*3.1.1.4 West Nile Virus*

An emerging zoonotic arbovirus, West Nile Virus (WNV), was first described in a sick woman located in the West Nile Uganda district in 1937 [37]. Sixteen years later WNV was detected in birds living in the Nile delta region, suggesting its transmission cycle involves mosquito vectors and birds – yet may infect humans [38]. It is now known WNV is capable of infecting both humans and other vertebrate species, with its sylvatic cycle infecting horses and humans as dead-end hosts and birds as the amplifying host. Unlike the previously mentioned viruses, WNV uses the *Culex* genus mosquitoes as its primary vector. Recently, additional mosquito genera, *Aedes* and *Ochlerotatus*, were identified as possible WNV vectors. Although this virus historically caused outbreaks in Africa, Asia, and the Middle East, cases of WNV are now common in Europe and the Americas. The first US case occurred in 1999 and within a decade cases were identified in Canada, Mexico, and South America – with cases as south as Argentina [37]. WNV has spread to all continents except Antarctica, increasing the risk of future and larger epidemics worldwide. WNV is now considered endemic in the US with as many as 47 US states reporting WNV cases each year [38]. Although the incidence of WNV has increased throughout the decades, most human WNV infection are asymptomatic [39]. About 1% of infected individuals experience severe neuroinvasive disease such as meningitis, encephalitis, and flaccid paralysis [39, 40]. The movement of migratory birds in addition to the local movement of sedentary birds are hypothesized to contribute to the global distribution of WNV [38]. Current public health programs aiming to reduce the spread of WNV rely on GIS and mosquito population control techniques. Furthermore, since WNV is able to infect horses and birds, many endemic areas have equine and sentinel programs focused on surveillance

and monitoring of WNV transmission. Moreover, recent mathematical and GIS models identified risk factors pushing WNV transmission such as populations living in poverty, environmental factors, and mosquito populations [41]. There are no current approved vaccines against WNV, leaving public health prevention programs and vector surveillance the main barrier between WNV causing larger human outbreaks.

#### *3.1.1.5 Crimean-Congo hemorrhagic fever virus*

A Nairovirus, Crimean-Congo hemorrhagic fever (CCHF), is an emerging infectious disease using *Hyalomma* genus ticks as its vector with distribution in Africa, Asia, and Europe [42]. CCHF was first described in the Crimean Peninsula less than a century ago, in 1944, during World War II when cases were brought on Soviet soldiers. Since then, the importance of CCHF has grown so much so that in the last 3 years the WHO considers it one of eight priority emergent pathogens [42]. Currently this zoonotic virus is endemic in approximately 50 countries throughout the world. Domesticated animals such as sheep, cattle, and goats as well as birds serve as the amplifying host, maintaining the transmission cycle alive in diverse regions. The Crimean-Congo hemorrhagic fever virus is transmitted to humans mainly through the bite of hard-bodied ticks yet can be transmitted with direct contract with blood and other infected bodily fluids. An infection typically comes directly from an infected tick or ticks on livestock that then bite humans. For those reasons many CCHF cases originate in individuals in agricultural jobs (direct) and nosocomial environments (direct bodily fluid contact). Most cases are asymptomatic or present mild symptoms such as fever, headaches, dizziness, and abdominal pain and myalgia [43]. In severe cases the course of infection includes an incubation period, pre-hemorrhagic, hemorrhagic, and convalescent phases [43, 44]. It is estimated approximately 10% of the cases will present severe disease with mortality rates ranging from 20- to over 30% in these severe cases [44]. Due to high mortality rates and global risk, the Centers for Disease Control and Prevention (CDC) considers CCHF virus a level 4 biosecurity risk pathogen [42]. There is currently no approved CCHF vaccine and treatment is usually supportive and symptomatic [42]. Fortunately, the current geographic distribution of the *Hyalomma* tick is limited to 50 degrees north latitude [45], preventing the disease to expand beyond this geographical limitation for now. Nonetheless, the climate change and increased environmental temperatures may provide the vector an opportunity to expand its traditional reach which may become an International Health Security threat. Consequently, CCHF prevention focuses on public health education, environmental programs, and physical barriers (e.g., thick clothing, long sleeve shirts, long sleeve bottoms) [43].

