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         <meta content="MDPI" name="citation_publisher"></meta>
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         <meta content="Flaviviruses in Europe: Complex Circulation Patterns and Their Consequences for the Diagnosis and Control of West Nile Disease " name="citation_title"></meta>
         <title>Flaviviruses in Europe: Complex Circulation Patterns and Their Consequences for the
            Diagnosis and Control of West Nile Disease
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            <meta content="Cécile Beck" name="citation_author"></meta>
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            <meta content="Miguel Angel Jimenez-Clavero" name="citation_author"></meta>
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            <meta content="Agnès Leblond" name="citation_author"></meta>
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In Europe, many flaviviruses are endemic (West Nile, Usutu, tick-borne encephalitis
            viruses) or occasionally imported (dengue, yellow fever viruses). Due to the temporal
            and geographical co-circulation of flaviviruses in Europe, flavivirus differentiation
            by diagnostic tests is crucial in the adaptation of surveillance and control efforts.
            Serological diagnosis of flavivirus infections is complicated by the antigenic similarities
            among the
            Flavivirus genus. Indeed, most flavivirus antibodies are directed against the highly immunogenic
            envelope protein, which contains both flavivirus cross-reactive and virus-specific
            epitopes. Serological assay results should thus be interpreted with care and confirmed
            by comparative neutralization tests using a panel of viruses known to circulate in
            Europe. However, antibody cross-reactivity could be advantageous in efforts to control
            emerging flaviviruses because it ensures partial cross-protection. In contrast, it
            might also facilitate subsequent diseases, through a phenomenon called antibody-dependent
            enhancement mainly described for dengue virus infections. Here, we review the serological
            methods commonly used in WNV diagnosis and surveillance in Europe. By examining past
            and current epidemiological situations in different European countries, we present
            the challenges involved in interpreting flavivirus serological tests and setting up
            appropriate surveillance programs; we also address the consequences of flavivirus
            circulation and vaccination for host immunity.

1. Introduction

West Nile virus (WNV) is a widespread re-emerging pathogen that belongs to the
            Flaviviridae family and
            Flavivirus genus and is one of the most threatening flaviviruses in Europe (for a recent review
            see [
            1]). This arbovirus is transmitted by mosquitoes in a cycle in which different species
            of birds act as reservoir hosts, amplifying the virus. Spillover from this cycle occasionally
            occurs and may cause West Nile disease in mammalian hosts. Horses and humans may be
            particularly affected, which is a matter of great concern to the veterinary and public
            health authorities of countries with West Nile cases. Although mammals are susceptible
            to WNV infection, most species are regarded as dead-end hosts; WNV does not efficiently
            replicate within their cells and they cannot transmit WNV to new vectors [
            2].

Most WNV infections are asymptomatic in horses and humans or are associated with an
            influenza-like illness (characterized by moderate to high fever, weakness, and myalgia).
            Only infrequently, in less than 1% infections in humans and 10% of infections in horses,
            do acute meningitis, encephalitis, or flaccid paralysis develop (the latter has only
            been reported in humans); neurological symptoms and lesions are not specific to WNV
            infections [
            3]. Consequently, laboratory tests are essential to confirm or exclude WNV infection.
            Because of the virus' low-level and short-term viremia in humans and horses as well
            as the late appearance of clinical signs when the viremic phase is over, the primary
            tools used to diagnose WNV consist of indirect or serological tests that aim to detect
            WNV antibodies. Rapid and high-throughput assays that do not require the use of infectious
            virus, such as ELISAs, hemagglutination-inhibition tests (HITs) or immunofluorescence
            assays (IFAs), are usually preferred (see
            Section 2.2). However, seropositivity has to be interpreted with care because of the frequent
            cross-reactions among flaviviruses observed in these tests; results should be systematically
            confirmed by comparative virus neutralization tests (VNTs) that use a panel of viruses
            known to circulate in the area under investigation [
            4,
            5]. Accordingly, serological tools have to be adapted to specific epidemiological situations
            involving WNV.

Since WNV was introduced into New York City in 1999, it has rapidly diffused throughout
            North America. It has infected tens of thousands of humans (>36,800) and horses (>25,000)
            according to the Centers for Disease Control and Prevention [
            6] and resulted in widespread bird mortality, causing dramatic declines in some wild
            bird species (e.g., American crows,
            Corvus brachyrhynchos) [
            7,
            8,
            9]. In stark contrast, in Europe, where the disease is re-emerging, WNV has caused
            only sporadic clinical cases and self-limited outbreaks until 2007, with no or isolated
            incidents of wild bird mortality [
            10,
            11]. Several non-mutually exclusive hypotheses have been proposed to explain the different
            patterns observed on the different continents. They each address one of the four primary
            components of the WNV epidemiological cycle: The virus, the host, the vector, and
            the environment. First, it has been suggested that the intrinsic virulence of WNV
            strains circulating in America and Europe could differ, with the North American strain
            being more virulent for birds [
            11,
            12,
            13]. Second, Palearctic versus Nearctic wild bird species have been hypothesized to
            differ in their susceptibility to WNV infection, with the former having co-evolved
            with WNV while the latter were initially naive hosts [
            14]. Third, mosquitoes found in North America and in Europe may differ in their competence
            as vectors [
            15]. Finally, the last hypothesis stresses the importance of past exposure to various
            flaviviruses; exposure to the wide diversity of flaviviruses circulating in Europe,
            and more generally in the western Palearctic [
            11,
            16], might confer partial or complete cross-protection to WNV (see
            Section 3 for further discussion). Other ecological factors could also, to some extent, account
            for these different WNV epidemiological patterns. In particular, biodiversity or species
            richness could potentially act as protective factors via a "dilution effect" or, conversely,
            they may facilitate WNV transmission [
            17,
            18,
            19].

The differences in West Nile virus transmission and clinical impact in Europe versus
            North America imply that diverse and adapted approaches for identifying and controlling
            WNV infections should be employed. Even within the Euro-Mediterranean, WNV outbreak
            frequency and severity decrease from east to west (eCDC [
            20,
            21]). As a consequence, intervention measures based on experience gained in distant
            or even neighbouring transmission areas can be misleading, and a detailed description
            of the eco-epidemiology of a particular WNV outbreak is needed to provide tailored
            and balanced public health responses. For instance, surveillance of avian mortality
            proved very useful in North America (where mass wild bird mortality events usually
            preceded human and domestic animal cases), but it has not yet been useful in Europe,
            with the exception of some of the European regions experiencing WNV lineage 2 circulation
            [
            22,
            23,
            24]. Passive or clinical surveillance of humans and horses as well as serological surveillance
            of wild birds or equines have been far more instructive in Europe, and their use should
            be considered by health authorities [
            25,
            26]. Moreover, entomological surveillance effectively predicts WNV activity and outbreaks,
            even though mosquitoes in Europe have been found to have lower infection rates than
            mosquitoes in the U.S. [
            27,
            28].

