Association of vaccination, international travel, public health and social measures with lineage dynamics of SARS-CoV-2.

Continually emerging SARS-CoV-2 variants of concern that can evade immune defenses are driving recurrent epidemic waves of COVID-19 globally. However, the impact of measures to contain the virus and their effect on lineage diversity dynamics are poorly understood. Here, we jointly analyzed international travel, public health and social measures (PHSM), COVID-19 vaccine rollout, SARS-CoV-2 lineage diversity, and the case growth rate (GR) from March 2020 to September 2022 across 63 countries. We showed that despite worldwide vaccine rollout, PHSM are effective in mitigating epidemic waves and lineage diversity. An increase of 10,000 monthly travelers in a single country-to-country route between endemic countries corresponds to a 5.5% (95% CI: 2.9 to 8.2%) rise in local lineage diversity. After accounting for PHSM, natural immunity from previous infections, and waning immunity, we discovered a negative association between the GR of cases and adjusted vaccine coverage (AVC). We also observed a complex relationship between lineage diversity and vaccine rollout. Specifically, we found a significant negative association between lineage diversity and AVC at both low and high levels but not significant at the medium level. Our study deepens the understanding of population immunity and lineage dynamics for future pandemic preparedness and responsiveness.

Bidirectional Movement of Emerging H5N8 Avian Influenza Viruses Between Europe and Asia via Migratory Birds Since Early 2020.

Migratory birds play a critical role in the rapid spread of highly pathogenic avian influenza (HPAI) H5N8 virus clade 2.3.4.4 across Eurasia. Elucidating the timing and pattern of virus transmission is essential therefore for understanding the spatial dissemination of these viruses. In this study, we surveyed >27,000 wild birds in China, tracked the year-round migration patterns of 20 bird species across China since 2006, and generated new HPAI H5N8 virus genomic data. Using this new data set, we investigated the seasonal transmission dynamics of HPAI H5N8 viruses across Eurasia. We found that introductions of HPAI H5N8 viruses to different Eurasian regions were associated with the seasonal migration of wild birds. Moreover, we report a backflow of HPAI H5N8 virus lineages from Europe to Asia, suggesting that Europe acts as both a source and a sink in the global HPAI virus transmission network.

Assessing the role of live poultry trade in community-structured transmission of avian influenza in China.

The live poultry trade is thought to play an important role in the spread and maintenance of highly pathogenic avian influenza A viruses (HP AIVs) in Asia. Despite an abundance of small-scale observational studies, the role of the poultry trade in disseminating AIV over large geographic areas is still unclear, especially for developing countries with complex poultry production systems. Here we combine virus genomes and reconstructed poultry transportation data to measure and compare the spatial spread in China of three key subtypes of AIV: H5N1, H7N9, and H5N6. Although it is difficult to disentangle the contribution of confounding factors, such as bird migration and spatial distance, we find evidence that the dissemination of these subtypes among domestic poultry is geographically continuous and likely associated with the intensity of the live poultry trade in China. Using two independent data sources and network analysis methods, we report a regional-scale community structure in China that might explain the spread of AIV subtypes in the country. The identification of this structure has the potential to inform more targeted strategies for the prevention and control of AIV in China.

A follow-up study shows that recovered patients with re-positive PCR test in Wuhan may not be infectious.

BACKGROUND: Previous studies showed that recovered coronavirus disease 2019 (COVID-19) patients can have a subsequent positive polymerase chain reaction (PCR) test for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after they are discharged from the hospital. Understanding the epidemiological characteristics of recovered COVID-19 patients who have a re-positive test is vital for preventing a second wave of COVID-19. METHODS: This retrospective study analyzed the epidemiological and clinical features of 20,280 COVID-19 patients from multiple centers in Wuhan who had a positive PCR test between December 31, 2019, and August 4, 2020. The RT-PCR test results for 4079 individuals who had close contact with the re-positive cases were also obtained. RESULTS: In total, 2466 (12.16%) of the 20,280 patients had a re-positive SARS-CoV-2 PCR test after they were discharged from the hospital, and 4079 individuals had close contact with members of this patient group. All of these 4079 individuals had a negative SARS-CoV-2 PCR test. CONCLUSIONS: This retrospective study in Wuhan analyzed the basic characteristics of recovered COVID-19 patients with re-positive PCR test and found that these cases may not be infectious.

Urbanization prolongs hantavirus epidemics in cities.

