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Deep Learning Technology: Sebastian Arnold, Betty van Aken, Paul Grundmann, Felix A. Gers and Alexander Löser. Learning Contextualized Document Representations for Healthcare Answer Retrieval. The Web Conference 2020 (WWW'20)
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Rhinoviruses are small, single-stranded RNA viruses in the picornavirus family that are responsible for more than half of all upper respiratory tract infections. In addition to exacerbating asthma and chronic obstructive pulmonary disease, rhinoviruses have also been associated with acute respiratory hospitalizations among children (30). In a large prospective study of US pneumonias, rhinoviruses have been identified as the second most prevalent etiology of pneumonia in children after respiratory syncytial virus and the first most common etiology among adults (31). There are more than 150 unique types of rhinoviruses. Among the three genotypes (A, B, and C) types A and C are most often associated with increased morbidity and bacterial secondary infection. In animals, rhinovirus type C has been associated with morbidity in chimpanzees (32). With an array of unique serotypes no vaccines or approved antiviral therapies have been commercially produced; however, experiments have suggested that vaccines and antiviral therapy may be possible (33, 34).
While there are several strains of coxsackievirus and EVs that can cause hand-foot-and-mouth disease (HFMD), EV71 is most commonly associated with severe disease outcomes. HFMD predominantly affects young children and is found worldwide but especially in the Asia-Pacific region. Although EV71 is not typically detected in animals, recent research has indicated that it infects non-human primates (38). Various antiviral therapies are currently under study, including small molecules, monoclonals, and antivirals. Vaccine candidates are also in development, with two vaccines currently available in China, which involve recombinant proteins, attenuated strains, inactivated whole-virus and virus-like particles, and DNA vaccines (39).
Dengue hemorrhagic fever (DHF) viral disease is a serious global mosquito-borne infection. The clinical manifestation ranges from mild febrile illness to severe sickness which may include dengue shock syndrome. The DHF virus belongs to the genus Flavivirus in the Flaviviridae family, which can usually be spread by mosquitoes of the genus Aedes aegypti, but less often through the genus Aedes albopictus. Also, this virus is a single-stranded positive-sense RNA virus that exists as four different serotypes (DEN-1, DEN-2, DEN-3, and DEN-4).
In Saudi Arabia, the disease is limited to the western and southwestern regions, such as Jeddah and Makkah where Aedes aegypti exists. However, all DHF cases in Saudi Arabia presented as a mild disease. In fact, the first experience of DHF virus isolation from Saudi Arabia was recorded during an outbreak of the virus in 1994, where the 289 confirmed cases reported in Jeddah were caused by DENV-2. However, during this first outbreak, in both summer and rainy season, at the end of the year, both DENV-2 and DENV-1 were isolated. In 1997, during the rainy season in Jeddah, there was an emergence of the DENV-3 virus. In subsequent years, from 1997–2004; the emergence of DHF occurred with the three identified serotypes (DENV-1, DENV-2, and DENV-3) isolated in Jeddah. Khan et al. reported the first outbreak of DHF viral infection in Makkah in 2004, and the isolated virus serotypes were DENV-2 and DENV-3. To prevent this outbreak, the Saudi Preventive Department in the MOH launched a comprehensive plan to control the disease, but other outbreaks occurred in Jeddah during the winter seasons of 2005 and 2006. However, Egger suggested that the reemergence of the disease in Saudi Arabia might be explained by the growing levels of urbanization, international trade, and travels.
In keeping with the findings of most previous studies, the epidemiological occurrence of DHF infection using the Saudi’s national data indicated that the majority (68%) of patients with dengue virus infection were Saudi nationals. On the contrary, from the epidemiological report based on Saudi’s national data in previous publications, an estimated 15% of patients with DHF presented in Jeddah. Kholedi et al. reported a higher percentage among patients with DHF infections in Jeddah, with about 51.9% and 48.1% among Saudi and non-Saudi patients, respectively. It was concluded that DHFV resurged sharply in Jeddah in 2004 with the number increasing dramatically to 1308 cases in 2006. Alzahrani et al., in another study, suggested 51.4% among patients in Saudi. In yet another recent study, the virus was reported as 38% in Saudi patients. All of these Saudi studies were conducted in Jeddah.
From Makkah City, the reported epidemiological study identified 63.4% of DHF infection cases among Saudi nationals. Similarly, a later study puts the estimate at more than 70% of Saudi nationals. These previously published studies suggest that differences in proportions may exist between Saudi nationals infected with DHF virus in Jeddah and Makkah City. Contrary to previous data from Jeddah, in Makkah, it was clear that the majority of patients presenting with clinically significant DHF were Saudi nationals. Therefore, these results emphasized the fact that Saudi nationals are at greater risk of DHF infection. The awareness of these results is considered a cornerstone to enhancing the ability of healthcare professionals’ identification of the disease; and this might play an important role in the development of effective eradication strategies for the disease in Saudi Arabia localities.
Furthermore, the first cases of the virus, confirmed in Al-Madinah in 2008, showed that the isolated virus serotypes were DENV-1 and DENV-2. In 2009, the MOH in Saudi Arabia reported a total of 3350 cases of the DHF infection, with an estimated case fatality rate of about 4.6 per thousand in Saudi Arabia. In August 2017, several countries in Asia, including Malaysia, Singapore, and Pakistan reported about 60,000, 1877, and 738 dengue cases including deaths, respectively. In the same period (2017), Saudi Arabia reported 39 confirmed dengue cases in Makkah, 19 of which occurred in August 2017, 60 suspected cases, and 15 cases pending laboratory confirmations. From these epidemic data indicating the reemergence of DHF infection in Saudi Arabia; Jeddah, Makkah, and Al-Madinah were shown to be the more susceptible areas, for this infectious disease, and this could be due to the fact that these cities are the sites of both the annual Hajj pilgrimage and/or the minor Umrah pilgrimage, which draw millions of Muslims to Saudi Arabia.
Currently, there are few epidemiological studies on DHF virus infection in Saudi Arabia. A study by Al-Azraqi et al. was conducted in 30 hospitals and 387 primary healthcare centers in two cities in the southern province of Saudi Arabia, particularly in Jizan, and Aseer. The study, which was limited to the seroprevalence among clinically suspected hospital-based patients, detected about 31.7% positive cases of dengue virus IgG among 965 randomly selected patients attending the outpatient clinics for any reason. The associated risk factors were male gender, younger age (15–29 years), lack of electricity, and having water basins in the house. The authors suggested that the virus may occur in sporadic cases in Jizan, due to the nature of the city. Jizan is relatively flat and located at sea level; thus the likelihood of the formation of small stagnant water following the rainfall in the city is high.
Interestingly, a retrospective cross-sectional study, which compared the clinical findings and/or the diagnostic laboratory results in uncomplicated patients, and patients who developed DHF, was conducted at Dr. Soliman Fakeeh Hospital in Jeddah, between January 2010 and June 2014. About 567 patients with a discharge diagnosis of DHF or dengue shock syndrome were identified. Of these, 482 (85%) were adult patients within the age range 14–73 years, and 15% were children with age ranging from 2 months to 13 years. However, among all these patients, 67% of the adults and 63% of the pediatric cases were males. The clinical data from the hospital showed that in the adult patients, about 98% made a full recovery without complications while two patients died.