Similar reasoning should be applied with respect to WNV diagnostic tools: Their validity
            in each specific WNV epidemiological situation should be verified to ensure that infections
            caused by varied WNV strains are detected [
            29]. This process is particularly important in Europe or Africa, where several genetic
            lineages circulate in overlapping areas; in contrast, only a single-lineage WNV strain
            (1a) was introduced into North America [
            30,
            31,
            32,
            33,
            34,
            35]. Furthermore, diagnostic tools should be specific enough to avoid detecting cross-reactions
            with closely related flaviviruses that may be circulating in the same areas. Many
            flaviviruses belonging to the Japanese Encephalitis serocomplex have a wide distribution
            range, including West Nile virus (WNV), Saint Louis encephalitis virus (SLEV) in the
            Americas, Murray Valley encephalitis virus (MVEV) in Australia, Japanese encephalitis
            virus (JEV) in southern Asia and Oceania, and Usutu virus (USUV) in Europe and Africa
            [
            36]. More specifically, in central and eastern Europe, the high prevalence of tick-borne
            encephalitis virus (TBEV) and human TBEV vaccination campaigns [
            37] frequently result in serological cross-reactions when routine diagnostic tests such
            as WNV ELISAs or IFAs are conducted [
            38,
            39,
            40,
            41]. The interpretation of serological test results may be even more problematic when
            investigating infections caused by flaviviruses belonging to the same serocomplex,
            such as WNV and USUV in Europe, since cross-neutralization will also be observed.
            In such situations, comparative VNTs that include every flavivirus suspected to circulate
            within a given area are called for. Therefore, prior knowledge of flavivirus diversity
            at the local level is essential before rigorous serological surveys can be undertaken.
            In the first section of this review, we assess current flavivirus diversity and the
            risk of future flaviviruses being introduced into Europe, which could impact the accuracy
            of WNV serological diagnoses. In the second section, we outline the challenges involved
            in interpreting the diverse range of WNV serological tests and setting up appropriate
            surveillance programs in reservoir or susceptible hosts. In the final section, we
            address the consequences of past exposure to flaviviruses for WNV immunity. Most studies
            investigating flavivirus cross-protection or infection facilitation have found that
            prior infection or vaccination with heterologous flaviviruses should provide partial
            protection against WNV, with more efficient protection being provided by more closely
            related viruses.

2. Flavivirus Diversity in Europe

The
            Flavivirus genus comprises 53 viruses (ICTV [
            42]). Many of them are human pathogens of concern, such as the viruses that cause dengue
            (DENV), yellow fever (YFV), Japanese encephalitis (JEV), West Nile (WNV), or tick-borne
            encephalitis (TBEV); they are transmitted by mosquitoes (DENV, YFV, JEV, WNV) or ticks
            (TBEV) [
            43,
            44].

Early attempts to define flavivirus relatedness were based on antigenic cross-reactivity
            in VNTs, HITs, and complement fixation tests (CFTs). Albeit imprecise, serological
            studies allowed different serocomplexes to be defined, including the JEV (WNV and
            USUV in Europe), YFV, DENV, and Ntaya virus (Bagaza virus—BAGV—in Europe) serocomplexes
            [
            5,
            45]. Molecular characterization of the flavivirus RNA genome allowed the precise taxonomic
            classification of flaviviruses and the study of their genetic evolution and dispersal
            [
            44,
            46,
            47]. Three distinct groups of flaviviruses were identified: tick-borne viruses, mosquito-borne
            viruses, and viruses with unknown vectors [
            47]. Mosquito-borne viruses can be further subdivided into
            Culex and
            Aedes clades, which also differ in their vertebrate hosts and pathogenesis (
            Figure 1).
            Culex-clade viruses have bird reservoirs, are neurotropic, and frequently cause meningo-encephalitis,
            while
            Aedes-clade viruses have primate reservoirs, are non-neurotropic, and mainly result in
            hemorrhagic diseases [
            43,
            48]. The tick-borne viruses also form two groups: One group circulates among seabirds,
            while the other, the tick-borne encephalitis group, is primarily associated with rodents.
            This latter group generally produces encephalitic disease, although Omsk Hemorrhagic
            Fever virus (OHFV) and Kyasanur Forest Disease virus (KFDV) also cause hemorrhagic
            diseases in humans. Interestingly, tick-borne flaviviruses seem to evolve at a slower
            rate than mosquito-borne flaviviruses, probably as a result of a slower virus replication
            rate in ticks and longer generation times of their tick hosts [
            49].

Figure 1

Genetic relatedness of flaviviruses, evaluated using genetic alignments of complete
                  genomic sequences. GenBank accession numbers are indicated on the tree branches of
                  each virus.

WNV: West Nile virus, JEV: Japanese encephalitis virus, USUV: Usutu virus, MVEV: Murray
               Valley encephalitis virus, ALFV: Alfuy virus, NTAV:Ntaya virus, DENV: Dengue virus,
               YOKV: Yokose virus, CFAV: Cell Fusing Agent virus, KRV: Kamiti River virus, MMLV:
               Montana Myotis Leukoencephalitis virus, RBV: Rio Bravo virus, MODV: Modoc virus, APOIV:
               Apoi virus, MEAV: Meaban virus, SREV: Saumarez Reef virus, TYUV: Tyuleniy virus, KSIV:
               Karshi virus, POWV: Powassan virus, DTV: Deer Tick virus, ALKV: Alkhurma virus, LGTV:
               Langat virus, OHFV: Omsk Hemorrhagic Fever virus, TBEV: tick-borne encephalitis virus,
               LIV: Louping Ill virus, YFV: Yellow Fever virus. 2 outgroups were used, HCV for Hepatitis
               C virus (
               Hepacivirus genus,
               Flaviviridae family) and BVDV for Bovine Viral Diarrhea virus (
               Pestivirus genus,
               Flaviviridae family). Flaviviruses and WNV strains isolated in Europe are underlined. The phylogenetic
               tree was constructed using neighbor-joining with Jukes–Cantor parameter distances
               (scale bar) in MEGA, version 5.2 [
               50]. A bootstrapped confidence interval (1000 replicates) and a confidence probability
               value based on the standard error test were also calculated using MEGA.

Many antigenically-related flaviviruses have been identified, and mosquito-borne flaviviruses
            have been found on every continent except Antarctica. Similarities in disease symptoms—only
            two syndromes, encephalitic and hemorrhagic, have been described in humans and animals—make
            it impossible to differentiate flavivirus infections clinically and precisely identify
            circulating flaviviruses. In the next subsection, we will describe flavivirus circulation
            and introduction risk in Europe (
            Figure 2).

Figure 2

Maps of the distributions of the main flaviviruses found in Europe.

Notes: (
               a) WNV—human cases were aggregated across a 10-year period (2003–2012, data obtained
               from the European Centre for Disease Prevention and Control (eCDC), World Organization
               for Animal Health (OIE), and scientific publications) and the numbers of cases per
               country are indicated; (
               b) TBEV—human cases were aggregated across a 10-year period (2000–2009) and the numbers
               of cases per country are indicated [
               51,
               52]; (
               c) USUV; (
               d) BAGV; and (
               e) LIV. For USUV, BAGV, and LIV, countries that reported clinical cases in wild birds
               (USUV, BAGV) or sheep, goats or horses (LIV) are highlighted in red.

2.1. Epidemiology of
               Flavivirus Infections in Europe

Tick-borne flaviviruses are among the most medically important arboviruses in Europe.
               TBEV severely infects more than 10,000 humans every year and is transmitted by
               Ixodes ricinus and
               I. persulcatus; most cases have occurred in central Europe (Western subtype), Finland, and the European
               part of Russia (Western and Siberian subtypes) [
               53] (
               Figure 2). Tick-borne flaviviruses also comprise the louping-ill virus (LIV) and OHFV. Louping-ill
               is a long-known disease of sheep [
               54] that has clear zoonotic potential. LIV is found in Norway, Spain, Ireland, Turkey,
               and Bulgaria, although it most commonly occurs on British Islands [
               53]; it is transmitted by
               I. ricinus ticks. OHFV, found in Russia, cycles between rodents (e.g., narrow-headed voles,

               Microtus gregalis or water voles,
               Arvicola terrestris) and
               Dermacentor reticulatus ticks in western Siberia, causing hemorrhagic diseases in humans and in some rodents
               (muskrats,
               Ondatra zibethicus) [
               55].

