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Influenza A (H5N1) virus is susceptible to Oseltamivir (Tamiflu) and Zanamivir (Relenza)70 but is resistant to Amantadine and Rimantadine.71,72 Treatment should be started within 48 hours of onset of fever, without waiting for laboratory confirmation.73,74 Mild cases are treated. A higher dose of 150mg twice daily and treatment for 7 to 10 days is required for the treatment of severe infections. Salicylate administration should be avoided in children younger than 18 years to prevent the possibility of Reye's syndrome. The effectiveness of Zanamivir in reducing the severity and duration of illness and in preventing complications has been proven in children from 5 to 12 years old.75
Anti-viral drugs are thought to be backbone of a management plan of an avian flu pandemic. Only two anti-viral drugs have shown promise in treating avian influenza: oseltamivir (Tamiflu®) and zanamivir (Relenza®). A treatment of Tamiflu® includes 10 pills taken over five days while Relenza® is administered by oral inhalation. The US Food and Drug Administration has approved both anti-viral drugs for treating influenza but only Tamiflu® has been approved to prevent influenza infection. Because antivirals can be stored without refrigeration and for longer periods than vaccines, developing a stockpile of antivirals has advantages as part of an overall strategy to control a flu epidemic. However, there are limitations to the use of antivirals: Tamiflu® needs to be taken within 2 days of initial flu symptoms for it to be effective, but many people may not be aware that they have the flu early in the disease. Some research in animals and recent experience in the use of the drug to treat human cases have also found that Tamiflu may be less effective against the recent strains for the current H5N1 virus than the 1997 strain. Improper compliance to antivirals by irresponsible individuals during an outbreak may results in the emergence of a drug-resistant strain. Lastly, there are current concerns about the safety of Tamiflu® which has been associated with increased psychiatric symptoms among Japanese adolescents.
Another potential preventive strategy for influenza is the use of antivirals either prophylactically or for early treatment. Currently, the most effective anti-influenza drugs are the neuraminidase inhibitors (NIs: oseltamivir, zanamivir and peramivir).49 M2 inhibitors (amantadine and rimantadine) are rarely used since they suffer from rapid development of virus resistance and virtually all currently circulating seasonal influenza A viruses have pre-existing resistance.50 Furthermore, M2 inhibitors do have considerable side effects and are not effective against influenza B viruses. Although influenza viruses can develop resistance to individual NIs quite rapidly, the risk of resistance development to the whole class of drugs is unlikely and lower than with M2 inhibitors, illustrated by the fact that virtually no cross resistance to oseltamivir and zanamivir has been identified.51 For travellers, the NIs may play a role in both pre- and post-exposure prophylaxis, with confirming data coming from both animal models (mouse and ferret) and human trials.52 NIs provide protective efficacy when used preventively in an outbreak situation, or soon after the first clinical symptoms, by reducing the duration and severity of symptomatic influenza.53,54 Furthermore, several 2009 pandemic period observational studies suggest that early treatment can reduce rates of hospitalisation and in-hospital mortality.55 Some consider the use of NIs controversial because almost all published studies have been industry-funded, and the reported effects are generally minor and there have been no large randomized control trials proving efficacy for post-exposure treatment.53,54 However, a recent independent meta-analysis showed that oseltamivir in adults with influenza accelerates clinical symptom alleviation, reduces risk of lower respiratory tract complications, and admission to hospital, while increasing the occurrence of nausea and vomiting.56
Although NIs have relatively mild side effects, their cost and modest efficacy suggest they should play only a limited role in routine pre-travel advice. However, elderly or other high-risk groups in which vaccine efficacy can be low, could be advised to consider bringing a NI for influenza early treatment, if access to medical care at the destination will be limited. Especially since in many countries NI requires a medical script to be purchased and may not be readily available resulting in an unnecessary delay. These drugs could also play a role in mass transportation settings like cruises or group travel. The use of NIs does lead to reduction in disease duration—if used within 48 h after first symptoms—about 1 day—and to reduction in disease severity, although this has been also a matter of debate.46 In specific cases, such reductions may be crucial: e.g. athletes, politicians, scientists and those travelling for business.57 The prophylactic use of NI decreases the chance of being infected.57 To our knowledge, and in light of the recent Olympics in Rio de Janeiro and upcoming sport events, NIs are not currently listed as prohibited substances by the World Anti-Doping Agency (WADA) [https://www.wada-ama.org/en/what-we-do/prohibited-list (26 October 2016, date last accessed)].