More recently in 28 January 2018, the MOH began an intensive campaign to eradicate the DHF virus from Saudi Arabian cities, to enhance public health awareness, and facilitate a change in hygiene behavior of citizens and residents. This resulted in a 50.7% reduction in the number of DHF infection among inpatient cases in Jeddah when compared to the same period in the previous year. However, the overall drop in DHF cases reached 38% in 2017, compared to the previous year. Furthermore, recently, it is well-known that in Saudi Arabia, the DHF infection has been limited to the western and southwestern regions such as Jeddah and Makkah where Aedes aegypti exists. However, all DHF cases in Jeddah, Saudi Arabia, were mostly mild cases and the prospect of dengue virus control lies with vector control, health education, and possibly vaccine use.
Waterbirds and shorebirds of the orders Anseriformes (mainly ducks, geese and swans) and Charadriiformes (mainly gulls, terns and waders) are considered the natural host reservoirs of LPAI viruses (see Fig. 1). In wild birds LPAI viruses predominantly infect epithelial cells of the intestinal tract, and are subsequently excreted in the faeces. However, infection of wild birds with LPAI viruses is typically sub-clinical and occurs in the absence of obvious lesions,,. Every year, LPAI viruses cause outbreaks amongst waterbirds. These outbreaks are most commonly associated with the increased presence of juvenile, immunologically naïve birds in the population and occur during migration when contact rates between, and within, populations are high. The relatively high virus prevalence in waterbirds may be due, in part, to virus transmission through the faecal–oral route via surface waters.
Influenza viruses from waterbirds can cross the species barrier and infect numerous other species (see Fig. 1). A recent example of bird-to-animal transmission is the mortality amongst harbour seals [Phoca vitulina] of the North-European coastal waters following infection with the LPAI H10N7 virus,,. Various outbreaks of LPAI H3, H4 and H7 viruses causing severe respiratory disease and mortality amongst harbour seals have also occurred in the past decades along the New England coast of the United States of America,,,. The exact transmission route between seals is unknown but it is likely to occur via the respiratory route, most probably whilst the seals are resting on land. It is currently unknown if adaptation of influenza viruses from waterbirds is needed to allow the virus to infect and transmit amongst seals. In addition to seals, LPAI viruses have been isolated from a long-finned pilot whale [Globicephala melas] and Balaenopterid whales (species unknown),, and serological evidence for infection was reported in various other marine mammal species (for review see). However, the available data is very limited and it is remains unclear if LPAI viruses can also cause outbreaks of disease in other marine mammals similar to harbour seals.
The MERS-CoV infection is considered to be a new respiratory disease with a dire global concern. MERS-CoV infections are caused by a newly emerging coronavirus (CoV), belonging to the designated lineage C of Betacoronavirus of the RNA family Coronaviridae. With respect to viral origin and transmission, bats are thought to be the reservoir host of Betacoronaviruses, and the African Neoromicia bats in particular are the natural reservoir of MERS-CoV.
Since its emergence in 2012 in Saudi Arabia, when an elderly patient (60 years old) with respiratory illness died after admission to a hospital in Jeddah, the disease was subsequently reported to have been transmitted to several countries worldwide, and has affected more than 1000 patients with over 35% fatality.
Moreover, a 60-year-old Saudi man was admitted to a private hospital in Jeddah, Saudi Arabia in June 2012 with a history of fever, severe acute respiratory syndrome with cough, expectoration, and shortness of breath. He did not smoke; and for the disease, which was suggested to be due to an animal transmission of coronaviruses, he was treated with oseltamivir, levofloxacin, and piperacillin-tazobactam. On day 11, he died. After this, a 61-year-old Saudi male with hypertension and diabetes with no history of smoking, reported for surgery. At the time of admission, he was asymptomatic. He was initially screened using nasopharyngeal swab, endotracheal aspirate, and serum sample for MERS-CoV per protocol with the MERS RRT-PCR assay. The results confirmed MERS-CoV infection. He died three days after admission. It was discovered that the patient owned a dromedary camel barn in Saudi Arabia, and had a history of close contact with camels, as well as a habit of raw milk consumption of an unknown duration.
Two studies have suggested a relationship between the infection and contact with dromedary camels. In addition to this, serological diagnostic methods have been used to confirm MERS-CoV infections in dromedary camels for at least 2–3 decades and has thus confirmed camels as an intermediate host for this virus. Thus, in 2012, a novel coronavirus (MERS-CoV) was isolated from two fatal human cases in Saudi Arabia and Qatar; and since then, more than 1400 clinical cases of MERS-CoV have been identified, and the great majority of the cases were from Saudi Arabia. This previous report author raised a thoughtful comment related to the emerging viral diseases “Why We Need to Worry about Bats, Camels, and Airplanes”. Moreover, another study suggested that MERS-CoV infection is usually transmitted from human’s direct contact with dromedary camels, especially when people drink the milk or use camel’s urine for medicinal purposes. More recently, a metagenomics sequencing analysis of nasopharyngeal swab samples from 108 MERS-CoV-positive live dromedary camels marketed in Abu Dhabi, United Arab Emirates, showed at least two recently identified camel coronaviruses, which were detected in 92.6% of the camels in that study. However, limited human-to-human infections have been reported.
The prevalence of MERS-CoV infections worldwide still remains unclear. In addition to this, the WHO reported about 1797 cases of these infections since June 2012, with about 687 deaths in 27 different countries, worldwide. Recently, a study was conducted from June 2012 to July 2016, during which samples were collected from MERS-CoV infected individuals, from the National Guard Hospital in Riyadh (the Saudi Arabian capital city), the MOH in Saudi Arabia, and other Gulf Corporation Council countries, to determine the prevalence of MERS-CoV. The epidemiologic data that were collected, showed that the highest number of cases (about 1441 of 1797 patients) were reported from Saudi Arabia (~93%). Among the 1441 MERS-CoV cases from Saudi Arabia, Riyadh was the worst-hit area with 756 infected cases (52.4%), followed by the western region of Makkah where 298 cases (20.6%) were reported.
Furthermore, this study also showed that the incidence of MERS-CoV infections was highest among elderly people aged ≥60 years; with speculation that there might be certain conditions or factors involved. It is considered that MERS-CoV infection might have a peculiar gender predisposition. Recent data examined the mortality in patients with MERS-CoV and the gender relationships, looking at the survival of cases among females and males. It was suggested that males have a higher risk of death; however, this was contradicted by the findings from two other studies which suggested that males have a low risk of death; while another survey which examined the influence of gender on 3-day and 30-day survival, found a low risk of death especially in the older age group. On the other hand, Badawi et al., suggested that MERS-CoV infections could be mild and may only result in death among patients suffering from any kind of immune system disorder and/or any chronic disease.