Urbanization and rural-urban migration are two factors driving global patterns of disease and mortality. There is significant concern about their potential impact on disease burden and the effectiveness of current control approaches. Few attempts have been made to increase our understanding of the relationship between urbanization and disease dynamics, although it is generally believed that urban living has contributed to reductions in communicable disease burden in industrialized countries. To investigate this relationship, we carried out spatiotemporal analyses using a 48-year-long dataset of hemorrhagic fever with renal syndrome incidence (HFRS; mainly caused by two serotypes of hantavirus in China: Hantaan virus and Seoul virus) and population movements in an important endemic area of south China during the period 1963-2010. Our findings indicate that epidemics coincide with urbanization, geographic expansion, and migrant movement over time. We found a biphasic inverted U-shaped relationship between HFRS incidence and urbanization, with various endemic turning points associated with economic growth rates in cities. Our results revealed the interrelatedness of urbanization, migration, and hantavirus epidemiology, potentially explaining why urbanizing cities with high economic growth exhibit extended epidemics. Our results also highlight contrasting effects of urbanization on zoonotic disease outbreaks during periods of economic development in China.

Transmission dynamics of re-emerging rabies in domestic dogs of rural China.

Despite ongoing efforts to control transmission, rabies prevention remains a challenge in many developing countries, especially in rural areas of China where re-emerging rabies is under-reported due to a lack of sustained animal surveillance. By taking advantage of detailed genomic and epidemiological data for the re-emerging rabies outbreak in Yunnan Province, China, collected between 1999 and 2015, we reconstruct the demographic and dispersal history of domestic dog rabies virus (RABV) as well as the dynamics of dog-to-dog and dog-to-human transmission. Phylogeographic analyses reveal a lower diffusion coefficient than previously estimated for dog RABV dissemination in northern Africa. Furthermore, epidemiological analyses reveal transmission rates between dogs, as well as between dogs and humans, lower than estimates for Africa. Finally, we show that reconstructed epidemic history of RABV among dogs and the dynamics of rabid dogs are consistent with the recorded human rabies cases. This work illustrates the benefits of combining phylogeographic and epidemic modelling approaches for uncovering the spatiotemporal dynamics of zoonotic diseases, with both approaches providing estimates of key epidemiological parameters.

Interannual cycles of Hantaan virus outbreaks at the human-animal interface in Central China are controlled by temperature and rainfall.

Hantavirus, a rodent-borne zoonotic pathogen, has a global distribution with 200,000 human infections diagnosed annually. In recent decades, repeated outbreaks of hantavirus infections have been reported in Eurasia and America. These outbreaks have led to public concern and an interest in understanding the underlying biological mechanisms. Here, we propose a climate-animal-Hantaan virus (HTNV) infection model to address this issue, using a unique dataset spanning a 54-y period (1960-2013). This dataset comes from Central China, a focal point for natural HTNV infection, and includes both field surveillance and an epidemiological record. We reveal that the 8-y cycle of HTNV outbreaks is driven by the confluence of the cyclic dynamics of striped field mouse (Apodemus agrarius) populations and climate variability, at both seasonal and interannual cycles. Two climatic variables play key roles in the ecology of the HTNV system: temperature and rainfall. These variables account for the dynamics in the host reservoir system and markedly affect both the rate of transmission and the potential risk of outbreaks. Our results suggest that outbreaks of HTNV infection occur only when climatic conditions are favorable for both rodent population growth and virus transmission. These findings improve our understanding of how climate drives the periodic reemergence of zoonotic disease outbreaks over long timescales.

Emergence and Adaptation of a Novel Highly Pathogenic H7N9 Influenza Virus in Birds and Humans from a 2013 Human-Infecting Low-Pathogenic Ancestor.

