The Lancet Regional Health - Europe 9 (2021) 100210

Contents lists available at ScienceDirect

The Lancet Regional Health - Europe

Series Viewpoint

Pandemics One Health preparedness for the next

A R T I C L E I N F O A B S T R A C T

Article History: The majority of emerging infectious diseases originate in animals. Current routine surveillance is focused on
Received 21 June 2021 known diseases and clinical syndromes, but the increasing likelihood of emerging disease outbreaks shows
Revised 12 August 2021 the critical importance of early detection of unusual illness or circulation of pathogens - prior to human dis-
Accepted 18 August 2021
ease manifestation. In this Viewpoint, we focus on one key pillar of preparedness—the need for early warning
Available online xxx
surveillance at the human, animal, environmental interface. The COVID-19 pandemic has revolutionized the
scale of sequencing of pathogen genomes, and the current investments in global genomic surveillance offer
great potential for a novel, truly integrated Disease X (with epidemic or pandemic potential) surveillance
arm provided we do not make the mistake of developing them solely for the case at hand. Generic tools
include metagenomic sequencing as a catch-all technique, rather than detection and sequencing protocols
focusing on what we know. Developing agnostic or more targeted metagenomic sequencing to assess
unusual disease in humans and animals, combined with random sampling of environmental samples captur-
ing pathogen circulation is technically challenging, but could provide a true early warning system. Rather
than rebuilding and reinforcing the pre-existing silo's, a real step forward would be to take the lessons
learned and bring in novel essential partnerships in a One Health approach to preparedness.
© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license
(http://creativecommons.org/licenses/by-nc-nd/4.0/)

1. Introduction to allow diagnosis of the etiology [1]. With the changing risks of
global spread, the timeliness of early detection is becoming a serious
The ongoing COVID-19 pandemic has highlighted how extremely factor in our ability to detect outbreaks at the stage when they still
vulnerable we are as a society when unforeseen infectious disease can be contained. The use of vaccines and/or non-medical interven-
events happen. The WHO R&D blueprint program, launched in 2016, tions is a second critical pillar in preparedness. This was highlighted
called for action for a list of potential pandemic threats, which subse- from a vaccine trial embedded in outbreak response towards the end
quently triggered the launch of ambitious vaccine development pro- of the West African outbreak of Ebola Zaire, in 2015-2016 [2], that
grams funded through the Coalition for Emerging disease was successful, despite the huge challenges of establishing a trial in
Preparedness Innovations (https://www.who.int/research-observa the midst of an outbreak [3]. Based on the trial outcomes, vaccination
tory/analyses/rd_blueprint/en/ and https://cepi.net), specifically ded- of at risk populations was done as part of the response to subsequent
icated to emerging infectious diseases (EID). outbreaks in Democratic Republic of Congo with some success,
The rationale was that the majority of emerging diseases come although community acceptance is not a given (https://www.msf.
from animals and are first detected by the time human disease out- org/drc-tenth-ebola-outbreak).
breaks occur in regions with sufficient health system infrastructure The Ebola example of preparedness is based on combining early
diagnosis of known risks, followed by public health measures and
risk-group targeted priority vaccination programs. It is a model for
DOI of original article: http://dx.doi.org/10.1016/j.lanepe.2021.100203, http://dx.doi.
prevention of Backspace high human health impact for known EIDs
org/10.1016/j.lanepe.2021.100213, http://dx.doi.org/10.1016/j.lanepe.2021.100215,
http://dx.doi.org/10.1016/j.lanepe.2021.100216, http://dx.doi.org/10.1016/j. that may cause outbreaks but do not (yet) spread very efficiently
lanepe.2021.100221, http://dx.doi.org/10.1016/j.lanepe.2021.100223, http://dx.doi. among humans. For highly transmissible EIDs, however, the bar is
org/10.1016/j.lanepe.2021.100192, http://dx.doi.org/10.1016/j.lanepe.2021.100219, even higher and early detection may not be sufficient. Here, early
http://dx.doi.org/10.1016/j.lanepe.2021.100231, http://dx.doi.org/10.1016/j.lanepe. warning surveillance programs are needed that allow early recogni-
2021.100230.
tion of unusual disease syndromes, as well as the ability to rapidly
* Corresponding author: Department of Viroscience, Erasmus Medical Centre, Rot-
terdam, The Netherlands. identify reservoirs and pre-diagnostic transmission following the
E-mail address: [email protected] (M. Koopmans). identification of the causative agent(s). Such surveillance is a