More recently, data regarding the mortality in patients with MERS-CoV have been published. According to Saudi Arabia’s MOH daily statements, dated from February 26 through March 3, laboratory-confirmed new cases of MERS-CoV and 2 deaths occurred. Recently, on February 26, patients infected while hospitalized at Riyadh included two men (23 and 59 years old) in stable condition, who were not healthcare workers. According to a February 27 update, a new case involved a 71-year-old man from the city of Buraydah who later died. Meanwhile, on March 1, another MERS-CoV infection in a Riyadh hospital patient, a 64-year-old man who was listed in critical condition and who likewise had contact with camels, as the other two patients, was reported. Thus, the MOH stated that the spillover from camels is thought to be the main source of MERS-CoV in Saudi Arabia, since all these patients were exposed to the animals before reporting ill.
Furthermore, an 83-year-old patient from Riyadh, and other two patients who had camel contacts from Hail city in the north central part of Saudi Arabia were listed in critical condition. The illness in these patients was reported on March 1. According to a March 3 statement, another patient, a 74-year-old man from Najran located in southern Saudi Arabia, was reported. The man was listed in a stable condition. Of these new cases, only one death, involving the 83-year-old man from Riyadh, according to the March 3 MOH statement, was reported. Still, much work is needed to detect the MERS-CoV infection risk in Saudi Arabia, because data showed increasing number of cases exist among the eight countries including Saudi Arabia. Thus, the emergence of MERS-CoV in the region and its continuing transmission from 2012–2017, currently poses one of the biggest threats to global health security. Most cases (over 85%) reported to date have been from countries in the region (e.g., Egypt) notably from Saudi Arabia, with 1527 cases including 624 deaths.
Frequent human-animal contact is the major cause for viral cross-species transmission. Next-generation sequencing is a highly efficient method for rapid identification of microorganisms and for surveillance of pathogens for infectious diseases. Animal models and other laboratory tests would be needed to pinpoint the causative agents. The novel coronaviruses in Wuhan likely had a bat origin, but how the human-infecting viruses evolved from bats requires further study. The human-infecting virus may become more infectious but less virulent as it continues to (co-)evolve and adapt to human hosts. Since Wuhan is one of the largest inland transportation hubs in China and the city has been closed off, it is urgently necessary to step up molecular surveillance and restrict the movement of people in and out of the affected areas promptly, in addition to closing the seafood markets. To prevent human-to-human transmission events, close monitoring of at-risk humans, including medical professionals in contact with infected patients, should also be enforced. Finally, virome projects should be encouraged to help identify animal viral threats before viral spillover or becoming pandemics.
Infectious agents may be transmitted to humans by direct contact, fomite or mechanical vector, or intermediate hosts in which the agent multiples or develops before transmission to animal or human (i.e., metazoonoses). Examples of infectious agents requiring an incubation period prior to transmission include arboviruses, plague, and schistosomiasis (31). In the case of toxoplasmosis infection, contaminated soil and water represent a key source of infection emanating from an intermediate host (33, 34). Indoor/outdoor cats are a significant carrier/transmitter of Toxoplasma, shedding the organism in its feces (34). Oocysts from Toxoplasma gondii also may be transported by cockroaches and other bugs and deposited onto food and later consumed by animals and humans (35). In a recent study, eating raw oysters, clams, or mussels was identified as a new risk factor for T. gondii infection (36). The T. gondii were believed to have originated from cat feces, which survived or bypassed sewage treatment and traveled to coastal waters through river systems.
Since the identification of the first coronavirus – infectious bronchitis virus (IBV) isolated from birds – many coronaviruses have been discovered from such animals as bats, camels, cats, dogs, pigs, and whales. They may cause respiratory, enteric, hepatic, or neurologic diseases with different levels of severity in a variety of hosts, including humans. Coronaviruses have positive-sense single-stranded RNAs, their genomic size are 26 to 32 kilobases, the largest for an RNA virus. And the viruses themselves appear crown-shaped under electron microscopy. Coronaviruses belong to the subfamily Coronavirinae in the family Coronaviridae in the order Nidovirales. Coronavirinae is further divided into four genera, Alpha-, Beta-, Gamma-, and Deltacoronavirus, based on their phylogenetic relationships and genomic structures.
Coronaviruses occasionally jump across host barriers, often with lethal consequences. The alpha- and betacoronaviruses only infect mammals and usually cause respiratory illness in humans and gastroenteritis in animals. Gamma- and deltacoronaviruses mainly infect birds, and no human infection has been reported. Six coronaviruses known to infect humans are 229E, NL63 (genus Alpha-), OC43, HKU1, SARS-CoV, and MERS-CoV (Beta-), whereas only SARS- and MERS-CoV have caused large worldwide outbreaks with fatality, others usually cause mild upper-respiratory tract illnesses. A novel coronavirus was identified in a pneumonia patient in Wuhan on January 9 of this year represents the seventh human-infecting coronaviruses.
Severe acute respiratory syndrome (SARS, induced by SARS-CoV) first emerged in Guangdong province, China in 2002 and quickly spread around the world, with more than 8000 people infected and nearly 800 died. The MERS-CoV is a new member of Betacoronavirus and caused the first confirmed case of Middle East Respiratory Syndrome (MERS) in Saudi Arabia in 2012. Over 2000 MERS-related infections have been reported as of 2019 with a ∼34% fatality rate (https://www.who.int/).
Human exposure may occur in many ways – preparing and consuming animal products, washing with, and drinking well water contaminated with animal fecal coliform, animal bites/scratches, and working in occupations involving regular contact with animals, manure, soil, and/or by-products (e.g., farmers, slaughtering plant workers). Even living down-wind of a farm field fertilized with animal manure poses a potential risk. A list of major sources and exposure routes of animal-to-people transmission of viruses and bacteria is shown in Figure 2. Factors influencing the probability of disease transmission involve the proximity and temporal contact with the infectious organism, length of time that the infectious agent is present, virulence of the agent, incubation period, stability of the agent under varying environmental conditions, population density of carrier animals, husbandry practices, and control of wild rodents and insects (31). The type and maintenance of animal housing also may affect the extent to which individuals working in or around such facilities are exposure to zoonotic viruses and bacteria. Often, animal containment structures (e.g., hen houses, pig pens, cattle barns, and horse stables) may be inadequately ventilated and/or have poor waste removal systems, increasing the exposure of animals and their caretakers to dust, fecal matter, and microbes (32).
