Zoonosis comes from 2 Greek words, zôon meaning animal, and nosos, disease. Rudolph Virchow coined the term to designate human diseases caused by animals after noting parallels in the parasitic trichinellosis found in pigs and humans.1 The term reverse zoonosis specifically refers to the natural transmission of disease and infection from humans to animals, with humans as the reservoir host replicating the infectious agent.2 It is also referred to as zooanthroponosis to differentiate it from zoonosis.3 However, as defined by the Joint Food and Agriculture Organization of the United Nations (FAO) and World Health Organization (WHO) Expert Committee on Zoonoses,4 the epidemiological term zoonosis encompasses diseases and infections naturally transmitted between any animal and another animal, human or non-human, without differentiation, that is, infections naturally transmitted from animals to humans and vice versa.3–5
The general term zoonosis implies that the risk factors for zoonosis are the same as for reverse zoonosis, albeit variable by animal type (eg, pet, livestock, or wildlife). In fact, by the very nature of their host range, zoonotic viruses are invariably capable of reverse zoonosis, whereby the virus transmits from humans to animals with the potential for virus reservoirs to form in animal populations.2,6
Research regarding zoonotic diseases often focuses on infectious diseases transmitted from animals to humans, accounting for 61% of infectious agents that affect humans.7,8 Of these pathogens, over 71% have wildlife origins.9 However, humans have also historically transmitted pathogens to animals as part of the ecosystem.10,11 For example, the review by Fagre et al12 identified 97 verified examples involving a wide range of pathogens transmitted from humans to wildlife. The first reports on human-to-animal transmission date back to 1998 and focused primarily on the influenza A virus (IAV).13 Interestingly enough, an outbreak of measles virus among 94 non-human primates over 2 months in 1996 was identified as reverse zoonosis and was associated with a measles outbreak in humans in the United States during the same period.11,14 However, the very first recorded examples of reverse zoonosis events probably extend to 1796 with the observations of Edward Jenner on cross-protection of variola virus, the cause of smallpox, by infection with cowpox virus;15 vaccinia virus, cowpox virus, and horsepox virus were frequently transmitted between humans and cattle and horses.15
According to Taylor et al,16 the timeframe for emerging pathogens in human populations is “usually over the last 20 years.” In the last 20 years, reverse zoonosis has increasingly garnered attention because of human disease outbreaks, particularly by members of the virus families Orthomyxoviridae (H5N1 and H1N1pdm09 viruses), Coronaviridae (SARS-CoV-1, MERS-CoV, SARS-CoV-2, and CCoV-HuPn-2018), Poxviridae (mpox and vaccinia virus), and arboviruses (VEEV, yellow fever virus, chikungunya virus, dengue virus, and zika virus) that have consistently emerged as important causes of zoonoses,11 and the human respiratory viruses (HRPV-3, HRSV, HMPV, and HRV-C) transmitted to endangered non-human primate species.17 These viruses and their roles in zoonotic diseases are addressed in the companion Currents in One Health by Kibenge, JAVMA, June 2023. Disease outbreaks involving these viruses have occurred worldwide in the face of dramatic anthropogenic activities in the ecosystem (eg, rising human population, globalization of humans and animal products, industrialized agriculture, growth of the companion animal market, urbanization, deforestation, illegal trading and consumption of wildlife, and climate change) against a backdrop of virus mutations.6,18,19 As a consequence, reverse zoonosis has become an emerging One Health aspect.
One Health, as defined by the One Health High Level Expert Panel (OHHLEP) (Figure 1),20 encapsulates collaborative concepts for experts and agencies working in human health, animal health, plant health, and ecosystems health to tackle complex issues that threaten the health and well-being of humans, animals, and ecosystems, recognizing the close link and inter-dependence of the health of all living species and ecosystems. This One Health approach is the best way to prevent and control viral zoonotic and reverse zoonotic diseases. Veterinarians are at the center of it, not only by being at the “front line” in terms of being the first to recognize incidents of reverse zoonosis but also at risk of spillover events from animal reservoirs.
