medRxiv preprint doi: https://doi.org/10.1101/2020.11.16.20232322; this version posted November 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Redding et al. – Lassa fever in Nigeria 1 Spatiotemporal analysis of surveillance data enables climate-based forecasting of 2 Lassa fever 3 1,2 2 3 3 4 Authors: David W. Redding* , Rory Gibb* , Chioma C. Dan-Nwafor , Elsie A. Ilori , 3 3,4 3 3 5 Yashe Rimamdeyati Usman , Oladele H. Saliu , Amedu O. Michael , Iniobong Akanimo , 3,5 ,2,5 6,7 8 6 Oladipupo B. Ipadeola , Lauren Enright , Christl A. Donnelly , Ibrahim Abubakar , Kate 1,2 3 7 E. Jones , Chikwe Ihekweazu 8 9 Affiliations: 1 10 Institute of Zoology, Zoological Society of London, Regent’s Park, London, NW1 4RY, United 11 Kingdom. 2 12 Centre for Biodiversity and Environment Research, Department of Genetics, Evolution and 13 Environment, University College London, Gower Street, London, WC1E 6BT, United Kingdom. 3 14 Nigeria Centre for Disease Control, Abuja, Nigeria. 4 15 World Health Organisation, Abuja, Nigeria. 5 16 Centers for Disease Control and Prevention, Abuja, Nigeria. 6 17 MRC Centre for Global Infectious Disease Analysis, School of Public Health, Imperial College 18 London, W2 1PG. 7 19 Department of Statistics, University of Oxford, OX1 3LB, United Kingdom. 8 20 Institute of Global Health, University College London, Gower Street, London, WC1E 6BT, United 21 Kingdom. 22 *These authors contributed equally to this work 23 24 Word count: Abstract 234, Main text 2427, Methods 3486 25 26 Lassa fever (LF) is an acute rodent-borne viral haemorrhagic fever that is a 27 longstanding public health concern in West Africa and increasingly a global health 1,2 28 priority. Recent molecular studies have confirmed the fundamental role of the rodent 29 host (Mastomys natalensis) in driving human infections, but LF control and prevention 30 efforts remain hampered by a limited baseline understanding of the disease’s true 3 31 incidence, geographical distribution and underlying drivers . Here, through analysing 8 32 years of weekly case reports (2012-2019) from 774 local government authorities (LGAs) 33 across Nigeria, we identify the socioecological correlates of LF incidence that together 34 drive predictable, seasonal surges in cases. At the LGA-level, the spatial endemic area of 35 LF is dictated by a combination of rainfall, poverty, agriculture, urbanisation and 36 housing effects, although LF’s patchy distribution is also strongly impacted by 37 reporting effort, suggesting that many infections are still going undetected. We show 38 that spatial patterns of LF incidence within the endemic area, are principally dictated 39 by housing quality, with poor-quality housing areas seeing more cases than expected. 40 When examining the seasonal and inter-annual variation in incidence within known LF 41 hotspots, climate dynamics and reporting effort together explain observed trends 42 effectively (with 98% of observations falling within the 95% predictive interval), 43 including the sharp uptick in 2018-19. Our models show the potential for forecasting LF 44 incidence surges 1-2 months in advance, and provide a framework for developing an NOTE: This preprint reports new research that has not been certified by peer review and should not be used to guide clinical practice. 45 early-warning system for public health planning. 1 medRxiv preprint doi: https://doi.org/10.1101/2020.11.16.20232322; this version posted November 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Redding et al. – Lassa fever in Nigeria 46 In 2018 and 2019, Nigeria recorded its highest annual incidence of Lassa fever (633 47 confirmed cases in 2018 and 810 in 2019, across 28 states), prompting national and 48 international healthcare mobilisation and raising concerns of an ongoing, systematic 1,2 49 emergence of LF nationally . Lassa virus (LASV; Arenaviridae, Order: Bunyavirales) is a 50 WHO-listed priority pathogen and a major focus of international vaccine development 3 51 funding and, although often framed as a global health threat, LF is foremost a neglected 52 endemic zoonosis. A significant majority of cases – including those from recent years in 4 53 Nigeria – are thought to arise directly from spillover from the LASV reservoir host, the 54 widespread synanthropic rodent Mastomys natalensis, although with hospital-acquired 5–7 55 infections potentially occurring in small clusters of human-to-human cases . Risk factors for 56 spillover, while not well understood, are thought to include factors that increase direct and 57 indirect contact between rodents and people, including ineffective food storage, housing 8,9 58 quality, and certain agricultural practices such as crop processing . Evidence of 59 correspondence between human case surges and