https://doi.org/10.1016/j.lanepe.2021.100210
2666-7762/© 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/)
2 F.M. Aarestrup et al. / The Lancet Regional Health - Europe 9 (2021) 100210

challenging yet crucial element of future preparedness. For diseases 1.2. The breakthrough of genomic surveillance
with prolonged incubation periods, or complications months after
initial infection, this is even more critical. Examples here are the Prior to the pandemic, genomic pathogen surveillance was slowly
impact on fetal development from Zika virus or Schmallenberg virus but gradually making its way into public health and clinical diagnostics.
infection during pregnancy in humans and animals, respectively, This was arguably most advanced in bacterial food safety where next
both detected long after the initial introduction and spread of the dis- generation sequencing and near-real time sharing of data between
ease in the Americas and Europe, respectively [4,5]. human clinical diagnostic, food and veterinary microbiology has been
It is now during the current COVID-19 pandemic that we should implemented in several countries; most noteworthy in the USA with
decide how we can use the current experiences for future outbreaks the GenomeTrakr programme that was initiated already in 2011 [10].
and pandemics in the years to come. As the majority of EID come The pandemic has clearly catapulted genomic surveillance to cen-
from animal reservoirs, risk-targeted surveillance should include ter stage. The scale of sequencing of SARS-CoV-2 genomes has out-
knowledge on the ecology of reservoir hosts and drivers for emer- paced all other surveillance systems, and the number of available
gence of outbreaks [6]. genomes after 18 months of SARS-CoV-2 is higher than those for
influenza, HIV and all foodborne bacterial species. Genomic sequenc-
1.1. One Health definition ing has been embraced as part of the essential public health toolbox,
driving massive investments in further development of sequencing
The need for a holistic perspective on infectious diseases has long capacity. Given the roll-out of vaccines, it is likely that this capacity
been recognized and there is no shortage of definitions of the One- will no longer be needed to the same scale in the near future. There-
Health concept. Following several decades of focus mainly on human fore, it is pertinent to consider what it would take to make the devel-
medicine this was revitalized in the early years of the 21st century, oping infrastructure and tools applicable for preparedness for other
most prominently at a meeting by the three global institutes with a future outbreaks and pandemic threats. This includes a critical
focus on human health, food- and environment, and animal health, appraisal of the data sharing infrastructures. Currently, pathogen spe-
respectively (WHO, FAO and OIE) in 2004. The parties convened a cific options are developed. For instance, for SARS-CoV-2, the data-
global think tank that concluded that the threat of EIDs was increas- base model for influenza virus surveillance was adopted [11]. This
ing, that there were shortfalls in the organisation of surveillance, and was developed in response to criticism from low and middle income
that new mechanisms of surveillance and response were required, countries (LMICs) that wanted some governance over who could do
"using new approaches (e.g. syndromic surveillance), using new tools what with data on pathogens from specific countries. Sharing of
(e.g. geographic information systems, remote sensing data and molecular pathogen genomic data across domains is further complicated, and
epidemiology) and bringing together different sectors and disciplines solutions chosen may differ regionally [12].
(e.g. medical, veterinary, population biology, information technology, An important question to consider is—what a future infrastructure
economics, social science and diagnostics)". https://apps.who.int/iris/ could look like. The next pandemic could be caused by a completely dif-
bitstream/handle/10665/68899/WHO_CDS_CPE_ZFK_2004.9.pdf. ferent pathogen and it would be logical to utilize a platform with a
This definition clearly was focussed on early detection of zoonotic broad focus, targeting all potential infectious agents. The world has an
