Avian Flu: A possible pandemic threat
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Article ID: WMC003830 ISSN 2046-1690 Avian Flu: A possible pandemic threat Corresponding Author: Dr. Hala Awadalla, professor, Institute of Environmental Studies and Research, Abbassia, 11566 - Egypt Submitting Author: Dr. Hala Awadalla, professor, Institute of Environmental Studies and Research, Abbassia, 11566 - Egypt Article ID: WMC003830 Article Type: Review articles Submitted on:17-Nov-2012, 12:12:00 AM GMT Published on: 17-Nov-2012, 10:22:41 PM GMT Article URL: http://www.webmedcentral.com/article_view/3830 Subject Categories:MICROBIOLOGY Keywords:, pandemic, H5N1, vaccine, antiviral agents How to cite the article:Awadalla H. Avian Flu: A possible pandemic threat . WebmedCentral MICROBIOLOGY 2012;3(11):WMC003830 Copyright: This is an open-access article distributed under the terms of the Creative Commons Attribution License(CC-BY), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Source(s) of Funding: None Competing Interests: None Additional Files: Figure WebmedCentral > Review articles Page 1 of 10
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Avian Flu: A possible pandemic threat
Author(s): Awadalla H
Abstract without a novel NA subtype) appears and spreads in
the human population, which has little or no immunity
to this novel HA. In the 20th century, three pandemics
were reported: in 1918, 1957, and 1968 and were
Background: Influenza viruses infect a wide range of
associated with substantial illness and death (Luke &
animal hosts and cause yearly wintertime epidemics
Subbarao, 2006). Influenza A viruses are perpetuated
among people living in temperate zones. Because of
in the wild birds of the world, predominantly in
their ability to mutate, re-assort gene segments, and
waterfowl, in which the 16 subtypes coexist in perfect
cross species, influenza viruses can also lead to
harmony with their hosts. Currently, influenza
pandemics in which immunologically naive people are
epidemics in the winter are caused by H3N2 and
exposed to a new, highly contagious subtype. In the
H1N1 influenza A and influenza B viruses. (Webster et
last century, these pandemics were caused by
al., 2006).
influenza viruses whose surface attachment proteins,
or hemagglutinins, were derived from birds, the natural Discussion
reservoir of influenza virus. Vaccines are the primary
means to provide protection for people at risk for
inter-pandemic influenza, and new vaccines, directed Pandemic Phases: In the 2009 revision of the phase
against avian-potentially pandemic-strains are now descriptions, WHO has retained the use of a
being tested. six-phased approach for easy incorporation of new
Aim: The aim of this study is to examine available recommendations and approaches into existing
information on influenza pandemic in order to create national preparedness and response plans.
awareness of preventive measures against influenza (WHO. Influenza pandemic preparedness, 2005).
pandemic and to suggest future research areas in
developing control strategies. Interpandemic period
Method: Data sources: Review of literature via
Internet, articles and journals. Data extraction: Phase 1, no viruses circulating among animals have
Abstracts and articles identified were accessed, read been reported to cause infections in human.
to establish relevance to this review. Data synthesis:
Important points were prioritized and then included as Phase 2, no new influenza virus subtypes have been
subtitles; below each subtitle, published works were detected in humans. As influenza virus subtype
included. circulating in animals is known to have caused
infection in human, and is therefore considered
Introduction potential pandemic threat.
Pandemic alert period
Influenza pandemics, defined as global outbreaks of
the disease due to viruses with new antigenic Phase 3, Human infection(s) with a new subtype has
subtypes, have exacted high death tolls from human caused sporadic cases but no human-to-human
populations. The last two pandemics were caused by transmission sufficient to sustain community level
hybrid viruses, or reassortants, that harbored a outbreaks; this may occur under some circumstances.
combination of avian and human viral genes. Avian
influenza viruses are therefore key contributors to the Phase 4 is characterized by Small cluster(s) with
emergence of human influenza pandemics. (Horimoto, limited human-to-human transmission but spread is
and Kawaoka 2001). highly localized, suggesting that the virus is not well
adapted to humans.