#### *3.1.1.6 Mayaro virus*

This emerging zoonotic pathogen is an enveloped +ssRNA virus belonging to the alphavirus genus of Togaviridae family [46]. Mayaro virus (MAYV) is part of the viruses of Semliki forest antigenic complex and causes Mayaro fever [46, 47]. Transmission of MAYV into humans occurs primarily through the bites of infected mosquitoes of the genus *Haemagogus* spp., especially *Haemagogus janthinomys*, with experimental studies showing the ability of MAYV to infect mosquitoes of another genus such as *Aedes aegypti*, *Culex*, *Mansonia*, *Psorophora*, and *Sabethes* [46, 48]. The sharing of common antigenic sites among viruses of Semliki complex causes serological misdiagnosis and underreporting of MAYV infection in endemic areas [46, 49]. MAYV infection produces self-limiting symptoms of fever, headache,

#### *Which Plagues are Coming Next? DOI: http://dx.doi.org/10.5772/intechopen.96820*

myalgia, arthralgias, maculopapular rash with more than 50% of them developing long-term incapacitating arthralgias. Sometimes Mayaro fever can result in complications resulting in hemorrhagic manifestations, neurological manifestations, myocarditis, intermittent fever, and death [46, 49]. Pharmaceutical countermeasures such as specific antiviral agent or licensed vaccine are not available against MAYV. Thus, prevention and control of MAYV infection is dependent on vector control techniques and barriers to prevent human-vector contact. This neglected tropical virus was first isolated from the sera of forest workers of Mayaro county, Trinidad and Tobago in August–September 1954 [50]. Even earlier evidence of transmission of MAYV in Panama and Colombia between 1904 and 1914 was provided by a retrospective study [51]. This was followed by reporting of MAYV infection in Brazil, Bolivia, Colombia, Surinam, Peru, Ecuador, French Guinea, Venezuela, and Haiti [46, 52]. Currently, the pathogen is endemic in regions of Central Brazil and the western coast of South America [52]. The import of MAYV cases in North America, Netherlands, France, and Germany in last decade shows the potential of travelling in introduction of agent in new areas [46, 52]. Infection with MAYV is detected in many vertebrate hosts such as nonhuman primates, rodents, sloths, small mammals, and birds with nonhuman primates (monkeys) being suspected of maintaining the enzootic cycle [46, 47]. The zoophagous nature of the *Heamagogus* spp. species results in the restriction of MAYV to rural areas with occasional outbreaks in humans [49]. However, the ability of MAYV to infect urban vectors like Aedes (*Ae. aegypti* and *Ae. albopictus*) suggest a potential future expansion and invasion of MAYV into urban areas of the world becoming an International Health Security threat [46, 52]. Anthropogenic changes, genomic mutations, insecticide resistance in vectors, globalization, climate change, and infection of urban mosquito vectors could result in epidemiological evolution of MAYV and MAYV fever becoming an International Health Security threat.

### *3.1.1.7 Chikungunya virus*

First reported in 1952 in Tanzania, Chikungunya virus (CHIKV) is an alpha virus apart of the Togoviridae family and transmitted by Aedes mosquitoes [53]. The word Chikungunya translates as "the disease that bends up the joints", which is one of the severe symptoms of the disease (i.e., arthritis) [54]. The main transmission among humans occurs through epizootic cycles, where vertebrates are the viral reservoirs and the mosquito acts as the vector [55]. Since its discovery, there were CHIKV outbreaks throughout Europe, India, and Asia. CHIKV was a mostly a forgotten infectious disease until its 2006 resurgence and widened global reach. In 2007, Europe reported its first autochthonous CHIKV infection and by 2013 it had found the Americas, first landing in Saint Martin and then spreading throughout South America [53]. In spite of underreporting and misdiagnoses cases have occurred in more than 45 countries [55]. Active outbreaks allow humans to become the reservoirs and continue to fuel the outbreak. Like Zika, the first autochthonous cases in the Americas were fairly recent, with CHIKV's first outbreak in the Northern and Northeastern regions of Brazil [53]. The most serious outbreak was probably the Reunion Island outbreak between 2005 and 2006, where nearly a third of the island's population (255,000) was infected and over 250 individuals died [56]. A CHIKV infection typically causes symptoms such as fever, arthralgia, myalgias, and skin rashes [55]. In a subset of cases, joint inflammation and arthritis lasting up to 4 months may occur [55]. The increased incidence of CHIKV over the recent decades in areas previously unaffected, in addition to the wide geographical range of its vector (i.e., the Aedes genus) lead to heightened concern of future outbreaks and adverse health outcomes. Moreover, recently CHIKV infection is

associated with abortion during the first and last trimesters of pregnancy, further emphasizing the need for CHIKV research and therapeutics [55].