To date, no animal norovirus have been detected in human stool, but some serological evidence hints to possible transmission from animals to humans. This includes a handful of studies that reported seroprevalence against bovine and canine norovirus in humans. A Dutch study compared antibody titres against GIII.2 VLPs from 210 bovine or porcine veterinary specialists against age, sex, and residence matched controls with the aim to evaluate whether higher exposure to animals is reflected in increased titers against animal noroviruses. More veterinarians had anti-GIII.2 IgG antibodies compared to the control group (28% versus 20%). Similarly, the seroprevalence of antibodies to canine GVI.2 VLPs was tested in a cohort of 373 veterinarians versus age, sex, and district matched controls. Of the veterinarians, 22.3% were seropositive for GVI.2 in comparison to 5.8% in the control group. Anti-GIII antibodies were also detected in 26.7% of adult blood donors in Sweden and in a birth cohort in India, which compared seroprevalence of mothers and their children. However, the possible presence of cross-reactive antibodies needs to be considered in these studies: the GIII.2 response was in part correlated with GI.1 response, but not with the GII.4 response. The finding that some sera contained higher antibody titers against GIII.2 than human norovirus indicates that not all anti-GIII.2 response can be explained by cross-reactivity. Importantly, no cross-reactivity between bovine GIII.2 and human GI.3, GII.1, GII.3, GII.4, GII.6 was detected when convalescent anti-GIII.2 sera of a gnotobiotic calf or specific anti-GIII.2 or GII.3 antibodies were used. Cross-reactivity between GVI.2 and GII.4 was assessed by pre-incubating GVI.2 positive sera with GVI.2 VLPs before assessing their binding to GII.4 or GVI.2. Preincubation with GVI.2 blocked binding to GVI.2 VLPs but had no effect on sera binding to GII.4, suggesting that these two genotypes share no conserved epitopes. In contrast, cross-reactivity was observed between more closely related human GIV.1 and canine GIV.2 noroviruses in an age stratified cohort of 535 people in Italy, where 28.2% of the sera reacted to both GIV.1 and GIV.2 VLPs and only 0.9% detected exclusively GIV.2 VLPs.
Two independent reviewers screened titles and abstracts for their relevance. We included publications that mentioned norovirus in the title or abstract but we excluded papers about food (oyster) and waterborne outbreaks, food surveillance or food related experiments, and oyster/seafood surveillance. We excluded papers on murine noroviruses as models. Papers describing norovirus surveillance in wild mice and papers using mice as model for human norovirus were included (Figure 5).
In a second round, we screened the papers for whether they described (1) animal surveillance studies to detect human or animal norovirus by PCR, sequencing or by serosurveillance including negative results; (2) experimental animal infections with human or animal norovirus; (3) human surveillance studies to detect animal norovirus by PCR, sequencing or by serosurveillance including negative results; (4) animal norovirus characterization including molecular assays and genome announcements.
It is well established based on several epidemiological studies that cattle are the primary reservoirs of IDVs. In addition, IDVs have also been isolated from a range of animals including pigs, sheep, goat, horses and camelids. While the precise role of IDVs in clinical disease in animals is not yet fully investigated, their role in causing respiratory infections in cattle has been implied. Two recent studies carried out metagenomic characterizations of the virome associated with bovine respiratory disease in feedlot cattle and found correlation of IDV presence with Bovine respiratory disease (BRD) clinical signs, raising exciting new prospects for understanding and combatting this complicated disease.
BRD complex is one of the major diseases affecting the cattle industry in the USA and around the world. Productivity losses due to BRD are estimated to be $23.60 per calf with an annual economic impact of more than one billion dollars to the U.S. cattle industry. BRD is associated by multiple pathogens and accounts for approximately 70–80% of the morbidity in the USA and 84.5–99.9% of the morbidity in Mexican feedlot cattle. BRD results in the use of widespread therapeutics and antibiotics in feedlots, which increasingly raises public health concerns of promoting antibiotic resistance. Pathophysiology of BRD involves complex interactions between host, pathogen, environment and management factors. In feedlot cattle, BRD is initiated by viral infection followed by stress due to travel which is typically followed by a secondary infection by resident bacteria. Viral infection can cause increased susceptibility to secondary bacterial infections by either immunosuppression or by damaging the epithelium of upper airways and injuring lung parenchyma which facilitates the migration of bacterial pathogens and colonization of the lower respiratory tract. Depending on several factors, the clinical outcome of BRD can be variable; however, higher morbidity and mortality are observed in the event of mixed viral and bacterial infections.
Many viral pathogens have been implicated in BRD, which include bovine viral diarrhea virus, bovine herpesvirus 1, bovine respiratory syncytial virus and bovine parainfluenza 3. Experimental studies in calves with IDV showed damage that results in the induction of inflammation in the trachea. IDV could be a significant player in BRD and could facilitate coinfections with other bovine pathogens. In addition to the animal health implications of IDVs, a recent study found IDV antibodies in 34 out of 35 persons that had contact with cattle and only 2 out of 11 that did not have any exposure to cattle. The results of this study raised the possibility that IDV could be relevant from a public health stand point and that it could pose a zoonotic risk to cattle-exposed workers. With much still to be characterized about the new IDV species, exploring its impact on human an animal health through epidemiological studies will be vital to understanding spread of this virus.
Influenza A virus has a wide range of hosts. Often the susceptibility of the species is dependent upon the characteristics of the virus and host. Numerous subtypes of influenza A viruses, including influenza A pandemic H1N1 2009 virus, have been shown to cross-species transmission. Since 2009, a novel influenza A virus (H1N1), now called A (H1N1) pdm09 influenza virus, has caused human influenza outbreaks in North America and a worldwide pandemic. To date, it has not only infected human, but also been reported interspecies transmission from humans to other animals, such as pigs, poultry, dogs.
Recently, the reports have shown that cats can also infected A (H1N1) pdm09 influenza virus. Due to frequent cohabitation and close contacts with humans and other animals, cats are uniquely positioned to serve as reservoirs for influenza virus infection both within a household and within the larger farm or rural environment in China. However, prevalence of A (H1N1) pdm09 influenza virus infection in cats in northeastern China is unknown. Therefore, the prevalence of A (H1N1) pdm09 influenza virus infections was performed among cats in northeastern China in this study.
A total of 1140 feline blood samples were collected from 56 different pet hospitals and four small animal shelters around northeastern China, from February 2012 to March 2013. The geographical and prevalent distribution of the samples has been concerned. Haerbin, Changchun and Shenyang were selected since they are the most densely populated area of commerce in northeastern China. Dalian was also included as it is the trade zone with large-scale breeding of poultry and pigs in northeastern China. The geographical location of serum samples of collection in northeastern China was displayed, please see the Figure 1. 660 blood samples from pet cats in hospitals and 480 blood samples from roaming cats were obtained. In each city, we selected the single largest small shelter. These serum samples were septed by centrifugation at 3,000 rpm for 15 min, and supernatants were transferred to a new eppendorf tubes and stored at-20°C until tested for antibodies against influenza A virus. Additionally, in order to have a timely data for pandemic (H1N1) 2009 prevalence in northeastern China, 115 blood samples were retrospectively analyzed from pet dogs and pet cats in Harbin in 2008. All samples were tested by hemagglutination inhibition (HI) and Neutralization (NT) assay, according to the recommended procedures as previously reported. HI titer ≥ 40 and NT titer ≥ 40 are considered as positive and indicate previous infection. Influenza virus used in this study was A/California/7/2009(H1N1pdm09) [pandemic (H1N1) 2009 virus]. We additionally studied the sera for HI antibodies against three other viruses: a human seasonal H1N1 influenza virus A/Brisbane/59/2007(H1N1) and A/canine/Guangdong/2/2011(H3N2), a recently circulating H3N2 canine influenza virus (CIV) in dogs in China. The comparison of categorical variables between cat samples was performed with chi-square test where appropriate. Statistical significance was defined as p < 0.05. The data was analyzed with SAS software, version 9.1.