Graphical definition of “One Health.” From WHO, 2021. Tripartite and UNEP support OHHLEP’s definition of “One Health”: Joint Tripartite (FAO, OIE, WHO) and UNEP Statement. Available at https://www.who.int/news/item/01-12-2021-tripartite-and-unep-support-ohhlep-s-definition-of-one-health (accessed December 25, 2021). Used under the Creative Commons Attribution-NonCommercial-ShareAlike 3.0 Intergovernmental Organization (CC BY-NC-SA 3.0 IGO) license (https://creativecommons.org/licenses/by-nc-sa/3.0/igo/). No changes were made.
Citation: American Journal of Veterinary Research 84, 6; 10.2460/ajvr.23.03.0053
Viruses with the potential for reverse zoonosis are characteristically those with a broad host range, most commonly RNA viruses, because of their high mutation rates, which provide a substrate for selection to infect new hosts.19,21,22 Such virus transfers are particularly important for susceptible wildlife whose numbers and behaviors would sustain ongoing transmission as natural virus reservoir hosts and with opportunities for potential re-transmission to humans.22 These viruses can switch hosts by acquiring mutations that change their pathogenicity or due to changes in behavior or socioeconomic, environmental, or ecologic characteristics of the hosts.23
A better understanding of viral reverse zoonoses is critical for the overall health of humans, animals, and ecosystems. However, this continues to be a formidable undertaking. The most studied and probably the best example of reverse zoonotic viruses are IAVs.21,24,25 The human-to-pig transmission of IAV represents the largest reverse zoonosis of a pathogen documented to date.26 In this Currents in One Health article, the author reviews host range as the main risk factor for reverse zoonosis, with an emphasis on IAV disease events in humans and other species in the context of a One Health approach to gain a better understanding of their transmission routes (Figure 2) to facilitate their control and prevent them from occurring. The recent major reverse zoonoses involving other virus groups (Coronaviridae, Poxviridae, arboviruses, and the human respiratory viruses transmitted to endangered nonhuman primate species) and the prevention and control of reverse zoonoses are addressed in the companion Currents in One Health by Kibenge, JAVMA, June 2023.
Emergence and transmission of influenza A viruses from aquatic wild bird reservoirs and zoonotic and reverse zoonotic events involving veterinary species. Adapted from Frymus, T., Belák, S., Egberink, H., Hofmann-Lehmann, R., Marsilio, F., Addie, D.D., Boucraut-Baralon, C., Hartmann, K., Lloret, A., Lutz, H., et al. 2021. Influenza Virus Infections in Cats. Viruses 13, 1435. https://doi.org/10.3390/v13081435. Used under the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Citation: American Journal of Veterinary Research 84, 6; 10.2460/ajvr.23.03.0053
Host Range and the Source of Infection
According to the Joint FAO/WHO Expert Committee on Zoonoses,4 the epidemiological term zoonosis encompasses diseases and infections naturally transmitted between any animal and another animal, human or non-human, without differentiation, that is, infections naturally transmitted from animals to humans and vice versa.3–5 Therefore, understanding the source of infection is essential for controlling and preventing disease spread. The idea of transmission under natural conditions excludes infection that does not involve interaction between live animals and humans, such as infection transmitted from contaminated soil, water, excreta, or dead animals, for example, hepatitis A virus, poliovirus, or rotavirus, which is referred to as sapronosis.3 However, the line between zoonosis and sapronosis based on the source of infection is unclear, and the term saprozoonosis is preferred.3,5 Thus, zoonotic agents can be transmitted from an infected to a susceptible vertebrate host by direct contact, contact with fomites contaminated by an infected vertebrate host, or by arthropod (insect or tick) transmission.5 According to Vourćh et al,10 infectious diseases in animals and humans can be classified into 5 classes according to the relative role of animals in transmission to humans. The classification uses the host range of a virus to differentiate zoonotic viruses—those whose host range includes humans and animals are placed in Classes 2–5—from all other viruses whose host range is exclusively animal, which is placed in Class 1.10 However, because all human viruses evolved from animal viruses,27 host range must be viewed in the prism of virus evolution, and zoonotic and reverse zoonotic viruses can only relate to contemporary animal and human viruses (Figure 3).22 Wolfe et al27 place such viruses at stage 4 of the 5 stages leading to a pathogen becoming exclusive to humans. At stage 4, the virus occurs in animal hosts and is naturally transmitted to humans (ie, typical zoonosis), but also has sustained human-to-human transmission without the involvement of animal hosts, for example, yellow fever virus, dengue virus, and IAVs,27 until a spillover event into a novel animal host population (ie, typical reverse zoonosis) occurs.