The CDC currently suggests that patients infected with avian influenza should be treated with oseltamivir or zanamivir. Furthermore, the curative use of NIs is recommended as early as possible, preferably within 48 h, for patients hospitalized with confirmed or suspected influenza, with severe, complicated, or progressive illness or at high risk for influenza-associated complications (e.g. children <2years, adults ≥65years, nursing home residents, individuals with major co-morbidities) according to CDC guidelines (www.cdc.gov/flu/professionals/antivirals/summary-clinicians.htm). Currently, oseltamivir is FDA registered for influenza treatment for any age and as chemoprophylaxis from 3 months of age. Age cut-offs for zanamivir use are currently 7 and 5 years, respectively. Prophylactic dosing with chloroquine—known to have some non-specific antiviral efficacy in vitro—did not translate into clinical protection in a large randomized controlled community trial during the H1N1 outbreak in 2009 and therefore does not seem to have a role in travel medicine regarding influenza prevention.58
Several studies have addressed the effectiveness of non-pharmaceutical interventions (NPIs) in reducing influenza virus spread, especially in the case of a pandemic. For seasonal influenza, most attention has been focused on hand hygiene and the use of facemasks. These NPI’s may be especially important when someone in the immediate environment or a travel companion is infected.38 For instance, careful hand hygiene and the use of facemasks appear to reduce household transmission of influenza virus when implemented within 36 h of symptom onset of the index patient.39 The general utility of hand hygiene and facemasks in reducing influenza spread has been confirmed by a recent meta-analysis40 although the quality of the data in many studies, particularly when children are involved, is relatively poor.41 Furthermore, in studies that focus on scenarios in which there is active, on-going influenza transmission in the population, like during a pandemic, large variation in effectiveness of these NPIs has been observed. Despite these limitations, there seems to be sufficient evidence to conclude that facemasks, hand hygiene and reduced crowding are effective in reducing the spread of influenza.42 Hand hygiene would be relatively simple for travellers to implement and several studies suggest that the use of alcohol based sanitizers and hand washing after touching contaminated surfaces can be effective.43,44
However, these trials were not conducted in travellers. Facemask usage in travellers is particularly controversial and may only have measurable impact when a close companion (i.e. shared living quarters) is infected.45 In mass gatherings, there seems to be a (very) modest decrease in risk of infection in persons using facemasks.46 Furthermore, the overall effectiveness of masks and respirators is likely dependent on consistent and correct usage.47 In this light, it is important to note that up to 40% of influenza cases may be transmitted prior to the onset of symptoms.48
Severely ill EHF patients require intensive supportive care, which is the mainstay of therapy.19 In October 1, 2014, 2 candidates for EHF vaccines had clinical-grade vials available for phase-1 clinical trials. One of these formulations was cAd3-ZEBOV (GlaxoSmithKline, Raleigh, SC, USA) and recombinant vesicular stomatitis virus - Zaire ebolavirus (rVSV-ZEBOV) (Public Health Agency in Winnipeg, Canada). A series of coordinated phase-1 trials will be initiated in more than 10 sites in Africa, Europe, and North America.25 Although no approved specific therapy is currently available in the treatment of EHF, several drugs such as brincidofovir, favipiravir, and ZMapp are under investigation for EHF. In the current outbreak, convalescent blood and plasma therapies have been used in a few patients. The numbers are too small to draw any conclusions on their efficacy.26
All participating patients were treated by twice daily oral administration of 75 mg oseltamivir. Patients were also given antibiotics based on blood and/or throat-swab specimens/sputum tests for bacterial infections. If no specific bacterial pathogens were detected from the specimens, advanced treatment was considered. Antibiotics given to H7N9-infected patients if applicable included moxifloxacin, sulbactam and cefoperazone, levofloxacin, meropenem, piperacillin, imipenem, and cilastatin. Some patients also received glucocorticoid therapy, intravenous immunoglobulin therapy, and TCM therapy. Only Chinese herbs prescribed according to specific syndromes were considered TCM in this study. Proprietary Chinese medicines and injections of Chinese medicines were excluded because they could contain certain western drug ingredients. These herbal TCMs were prescribed following group discussions of TCM experts from Longhua Hospital, Shanghai University of TCM, Department of TCM of Zhongshan Hospital, Fudan University, and XR Chen in our hospital. Based on syndrome differentiation criteria from Wei-Qi-Ying-Xue and clinic programs of influenza A H7N9 implemented by the National Health and Family Planning Commission of P. R. China, Yinqiao Powder and Hoisting Powder were prescribed for patients with mild syndromes and Qingwen-Baidu-Decoction was prescribed for critically ill patients. TCMs were taken orally twice daily at 150 ml decoction per dose. The purchase, decoction, and administration of Chinese herbs were supervised by Pharmacy Department of TCM in Shanghai Public Health Clinical Center.