diseases. A report by the World Bank also made the case for One established, global, neutral data-sharing platform in place, namely
Health surveillance based on economic assessment of the net benefits http://www.insdc.org/. This resource is currently mostly focused on
of prevention [7]. research data [13], and separate databases have been developed to
Since then the concept has been widely used and many people share time-sensitive data for surveillance [14-17]. A disadvantage of
and groups have claimed to be doing OneHealth research. The World this approach is that there is no public repository of this data, and that
Health Organization today uses the following definition: 'One Health' publicly released data are incomplete. There is an increasing call for
is an approach to designing and implementing programmes, policies, open sharing of data for the research community, and the European
legislation and research in which multiple sectors communicate and Commission has invested in the European Open Science cloud, building
work together to achieve better public health outcomes (https:// on the long-established infrastructures for biodata [18]. While custom-
www.who.int/news-room/q-a-detail/one-health). However, despite built fit for purpose databases may still be the norm, in years to come, a
the meetings, policy statements, and research projects, some of the longer term strategy for data-sharing that compensates for the fragmen-
key recommendations from the 2004 report were not implemented. tation and that focuses on improving the already existing global data
Also, one can argue whether this anthropocentric definition of One infrastructures is necessary [19]. The willingness to move towards full
Health is sufficiently balanced with threats to animal health and eco- open sharing of data also has not been fully endorsed. In particular, sci-
system health from the same global processes driving disease emer- entists from LMICs have expressed that this was a "first world" way of
gence [8]. Recently, a formal expert panel was established to advise thinking, and that there is a need for controlled access solutions to avoid
the tripartite (WHO, FAO, OIE), and the UN environmental program a further deepening of the gap in research contributions from LMIC [20].
on the future needs of One Health surveillance. This group assumes a In addition, while FAIR data is advocated widely, the reality is much
wider definition of One Health, and is currently reviewing regional more challenging. The interpretation of what is allowed under the Gen-
examples of integrated One Health surveillance to assess scalability eral Data Protection Regulation differs between institutes, countries,
of these systems to other regions starting from a systematic review and continents, making sharing of patient related information a formi-
listing examples for West Nile, avian influenza, rabies, Rift valley dable challenge. Similarly, the Nagoya protocol, developed to protect
fever and others [9]. national resources, has turned out to be a considerable barrier to inter-
In May 2021, in preparation of the World Health Assembly, lead- national sharing of samples and even sequence data. As the Nagoya pro-
ers of the EU, the G7, and the G20 emphasized the need for future tocol also specifies that decisions on data exchange can no longer be
preparedness. The European commission has launched an initiative made by researchers or research institutes, a new burocracy is develop-
to develop infrastructure for preparedness for SARS COV 2 variants ing with the risk of increasing barriers to data sharing. Thirdly, sharing
and future pandemic threats. This involves significant investments in of data in a structured manner requires the agreement on standards,
development of infrastructure for detection, and for development another issue that is far from solved. These issues have been recognized
and production of vaccines (https://ec.europa.eu/commission/press at the level of international organizations and the European commis-
corner/detail/en/fs_21_650). This also offers a huge opportunity to sion, and will need to be resolved to be able to fully capitalize on the
establish the integrated infrastructure recommended 17 years ago. potential of the rapidly increasing data for health [21].
 F.M. Aarestrup et al. / The Lancet Regional Health - Europe 9 (2021) 100210 3