#### *3.1.2 Bacteria*

### *3.1.2.1 Rickettsia prowazekii*

As one of oldest infectious diseases known to mankind, Typhus, caused by the bacteria *Rickettsia prowazekii* and *R. typhi*, continues to be an International Health Security threat. Due to the nature of the outbreaks caused by *R. prowaszekii*, having higher mortality rates [57] and a recently discovered animal reservoir (i.e., flying squirrel) [58, 59], only *R. prowazekii* will be covered in this section. *R. prowazekii*'s, the cause of epidemic typhus, history is unclear. Some scholars believe epidemic typhus to be have caused the 430 BC plague of Athens [57, 60, 61] where it killed 25% of the population [61]. While the origins of this pathogens may be unclear, it is certain it continues to be part of an International Health Security program today. Typhus is also referred to as a pestilential disease, or an infectious disease killing a large number of individuals, that is commonly used in old world diseases. Epidemic typhus is usually associated with cold months and poor sanitary conditions are conducive to lice proliferation [60]. Until the late 1900s, *Pediculus humanus corporis* (i.e., human body lice) was thought to be the only vector for *R. prowazekii* until the late 1970s when a US outbreak seemed to inculpate *Glaucomys Volans* (i.e., southern flying squirrel) [58, 59]. Infection occurs when an infected human body louse defecates on an individual and its feces, containing R. prowazekii, enters the bite site or wound [57, 60]. Transmission via flying squirrel is not yet completely understood [60], however it is thought to spread through aerosolized ectoparasite feces [57, 60]. Currently, epidemic typhus is endemic in South America, Africa, and Asia [57, 60]. Outbreaks propagate especially following famines, climate changes, wars, and social unrest all of which are currently present in the world [57, 60]. One of the most recent largest outbreaks was reported during the Burundi civil war in 1997, where approximately 100,000 individuals were infected and the case fatality rate was 15% [60]. Clinical manifestation of Typhus includes skin rashes (crucial for clinical diagnosis), fever, headaches, and cough [57, 60]. Without treatment, the case fatality rate could be as high as 60%, however, currently with treatment is closed to 4% [60]. Unlike the previously mentioned pathogens, once infected with *R. prowazekii* individuals may stay infected for life. This is even more alarming given a recrudescence may cause Brill-Zinsser disease [57, 60, 62]. Currently, epidemic typhus is treated using antibiotics (doxycycline) and there is no approved vaccine. Given infection by inhalation it is possible R. prowazekii may be used as a biological weapon and is warrants additional research and funding [60, 63, 64]. With the current International Health events including refugee camps, wars, and populations living in unsanitary condition, epidemic typhus may continue to produce outbreaks similar to the Burundi outbreak and therefore vaccine development should be encouraged.

#### *3.1.2.2 Yersinia pestis*

Perhaps the most infamous infectious disease, the Black Plague or Black Death, is caused by *Yersinia pestis*. *Y. pestis*, a bacterium, has caused multiple plagues throughout the history of mankind [60, 64]. The earliest epidemic caused by *Y. pestis* killed approximately 30 to 50 million people in the 541–542 AD Plague of Justinian [64]. Since then, there were four additional pandemics caused by this pathogen, the Black death (1347–1351), Italian plague (1629–1631), Great plague of