NDV vaccine strains show promise as a base from which to develop effective vaccines against pathogens that infect animals and humans. Most NDV-vectored vaccines used for poultry are bivalent and provide protective efficacy against virulent NDVs and several foreign pathogens. NDV-vectored poultry vaccines have been developed to provide protection against HPAIV (A/H5 and A/H7), IBDV, ILTV, IBV, and aMPV. Safe NDV-vectored vaccines have been developed as antigen delivery vaccines for veterinary and human use. Such vaccines express the foreign target antigen and induce robust immune responses at both the local and systemic level as shown with NDV-vectored veterinary vaccines in cattle/sheep (e.g., BHV-1, BEFV, RVFV, and VSV), dogs/cats (e.g., CDV and RV), pigs (e.g., NiV), and horses (e.g., WNV). NDV-vectored human vaccines currently under development aim to provide protection against HIV, HPIV-3, and RSV, newly emerging zoonotic viruses (e.g., HPAIV A/H5, SARS-CoV, EBOV, and NiV), and noncultivable human viruses (e.g., human papillomavirus, hepatitis C virus, and NoV). A primary vaccination by an NDV-vectored vaccine expressing a foreign protein can be effective but the efficacy of an updated or new vaccine based on the NDV vector may be reduced by pre-existing NDV antibodies, which could limit the continuous use of NDV vector vaccines in human.
In conclusion, NDV vaccine strains are attractive vectors that can be used to develop effective vaccines against pathogens that infect animals and/or humans; such vaccines are safe and efficient, and provide high levels of protective immunity, although there is a risk that previous vaccinations can reduce the efficacy of the vectored vaccine.
The HACCP framework enables the identification of risks within a system and the design of control methods. It does not contain the scope for monitoring or ensuring compliance of the control points identified; such control should be applied via other means. Given that EIDs are appearing with increasing frequency, often in countries where they place additional strain on already over-burdened public health and healthcare systems, being able to rapidly identify and design strategies for control has valuable application in responding to emerging health threats such as the Middle East Respiratory Syndrome (MERS) virus which first appeared in Saudi Arabia in late 2012 or the rapidly spreading outbreak of a novel avian influenza A H7H9 in China since March 2013. Conducting detailed, timely and comprehensive field investigations into HPAI H5N1 outbreaks is hampered by the majority of cases occurring in developing countries. Advantages to such a framework are that it requires minimal resources and can be implemented by local health officials and international expertise, if required, can be provided remotely. It also complements recently developed diagnostic statistical models for known pathogens. Subsequent detailed and time-consuming experimental analyses can then be conducted if required. Whereas in-depth epidemiological studies can take weeks or months to produce results and recommendations the HACCP framework may provide a means of producing a response within days of an outbreak occurring.
This study protocol was reviewed and approved by the Institutional Review Board at the Guangdong Center for Disease Control and Prevention.
Bivalent NDV-vectored vaccines, which have been developed to prevent diseases of economic importance to the poultry industry, have advantages over traditional vaccines (Table 3). Examples include infectious bursal disease virus (IBDV), infectious bronchitis virus (IBV), infectious laryngotrachitis virus (ILTV), and avian metapneumovirus (aMPV).
IBDV, a birnavirus that infects chickens, is an important pathogen that causes severe immunosuppression and high mortality in young chickens. Live attenuated vaccines of moderate virulence (especially widely used intermediate plus vaccines) are used widely to prevent infectious bursal disease (IBD); however, they can cause severe side effects (symptoms consistent with IBD) in young chickens. Huang et al. developed a NDV-vectored IBDV vaccine (rLaSota/VP2) expressing the VP2 gene of IBDV, which is responsible for protective immunity against IBDV. The VP2 gene is inserted into the 3'-end non-coding region of the NDV genome. The live IBV vaccine is very safe in young chickens and protects SPF chickens against virulent NDV and virulent IBDV.
