REVIEW

Zoonotic viral diseases and the frontier of early diagnosis,

control and prevention

J . L . H E E N E YDepartment of Virology, BPRC, Rijswijk, and the Department of Medical Microbiology, University of Leiden, Leiden, The Netherlands

Abstract. Heeney JL. Zoonotic viral diseases and

the frontier of early diagnosis, control and

prevention (Review). J Intern Med 2006; 260:

399–408.

Public awareness of the human health risks of

zoonotic infections has grown in recent years.

Currently, concern of H5N1 flu transmission from

migratory bird populations has increased with foci of

fatal human cases. This comes on the heels of other

major zoonotic viral epidemics in the last decade.

These include other acute emerging or re-emerging

viral diseases such as severe acute respiratory

syndrome (SARS), West-Nile virus, Ebola virus,

monkeypox, as well as the more inapparent insidious

slow viral and prion diseases. Virus infections with

zoonotic potential can become serious killers once

they are able to establish the necessary adaptations

for efficient human-to-human transmission under

circumstances sufficient to reach epidemic

proportions. The monitoring and early diagnosis of

these potential risks are overlapping frontiers of

human and veterinary medicine. Here, current viral

zoonotics and evolving threats are reviewed.

Keywords: early diagnosis, Ebola, emerging

diseases, H5N1 flu, severe acute respiratory

syndrome, vaccines, West-Nile, Zoonosis, review.

Introduction

Of the >1400 documented human pathogens,

approximately 64% are zoonotic (from nonhuman

vertebrate hosts) [1–3]. Viruses and prions represent

just under 5% of the total list of human pathogens.

However, of the emerging or remerging diseases

there is a disproportionate number which are due to

RNA viruses (37%). The RNA viral families, Bun-

yviridae, Flaviviridae, Togaviridae and Reoviridae

contain viruses which represent more than half of

the currently defined viral zoonoses [2, 4].

Interestingly, a characteristic of most zoonotic

viral pathogens is that they are not readily trans-

missible from humans to humans. In the majority

of cases, humans are commonly dead-end hosts [5].

There are important exceptions but in most cases a

virus will require certain genetic adaptations (or

acquisition of genetic information from human

adapted viruses) for new variants within the new

human host to persist and to become successful in

human-to-human spread [6–8]. In extreme cases, it

is believed that certain animal viruses, following

transmission to humans, adapt to the new host so

effectively that they become almost exclusively

transmitted from humans to humans (i.e. measles

and influenza) [2, 8, 9]. Fortunately, these are

relatively infrequent events and it is estimated that

only about 25% of zoonotic pathogens are capable

of some person-to-person spread [1]. Most acute

viral zoonoses do not persist long in human

populations without repeated reintroductions from

a nonhuman reservoir (for instance Ebola virus)

[10–12].

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Changes in behaviour, population dynamics and

imbalances in complex eco-systems are events often

associated with the emergence of zoonotic infections

[1, 13–15]. The clinical indications of zoonotic

infections are as diverse as the agents that cause

them [4, 16–18]. Early identification is dependent

on astute diagnostic prowess, recognition of the

unusual, an investigative history with a rapid and

comprehensive laboratory analysis [19–22]. Aetio-

logical identification and epidemiological assessment

requires effective communication and collaboration

[22–26]. Classically, identification of emerging zoo-

noses follows recognition of a health problem in the

human population, while generally only later is the

link made with an asymptomatic host reservoir or a

disease outbreak in a susceptible animal population

[12, 22, 25]. An important change in this trend has

developed based on scientific understanding of avian

flu, widespread media interest, and increased public

awareness coupled with international surveillance

and national intervention programmes [12, 27–31].

Avian flu and pandemic influenza

Clinical symptoms of Avian Influenza (Bird Flu,

influenza type A viruses) may vary from typical

human (influenza type B) influenza-like symptoms

characterized by fever, cough with pharyngitis and

muscle aches to conjunctivitis (for instance with

type A, H7), pneumonia or severe respiratory

distress and pleural effusion [19, 32–34]. Influenza

viruses are RNA viruses of the family Orthomyxov-

iridae, of which three types (A, B and C) are

recognized. The surface antigens haemaglutinin

(H) and neuraminidase (N) are of particular import-

ance and are used in the classification of the subtype

A viruses. Influenza subtypes A viruses naturally

infect the intestinal tract of wild birds and are

frequently asymptomatic in natural hosts. Shore-

birds and wildfowl are the most likely natural

reservoir [12, 14, 35, 36]. However, influenza A

can infect and cause disease in domestic birds, pigs,

horses, other animals as well as humans [36, 37].