Since its emergence in 2013, the H7N9 low-pathogenic avian influenza virus (LPAIV) has been circulating in domestic poultry in China, causing five waves of human infections. A novel H7N9 highly pathogenic avian influenza virus (HPAIV) variant possessing multiple basic amino acids at the cleavage site of the hemagglutinin (HA) protein was first reported in two cases of human infection in January 2017. More seriously, those novel H7N9 HPAIV variants have been transmitted and caused outbreaks on poultry farms in eight provinces in China. Herein, we demonstrate the presence of three different amino acid motifs at the cleavage sites of these HPAIV variants which were isolated from chickens and humans and likely evolved from the preexisting LPAIVs. Animal experiments showed that these novel H7N9 HPAIV variants are both highly pathogenic in chickens and lethal to mice. Notably, human-origin viruses were more pathogenic in mice than avian viruses, and the mutations in the PB2 gene associated with adaptation to mammals (E627K, A588V, and D701N) were identified by next-generation sequencing (NGS) and Sanger sequencing of the isolates from infected mice. No polymorphisms in the key amino acid substitutions of PB2 and HA in isolates from infected chicken lungs were detected by NGS. In sum, these results highlight the high degree of pathogenicity and the valid transmissibility of this new H7N9 variant in chickens and the quick adaptation of this new H7N9 variant to mammals, so the risk should be evaluated and more attention should be paid to this variant.IMPORTANCE Due to the recent increased numbers of zoonotic infections in poultry and persistent human infections in China, influenza A(H7N9) virus has remained a public health threat. Most of the influenza A(H7N9) viruses reported previously have been of low pathogenicity. Now, these novel H7N9 HPAIV variants have caused human infections in three provinces and outbreaks on poultry farms in eight provinces in China. We analyzed the molecular features and compared the relative characteristics of one H7N9 LPAIV and two H7N9 HPAIVs isolated from chickens and two human-origin H7N9 HPAIVs in chicken and mouse models. We found that all HPAIVs both are highly pathogenic and have valid transmissibility in chickens. Strikingly, the human-origin viruses were more highly pathogenic than the avian-origin viruses in mice, and dynamic mutations were confirmed by NGS and Sanger sequencing. Our findings offer important insight into the origin, adaptation, pathogenicity, and transmissibility of these viruses to both poultry and mammals.

Anthropogenically driven environmental changes shift the ecological dynamics of hemorrhagic fever with renal syndrome.

Zoonoses are increasingly recognized as an important burden on global public health in the 21st century. High-resolution, long-term field studies are critical for assessing both the baseline and future risk scenarios in a world of rapid changes. We have used a three-decade-long field study on hantavirus, a rodent-borne zoonotic pathogen distributed worldwide, coupled with epidemiological data from an endemic area of China, and show that the shift in the ecological dynamics of Hantaan virus was closely linked to environmental fluctuations at the human-wildlife interface. We reveal that environmental forcing, especially rainfall and resource availability, exert important cascading effects on intra-annual variability in the wildlife reservoir dynamics, leading to epidemics that shift between stable and chaotic regimes. Our models demonstrate that bimodal seasonal epidemics result from a powerful seasonality in transmission, generated from interlocking cycles of agricultural phenology and rodent behavior driven by the rainy seasons.

Contrasting effects of host species and phylogenetic diversity on the occurrence of HPAI H5N1 in European wild birds.

Studies on the highly pathogenic avian influenza (HPAI) H5N1 suggest that wild bird migration may facilitate its long-distance spread, yet the role of wild bird community composition in its transmission risk remains poorly understood. Furthermore, most studies on the diversity-disease relationship focused on host species diversity without considering hosts' phylogenetic relationships, which may lead to rejecting a species diversity effect when the community has host species that are only distantly related. Here, we explored the influence of waterbird community composition for determining HPAI H5N1 occurrence in wild birds in a continental-scale study across Europe. In particular, we tested the diversity-disease relationship using both host species diversity and host phylogenetic diversity. Our results provide the first demonstration that host community composition-compared with previously identified environmental risk factors-can also effectively explain the spatial pattern of H5N1 occurrence in wild birds. We further show that communities with more higher risk host species and more closely related species have a higher risk of H5N1 outbreaks. Thus, both host species diversity and community phylogenetic structure, in addition to environmental factors, jointly influence H5N1 occurrence. Our work not only extends the current theory on the diversity-disease relationship, but also has important implications for future monitoring of H5N1 and other HPAI subtypes.

A maximum curvature method for estimating epidemic onset of seasonal influenza in Japan.

BACKGROUND: Detecting the onset of influenza epidemic is important for epidemiological surveillance and for investigating the factors driving spatiotemporal transmission patterns. Most approaches define the epidemic onset based on thresholds, which use subjective criteria and are specific to individual surveillance systems. METHODS: We applied the empirical threshold method (ETM), together with two non-thresholding methods, including the maximum curvature method (MCM) that we proposed and the segmented regression method (SRM), to determine onsets of influenza epidemics in each prefecture of Japan, using sentinel surveillance data of influenza-like illness (ILI) from 2012/2013 through 2017/2018. Performance of the MCM and SRM was evaluated, in terms of epidemic onset, end, and duration, with those derived from the ETM using the nationwide epidemic onset indicator of 1.0 ILI case per sentinel per week. RESULTS: The MCM and SRM yielded complete estimates for each of Japan's 47 prefectures. In contrast, ETM estimates for Kagoshima during 2012/2013 and for Okinawa during all six influenza seasons, except 2013/2014, were invalid. The MCM showed better agreement in all estimates with the ETM than the SRM (R2 = 0.82, p < 0.001 vs. R2 = 0.34, p < 0.001 for epidemic onset; R2 = 0.18, p < 0.001 vs. R2 = 0.05, p < 0.001 for epidemic end; R2 = 0.28, p < 0.001 vs. R2 < 0.01, p = 0.35 for epidemic duration). Prefecture-specific thresholds for epidemic onset and end were established using the MCM. CONCLUSIONS: The Japanese national epidemic onset threshold is not applicable to all prefectures, particularly Okinawa. The MCM could be used to establish prefecture-specific epidemic thresholds that faithfully characterize influenza activity, serving as useful complements to the influenza surveillance system in Japan.

