improvements over time for certain milestones including laboratory confirmation and diagnostics development, while this was not as apparent for others, as the identification of zoonotic hosts. To more efficiently respond to emerging threats, the global health community should widely assess and tackle specific delays in implementing response interventions by addressing challenges in the sharing of information, data and resources, as well as efficiency, quality, transparency and reliability of reporting events.

January 2013, WHO organized the first international meeting on MERS, to perform a risk assessment involving affected countries and international experts, as well as to develop a gap analysis and identify next steps in the global response (Milestone 12) [32].

I Epidemic phase: detection in camels and implementation of containment, control and mitigation strategies (Supplementary Figure S1.2)
In August 2013, scientists first reported findings of a serological studies showing that camels had antibodies against MERS-CoV (Milestone 1) [37][38][39][40][41][42][43], closely followed by the laboratory confirmation detecting the virus in camels linked to confirmed human cases (Milestone 2) [44][45][46][47][48][49]. Both findings (antibodies and the virus) were reported to the international community, through WHO, before the scientific findings were published in peerreviewed journals, which decreased the timeline for informing response measures [30,74]. A belated serological survey of camels from Saudi Arabia revealed that MERS-CoV has been circulating in these animals and countrywide since at least 1992 [41], with camels being asymptomatic or exhibiting only mild symptoms [73].
With the performance of the first serological and epidemiological studies in animals (Milestone 10), the validation of a serologic assay for specific use in camels was also achieved (Milestone 5) [37]. Following these scientific outcomes, on November 2013, WHO for the first time advised the uptake of hygiene measures to prevent zoonotic infections focused on people at high risk of severe disease and in close contact with camels (Milestone 13) [30]. Four months later, the WHO published a statement on its website recognizing camels as a source of human infections (Milestone 7) [50]. The first global advise on infection prevention and control (IPC) measures targeted at nosocomial transmissions was published on May 2013 (Milestone 13) [51]. The delay in developing the guidance on IPC measures was mostly related to the dependence on the understanding of how transmission takes place. This followed the evidence that MERS could be acquired in health care facilities, as it was the first-time health care workers were diagnosed with MERS-CoV after exposure to patients [30].
Following the recognition of zoonotic transmission, it was organized the first international meeting engaging the Tripartite partnership for One Health (OH) engaging the following organizations: WHO, FAO (Food and Agriculture Organization) and WOAH (World Organization for Animal Health, previously named and identified in the Supplementary Figures S1-5 and Supplementary Tables S1-3 as OIE). It took place in December 2013, in Egypt, representing the development of the first joined risk assessment at the animal human interface (Milestone 12). In addition, it also represented the first global effort to coordinate multinational studies (case-control and sero-epidemiological) for human and animal infections to address critical knowledge gaps surrounding the transmission route of MERS-CoV, and help in determining risk factors that present opportunities for transmission (Milestone 14) [52]. In a next meeting, five months later in Oman, global advice for animal surveillance and management of MERS-CoV positive camels was given in the Muscat Declaration (Milestone 6) [53].