The influenza A subtypes known to infect both birds

and people include H5, H7 and H9 [23, 38–40].

Influenza type B viruses, unlike A, are primarily

found only in humans and may cause epidemics

with morbidity and mortality (especially in the

elderly), but are not known to causes the pandemics

associated with influenza A [4, 32]. Strains of

influenza B appear regularly replacing older type B

strains by the process of amino acid selection called

antigenic drift. Thus, human influenza vaccines

require constant updating to keep up with strain

differences [29, 41, 42]. Influenza type C is relatively

stable compared with types A and B. It infects

humans, is less common, causes a very mild

respiratory illness or no symptoms and is not

reported to cause epidemics.

Antigenic drift and antigenic shift

In 2003, an outbreak of highly pathogenic influenza

A subtype H7N7 rapidly spread to 255 poultry

farms in the Netherlands. Causing high mortality in

chickens, this subtype was thought to be of low risk

of transmission [39]. The outbreak investigation

revealed a high incidence of conjunctivitis and flu

like symptoms in humans and one fatality in a

veterinarian directly involved in handling infected

poultry. Evidence of person-to-person transmission

was also documented [39].

The recent spread of A/H5N1 by migratory water

fowl in Asia which began in 2003 as large scale die-

offs in commercial poultry and duck farms in

Thailand, Vietnam, South Korea and Japan became

full scale outbreaks in 2004 [13, 14, 34, 35]. The

westward spread (Fig. 1) has continued on a yearly

basis since with the spread through Indonesia,

China, Kazakhstan, Mongolia, Russia, Iraq, Turkey,

Europe and Africa [13, 14, 34, 43]. Cases have not

been limited to domestic birds, but also included

domestic carnivores, captive tigers, leopards and

humans with >100 confirmed fatalities [13, 34, 43].

In contrast to A-H7N7, conjunctivitis is not

observed and upper respiratory tract symptoms are

more infrequent [9]. High fever with flu-like illness

with lower respiratory tract symptoms manifest

early. Diarrhoea, vomiting with abdominal and

pleuritic pain progress to respiratory distress. Almost

all patients have clinically apparent pneumonia.

Progression to respiratory or multi-organ failure is

common in hospitalised patients where the fatality

rate is high (on average 9–10 days after clinical

onset), although the overall rate is estimated to be

lower [19, 32, 33].

Diagnosis based on clinical presentation, history

of contact with sick or dying birds or contact with ill

individuals and who have had such contact, is

confirmed by laboratory virology, best performed by

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4 0 0 J . L . H E E N E Y

RT-PCR assays. Although PCR assays are often more

sensitive and more specific, they currently may not

be as quick to be performed in diagnostic laborat-

ories as commercial antigen capture tests [33].

The occurrence of human influenza A-H5N1 has

to date paralleled large outbreaks of avian influenza

A-H5N1 with exposure to poultry a week before

onset of illness [34, 43]. Human to human trans-

mission has so far been limited and infrequent, but it

is important that vigilance be maintained as the

avian epidemic with transmission to humans con-

tinues [1, 23, 34].

Unlike influenza types B and C, type A is notorious

for undergoing antigenic shift. Many RNA viruses

replicate their genomes imperfectly, giving rise to

amino acid changes which may ultimately be

selected for in a previously immune population. In

addition to this relatively slow seasonal evolution of

‘antigenic drift’, influenza subtype A viruses are able

to undergo genetic exchange (re-assortment) of one

or more of the eight segmented single stranded RNA

with other A subtype viruses [42]. One of the major

concerns is that the current pattern of limited person

to person spread could suddenly change, for

instance antigenic shift resulting in a highly patho-

genic new variant which is readily transmitted

between humans [8, 29, 42]. Since there is little or

no immunity to H5N1 in the human population, a

pandemic situation could arise with little or no ‘herd

immunity’ to slow widespread transmission in the

human population [23, 43]. Clearly, this situation

illustrates the need for careful collaboration between

human and veterinary medicine in closely monitor-

ing avian influenza and implementing outbreak

control measures as early as possible [10, 18, 21–

23, 25, 26, 38, 40, 41].