#### *Which Plagues are Coming Next? DOI: http://dx.doi.org/10.5772/intechopen.96820*

London (1664–1666), and the Third plague (1885) [64]. In total, the five pandemics caused by *Y. pestis* are estimated to have killed over 250 million people. Cases of the plague still exist, yet the discovery of antibiotics has greatly reduced the global burden of this disease [60]. There are five forms of plague, all affecting the human body differently and having different mortality rates, bubonic, septicemic, pneumonic, meningeal, and pharyngeal [64]. However, there are typically three types of plagues described in the literature and main causes of outbreaks: bubonic, septicemic, and pneumonic [64, 65]. Today most human cases of plague are of the bubonic or pneumonic form, caused by spillover of an infected flea (bubonic) or by the inhalation of infectious droplets (pneumonic) [66]. The transmission of *Y. pestis* relies on rats (*Rattus rattus*) and its ectoparasite the rat flea (*Xenopsylla pheopis*). Conversely, in 1941 body lice and human fleas were found to be infected with the plague, indicating other vectors may exist. Currently there are no documented cases of plague being transmitted by body lice or human fleas to humans [66], yet some scholars suggest previous epidemics were caused by plague infected lice based on genomic evidence and paleomicrobiology [60]. Buboes or swollen lymph nodes are classical characteristics for Bubonic plague and typically are transmitted from rodents [66]. Septicemic plague is a severe form of bubonic plague where the bacteria enter the blood stream. Pneumonic plague affects the lungs and is transmitted by aerosolized bacteria [66]. Due to the respiratory nature of pneumonic plague, pneumonic plague can be spread person to person yet usually the high case fatality rates end the outbreaks quickly [66]. The case fatality rate, in the absence of treatment, for pneumonic plague can near 100%, while bubonic plague being around 40–70%, and septicemic around 50% [65, 66]. As mentioned, the plague took millions of live throughout the history of mankind and continues to do so to this day. The largest (n = 2348 cases) latest outbreak occurred in Madagascar late in 2017, with 70% of the cases diagnosed as pneumonic plague and 202 deaths occurring [67]. While the probability of a pandemic caused by the plague has decreased, a recently discovered multidrug resistant strains of *Y. pestis* has raised alarms for potential future outbreaks becoming of International Health Security concern [65, 67]. The Madagascar strain (MDR *Y. pestis* plasmid pIP1202) was found to be resistant to eight common antibiotics (i.e., streptomycin, chloramphenicol, tetracycline, sulfonamides, ampicillin, kanamycin, spectinomycin, and minocycline) [68, 69]. Currently, there are still antibiotics (e.g., doxycycline) successful in treating MDR plague. Moreover, the high mortality rate in conjunction with the ability to be transmitted person-to-person leads *Y. pestis* to be classified as a Category A biothreat agent (i.e., high priority agent) [70, 71]. Without an approved vaccine available and the presence of a multidrug resistant plague, the Black Death may re-emerge from the history books.

#### *3.1.2.3 Francisella tularensis*

The causative agent of tularemia, *Francisella tularensis*, is transmitted to humans by different types of arthropods (e.g., ticks, flies, mosquitoes) or ingesting contaminated meat or water [65, 66]. First described in the 16th century, Tularemia affects mostly in the northern hemisphere [67]. It is now hypothesized Tularemia arrived from the Middle East to Central Anatolia since 14th century BC [67]. Due to its survival in water and its transmission, it may also be considered a waterborne pathogen [66]. The two main transmission cycles, terrestrial and aquatic, utilize different reservoirs and vectors and are differentiated by subspecies tularensis (also called Type A) and holarctica (also called Type B) [65]. Type A, being terrestrial and using mainly ticks, mosquitoes, and flies in its transmission cycle will be covered in this section. The most understood and established vector for *F. tularensis* is

the tick (e.g., *Dermacentor andersoni*, *D. variabilis*, and *A. americanum*). Mosquitoes and flies are thought to be mechanical vectors and their role in transmission is not fully understood [65]. The infectious dose for contradicting tularemia is extremely low, with only 10 *F. tularensis* bacteria needed to establish an infection subcutaneously and 25 when in aerosol form [65]. Disease typically is one of two forms either the ulceroglandular form (i.e., the most common) or the typhoidal form (i.e., the most severe form) [65]. There is currently no vaccine available against Tularemia and antibiotic treatments (doxycycline and ciprofloxacin) exist [68]. Due to its multiple forms of transmission in addition to mortality rate (30–60%) [65, 68], the pathogen is considered a Category A biothreat agent and requires a level 3 biocontainment [65, 68, 69]. This would not be the first time *F. tularensis* is considered a biological warfare agent, according to some scholars *F. tularensis* was used in the 1320–1318 BC Neshite-Arzawan conflict as a biological agent [67], warranting a need for further research and vaccine development as it constitutes an International Health Security threat.