1.3. Early detection generation of massive amounts of data that do not provide meaning-
ful surveillance information [26]. Finally, cost of using genomic tech-
Whether it is risk-targeted monitoring, syndromic surveillance, or nologies may be a barrier. Genome-based surveillance and
clinical diagnostic evaluation, engagement of citizens, care providers, metagenomic sequencing are more expensive than traditional patho-
veterinarians, farmers, and others involved in collection of essential gen targeted detection, although there is economy of scale when
samples is critical to the success of such programs. Studies have combining sequencing capacity for multiple purposes [27]. A recent
clearly shown that capacity building only happens when the individ- study found that the costs per sample varied greatly, depending on
uals that need to build a novel capacity also feel they are contributing how the sequencing effort and data analytics were organized, ranging
and have something to offer [22]. A potential way of promoting this from 15 to > 700 euro per sample. There was an inverse relationship
is to provide frontline settings with a capacity to analyse their own between per sample costs, sample volume, and batch sizes, which in
data, and contribute to conclusions and/or publications prior to shar- turn were determined by the breadth of applications for which the
ing them publicly. Thus, we can for example focus resources on open sequencing capacity had been established (single pathogen to multi-
science, non-commercial web-based solutions [23-25] that will allow purpose). Therefore, with proper preparation, genome-based surveil-
relatively un-experienced scientists in the clinical and veterinary lance can be made cost effective.
frontline to complete simple analyses of their data and thereby take
part in the research on global issues and not simply see their data 1.4. The need for One Health surveillance
being exploited by others. Furthermore, collaboration can also be
improved through international clinical trial networks set up to rap- A future catch-all infrastructure would not be limited to surveil-
idly respond to new infections. For instance, REMAP-CAP is an adap- lance based solely on human clinical cases, but also need to improve
tive platform trial evaluating potential treatments for COVID-19 in the generation and access to data also from other reservoirs (Fig. 1).
321 clinical sites in five continents. VEO is a project that aims to While the human clinical diagnosis in many countries has been either
develop smart strategies for surveillance and is sampling the virome fully paid or supported by governmental funding and/or heavy invest-
in large cities to assess how this methodology could be employed ment from large international funding organizations, this has not been
cease, cease to exist, as in stop existing. the same for livestock clinical diagnostics, which basically has to be
However, improving capacity in the frontline is not sufficient. Eas- paid by the farmers. More control on limiting disease transmission
ier access to reference testing and verification is needed, particularly between livestock is in place compared to humans, but host jumps into
when symptoms are seen and a known causative agent can not and between livestock also can occur; emergence of novel diseases in
immediately be identified. Establishing international networks livestock will both have effect on livestock production and be a poten-
between clinical laboratories, public health institutions and acade- tial reservoir of diseases that might jump further to humans.
mia, and the ability to provide reference testing without repercus- Most novel diseases likely circulate for some time in animals and
sions for the requesting individual would be key to make this humans before they eventually are detected in clinical cases. There is
happen. And while the metagenomic sequencing of samples does thus a need to collect standardised samples that represent the human
hold promise, it is unlikely to provide early warning surveillance and animal microbiome (bacteriome and virome) in a comparable
unless it is embedded in well thought through sampling strategies, way over time and between countries. Samples should be stored in a
guided by ecological and epidemiological knowledge to avoid way that would allow for immediate re-analyses if new diseases

