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InFocus

Influenza virus continually evolving

OLIVER DAVIS provides an overview of equine influenza

AN awful lot is being said about
influenza these days. We’re
bombarded with reports on “pig
flu”, “bird flu”, H1N1 pandemics
– over a period of time it’s easy to
lose the forest for the trees. How
can we summarise influenza and
how it relates to us, and
particularly the horse?

Influenza viruses are classified
into types A, B, and C which can be
traced back phylogenetically to a
single avian virus which diverged
approximately 8,000 years ago to
create the C virus
gene. A further split
occurred again 4,000
years later to form
the respective A and
B virus gene we
recognise today.1

Influenza A
viruses cause all
clinically significant
influenza diseases in
mammals and birds,
including epidemics
and pandemics.
Influenza B and C
viruses are mainly
isolated from humans and are less
pathogenic than Influenza A viruses.

Influenza viruses belong to the
family of Orthomyxoviridae and have a
segmented, single-stranded RNA
genome which is imbedded in the
nuclear matrix. Two types of
glycoproteins protrude out of the
nucleoprotein and through the
surrounding envelope – the
Hemagglutinin (HA) and
Neuraminidase (N).

HA is vital to the binding and
entry into the host cell. NA plays a
fundamental role in the release of
freshly budding virions from the cell.
The glycoproteins are also key
stimulators of the body’s immune
response and therefore confer the
influenza virus with its specific
antigenic properties.

A systematic code is employed to
describe influenza viruses. This includes the virus type (A, B or C),
followed by the animal species, place
the virus was discovered, isolate
number, isolation year, followed in
parentheses by the H and N
subtypes. For example, the first virus
isolated from horses was found in
Prague in 1956:
A/equi/Prague/1/56(H7N7).

Aquatic birds remain the natural
reservoir for influenza A viruses and
serve as a springboard for infecting
the various species that come into
contact with them.

Although we tend
to think of influenza
as an infectious
disease that only
affects humans,
horses, pigs and
birds, it is becoming
increasingly evident
that this assumption
is incorrect.

Interspecies
transmission of EI
from horses to dogs
by an H3N8 virus has
been reported on several occasions,
including a widely reported outbreak in 2004 in which eight out of 24
racing greyhounds died from
haemorrhagic pneumonia following
infection from contagious equine
influenza.2 Furthermore, it has been
shown that H3N8 infection can be
transmitted to other dog
populations.3

Infection concern

In Asia, respiratory disease in dogs
has been reported following infection
with H3N2 and the highly pathogenic
avian influenza virus H5N1. N5N1
has also been shown to infect large
felids4,5 and domestic cats6, a fact that
has caused concern recently for both
veterinary and public health.
Reassuringly, there have been no
reports to date of humans
contracting the infection from
diseased dogs or cats.

What makes the influenza virus
so resilient is the ability to change its
antigenic profile over a period of
time. It is able to do this through the
use of antigenic shift and drift. A closer
look at the make-up of the influenza
virus will help understand these
properties better.

As all viruses, the influenza virus
in effect “borrows” the host cell’s
own genetic reproducing capabilities.
However, since the virus’s RNA
polymerase does not have a double-
checking mechanism, random point
mutations occur relatively frequently.
This antigenic drift helps to evade the host’s immune response.
Another characteristic feature of the RNA genome is that it is
segmented. This is important when
two or more different influenza virus
strains invade the same host cell:
similar to predisposing tear lines in
continuous feed computer paper, the
segmented areas can swap with other
influenza virus strains to form a new
subtype which consists of a mixture
of surface glycoproteins from the
original strains.

Not only have the features of
antigenic shift and drift allowed for
the influenza virus to continually
evolve, unfortunately natural
infection confers only a very limited
immunity of short-term duration.
Regular widespread vaccination with
relevant strains remains the only
suitable method to protect against
infection.

Different rate

Interestingly, the rate of antigenic
change is not the same for each
species. In horses, for instance, the
natural evolution of the influenza
virus is slower than in humans. Since
being isolated in 1956, two major
subtypes have evolved for equine
influenza: Subtype 1 (A/Equi-
1H7N7) which is no longer in
circulation worldwide and Subtype 2
(A/Equi-2 H3N8) which has split
into two lineages, a “European”
lineage and an “American” lineage.
Currently, it is the “American” lineage
that is actively evolving and causing
EI outbreaks throughout the world.