Westward Spread of Highly Pathogenic Avian Influenza A(H7N9) Virus among Humans, China.

We report infection of humans with highly pathogenic avian influenza A(H7N9) virus in Shaanxi, China, in May 2017. We obtained complete genomes for samples from 5 patients and from live poultry markets or farms in 4 cities. Results indicate that H7N9 is spreading westward from southern and eastern China.

Landscape and rodent community composition are associated with risk of hemorrhagic fever with renal syndrome in two cities in China, 2006-2013.

BACKGROUND: Hemorrhagic fever with renal syndrome (HFRS) is a rodent-borne disease caused by hantaviruses. Landscape can influence the risk of hantavirus infection for humans, mainly through its effect on rodent community composition and distribution. It is important to understand how landscapes influence population dynamics for different rodent species and the subsequent effect on HFRS risk. METHODS: To determine how rodent community composition influenced human hantavirus infection, we monitored rodent communities in the prefecture-level cities of Loudi and Shaoyang, China, from 2006 to 2013. Land use data were extracted from satellite images and rodent community diversity was analyzed in 45 trapping sites, in different environments. Potential contact matrices, determining how rodent community composition influence HFRS infection among different land use types, were estimated based on rodent community composition and environment type for geo-located HFRS cases. RESULTS: Apodemus agrarius and Rattus norvegicus were the predominant species in Loudi and Shaoyang, respectively. The major risk of HFRS infection was concentrated in areas with cultivated land and was associated with A. agrarius, R. norvegicus, and Rattus flavipectus. In urban areas in Shaoyang, Mus musculus was related to risk of hantavirus infection. CONCLUSIONS: Landscape features and rodent community dynamics may affect the risk of human hantavirus infection. Results of this study may be useful for the development of HFRS prevention initiatives that are customized for regions with different geographical environments.

Avian influenza H5N1 viral and bird migration networks in Asia.

The spatial spread of the highly pathogenic avian influenza virus H5N1 and its long-term persistence in Asia have resulted in avian influenza panzootics and enormous economic losses in the poultry sector. However, an understanding of the regional long-distance transmission and seasonal patterns of the virus is still lacking. In this study, we present a phylogeographic approach to reconstruct the viral migration network. We show that within each wild fowl migratory flyway, the timing of H5N1 outbreaks and viral migrations are closely associated, but little viral transmission was observed between the flyways. The bird migration network is shown to better reflect the observed viral gene sequence data than other networks and contributes to seasonal H5N1 epidemics in local regions and its large-scale transmission along flyways. These findings have potentially far-reaching consequences, improving our understanding of how bird migration drives the periodic reemergence of H5N1 in Asia.

Re-emerging of rabies in Shaanxi province, China, from 2009 to 2015.

To explore the epidemiological, phylogeographic, and migration characteristics of human rabies in Shaanxi province, China from 2009 to 2015. The collected data were described and the sequenced glycoprotein (G) and nucleoprotein (N) genes were implemented to estimate the evolutionary rates and phylogeographic patterns using BEAST v.1.8.2. A total of 269 rabies cases were reported and 70.26% of the cases were male and 61.71% were between the ages of 19-59. The majority of the cases were farmers (83.27%). The estimated evolutionary rate of the N genes was 2.4 × 10-4 substitutions/site/year and the G genes was 3.4 × 10-4 . The time of the most recent common ancestor (TMRCA) was estimated around 1990. We detected viral migration paths from Sichuan, Guizhou, and Hunan to Hanzhong prefecture of Shaanxi and then spreaded to Xi'an and other prefectures. The main population affected by rabies virus was male adult farmers. The evolution rate of rabies viruses in Shaanxi was similar with the prior results reported by others and the ancestor virus should be circulating in neighboring province Sichuan around 1990 and then transmitted to Shaanxi. Promptly standard wound treatment and timely post-exposure prophylaxis should be compulsory for the dog-bitten victims.

