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Another treatment option is the use of anti-viral medications. The two main classes of antivirals available at present are the neuraminidase inhibitors and the adamantanes. There has been an emergence of resistance to adamantanes for seasonal influenza leading many to reconsider them as agents in the treatment of pandemic avian influenza. In preliminary studies using oseltamivir or zanamivir, patients showed a reduction in the duration of symptoms ranging from 1–2 days. Whether a 1–2 day reduction in symptoms will translate into reduced absenteeism, cost-savings and disease transmission is unknown. Additionally, the cost-benefit of stockpiling anti-virals for treatment of pandemic influenza remains unknown. As noted previously, oseltamivir has also demonstrated resistance. Adding to the complexity of managing H5N1 treatment, is once again the manner in which one decides who receives the medication and the fact that the modest reduction in influenza symptoms will depend on timing of administration of the drug. In individuals with confirmed H5N1 influenza that were treated with oseltamivir, mortality was still close to 80%. It has also been noted by Tambyah, that despite guidelines from the World Health Organization concerning the use of anti-virals in pandemic avian influenza, there remains little 'level 1' clinical evidence to support such guidelines. More recently, a group in Singapore has gathered a set of practical guidelines for clinicians encountering H5N1 avian influenza in humans. Despite the lack of scientific evidence for their effectiveness in a pandemic situation, governments and many employers are stockpiling anti-virals to be used not only as therapy for ill individuals, but also as prophylaxis for critical staff. This may be driven by the recognition that once the pandemic is recognized, it will be nearly impossible to purchase these products. It reflects a significant investment: at approximately $3/pill, an eight week course would cost over $200 per employee. A company of 1000 employees would need to invest $200,000 on a product which they hope they will never use, is unproven, and has a limited shelf life. Again, one is faced with decisions regarding dispensing medication – to all workers, critical workers, families?
Although there are superb examples of effective antiviral drugs that target viral replication, such as the DNA chain-terminators used in the treatment of various herpes viruses and the numerous drugs that interfere with the replication of human immunodeficiency virus type 1 (HIV-1) (reviewed in), for the vast majority of human viral pathogens there is a vast shortage of effective therapies. Importantly, to date, only one antiviral drug has been utilized during a henipavirus outbreak, ribavirin, which was first synthesized in1972. It is perhaps the best known alternative drug therapy, exhibiting antiviral activity against a variety of mostly RNA viruses. Ribavirin is an accepted treatment for several viral infections including RSV, arenaviral hemorrhagic-fevers such as Lassa virus and some members of the family Bunyaviridae (reviewed in). Because of its global availability and broad antiviral properties it is often employed for the treatment of viral diseases under conditions where no other options are available except supportive care. During the NiV encephalitis outbreak in Malaysia, there was evidence that ribavirin exhibited some clinical benefit with an apparent 36% reduction in mortality with little evidence of serious side effects. Thus, ribavirin appears to be one available antiviral option; however, with fatality approaching 75% in the most recent NiV outbreaks in Bangladesh and India, a more effective repertoire of antiviral agents is needed.
HeV and NiV are transmitted oranasally, spread systemically and infected individuals succumb to disease within 7 to 10 days. Clinical and experimental data demonstrate that multiple organ systems are affected and that the lungs and brain are major sites of virus replication. Viremia has been documented in both clinical and experimental infections; however, the kinetics and duration vary. For both viruses, acute and late-onset encephalitis has been documented clinically. The initial sites and duration of henipavirus replication upon infection are largely unknown, mainly due to a lack of extensive in vivo experiments. Consequently, the optimal target and time frame for drug intervention are not known. Theoretically, therapeutics that target the mucosa should reduce viral loads in the lung. Intravenous agents should decrease viral loads and reduce systemic spread. Although targeting the CNS may prove difficult, a significant reduction in viral loads peripherally may enable the host to generate a protective immune response.
To date, all novel henipavirus therapeutic agents that have been identified target and interfere with HeV and NiV virus entry and these candidates can be divided into two categories: those used for prevention of disease, including various vaccines, and those used for treatment post-exposure which includes antibodies, fusion inhibitors and soluble receptor molecules. The scope of this review will be limited to those agents tested using infectious HeV or NiV in vitro or in vivo.