The most recent major epidemic
occurred in 2007 when EI struck
Australia7 and spread swiftly
throughout the naïve population,
affecting over 47,000 horses8 and
virtually bringing the equine industry
to its knees. In response to this, the
OIE has recommended that
manufacturers update the strains to
ensure protection against a Sydney
’07 viral type strain.9,10,11

There are currently four influenza
vaccines in the UK that are licensed
for use in horses. All of these have
proven efficacy against equine
influenza. Although not all have yet
managed to update their strains, most
manufacturers have conducted
clinical trials to demonstrate that
their vaccine can cross-protect
against the Sydney ’07 strain.

However, as the manufacturers do
implement the update, don’t expect
to see Sydney ’07 in the list of
employed strains. What you will find
is an American lineage strain that is
closely related to the virus that was
isolated in South Africa in 2003. This appears to be more virulent and
immunogenic than the strains
recovered from the most recent
outbreaks.

A differing feature between the
licensed vaccines is the technology
employed to induce an immune
response. Not only are there
differences in the adjuvant, the
immune-enhancing medium which
carries the viral suspension, but
pharmaceutical companies have
chosen different technologies to
manufacture their vaccine.

These range from a relatively
simple whole virus technology which
uses the entire killed virus, to sub-unit
technology which only includes the
major antigen stimulating components
(HA and/or N) of the virus. There is
also a genetically modified equine
influenza vaccine available which
employs a canary pox virus as a vector.

Although the vaccines will all have
similar qualities, careful scrutiny of the
data sheet is advisable.

References

  1. Yoshiyuki, S. and Masatoshi, N. (2002)
    Origin and Evolution of Influenza Virus
    Hemagglutinin Genes. Mol. Biol. Evol. 19: 501-
    509.
  2. Crawford, P., Dubovi, Castleman,
    Stephenson, Gibbs, W., Chen, L., Smith, C.,
    Hill, R., Ferro, P., Pompey, J., Bright, R. and
    Medina, M., Influenza Genomics Group,
    Johnson, C., Olsen, C., Cox, N., Klimov, A.,
    Katz, J. and Donis, R. (2005) Transmission of
    Equine Influenza Virus to Dogs. Science 310:
    482-485
  3. Yamanaka, T., Nemoto, M.,Tsujimura, K.,
    Kondo, T. and Matsumura, T. (2009)
    Interspecies transmission of equine influenza
    virus (H3N8) to dogs by close contact with
    experimentally infected horses. Veterinary
    Microbiology
    139 (3-4): 351-355.
  4. Keawcharoen, J., Oraveerakul, K., Kuiken,
    T., Fouchier, R.A., Amonsin, A., Payungporn,
    S., Noppornpanth, S., Wattanodorn, S.,
    Theambooniers, A., Tantilertcharoen, R.,
    Pattanarangsan, R., Arya, N., Ratanakorn, P.,
    Osterhaus, D.M. and Poovorawan, Y. (2004)
    Avian influenza H5N1 in tigers and leopards.
    Emerg. Infect. Dis. 10: 2,189-2,191.
  5. Amonsin, A., Payungporn, S.,
    Theamboonlers, A., Thanawongnuwech, R.,
    Suradhat, S., Pariyothorn, N.,Tantilertcharoen,
    R., Damrongwantanapokin, S., Buranathai, C.,
    Chaisingh, A., Songserm, T. and Poovorawan,
    Y. (2006) Genetic characterization of H5N1
    influenza A viruses isolated from zoo tigers in
    Thailand, Virology 344 (2): 480-491.
  6. Kuiken, T., Rimmelzwaan, G.F., Van Riel, D.,
    van Amerongen, G., Baars, M., Fouchier, R.
    and Osterhaus, A. (2004) Avian H5N1
    influenza in cats. Science 306: 241.
  7. Cowled, B., Ward, M., Hamilton, S. and
    Garner, G. (2009) The equine influenza
    epidemic in Australia: Spatial and temporal
    descriptive analyses of a large propagating
    epidemic. Preventive Veterinary Medicine 92 (1-2):
    60-70.
  8. 8. www.dpi.nsw.gov.au/agriculture…
    horses/health/general/influenza/summary-of-
    the-200708-ei-outbreak.
  9. Bryant, N., Paillot, R., Rash, A., Medcalf, E.,
    Montesso, F., Ross, J., Watson, J., Jeggo, M.,
    Lewis, N., Newton, J. and Elton, D. (2010)
    Comparison of two modern vaccines and
    previous influenza infection against challenge
    with an equine influenza virus from the
    Australian 2007 outbreak. Vet. Res. 41: 19
  10. AHT trial (2009) EQ-230-2008.
    11. Intervet Subject Report EQC 06-12-036A.

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