## *3.1.2.4 Elizabethkingia anophelis*

A newly uncovered bacterium, *Elizabethkingia anophelis* was discovered in 2011 in the midgut of an *Anopheles gambiae* mosquito [70–73]. Less than a decade since its discovery this pathogen has caused human disease in Asia [73–75], North America [76, 77], Europe [72, 78], and Africa [79]. The route of transmission remains unclear, although it is theorized mosquitoes transmit the bacteria to humans [80]. In Hong Kong there is evidence of perinatal vertical transmission [80] and both an outbreak in Singapore and Greece link *E. anophelis* cases to the water sources [78, 81]. The pathogen recently gained international attention by a large outbreak occurring in Wisconsin, USA, where over 60 cases were identified and 18 deaths occurred [71]. Clinical symptoms may include mostly sepsis, meningitis, fever, bacteremia, and pneumonia [71, 72, 76, 78], among others. Currently the case fatality rate is estimated between 23–70% [71–74, 80]. Disease was usually present in neonates, the elderly, chronic illness or immunocompromised individuals [80]. With increasing prevalence of people with co-morbidities this agent may see increased cases in the years to come. Since discovery, *E. anophelis* is found to be resistant to beta-lactam antibiotics and aminoglycosides [82], yet susceptible to minocycline, levofloxacin, among others, complicating treatment. With less than a decade since its discovery there are many knowledge gaps in all aspects of this pathogen from transmission cycle to disease manifestations. More research is warranted in addition to sustaining current mosquito control programs and surveillance.

#### **3.2 Airborne**

In the last century, some of the deadliest pandemics were spread through respiratory droplets or aerosols. Globalization and shortening of travel time have further increased the speed of spread of airborne diseases. Scientific advances in vaccine development and antimicrobials has helped to counter these outbreaks however risk of massive outbreaks due to emerging and re-emerging pathogens remain and is an International Health Security issue. The 2019 coronavirus disease (COVID-19) pandemic has shown the susceptibility of human population to novel emerging or re-emerging pathogens and its significant effect on economic, social, and human health. It has also shown the ability of a pathogen to rapidly disseminate through airborne or respiratory route and the difficulties associated with prevention and control measures. The majority of pathogens require isolation, quarantine and

#### *Which Plagues are Coming Next? DOI: http://dx.doi.org/10.5772/intechopen.96820*

respiratory precautions (surgical masks, personal protective equipment in hospitals, cleaning of surfaces, disinfection of surfaces, and hand hygiene) as prevention and control measures. Dangerous pathogens such as viruses, bacteria, or fungi transmitted from environment, animals or humans through respiratory route and having potential to cause epidemics and/or global pandemics are listed below along with the available medical countermeasures.

#### *3.2.1 Viruses*

#### *3.2.1.1 Variola virus*

*Variola virus*, a member of the *Orthopoxvirus* genus is the causative agent of smallpox. Before the 15th century, the disease was limited only to the continents of Europe and Asia. The smallpox was introduced into the Americas, Africa, and Australia between 15th and 18th century due to European colonialism and resulted in massive outbreaks with high case-fatality rates due to immunological naïve populations [83]. The variola virus was transmitted in humans predominantly through respiratory droplet nuclei. It can also transmit the infection through contact with body fluids, skin lesions, and scab fluids of infected person. The smallpox virus is limited to the human population with no animal reservoir [83, 84]. The global health campaign for smallpox eradication resulted in the eradication of smallpox in 1980 with the last natural case of smallpox in Somalia in 1977 [83]. In 1978, the accidental laboratory release of variola virus in Birmingham, United Kingdom and the resulting infection and death of a photographer due to smallpox is the last known death due to smallpox in the world with her mother being the last known case of smallpox. The eradication of smallpox was followed by cessation of smallpox vaccination programs and that has resulted in the mankind losing immunity to smallpox and other orthopoxviruses [84].