A total of 1255 serum samples were examined by NT and HI for pandemic (H1N1) 2009 antibodies. The serological screening revealed 21% pandemic (H1N1) 2009 infection in cats in northeastern China based on NT. It also showed a higher prevalence rate of pandemic (H1N1) 2009 infection in pet cats (30.6%) than roaming cats (11%) based on NT (p = 0.0032, Table 1). The results from HI also showed a trend of difference in term of species of cats and it was statistically significant (P = 0.002). The prevalence of the infection also showed a geographical difference in roaming cats as prevalent in Harbin and Changchun (20.8% and 23.3%) and absent in Shenyang and Dalian (Table 1). In addition, the factors of the gender and age of the cats were also analyzed as contributors to pandemic (H1N1) 2009 prevalence. In the Table 2, while no influence of age (seropositive data not shown) was found on cats infection with pandemic (H1N1) 2009, genders associated with the pandemic (H1N1) 2009 seropositivity by both HI and NT assay was significantly (p < 0.05). In addition, a total of 115 serum samples collected in 2008 had no HI or NT antibodies against A/California/7/2009 (data not shown). To rule out non-specific cross-reactivity, 1140 serum samples were titrated against seasonal influenza viruses (H1N1). Only twenty-four samples had a HI titer of 1:40 against H1N1 (Table 3). Only ten of these forty seasonal influenza positive-samples were also HI and NT positive for A/California/7/2009(H1N1pdm09). A total of 111 (9.7%) sera were positive by HI assay against H3N2 CIV (Table 3).
Few seroprevalence studies on pandemic (H1N1) 2009 infections have been attempted in cats worldwide. The prevalence of this virus infection in cats in mainland China remains unknown. This is the first survey on the seroprevalence of pandemic (H1N1) 2009 infection in cats in northeastern China. Of all sera from cats in this study, 21% was identified as pandemic (H1N1) 2009 positive. In another conducting the seroprevalence of antibodies against (H1N1) pdm09 among cats in small cities of southern China was only 1.2% in 2011. Our increased antibody prevalence might be explained a number of ways. Perhaps cats were at a higher probability of infection in northeastern China, due to they exposures in dense populations of humans with high influenza A (H1N1) pdm09 attack rates. The difference might also be explained by the one year temporal difference between cats sampled in southern China in that the northeastern China cats had 1 more years to acquire influenza A (H1N1) pdm09 virus infection. Additionally, the prevalence of seropositive pandemic (H1N1) 2009 in male cats versus female cats suggests that the male cats may be more susceptible (P < 0.05) to the pandemic (H1N1) 2009 infections (Table 2). We hypothesize that relatively high A (H1N1) pdm09 transmission may have occurred between humans and cats during the period of virus infection in the human population. This hypothesis is supported by our observation that pet cats were more likely to have evidence of previous infection with A (H1N1) pdm09 that were roaming cats (30.6% vs11%, P = 0.0032) and also suggests a likely transmission between infected owners and their pets by close contact. Serological evidence of A (H1N1) pdm09 in domestic cats has been reported in the past. In a sero-survey conducted in Italy in 2009, a contrary low prevalence had been observed among dogs, while no cats were reported to have antibodies against A(H1N1)pdm09 in the screen. A similar high prevalence of 21.8% and 22.5% were recorded in a population of cats in the United States, but the study sample comprised animals with a history of respiratory disease. We hypothesized the sustained transmission of the influenza A (H1N1) pdm09 virus in the human population in our study area. In addition, it should be noted that 240 samples from the two small animal shelters in Harbin and Changchun had exposure to pandemic (H1N1) 2009 before sample collection. The higher prevalence of seropositive pandemic A (H1N1) pmd09 among Harbin and Changchun cats versus Shenyang and Dalian is unexplained.
Since cats may be exposed to different influenza virus subtypes, including human-avian and avian-origin influenza viruses, their potential role in the epidemiology of influenza virus should be further investigated. In summary, this study has observed a relatively high seroprevalence of pandemic (H1N1) 2009 in cats in northeastern China, similar seroprevalence studies should be conducted elsewhere. The studies showed that the prevalence for A (H1N1) pdm09 in human was correlated with age and population density. Preexisting antibody may have protected the very old from A (H1N1) pdm09 infection, while original antigenic sin and immunosenescence may have contributed to greater severity once infected. Compare with all serum samples collected in 2008 had no HI and NT antibodies against A/California/7/2009, these results reflect the pandemic (H1N1) 2009 had been spread in cats. Concerns of rapid spread in small animal shelters and household may be needed. These observations highlight the need for monitoring cats in pet hospitals and small animal shelters are necessary for us to understand what roles cats plan in the ecology of influenza A virus.
Influenza viruses are known to constantly evolve and cross species barriers. The genetic diversity of influenza viruses is ever increasing with more novel influenza subtypes being discovered periodically. The purpose of this review is to provide an up-to-date overview of ecology and evolution of influenza viruses including the novel influenza viruses in bats and cattle. In addition, we discussed the growing complexity of influenza virus–host interactions and highlighted the key research questions that need to be answered for a better understanding of the emergence of pandemic influenza viruses.
The Paramyxoviridae family within the order of Mononegavirales includes a large number of human and animal viruses that are responsible for a wide spectrum of diseases. Measles virus (MV) is one of the most infectious human viruses known, and has been targeted by the World Health Organization for eradication through the use of vaccines. The paramyxovirus family includes several other viruses with high prevalence and public health impact in humans, like respiratory syncytial virus (RSV), human metapneumovirus (HMPV), mumps virus (MuV), and the parainfluenza viruses (PIV). In addition, newly emerging members of the Paramyxoviridae family – hendra and nipah virus – have caused fatal infections in humans upon zoonoses from animal reservoirs,,. In animals, Newcastle disease virus (NDV) is and Rinderpest virus (RPV) was among the viruses with the most devastating impact on animal husbandry. Members of the Paramyxoviridae family switch hosts at a higher rate than most other virus families and infect a wide range of host species, including humans, non-human primates, horses, dogs, sheep, pigs, cats, mice, rats, dolphins, porpoises, fish, seals, whales, birds, bats, and cattle. Thus, the impact of paramyxoviruses to general human and animal welfare is immense.
The Paramyxoviridae family consists of two subfamilies, the Paramyxovirinae and the Pneumovirinae. The subfamily Paramyxovirinae includes five genera: Rubulavirus, Avulavirus, Respirovirus, Henipavirus and Morbillivirus. The subfamily Pneumovirinae includes two genera: Pneumovirus and Metapneumovirus
. Classification of the Paramyxoviridae family is based on differences in the organization of the virus genome, the sequence relationship of the encoded proteins, the biological activity of the proteins, and morphological characteristics,. Virions from this family are enveloped, pleomorphic, and have a single-stranded, non-segmented, negative-sense RNA genome. Complete genomic RNA sequences for known members of the family range from 13–19 kilobases in length. The RNA consists of six to ten tandemly linked genes, of which three form the minimal polymerase complex; nucleoprotein (N or NP), phosphoprotein (P) and large polymerase protein (L). Paramyxoviruses further uniformly encode the matrix (M) and fusion (F) proteins, and – depending on virus genus – encode additional surface glycoproteins such as the attachment protein (G), hemagglutinin or hemagglutinin-neuraminidase (H, HN), short-hydrophic protein (SH) and regulatory proteins such as non-structural proteins 1 and 2 (NS1, NS2), matrix protein 2 (M2.1, M2.2), and C and V proteins,.