Severe acute respiratory syndrome

The clinical presentation and travel history of

persons with severe acute respiratory syndrome

(SARS) or influenza AH5N1 may overlap. Typically,

patients present with a nonspecific illness manifest-

ing fever, malaria, myalgia with chills, rigour or

diarrhoea in some cases [44]. While the clinical and

radiographic features of most viral pneumonias are

Fig. 1 The westward spread of Avian influenza H5N1. The seasonal North to South migratory routes ‘flyways’ correspond to overlapping

large shaded colour regions. The first cases of highly pathogenic avian influenza (HPAI) H5N1 in 1997 were identified in poultry farms and

markets in Hong Kong along with the first documented human fatality. HPAI H5N1 reappeared in 2002 in Hong Kong. In 2003 this

variant began spreading throughout the poultry industry in large areas of Southeast Asia and by March 2004 there were 23 confirmed

human cases of which 16 were fatal. By the first half of 2005 the virus had reached the north-west boarder of China (red dots), and by late

2005 (yellow dots) had reached central and south Western Russia, Turkey and had entered Europe in Romania and Croatia. In the first half

of 2006 many countries in Europe (purple dots) had reported cases including recent documentation of H5N1 in a dead swan in Scotland.

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not distinctive, SARS in contrast does not typically

have upper respiratory symptoms. A good clinical

history will be essential when considering exposure

and risk factors. Travel and contacts and contact

with specific types of animals, food handlers, farms

or markets will be important indications [45–48].

Before laboratory results, distinguishing clinical

features include a lack of upper respiratory tract

symptoms, a distinguishing feature from coughs and

dyspnoea observed in most SARS patients [6, 19,

20, 24].

In the differential diagnosis, influenza A should be

considered and laboratory sub-typing requested.

Both SARS and pandemic influenza are zoonotic in

origin, hence early veterinary detection and surveil-

lance of animals, coupled with human surveillance

and early detection will be key to preventing

epidemics [6, 19, 21, 22, 24, 40, 49].

There are important differences in the dynamics of

infection between SARS and influenza A/H5N1

which have had an impact on control. When SARS

was transmitted from animals it adapted to be able

to be efficiently transferred from human to human,

and within weeks had spread to other continents by

airline passengers [6]. Before the 2002/2003 epi-

demic, serological evidence suggested that transmis-

sion to wild animal market workers from animals

had already occurred. The interpretation is that the

earlier SARS–CoV variants were less adapted for

human infection, and human to human transmis-

sion of earlier variants was relatively inefficient.

Fortunately, as of April 2006, the current H5N1

avian flu is still inefficient at being transmitted from

humans to humans [32]. There are important risk

differences that are critical to consider with these

two zoonotic respiratory diseases. First, the popula-

tion dynamics and ecosystems of the two natural

host reservoirs are different. While the SARS–CoV

was probably transmitted to humans handling palm

civets, current data suggest that Horseshoe Bats are

the leading contenders as natural reservoirs [46, 47]

suggesting a complex and possibly localised ecosys-

tem. In comparison, the ecosystems of migratory

waterfowl currently distributing influenza A H5N1,

are vast (Fig. 1) and involve the interaction of many

susceptible species [14]. The closing of wildlife

markets in Guangdong province may certainly

reduce risks of SARS in humans, but with respect

to H5N1 the indoor confinement of domestic birds

along the vast migratory routes of wild fowl is a tall

order. Early diagnosis and rapid response pro-

grammes such as surveillance fever clinics supported

by a panel of rapid antigen tests and RT-PCR assays,

greatly increase speed and accuracy of clinical

laboratory reporting for both SARS–CoV and influ-

enza A and subtypes [24]. Fortunately, with SARS

the onset of symptoms in exposed infected individ-

uals precedes the period of high infectivity [20, 40].

Thus, fever surveillance, recognition and rapid

quarantine were effective in ultimately controlling

the 2003 SARS epidemic [24, 40]. Importantly,

however, in contrast with influenza A, a patient

may become infectious before clinical illness, mark-

edly reducing the effectiveness of quarantine in the

case of a human epidemic or pending pandemic

[40].

Flaviviruses and epidemics

These positive-stranded RNA viruses are commonly

transmitted by different species of mosquitoes. It is

the population dynamics and seasonal distribution of

the mosquito vectors and their potential hosts which

greatly influence the epidemiology of flavivirus

diseases. The genus Flavivirus includes West Nile

virus (WNV), Japanese encephalitis virus (JEV), St

Louis encephalitis (StLE), and Murray Valley enceph-

alitis, which belong to the JEV antigenic group, as

well as Dengue virus (DV) and Yellow Fever virus

(YFV) [4]. In general, flavivirus infections can

present as three clinical syndromes; 1) fever with

arthralgia and rash; 2) viral haemorrhagic fever

(VHF); and 3) neurological disease [50–53].