Host range of zoonotic and reverse zoonotic viruses. Green arrows indicate human and terrestrial animal viruses evolved from aquatic vertebrate viruses. Contemporary human and animal viruses have a broad host range, including human and animal hosts (zoonotic viruses, ie, transmitted between human and animal hosts) or have a narrow host range, such as exclusively humans or animals. The blue arrow indicates reverse zoonotic viruses (ie, transmitted from the human reservoir to animal hosts), which is only possible in certain situations. For example, humans do not transmit the rabies virus to animal hosts because humans do not bite animals, or in the case of eastern equine encephalitis virus or West Nile virus, humans are dead-end hosts because they do not develop high enough viremia to transmit the virus during a blood meal by an arthropod vector.
Citation: American Journal of Veterinary Research 84, 6; 10.2460/ajvr.23.03.0053
For many viruses, infection of the animal and human occurs from a shared vector or environmental exposure such as in a home, animal hospitals/veterinary clinics, on animal farms, during hunting, in public settings (eg, zoos, national wildlife parks, wet markets, auction markets, country/province/state fairs, petting zoos, animal swap meets, pet stores, nature parks, educational farms, and daycares or schools), in animal research facilities, and animal shelters. In addition, vigilance is essential at the international borders where disease agents can be introduced to national animal and human populations.
Fomite transmission, such as clinical personnel transferring feline calicivirus (FCV) to a cat brought into a veterinary clinic, is not reverse zoonosis because FCV does not replicate in humans (ie, humans are not a reservoir host for FCV). However, in some situations, it may not be easy to categorize the transmission as a zoonosis (animal to human) or a reverse zoonosis (human to animal). For example, the simultaneous influenza outbreaks in humans and pigs during the 1918 pandemic raised questions if the virus had been transmitted from pigs to humans or humans to pigs.26 Likewise, as Weese28 expounded, in SARS-CoV-2 transmission between humans and pet animals, it is challenging to define the transmission as a zoonosis (pet animal to human) or a reverse zoonosis (human to pet animal). In fact, in some IAV transmissions in China, it was impossible to infer the direction of transmission since dogs and cats are naturally susceptible to IAV strains from other hosts, including birds and mammals.29
Arboviruses, where the arthropod is infected by biting a human with or without spillback to animals, represent true viral reverse zoonoses because they involve the transmission of a virus replicating from a human host to an animal host.30 However, transmission from human to vertebrate animals depends on several factors for most arboviruses. For example, humans are usually dead-end hosts for the equine encephalitis viruses (eastern equine encephalitis virus and western equine encephalitis virus), except for Venezuelan equine encephalitis virus where humans have a high enough viremia that they can be a source of virus for the arthropod vectors.31 In the case of the urban arbovirus infections of yellow fever virus,32 dengue virus, zika virus, and chikungunya virus, humans are a source of viruses for wild animals in the sylvatic cycle.10
Risk Factors for Reverse Zoonosis
The main risk factor for the emergence of viral reverse zoonotic diseases is the virus host range in an environment of human activities that facilitate viral zoonoses. The main risk factors that facilitate viral zoonotic diseases are anthropogenic (ie, human-initiated) activities in the ecosystem against a backdrop of virus mutations.18,19 The increasing human-to-human and human-to-animal interaction as a result of the rising human population, globalization of humans and animal products, industrialized agriculture, growth of the companion animal market, urbanization, growing deforestation, increased hunting and illegal trading and consumption of wildlife (wild meat, sometimes called “bushmeat”), habitat destruction, ecological tourism (or ecotourism), land reclamation, and climate change, which are all anthropogenic activities and changes in the ecosystem,33 