II Epidemic phase: containment, control and mitigation also at the animal-human interface (Supplementary Figure S1.3)
With the confirmation of camels as a source of MERS-CoV zoonotic transmission, on July 2014 the WOAH recognized MERS as an emerging disease in camels with zoonotic potential, and requested countries to notify and report positive camels (Milestone 3) [54]. This notification occurred after deliberations on whether MERS fulfilled the criteria of a notifiable disease; since MERS-CoV does not cause significant disease in animals it cannot be included in the OIE (WOAH) List of Diseases, while at the same time laboratory and epidemiological evidence supported the inference of zoonotic transmission [22].
The WOAH expert group also made recommendations for developing a case definition for camel infections, considered as PCR positive animals (Milestone 4). To support case finding and management, experts noted that validation of the available (PCR) diagnostics for animal surveillance according to the WOAH standards was still needed [54]. Further guidance for the implementation of camel surveillance and management of positive cases was provided in April 2015, in a OH international meeting organized in Qatar [55].
In line with IPC measures, WHO developed a guidance to avoid MERS-CoV transmission from animals to humans with the support from WOAH [54]; and one year after that, stated on its MERS website that stopping zoonotic transmission of the virus was the only way to mitigate nosocomial outbreaks [56]. Meanwhile, the publication of many scientific studies regarding epidemiological, virologic, clinical and environmental investigations, enhanced knowledge regarding human as well as animal MERS-CoV infections. One meta-study showed however, that the majority of publications on epidemiology of MERS outbreaks (from 2013 to 2015 in Al-Hasa, Jeddah and Riyadh) were performed after the outbreaks had ended [16]. Throughout the epidemic, delays in official notification and reporting for human cases were noticed, when countries struggled to timely notify all new cases and to report detailed epidemiological and clinical information on confirmed and suspected cases, which were essential for updating risk assessment, case definition, guidance for treatment, and case management [30,68,69]. One study mentioned specifically that detailed epidemiological data on non-human exposures, such as direct or indirect animal exposure, was limited for a long period of time to only a few case-control studies [63]. Finally, in October 2015, globally coordinated efforts to perform multinational animal studies were initiated through funding from the United States Agency for International Development (USAID) [57]. At this phase, most milestones identified for the MERS epidemic were executed, although even until today, no vaccines and therapeutics have been available to counteract the epidemic. After the activation of the notification and reporting of animal cases, the WOAH started publishing country reports; and on May 2017, they published an official case definition for reporting confirmed and suspected camel infections [58], which supported countries to implement and execute animal surveillance and investigations. Among other factors, the late guidance for identification and collection of data on camel infections hindered the control of zoonotic spillovers and further nosocomial outbreaks. The transition phase was also marked by additional efforts to coordinate research and development (R&D) strategies at the international level to move the development of targeted medical countermeasures against MERS-CoV forward. In December 2015, MERS was considered a priority disease under the WHO's Blueprint strategy [59], and five months later, the first roadmap for MERS R&D was published [24]. One year later, the first Target Product Profile for MERS-CoV vaccines was published by WHO followed by more support and funding from the Coalition for Epidemic Preparedness and Innovation (CEPI), to push forward vaccine development [60]. With this push for R&D, many animal studies and clinical trials were performed to test therapeutics and vaccines, besides other epidemiological and clinical evaluation on human and animals.
Enzootic phase: continued zoonotic transmission and emergence of cases (Supplementary Figure S1.5) Containment efforts are described to support continuous case finding and management though surveillance, cross sectorial investigations and sharing of information. In addition, the implementation of IPC measures, especially targeted at mass gathering events in the Arabian Peninsula region, were noted. Finally, progress in R&D efforts positively marked this phase [61]. Studies published at this phase helped in the understanding and management of nosocomial outbreaks [62], the geographic scope of MERS-CoV circulation in camels, and provided an overview of the amount of zoonotic transmission taking place [63].
Although a decrease in the number and scale of MERS outbreaks is featured in this phase, it is also marked by the constant emergence of community cases due to zoonotic transmission. One study showed that contact with dromedaries likely played an important role in the continued introduction of MERS-CoV into the human population by revealing that among all cases reported to the WHO between January 2015 and mid-April 2018, which were primary cases, over half of them had a zoonotic link [63]. Additionally, persistent knowledge gaps are still present regarding the extent of MERS-CoV circulation and the mechanisms of transmission within dromedary camel herds. A complete understanding of factors related to zoonotic transmission and differences in circulating strains is also lacking. These gaps, added to the lack of medical countermeasures, made it difficult to implement efficient response measures to stop zoonotic transmission and therefore avoid new human infections [61]. The timeline is depicted in the bottom, with response events chronologically positioned and clustered according to the type of response intervention they relate to. Events related to the response at the public health domain (focused exclusively on human health) are depicted within blue boxes, while events related to the response at the animalhuman interface (also involving the animal health domain) are depicted in green boxes. Full (colored) boxes represent events that mark the execution of outbreak milestones numbered according to Fig. 2 in the main manuscript. The references used in the timeline, as well as reported meetings organized and guidelines published can be found in Supplementary Tables S1.1-3. The timeline is depicted in the bottom, with response events chronologically positioned and clustered according to the type of response intervention they relate to. Events related to the response at the public health domain (focused exclusively on human health) are depicted within blue boxes, while events related to the response at the animalhuman interface (also involving the animal health domain) are depicted in green boxes. Full (colored) boxes represent events that mark the execution of outbreak milestones numbered according to Fig. 2 in the main manuscript. The references used in the timeline, as well as reported meetings organized and guidelines published can be found in Supplementary Tables S1.1-3. Figure S1.3. II Epidemic phase: containment, control and mitigation also at the animal-human interface, July 2014 -October 2015 (n=2 Milestones). It is marked by the generalized recognition of camels as a MERS-CoV source of infection, and the implementation of more robust response measures at the animal-human interface. The timeline is depicted in the bottom, with response events chronologically positioned and clustered according to the type of response intervention they relate to. Events related to the response at the public health domain (focused exclusively on human health) are depicted within blue boxes, while events related to the response at the animalhuman interface (also involving the animal health domain) are depicted in green boxes. Full (colored) boxes represent events that mark the execution of outbreak milestones numbered according to Fig. 2 in the main manuscript. The references used in the timeline, as well as reported meetings organized and guidelines published can be found in Supplementary Tables S1.1-3. The timeline is depicted in the bottom, with response events chronologically positioned and clustered according to the type of response intervention they relate to. Events related to the response at the public health domain (focused exclusively on human health) are depicted within blue boxes, while events related to the response at the animalhuman interface (also involving the animal health domain) are depicted in green boxes. Full (colored) boxes represent events that mark the execution of outbreak milestones numbered according to Fig. 2 in the main manuscript. The references used in the timeline, as well as reported meetings organized and guidelines published can be found in Supplementary Tables S1.1-3. The timeline is depicted in the bottom, with response events chronologically positioned and clustered according to the type of response intervention they relate to. Events related to the response at the public health domain (focused exclusively on human health) are depicted within blue boxes, while events related to the response at the animalhuman interface (also involving the animal health domain) are depicted in green boxes. Full (colored) boxes represent events that mark the execution of outbreak milestones numbered according to Fig. 2 in the main manuscript. The references used in the timeline, as well as reported meetings organized and guidelines published can be found in Supplementary Tables S1.1-3.    Table S1.2. Description of regional and international meetings that took place throughout the epidemic phases (of alert phase; I epidemic phase; II epidemic phase; transition phase; and enzootic phase) addressing the response to MERS-CoV, April 2012 -December 2018 (n=33 meetings).