Viral vectors have potential as novel vaccine candidates in times of pressing need for game-changing vaccines that induce broadly protective immunity against a wide variety of influenza viruses. The major advantage of viral vectors is the possibility of expressing any foreign antigen with or without modification in vivo. Since the proteins are expressed in their native confirmation, antibody responses of the desired specificities are induced. In addition, viral vectors allow de novo protein synthesis in the cytoplasm of infected cells facilitating endogenous antigen processing and MHC class I presentation of immunogenic peptides, which is a requirement for the efficient induction of virus-specific CD8+ T-cell responses. Although all vectors discussed have their own respective advantages and disadvantages, most are replication-deficient in mammalian host cells and are therefore safe for human use, even in immunocompromised individuals. Pre-existing immunity to the vector may pose a problem for some vectors, however there are viral vectors available (like VSV) for which the human population is immunologically naïve. Other vectors (like MVA) proved to be immunogenic even in the presence of pre-existing immunity. For some vector technologies there are some safety concerns, like the use of herpes viruses that persistently infect their hosts and DNA vaccines that might integrate into the host genome. These properties might restrict their applicability as prophylactic vaccines.
As discussed in this review, viral vectors as potential influenza vaccine candidates were not only evaluated in animal models and humans, they were also extensively tested in influenza A virus reservoir species. Vaccination of reservoir species could potentially limit transmission of avian and swine influenza A virus transmission, and therefore limit the zoonotic transmission of these potential (pre-)pandemic viruses to the human host.
In the future, more novel vector-based influenza candidate vaccines will be developed and tested in clinical trials. There is potential for improvement by the modification of viral antigens, like the ‘headless’ or ‘shielded’ HA constructs, to broaden the reactivity of vaccine induced antibodies. In addition to modifying influenza virus antigens, post-translational modifications and modifications to promoter sequences could also alter and improve the immunogenicity.226,227 The biggest challenge of taking vector-based vaccines to the market may be obtaining approval from the regulatory authorities. Only when their safety and superiority over existing vaccine formulations have been demonstrated, implementation of these novel vector-based vaccines may be considered.
Newcastle disease virus (NDV) is an attractive vaccine vector for both human and animal pathogens. The live attenuated vaccine strains used as vaccine vectors have a proven track record of safety and efficacy. NDV vectors not only induce robust humoral and cellular immune responses but also induce mucosal immune response. Therefore, NDV can be a vector of choice for mucosal immunization. The ability of NDV to infect a wide variety of non-avian species makes it a potential vector for other animals. NDV is also a promising vaccine vector for use in humans. One advantage is that most humans do not have pre-existing immunity to NDV. NDV-vectored vaccines have also become available commercially (i.e., H5N1 HPAIV vaccine for poultry).
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 use of safe and efficacious vaccines has been crucial to prevention strategies for several important viral pathogens in humans. Presently, there are some sixteen FDA-approved vaccines routinely used to prevent infection by virulent human pathogens and the majority comprise live-attenuated virus preparations (reviewed). Although new reverse genetics systems have been developed for NiV, it is unlikely that a live-attenuated vaccine will be approved for any BSL4 virus including HeV and NiV. All successful human viral vaccines induce neutralizing antibodies that can cross-react with immunologically relevant strains of a virus. Furthermore, neutralizing antibodies are the key vaccine-induced protective mechanisms in the case of some well known human paramyxoviruses such as mumps and MeV [60, 61]. For paramyxoviruses, it is the envelope glycoproteins that elicit the majority of neutralizing antibody in an infected host. Indeed, for henipaviruses, it has been demonstrated that immunization of animals with recombinant NiV and HeV F or G glycoproteins, either as a live vaccinia virus vector or purified protein preparation can elicit potent cross-reactive virus neutralizing humoral responses in hamsters and rabbits, respectively [62, 63].