Cross-border spread, lineage displacement and evolutionary rate estimation of rabies virus in Yunnan Province, China.

BACKGROUND: Rabies is an important but underestimated threat to public health, with most cases reported in Asia. Since 2000, a new epidemic wave of rabies has emerged in Yunnan Province, southwestern China, which borders three countries in Southeast Asia. METHOD: We estimated gene-specific evolutionary rates for rabies virus using available data in GenBank, then used this information to calibrate the timescale of rabies virus (RABV) spread in Asia. We used 452 publicly available geo-referenced complete nucleoprotein (N) gene sequences, including 52 RABV sequences that were recently generated from samples collected in Yunnan between 2008 and 2012. RESULTS: The RABV N gene evolutionary rate was estimated to be 1.88 × 10-4 (1.37-2.41 × 10-4, 95% Bayesian credible interval, BCI) substitutions per site per year. Phylogenetic reconstructions show that the currently circulating RABV lineages in Yunnan result from at least seven independent introductions (95% BCI: 6-9 introductions) and represent each of the three main Asian RABV lineages, SEA-1, -2 and -3. We find that Yunnan is a sink location for the domestic spread of RABV and connects RABV epidemics in North China, South China, and Southeast Asia. Cross-border spread from southeast Asia (SEA) into South China, and intermixing of the North and South China epidemics is also well supported. The influx of RABV into Yunnan from SEA was not well-supported, likely due to the poor sampling of SEA RABV diversity. We found evidence for a lineage displacement of the Yunnan SEA-2 and -3 lineages by Yunnan SEA-1 strains, and considered whether this could be attributed to fitness differences. CONCLUSION: Overall, our study contributes to a better understanding of the spread of RABV that could facilitate future rabies virus control and prevention efforts.

Genetic evidence for avian influenza H5N1 viral transmission along the Black Sea-Mediterranean Flyway.

The current epidemic of highly pathogenic avian influenza H5N1 virus is considered to pose a significant threat to the health of wild and domestic avian species, and even to human beings. The Black Sea-Mediterranean Flyway is one of the most important epidemic areas of H5N1. However, the epidemic along this flyway has not been fully explored. To better understand the role of hosts in the spread and evolution of H5N1 virus along the flyway, a phylogeographic study was conducted using haemagglutinin (HA) gene sequences obtained during 2005-2013. To infer phylodynamic spread in time and space, we used a flexible Bayesian statistical framework and modelled viral spatial diffusion as a continuous-time Markov-chain process along time-measured genealogies. Our results revealed that H5N1 virus isolated from wild birds showed an increase in genetic variation of HA gene from 2005-2007. The mean genetic distance of viruses isolated from poultry reached its peak in 2010, and dropped in 2011, increasing again in 2012-2013. The reconstruction of virus circulation revealed a different viral-migration network of H5N1 virus by different hosts. Western Russia constituted a link in viral migration from Russia to Europe and Africa. Cross-species transmission of H5N1 viruses predominated in the migration network of the Black Sea-Mediterranean Flyway. This might be due to the migration of birds across long distances and interaction between local poultry and migratory birds. Additionally, the short-distance spread of H5N1 viruses among poultry followed local transportation networks. Such findings will aid in developing effective disease control and prevention strategies.

Surface water areas significantly impacted 2014 dengue outbreaks in Guangzhou, China.

Dengue transmission in urban areas is strongly influenced by a range of biological and environmental factors, yet the key drivers still need further exploration. To better understand mechanisms of environment-mosquito-urban dengue transmission, we propose an empirical model parameterized and cross-validated from a unique dataset including viral gene sequences, vector dynamics and human dengue cases in Guangzhou, China, together with a 36-year urban environmental change maps investigated by spatiotemporal satellite image fusion. The dengue epidemics in Guangzhou are highly episodic and were not associated with annual rainfall over time. Our results indicate that urban environmental changes, especially variations in surface area covered by water in urban areas, can substantially alter the virus population and dengue transmission. The recent severe dengue outbreaks in Guangzhou may be due to the surge in an artificial lake construction, which could increase infection force between vector (mainly Aedes albopictus) and host when urban water area significantly increased. Impacts of urban environmental change on dengue dynamics may not have been thoroughly investigated in the past studies and more work needs to be done to better understand the consequences of urbanization processes in our changing world.