ALERT PHASE
Technical consultative meeting on novel coronavirus infection Cairo, Egypt 14-16 Jan 2013 Review and discuss the scientific and public health understanding of the emergence of nCoV to date, identify critical knowledge gaps in understanding the current risk and identify the next steps to improve knowledge and close up the research gap for public health action at the national and international level. In each meeting session, available scientific information and up-to-date evidence on nCoV were presented and discussed by the participants. The sessions included ( Overview and update on the outbreak, country specific updates, technical guidance on surveillance, outbreak and preparedeness for mass gatherings, technical support and interim guidance for cases' management, technical guidnace and support for laboratory diagnostics, guidance on infection prevention and control, reflections on media and risk communication.

WHO-ISARIC joint MERS-CoV Outbreak Readiness
Workshop: Clinical management and potential use of convalescent plasma Geneva, Switzerland 10-12 Dec 2013 Participants agreed to work towards developing a regional clinical research network and agreed on: 1) conducting a feasibility survey in the countries to identify suitable sites and current capacities for clinical research studies, 2) developing a multi-center retrospective case series and prospective study to characterize the disease course, prognostic factors, and outcomes with current treatment approaches, 3) exploring local processes for convalescent plasma collection from MERS-CoV-infected patients (directed donations) and using it as a therapeutic intervention in the context of a prospective observational study with serial virologic sampling, and 4) developing a randomized controlled trial of an antiviral intervention. WHO Consultative meeting to determine a public health research agenda on MERS-CoV The Emergency Committee providing expert technical advice to the WHO Director-General in accordance to the IHR (2005). The Committee constantly concluded that based on available information, and using a risk-assessment approach, the conditions for a PHEIC have not been met. Declaration warned countries in the region and beyond of the need for public health and veterinary authorities to carry out coordinated investigations, and share information and results.Participants in the MERS consultation agreed that there is also a vital need to raise awareness among the public at large about the importance of seeking medical attention, the nature of the disease, and ways to avoid it.
EMRO sub-regional workshop on improving infection prevention and control measures in health facilities for acute respiratory infection and specifically for MERS-CoV The group reviewed the WHO current interim general recommendations on MERS-CoV transmission from animals to humans and the interim recommendations for at risk groups. The group was supportive of the recommendations and suggested they should apply to countries where there was a risk of transmission of MERS-CoV from camels to humans.
The group reviewed the current state of knowledge and made a series of recommendations with regard to animal health management, need for further studies, surveillance activities and on revising the OIE Q&A. The OIE Q&A have been amended accordingly.

