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Review Article
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Swine Flu is Back Again: A Review |
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Kuldeep Dhama,
Amit Kumar Verma,
S. Rajagunalan,
Rajib Deb,
K. Karthik,
Sanjay Kapoor,
Mahima ,
Ruchi Tiwari,
Parmod Kumar Panwar
and
Sandip Chakraborty
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ABSTRACT
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Flu viruses have mainly affected humans, birds and pigs worldwide. During the past 10 years these viruses are in limelight at a global level due to pandemic threats of Avian / Bird Flu and Swine Flu and their public health impacts, with added pandemic of swine flu virus recently. The current ongoing episodes of bird flu and swine flu are beyond the control, when and where or which country they start with nobody can predict. The continuous evolution and emergence of new strains indicate that the flu viruses are becoming more and more dangerous and this situation has posed a challenge to researchers to discover effective vaccines and therapeutics. Moreover, the role of pig as mixing bowl for the virus to get reassorted has added to the complicated epidemiological scenario. The swine flu H1N1 reassorted subtype caused the first global pandemic in last 40 years, resulting in substantial illness, hospitalizations of millions of peoples and thousands of deaths throughout the world. A pace is there within these novel and emerging flu viruses and the scientific community, where the scientific community has to win the race so as to save the mankind. In this review, a brief overview on swine flu is presented highlighting the characteristics of the causative virus, the disease and its public health consequences, advances made in its diagnosis, vaccine and control, precautionary measures to be adapted in the wake of an outbreak.
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How
to cite this article:
Kuldeep Dhama, Amit Kumar Verma, S. Rajagunalan, Rajib Deb, K. Karthik, Sanjay Kapoor, Mahima , Ruchi Tiwari, Parmod Kumar Panwar and Sandip Chakraborty, 2012. Swine Flu is Back Again: A Review. Pakistan Journal of Biological Sciences, 15: 1001-1009. DOI: 10.3923/pjbs.2012.1001.1009 URL: https://scialert.net/abstract/?doi=pjbs.2012.1001.1009
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Received: November 19, 2012;
Accepted: January 28, 2013;
Published: March 07, 2013
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INTRODUCTION
Flu viruses affect a variety of animal species including pigs, horses, marine
mammals, birds and also have caused human pandemics killing millions of people
worldwide (Dhama et al., 2005, 2008;
Chen et al., 2012; Mancini
et al., 2012; Stack et al., 2013).
With the improvement in transport and globalization, introduction and emergence
of new influenza types and subtypes occur (Starbuck et
al., 2012). Therefore, World Health Organization (WHO) has declared
the threat of pandemic influenza posing a significant public health problem
all over the world (Patriarca and Cox, 1997; King
et al., 2004; Centers for Disease Control and
Prevention CDC, 2009; WHO, 2009; Ali
et al., 2012). During the past 10 years these have been in limelight
at a global level due to pandemic threats of Avian/Bird Flu and Swine Flu. Bird
flu virus has caused severe economic losses to poultry industry and particularly
since 2003 the H5N1 subtype has affected more than 60 countries resulting in
loss of more than 300 million birds and 365 human lives (out of 617 affected)
(Nayak et al., 2010). Alarming situation appeared
again in 2009 when the reassortant H1N1 Swine Flu virus also knocked the door,
reaching a pandemic status within few days, killing thousands of humans (WHO,
2009). The current ongoing episodes of bird flu and Swine Flu are beyond
the control, when, where and which country will be affected, nobody can predict.
The continuous evolution and emergence of new strains indicates that the flu
viruses are becoming more and more dangerous (Guan
et al., 2012), posing challenge to researchers to discover effective
vaccines and therapeutics (Verma et al., 2012).
Recent studies have indicated that human deaths due to swine flu might be much
more as the disease is under reported or not diagnosed in many instances. Apart
from these, Human Flu virus (H1N1) also causes approximately 36,000 deaths and
more than 200,000 cases every year responsible for loss of over $10 billion
in United States. Presently, another novel reassorted swine flu subtype H3N2
has emerged and is causing the menace (Jin and Mossad,
2012). In this review a brief overview on swine flu is presented highlighting
the characteristics of the virus, disease and its public health consequences,
advances made in diagnosis, control vaccine and precautionary measures to be
adapted in the wake of an outbreak.
ETIOLOGY
Influenza viruses are enveloped RNA viruses belonging to Orthomyxoviridae family.