The variola virus is recognized as a huge threat to human health if used as bioweapon. This was based on the ability of Soviet Union to weaponize smallpox in the 1980s [83]. In 1994, the WHO Committee on orthopoxviruses decided, the stocks of variola virus DNA should be kept at only two international laboratories in world, namely Centers for Disease Control and Prevention (United States) and State Research Center of Virology and Biotechnology -VECTOR institute (Russia) [84]. However, fear remains that secret variola virus stocks could be kept illegally somewhere and be used in bioterrorist attacks; therefore, it is a threat for the International Health Security [83]. Genomic studies on orthopoxviruses has suggested the deletion of genes as an important concept for the reductive evolution of orthopoxviruses in adapting to new host species or emergence of new virus species [83, 85]. The existence of zoonotic orthopoxviruses with the ability to cause sporadic human cases raises the possibility of reemergence of variola virus as part of these natural evolution of orthopoxviruses [84]. Like the introduction of the smallpox in the Americas, either the release of variola virus intentionally or its reemergence as part of natural evolution can result in public health emergency of global concern with high fatality. This concern is mainly due to a huge proportion of the world being immunologically naïve, increased percentage of immunologically suppressed population, and globalization resulting in rapid spread of virus [83]. The effective vaccine and two antiviral drugs (brincidofovir and tecovirimat) are available pharmaceutical measures to fight any future outbreak due to either natural evolution or bioterrorist attack [83]. However, the lack of practical knowledge among healthcare professionals related to smallpox clinical characteristics may further delay early diagnosis, treatment and control of the outbreak.

#### *3.2.1.2 Monkeypox virus*

Monkeypox virus, has emerged as the most common pathogenic Orthopoxvirus and causes a zoonotic disease Monkeypox [86]. Similar to the variola virus, transmission is through respiratory droplets/secretions or contact with the lesion material [86]. Monkeypox is endemic in Central and West Africa with similar clinical manifestations as smallpox and a case-fatality rate of 10% [83, 84]. The clinical manifestations include fever, myalgia, exhaustion followed by appearance of rash and lymphadenopathy in 1–3 days [86, 87]. Monkeypox virus can infect a wide range of mammalian species with various species of African rodents acting as natural reservoir [88]. Monkeypox virus usually results in sporadic cases due to low efficiency of person-to-person transmission and occurs mainly from primary human cases but never from secondary cases [83, 84, 86]. However, during the recent outbreaks in Nigeria and Democratic republic of Congo (DRC), increased person-to-person transmission was observed along with associated imported cases in UK, US, Israel and Singapore [83, 89]. Additionally, in the US Midwest outbreak, the virus showed the ability to infect intermediate hosts (prairie dogs) from natural reservoirs and subsequently infect humans [90]. Infection with a Orthopoxvirus or smallpox vaccination provided protection against monkeypox virus and thus smallpox eradication and cessation of vaccination has resulted in decreasing number of vaccinated individuals [90]. Currently the monkeypox virus is in stage-3 of pathogen evolution to cause disease and phase-3 of WHO pandemic security alert level. The risk factors of absence of population-scale immunity, increasing efficiency of person-to-person transmission, and the presence of animal reservoir along with potential intermediate host suggests that monkeypox is no longer a rare disease and has potential to cause widespread epidemics becoming a threat for International Health Security. There is currently no approved antiviral or detailed case management for monkeypox however, selective agents developed for smallpox virus could be tested for treatment efficacy in case of outbreaks [89].

#### *3.2.1.3 Nipah virus*

Nipah virus is an emerging zoonotic -ssRNA virus belonging to the Henipavirus genus and Paramyxoviridae family. The natural reservoirs of Nipah virus are the Pteropid bats (fruit bats) with pigs acting as intermediate hosts [91, 92]. The fruits bats are limited to farms and orchards in the tropical and subtropical regions of Asia, East Africa, and Australian continents [91, 92]. The consumption of fruits by pigs which are contaminated or partially eaten by the Nipah virus infected Pteropod bats results in the spillover of the virus to intermediate hosts [93]. The transmission of the virus from intermediate hosts to humans is through direct contact with the excretions and secretions of infected pigs such as urine, saliva and respiratory secretions [92, 93]. The animal to human route is the primary mode of transmission with limited person-to-person transmission through direct contact with respiratory droplets or fomites. The major clinical manifestation of Nipah virus infection is acute encephalitis with headache, fever, vomiting, and dyspnea [92].