have increased the incidence of viral diseases naturally transmitted from animals to humans and vice versa.32,34–36 For example, the emergence of zoonotic pathogens of wildlife origin correlates strongly with human density and the global distribution of wildlife biodiversity.34,35,37 In another wildlife situation, ecotourism and research have been developed to reduce the decline of endangered species from hunting and habitat loss.38 However, it is now accepted that human diseases can be transmitted to free-living, habituated apes.39 The pathogen transmission across species is attributed to the close phylogenetic relationship between humans and other Hominidae species (the great ape families comprising chimpanzees, bonobos, gorillas, and orangutans).14,27,39
Viruses with the potential for reverse zoonosis are characteristically those with a broad host range, most commonly RNA viruses, because of their high mutation rates (10−3 to 10−5 errors per nucleotide and replication cycle), high yields, and short replication times,40 which provides a substrate for selection to infect new hosts.19,21,22 In host switching, repeated contact between infected and susceptible vertebrate hosts facilitates the virus’ adaptation to the susceptible host due to the virus mutation via mechanisms such as random mutation, recombination, and gene reassortment. However, successful cross-species transmission does not guarantee that this will be followed by efficient spread into the new population. Other factors, such as transmission between hosts in the new species and other factors unique to the environment of the new host, need to be considered, as was reviewed by Alvarez-Munoz et al (Figure 4).19
Depiction of the different factors related to the characteristics inherent to RNA viruses which facilitate infection, promote interspecies jump, and assist in generating zoonotic infections with pandemic potential. From Alvarez-Munoz, S., Upegui-Porras, N., Gomez, A. P., Ramirez-Nieto, G. 2021. Key Factors That Enable the Pandemic Potential of RNA Viruses and Inter-Species Transmission: A Systematic Review. Viruses 13, 537. https://doi.org/10.3390/v13040537. Used under the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
Citation: American Journal of Veterinary Research 84, 6; 10.2460/ajvr.23.03.0053
Influenza A Viruses
Influenza viruses are classified in the family Orthomyxoviridae, order Articulavirales, which comes from the Latin “articulata,” meaning segmented. Virions are 80–120 nm in diameter, enveloped, and contain a segmented negative-sense single-stranded RNA genome, with the number of genome segments depending on the genus. Influenza viruses are classified into 4 genera: Alphainfluenzavirus, Betainfluenzavirus, Gammainfluenzavirus, and Deltainfluenzavirus, each with a single ratified species: influenza A virus (IAV), influenza B virus (IBV), influenza C virus (ICV), and influenza D virus (IDV), respectively.41 IAV is further classified into subtypes based on the antigenicity of 2 envelope glycoproteins, rod-shaped haemagglutinin (HA), and mushroom-shaped neuraminidase (NA). There are 16 HA and 9 NA subtypes, such as H1N1, H5N1, and H7N2.42,43 Wild migratory aquatic birds (water birds: ducks, geese, and swans; and shore birds: gulls, terns, and waders) are considered the primordial reservoir of all influenza viruses for avian and mammalian hosts.24,44 All combinations, a total of 144 IAVs subtypes, can occur in birds. However, only a limited range of combinations are recognized as important pathogens in mammals (eg, H7N7 and H3N8 in horses; H3N8 and H3N2 in dogs; H1N1, H1N2, and H3N2 in pigs; and H1N1, H2N2, and H3N2 in humans).10,24,42 The most ubiquitous HA subtype of IAVs is the H3, with a wide host range that includes humans, horses, dogs, cats, seals, poultry, pigs, and wild aquatic birds.45 Additionally, highly divergent and diverse IAVs representing novel influenza A-like virus subtypes designated “H17N10” and “H18N11” have been discovered in rectal swabs collected from fruit bats from Central and South America.46 Sequences of novel influenza A-like viruses have also been detected in oropharyngeal swabs of Colombian bat species.47