The influenza (flu) viruses are highly contagious, able to spread very fast
and easily across continents. These viruses has the ability to continuously
change, resulting in emergence of new viral strains by genetic shift, point
mutations and other mechanisms, posing threats to the host species particularly,
in birds and humans (Dhama et al., 2005; Pawaiya
et al., 2009; Lambert and Fauci, 2010; Hao,
2011). Type A influenza viruses are divided into 17 H (haemagglutinin) and
10 N (Neuraminidase) subtypes which can give rise to many possible combinations
(designated as H1N1, H1N2
.H2N1, H2N2
.H5N1, H5N2
. and so on)
(Dhama et al., 2005; Tong
et al., 2012). The haemagglutinin (HA) plays role in attachment of
the virus to the surface of infected cells while the neuraminidase (NA) plays
role in release of the progeny viruses from the infected cells therefore NA
plays role in spread of the virus (Wang et al., 2009).
The influenza viruses primarily affect birds, pigs, equines and humans and are
of significant concern as they could cause epidemics and pandemics. Of major
concern are the influenza/flu viruses affecting birds, pigs and humans. Birds
have alpha 2,3 sialic acid receptors in lungs while humans have alpha 2,6 receptors
but swine have both the receptors, therefore pigs can be infected with avian,
human and swine influenza viruses thus acting as a mixing vessel
(Ito et al., 1998; Dhama
et al., 2005).
How the virus keeps on changing? Influenza/flu viruses keep on changing
continuously giving rise to emergence of new viral strains. Genetic shift, point
mutations and other mechanisms altogether help evolve more and more lethal flu
viruses, posing threats to the host species particularly the birds and human
beings (Dhama et al., 2005; Pawaiya
et al., 2009; Lambert and Fauci, 2010;
Hao, 2011).
Genetic or antigenic shift (reassortment/genomic mixing): Due to their
eight segmented genome influenza viruses are capable of rapid evolution during
mixed infections with different flu viruses (human, avian, swine) -A completely
new subtype or a novel strain gets evolved (Chen et
al., 2012).
Point mutations or antigenic drift: Point mutations are accumulated during virus replication and causes gradual evolution or acquisition of new strains of the same subtype, especially in the HA and NA glycoprotein genes, this process allows virus to escape the immune system and cause epidemics. These major antigenic changes in HA or NA, results in periodic pandemics.
Swine influenza virus (SIV): The classical swine flu virus (H1N1) was
isolated for the first time in 1930 from a pig. Swine influenza
or Swine flu is a respiratory disease of pigs, caused by the swine
flu virus and affects swine population round the year (Pawaiya
et al., 2009; Said et al., 2013).
During colder weather and winter months disease outbreaks are commonly seen.
Among pigs H1N1, H1N2, H3N2 and H3N1 influenza virus subtypes are frequently
reported, they could also be infected with H4N6 and H9N2 subtypes. The swine
flu viruses do not normally infect humans. However, as pigs could act as mixing
vessel for influenza viruses, events of reassortment and mutation would results
in emergence of a novel influenza virus capable of causing human pandemics.
Such an event started in April 2009 with H1N1 swine flu virus subtype (Garten
et al., 2009; Pawaiya et al., 2009;
Mak et al., 2012). This novel H1N1 reassortant
virus has acquired the competence of rapid human to human spread without affecting
pigs and has resulted in pandemic among in humans in many countries worldwide
(Garten et al., 2009). The recently emerged H3N2
is a new reassorted subtype also has resulted in deaths of some children in
United States (18 deaths in 1 week in Pennsylvania) (Chen
et al., 2012). The major reservoirs of H1N1 and H3N2 influenza viruses
are the pigs, in which influenza viruses reassort and could give rise to human
pandemics.
EPIDEMIOLOGY, PUBLIC HEALTH IMPORTANCE AND PANDEMIC POTENTIALS/THREAT
Influenza viruses have affected animals and humans worldwide from time to time
in the form of severe disease outbreaks, epidemics and even pandemics, causing
severe economic losses and even threats to mankind (Dhama
et al., 2005; Pawaiya et al., 2009).
Pregnant women are at higher risk so World Health Organization (WHO,
2009) recommended the use of swine influenza vaccine in pregnancy. Direct
transmission of influenza viruses can occur from pigs to humans and from humans
to pigs.