Fig. 1. Examples for catch-all surveillance, combining disease surveillance in animals and humans targeting known diseases (top row), with catch-all metagenomic surveillance
capturing circulation on other pathogens in livestock or humans (in this example depicted as wastewater metagenomics in slaughterhouses and urban sewage, respectively). Addi-
tional metagenomic sequencing could include other environmental samples, samples from wild-life and from vectors.
4 F.M. Aarestrup et al. / The Lancet Regional Health - Europe 9 (2021) 100210

emerge. Potential sampling sites could be long distance planes, urban References
metro-stations or urban sewage followed by metagenomic analyses,
as previous piloted [28-31]. This could potentially be combined with [1] Machalaba CM, Karesh WB. Emerging infectious disease risk: shared drivers with
environmental change. Rev Sci Tech 2017;36:435–44.
similar surveillance of animal waste (Fig. 1). While having the poten- [2] Henao-Restrepo AM, Camacho A, Longini IM, et al. Efficacy and effectiveness of an
tial to continuously identify trends of endemic diseases and antimi- rVSV-vectored vaccine in preventing Ebola virus disease: final results from the
crobial resistance, such a metagenomics approach has the clear Guinea ring vaccination, open-label, cluster-randomised trial (Ebola Ça Suffit!).
Lancet 2017;389:505–18.
advantage of allowing for rapid re-analyses of the data if a potential
[3] Walldorf JA, Cloessner EA, Hyde TB, MacNeil A, CDC Emergency Ebola Vaccine
novel pathogen is detected and could thereby facilitate a rapid global Taskforce. Considerations for use of Ebola vaccine during an emergency response.
overview of potential transmission and reservoir. Sampling of sewage Vaccine 2019;37:7190–200.
[4] Faria NR, Quick J, Claro IM, et al. Establishment and cryptic transmission of Zika
also overcomes concerns regarding ethical and GDPR concerns
virus in Brazil and the Americas. Nature 2017;546:406–10.
because the samples are already anonymized. For any future design, [5] Hoffmann B, Scheuch M, Ho € per D, et al. Novel Orthobunyavirus in Cattle, Europe,
it is crucial to allow for a mixture of lower cost solutions, in which 2011. Emerg Infect Dis 2012;18:469–72.
the collection of samples for metagenomic agnostic testing could be [6] Sikkema RS, Koopmans MPG. Preparing for Emerging Zoonotic Viruses. Encyclo-
pedia Virol 2021:256–66.
embedded if needed. Also, while promising, the true added value of [7] World Bank. People, Pathogens and Our Planet: The Economics of One Health.
adding metagenomics to surveillance can only be decided by care- Washington, DC. https://openknowledge.worldbank.org/handle/10986/11892.
fully designed studies. A recent successful example of this model is [8] Zinsstag J, Schelling E, Waltner-Toews D, Tanner M. From "one medicine" to "one
health" and systemic approaches to health and well-being. Prev Vet Med
the discovery of SARS-CoV-2, that was identified through metage- 2011;101:148–56.
nomic sequencing in samples from patients that had been sent to [9] Bordier M, Uea-Anuwong T, Binot A, Hendrikx P, Goutard FL. Characteristics of ssalth
specialised laboratories as part of the Chinese metagenomic disease surveillance systems: a systematic literature review. Prev Vet Med 2020;181:104560.
[10] Timme RE, Sanchez Leon M, Allard MW. Utilizing the Public GenomeTrakr Data-
detection program [32]. base for Foodborne Pathogen Traceback. Methods Mol Biol 2019;1918:201–12.
We can also improve the environment, wildlife and vector surveil- [11] Shu Y, McCauley JGISAID. Global initiative on sharing all influenza data - from
lance. Sentinel surveillance of wild birds is already in place for avian vision to reality. Euro Surveill 2017;22:30494.
[12] Dos S Ribeiro C, Koopmans MP, Haringhuizen GB. Threats to timely sharing of
flu in some countries and in an informal international collaboration
pathogen sequence data. Science 2018;362:404–6.
[33]; similarly, there are examples of regional initiatives and projects [13] Harrison PW, Ahamed A, Aslam R, et al. The European Nucleotide Archive in 2020.
targeting mosquitos and ticks for surveillance of specific vector borne Nucleic Acids Res 2021;49:D82–5.
[14] Mulder AC, Kroneman A, Franz E, et al. HEVnet: a One Health, collaborative, inter-
diseases. Such initiatives could be expanded to not only focus on a
disciplinary network and sequence data repository for enhanced hepatitis E virus
single disease, but for detection of a combination of infectious agents molecular typing, characterisation and epidemiological investigations. Euro Sur-
of importance and agnostic metagenomics. veill 2019;24:1800407.
lix B, Danan C, Van Walle I, et al. Building a molecular Listeria monocytogenes
[15] Fe
database to centralize and share PFGE typing data from food, environmental and