Several other tick-borne flaviviruses have thus far not been found to cause disease
               in humans or animals, and their potential pathogenicity in humans and animals is consequently
               unknown. Meaban virus (MEAV), which is transmitted by soft
               Ornithodoros maritimus ticks among seabirds and was first identified in Brittany, France, is one such flavivirus
               [
               56]. Tyuleniy virus (TYUV) also belongs to the seabird tick-borne flavivirus group and
               has been isolated from ticks on the Atlantic coast of France, the Lofoten Islands
               (Norway), the western U.S. coast, and northern Russia. In contrast to MEAV, TYUV has
               been implicated in three cases of human illness so far [
               57].

A wider diversity of tick-borne flaviviruses has been detected in Europe than in North
               America; the Powassan virus is the major tick-borne flavivirus found to be pathogenic
               in humans in North America. Mosquito-borne flaviviruses are similarly more diverse
               in Europe than in North America; specifically, WNV and USUV are widely distributed
               throughout Europe, and BAGV was identified in Spain [
               58].

Of all the mosquito-borne flaviviruses, WNV has the most widespread geographical distribution
               and the largest vector and host range [
               58]. It was first described in Europe in the 1960s when seropositive animals or virus
               isolates were discovered in France, Portugal, and Cyprus [
               59,
               60]. WNV has historically been considered less pathogenic in humans than DENV or YFV.
               However, more virulent genotypes have emerged since 1998: Isolates from Israel (1998),
               Hungary (2003), or North America (1999) belonging to the Israelo-American cluster
               of WNV lineage 1a are highly pathogenic in birds and mammals [
               8,
               31,
               61], and lineage 2 viruses have caused an increasing number of WNV outbreaks in Europe
               since 2008 [
               62,
               63]. In Europe, WNV has mainly been reported in central and south-eastern Europe, regions
               in which WNV infections and virulence have recently increased, and the implicated
               viruses have spread to new areas, including Bulgaria and Greece in 2010, Albania and
               Macedonia in 2011, and Croatia, Serbia, and Kosovo in 2012. Accordingly, alarming
               outbreaks were reported in several European countries in 2010; 261 confirmed human
               cases, including 34 deaths, occurred in Greece, 57 cases and five deaths occurred
               in Romania, and 480 cases and six deaths occurred in Russia [
               34,
               62,
               64]. Another European country, Italy, has also experienced numerous WNV epidemics caused
               by genetically divergent isolates; starting in 2008 and 2010, lineage 1 and 2 strains
               respectively caused outbreaks at locations across the country (e.g., Emilia-Romania
               in the northeast, Tuscany, Sardinia, and Lazio in the center, and Sicily and Molise
               in the south) [
               27,
               65].

USUV is a flavivirus that originated in Africa and is closely related to WNV. It is
               transmitted by
               Culex mosquitoes and was most probably introduced into Europe by migrant birds; retrospectively,
               it was first identified in cases of wild bird die-offs in 1996 in Tuscany, Italy [
               66]. In contrast to WNV, it rarely causes severe neurological symptoms in humans, but
               virulent strains have caused considerable bird mortality, especially in blackbirds
               (
               Turdus merula) in central Europe, starting in Austria in 2001 [
               67,
               68]. USUV is known to circulate in Hungary, Switzerland, Italy, Spain, the Czech Republic
               and Germany [
               69,
               70,
               71,
               72,
               73,
               74,
               75], and USUV neutralizing antibodies were recently found in animals in France and Croatia
               [
               76,
               77].

BAGV is identical to Israel turkey meningoencephalitis virus (ITMV), which was first
               described in Israel in 1960 based on samples taken from neurologically afflicted turkeys.
               It has more recently been found in infected partridges and pheasants in southern Spain
               [
               78]. Anti-BAGV antibodies were recently found in the sera of encephalitic patients in
               India, underscoring the virus' zoonotic potential [
               79].

Far more flaviviruses have been identified in recent years in Europe. For instance,
               flaviviruses that exclusively infect insects were discovered in Italy and Spain [
               80,
               81], a JEV or a JEV-like virus was found in
               Culex pipiens in northern Italy [
               82], and Lammi virus, a new flavivirus phylogenetically related to
               Aedes-borne viruses, was identified in Finland [
               83]. The main concern with the large and expanding diversity of flaviviruses in Europe
               is that more and more regions are reporting co-circulation of different flaviviruses;
               for instance, WNV and USUV co-circulate in northeastern Italy [
               84] and BAGV and WNV co-circulate in southern Spain [
               85]. Future introductions of tick-borne and mosquito-borne flaviviruses should be anticipated,
               and the expanding range of flavivirus vectors should be taken into account. Several
               risk-assessment studies have examined potential introduction routes and scenarios
               using information on reservoir hosts or infected vectors [
               86,
               87,
               88,
               89,
               90]. Among all the flavivirus vectors,
               Aedes albopictus, which vectors DENV and Zika virus, provides a striking example of the successful
               invasion of new territories [
               91,
               92]; it was responsible for autochthonous DENV infections in France and Croatia in 2010
               [
               93,
               94].

2.2. Vaccination Programs in Europe

In Europe, a few human vaccines against flaviviruses are available, specifically those
               against TBEV, JEV, and YFV (see
               Table 1); it is noteworthy that no human vaccine against WNV has yet been developed [
               37]. WNV can induce severe neurological symptoms in older or immunosuppressed patients,
               which renders vaccine development more challenging since the safe and efficient introduction
               of vaccinal antigens into weakened immune systems requires innovative strategies [
               95]. Because extensive reviews on WNV vaccines on the market and in development have
               been published recently [
               4,
               96], this review will focus on the vaccination programs against flaviviruses currently
               in place in Europe and the regional differences they demonstrate. The objective is
               to highlight expected sources of variation when serologically screening humans or
               animals for WNV. Indeed, up to now, no diagnostic tool has been able to distinguish
               between naturally infected and vaccinated people or animals, and thus vaccination
               history should be carefully considered by clinicians and diagnosticians when interpreting
               the serological results of flavivirus screening tests.

In the case of WNV, only veterinary vaccines are currently used in Europe and have
               proven to be very effective in protecting horses from meningoencephalitis in North
               America [
               97]. While four vaccines are currently available in the U.S. (two inactivated, one DNA,
               and one canarypox recombinant, see
               Table 1), only one of the inactivated vaccines (EQUIP
               ® WNV, formerly Duvaxyn
               ® WNV, Fort Dodge Animal Health/Pfizer) and the canarypox recombinant vaccine (PROTEQ
               WEST NILE
               ®, Merial/Sanofi Aventis) have been commercialized in Europe (since 2009 and 2011,
               respectively). Immunization schedules involve administrating two doses of vaccine
               3 to 6 weeks apart and annual boosters before the WNV transmission season (occurring
               in August–October in Europe for mammalian hosts). The emergence and pathogenicity
               of lineage 2 WNV strains in Europe has put into question the ability of existing WNV
               vaccines, which were developed from North American lineage 1 isolates, to provide
               protection against European WNV isolates. Both inactivated and canarypox vaccines
               have been shown to protect against virulent lineage 2 strains in immunochallenged
               mice and horses, respectively [
               98,
               99]. It should be noted, however, that since WNV outbreaks in horses in Europe have
               been limited and unpredictable, the two WNV vaccines have been used sparingly in European
               countries, predominantly in Italy and in Hungary (S. Lecollinet, pers comm.).