IBV, a coronavirus that infects birds, causes respiratory disease and renal disorders (the nephropathogenic strain) in poultry and poor egg production in laying hens worldwide. Currently available live attenuated IBV vaccines risk giving rise to new variants through recombination with field IBVs. This often reduces the efficacy of IBV vaccines. Importantly, live IBV vaccines interfere with the live attenuated NDV vaccine. To overcome the limitations of currently available live vaccines, Toro et al. developed a NDV-vectored IBV vaccine (rLS/IBV.S2) expressing the S2 subunit of the IBV S glycoprotein. Oculo-nasal immunization of chickens (1.0×107 EID50/dose) provided complete protection from clinical disease (mortality) after challenge with a lethal dose of virulent NDV (CA02). The protective efficacy of the rLS/IBV.S2 vaccine was also assessed using a heterotypic protection approach based on priming with a live attenuated IBV Mass-type vaccine followed by boosting with rLS/IBV.S2. The vaccine protected chickens against clinical disease after lethal challenge with a virulent Ark-type IBV strain, leading to a significant reduction in virus shedding when compared with that in unvaccinated/challenged chickens.
ILTV, a herpesvirus that infects birds, causes respiratory disease in chickens. Currently available live attenuated ILTV vaccines are effective, but there are concerns about safety in chickens because of the risks of virulence acquirement and latent infections during bird to bird transmission. Bivalent NDV-vectored vaccines against ILTV have been developed to overcome side effects associated with the live ILTV vaccine. Kanabagatte Basavarajappa et al. developed a NDV-vectored ILTV vaccine (rNDV gD) expressing glycoprotein D (gD) of ILTV. The protective efficacy of the rNDV gD vaccine against challenge with virulent ILTV and virulent NDV was then evaluated in SPF chickens. Immunizing chickens with rNDV gD (106 TCID50/dose) via the oro-nasal route induced a strong antibody response and provided a high level of protection against subsequent challenge with virulent ILTV and NDV, indicating that rNDV gD has potential as a bivalent vaccine.
The sponsor of the study had no role in the study design, data collection, data analysis, data interpretation, writing of the report, or the decision to publish. The corresponding author had full access to all the data in the study and had final responsibility for the decision to submit for publication. The views expressed are those of the authors and do not necessarily represent the policy of the China CDC or the institutions with which the authors are affiliated.
The current danger to people from avian influenza has been recognized. The World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) have adopted measures to prevent the emergence of avian influenza in Asia and control its wider transmission.54 The CDC's response has been focused on enhancing surveillance and laboratory testing for human avian influenza (Table 2).55
The Chinese government also exerts great importance on the prevention and control of avian influenza. The Chinese Center for Disease Control and Prevention has published interim guidelines to limit the possibility of human infections during outbreaks of avian influenza in domestic birds and poultry in Mainland China.56-59 In addition, the Chinese government has taken a series of concrete measures in this regard:
First, the Chinese Ministry of Public Health has formulated a series of clinical management measures for human influenza A (Table 3).60-67
Secondly, China established a national command headquarters in January 2004, headed by the Vice Premier, in order to oversee the response to avian influenza.68 These command headquarters have formulated medium- and long-term measures, shown in Table 4.69
The WHO Vaccine Composition Meeting for the 2014-2015 season held in February 2014 in Geneva approved that A/California/7/2009 (H1N1)pdm09-like virus, A/Texas/50/2012 (H3N2)-like virus, and B/Massachusetts/2/2012-like virus should be included in the trivalent vaccine formulation in the Northern Hemisphere.52 Consequently, the aforementioned novel avian strains are out of scope of the current vaccine formulation indicating the severity of the situation if the H7N9 influenza has global dissemination.
Laboratory testing in preliminary cases showed that neuraminidase inhibitors (oseltamivir, zanamivir) were effective against H7N9 infections, but the adamantanes were not. In addition, early treatment with neuraminidase inhibitors have been reported to restrict the severity of illness.34,53
In the words of the late Director General of World Health Organization, Dr Lee Jong Wook, '"it is only a matter of time before an avian flu virus acquires the ability to be transmitted from human to human, sparking the outbreak of human pandemic influenza...we don't know when this will happen but we do know that it will happen". Factors that suggest that an AI pandemic would be less severe than past influenza pandemics include advances in medicine such as the availability of antiviral medications and vaccines, and international surveillance systems. However, there are also factors that suggest than an avian influenza pandemic could be worse than the 1918 pandemic, such as a more densely populated world, a larger immunocompromised population of elderly and AIDS patients, and faster air travel and interconnections between countries and continents which will accelerate the spread of disease. Nevertheless, unlike the past, we have the prior knowledge of a possible impending pandemic and the knowledge of how to contain and control it. Preparedness, vigilance and cooperation, on local, national and international levels, are our best weapons against a deadly bird flu pandemic.