With respect to WNV infection, most are either

asymptomatic or may cause mild disease which may

go unreported [54, 55]. A mild clinical expression of

the infection ‘West Nile Fever’ is accompanied by

arthralgia and rash. Of persons with WNV infection,

roughly 50% develop a rash within a week with

lymphadenopathy which resolves. Less frequently,

but more importantly, dissemination to the central

nervous system may occur with clinical evidence of

spread developing approximately 2 days after peak

viraemia [56, 57]. Unlike with other arboviral

infections which cause encephalitis there is no

vasculitits, inflammatory infiltrates are minimal

and associated with neuronal proliferation and

microglial nodule formation [56, 57]. Fatalities are

often associated with inflammation in the brainstem

although other regions are involved [51, 53].

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4 0 2 J . L . H E E N E Y

In North America, the epidemic is associated with

disease in horses and birds, particularly related

members of the crow family which are highly

susceptible and whose mortality is unusually high

[50, 58, 59]. Seasonal cycles are associated with a

westward North America spread and following the

migratory routes of birds which are believed to be

amplification hosts as well as hosts of mosquitoes of

the Culex genus [15, 55, 59–61]. It is believed that

mammals do not sustain a viraemia sufficient for

further transmission [54, 55, 59, 60, 62].

Diagnosis can be confirmed by antigen specific

IgM in blood or CSF [62]. Clear effective treatment

has not been delineated. Other arboviral infections

should be ruled out. Prophylactic vaccine candidates

for humans are in clinical trials and at least two

WNV vaccines have been licensed for use in horses

[50]. While WNV is spreading seasonally in North

America, JEV is expanding in Australasia and is the

most important cause of arboviral induced enceph-

alitis worldwide [15, 63]. Again Culex sp. mosqui-

toes are the most important vector associated with

enzootics in the tropics. The cycle is maintained in

waterfowl and swine are believed to be the most

important amplifying hosts [63]. A formalin inacti-

vated vaccine is used prophylactically internation-

ally while a live attenuated vaccine strain is used

primarily in China [63, 64].

Dengue virus infection can be caused by four

distinct serotypes and in contrast to the encephalitic

disease potential of JEV and WNV, is best known for

its ability to cause fatal haemorrhagic disease [15,

52, 65]. Of all flaviviruses, DV causes the greatest

incidence of human illness, and is transmitted

primarily from person to person by Aedes aegypti

mosquitoes in endemic regions. Indeed, there has

been a global resurgence of Dengue and this has

been attributed to regional population growth

around large cities, increased transportation and

failing public health control measures [15, 58, 65,

66].

Yellow fever characteristically causes haemor-

rhagic fever with marked hepatic, renal and myo-

cardial injury with high mortality. Originally

endemic in Sub-Saharan Africa, it was believed to

be introduced into South America by the slave trade.

In urban areas, human-to-human transmission is

associated with Aedes aegypti mosquitoes, while as a

zoonosis it is transmitted by different Aedes species

from viremic nonhuman primate reservoirs in the

tropical forests of Africa and South America [15].

The live attenuated 17D vaccine developed in the

1930s, originally believed to be amongst the safest,

has recently been associated with a number of

fatalities [67].

Viral haemorrhagic fever

The clinical syndrome known as VHF can be caused

by a number of different RNA viruses belonging to

four diverse families. These include (i) the Flavivir-

idae, including dengue (DV) and YFV (mentioned in

the previous section); (ii) the Arenaviridae [for

example Lassa fever virus (LFV)], (iii); Bunyaviridae

[as represented by Rift Valley Fever (RVF)], and (iv);

the Filoviridae, the best known of which are the

Ebola related viruses [15–17, 31, 68–70].

These viral infections warrant special emphasis,

as they are associated with acute contagious

epidemics with high rates of life threatening illness

and high mortality. They represent infections that

must be reported and authorities mobilised for

containment and quarantine due to their potential

for rapid human-to-human dissemination. VHFs are

characterised by a febrile multi-systemic syndrome

with loss of micro vascular integrity, bleeding

diathesis, multi-organ failure and shock. Clinical

manifestations of VHF often overlap and vary

between individuals and aetiological agents making

an aetiological diagnosis based on clinical presenta-

tion unlikely in the absence of a revealing patient

history. The incubation period varies from 48 hours

up to 21 days with an apparent acute onset.