Outside of Europe, WNV vaccination programs have been implemented to protect highly
               susceptible domestic bird species, e.g., geese (inactivated vaccine available in Israel
               [
               100]) and endangered bird species (DNA vaccine in California condors (
               Gymnogyps californianus) [
               101] or inactivated and canarypox recombinant vaccines commercialized for horses used
               in scrub-jays (
               Aphelocoma insularis) [
               102]. DNA vaccines have been also used to experimentally reduce WNV viremia in bird reservoir
               hosts, such as crows (
               Corvus brachyrhynchos and ossifragus) [
               103,
               104] and American robins (
               Turdus migratorius) [
               105], in the lab. The latter species is considered to play a key role in virus amplification
               in the U.S. Nonetheless, to our knowledge, birds have never been vaccinated against
               WNV, nor against other flaviviruses, in Europe.

In humans, YFV and JEV vaccines are recommended for European travellers visiting areas
               in which the viruses are endemic, e.g., tropical and subtropical regions of Africa
               and South America or Southeast Asia, respectively. Vaccination against YFV is still
               based on the highly effective and relatively safe 17D live-attenuated vaccines initially
               developed in 1937 by Max Theiler [
               37,
               106]; protection lasts for at least 10 years. Inactivated and live-attenuated vaccines
               are also available for the immunoprophylaxis of Japanese encephalitis (
               Table 1). Inactivated vaccines were originally derived from infected primary cells (mouse
               primary cell cultures), but the IXIARO
               ® vaccine, based on the formalin-inactivated attenuated SA14-14-2 JEV strain grown
               in Vero cells, has demonstrated excellent safety and immunogenicity profiles; it is
               now the only JEV vaccine licensed in Europe, the U.S., or Australia [
               107,
               108]. In the case of TBEV, the epidemiological situation is different. TBEV circulates
               endemically in Europe and causes more than 10,000 severe cases requiring hospitalisation
               every year. TBEV vaccination of people with a high risk of exposure should therefore
               be encouraged.

ijerph-10-06049-t001_Table 1

Table 1

Types of flavivirus vaccines approved for use in target species (humans and horses)
                     in Europe or elsewhere in the world if not available in Europe.

hsidesgroups

Virus

Vaccine form

Antigen

                        4centermiddle1Human vaccine
                        3centermiddle1JEV
                        centermiddle11Inactivated vaccine

Ixiaro
                           ®—licensed in Europe, JE-VAX
                           ®—commercialization stopped

                        centermiddle11Whole virus

                        centermiddle11Attenuated JEV vaccine (strain SA14-14-2)

Available only in China and South Korea

                        centermiddle11Whole virus

                        centermiddle11Chimeric vaccine combining the YFV non structural (NS) proteins and the JEV prM-E

Chimeri Vax-JE
                           ®

Available only in Australia and Thailand

                        centermiddle11Precursor membrane-Envelope (prM-E)

                        centermiddle11TBEV
                        centermiddle11Inactivated vaccine

Ticovac
                           ® or Encepur
                           ® or FSME-Immune
                           ®—licensed in Europe

TBE Moscow vaccine
                           ® and EnceVir
                           ®—licensed in Russia strain from Brazil); attenuated by passage through embryonated
                           eggs

Stamaril
                           ® or YF-VAX
                           ®—licensed in Europe and the rest of the world

                        centermiddle11Whole virus

                        centermiddle11YFV
                        centermiddle11Live-attenuated vaccine (Rockefeller 17D strain or 17DD strain from Brazil); attenuated
                           by passage through embryonated eggs

Stamaril

®
 or YF-VAX

®
—licensed in Europe and the rest of the world

                        centermiddle11Whole virus

                        5centermiddle1Horse vaccine
                        centermiddle11JEV
                        centermiddle11Inactivated vaccine

Nisseiken
                           ®

Available only in Japan

                        centermiddle11Whole virus

                        4centermiddle1WNV
                        centermiddle11Inactivated vaccine + adjuvant

West Nile-Innovator
                           ® (U.S.) or Vetera
                           ® WNV (U.S.) or EQUIP
                           ® WNV (Europe)

                        centermiddle11Whole virus

                        centermiddle11Chimeric recombinant canarypox virus

Recombitek
                           ® Equine WNV (U.S.), Proteq West Nile
                           ® (Europe)

                        centermiddle11prM-E

                        centermiddle11Chimeric vaccine combining YFV NS proteins and WNV prM-E

PreveNile
                           ®

Available only in the U.S., recalled in 2010

                        centermiddle11prM-E

                        centermiddle11DNA vaccine + adjuvant

West Nile-Innovator
                           ® DNA

Available only in the U.S.

                        centermiddle11prM-E

TBE can be effectively prevented in the field using purified inactivated whole virus
               vaccines that are produced in Europe and Russia from cell cultures (such as FSME-IMMUN
               ® or Encepur
               ®, manufactured in Austria and Germany, respectively) and that are administered over
               the course of a comprehensive vaccination program that comprises multiple boosters.
               Their use varies widely in areas in which the virus is endemic, with high vaccination
               coverage in Austria (88%) and in the Sverdlovsk region of Russia, where a mass immunization
               program was initiated in 1996 [
               37,
               109].

In general, Europe has experienced complex and varied situations with regards to the
               natural occurrence of flaviviruses and flavivirus vaccination programs, which complicates
               the use of WNV serological diagnostic tools.

3. Serological Cross-Reactions between West Nile and Related Flaviviruses

Flaviviruses are antigenically related, as originally shown by HITs [
            110], ELISAs, or VNTs [
            45]. Although broad serological cross-reactions in general and cross-neutralizations
            in particular are observed and allowed defining serocomplexes, their extent and duration
            are strongly dependent on amino acid similarity in a few viral proteins [
            5,
            111].

3.1. Viral Determinants of Serological Reactions

Flaviviruses consist of enveloped and spherical particles surrounding a ssRNA+ genome
               of about 11 kb (
               Figure 3). The flavivirus genome comprises a single open reading frame that codes for three
               structural proteins, the envelope protein (E), the precursor membrane (prM), the capsid
               (C), and at least seven nonstructural proteins (NS1, 2A, 2B, 3, 4A, 4B and 5).

Figure 3

Organisation of the flavivirus genome.

The immunodominant antigens of the viral particle are the E, the prM, and NS1 proteins,
               and most serological tools rely on the detection of anti-E and/or anti-NS1 antibodies.
               The major neutralizing determinants are present in the E protein [
               112]. Upon folding, the E protein has three structural domains, DI, DII, and DIII, which
               are separated by short flexible hinges and organized as antiparallel homodimers in
               mature virions. As a result of this conformation, antibodies can more readily access
               the outer or lateral surfaces but have a harder time reaching the inner surfaces [
               113]. The center of DI connects with both DII, which is an elongated finger-like domain
               that contains a highly conserved hydrophobic fusion loop and is involved in endosomal
               membrane fusion, and DIII, which is an immunoglobulin-like domain that mediates virus
               attachment to host cells [
               114,
               115].

DI and DIII contain virus-specific epitopes, as evidenced in a study of monoclonal
               antibodies that found that certain consensus epitopes are common to WNV strains but
               are distinct in other flaviviruses [
               116]. The epitopes recognized by broadly cross-reactive antibodies have been mapped to
               the fusion peptide loop located at the tip of DII, a region that is highly conserved
               among all flaviviruses [
               117,
               118]. DIII is also recognized by strongly neutralizing antibodies, and WNV resistance
               to antibody-mediated neutralization was correlated with mutations in DIII epitopes
               [
               116,
               119]. However, the titer of antibodies against DIII does not necessarily correlate with
               the clinical outcome in human patients [
               120]. Conversely, the fusion loop of DII, which is cryptic in mature virions, does not
               contribute to flavivirus neutralization [
               120,
               121]. Nevertheless it has been shown in rodent models that protection against WNV can
               be afforded by poorly neutralizing anti-DII antibodies [
               120,
               122], presumably because their Fc portions interact with complement factors and with
               Fc receptors on monocytes and macrophages [
               122,
               123].