Influenza develops in both pandemic and
interpandemic forms. Fortunately, pandemics occur
Phase 5 is characterized by Larger cluster(s) but
infrequently. Interpandemic influenza, although less
human-to-human spread still localized (two countries
extensive in its impact, happens virtually every year
in one WHO region), suggesting that the virus is
(Dolin, 2005). An influenza pandemic occurs when an
becoming increasingly better adapted to humans, but
influenza strain with a novel HA subtype (with or
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may not yet be fully transmissible (substantial during replication and are highly prone to variation.
pandemic risk). However, all 16 HA subtypes, including H5N1, have
until recently been considered to be benign in their
Pandemic period natural hosts, however this benign equilibrium
between the influenza virus and its host may have
Phase 6 is characterized by community level changed (Webster et al, 2006).
outbreaks in at least one other country in a different
WHO region in addition to the criteria defined in phase The most important implication of phenogenetic
5. studies is that the ancestral viruses that caused
Spanish influenza in 1918, as well as the viruses that
post-peak period, during this period pandemic disease provided gene segments for the Asian/1957 (H2N2)
levels will have dropped below peak observed levels, it and Hong Kong /1968 (H3N2) pandemics, are still
will be of uncertain if additional waves will occur and circulating in wild birds, with few or no mutational
countries will need to be prepared for a second wave. changes (Wright & Webster, 2001).
At this stage, it is important to maintain surveillance
and update pandemic preparedness and response Taubenberger et al. (2006) reported that the 1918
plans accordingly. virus did not originate through a reassortment event
involving a human influenza virus: all eight genes of
Fig 1: The current WHO phase of pandemic alert the H1N1 virus are more closely related to avian
(WHO,2009) influenza viruses than to influenza from any other
species, indicating that an avian virus must first infect
Evolutionary pathways of influenza viruses: humans and then adapt to them in order to spread
from person to person. Thus, pandemic influenza may
Webster et al., (1992) described the ecology of originate through at least two mechanisms:
influenza viruses, they suggested that all mammalian reassortment between an animal influenza virus and a
influenza viruses are derived from avian influenza human influenza virus that yields a new virus strain,
reservoirs, support for this theory results from and direct spread and adaptation of a virus from
phenogenetic analyses of nucleic acid sequences of animals to humans.
influenza A viruses from a variety of hosts, geographic
regions, and virus subtypes It is important to mention that influenza A/ H1N2
viruses, which emerged during 2001 are genetic
Influenza viruses in wild aquatic birds appear to be in reassortants between H1N1 and H3N2 subtype
evolutionary stasis, with no evidence of net evolution viruses which have circulated in the human population
over the past 60 years. phenogenetic analyses of since 1977. They possess a H1 hemagglutinin
amino acid showed that avian influenza viruses, unlike antigenically and genetically similar to contemporary
mammalian strains, had low evolutionary rates A/New Caledonia/20/99 (H1N1)-like viruses and seven
(Gorman et al, 1990). genes closely related to those of recent
Nucleotide changes have continued to occur at a A/Moscow/10/99 (H3N2)-like viruses. The viruses
similar rate in avian and mammalian influenza viruses, have spread into many regions of the world and have
but these changes no longer result in amino acid predominated over H1N1 viruses in several countries,
changes in the avian viruses, whereas all eight (e.g.Egypt) (Gregory et al, 2002).
mammalian influenza gene segments continue to
accumulate changes in amino acids. The high level of Fig. 2: Cumulative Number of Confirmed Human
genetic conservation suggests that avian influenza Cases of H5N1 (WHO, 2009)
viruses in their natural reservoirs are approaching or Next pandemic:
have reached an adaptive optimum, where in
nucleotide changes provide no selective advantage. All past influenza pandemics occurring during the 20th
This means that the source of genes for pandemic century apparently arose from the Eurasian avian
influenza viruses exists phenotypically unchanged in lineage of viruses. Over the past several years, a great
aquatic bird reservoir (Wright & Webster, 2001). deal of attention has been focused on the role of avian
influenza viruses as the source of the next pandemic
This lack of change is surprising because influenza strain.