Typically, prodromal syndromes include fever, myal-

gia and anthralgias, headache with nausea, vomit-

ing or diarrhoea. Externally, there is often evidence

of a progressive diathesis manifested as conjunctival

and mucosal haemorrhage, haematuria, melina and

disseminated intravascular coagulation are observed

with hypotension, leukopenia and thrombocytope-

nia. As the syndrome progresses, neurological

manifestations such as delirium, seizures and coma

precede multiple system failure, shock and death

[16, 17, 31, 70, 71].

Generally, Arenavirus VHFs progress more slowly

and may have a lower mortality rate than Filovi-

ruses (i.e. Ebola-Zaire) [70]. While, in addition to

supportive care, therapeutic options may be limited,

rapid etiologic diagnosis may facilitate treatment

decisions such as intravenous Ribavirin therapy (not

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generally effective against Filoviruses and Flavivi-

ruses) [16, 17, 70]. Viral diagnostics are most

advisable by immediate contact with specialised

laboratories. Assays include PCR for multiple VHFs,

antigen capture and IgM ELISAs [71, 72]. As the

acute symptoms for VHFs are not usually indicative

of a specific aetiology, the speed of treatment and

quarantine are essential. An early aetiological diag-

nosis will guide treatment and containment of

others exposed but not yet symptomatic. The extent

of human-to-human spread depends on the nature

of the aetiological agent, and the nature of the

exposure (i.e. contact with body fluids or aerosol

from a vector such as rodents versus a bite from an

infected tick or mosquito).

The epidemiology of the agents which cause VHF

is generally variable and diverse. The Filoviruses

such as Ebola and Marburg are generally endemic in

certain regions of Africa [73, 74], and their natural

reservoirs still undefined, they are highly contagious

by contact and aerosol and recent international air

travel from a high-risk region must be considered in

any patient exhibiting unusual symptoms. Other

VHF viruses are transmitted to humans from ticks

[Congo–Crimean haemorrhagic fever (CCHFV)],

mosquitoes (Yellow fever and Dengue Fever Viruses)

or feces or urine from rodents [i.e. Arenaviruses

such as LFV, Argentinean haemorrhagic Fever

(Junin) and Bolivian haemorrhagic (Machupo) fever

viruses]. With the exception of Dengue, all of these

HFV are infectious by aerosol or fomites and human-

to-human transmission is frequently nosocomal

from viremic patients. The clinical diagnosis is

greatly facilitated by a detailed travel or contact

(i.e. nosocomial) history [16, 17, 31, 68, 70].

Contact with a rodent infested environment or bites

by ticks (e.g. CCHFV) or travel or stay in mosquito

prevalent regions where YFV or DV are known to

persist, provide time saving leads.

Emerging viral disease trends

Over the past decade, there has been an observed

increase in the number of zoonotic and vector-borne

viral diseases world wide, but particularly in South-

east Asia and the South Pacific ([75], WHO, CDC

databases). While SARS has come and gone, H5N1

continues its seasonal westward march from the

Western Pacific now eastwards over Europe to the

British Isles (Fig. 1). Seasonal migration habitats of

waterfowl that naturally asymptomatically carry

type A influenza is the main route of movement

between continents. Overlapping migration routes

and breeding grounds may in part explain how such

viruses are transmitted between migrating popula-

tions of birds [14]. In the case of vector-borne

diseases, the westward spread of WNV across North

America is a graphic example of a vector-ecosystem

shift causing seasonal spread and advance from the

Atlantic to the Pacific coasts of North America [76].

As WNV represents a new ‘emerging vector-borne’

viral disease in North America, it is a re-emerging

disease in Europe [77].