3-5 Sep 2014
The workshop focused on plans to enhance surveillance for severe acute respiratory infections for early detection, recognition and response to MERS-CoV, as well as public health measures that could effectively early detect any imported case of Ebola virus disease, as well as limit local transmission once a case associated with international travel is imported. WHO organized a meeting with medical missions of the top 10 countries sending pilgrims to Mecca for the Hajj Jeddah, Saudi Arabia

16-17 Sep 2014
The participants reviewed and discussed overall preparedness measures for MERS-CoV during and after Hajj and identified better ways to enhance surveillance and exchange of information. A WHO team was deployed to Jeddah and Mecca during the Hajj to oversee the preparedness and surveillance activities related to MERS-CoV. This team provided support for coordination and information sharing between WHO, the SAU Ministry of Health and other countries sending large numbers of pilgrims. At the meeting, four strategic goals were agreed upon in principle. The first is to establish a surveillance network of coronavirus laboratories as an early warning system to identify circulating species and strains in animal populations, new outbreaks in human populations and emerging strains in all populations. The second is to acquire a better understanding of MERS-CoV pathogenesis, natural history and veterinary and human epidemiology. The third is to develop, manufacture, test, license and use improved diagnostics, preventives and therapeutics that enable the interruption of transmission between humans and from dromedary camels to humans. The fourth is for the global donor community to establish a mechanism that provides a line of-sight for manufacturers from preclinical proof-of-concept studies to post-licensing procurement of MERS-CoV products, by initiating a public-health financial model for emerging pathogens prioritized by the WHO blueprint process. The goal of the meeting was to determine the current status of scienti c knowledge on MERS-CoV and identify major gaps that require further studies, in order to better understand the disease dynamics at the interface between humans and animals, and to develop practical approaches to control and minimize the impact of this virus. The meeting also aimed at fostering collaboration and partnerships between institutions and organizations working on MERS-CoV at the humananimal interface. EMRO training workshop aimed at initiating the sentinel site surveillance system for Severe Acute Respiratory Illness (SARI) and Influenza-Like Illness (ILI) To discuss previously conducted studies of respiratory virus persistence and plan for future observational and experimental studies of environmental and air sampling of MERS-CoV. The participants in this meeting discussed the potential role of environmental contamination and airborne transmission of MERS-CoV in health-care settings based on their own research and developed a plan for future research to be conducted experimentally and observationally where MERS patients are treated. In addition, several additional key issues involving the Member Countries of the region, with special emphasis on the following matters were fruitfully deliberated including A fully functional regional network of expertise for camel diseases, CAMENET, undertaking research in camel disease diagnostics and epidemiology, including related to MERS-CoV WHO officials met with the Ministry of Health of Saudi Arabia Saudi Arabia 18-21 Nov 2017

ENZOOTIC
Senior officials responsible for MERS-CoV surveillance, case management, infection prevention and control, data collection and analysis, data base management and training met in Saudi Arabia. The Ministry of Health also arranged for a joint informal meeting with Ministry of Agriculture officials to discuss their ongoing surveillance and research activities in dromedary camel population. For the purposes of the R&D Blueprint, WHO uses a special tool for determining which diseases and pathogens to prioritize for research and development in public health emergency contexts. This tool seeks to identify those diseases that pose a public health risk because of their epidemic potential and for which there are no, or insufficient, countermeasures. The diseases identified through this process are the focus of the work of R& D Blueprint. This is not an exhaustive list, nor does it indicate the most likely causes of the next epidemic. Experts consider that given their potential to cause a public health emergency and the absence of efficacious drugs and/or vaccines, there is an urgent need for accelerated research and development for*: Crimean-Congo haemorrhagic fever (CCHF), Ebola virus disease and Marburg virus disease, Lassa fever, Middle East respiratory syndrome coronavirus (MERS-CoV) and Severe Acute Respiratory Syndrome (SARS), Nipah and henipaviral diseases, Rift Valley fever (RVF), Zika, and "Disease X". Disease X represents the knowledge that a serious international epidemic could be caused by a pathogen currently unknown to cause human disease, and so the R&D Blueprint explicitly seeks to enable cross-cutting R&D preparedness that is also relevant for an unknown "Disease X" as far as possible. WHO HQ and AFRO held a planning meeting

15-16 Feb 2018
To discuss MERS-CoV and emerging respiratory disease-related activities for the African Region. The meeting brought together more than 120 experts and professionals from industry, academia, international agencies and government. Progress on the development and trials of dromedary and human vaccines were presented. WHO EMRO training Riyadh, Saudi Arabia

1-5 Jul 2018
Training on building national and subnational rapid response capacity for detection and response to MERS suspect cases and outbreaks.