viruses are segmented, negative - stranded RNA
viruses that have no quality control mechanisms Avian influenza was first identified in Italy more than
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100 years ago. Pigs have receptors for avian and are still rare and the virus does not spread easily from
human influenza viruses and are susceptible to both; birds to humans or readily from person to person
therefore, pigs have been considered logical (Saeed & Hussein , 2006)
intermediary hosts for viral reassortment between
avian and human influenza strains (Horimoto & The current epidemic of H5N1 highly pathogenic avian
Kawaoka, 2001). However, the role of pigs in creation influenza in Southeast Asiaraises serious concerns
of pandemic strains is still under investigation. It is not that genetic reassortment will result in the next
clear whether avian strain could directly cause a global influenza pandemic. There have been 164 confirmed
pandemic in humans or reassortment in another cases of human infection with avian influenza since
animal host is a necessary step (Webster, 1997). 1996. In 2004 alone, there were 45 cases of human
H5N1 in Vietnamand Thailand, with a mortality rate
The last two pandemic viruses resulted from over 70%. In addition to the potential public health
combinations of avian and human influenza viruses hazard, the current zoonotic epidemic has caused
(wild birds are considered the reservoir for type A severe economic losses. (Zeitlin & Maslow , 2006)
influenza viruses). Many persons believe that these
new viruses emerged when an intermediate host, such In six countries this virus has also caused fatal human
as pig, was infected by both human and bird influenza infections. This has sparked fears that this agent may
A viruses at the same time. A new virus was created. be the progenitor of a new pandemic influenza virus.
Events inHong Kongin 1997, however, showed that During summer 2005 the disease has slowly spread
this is not the only way that human can become westward. Isolated outbreaks have been reported from
infected with a novel virus. Sometimes; an avian Kazakhstan, Russia, Romania, Turkey, Croatiaand
influenza virus can jump the species barrier and move Ukraine. Migratory birds have been tentatively
directly from chickens to humans and cause the accused for spreading the infection along their flyways.
disease. So the direct contact with infected poultry is (Werner, 2006)
the route of transmission (Chotpitayasunondh, et al,
2006). In addition to a growing list of avian species This rapid rate of spread of virus along with notoriety
that can be infected with H5N1 virus, the virus has of the virus for frequent genetic re-assortment, which
infected several mammalian species, including tigers, might enable H5N1 to infect human beings, threatens
leopards and pigs (Fauci, 2006) . of possible influenza pandemic since the last
pandemic in 1968. The human influenza caused by
Influenza viruses are impossible to eradicate, as there this subtype of the virus (H5N1) has high case fatality
is a large reservoir of all subtypes of influenza A of 54% and majority of affected humans are between
viruses in wild aquatic birds. In agricultural – based the ages of 5 to 23 years. (Lahariya , et al, 2006)
communities with high human population density such
as are found inChina, conditions exist for the Human infection with avian influenza virus:
emergence and spread of pandemic viruses. It is also
impossible to predict when the next pandemic will Influenza A viruses causes natural infections of
occur. Moreover, the severity of illness is also humans, some other mammals and birds. Few of the
unpredictable, so contingency plans must be put in 16 haemagglutinin and nine neuraminidase subtype
place now during the inter–pandemic period. These combinations have been isolated from mammals, but
plans must be flexible enough to respond to different all subtypes have been isolated from birds (Alexander
levels of disease (Cox, et al, 2003). , 2006), of the 16 avian influenza virus subtypes,
H5N1 is of particular concern for several reasons.
We cannot predict when the next influenza pandemic
will occur, or which influenza virus subtype will cause it. H5N1 mutates rapidly and has a documented
Forecasts of the severity of the next influenza propensity to acquire genes from viruses infecting
pandemic differ in their predictions of deaths based on other animal species. Its ability to cause severe
the models used. Modeling based on the pandemic of disease in humans has now been documented (WHO:
1968 projects 2 million - 7.4 million excess deaths Avian influenza, fact sheet, 2004).
worldwide (Luke & Subbarao, 2006).
The virus has spread rapidly throughout poultry flocks
The H5N1 virus has infected birds in more than 30 in Asia over the past 2 years and now appears to be
countries in Asia, Europe and Africa, while further endemic in easternAsia(Kaye & Pringle, 2005)
geographical spread remains likely. Human infections
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It has shown a propensity to acquire genes from Development of effective vaccines against highly
viruses infecting other animal species. It causes pathogenic avian influenza H5N1 viruses with the
severe disease in humans, with a high case-fatality potential to cause a pandemic is a public health
rate (reportedly at about 70%, although adequate priority (Hoelscher et al., 2008). A two-dose vaccine
surveillance data are lacking to accurately define the regimen of either 7.5 microg or 15 microg of
rate). hemagglutinin antigen without adjuvant induced
neutralizing antibodies against diverse H5N1 virus
The potential of exposure and infection of humans is strains in a high percentage of subjects, suggesting
likely to be ongoing in ruralAsia, where many that this may be a useful H5N1 vaccine.