There were several zoonotic influenza strains that infected poultry and human during the past decade in Taiwan (Figure 2). In April 2009, a new strain of H1N1 from Mexico was found to be a novel strain of influenza for which current vaccines against seasonal flu provided little protection. This new H1N1 strain resulted from a reassortment of bird, swine, and human flu viruses. In June 2009, the WHO declared the outbreak of a pandemic which was named as pandemic H1N1/09 virus (pdmH1N1) in July 2009. It is possible that the virus has been circulating in human population since some time in the past and had not been detected.
The first case of H1N1 detected in Taiwan was confirmed on May 20, 2009, and another 9 positive cases in a row were identified within a week. The pdmH1N1 virus was isolated in late May 2009, causing a community outbreak in early July and then spreading islandwide. Taiwan CDC provided free seasonal influenza vaccine started from October; people received their vaccination at over 3,500 contracted hospitals and clinics. Then the Taiwan government approved an inactivated vaccine with influenza A/California/7/2009 (H1N1) strain known as AdimFlu-S (Adimmune Corporation, Taichung, Taiwan) and initiated mass vaccinations in November. Free AdimFlu-S vaccines were provided giving the priority to schoolchildren, the elderly, and front-line healthcare personnel. Due to the delay in vaccine development and delivery in 2010, health authorities used both vaccination and school closure to control pdmH1N1 [22–24]. Overall, the vaccine coverage rates were 76.9% for children and 24.6% for civilians in late July 2010 [22, 24, 25].
Confirmed case of pdmH1N1 influenza virus infection in Taiwan is defined as an individual with laboratory-confirmed pdmH1N1 influenza virus infection by one or more of the following tests: (1) real-time reverse transcriptase-polymerase chain reaction (RT-PCR), viral culture, or fourfold rise in pdmH1N1 influenza virus-specific neutralizing antibodies; (2) viral culture and (3) RT-PCR which can reliably identify the presence of pdmH1N1 influenza virus in specimens, especially RT-PCR, which has the highest sensitivity and specificity. With RT-PCR, pdmH1N1 influenza virus will test positive for influenza A and negative for seasonal H1 or H3. Meanwhile, commercially available rapid influenza diagnostic tests (RIDTs) detect influenza viral nucleoprotein antigen and are capable of providing results within 30 minutes. The sensitivity of RIDTs for detecting pdmH1N1 influenza varied from 10% to 70% and is directly related to the amount of virus in the specimen but inversely related to the threshold cycle value of the test. Rapid tests for influenza may detect the antigen from either influenza A or B in respiratory specimens with a high specificity (>95%), but the negative result from a rapid test does not rule out influenza infection, and most of rapid tests cannot distinguish pdmH1N1 from H3N2 influenza A viruses.
The oseltamivir-resistant pandemic influenza A (H1N1) virus strain in Taiwan was first isolated from a 20-year-old male in October 2009. The H1N1 virus isolated before the patient received oseltamivir treatment was sensitive to oseltamivir. However, three days after initiation of treatment, the virus isolated from the same patient shows a mutation involving the substitution of a histidine for tyrosine at position 275 (H275Y), which is resistant to oseltamivir. Oseltamivir treatment was not associated with statistically significant reduction in the duration of viral shedding, thereby proving ineffective in preventing viral spread in community. The role of swine in the genesis of this pandemic was again apparent. The lesson learned is that the pandemics of influenza can arise anywhere in the world and that global surveillance is merited.
Influenza A viruses (Family Orthomyxoviridae) impose a large burden on both human and animal health worldwide. Influenza A viruses can be categorised into different subtypes based on genetic and antigenic differences in the two surface glycoproteins of the virus, the haemagglutinin (HA) and neuraminidase (NA). Wild waterfowl and shorebirds are the natural reservoirs of influenza A virus and can be infected with viruses harbouring combinations of 16 different HA subtypes and nine different NA subtypes. Recently, two novel influenza A virus subtypes (H17N10 and H18N11) have been identified in rectal swabs collected from the little yellow-shouldered bat [Sturnira lilium] and the flat-faced fruit-eating bat [Artibeus jamaicensis planirostris],,. Influenza viruses of this subtype have not been isolated from any other animal order and it is unknown whether these viruses might be able to cross the species barrier. In contrast, there is significant inter-species transmission of influenza viruses from waterbirds, such that animals ranging from domestic poultry to humans can also become infected. Accordingly, infection with influenza virus has wide-reaching ramifications. For example, whilst some influenza virus strains are largely asymptomatic in chickens (and are hence referred to as low pathogenic avian influenza [LPAI] viruses) others cause severe disease in chickens that is often fatal within 48 h (and are hence referred to as highly pathogenic avian influenza [HPAI] viruses). Outbreaks of HPAI viruses can cause devastation for the poultry industry resulting in the mass slaughter of millions of birds. Similarly, outbreaks of influenza viruses amongst thoroughbred horses have disrupted numerous race meetings and resulted in the death of infected horses. In humans, seasonal influenza viruses are a significant cause of morbidity and mortality and constitute an economic burden of $10.4 billion dollars per year in the U.S.A. alone. The diversity and complexity of influenza virus infections across so many different animal species suggests that a one-health approach is the only comprehensive way to reduce the burden of disease. Here, we seek to highlight how influenza viruses spread from their natural avian hosts to mammals, and what the virus needs to overcome in order to ensure the success of these inter-species transmission events. We highlight the consequences that this inter-species transmission has, not only for human health, but also for the health of wild animals and the success of industries such as poultry farming.