The first successful experimental henipavirus vaccine utilized recombinant vaccinia viruses that encoded NiV F or G glycoprotein. In these studies, vaccination protected against NiV challenge in golden hamsters and importantly, protection lasted five months post-challenge suggesting protection potentially from late-onset disease symptoms. Although important for proof of principle, these recombinant viruses are not a viable human vaccine candidate due to the inherent risks of vaccinia virus vaccination. Poxvirus vectors have emerged as licensed veterinary vaccines as well as candidate vaccines for humans. Concerns about the safety of wild-type vaccinia virus have been addressed with the advent of attenuated poxviruses such as modified vaccinia virus Ankara (MVA), which is considered the vaccinia virus strain of choice for clinical investigation. Although, recombinant MVA expressing HeV F or G has been generated, neither has been tested as a vaccine candidate (Bossart, K. and Broder, C.; unpublished data). Other poxvirus vectors shown to be attenuated in humans, such as the avipoxviruses, have also been explored as live vaccine vectors (reviewed in [65, 66]) and licensed feline, canine and equine canarypox virus-based vaccines are commercially available. Recently, recombinant canarypox virus-based vaccines encoding NiV F or G successfully protected pigs from NiV challenge. Interestingly, neutralizing antibodies and cell mediated immunity were examined and the study suggested that G-containing recombinant canarypox vaccines could elicit protective humoral and type 1 cell-mediated immune responses. Understanding and optimizing the immune response to henipaviruses represents a key aspect of human vaccine development. Importantly, this was the first report of recombinant canarypox virus vaccines being used in pigs and represents significant progress towards a veterinary vaccine for NiV. Furthermore, if evaluated successfully in an independent animal model, recombinant NiV F- and G-containing canarypox vaccines could potentially be used as human NiV vaccine candidates.
Recombinant subunit immunogens represent a viable avenue of vaccine development for the henipaviruses. These vaccines can be quickly implemented, are quite simple, and can be administered with no risk of infection. Recently, recombinant, soluble, oligomeric versions of the G glycoprotein of both HeV and NiV (sG) were generated as potential subunit vaccines. Recombinant, purified sG preparations have been shown to be ideal immunogens that retain a number of important functional and antigenic properties including the ability to bind virus receptor, block virus infection, and elicit a robust polyclonal neutralizing antibody response in rabbits and mice. The sG glycoprotein can also capture and isolate virus-specific neutralizing human monoclonal antibodies (mAbs) from naive recombinant libraries. When HeV and NiV sG were used as subunit vaccines in a cat NiV challenge model, all animals were protected from disease. The serum neutralization titers were on the order of 1:20,000 and represented the highest titers against henipaviruses obtained to date. The high neutralizing antibody titers and the absence of NiV genome in all vaccinated animals following challenge suggested that the sG subunit vaccines elicited sterilizing immunity. Unlike previous vaccines strategies, heterotypic protection was achieved where the attachment glycoprotein from HeV protected against challenge with NiV. If evaluated successfully in an additional animal model, these subunit vaccines may also represent viable human vaccine candidates. All of the potential vaccines discussed thus far are summarized in Table 2.
In order for a henipavirus vaccine to be considered for human use, not only does it need to be successful in two animal models, a natural route of infection should be used in protection studies, the mechanism and limits of protection should be elicited, and the highest standards should be used for reagents production to assure safety and success in human trials. Additionally, for HeV and NiV, we believe it would be ideal to have one vaccine that protects against both viruses. All of the above vaccine trials offer critical data towards these goals, but further refinement of reagents and protocols are necessary. Firstly, the selection of adjuvant will be important in human use. Secondly, a correlation between vaccine dose and protection will need to be established to ensure that vaccine preparations induce protective immune responses well above sub-optimal levels. Correlations of immunity will also be critical, including antibody subclasses such as IgA, IgG and IgM and their location (serum vs mucus membranes). Finally, it will be important to determine the role of cell-mediated type 1 immune responses in the strength and longevity of protective immunity.
To address these concerns, a new sG subunit vaccine trial has been initiated. HeV sG was chosen as the antigen because, based on previously established G-specific cross neutralization titers [43, 70], it can elicit the best cross-reactive henipavirus immune response (see Table 3). Varying doses of sG were employed in hopes of correlating protection with vaccine dose. Additionally, small CpG DNA molecules were used as the adjuvant for several reasons. Recent studies have demonstrated that CpG molecules can elicit mucosal and systemic type 1 cell-mediated immune responses regardless of the route of vaccine delivery. Equally important, several CpG molecules have been approved by the FDA for use in humans and numerous others are in clinical trials. All vaccinated animals were challenged oronasally with 50,000 TCID50 of a low passage NiV isolate. Preliminary pre-challenge results are summarized in Table 4. As expected, different doses of sG induced varying levels of serum neutralizing antibody, and titers were significantly lower to NiV as compared to HeV. Antigen-specific IgG and IgM were detected in all sera from all vaccinated animals, and sG-specific IgA was present in serum from one high dose animal. Interestingly, HeV sG-specific IgA was detected in the mucosal washes from all vaccinated animals. Post-challenge titers and protection from disease are not yet known, however, the data generated in the current vaccine trial will be valuable for future development of a human henipavirus vaccine.