IAVs are prone to random mutations (pinpoint mutations or single nucleotide polymorphism) and gene reassortment. This gives rise to viruses with higher virulence and novel antigenic types that may lead to epidemics and pandemics. The antigenic shift involves gene reassortment of HA and NA gene segments during mixed infections. The new virus strain may cause a pandemic or a reassortant virus with potentially enhanced pathogenicity and lethality. In contrast, antigenic drift involves an accumulation of single-base mutations in HA and NA genes, and the resulting new virus strain can cause an epidemic. These changes are important in the evolution of IAVs.43 Domestic poultry (ducks, turkeys, and chickens) and pigs are intermediate hosts for the virus infecting humans or horses. The pig is considered a “mixing vessel” because it can be infected by avian and human IAVs, allowing these viruses to acquire genes via reassortment between parental virus subtypes.44
In some cases, humans can also serve as a mixing vessel because avian IAVs can directly infect them. Since 1996, 11 subtypes of avian IAVs have been documented to spread directly from infected chickens to humans (H3N8, H5N1, H5N6, H5N8, H6N1, H7N3, H7N7, H7N9, H9N2, H10N3, and H10N8).22,29,48 Humans can transmit the virus back to pigs, poultry, cats, and dogs (reverse zoonosis).10,42 Humans transmit far more influenza viruses to pigs than pigs transmit to humans. The human-to-pig transmission of IAV represents the largest reverse zoonosis of a pathogen documented to date.26 Cats and dogs are particularly susceptible to IAVs and appear dead-end hosts. However, each can serve as a mixing vessel for IAV strains of diverse origins and transmit them to humans.29,42
The IAV HA protein is responsible for binding to cell surface glycan receptors containing terminal sialic acid and for membrane fusion between the viral and endosomal membranes during virus entry. These functions require cleavage of the HA precursor for activation of HA. Galloway et al49 analyzed the cleavage-activation and membrane fusion characteristics for the 16 HA subtypes. They showed substantial differences between the subtypes that may influence transmission among hosts and establishment in new species.49
Wild birds can carry low pathogenic avian influenza (LPAI) viruses between continents. On the other hand, LPAI viruses (H5 and H7 subtypes) can mutate into highly pathogenic avian influenza (HPAI) viruses as a result of insertion mutations in the cleavage site of the HA gene or deletion mutations in the NA gene and cause clinical disease in birds (mainly in domestic poultry) and mammals (mainly in humans). Both LPAI (H7N1, H7N2, H7N3, H9N2, or H10N7) and HPAI (H7N7 – 1 case fatal, H5N1 – 53% mortality rate, H7N9 – 34% mortality rate) viruses can infect humans.29 However, the species barrier between birds and mammals is considerable. Therefore, an adaptation of avian IAVs is needed for efficient replication and transmission in mammals. This adaptation includes HA’s hallmark receptor-binding specificity switch from the avian-type α2,3- to the (mammalian) human-type α2,6-linked sialic acid receptor.50 In China, H9N2 has gradually replaced H5N6 and H7N9 as the most prevalent AIV subtype in chickens and ducks and has caused numerous human infections.48 Indeed, in comparison with other currently circulating avian IAVs, H9N2 has clear potential to infect humans not only because almost all subtype H9 avian IAVs possess the human-type receptor-binding ability, but it has also notoriously been the donor for the complete or partial set of internal genes for most avian IAVs infecting humans.51 Adaptation of avian IAVs to mammals also requires mutations in the polymerase complex; the E627K mutation in PB2 has been identified as an important host range determinant that likely stimulates virus replication at the lower temperatures of the upper respiratory tract in mammals.52 In addition, the NA presents a species barrier. It contains a second sialic acid-binding site (2SBS) in avian IAVs that is absent in the 2SBS in human IAVs, which affects NA catalytic activity.25 Thus, complementary changes in NA are considered to restore the HA-NA-receptor balance required for virus fitness. Furthermore, phylogenetic analyses of field avian IAVs show that mutations in the 2SBS precede mutations in HA that reduce the binding of avian-type receptors and increase the binding of human-type receptors. Thus, 2SBS mutations in NA can drive the acquisition of HA mutations that restore the HA-NA balance and confer increased zoonotic potential.25