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.
To evaluate the efficacy of multivalent DNA vaccines, initial studies were performed in mice. Expression vectors encoding HAs from ten phylogenetically diverse strains of influenza viruses were generated by synthesis of cDNAs (see Materials and Methods) in plasmid expression vectors, pCMV/R or pCMV/R 8κB, which mediates high level expression and immunogenicity in vivo
,,. Animals were immunized with each expression vector intramuscularly (IM) at three week intervals, and the antisera were evaluated on day 14 after the third immunization for their ability to neutralize HPAI H5N1 pseudotyped lentiviral vectors as previously described,. We have previously shown that lentiviral assay inhibition (LAI) yields similar results to microneutralization and HAI analyses with higher sensitivity in mice,. Significant neutralizing antibodies generated to homologous HAs were detected consistently by LAI with few exceptions, while cross reactivity to a standard isolate, A/Vietnam/1203/2004, was variable. For example, IC90 titers exceeding 1∶800 were observed against A/chicken/Nigeria/641/2006 and A/Hong Kong/156/1997, while a lesser response was detected for the A/chicken/Korea/ES/2003 strain (Fig. 1). Heterologous neutralization to A/Vietnam/1203/2004 was variable and did not fully correlate with the degree of relatedness of the specific HA. The ability of these immunogens to generate robust cross-reactive antibodies is consistent with previous observations,,.
Influenza viruses comprise 4 types: A, B, C, and D. Influenza A viruses are further classified into subtypes on the basis of the characteristics of the 2 main surface glycoproteins, hemagglutinin (HA) and neuraminidase (NA), and numbered accordingly. While only 2 influenza A virus subtypes (H3N2 and H1N1pdm09) are circulating among humans, the natural reservoir for nearly all influenza A viruses is wild waterfowl. Of the 18 HA and 11 NA influenza A virus subtypes, all but H17N10 and H18N11 viruses have been identified in birds. Some influenza A viruses circulate among pigs, and others have been identified in a wide number of animal species.
Only influenza A viruses cause seasonal influenza epidemics and rare pandemics among people. Influenza B viruses can cause seasonal epidemics, influenza C viruses typically cause mild respiratory illness and do not cause epidemics, and influenza D viruses primarily affect cattle and are not known to cause illness in people.9
Novel influenza A viruses refer to viruses of animal origin that have infected humans and that are antigenically and genetically distinct from seasonal influenza A viruses circulating among people. We closely monitor novel influenza A viruses, because influenza A viruses continue to evolve and because zoonotic transmission could herald an increasing pandemic influenza health threat. If a novel influenza A virus acquires the ability for sustained human-to-human transmission, a pandemic can result. Accordingly, early detection of pandemic-potential viruses may aid in the control and possible prevention of the next pandemic. Although a swine-origin influenza A virus caused the 2009 H1N1 pandemic,10,11 and sporadic transmission of swine-origin influenza A viruses to humans (termed “variant viruses”) continue to be detected in the United States and in other countries with appropriate laboratory capacity, the public health threat posed by avian influenza A viruses appears to be higher because of their diversity and wide circulation among birds worldwide; the birds' migratory flyways may also be conducive to spread of influenza A viruses. Furthermore, some previous pandemic influenza A viruses have been partly of avian origin.11
Polio’s most visible current-day legacy is the permanently paralyzed victims on the streets of affected countries worldwide. In 1988, the World Health Assembly resolved to eradicate polio and as a result the global incidence of polio associated with wild polioviruses decreased from an estimated 350,000 cases in 1998 to 1,997 cases in 2006, and subsequently to 222 cases reported as of January 22, 2013 (symptom onset during 2012, reported in January 2013) (28,29). The number of countries that continue to have endemic circulation of polio has been reduced to three: Pakistan, Afghanistan, and Nigeria. Although transmission of types 1 and 3 polio continue to be reported, albeit in declining numbers, wild type 2 polio virus circulation was last reported in October 1999 (30) from Aligarh, Western Uttar Pradesh, India (31). The elimination of type 2 polio was a milestone for the Global Polio Eradication Initiative, which allowed strategies to focus on the eradication of poliovirus types 1 and 3 (30,32). In December 2011, the CDC Director activated the CDC Emergency Operations Center for the final push toward eradication. Eradicating the final 0.06% of polio is likely to be the greatest challenge. In the GDD Operations Center we monitor not only countries with endemic circulation, but also countries that report imported cases, which during 2012 was limited to Chad (28). Figure 2 shows CDC’s international responses to requests for assistances by countries experiencing cases or outbreaks of polio from January 2007 to August 2012, as reported to the GDD Operations Center. The importance of monitoring polio infections is critical now and will continue to be paramount in the post-eradication era, as even one case will represent an international public health emergency.