Routine diagnosis of paramyxovirus infections in humans and animals is generally performed by virus isolation in cell culture, molecular diagnostic tests such as reverse transcriptase polymerase chain reaction (RT-PCR) assays, and serological tests. Such tests are generally designed to be highly sensitive and specific for particular paramyxovirus species. However, to detect zoonotic, unknown, and newly emerging pathogens within the Paramyxoviridae family, these tests may be less suitable. Development of virus family-wide PCR assays has greatly facilitated the detection of previously unknown and emerging viruses. Examples of such PCR assays are available for the flaviviruses, coronaviruses, and adenoviruses. For the Paramyxoviridae, Tong et al. described semi-nested or nested PCR assays to detect members of the Paramyxovirinae or Pneumovirinae subfamily or groups of genera within the Paramyxovirinae subfamily. Although these tests are valuable for specific purposes, nesting of PCR assays and requirement for multiple primer-sets are sub-optimal for high-throughput diagnostic approaches, due to the higher risk of cross-contamination, higher cost, and being more laborious.” Here, a PCR assay is described that detects all genera of the Paramyxoviridae with a single set of primers without the requirement of nesting. This assay was shown to detect all known viruses within the Paramyxoviridae family tested. As the assay is implemented in a high-throughput format of fragment analysis, the test will be useful for the rapid identification of zoonotic and newly emerging paramyxoviruses.
In the last few years, a number of viruses have been found in association with enteric disease in cats. Many of them have been discovered serendipitously, using advanced molecular techniques to screen feline stool samples. The epidemiology of these newly discovered viruses is still largely unexplored, but several pieces of evidence suggest their possible role as primary causative pathogens or synergistic agents in feline gastrointestinal disease. In order to obtain a complete picture, each novel enteric virus should be included in the panel of pathogens for routine testing of cases of feline enteritis. Furthermore, large structured epidemiological studies and experimental infections might help to clarify any possible association with enteric diseases.
Interestingly, some of the viruses considered in this review have also been identified in the canine fecal virome, suggesting the possibility of inter-species circulation between the two carnivore species. Cats and dogs may harbor NoVs of the same genogroups and genotypes, GIV.2 and GVI.2. Binding of GVI.2 and GVI NoVs in dog tissues has been demonstrated to be mediated by the presence of the H and A antigens of the histo-blood group antigen (HBGA) family. Accordingly, it has been hypothesized that dogs and cats share a similar pattern of HBGAs as the attachment factor for NoV infections. Meanwhile, novel carnivore protoparvoviruses identical to each other in their capsid gene (>99.9% nt identity) have been found in stool and respiratory samples either in cats or dogs. Since a few aa mutations in the VP2 can modify the host range of FPV and CPV-2, it has been hypothesized that the novel carnivore protoparvovirus 2 has recently crossed the species barrier from a yet unidentified source, with a recent bottleneck event in the evolution of this virus in domestic carnivores.
The global distribution of cats and their close contacts with humans represents an additional reason to better understand the composition of their enteric virome. Historical evidence suggest that some feline viruses are potentially zoonotic. Infection of young children by rotavirus strains of feline origin has been documented in Italy and more recently, in Germany. The discovery of GIV.2 NoVs in cats and dogs genetically closest related to human GIV.1 NoVs has raised public health concerns about potential interspecies transmission between humans and pets. This eventuality has been demonstrated in a serosurvey performed in Italy on a collection of human serum samples, in which specific IgG antibodies against VLPs based on the lion GIV.2 NoV have been detected with prevalence ranging from 6.8% to 15.1% among different age groups. Furthermore, in a study conducted in Portugal, the presence of antibodies to GVI.2 NoV were found in 22.3% of the veterinarians and 5.8% of the control group, revealing for the small animal veterinarians an increased risk for exposure to this virus. Besides NoVs, the zoonotic potential is also suspected for other caliciviruses as the novel 2117-like vesiviruses (VeVs), firstly identified in dog stool samples in Italy. IgG antibodies against the canine 2117-like VeVs have been detected in 7.8% of Italian human sera and, more recently, the RNA of a 2117-like VeV was detected in the feces of a clinically healthy cat. Accordingly, understanding the ecology of novel enteric viruses in cats will be helpful also to assess more precisely if and to which extent pets may pose a risk of infection for humans.
There is a dual naming system for some HAstV species due to the simultaneous characterization of these viruses by different researchers; these viruses are termed VA/HMO named for VA—Virginia and HMO—Human-Mink-Ovine-like viruses, due to their genetic relatedness to previously characterized mink and sheep viruses. In 2009, VA2/HMO-A strains were detected in children with non-polio acute flaccid paralysis in Nigeria, Pakistan, and India. The prevalence of VA2/HMO-A viruses in stools ranges from 0.3% to 2.3%, with strains also detected in Egypt, Japan, USA, Kenya, and China. VA4 has only been detected in Nepal and the BF34 strain has only detected in Burkina Faso.
The first “non-classic” HAstV strain characterized was MLB1, the virus was detected in a stool sample from a 3 year old Australian child with acute diarrhea in 1999; the child had previously received a liver transplant. The majority of MLB1 strains characterized to date have been detected in India, Kenya, and Japan with limited detected in the USA, China, Bhutan, Egypt, Brazil, and Italy and prevalence has been reported in the range of 0.2% to 9%. However, a seroepidemiologic study in the USA revealed that primary exposure to MLB1 occurs in childhood and that seropositivity reached 100% by adulthood suggesting the widespread circulation of the virus in the human population. MLB2 viruses were first identified in Vellore, India with the majority of strains subsequently identified in Japan, The Gambia, and Switzerland with limited detection in Turkey, USA, Kenya, China, and Thailand and prevalence reported in the range of 0.3% to 1.5%. MLB2 has been associated with meningitis and other CNS complications and has been detected in immunocompromised children. MLB3 viruses were first detected in India in 2004, with subsequent detection in Kenya and The Gambia and the prevalence in stools ranges from 0.6% to 3.1%.
Influenza A viruses (IAV), members of the RNA family Orthomyxoviridae, have up to 144 subtypes according to the variation/combination of the surface glycoproteins hemagglutinin and neuraminidase. IAV are further classified to human influenza, swine influenza (SIV), bat influenza, equine influenza and avian influenza viruses (AIV). SIV and AIV transmit from swine or birds to humans, respectively, mostly via direct contact with infected animals. The infection in humans ranges from mild self-limiting respiratory-like illness to death.