Influenza A(H1N1)pdm09
The 2009 H1N1 pandemic was the fourth influenza pandemic, after the first one in 1918 by the H1N1 virus, the second in 1957 by H2N2 virus, and the third one in 1968 by H3N2 virus. The 1918 virus jumped from avian reservoirs and was transmitted to pigs and then humans and was carried from North America to Europe by American troops and caused the pandemic of 1918. The 1957 and 1968 viruses resulted from gene reassortment between viruses from wild ducks and humans. The pandemic Influenza A (H1N1) 2009 (H1N1pdm09) virus, which was first identified in Mexico in April 2009 in a 6-year-old boy with respiratory disease (but negative to H1N1 seasonal IAV that had been circulating in the population since 1977), emerged as a triple reassortant virus in pigs;53 it was first recognized in pigs in Canada in May 2009, with respiratory disease, and in turkeys in Chile in June 2009 with a severe drop in egg production.54 One of the triple reassortant viruses or TRIGs (triple reassortant viruses carrying influenza genes) of avian, swine, and human origin led to the H1N1pdm09 virus. These viruses show great reassortment flexibility and are efficiently transmitted between humans, pigs, and poultry. They emerged in North America in the 1990s.55 TRIGs of H3N2, H1N1, and H1N2 are circulating in swine in North America and, since 2011, have been sporadically infecting humans as variant influenza viruses (H3N2v, H1N1v, and H1N2v). During the 2009 pandemic, several human infections of the H1N1pdm09 virus worldwide were epidemiologically linked to infections in several animal species, including pigs, turkeys, cats, dogs, ferrets, and wildlife.56
AIV H5N1
The first direct transmission of HPAI H5N1 from chickens to humans occurred in Hong Kong in 1997 and was traced back to LPAI in wild and domestic waterfowl in Guangdong province, China, in 1996.57 In this outbreak, 18 people were infected, and 6 of them died; as result, the Hong Kong government ordered the slaughter of all poultry, 1.5 million chickens, ducks, and turkeys, to control the disease.57 The virus re-emerged in Hong Kong in 2002 with increased pathogenicity for wild migratory birds.58 Since 2003, AIV H5N1 has occurred in Southeast Asia, spreading initially to Europe and North Africa,59–61 and most recently to the Americas,62 posing a pandemic threat. As of January 26, 2023, 868 infected people and 457 deaths (case fatality rate 53%) in 21 countries have been reported worldwide to WHO.63 Since 2003, this pandemic threat has remained at stage 3 on the WHO pandemic scale because it has not resulted in human-to-human transmission sufficient to sustain community-level outbreaks.64 However, the current outbreak of AIV H5N1 in animals is the largest in Europe and North America and has involved captive and wild birds, mammalian wildlife,50,53 and in Spain, farmed mink.65 The outbreak is driven by H5N1 clade 2.3.4.4b viruses, which emerged in the Netherlands in October 2020 before spreading through Europe, Asia, and Africa.66 A recent report by the European Food Safety Authority (EFSA) and other agencies found that since October 2021, more than 58 million birds have died or been culled in H5N1-affected poultry establishments in 37 European countries.60 The virus arrived on the Atlantic coast of North America in December 2021, rapidly spreading to the United States, Canada, and Mexico. In the United States, the epidemic began in Indiana in February 2022. In the past 15 months, it has killed nearly 60 million commercial and backyard poultry and unknown thousands, perhaps millions, of wild birds in 48 states. It is the largest and probably the costliest animal disease outbreak in the United States’ history.62 AIV H5N1 was first detected in South America in Peru in November 2022 and subsequently in other South American countries, including Colombia, Venezuela, Chile, Bolivia, Guatemala, Uruguay, and Argentina.67 The list of mammals with confirmed infections in Europe and the Americas includes badger, black bear, bobcat, coyote, dolphin, ferret, fisher cat, fox, leopard, lynx, opossum, otter, pig, polecat, porpoise, raccoon, raccoon dog, striped skunk, harbor seal, grey seal, sea lions – presumably infected through scavenging on infected dying wild birds or bird carcasses or ingestion of contaminated water or feces.66,68 Most recently, one domestic dog in Canada and three domestic cats in the United States tested positive for AIV H5N1.69