The NS1 protein also participates in protective immunity against flaviviruses. It
               is unique in that it is the only glycoprotein that is secreted by flavivirus-infected
               cells and is also exposed at the surface of infected cells [
               124,
               125]. Protective immunity is believed to result when anti-NS1 antibodies bind to NS1
               proteins associated with the cell surface, which facilitates the phagocytosis by activated
               Fc-γ receptors and clearance of infected cells [
               116,
               126].

3.2. WNV Serological Diagnostic Tools

Many diverse serological tools are available to diagnosis or screen for WNV antibodies
               [
               127]. The most commonly used are VNTs (PRNTs or micro-VNTs), IFAs, and ELISAs. The principles
               underlying these methods as well as their advantages and drawbacks are summarized
               in
               Figure 4(a).

Figure 4

(
                     a) Main serological tests used to diagnosis WNV (
                     b) Illustrations of the three different ELISA methods: Competitive, indirect IgG, and
                     MAC (the numbers indicate step order).

3.2.1. PRNT/Micro-VNT

The gold standard WNV serological test is still the plaque reduction neutralization
                  test, which is performed according to standard protocols with a threshold plaque reduction
                  level of 90% (PRNT90) [
                  128,
                  129]. In this test, the ability of antibodies to reduce lysis plaque number in cell cultures
                  is visually quantified; a sample is considered seropositive if the threshold level
                  (relative to the control) is attained. The micro-virus neutralization test (micro-VNT)
                  is a modification of the PRNT and allows a larger number of samples to be screened
                  using cell microplates.

Overall, VNTs are time consuming and require that infectious virus be handled in Biosafety
                  Level 3 (BSL-3) facilities or that a chimeric flavivirus such as the YFV/WNV recombinant
                  virus (ChimeriVax
                  ® WN) be handled in BSL-2 facilities. They have a higher level of specificity but are
                  less sensitive than ELISAs [
                  130], and their sensitivity may depend on the WNV strain involved [
                  131].

3.2.2. Hemagglutination Inhibition Tests (HITs) and Complement Fixation Tests (CFTs)

HITs are still used in some laboratories, whereas CFTs are hardly ever performed because
                  it is difficult to maintain the satisfactory quality controls they require [
                  68]. HITs exploit the ability of the E protein to aggregate avian erythrocytes in the
                  absence of anti-E neutralizing antibodies. Test results are affected by the presence
                  of non-specific inhibitors [
                  132]. HITs are less sensitive than ELISAs and present the same drawbacks, e.g., a high
                  level of antibody cross-reactivity [
                  130,
                  133].

3.2.3. Immunofluorescence Assays

IFAs use slides coated with flavivirus-infected cells. Serum samples are deposited
                  on the slides, and the attachment of antibodies is revealed using fluorophore-conjugated
                  immunoglobulins that demonstrate specificity to anti-species IgGs or IgMs. This method
                  is fast and easy to perform and may be used to differentiate between IgM and IgG antibody
                  responses. However, it is not adapted for screening purposes. IFA slides coated with
                  WNV, JEV, YFV, and DENV are commercially available for the diagnosis of human infections
                  [
                  39]. BSL-3 facilities are not required because inactivated virus is bound to the slides.
                  When dealing with antibodies against viruses within the JEV serocomplex, IFAs demonstrate
                  greater specificity in detecting IgMs than do ELISAs; in contrast, IFAs show the same
                  level of specificity as competitive and IgG indirect ELISAs when detecting IgGs [
                  39,
                  134].

3.2.4. ELISA

ELISAs are preferred screening tools because of their rapidity, sensitivity, reproducibility,
                  and affordability. Three different assays are commonly used: The competitive ELISA,
                  the indirect IgG ELISA, and the IgM antibody-capture (MAC) ELISA (
                  Figure 4(b)). Ready-to-use diagnostic kits for veterinary and human purposes are commercially
                  available.

The MAC-ELISA is suitable for detecting acute infections (8–60 days post-infection)
                  in humans and horses; however, its usefulness in determining acute infections is questionable
                  in humans, in whom WNV IgMs have been reported occasionally to persist for over a
                  year [
                  4]. This test is a highly valuable tool because IgM antibodies are hard to detect using
                  VNTs or HITs [
                  133,
                  135] and exhibit less cross-reactivity than IgG antibodies [
                  136,
                  137].

Indirect IgG ELISAs require the use of adapted anti-species conjugated antibodies
                  [
                  4,
                  138]. Because of the wide variety of WNV hosts, veterinary diagnostic laboratories are
                  gradually replacing indirect IgG tests with competitive (or blocking) ELISAs, which
                  allow the testing of samples from virtually all animal species [
                  139]. This versatility relies on the ability of WNV antibodies present in the sample
                  to compete for antigenic binding sites with WNV-specific monoclonal antibodies. Competitive
                  ELISAs are the most sensitive of all the developed serological technologies, but they
                  are most appropriate for screening purposes because of their lower level of specificity.

The sensitivity and specificity of ELISAs are strongly influenced by the nature of
                  the bound antigen. Attempts have been made to improve ELISA specificity using a recombinant
                  version of the DIII of the E protein [
                  140,
                  141] or by substituting NS1 [
                  142] for the whole virus or prM-E antigens. E-DIII ELISAs are able to differentiate between
                  infections caused by flaviviruses belonging to JEV or TBEV serocomplexes [
                  140] as well as between those caused by WNV and other flaviviruses belonging to the JEV
                  serocomplex, such as JEV, MVEV, and SLEV [
                  141]. NS1 ELISAs can differentiate between infections caused by WNV and those caused
                  by JEV or SLEV in animals and do not react with sera originating from animals vaccinated
                  with most DNA or recombinant WNV vaccines (
                  Differentiating Infected from Vaccinated Animals—DIVA
                  —strategies) [
                  96,
                  142,
                  143].

3.2.5. Microsphere Immunoassays

Microsphere immunoassays are potentially useful tools because of their multiplexing
                  capacity; they couple different flavivirus antigens to fluorescent and differentiable
                  beads [
                  144]. Nevertheless, cross-reactivity within the JEV serocomplex among antibodies targeting
                  the E antigen occurs as frequently in microsphere immunoassays as in ELISAs, and specificity
                  thus needs to be improved.

In conclusion, the specificity of many serological tests is still an issue of major
                  concern. High-throughput screening tests that perform at high level of specificity
                  are crucial, and recent improvements have been made in this field [
                  96]. The improved selection of relevant epitopes from a wider range of monoclonal antibodies
                  that target different flaviviruses will surely help determine the precise antigenic
                  sites that differ among these flaviviruses and will thus ultimately lead to the development
                  of more specific diagnostic tests [
                  145].

3.3. Misinterpretation in the Diagnosis and Surveillance

Serological cross-reactivity may lead to the misinterpretation of diagnostic test
               results obtained from suspected clinical cases and samples collected during WNV epidemiological
               serosurveys. Awareness of possible cross-reactions is essential given that the aim
               of such investigations is to correctly identify the viruses responsible for the observed
               serological reactions. The nature and prevalence of cross-reactions differ depending
               on the target species and geographical location. Overall, the risk of cross-reactions
               exists wherever multiple flaviviruses co-circulate, including in Europe.

3.3.1. Difficulties for Accurate Diagnosis

The serological diagnosis of WNV infection is complicated by the fact that the patients
                  or animals may have previously been exposed to or vaccinated against cross-reacting
                  viruses. In this context, it is essential to use tests that are both sensitive enough
                  to detect WNV infection and specific enough to distinguish an acute WNV infection
                  from one caused by a closely related virus or remnants of prior WNV exposure. Here,
                  we report the results of field and experimental studies that have compared diverse
                  serological methods with the objective of optimizing the specificity of the serological
                  diagnosis of WNV infection.

