Phylodynamic Assessment of Control Measures for Highly Pathogenic Avian
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bioRxiv preprint doi: https://doi.org/10.1101/2021.06.23.449570; this version posted June 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Phylodynamic assessment of control measures for highly pathogenic avian 2 influenza epidemics in France 3 Debapriyo Chakraborty1*, Claire Guinat2,3, Nicola F. Müller4, Francois-Xavier Briand5, 4 Mathieu Andraud5, Axelle Scoizec5, Sophie Lebouquin5, Eric Niqueux5, Audrey Schmitz5, 5 Beatrice Grasland5, Jean-Luc Guerin1, Mathilde C. Paul1 and Timothée Vergne1 6 7 1IHAP, Université de Toulouse, INRAE, ENVT, 23 Chemin des Capelles, 31300 Toulouse, 8 France. 9 2Department of Biosystems Science and Engineering, ETH Zurich, Basel, Switzerland 10 3Swiss Institute of Bioinformatics (SIB), Switzerland 11 4Vaccine and Infectious Disease, Fred Hutchinson Cancer Research Centre, Seattle, 12 Washington State, USA 13 5The French Agency for Food, Environmental and Occupational Health & Safety (ANSES) 14 Laboratory of Ploufragan-Plouzané-Niort, Ploufragan, France 15 *Corresponding author email: [email protected] 16 17 18 19 20 1 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.23.449570; this version posted June 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 21 Abstract 22 Phylodynamic methods have successfully been used to describe viral spread history but their 23 applications for assessing specific control measures are rare. In 2016-17, France experienced 24 a devastating epidemic of a highly pathogenic avian influenza virus (H5N8 clade 2.3.4.4b). 25 Using 196 viral genomes, we conducted a phylodynamic analysis combined with generalised 26 linear model and showed that the large-scale preventive culling of ducks significantly 27 reduced the viral spread between départements (French administrative division). We also 28 found that the virus likely spread more frequently between départements that shared 29 borders, but the spread was not linked to duck transport between départements. Duck 30 transport within départements increased the within-département transmission intensity, 31 although the association was weak. Together, these results indicated that the virus spread in 32 short-distances, either between adjacent départements or within départements. Results also 33 suggested that the restrictions on duck transport within départements might not have 34 stopped the viral spread completely. Overall, by testing specific hypothesis related to 35 different control measures, we demonstrated that phylodynamics methods are capable of 36 investigating the impacts of control measures on viral spread. 37 38 39 40 41 2 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.23.449570; this version posted June 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 42 Introduction 43 During the winter of 2016, an epidemic of the highly pathogenic avian influenza (HPAI) virus 44 occurred in France. It resulted in 484 infected poultry farms and approximately 7 million 45 culled birds [1]. It remains critically important to learn as much as possible from this 46 devastating epidemic, particularly as France once again experienced an HPAI outbreak in 47 December 2020 [2]. The 2016-17 epidemic was caused by an H5N8 virus of the lineage 48 2.3.4.4b (A/Gs/Gd/1/96 clade) of Asian origin that was likely introduced by migratory birds 49 [3]. The epidemic was largely concentrated in southwest France, encompassing the Occitanie 50 and the Nouvelle-Aquitaine régions (the largest French territorial administrative division) [4]. 51 The first incidence in poultry was recorded, using clinical symptoms, in a duck breeding farm 52 in the eastern Tarn département (administrative division equivalent to county or district) on 53 25 November 2016 and the infection was confirmed—based on lab diagnosis—on 28 54 November (Fig. 1). Subsequently, the epidemic spread westwards [1], following the westerly 55 distribution of poultry farms within the region . The last case of the epidemic was reported 56 on 23 March 2017 [1]. 57 Two major outbreak responses, namely preventive culling and stopping the transport 58 of foie gras ducks between farms, were implemented during the epidemic. Culling was 59 implemented locally in infected farms during the initial phase of the epidemic. However, 60 these local measures proved to be insufficient in curbing the rapid spread of the virus. 61 Consequently, there were three phases of large-scale culling. On 4 January 2017, all duck 62 farms located in 150 communes across four départements, namely Gers, Landes, Pyrenees- 63 Atlantiques and Hautes-Pyrenees, were notified to be preventively culled (Fig. 1). On 14 64 February, the number of communes under notification was doubled. On 21 February, the 3 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.23.449570; this version posted June 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 65 notified areas were increased for the last time to include more than 500 communes in total. 66 Additionally, following detection, ducks could not be moved from or to infected farms [5]. 67 Epidemiological studies based on incidence data have provided important insights 68 into the HPAI epidemic patterns [1] and the control measures [5,6]. Additionally, a recent 69 phylogenetic study analysed 196 viral sequences that were identified in poultry farms and 70 reported that the genotype that caused the large-sale epidemic in southwest France was 71 associated with five geographic clusters that could be the consequence of a few long- 72 distance transmission events followed by local spread [3]. However, the ecological and 73 epidemiological drivers of these transmission patterns are still unknown. To fill this gap, we 74 used a phylodynamic framework that we applied to the 2016-2017 epidemic data. Viral 75 phylodynamics is the study of viral phylogenies and how they are shaped by potential 76 interactions between epidemiological, immunological and evolutionary processes [7,8]. 77 These methods can detect spatio-temporal patterns of epidemics based on viral genomic 78 data, which represent a powerful source of information and are complimentary to 79 epidemiological data [9]. Although phylodynamics methods are frequently used for 80 reconstructing epidemic patterns, their application in assessing control measures is still rare 81 [10]. Here, we used a phylodynamic framework to quantify the HPAI epidemic in southwest 82 France and tested the effect of large-scale culling, along with other potential ecological and 83 epidemiological drivers. Doing so, we underscore the versatility of phylodynamics methods 84 in addressing both, specific control measure-based questions, as well as more broad ones 85 regarding viral spread history. 4 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.23.449570; this version posted June 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 86 87 Figure 1. The spatio-temporal dynamics of the 2016-17 H5N8 epidemic in southwest France. 88 The bars represent the daily number of infected farms identified in each département, with 89 each département represented by a different colour. The number of infected farms 90 represented those that were confirmed through PCR diagnostics during the epidemic period. 91 The notification dates of the three culling phases are marked by three vertical lines. Inset. 92 Location of southwest France with each study département marked with a specific colour 93 corresponding to the source of samples. 94 95 Results 96 Viral phylogeny and spread history 97 To infer the phylogeny and the geographical spread of H5N8, we used a recently 98 developed phylodynamic model called the marginal approximation of the structured 99 coalescent (MASCOT) [11]. It models the coalescence of lineages within and the migration of 100 lineages between geographical units and has been applied elsewhere to study the spread of 5 bioRxiv preprint doi: https://doi.org/10.1101/2021.06.23.449570; this version posted June 23, 2021. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 101 viral epidemics [12,13]. In our study, the geographical unit was the département as it was 102 considered to provide a good compromise between the precision of the epidemiological 103 inference and computational constraints, given the amount of data available. In Fig. 2A, we 104 showed the evolutionary relationship between viral lineages from different départements in 105 the form of a time-scaled summarised phylogenetic tree. Additionally, we show the most 106 likely viral spread history of the lineages between départements, each of which is 107 represented by a different colour. A change in colour across tree branches represents spread 108 events between départements. We inferred Tarn to be the most likely source of all the viral 109 lineages in southwest France (median posterior probability = 0.75, 95% credible interval; CI = 110 0.16-1).