households keep free-ranging poultry flocks for (ClinicalTrials.gov number, NCT00349141.) 2008
income. (Stohr, 2005). Massachusetts Medical Society (Ehrlich et al., 2008)
Another randomised, dose comparison, parallel
Vaccination is the best option by which spread of a assignment, multicentre trials conducted in Australia,
pandemic virus could be prevented and severity of healthy adult volunteers received two doses of vaccine
disease reduced. Production of live attenuated and (phase I trial; N=400, phase II trial; N=400) (Nolan et
inactivated vaccine seed viruses against avian al., 2008)
influenza viruses, which have the potential to cause
pandemics, and their testing in preclinical studies and Antiviral agents can be used to treat influenza infection
clinical trials will establish the principles and ensure and can be taken as chemoprophylaxis during
manufacturing experience that will be critical in the influenza outbreaks (Stephenson & Democratis,
event of the emergence of such a virus into the human 2006). Oseltamivir (Tamiflu®) has been shown to be
population. (Luke & Subbarao, 2006). effective in the treatment and prevention of epidemic
influenza infection in adults, adolescents and children (
Inactivated vaccines against avian influenza subtypes 1 year). Although oseltamivir has not been approved
require 2 doses and administration with adjuvant to for prophylactic use in children, it has been shown to
achieve the desired level of the neutralizing antibody. be effective. Oseltamivir is also active against avian
The precise antigenic properties of a nascent influenza virus strains. Evidence suggests that lower
pandemic strain cannot be predicted, so available doses or shorter durations of
vaccines may be poorly antigenically matched to the treatment/chemoprophylaxis other than those
pandemic virus. Manufacturing capacity, the ability of approved may not be effective and may contribute to
candidate vaccine stains to grow well in eggs, and emergence of viral resistance. (Ward1 , et al, 2005)
biological safety containment of parent strains for
vaccine development are all problems to be addressed. Conclusion(s)
Efforts are under way to develop and evaluate live,
attenuated vaccines against potential pandemic
strains of influenza along a track that parallels the Avian influenza refers to a large group of different
development and evaluation of inactivated virus influenza viruses that primarily affect birds. On rare
vaccines (Luke & Subbarao, 2006). occasions, these bird viruses can infect other species,
including pigs and humans. The vast majority of avian
To date, vaccines have been shown to be safe and influenza viruses do not infect humans. An influenza
well tolerated, but have required multiple doses and pandemic happens when a new subtype emerges that
dosage levels higher than traditionally needed for has not previously circulated in humans.
seasonal influenza vaccines in order to generate An influenza pandemic is a rare but recurrent event.
immune responses thought to be protective, Three pandemics occurred in the previous century:
(Campbell, 2006). If the emerging avian influenza or “Spanish influenza” in 1918, “Asian influenza” in 1957,
another new virus creates a pandemic, severely and “Hong Konginfluenza” in 1968.
limited supplies of vaccines and antiviral medications
The keystone of influenza prevention is vaccination;
are likely (Temte, 2006). Efforts must be concentrated
vaccine preparation should be by genetic
on early detection of bird outbreaks with aggressive
reassortment of high-yield seed viruses of all
culling, quarantines, and disinfection. To prepare for
hemagglutinin subtypes. The recommendation
and prevent increased human cases, it is essential to
assumes that the next pandemic virus is unpredictable,
improve detection methods and stockpile effective
but it will come from one of the 16 hemagglutinin
antiviral. (Zeitlin & Maslow, 2006).
subtypes of avian or mammalian strains of influenza A.
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Illustrations
Illustration 1
The current WHO phase of pandemic alert (WHO,2009)
The current WHO phase of pandemic alert (WHO,2009)
WebmedCentral > Review articles Page 8 of 10WMC003830 Downloaded from http://www.webmedcentral.com on 19-Nov-2012, 09:53:36 AM Illustration 2 Cumulative Number of Confirmed Human Cases of H5N1 (WHO, 2009) Cumulative Number of Confirmed Human Cases of H5N1 (WHO, 2009) WebmedCentral > Review articles Page 9 of 10
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