The Nipah virus outbreaks are limited to Asian continent with Malaysia (43%), Bangladesh (42%), and India (15%) reporting the incident cases worldwide [92]. The first outbreak of Nipah virus was identified in Malaysia in 1998 which spread to Singapore in 1999. This was mainly due to the importation of infected pigs from Malaysia to Singapore and the spillover of infection among pig farmers and abattoir workers [94]. This was followed by outbreak in Bangladesh in 2001 and neighboring India. In Bangladesh cases are identified nearly every year while India has reported outbreaks in 2001, 2007, and 2018 [92, 93]. All the Nipah virus outbreaks reported

#### *Which Plagues are Coming Next? DOI: http://dx.doi.org/10.5772/intechopen.96820*

till now had limited person-to-person transmission with R0 < 1 [93]. However, due to the high rate of mutations in the RNA virus, it has the potential of generating a strain with R0 > 1 [93]. Currently the disease is in the stage-3 of pathogenic evolution with phase-3 on pandemic alert scale. There is currently no medical countermeasure (antiviral or vaccine) approved or available against Nipah virus [92]. The genomic heterogeneity combined with the known susceptibility in humans and ability to cause person-to-person transmission suggests a future pandemic risk of Nipah virus and thus the listing of Nipah virus diseases as one of the WHO priority diseases with greatest danger for International Health Security [93, 95].

## *3.2.1.4 Hendra virus*

Similar to the Nipah virus, Hendra virus is an emerging zoonotic pathogen belonging to the genus Henipavirus and family Paramyxoviridae. The Pteropid bats (Australian flying foxes) are the natural host with horses acting as amplifying hosts [91, 96]. Human disease follows transmission through contact with respiratory secretions of infected hosts while no person-to-person has been documented until now [96]. The clinical feature of Hendra virus disease in humans is acute encephalitis with or without influenza-like illness [96]. The first outbreak was identified in 1994 in Australia and the disease has been limited to Australia. There have been 7 human cases until now with a high case-fatality rate of 57% [96]. Currently, the disease is limited to stage-2 of evolution with phase-2 of pandemic alert level. There is currently no medical countermeasure (antiviral or human vaccine) approved against Hendra virus; however. an equine subunit vaccine is approved in Australia [92, 96]. The identification of virus in horses and presence in Pteropid bats underpins the potential of virus to cause large outbreaks in future becoming a threat for International Health Security.

#### *3.2.1.5 Influenza viruses*

These are a group of four types of enveloped -ssRNA Influenza viruses (A, B, C and D) belonging to the Orthomyxoviridae family of virus and are the common etiologic agent of respiratory infections in humans [97]. The virus is transmitted from person-to-person through respiratory droplets or contact with fomites [68]. Of the four types of influenza viruses, Influenza A and B cause disease in humans with influenza A having the ability to infect hosts of multiple species (pigs, horses, aquatic birds and poultry) in addition to humans [68, 98]. Influenza A undergoes antigenic drift and antigenic shift and thus causes seasonal epidemics and global pandemics while Influenza B undergoes only antigenic drift and is responsible for only seasonal epidemics [68, 99]. Antigenic drift is due to point mutation and results in minor genomic changes while antigenic shift is due to genetic reassortment and results in major genomic changes [68]. The antigenically different 18 hemagglutinin and 11 neuraminidase proteins further divides influenza A viruses into various subtypes i.e. H1N1, H3N2, H5N1, H7N9, H5N8.

Influenza A viruses have caused the highest number of known global pandemics in human history with Spanish flu (H1N1) in 1918, Asian influenza (H2N2) in 1957, Hong Kong influenza (H3N2) in 1968, and Swine flu (H1N1) in 2009 [100]. The seasonal influenza is responsible for annual epidemics in the human population with approximately 5–15% of the total world population being affected annually [68]. The clinical features of influenza infection include myalgia, headache, fever, sore throat, and non-productive cough with nearly 50% of infections asymptomatic [98]. The worldwide dissemination of avian influenza A viruses in domestic poultry flocks and birds and the demonstrated ability to infect humans has raised