Use of ELISAs

ELISAs are the most commonly used diagnostic assays because of their simplicity and
                     relatively low cost; they also require few specialized apparatus and facilities. When
                     WNV first emerged on the North American continent in 1999, samples of serum and cerebrospinal
                     fluid from the first eight patients hospitalized with viral encephalitis and meningitis
                     tested positive for anti-SLEV antibodies based on IgM-capture and indirect IgG ELISAs;
                     SLEV is a common flavivirus that is an enzootic of North America [
                     146]. However, doubt remained as to whether SLEV was the etiologic agent because the
                     clinical manifestations were not those typically associated with SLEV infection, polymerase
                     chain reactions using SLEV-specific primers yielded negative results, and serological
                     testing using a SLEV-specific PRNT revealed only low levels of neutralizing antibodies
                     [
                     146,
                     147]. WNV was later identified as the cross-reactive etiologic agent [
                     148].

Similar misinterpretations of serological results may occur in Europe because those
                     being tested may have been exposed to co-circulating or newly emerging flaviviruses
                     or have encountered flaviviruses while traveling. For example, although successive
                     experimental infections in horses have suggested that WNV-specific competitive ELISAs
                     using anti-NS1 MAb 3.1112G as a conjugate are highly specific for WNV [
                     149], high rates of false-positives were obtained for human sera from patients with confirmed
                     DENV infections [
                     150]. This serological method therefore cannot be used to accurately diagnose WNV infections
                     in humans in areas where other flaviviruses, such as DENV, are endemic. Similarly,
                     during the 2010 WNV outbreak in Greece, commercially-available ELISA kits were used
                     to test for IgMs and IgGs against WNV, DENV, and TBEV in sera and cerebrospinal fluid
                     sampled from patients suffering from encephalitis or meningitis. A high degree of
                     cross-reactivity was observed between WNV and DENV IgMs, although the WNV-specific
                     antibodies clearly demonstrated a stronger serological response [
                     151]. In this study, none of the patients were vaccinated against JEV, YFV, or TBEV.
                     Knowing patient vaccine history is important when interpreting serological results
                     because vaccination may interfere with the accurate diagnosis of acute WNV infection
                     in humans and horses. For instance, Shirafuji
                     et al. [
                     152] showed, using WNV and JEV MAC-ELISAs, that horses experimentally infected with WNV
                     tested negative for WNV IgM antibodies if they had previously been vaccinated against
                     JEV, whereas WNV IgM antibodies were detected in the non-vaccinated group. In addition
                     to vaccination records, the travel history of each patient needs to be considered
                     because WNV serodiagnosis should take into account the possibility of prior exposure
                     to naturally circulating flaviviruses [
                     39].

Other methods, such as IFAs that detect IgMs or ELISAs that use virus-specific epitopes
                     such as rEDIII, may prove to have greater specificity than above-mentioned ELISAs.
                     However, studies consistently discourage basing a flavivirus serodiagnosis on single
                     assay and only searching for a single virus [
                     39]. Furthermore, if multiple flavivirus infections or vaccination against other flaviviruses
                     are likely, then repetitive sampling is of great importance, as the etiological virus
                     could be misdiagnosed if only a single sample is tested [
                     149]. Even though it is difficult to do in the field, physicians and veterinarians are
                     strongly encouraged to collect both acute and convalescent sera, spaced about 2–3
                     weeks apart, in order to pick up on seroconversions and identify false negatives that
                     result from delayed IgG and IgM responses in individuals with acute WNV infections.
                     Overall, this level of complexity in flavivirus diagnosis likely leads to an underestimation
                     of the incidence of acute WNV infections worldwide.

Use of Virus Neutralization Tests

As mentioned earlier, VNTs have a high degree of specificity for target flaviviruses,
                     but cross-neutralization by antibodies against viruses within the same serocomplex
                     is still observed. As a result, a thorough comparison of the end point titers obtained
                     using other flaviviruses known to be endemic in the area should be performed [
                     45,
                     153]. Virus identification thus relies on finding the virus associated with the highest
                     neutralization titers, provided that said titers are at least fourfold higher than
                     those associated with the second-ranked virus; however, difficulties may nonetheless
                     arise if two consecutive flavivirus infections take place [
                     154].

As a consequence, diagnostically differentiating among viruses may be hard in areas
                     in which flaviviruses are hyperendemic [
                     155]. In particular, it has been experimentally shown that horses previously vaccinated
                     against JEV had higher neutralizing antibody titers against both JEV and WNV after
                     a WNV challenge and that their levels of JEV-neutralizing titers were higher than
                     or equal to their levels of WNV-neutralizing titers [
                     152].

3.3.2. Challenges for WNV Surveillance Programs

The use of tests with high levels of specificity is even more important in WNV serological
                  surveillance because the expected prevalence in the target population is lower and
                  therefore the risk of obtaining false positives is higher. Another technical constraint
                  is the necessity to rapidly and simultaneously screen large numbers of samples; this
                  need makes ELISAs the method of choice since they are inexpensive and safe to perform
                  under minimal biocontainment conditions. However, confirmation of sample seropositivity
                  using VNTs is required to specifically identify the virus(es) responsible for the
                  observed serological reactions. Because PRNT90 lacks sensitivity in weakly exposed
                  populations, some authors have suggested that PRNT50 should be used in serological
                  surveys; however, this latter test is not reliable enough to obtain robust conclusions
                  [
                  131,
                  156,
                  157].

In humans, serosurveys most often rely on sera collected from healthy blood donors
                  whose vaccination and travel histories are unknown even though such factors may strongly
                  affect the results of the serological tests used to detect WNV-specific antibodies.
                  For example, in North Tyrol, initial ELISA results suggested that WNV seroprevalence
                  was 46.2%; however, comparative neutralization tests revealed the existence of cross-reactions
                  with anti-TBEV antibodies or other vaccine-associated flaviviral antibodies, which
                  generated false positives. Accounting for these false positives, WNV seroprevalence
                  was found to be 0.5% instead [
                  158]. In particular, it has been shown that people vaccinated against YFV are more likely
                  to neutralize WNV than those not vaccinated against YFV [
                  38].

Estimating the likelihood of encountering cross-reactions is particularly important
                  in studies that use animal sentinels such as horses or captive birds to rapidly detect
                  WNV circulation [
                  26,
                  156,
                  159,
                  160]. Depending on the geographical location, serological diagnostic algorithms may help
                  differentiate WNV from other, co-occurring flaviviruses [
                  154].

The results of serosurveys of free-ranging birds are particularly complex to interpret
                  because some species are long-distance migrants that may encounter WNV and other flaviviruses
                  at a large variety of exposure sites [
                  87,
                  161]. However, sedentary bird species in Europe may also be exposed to a wide diversity
                  of flaviviruses [
                  16,
                  67,
                  78]. Parallel titration for antibodies against several flaviviruses using VNTs is therefore
                  essential in identifying exposure to potentially emerging flaviviruses and is even
                  more crucial in assessing the continued transmission of introduced flaviviruses in
                  Europe [
                  68,
                  76,
                  85,
                  132,
                  162,
                  163,
                  164]. Similar constraints exist in serosurveys of wild ungulates because the diversity
                  of the flaviviruses that may circulate in these species is poorly known [
                  165].