Dengue and Japanese encephalitis viruses repre-

sent the major vector-borne disease agents with

high numbers of human infections, but for which

accurate incidence markers remain difficult to

obtain (Table 1). Most emerging viruses have been

zoonotic, many of which are transmitted by bat

species (i.e. Nipah, Rabies and Hendra), but not

exclusively (as with Rabies). The cases of new

zoonotic infections can be incidental and disappear

Table 1 Estimated worldwide

morbidity and mortality figures of

selected viral zoonotic diseases,

2000–2005

Viral disease Estimated cases Estimated fatalities

H5/NI avian influenza 145 77

SARS corona virus 8102 774

West Nile disease (USA only) 19 525 771

Japanese encephalitis virus Approx. 30 000–50 000 Approx. 9000–15 000

Dengue virus Approx. 50 million Approx. 25 000 (DHF)

Ebola/Marburg 774/528 485/457

Lassa fever virus Approx. 100 000–300 000 5000

Nipahvirus 276 106

Hendravirus 3 2

Rabies NA 30 000

Prion diseases/TSE (vCSD) 188 182

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4 0 4 J . L . H E E N E Y

once the cause has been identified and preventative

measures taken (Nipah virus 1998–1999)

(Table 1).

Discussion

The early identification and diagnosis of viral

zoonoses are of great importance with respect to

treatment, containment and public health control.

The infectious disease dynamics of viral zoonoses are

very diverse and will have distinct prevention and

control strategies. Classical examples such as rabies

require careful monitoring of natural reservoirs, and

implementation of prophylactic vaccination of wild-

life in endemic regions. Cases in humans are limited

to exposed individuals and human-to-human spread

is highly unlikely. Early identification of the risk of

exposure and prophylactic immunotherapy are

effective in limiting the number of cases with fatal

consequences. At the other extreme are the highly

contagious viral pathogens which cause acute

diseases such as the respiratory, neurologic and

haemorrhagic fever diseases reviewed here. Each of

the viral agents which cause these diseases has an

unique aecology with their natural host, some of

which we are just beginning to understand, and

others where even the natural reservoir has yet to be

identified [74, 78]. New rapid diagnostic assays

based on PCR technology are potentially capable of

simultaneously identifying up to 10 different aetio-

logical agents which have the potential to cause

VHF syndrome [72].

There will undoubtedly be new zoonotic viruses

for which we must always be vigilant. There will not

always be acute symptoms and an epidemic may not

be initially apparent. Examples of this latter category

include the slow viral or prion diseases which may

be transmitted asymptomatically, potentially caus-

ing disease in humans a decade or more after

exposure has occurred [30]. The great BSE risk was

caused by the presence of potentially pathogenic

prions in the food chain and a potential asympto-

matic period as long as four to five decades. Similar,

in that it is transmitted between asymptomatic

individuals, HIV has had its origins from Zoonotic

cross-species transmissions from nonhuman pri-

mates [79, 80]. Having adapted to be efficiently

transmitted from humans-to-humans, HIV had

devastating effects early in the human epidemic

when it entered national blood supplies and was

widely transmitted unknowingly [5, 11].

The development of vaccines for the control of

potential zoonotic infections in wildlife (i.e. rabies

vaccines for foxes and raccoons) as well as the

prevention of spread and disease in humans is

ongoing. In some cases, there are good candidate

vaccines [81] but the risk of human disease may be

perceived to be too low to be economical [64], or

there may be insufficient supplies for the entire

population [29].

Fig. 2 The diagnosis, treatment and control of emerging zoonotic diseases and the public health continuum.

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Vaccines have been very successful at eradicating

devastating human diseases such as smallpox.

However, immunological niches for new emerging

diseases such as monkeypox may be created, and

for these possibilities we must remain vigilant

[74, 82].

The early identification, control and prevention of

re-emerging viral zoonotics lies not only with

clinicians and public health experts, but importantly

with veterinarians, animal scientists and wildlife

ecologists [10, 21]. The early identification of

perturbations in ecosystems, from die-offs of wildlife

or domestic animals (Fig. 2), especially those which

interface with wildlife (i.e. Nipha virus), is critical for

future prevention and control [83]. It is our aware-

ness and surveillance of the animal and human

health continuum which will facilitate early identi-

fication and control of new emerging and

re-emerging viral zoonotics [27].

Conflict of interest statement

No conflict of interest was declared.

Acknowledgements

For the assistance of Thea de Koning and H. van

Westbroek I am greatly indebted. I would especially

like to acknowledge the teamwork of H. Niphuis, N.

Beenhakker and D. Davis for the difficult task of

unravelling disease statistics and estimates from

various international databases.

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Correspondence: J. L. Heeney, Department of Virology, BPRC,

Rijswijk, and the Department of Medical Microbiology, University

of Leiden, Leiden, The Netherlands.

(fax: +31 15 284 2601; e-mail: heeney@bprc.nl).

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4 0 8 J . L . H E E N E Y