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.
Outbreaks of Ad in the general population have been characterized by infection due to novel viruses such as Ad7h, Ad7d2, Ad14a, and Ad3 variants. These novel viruses are sometimes associated with high attack rates and a high prevalence of pneumonia. Severe mortality is also prevalent among patients with chronic disease and in the elderly.
One of the most important novel serotypes, Ad14, previously rarely reported, is now considered as an emerging Ad type causing severe and sometimes fatal respiratory illness in patients of all ages (45). Beginning in 2005, Ad14 cases were suddenly identified in four locations across USA (46); the strain associated with this outbreak was different than the original Ad14 strain isolated in 1950s. The novel strain, Ad14a, has now spread to numerous US states and is associated with a higher rate of severe illness when compared to other Ad strains.
Novel Ad species have also been recently detected in cross-species infections from non-human primates to man in USA and between psittacine birds and man in China (47). These cross-species infections indicate that Ads should be monitored for their potential to cause cross-species outbreaks. In a recent review of the risks of potential outbreaks associated with zoonotic Ad (48), it was noted that intense human–animal interaction is likely to increase the probability of emergent cross-species Ad infection. Additionally, the recombination of AdVs with latent “host-specific” AdVs is the most likely scenario for adaptation to a new host, either human or animal.
Currently, there are no FDA approved antivirals for Ad infection; however, the best antiviral success has been seen with ribavirin, cidofovir, and most recently brincidofovir an analog of cidofovir (49).
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.
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.
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.
While the world waits for an effective pharmaceutical intervention, non-pharmaceutical controls will need to be considered to combat the spread of illness in the community and the workplace.
Low has outlined and adapted five non-pharmaceutical public health interventions that would aid in the mitigation of pandemic influenza. They include: hand hygiene and respiratory etiquette, human surveillance, rapid viral diagnosis, provider and patient use of masks and other personal protective equipment and isolation of the sick. All of these interventions will need to be coordinated at organizational and government levels due to the tremendous interrelationships affected by a pandemic. Some of the above interventions have some unique implications from an occupational medicine perspective.
Hygiene and respiratory etiquette are particularly effective in reducing the spread of infectious disease and represent a key defense against nosocomial infection in hospitals. This also applies to a workplace where people are in close proximity to one another where viral droplets may exist in the air and on equipment or surfaces used by multiple people each day. The spread of infection between employees is one possible transmission pathway, however the occupational medicine professionals of large and complex organizations must also consider the families of the employees and the consumers of products where interaction occurs with the public. Protection of the consumer raises the issue of due diligence which can be complex for service oriented organizations. Hand washing, social distancing and respiratory etiquette, if normalized and rigorously adopted, may provide the most effective (certainly most cost effective) means of protection.
Highly pathogenic avian influenza virus (HPAIV) is an economically important pathogen of poultry worldwide. The outbreaks involving H5N1 or H7N7 influenza viruses resulted in lethal infections in poultry and the death of a limited number of people. Therefore, vaccination of poultry against HPAIV could play an important role in reducing virus shedding and raising the threshold for infection and transmission. However, development of vaccines against HPAIV has been hampered due to poor immunogenicity of the virus. Furthermore, inactivated vaccines are not commonly used because of the high cost due to the requirement of enhanced biosafety level 3 containment and the difficulty in “differentiating infected from vaccinated animals” (DIVA). The use of live attenuated influenza viruses as vaccines in avian or mammalian species can also raise a major biosafety concern, because the vaccine viruses may become virulent through mutation or genetic reassortment with circulating strains. Alternatively, NDV can be an ideal vaccine vector for development of an avian influenza vaccine. NDV infects via the intranasal route and therefore induces both local and systemic immune responses at the respiratory tract. Therefore, it provides a convenient platform for rapid, efficient, and economical immunization. In fact, NDV has been most commonly used as a vaccine vector against AIV. Protective efficacy of NDV-vectored vaccines has been evaluated and verified by many different vaccination studies.