Determining the age of seropositive hosts is of the utmost importance in WNV serosurveys,
                  even if age can only be estimated, as is the case for wild animals. Younger animals
                  should be excluded from immunological analyses because the presence of maternal antibodies
                  in their systems could lead to a misinterpretation of the results. Maternal antibodies
                  against WNV have been shown to remain detectable in the serum of horses for up to
                  120 days [
                  166] and of birds for up to 9 days in passerines [
                  167] and 42 days in domestic chicken [
                  168]. If young animals that are old enough to have cleared maternal antibodies are seropositive,
                  it suggests that recent transmission has occurred within a group or population, and
                  the results may thus help identify the time period during which the virus was circulating
                  [
                  76,
                  132]. Furthermore, enzootic or epizootic circulation patterns can also be inferred by
                  analyzing seroprevalence across different age classes; enzootic transmission should
                  be associated with increased seroprevalence rates in older individuals [
                  19,
                  169].

As previously mentioned, the level of serological cross-reactivity frequently observed
                  among flaviviruses can lead to diagnostic misinterpretation, but it could also have
                  a beneficial effect by ensuring partial or complete cross-protection against serial
                  flavivirus infections. On the other hand, it could also facilitate subsequent flavivirus
                  infections via a mechanism called antibody-dependent enhancement (ADE), which has
                  mainly been described for the dengue flavivirus but is possibly applicable to other
                  flaviviruses.

4. Antibody-Dependent Cross-Protection or Enhancement among Flaviviruses

Few flavivirus vaccines are currently available for human use, and two in particular
            are lacking: those against the widespread DEN and WN viruses. It is therefore of utmost
            interest to evaluate the capacity of flavivirus vaccines to protect against heterologous
            flaviviruses. Cross-protection can most easily be assessed using vaccination trials
            that employ appropriate experimental conditions: experiments in which animal models
            have been chosen, appropriately controlled, and immunologically challenged after initial
            vaccination or infection with heterologous flaviviruses. Furthermore, using VNTs,
            the neutralizing capacities of sera obtained from vaccinated target species can be
            analysed and may also provide the scientific and medical community with valuable information.

4.1. Evaluation of Cross-Protection in Animal Models

Several animal models have been used to assess the level of heterologous protection
               against flaviviruses; these models include two epidemiologically important bird species,
               house finches (
               Haemorhous mexicanus) and red-winged black birds (
               Agelaius phoeniceus), as well as four mammal species, Syrian golden hamsters (
               Mesocricetus auratus), Swiss mice (
               Mus musculus), bonnet macaques (
               Macaca radiata) and pigs (
               Sus domesticus). The major results of studies addressing this topic are summarized in
               Table 2.

These animal models illustrate that prior immunization with heterologous flaviviruses
               and a challenge with a virulent strain generally induce immune booster effects, marked
               by an increase in neutralizing antibodies, a reduction or absence of the viremic phase
               after challenge, and subsequent complete or partial clinical protection (evaluated
               only when the challenge flavivirus was pathogenic in the animal species). This protective
               effect was readily observed for flaviviruses belonging to the same serocomplex.

ijerph-10-06049-t002_Table 2

Table 2

Assessment of the heterologous protection afforded by prior flavivirus infection or
                     vaccination in animal models.

hsidesgroups

Species (sample size)

Infection or Vaccination

Challenge

Heterologous protection

Publication

                        4centermiddle1Birds
                        centermiddle11House finches (8)
                        centermiddle11SLEV Kern217 virulent strain
                        centermiddle11WNV NY99 virulent strain
                        centermiddle11Complete clinical protection (0/8 death
                           vs. 3/4 deaths in control group), but insufficient virological protection (viremia, mean
                           of 4.6 (2.7–6.4) log

10
 PFU/mL considered sufficient to infect susceptible mosquitoes)

                        centermiddle11[
                           170]

                        centermiddle11House finches (8)
                        centermiddle11WNV NY99 virulent strain
                        centermiddle11SLEV Kern217 virulent strain
                        centermiddle11Sterilizing immunity: absence of viremia (0/8
                           vs. 4/4 in control group)

                        centermiddle11[
                           170]

                        centermiddle11Red-winged blackbirds (8)
                        2centermiddle1WNV NY99 virulent strain
                        centermiddle11JEV virulent Indian strain (genotype III)
                        2centermiddle1Nearly complete virological protection (1/16 viremic birds
                           vs. 16/16 controls)

                        2centermiddle1[
                           171]

                        centermiddle11Red-winged blackbirds (8)
                        centermiddle11JEV virulent Vietnamese strain (genotype I)

border-top: solid thin
                        10centermiddle1Mammals
                        centermiddle11Pigs (2)
                        centermiddle11MVEV virulent OR2 strain
                        centermiddle11JEV virulent Nakayama strain
                        centermiddle11Sterilizing immunity: absence of viremia (0/2
                           vs. 1/1 in control group)

                        2centermiddle1[
                           155]

                        centermiddle11Pigs (2)
                        centermiddle11WNV mildly virulent KUN HU6774 strain
                        centermiddle11JEV virulent Nakayama strain
                        centermiddle11Sterilizing immunity: absence of viremia (0/2
                           vs. 1/1 in control group)

                        centermiddle11Bonnet macaques (3)
                        centermiddle11Formalin-inactivated JEV strain (733913)
                        centermiddle11WNV virulent 68856 strain
                        centermiddle11Complete clinical protection (0/3 death
                           vs. 2/3 deaths in control group)

                        2centermiddle1[
                           172]

                        centermiddle11Bonnet macaques (5)
                        centermiddle11Formalin-inactivated WNV strain (68856)
                        centermiddle11JEV virulent 733913 strain
                        centermiddle11Partial clinical protection (1/5 death
                           vs. 1/1 death in control group)

                        centermiddle11Hamsters (30)
                        centermiddle11JEV SA14-2-8 vaccine strain
                        centermiddle11WNV virulent NY99 strain
                        centermiddle11Complete clinical protection (0/30 death
                           vs. 14/30 deaths in control group). Viremia lowered by about 3 log

                        3centermiddle1[
                           173]

                        centermiddle11Hamsters (32)
                        centermiddle11SLEV virulent Be Ar 23379 strain
                        centermiddle11WNV virulent NY99 strain
                        centermiddle11Complete clinical protection (0/32 death
                           vs. 14/30 deaths in control group). Viremia lowered by about 4 log

                        centermiddle11Hamsters (30)
                        centermiddle11YF 17D vaccine strain
                        centermiddle11WNV virulent NY99 strain
                        centermiddle11Partial clinical protection (4/30 deaths
                           vs. 14/30 deaths in control group). Viremia slightly lowered

                        centermiddle11Hamsters (50)
                        centermiddle11DENV-2 New Guinea C strain
                        centermiddle11WNV virulent strain
                        centermiddle11Partial clinical protection (8/50 deaths
                           vs. 50/50 deaths in control group).

                        centermiddle11[
                           174]

                        centermiddle11Swiss mice (29)
                        centermiddle11DENV-2 New Guinea C strain
                        centermiddle11JEV virulent Peking strain
                        centermiddle11Complete clinical protection (0/29 deaths
                           vs. 38/60 deaths in control group). Sterilizing immunity: absence of viremia.

                        2centermiddle1[
                           175]

                        centermiddle11Swiss mice (45)
                        centermiddle11DENV-2 New Guinea C strain
                        centermiddle11SLEV virulent Pinellus P 15 strain
                        centermiddle11Partial clinical protection (17/45 deaths
                           vs. 80/90 deaths in control group).