We developed a protocol (#2007-10) for surveillance and it was approved by ICDDR,B’s following institutional review boards: ‘Research Review committee’, ‘Ethical Review Committee’, and ‘Animal Experimentation Ethics Committee’. The surveillance components were implemented according to the protocol and all methods were performed in accordance with the relevant guidelines and regulations. During the sample collection, we described to the waterfowl owners the purpose of this surveillance, expected outcome, process of sampling, potential harm and benefits of being included in the study and obtained informed consent.
The highly pathogenic H5N1 influenza virus causes lethal multi-organ disease in poultry, resulting in significant economic losses and a public health concern in many parts of the world. The greatest threats posed by this virus are its ability to cause mortality in humans, its potential to compromise food supplies, and its possible economic impacts. Viral maintenance in poultry potentiates the risk of human-to-human transmission and the emergence of a pandemic strain through reassortment. An effective, safe poultry vaccine that elicits broadly protective immune responses to evolving flu strains would provide a countermeasure to reduce the likelihood of transmission of this virus from domestic birds to humans and simultaneously would protect commercial poultry operations and subsistence farmers.
DNA vaccines have been shown to elicit robust immune responses in various animal species, from mice to nonhuman primates–. In human trials, these vaccines elicit cellular and humoral immune responses against various infectious agents, including influenza, SARS, SIV and HIV. In addition to their ability to elicit antibody responses, they also stimulate antigen-specific and sustained T cell responses–,,,. DNA vaccination has been used experimentally against various infectious agents in a variety of mammals, including cattle (against infectious bovine rhinotracheitis/bovine diarrhea virus, leptospirosis and mycobacteriosis),, pigs (against classical swine fever virus and mycoplasmosis), and horses (against West Nile virus and rabies). In addition, DNA vaccines have been tested against avian plasmodium infection in penguins and against influenza and infectious bursal disease in chickens,,, duck hepatitis B virus in ducks, and avian metapneumovirus and Chlamydia psittaci in turkeys, (reviewed in ref.). While they have been used in chickens to generate antisera to specific influenza viruses and confer protection against the low pathogenicity H5N2 strain, there is only one previous report of a monovalent DNA vaccine effective against H5N1 (and that only against a matched H5N1 isolate); no protection with multivalent DNA vaccines against heterologous strains has been reported.
Development and characterization of a DNA vaccine modality for use in poultry offers a potential countermeasure against HPAI H5N1 avian influenza outbreaks. The virus can infect humans, typically from animal sources, including commercial and wild avian species, livestock, and possibly other non-domesticated animal species–. While there is marked diversity in the host range of type A influenza viruses, many experts have speculated that a pandemic strain of type A influenza could evolve in avian species or avian influenza viruses could contribute virulent genes to a pandemic strain through reassortment,. Thus, there is reason to consider vaccination of poultry that would stimulate potent and broad protective immune responses,,. In undertaking such efforts, it is important that there be a differentiation of infected from vaccinated animals so that animals can be protected and permit monitoring of new infections using proven and sensitive methodologies.
In this study, we used an automated high capacity needle-free injection device, Agro-Jet® (Medical International Technology, Inc., Denver, CO) to explore the feasibility of DNA vaccination of poultry. After optimization of injection conditions, alternative multivalent DNA vaccine regimens were analyzed and compared for magnitude and breadth of neutralizing antibodies, as well as protective efficacy after challenge in mouse and chicken models of HPAI H5N1 infection. The findings suggest that it is possible to develop a multivalent DNA vaccine for poultry that can protect against multiple HPAI H5N1 strains and that could keep pace with the continued evolution of avian influenza viruses.