For the generation of vaccines, a major protective antigen, hemagglutinin (HA) of HPAIV has been placed between the P and M genes or between the F and HN genes in lentogenic NDV strains LaSota or B1. To address a safety concern, an NDV-vectored vaccine was further generated by replacing the polybasic cleavage site in HPAIV HA with that from a low-pathogenicity strain of influenza virus. In addition, the HA gene has been modified to enhance its expression levels by NDV. Specifically, elimination of an NDV transcription termination signal-like sequence located within the HA open reading frame of H5 enhanced expression levels of HA protein by NDV and completely protected chickens after challenge with a lethal dose of velogenic NDV or highly pathogenic AIV, respectively. In addition, the ectodomain of an H7N7 or H5N1 avian influenza virus HA was fused with the transmembrane and cytoplasmic domains derived from the F protein of NDV. This approach resulted in enhanced incorporation of the foreign protein into virus particles and the protection of chickens against both HPAIV and a highly virulent NDV. These studies also demonstrated that NDV can be used to generate a bivalent vaccine.
Although use of avirulent NDV vectors has been effective in protecting chickens against clinical disease and mortality, some studies also found virus shedding in chickens after challenge with HPAIV. To enhance the replication of vaccine virus, attenuated mesogenic NDV strain BC has been generated by changing the multibasic cleavage site sequence of the F protein to the dibasic sequence of strain LaSota. Additionally, the BC, F, and HN proteins were modified in several ways to enhance virus replication. The modified BC-based vectors replicated better than LaSota vector, and expressed higher levels of HA protein and provided complete protection against challenge virus shedding, suggesting its potential to be safely used as a vaccine vector.
For effective human vaccines against HPAIV, the immunogenicity of NDV expressing the HA of H5N1 was evaluated in African green monkeys by the intranasal route of administration. Two doses of NDV-vectored vaccine (2 × 107 PFU) induced a high titer of H5N1 HPAIV-neutralizing serum antibodies in all of the immunized monkeys. Moreover, a substantial mucosal IgA response was induced in the respiratory tract, which can potentially reduce or prevent transmission of the virus during an outbreak or a pandemic. The intranasal route of administration is also advantageous for needle-free immunization and is thus suitable for mass immunization. The protective efficacy of vaccine viruses was evaluated in African green monkeys by the intranasal/intratracheal route or by the aerosol route of administration. Each of the vaccine constructs was highly restricted for replication, with only low levels of virus shedding detected in respiratory secretions. All groups developed high levels of neutralizing antibodies against homologous (A/Vietnam/1203/04) and heterologous (A/egret/Egypt/1162-NAMRU3/06) strains of HPAIV and were protected against challenge with 2 × 107 PFU of homologous HPAIV. This study demonstrated that needle-free, highly attenuated NDV-vectored vaccines were immunogenic and protective in a nonhuman primate model of HPAIV infection.
(“Norovirus”/exp OR “norovirus infection”/exp OR (Norovirus* OR Norwalk OR “small round-structur*” OR srsv*):ab,ti) AND ([animals]/lim OR “reservoir”/exp OR (nonhuman/de NOT human/exp) OR “zoonosis”/de OR “disease model”/de OR (animal* OR reservoir* OR nonhuman* OR non-human* OR animal* OR rat OR rats OR mouse OR mice OR murine OR dog OR dogs OR canine OR cat OR cats OR feline OR rabbit OR cow OR cows OR bovine OR rodent* OR sheep OR ovine OR pig OR swine OR porcine OR veterinar* OR chick* OR baboon* OR nonhuman* OR primate* OR cattle* OR goose OR geese OR duck OR macaque* OR avian* OR bird* OR mammal* OR poultry OR bat OR porpoise* OR zoono* OR farm OR farms OR “disease model*”):ab,ti)
During the last two decades, scientists have grown increasingly aware that viruses are emerging from the human–animal interface. In order to combat this increasingly complex problem, the One Health approach or initiative has been proposed as a way of working across disciplines to incorporate human, animal, and environmental health. Of particular concern are emerging respiratory virus infections; in a recent seminar given by the National Institute of Health on emerging and re-emerging pathogens, nearly 18% were respiratory viruses (1). Among the recently emerged respiratory pathogens contributing to the high burden of respiratory tract infection-related morbidity and mortality, displayed graphically in Figure 1, are influenza viruses, coronaviruses, enteroviruses (EVs), and adenoviruses (Ads). In this report, we summarize the emerging threat characteristics of these four groups of viruses.
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.
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/).