Due to the very low pork production in Egypt, swine influenza is not a major ZD, although serosurveillance indicated infections of humans in 1979–1980. On the contrary, AIV are very important zoonotic viruses in Egypt. Poultry industry in Egypt was estimated in 2006 to be one billion birds with several millions of labors. In late 2005, the Asian highly pathogenic (HP) AIV of subtype H5N1 was firstly detected in wild migratory birds in a northern Egyptian wetland. In February 2006, the virus transmitted to domestic commercial and backyard birds and in March the first human case was recorded. To date, the virus is endemic in Egyptian birds causing tremendous economic impact despite the mass vaccination intervention strategy. Another AIV subtype is H9N2 which, in poultry, did not cause severe illness unless the infection is complicated by secondary bacterial infection or immunosuppression. The endemic H9N2 in Egyptian poultry was firstly detected in 2011 and vaccination is widely used to control the infection.
In humans, Egypt is the country with the highest recorded cases worldwide. The fatality rate in Egypt is lower than the global rate. Thus, lower virulence and subsequent adaptation of the virus in human has been assumed. Many mutations that enhance virus binding to mammalian type receptors have been studied. Subclinical infection in human has been reported as revealed by serological surveillance. Nevertheless, a recent study has shown that the virus has not yet acquired the aerogenic transmissibility as naïve ferrets cohoused with inoculated ferrets did not acquire infection. The Egyptian H5N1 viruses are highly susceptible to antiviral drugs (Oseltamivir), but are resistant to amantadine. Infection is usually acquired by intensive contact particularly with backyard birds. Women and children are mostly affected. To date, there are 3 human infections by H9N2 viruses reported to the WHO. Subclinical infection in poultry workers and co-infection of poultry and human with H5 and H9 in Egypt have been reported. Moreover, serosurvey revealed the presence of antibodies against H7 viruses in poultry and in humans, but no virus was isolated, so far.
Middle East Respiratory Syndrome (MERS) caused by a newly emerging coronavirus (CoV), designated lineage C of Betacoronavirus, in the RNA family Coronaviridae. It was firstly reported in Saudi Arabia in a patient with respiratory illness in 2012 and transmitted to several countries not only in the Middle East (ME) but also in Africa, Asia and Europe. The virus is usually transmitted from dromedary camels via direct contact or consumption of milk or medicinal use of camel urine. Also, bats and alpacas were considered reservoir hosts. However, limited human-to-human infections have been also reported. The infection can be mild or fatal in those patients with immune system disorders or chronic diseases.
In Egypt, out of 110 swabs and 52 serums collected in June–December 2013 from clinically healthy imported or locally reared camels in abattoirs, 4 and 48 positive samples were detected, respectively. Attempts to isolate the virus in cell culture were not successful. None of 179 samples collected from workers in these abattoirs were positive by RT-PCR. In another study, in June 2013, all serum samples collected from humans, cows, water buffaloes, goats and sheep were negative for MERS-CoV antibodies. Conversely, 94% of serum samples collected from dromedary camels were positive for MERS-CoV. From June 2014 to February 2016, 2541 sera, 2825 nasal swabs, 114 rectal swabs, 187 milk samples, and 26 urine samples were collected from camels in different sectors in Egypt (importation quarantines, markets, abattoirs, free-roaming herds and farmed breeding herds). Results revealed 71% seropositivity and 15% of other samples were positive by RT-PCR. Seroprevalence was 90% in imported camels and 61% in locally raised camels, likewise RNA detection rates were 21% and 12%, respectively. Both juveniles and adult camels were positive by 82% and 37% seropositivity and similar RT-PCR detection rates of 15% and 16%, respectively.
In humans, from 2012 to 2015, none of nasopharyngeal and oropharyngeal swabs collected from 3364 returning Egyptian pilgrims were positive for MERS-CoV. To January 2017, only one human case was reported from Egypt in April 2014.
Pigs have been implicated in several outbreaks of emerging infections. Starting in September 1998, clusters of human cases of encephalitis began to be reported from the Malaysian states of Perak and Negri Sembilan. By far the most extensive outbreak was in the village of Sungai Nipah near the city of Bukit Polandok. Almost all of the cases had a direct link to the local piggeries, and coincided with accounts of illness amongst pigs 1 to 2 weeks beforehand. A total of 265 cases were notified, with mortality approaching 40%. In March 1999, infection developed in 11 Singaporean abattoir workers handing pig carcasses, one of which proved fatal. Initially these outbreaks were believed due to Japanese encephalitis (JE), but a number of cases had been vaccinated previously against JE virus and there was no evidence of JE virus antibodies among the remainder. The link with Hendra virus soon followed after the isolation of virus from an infected pig farmer. The new agent, now named Nipah virus after the locality it was first reported, shares 80% sequence homology with Hendra virus, with both viruses now being regarded as members of the henipaviruses within the Paramyxoviridae family. It is clear that Nipah virus is widely distributed across Northeast India, Bangladesh and Southeast Asia, with phylogenetic analyses revealing the virus to be diverging within specific geographical localities.
Since Balayan et al.27 first showed that pigs could be infected with hepatitis E virus (HEV), there has been interest in the zoonotic potential of this agent, especially in rural areas of the Indian Subcontinent where a high mortality rate is frequently observed amongst pregnant women. HEV appears ubiquitous in pigs and poultry, regardless as to whether there is evidence of infection in the local community. Pigs become infected around 3 months of age but suffer only a mild, transient infection.
The worldwide distribution of infected pigs means there is ample opportunity for transmission, especially in Southeast Asia where most pigs are kept in family smallholdings. Antibody prevalence as a result is higher than compared to the general population, for example Hsieh et al.28 found 27% of Taiwanese pig handlers were seropositive, compared to 8% in the general population. Swine had become infected by the fecal–oral route, with pig feces containing large quantities of virus. It is not clear whether humans have been directly infected via this route or if there is a common source or reservoir.
Cross-species transmission is likely to be dependent upon genotype: most swine isolates are genotype 3 or 4 whereas the majority of human infections are of genotype 1 and 2. Pigs are not alone in being susceptible to HEV, with various reports of rats, lambs, dogs, cats, goats, cattle and chickens also being susceptible. Chicken isolates are only 62% identical in genome sequence with human and swine isolates leading to the suggestion that HEV in poultry may represent a distinct genus.29 As with swine HEV, serological studies have shown that approximately 70% of poultry flocks in the United States are infected with HEV.30 There is no evidence of transmission from poultry to humans, but of course this could change, especially since work so far has shown isolates are genetically heterogeneous and thus adaptation could readily occur.
Swine in the Philippines have been found to act as reservoirs for Reston virus, a filovirus related to Ebola and Marburg viruses. This was discovered during an unusually severe outbreak of porcine reproductive and respiratory syndrome. Reston virus was first identified in 1990 among non-human primates imported from the Philippines to several primate handling facilities in the United States and Europe, but in contrast to its African relatives Reston virus does not appear to cause human illness, although there is ample evidence of Reston viral antibodies in primate holding facilities31 and among those working with swine.32
Pigs are susceptible to human, avian and swine influenza viruses, and thus play an important role in the epidemiology of human influenza. Influenza A virus is one of the comparatively few viral respiratory pathogens of pigs. Currently, three subtypes circulate in swine: H1N1, H1N2 and H3N2. In contrast to human influenza, the properties of swine influenza differ from region to region. The predominant subtype in Europe is of avian origin, most likely introduced into pigs in 1979 from wild aquatic birds, such as ducks. In contrast, there are two distinct subtypes circulating in North America, the classical H1N1 subtype introduced into pigs shortly after the 1918 human pandemic, and the second a reassortment between H1N1 with either H3N2 or H1N1 viruses.