the potential of future pandemic due to avian influenza A viruses which is of main International Health Security concern [101]. In 1997, an outbreak of H5N1 in Hong Kong resulted in 18 human cases and resulted in six deaths [102]. This was followed by continuous circulation of H5N1 strain in China with the widespread geographical distribution of this epizootic strain. Between 2003 and 2009, H5N1 resulted in 4o3 human cases with a high case fatality rate of 63%. Despite the high fatality, biological barriers prevent efficient binging of influenza virus to human receptors and thus the virus continues to have inefficient person-to-person transmission [102]. Similar human infections resulting in small outbreaks have been seen in H5N8 and H7N9 strains of avian influenza A viruses [101, 102]. However, the high propensity of influenza virus to undergo mutational changes may result in a complete species switch and lead to a pandemic which becomes an International Health Security threat.

M2 proton channel inhibitors (amantadine and rimantadine) and neuraminidase inhibitors (oseltamivir, zanamivir, peramivir) are the traditional antiviral drugs approved for influenza prevention and treatment [103]. All the influenza A viruses are resistant to M2 proton channel inhibitors making the neuraminidase inhibitors the drugs of choice against influenza viruses. Balovir Marboxil, a viral replication inhibitor was approved by FDA in 2018 but rapid emergence of resistance has prevented its routine use [103]. The seasonal influenza inactivated vaccine requires yearly evaluation due to genomic heterogeneity and is effective mainly against the vaccine strains [68]. Thus, the antigenic shift that results in emergence of pandemic strain would make seasonal vaccines ineffective. Currently, the influenza A virus are in different stages of pathogenic evolution ranging from stage-2, stage-3 or stage-5 and have a phase-3 or phase-5 pandemic alert level depending on serotype [68, 101]. The ability of influenza virus to infect multiple species, cross species barrier, and high genomic variability resulting in novel viruses with low immunity among the population are the reasons behind the constant threat of pandemic by influenza A viruses.

#### *3.2.1.6 SARS-CoV-2*

In 2019, a novel zoonotic beta-coronavirus (+ssRNA) emerged as the cause of viral pneumonia in Wuhan, China and was later named as *Severe Acute Respiratory Syndrome-related coronavirus-2* (SARS-CoV-2). SARS-CoV-2, the etiologic agent of COVID-19 is transmitted from person-to-person predominantly through respiratory droplets and secretions [68, 104]. The SARS-CoV-2 causes an influenza like illness with severe cases presenting with dyspnea, septic shock, and acute respiratory distress. The mammalian reservoir for the virus is believed to be bats and contact with contaminated live animals is believed to be the cause of spillage of virus into humans [68, 104]. The virus rapidly spread globally affecting 218 countries in 6 continents with the outbreak being declared a global pandemic by WHO on March 11th, 2020 [104, 105]. According to WHO, a total of 83,910,386 cases of COVID-19 has been reported till January 4, 2021 with 1,839,660 of them having fatal outcome. A new variant of SARS-CoV-2 known as B.1.1.7 emerged in the United Kingdom in late September, 2020 due to N501Y mutation and has nearly 71% (95% CI: 67%–75%) higher rate of transmission than previous variant [106]. As of January 4th, 2021, three types of vaccines have been approved in United States and United Kingdom for emergency use for prevention of COVID-19 [107, 108]. This includes the mRNA vaccine by Pfizer/BioNTech, Moderna and non-replicating vector vaccine by AstraZeneca/University of Oxford [107, 108]. Additionally, the Russian Sputnik (vector) and Chinese Sinopharm (inactivated) vaccines have been approved in other parts of world to fight the COVID-19 pandemic [109, 110].

#### *Which Plagues are Coming Next? DOI: http://dx.doi.org/10.5772/intechopen.96820*

Antiviral remdesivir is the only therapeutic agent approved by FDA against SARS-CoV-2 with baricitinib currently under emergency use authorization for therapy in combination with remdesivir [111]. Currently, the SARS-CoV-2 pathogen is in the stage-5 of pathogenic evolution with ongoing global pandemic and becoming a menace for International Health Security. Despite the authorization of vaccine, the challenges associated with logistics of vaccination and emergence of new variants of SARS-CoV-2 suggests that SARS-CoV-2 will continue to be an agent of public health concern for years to come.