Alkhurma hemorrhagic fever virus (AHFV) in humans was discovered in 1994. The first case reported in a butcher from the city of Alkhurma, a district south of Jeddah in Saudi Arabia, died of hemorrhagic fever after slaughtering a sheep. The viral infection has a reported fatality rate of up to 25%. Interestingly, one of the previous reports regarding this disease showed a misunderstanding of the real name of this infection, called Alkhurma, not Alkhumra. Because subsequent cases were diagnosed in patients from the small town known as Alkhurma in Jeddah from where the virus got its scientific name; the name was accepted by the International Committee on Taxonomy of Viruses. Thus, based on evidence, the first case was confirmed to be the butcher, following the slaughtered sheep. Therefore, a study was conducted among affected patients to address this disease as a public health issue. Blood samples were collected from household contacts of patients with laboratory-confirmed virus for follow-up testing by enzyme-linked immunosorbent serologic assay (ELISA) for AHFV-specific immunoglobulin (Ig) G. Samples from persons seeking medical care were tested by ELISA for AHFV-specific IgM and IgG using AHFV antigen. Viral-specific sequence was performed by reverse transcription PCR (TiBMolbiol, LightMix kit; Roche Applied Science, Basel, Switzerland). A total of 11 cases were identified through persons seeking medical care, whose illnesses met the case definition for AHFV, and another 17 cases were identified through follow-up testing of household contacts.
Subsequently, the virus was isolated from six other butchers of different ages (between 24 and 39 years) from the city of Jeddah, with two deaths. The diagnosis was established from their blood sample tests. The serological tests later confirmed four other patients with the disease. From 2001 to 2003, the study on the virus initial identification in the city of Alkhurma again identified 37 other suspected cases; with laboratory confirmation of the disease in 20 (~55%) of them. Among the 20, 11 (55%) had hemorrhagic manifestations and 5 (25%) died. The virus was later identified in three other locations: from the Western Province of Saudi Arabia (Ornithodoros savignyi and Hyalomma dromedarii were found by reverse transcription in ticks) and from samples collected from camels in Najran. AHFV virus was considered as one of the zoonotic diseases; however, the mode of transmission is not yet clear. Recently, it was suggested that the disease reservoir hosts may include both camels and sheep. The virus might also be transmitted as a result of skin wounds contaminated with the blood or body fluids of an infected sheep; through the bite of an infected tick, and through drinking of unpasteurized or contaminated milk from camels.
In humans, this zoonotic disease may present with clinical features ranging from subclinical or asymptomatic features to severe complications. It is related to Kyasanur Forest disease virus, which is localized in Karnataka, India. However, epidemiologic findings suggest another wider geographic location for the disease in western (including Jeddah and Makkah) and southern (Najran) parts of Saudi Arabia, and the virus infections mostly occur in humans. A study was conducted by Alzahrani et al. in the southern part of Saudi Arabia particularly in the city of Najran (with populations of ~250,000), an agricultural city in Saudi Arabia, where domestic animals are reared at the backyard of owners. After the initial virus identification, from January 2006 through April 2009, 28 persons with positive serologic test results were identified. Infections were suspected if a patient had an acute febrile illness for at least two days; when all other causes of fever have been ruled out. Additionally, data analysis indicated that patients infected with the virus were either in contact with their domestic animals, involved in slaughtering of the animals, handling of meat products, drinking of unpasteurized milk, and/or were bitten by ticks or mosquitoes. Symptoms consistent with AHFV infection—including fever, bleeding, rash, urine, color change of the feces, gum bleeding, or neurologic signs—then develop. Fortunately, infected patients responded to supportive care (including intravenous fluid administration and antimicrobial drugs when indicated), with no fatal cases.
In summary, AHFV is a zoonotic disease with clinical features ranging from subclinical or asymptomatic features to severe complications. Another study highlighted different characteristics of the exposure to the blood or tissue of infected animals in the transmission of AHFV to humans. Of the 233 patients confirmed with infections, 42% were butchers, shepherds, and abattoir workers, or were involved in the livestock industry. More recently, a study on infection using C57BL/6J mice cells showed that the clinical symptoms of the disease were similar to the presentations in humans. However, Alkhurma disease resulted in meningoencephalitis and death in Wistar rats, when high titers to the infection occurred. In addition, exposures to mosquito bites are regarded as potential sources of transmissions of the infection; however, very few available data support this. Although, available data shows that Alkhurma virus has been isolated following mosquito bites. However, another study suggested that mosquitoes may play a role only as a vector in the transmission of the disease.