Located in southern China, Guangdong Province is home to some of the world’s largest populations of humans, chickens, ducks and pigs and has been associated with human outbreaks of severe acute respiratory syndrome (SARS) and highly pathogenic H5N1 avian influenza infections. This region of China has been considered an epicenter of novel influenza virus generation. In recent years, a variety of novel swine and avian viruses have been detected in pigs and poultry in Guangdong Province. The human H7N9 influenza strain, first detected in March 2013, has quickly spread among poultry flocks in at least ten of China’s provinces, causing rapidly progressing lower respiratory tract infections in humans. As of 29 August 2014 at least 365 human infections have been identified (111 deaths) and have been reported to the World Health Organization. In Southern China, an increasing number of human H7N9 infections have aroused public awareness of zoonotic avian influenza transmission but the novel H7N9 is not the only influenza problem. On 30 November 2013, the first human infection with H10N8 avian influenza virus (AIV) was found in a 73-year-old woman living in Nanchang City, China. She died nine days after the onset of illness. As of 15 February 2014, two additional human infections with H10N8 had been documented in Jiangxi Province, with one of them resulting in a second death. The origins of the H10N8 viruses’ HA and NA gene segments were similar and thought to have moved first from wild birds to ducks and then to chickens. The six internal gene segments were similar to those of the H9N2 influenza viruses frequently detected in chickens. Notably, the H10N8 virus emergence coincided with a second wave of the human H7N9 AIV outbreak, and subsequent to the human index case, more H10N8 AIV infections have been detected in both avian species and humans.
As H10N8 AIV was first identified in a duck from Guangdong Province in 2012 and there is also evidence of H10N8 infected dogs in this region, it seems important to understand whether subclinical human infection with the H10N8 virus occurred before 30 November 2013. Hence, we conducted a retrospective cross-sectional, seroepidemiological study among animal workers in Guangdong Province.
All studies were individually assessed with regard to study design and potential bias or confounding. No study was excluded based on these criteria, but major limitations of specific studies are discussed in the text.
The following information was retrieved from the included studies: location, influenza strain, type and date of intervention, data collection methods, main outcomes and findings. Because of the differences in study design, data analysis and reporting methods, the computation of a pooled estimate of intervention effectiveness was not possible within this group of studies. To compare findings across studies, standardized outcome measures were computed as i) relative risk reduction (RRR) of AIV-detection in LPMs and ii) incidence rate ratios (IRRs) of H7N9-incidence in humans. When necessary, raw data was retrieved from supplementary materials.
Avian influenza refers to the infection of birds with avian influenza type A viruses. These viruses occur naturally among wild aquatic birds worldwide and can infect over 100 domestic sources of poultry as well as other birds and animal species. Avian influenza viruses do not normally infect humans, but human infections may occur after contact with infected birds or their secretions or excretions, or through limited human-to-human transmission. Given the significant global improvements in laboratory characterization and surveillance, additional novel avian viruses are likely to be identified. Following the appearance of the H5N1virus in 1997, ongoing surveillance efforts have already improved not only the detection of the H7N9 (in 2013), H10N8 (in 2013) and H5N6 subtypes (in 2014), which have all caused severe infections, but also the detection of other subtypes such as H6N1, H7N2, H7N3, H7N7, H9N2 and H10N7, which have resulted in mild infections in a limited number of humans.
Each new virus may have a distinct potential for animal-to-human transmission or to cause mild, severe or even fatal human illness. On the basis of the molecular characteristics of the viruses and their ability to result in disease and mortality in chickens in a laboratory setting, avian influenza A viruses have been classified into the following two categories: low pathogenic avian influenza (LPAI) A viruses and highly pathogenic avian influenza (HPAI A viruses. The majority of those isolated have been LPAI A viruses, although HPAI A viruses have occasionally been detected. Notably, the case fatality rate (CFR) among human cases of avian influenza has ranged from 36%–60% overall, which is alarmingly high compared with all previous outbreaks of human cases of seasonal influenza in the United States, for which the CFR has ranged from 0.04%–1.0%. This high level of illness severity and high mortality rate was unexpected and increased disease burden, resulting in concern among clinicians and public health officials; however, the risk factors that are most highly associated with the deaths from avian influenza were not clear.
On the basis of laboratory-confirmed deaths and the number of survivors, we examined human HPAI and LPAI infections in terms of the overall population, pediatric and clustered cases, with the aim of identifying the high-risk factors that are associated with fatal outcomes. This research will improve the clinical outcome and will also be helpful in decreasing the disease burden for these novel avian influenza viruses.