4.2. Evaluation of Cross-Protection in the Field

Credible data on heterologous protection in the field have mainly been obtained by
               studying the
               in vitro neutralization capacity of human sera sampled from vaccinated individuals. Mansfield

               et al. [
               38] used PRNTs to investigate flavivirus cross-reactivity in sera from a human cohort
               with a history of vaccinations against TBEV, JEV, and YFV. The PRNTs indicated that
               64% (16/25), 89% (25/28), and 35% (9/26) of the samples tested contained TBEV, JEV,
               and YFV neutralizing antibodies, respectively. Neutralization of LIV, DENV-2, and
               WNV occurred in 88% (22/25), 38% (10/26), and 53% (15/28) of cases, respectively;
               in contrast, no significant neutralization of MVEV was observed. Vaccination history
               modified WNV cross-neutralization efficacy: individuals that had received the three
               vaccinations had an increased chance of being WNV-neutralizing-antibody positive than
               individuals vaccinated against TBEV and JEV alone.

It was clear that, in humans, vaccination against TBEV and JEV could elicit an antibody
               response capable of limited WNV neutralization. Although this study did not control
               for variables such as the age of the subjects or the time between YFV vaccination
               and blood sampling, the results suggested that the additional vaccination against
               YFV enhanced the ability of sera to neutralize WNV [
               38]. This finding differs from that of a previous study that concluded that JEV vaccination
               was more effective than YFV vaccination at eliciting WNV cross-protection through
               cross-reactive antibody responses [
               176]. Current vaccines against YFV are live-attenuated rather than inactivated and are
               thus likely to be more immunogenic, stimulating a broader spectrum of responses and
               inducing a strong humoral and cell-mediated immune response. Interestingly, a recently
               published preclinical assessment of JE-ADVAX®, a new candidate JEV vaccine that consists
               of an inactivated JEV strain and a delta inulin adjuvant, suggested that the vaccine
               was capable of inducing robust cross-protective immunity against a virulent WNV strain
               used to challenge a murine model [
               177]. This study and others testing the antigenicity of inactivated and adjuvanted or
               non-adjuvanted JEV vaccines (JE-VAX
               ®) compared to that of live-attenuated JEV vaccines (the SA-14-14-2 strain used in
               China) stress the importance of adjuvant formulation in the induction of high-quality
               heterologous immunity by inactivated flavivirus vaccines [
               123,
               178].

Most individuals vaccinated against TBEV demonstrated a LIV neutralizing response.
               There is currently no human vaccine available for tick-borne flaviviruses, apart from
               TBEV, but the results presented by Mansfield
               et al. [
               38] suggest that vaccination against TBEV may offer partial protection against LIV infection
               in humans. Moreover, a TBEV vaccine based upon the European prototype Neudoerfl strain
               was recently shown to induce cross-reactive antibodies in humans, both against other
               TBEV subtypes as well as against more distantly related flaviviruses, such as OHFV
               [
               179].

Cross-reactivity among antibodies against flaviviruses could significantly contribute
               to the development of effective broad-spectrum human vaccines against WNV and other
               existing or emerging flaviviruses. ChimeriVax technology has utilized this cross-reactivity
               to its advantage in the development of vaccine candidates [
               178,
               180]. Ultimately, chimeric vaccines that assemble components from different individual
               flaviviruses would be of great help in countries dealing with different flaviviruses.

The results of all of the studies presented in
               Section 3.1 and
               Section 3.2 concur in finding that at least partial immunity to heterologous flaviviruses is
               afforded by available or candidate vaccines. Nevertheless, since the extent and duration
               of cross-neutralization and cross-protection are strongly dependent on the degree
               of amino acid similarity among flaviviruses, it is likely that vaccination against
               more distantly related flaviviruses will not be as efficient in inducing protection
               [
               37]. The following question remains to be addressed: In the case of non-optimal cross-reactions,
               could vaccination or infection result in ADE-mediated disease exacerbation, as frequently
               described for DENV?

4.3. ADE Risk

In some instances, the presence of cross-reacting antibodies acquired during a primary
               infection could increase the infectivity and exacerbate the disease outcome of a second,
               antigenically-related virus. This phenomenon, called ADE, has been observed
               in vitro, and is still the subject of debate for a few viruses, including
               Flavivirus species such as DENV. The most severe form of the disease, dengue hemorrhagic fever
               or shock syndrome (DHF/DSS), mainly occurs after two or more consecutive infections
               with different DENV serotypes (DENV strains are classified into four serotypes, 1–4)
               [
               181,
               182,
               183] and may be mediated by the interaction of IgG-virus immunocomplexes with Fc-γ receptor-bearing
               cells, such as monocytes/macrophages, dendritic cells, and endothelial cells, which
               subsequently become infected [
               182]. Whether this phenomenon also occurs as a result of consecutive infections with
               other flaviviruses is still a matter of speculation. On the one hand, experimental
               studies have shown that the ADE of WNV infections can be induced
               in vitro using rabbit hyperimmune antisera developed against a wide range of flaviviruses,
               including members of both the JEV and TBEV serocomplexes, whereas the ADE of TBEV
               infections is only elicited
               in vitro by members of its own serocomplex [
               184]. On the other hand, evidence of the ADE of flavivirus infections in nature is still
               lacking. However, obtaining evidence of ADE is not straightforward given that the
               distribution of many flaviviruses is either geographically [
               36] and/or ecologically [
               16] restricted. Nevertheless, as flaviviruses emerge in areas outside of their traditional
               geographical ranges, the co-circulation of different flaviviruses within the same
               area is becoming more common. For instance, co-circulation has already been observed
               in areas of central and eastern Europe, where the recently emerged WNV strain co-occurs
               with endemic TBEV. A recent report describing an unusually severe TBEV case in a patient
               in Hungary previously exposed to WNV suggested that the case's severity could result
               from ADE [
               185].

As previously mentioned, human vaccines against flaviviruses (JEV, YFV, TBEV) could
               ensure partial cross-protection against heterologous flaviviruses within the same
               serocomplex. At the same time, there is limited experimental evidence of ADE subsequent
               to vaccination and virus challenge. In mice, antibodies elicited by inactivated-JEV
               vaccines could enhance pathogenesis via ADE when mice were challenged with a heterotypic
               flavivirus such as MVEV [
               178]. Consequently, the risk that vaccination will facilitate a subsequent flavivirus
               infection, although likely to be low, deserves further consideration, and appropriate
               studies should be carried out to address ADE occurrence
               in vitro and
               in vivo [
               123].

5. Conclusions

European countries are currently facing clinical outbreaks or silent circulation of
            a wide diversity of flaviviruses, and it is expected that circumstances will become
            even more complex in the coming years as human travel continues to intensify, the
            trade of animals and goods facilitate virus emergence through the importation of infected
            vectors and/or reservoir hosts [
            88,
            186], and heretofore unknown flaviviruses that already established in Europe are discovered.
            WNV diagnosis and surveillance protocols and schemes clearly need to be improved in
            Europe and across the globe. The specificity of serological laboratory tests should
            be enhanced and adapted to specific epidemiological patterns. Moreover, serological
            surveys should be accompanied by complementary analyses, such as mosquito or animal
            sentinel surveys aimed at collecting infected samples and identifying the molecular
            diversity of circulating flaviviruses. Recent developments in surveillance systems
            have been driven by improved cost/efficiency ratios and consist of implementing risk-based
            surveillance systems [
            187,
            188] in limited geographic areas where flaviviruses are likely to occur.

Acknowledgments

We gratefully acknowledge Anne-Sophie Martel's precious contribution to this collaborative
               work and we thank Jessica Pearce-Duvet for her excellent editing services. This research
               was supported by the European Commission grants, the HEALTH.2010.2.3-3-3 261391 Euro
               West Nile project and the EU-RL on equine diseases, and by the ANR (11 BSV7 003 EVEMATA
               grant).

Conflicts of Interest

The authors declare no conflict of interest.

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