seasonal rainfall patterns suggests that LF is 10 60 a climate-sensitive disease , whose incidence may be increasing with regional climatic 11 61 change . The present-day incidence and burden, however, remain poorly defined, because 62 LASV surveillance has historically been opportunistic or focused on known endemic districts 12 63 with existing diagnostic capacity , and often-cited annual case estimates (of up to 300,000) 64 are consequently based on only limited serological evidence from a handful of early 13,14 65 studies . This, alongside LF’s nonspecific presentation, means that many mild or 15,16 66 subclinical infections (possibly around 80% of cases) are thought to go undetected . The 17 67 patchy understanding of LF’s true annual incidence and drivers hinders disease control and 68 provides limited contextual understanding of whether the recent surges in reported cases 69 result from improvements in surveillance or a true emergence trend. 70 To address this, we analyse the first long-term spatiotemporal epidemiological dataset 71 of acute human Lassa fever case data, systematically collected over 8 years of surveillance in 72 Nigeria. This dataset, collated by the Nigeria Centre for Disease Control (NCDC), consists of 73 weekly epidemiological reports of acute human LF cases collected by all 774 local 74 government authorities (LGAs) across Nigeria between January 2012 and December 2019 75 (Figure 1). Throughout the study period, 161 LGAs from 32 of 35 states reported cases, with 76 a mean annual total of 276 (range 25 to 816) confirmed cases, though with evidence of 77 pronounced spatial and temporal clustering. For example, most cases (75%) are reported from 78 just 3 of the 36 Nigerian states (Edo, Ondo and Ebonyi), with lower incidence overall in 79 northern endemic states, in areas notably distant from diagnostic centres. There is consistent 80 evidence of seasonality in all areas across the reporting period, with the exception of 2014- 81 15, when a lull in recorded cases was coincident in timing with the West African Ebola 82 epidemic (Extended Data Figure 1). Annual dry season peaks of LF cases typically occur in 18,19 20 83 January, confirming past hospital admissions data from Nigeria and Sierra Leone , with 84 some secondary peaks evident in early March and, increasingly, a small number of cases 85 detected throughout the year (Figure 1). Both overall temporal trends and cumulative case 86 curves suggest that 2018 and 2019 appear to be markedly different from previous years, with 87 very high peaks in confirmed cases extending from January into March, and high suspected 88 case reporting continuing throughout 2019 (Figure 1, Extended Data Figure 1). 2 medRxiv preprint doi: https://doi.org/10.1101/2020.11.16.20232322; this version posted November 18, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. All rights reserved. No reuse allowed without permission. Redding et al. – Lassa fever in Nigeria 89 Improvements to country-wide surveillance could, however, be driving any apparent 90 increase in both the incidence and geographical extent of LF in Nigeria. For instance, during 91 the 2012-2019 monitoring period, within-country LF surveillance and response was 92 strengthened under NCDC co-ordination, with a dedicated NCDC Technical Working Group 93 (LFTWG) established in 2016, the opening of three additional LF diagnostic laboratories in 94 2017-19 (to a total of five; Figure 2), the ongoing roll-out of country-wide intensive training 21 95 on LF surveillance, clinical case management and diagnosis (Extended Data Table 1) , and 22 96 the deployment of a mobile phone-based reporting system to 18 states during 2017 97 (Methods). The result of these improvements is apparent in the smoother case accumulation 98 curves in 2018-19 than observed previously (Extended Data Figure 1), as well as the notable, 99 marked increase in the geographical extent of LF case reports over time. From 2012 to 2015 100 most reported cases originated from Esan Central in Edo state, the location of Nigeria’s 101 longest-established LF diagnostic laboratory and treatment centre at Irrua Specialist Teaching 18,19 102 Hospital (ISTH) (Figure 2). The geographical extent of suspected and confirmed case 103 reports rapidly expanded across Nigeria from 2016 (Figure 2), with a contemporaneous 104 decline in cases from Esan Central. This process can be seen clearly in LGAs surrounding 105 Esan Central (Figure 2, inset) and may reflect increasingly precise attribution of the true 106 geographical origin of cases. 107 To determine the influence of socioecological factors on the geographical distribution 108 of LF risk, we analysed the spatial correlates of annual LF confirmed case occurrence and 109 incidence from 2016 to 2019 inclusive (i.e.