2. Conclusion animal strains throughout Europe. J Microbiol Methods 2014;104:1–8.
[16] Harvala H, Jasir A, Penttinen P, Pastore Celentano L, Greco D, Broberg E. Surveil-
lance and laboratory detection for non-polio enteroviruses in the European
The close interactions between humans, animals and the environ- Union/European Economic Area, 2016. Euro Surveill 2017;22:16–00807.
ment do hold a risk of emergence of infectious diseases, and their likeli- [17] Zhou Z, Alikhan NF, Mohamed K, Fan Y, Agama Study Group, Achtman M. The Entero-
hood is increasing. Therefore, preparing for future epidemics and Base user's guide, with case studies on Salmonella transmissions, Yersinia pestis phy-
logeny, and Escherichia core genomic diversity. Genome Res 2020;30:138–52.
pandemics needs special focus on understanding complexity of the [18] Anon. European Open Science Cloud. Nat Genet 2016;48:821.
interactions between humans, animals and the environment, the differ- [19] van Noorden R. Scientists call for fully open sharing of coronavirus genome data.
ent farming systems with their levels of biosecurity, prevention of dis- Nature 2021;590:195–6.
[20] Maxmen A. Why some researchers oppose unrestricted sharing of coronavirus
ease introduction - for instance through vaccines-, and rapid control of genome data. Nature 2021;593:176–7.
outbreaks by containment measures. The pandemic has shown the criti- [21] Dos S Ribeiro C, Koopmans MP, Haringhuizen GB. Threats to timely sharing of
cal importance of collaboration beyond the "normal" infrastructures, pathogen sequence data. Science 2018;362:404–6.
[22] Faure MC, Munung NS, Ntusi NAB, Pratt B, de Vries J. Mapping experiences and
networks, and disciplines. This also applies to the use of genomics and perspectives of equity in international health collaborations: a scoping review.
open data infrastructures. The current investments in global genomic Int J Equity Health 2021;20:28.
surveillance offer great potential, precluded we do not make the same [23] Larsen MV, Cosentino S, Rasmussen S, et al. Multilocus sequence typing of total-
genome-sequenced bacteria. J Clin Microbiol 2012;50:1355–61.
old mistake of developing them solely for the case at hand. Rather than [24] van Beek J, de Graaf M, Al-Hello H, et al. NoroNet. Molecular surveillance of noro-
rebuilding and reinforcing the pre-existing silo'’, a real step forward virus, 2005-16: an epidemiological analysis of data collected from the NoroNet
would be to bring these novel essential partnerships together [34]. network. Lancet Infect Dis 2018;18:545–53.
[25] Bortolaia V, Kaas RS, Ruppe E, et al. ResFinder 4.0 for predictions of phenotypes
from genotypes. J Antimicrob Chemother. 2020;75:3491–500.
Contributors [26] Gray GC, Robie ER, Studstill CJ, Nunn CL. Mitigating Future Respiratory Virus Pan-
demics: New Threats and Approaches to Consider. Viruses 2021;13:637.
[27] Alleweldt F, Kara Ş, Best K, et al. Economic evaluation of whole genome sequenc-
Frank Aarestrup and Marion Koopmans drafted the first version. ing for pathogen identification and surveillance - results of case studies in Europe
Marc Bonten reviewed and edited substantially. All authors approved and the Americas 2016 to 2019. Euro Surveill 2021;26:1900606.
[28] Nordahl Petersen T, Rasmussen S, Hasman H, et al. Meta-genomic analysis of toi-
the final version of the manuscript.
let waste from long distance flights; a step towards global surveillance of infec-
tious diseases and antimicrobial resistance. Sci Rep 2015;5:11444.
[29] Hendriksen RS, Munk P, Njage P, et al. Global monitoring of antimicrobial resistance
Declaration of Interests based on metagenomics analyses of urban sewage. Nat Commun 2019;10:1124.
[30] Nieuwenhuijse DF, Oude Munnink BB, Phan MVT, et al. Setting a baseline for
Funding to the institution. No involvement in the writing. None global urban virome surveillance in sewage. Sci Rep 2020;10:13748.
[31] Danko D, Bezdan D, Afshin EE, et al. A global metagenomic map of urban micro-
other to declare. biomes and antimicrobial resistance. Cell 2021;184:3376–93.
[32] Wu F, Zhao S, Yu B, et al. A new coronavirus associated with human respiratory
disease in China. Nature 2020;579:265–9.
Acknowledgements [33] Lycett SJ, Pohlmann A, Staubach C, et al. Genesis and spread of multiple reassor-
tants during the 2016/2017 H5 avian influenza epidemic in Eurasia. Proc Natl
This work was supported by the European Union's Horizon H2020 Acad Sci USA 2020;117:20814–25.
[34] Bedford J, Farrar J, Ihekweazu C, Kang G, Koopmans M, Nkengasong J. A new
grants VEO (874735), RECOVER (101003589), ECRAID (965313) and twenty-first century science for effective epidemic response. Nature
Novo Nordisk Foundation (NNF16OC0021856). 2019;575:130–6.