Domesticated pigs have often been regarded as a mixing vessel for influenza viruses and reassortment of the seven viral gene segments presenting an opportunity for new human strains to arise. Until 2009, however, swine influenza was not regarded as a significant cause of serious disease in humans. Cases of human infection began to emerge towards the end of April 2009 in what is normally regarded as the influenza season in the northern hemisphere. Beginning first in Mexico, the new virus subtype often referred to as “swine flu” by the popular press, spread rapidly throughout the world in a matter of weeks.
Analyses of human isolates quickly showed the unusual nature of this swine-origin influenza virus as being a triple reassortment virus containing genes from avian, human and “classical” swine influenza viruses. The ancestors of this virus had probably been circulating in pig populations for over 10 years but had remained undetected.33 At the time, there was considerable uncertainty as to the pathogenic potential of this virus but data soon showed the severity for humans to be less than that seen with the 1918 pandemic but on a par with the 1957 “Hong Kong” pandemic. Transmissibility appeared higher than is normally the case for seasonal influenza with a higher than normal attack rate. Importantly, younger age groups appeared more susceptible, possibly due to partial immunity among older cohorts as a result of being infected during previous pandemics.
Infectious diseases have been emerging and reemerging over millennia. Human immunodeficiency virus (HIV), severe acute respiratory syndrome coronavirus (SARS-CoV), and the most recent 2009 pandemic H1N1 influenza virus are only a few of many examples of emerging infectious pathogens in the modern world. Each of these diseases has global societal and economic impact related to unexpected illnesses and deaths, as well as interference with travel, business, and daily activities. To overcome emerging, reemerging, as well as stable infectious diseases, the demand for development of efficient vaccines has greatly increased. Historically, live attenuated vaccines have provided the most effective protection against viral infection and disease. However, there have been safety concerns with the risk of reversion to the wild-type pathogen phenotype as shown with some traditional live attenuated vaccines such as the polio vaccine. Furthermore, development of live attenuated vaccines has not been successful for many important pathogens. On the other hand, inactivated vaccines are generally not very effective and require a high containment laboratory for cultivation of highly virulent pathogens. Also, there is a risk of incomplete inactivation for inactivated vaccines. Therefore, there is a need for an alternative approach for development of vaccines.
Replicating viral vector vaccines offer a live vaccine approach without requiring involvement of the complete pathogen or cultivation of the pathogen. Replicating viral vectors have the ability to synthesize the foreign antigen intracellularly and induce humoral, cellular, and mucosal immune responses. Specifically, vectored vaccines can have advantages for (i) viruses for which a live attenuated vaccine might not be feasible (i.e., HIV); (ii) viruses that do not grow well in vitro (i.e., human papillomavirus, hepatitis C virus, and norovirus); (iii) highly pathogenic viruses that present safety challenges during vaccine development (i.e., SARS-CoV and Ebola virus); (iv) viruses that lose infectivity due to physical instability (i.e., respiratory syncytial virus (RSV)); and (v) viruses that can exchange genes with circulating viruses (i.e., coronaviruses, influenza viruses, and enteroviruses). A vectored vaccine can be rapidly engineered against a newly emerging pathogenic virus by inserting the gene of the protective antigen of the virus into the genome of the viral vector. In general, the magnitude of the immune response to live viral vector vaccines is substantially greater and broader than that induced by vaccines based on subunit proteins or inactivated viruses. Furthermore, manufacturing of vectored vaccines against highly pathogenic viruses do not require a high level of biosafety containment laboratories.
Newcastle disease virus (NDV) is a fast-replicating avian virus that is prevalent in all species of birds. In most avian species, NDV infections do not result in disease. In chickens, NDV causes a highly contagious respiratory and neurologic disease, leading to severe economic losses in the poultry industry worldwide. NDV strains vary widely in virulence. Based on the severity of the disease in chickens, NDV strains are classified into three pathotypes: lentogenic strains which cause mild or asymptomatic infections that are restricted to the respiratory tract; mesogenic strains which are of intermediate virulence; and velogenic strains which cause systemic infections with high mortality. Naturally occurring low-virulent NDV strains, such as LaSota and B1, are widely used as live attenuated vaccines to control Newcastle disease in poultry. Although NDV primarily infects avian species, many non-avian species have also been shown to be naturally or experimentally susceptible to infection. The advent of a reverse genetics system to manipulate the genome of NDV not only allowed us to study the molecular biology and pathogenesis of NDV but also to develop NDV as a vaccine vector against diseases of humans and animals. NDV vector has several advantages over other replicating viral vectors.
Avirulent NDV strains are highly safe in avian and non-avian species. NDV replicates well in vivo and induces a robust immune response. In contrast to adeno, herpes, and pox virus vectors whose genome encodes a large number of proteins, NDV encodes only seven proteins and is thus less competition for immune responses between vector proteins and the expressed foreign antigen. NDV replicates in the cytoplasm, does not integrate into the host cell DNA, and does not establish persistent infection. Recombination involving NDV is extremely rare. NDV has a modular genome that facilitates genetic manipulation. NDV infects via the intranasal route and therefore induces both mucosal and systemic immune responses. A wide range of NDV strains exists that can be used as vaccine vectors. NDV-vectored vaccine can also be used as a “differentiating infected from vaccinated animals” (DIVA) vaccine. In this review article, we have reviewed the biology of NDV, development of reverse genetic systems for generation of NDV-vectored vaccines, and use of NDV vector for development of human and veterinary vaccines.
FRZ and HYC designed the experiments. XY, DHZ carried out the test. PW,CGL and FRZ drafted the manuscript. All authors have read and approved the final manuscript.
Occupational medicine professionals are uniquely positioned to provide information on the potential impact of a pandemic influenza. Indeed, infectious disease may disproportionately impact the occupational environment. This is due to factors associated with transmission such as the proximity of co-workers to one another in the workplace, during the daily commute to work, or simply dealing face to face with customers. Of particular concern is the health and safety of those health care professionals caring for infected patients. The recent experience with Severe Acute Respiratory Syndrome (SARS) provides some useful insight into the consequences of a novel infection on a modern society and more specifically on the health care community.
There are many similarities between the SARS epidemic and the anticipated experience with avian influenza. Both have been associated with food and animals. In the early stages of SARS, more than a third of infected humans were food handlers, and it was later inferred that the SARS coronavirus had originated in civet cats, and that the first transmission of infection to humans may have occurred in those workers handling civet cats. However, the greatest impact of SARS was subsequently felt in health care workers where they were estimated to have accounted for over 20% of total SARS cases in Singapore and 40% in Canada. Thus, not only are individuals working closely with infected animal hosts at risk for first line crossover transmission of an emerging virus but they are also at risk of acquiring the virus from coworkers, or in the case of health care professionals, from patients.