The most sustained mammal-to-mammal transmission of the AIV H5N1 was the 2022 farmed mink outbreak in Spain,65 associated with several virus mutations. Interestingly, these mutations were initially identified in H5N1 viruses in gulls in the Netherlands and Belgium between June and October 2022, which had emerged from reassortment events with viruses of the gull-adapted A(H13) subtype.65 All 4 virus isolates from the minks contained a methionine at position 396, located in 2SBS in the NA glycoprotein, which is highly conserved as isoleucine in all NA subtypes of avian IAVs and is mutated in all human (pandemic) viruses and several other viruses adapted to mammalian host species.25 Thus, preservation of 396I or mutation in the 2SBS is likely to be a viral host range determinant25 and could be an early adaptation signal that should be included in the analysis of the pandemic potential of emerging IAVs.59 Such mutations support undertaking “genomic surveillance” to rapidly identify viruses with zoonotic mutations.68 However, genomic comparisons do not indicate whether disease emergence is likely.10
The risk factors for reverse zoonosis in IAV infections are similar to those during the 2009 influenza A(H1N1) pandemic.70 They include interaction between infected humans and susceptible animals and the ability to establish a reservoir in the animal host population from which reintroduction into humans (ie, spillover event) can occur,70 that is, host range is the main risk factor for viral reverse zoonosis. Ideally, the best way to prevent animal infections transmitted from humans is to reduce contact with wildlife animal species and, where effective vaccines are available, to vaccinate the main reservoir—humans71 and susceptible farmed and pet animals. The latter needs to be strongly promoted by veterinarians in their practices. After the re-emergence of HPAI H5N1 virus in humans in 2003, the international organizations WHO, WOAH, FAO, UNICEF, the World Bank, and the United Nations System Influenza Coordination (UNISIC) developed a strategic framework for reducing risks of infectious diseases at the animal-human-ecosystem interface.72 It is generally accepted that vaccination is the best method for preventing and controlling influenza;73 there continues to be an interest in developing either a “universal influenza virus vaccine” or a “broadly protective” vaccine against all strains of IAVs.74 These vaccines would protect farmed and pet animals against reverse zoonosis and prevent any spillover of IAVs into the human population and wildlife. However, the vaccination of commercial poultry against HPAI viruses remains controversial despite its use by some 30 countries since 2005, with the European Union to start by May 2023, whereas the United Kingdom allows vaccination only in zoos and the United States does not plan to vaccinate.75
Conclusion
The main risk factor for the emergence of viral reverse zoonotic diseases is the virus host range in an environment of human activities that facilitate viral zoonoses, which can be managed using a One Health approach. The human-to-pig transmission of IAV represents the largest reverse zoonosis of a pathogen documented to date. At the same time, the 2022 farmed mink outbreak in Spain was the most sustained mammal-to-mammal transmission of the HPAI H5N1 since its re-emergence in humans in 2003. Therefore, the best way to mitigate the impact of reverse zoonosis of IAV infections is by vaccinating humans and susceptible farmed and pet animals.
Acknowledgments
No third-party funding or support was received in connection with the writing of the manuscript. The author declares that there was no conflict of interest.
Dr. Kibenge serves as Associate Editor for the Journal of the American Veterinary Medical Association (JAVMA). He declares that he had no role in the editorial direction of this manuscript.
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