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.
A SuperScript III One-Step reverse transcription kit (Invitrogen, Bleiswijk, The Netherlands) was used to synthesize cDNA from extracted RNA. The optimized RT mixture contained 11 µL of RNA extract, 1 µL (500 µg/mL) Random Primers (Promega, Leiden, The Netherlands), 0.5 µL (40 U/µl) Ribinuclease Inhibitor (Promega), and 1 µL (10 mM each) deoxynucleoside triphosphates (Roche) in a 13.5 µL volume. After a 5 min incubation at 65°C for optimal primer hybridisation to template, 4 µL (10×) First-Strand buffer, 1 µL (0.1 M) DTT, 0.5 µL (40 U/µl) Ribinuclease Inhibitor (Promega) and 1 µL (200 U/µL) SuperScript III Reverse Transcriptase was added to the mixture in a 20 µL volume. The RT mixture was sequentially incubated at 25°C for 5 min and 42°C for 1 hour to obtain cDNA.
PCR was optimized with respect to enzymes, primer sets, and concentrations of reagents as well as cycling parameters. The PCR mixture contained 50 pmol of each forward and reverse primer, 4 µL of cDNA, 1 µL (10 mM each) deoxynucleoside triphosphate, 5 µL 10× PCR Gold buffer, 8 µL (25 mM) MgCl2, and 0.5 µL (2.5 U/µL) AmpliTaq Gold DNA Polymerase (Applied Biosystems, Bleiswijk, The Netherlands). Water was then added to achieve a final volume of 50 µL. The PCR mixture was incubated at 94°C for 10 min, then 35 cycles at 94°C for 15 s, 41°C for 30 s, 72°C for 30 s, and a final extension at 72°C for 7 min.
Z-LS, BA, BH, and SOO conceptualized and designed the study. Z-LS, BA, BH, SO, and VO coordinated the study and the field work. BA, SO, VO, and SOO participated in the field work. Z-LS and BA supervised the study. BA, SOO, BH, and X-LY designed and coordinated the experiments. SOO and GO managed the storage and retrieval of specimen. BL and BH coordinated the laboratory skills training. BA and VO were responsible for application and acquisition of ethics permit. SOO performed the experiments, and analyzed and interpreted the data. KK, YF, and X-SZ assisted with data analysis. SOO and BH drafted the manuscript.
Influenza is among the major infectious disease problems affecting animal and human health globally. Several human influenza pandemics have been recorded since 1590 AD, with the most significant of those being the “Spanish flu” of 1918, often referred to as the “mother of all pandemics”. Spanish flu pandemic is believed to have affected approximately 25–30 percent of the world’s population and caused more than 50–60 million human deaths globally. Influenza infections in humans occur either as epidemic (seasonal or interpandemic) influenza caused by influenza A and B viruses, or as sporadic pandemic influenza caused by influenza A viruses. Study of influenza pandemics has been of great interest to epidemiologists. Influenza epidemics and pandemics have been repeatedly occurring for centuries, but to date the ability to predict a pandemic has not been achieved.
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.
The enteric viral infections, mainly rotavirus, are a global cause for concern. Among the four serogroups of rotaviruses identified in poultry, the RVD has gained more importance due to its involvement in runting and stunting syndrome. With the advent of molecular techniques, the diversity of RVD strains is beginning to be explored. However, still, the exact prevalence and annual losses associated with RVD in poultry industry are unknown. There are many gaps that need to be filled and warrant attention, such as:
▪Studies on host–pathogen interactions, whether they are alike other enteric viruses or not.▪As RVD is found in both symptomatic and asymptomatic birds, factors responsible for its virulence and pathogenicity are to be studied.▪To date, very few sequences are available, and only for some of the genes of RVD strains. Once enough sequence data are available, a nucleotide sequence-based classification system can be established for RVD, as was achieved for RVAs.▪Only one complete genome sequence is available so far, despite the widespread distribution of RVD in chickens.▪The function of additional ORF (ORF-2) encoded by the 10th segment of RVD is still not defined.▪The development of sensitive and specific diagnostic tests, including the improvement of available ones, is of prime importance.▪The development of specific treatment by means of antivirals.
Once the basic information is available about RVD, its prevention should acquire the attention of researchers by means of developing vaccines to prevent its spread and to save one of the fastest-growing sectors, the poultry industry.
Influenza viruses belong to the family of Orthomyxoviridae, are an important cause of acute respiratory infections and cause annual epidemics in the human population. Although in most cases infections are self-limiting and restricted to the upper respiratory tract, certain patient groups (such as the elderly) are at risk of developing complications leading to high morbidity and mortality. Vaccines against circulating influenza strains are readily available and are trivalent or quadrivalent, designed to protect against influenza viruses of both the A(H1N1) and A(H3N2) subtype, and against one or both lineages of influenza B virus.
Several different vaccine formulations are available: trivalent or quadrivalent inactivated virus vaccines (TIV or QIV, either whole virus, split virus or subunit vaccines) or live attenuated influenza virus vaccines (LAIV). Most vaccines are produced in embryonated chicken eggs, but vaccines produced in mammalian or insect cells are also available. Inactivated vaccines are administered intramuscularly (IM) or sometimes intradermally and predominantly aim at the induction of serum antibody responses against the viral hemagglutinin (HA) and neuraminidase (NA) to a lesser extent. Protection from disease is mainly mediated by virus neutralizing antibodies against HA, but NA-specific antibodies also contribute to protective immunity.1 Currently licensed LAIV are administered locally via nasal spray. Viruses are attenuated by the choice of a viral backbone of cold-adapted viruses and are therefore temperature-sensitive and replicate only locally after administration at the mucosa of the nasopharynx.2 In addition to serum antibodies, immunization with LAIV also induces mucosal antibodies and cytotoxic T-lymphocytes (CTL).
Although currently available influenza vaccines are effective in reducing morbidity and mortality caused by seasonal influenza viruses, they have several limitations. Mainly, continuous antigenic drift of seasonal influenza viruses complicates the production of effective vaccines. The vaccine strains need to be updated almost annually in order to achieve a good antigenic match with the epidemic virus strains. If the vaccine strains do not antigenically match the circulating strains, vaccine efficacy is reduced considerably, as was the case in the 2014-2015 influenza season.3-5 Furthermore, the seasonal influenza vaccines will afford little or no protection against antigenically distinct pandemic influenza viruses, which are often of alternative subtypes to which antibodies are virtually absent in the human population. During the last decades zoonotic transmissions of highly pathogenic avian influenza viruses, in particular those of the H5N1 subtype, have been reported regularly. The capacity of A(H5N1) and avian viruses of other subtypes including A(H5N6),6 A(H7N7),7 A(H7N9),8 A(H9N2)9 and A(H10N8)10 to infect humans fuelled the fear for a pandemic outbreak caused by any of these viruses.
H5N1 vaccines that were produced according the procedures used for the production of seasonal influenza vaccines proved to be poorly immunogenic and in most cases the use of adjuvants was required for the efficient induction of protective antibody levels.11 Furthermore, the pandemic of 2009 caused by swine-origin influenza viruses of the A(H1N1) subtype (H1N1pdm09) taught an important lesson. The production of tailor made pandemic influenza vaccine proved to be a time-consuming process and in many countries vaccines became available after the peak of the pandemic.12
These limitations of the currently available vaccine production technologies and vaccines underscore the pressing need for game-changing vaccines. In addition to improving immunogenicity in the high risk groups, novel vaccines are required that induce long-lasting immunity against a wide range of influenza viruses and that can be produced rapidly in the face of a pandemic outbreak. To improve immunogenicity of influenza vaccines specifically in the elderly, high-dose vaccines and an adjuvanted vaccine have been developed. The latter has been in use in Europe and the US since 1997 and 2015, respectively.
The use of viral vectors for influenza vaccine production may be a solution to some of the problems discussed above. In this review we discuss various viral vectors that have been tested as candidate influenza vaccines in animal models and in clinical trials. Most viral vectors are considered live vaccines but their replication is attenuated or even deficient. Therefore, vector-based vaccines are considered safe in general and some of them can even be safely used in immunocompromised. Despite their attenuated phenotype, viral vectors are immunogenic and induce virus-specific antibody and T cell responses after systemic or parenteral administration. Additionally, most viral vectors can easily be propagated to high virus titers and it is relatively easy to insert genes encoding antigens of choice into the vector. Viral vector technology also allows the production of modified influenza viral antigens in vivo. These modifications can improve the immunogenicity of the influenza viral proteins or alter the specificity of the immune response. In this review, we discuss reports on vectored influenza vaccines and discuss their advantages and disadvantages.