The 20th century Human Influenza Pandemics:
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Spanish flu: (1918-1919): H1N1, an estimated 50 million
deaths |
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Asian flu (1957): H2N2, 1-2 million deaths |
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Hong kong flu (1968-1969): H3N2, 1-2 million deaths |
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Swine flu (2009- till date): H1N1, H3N2, 18,000 deaths |
Key facts:
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In humans H1N1, H1N2 and H3N2 subtypes circulate commonly
among people around world |
• |
Few influenza virus subtypes (H5N1, H7N2, H7N3, H7N7, H9N2 and H10N7)
have jumped the species barrier from water fowl/ birds to humans (Musa
et al., 2009; Pawaiya et al., 2009;
Murcia et al., 2012) |
• |
H5N1 caused severe economic losses to poultry industry worldwide and zoonotic
threat to mankind, starting from 2003 and still continuing (Sarkar
et al., 2012) |
• |
Pigs are considered as donator of the virus relatively easily, can
act as mixing vessel or mixing bowl for genetic
reassortment and pandemic influenza viruses could originate from these
intermediate hosts. Pigs can spread the flu viruses in an open pathway
without any barrier (Chambers et al., 1991;
Schultz et al., 1991; Ma
et al., 2008; Kuntz-Simon and Madec, 2009)
which has been depicted in Fig. 1 |
• |
The H1N1 subtypes had two genes from flu viruses that normally circulate
in pigs in North America, Europe and Asia along with avian and human influenza
virus genes, thus it is a quadruple reassortant virus with acquisition
of man to man transmission capability |
• |
The avian influenza virus (AIV) has yet to acquire the ability of rapid
spread from human to human, as has been observed for the swine flu virus
(H1N1 subtype) causing pandemic |
• |
H1N1 swine flu virus (H1N1 triple human/avian/swine reassortant virus)
caused human pandemic recently, started (Garten et
al., 2009; Pawaiya et al., 2009;
Shinde et al., 2009; Smith
et al., 2009; Levy et al., 2013) |
• |
In 2011, a swine-origin influenza A (H3N2) virus infection were identified
in two children (5 years of age) with history of contact with pigs and both
had received seasonal influenza vaccine in 2010 (which contained the pandemic
H1N1 swine flu virus strain) in US |
• |
Currently H3N2 virus, a novel reassortment from swine has also been reported
in August, 2012, with confirmed human cases affecting, children primarily
in US (154) (Skowronski et al., 2012) and
Ohio (79) with history of exposure to pigs |
This is especially important in the context of the concept of original
antigenic sin which postulates that if a person in his childhood gets
exposed to an influenza virus for the first time, strongest immunity develops
in the later years to come. As a result of this people born before 1957 may
show the greatest natural immunity to the A/H1N1pdm pandemic virus circulating
at present (Chowell et al., 2011; Rifkin
and Schaal, 2012).
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Fig. 1: |
Role of pigs in evolution of pandemic swine flu virus |
SWINE FLU HUMAN PANDEMIC (NOVEL REASSORTANT H1N1 VIRUS) (2009-2012)
The H1N1 virus which causes swine flu, first appeared in Mexico in 2009 and
rapidly spread around the world. Within 03 Months of the start of swine flu
H1N1 human pandemic in April 2009 about 135 countries were affected with nearly
one lakh of human cases and more than 500 deaths in USA alone (case fatality
rate of nearly 0.5%) (Centers for Disease Control and Prevention
CDC, 2009; Pawaiya et al., 2009; WHO,
2009) (Table 1). Recent studies also indicate that the
swine flu H1N1 pandemic would have killed many a thousands more since all the
cases were not reported and many would have went undiagnosed and was estimated
to be nearly 200,000 human casualties around the world. H3N2 which is new subtype
has accounted for 145 cases.
High risk persons are those affected with chronic diseases of liver, lung, heart, kidney; and having diabetes, immunosuppression and neurological diseases. Indian scenario: In India, swine flu has resulted in human casualties of 981 in 2009, 1,763 in 2010 and 75 in 2011. Swine flu is back in India on May 2012 resulting 129 cases with 12 deaths reported during this period of time. The major sufferer of this attack is Maharashtra with 69 cases and 6 deaths, followed by Rajasthan 28 cases and 5 deaths. One death has been reported from Andhra Pradesh as well. No deaths from Karnataka though there were affected cases. Recently in 2013, 456 cases along with 94 deaths have been reported so far in various states including, Rajasthan, Punjab, Haryana, Delhi, Himachal Pradesh. Opportunities for emergence and spread of influenza viruses:
• |
A flu virus acquiring the lethal killing weapon of bird flu
(H5N1) virus and rapid spread abilities of swine flu (H1N1) virus would
evolve into a new/novel influenza virus and may result in as a probable
pandemic threat to mankind. World population would be "immunologically naive"
to this kind of a virus, permitting explosive spread of the disease that
could cause serious socio-economic and public health consequences (Pawaiya
et al., 2009) |
• |
Overcrowding due to increasing human population of 7 billion (Mahima
et al., 2012), increasing modern pig and poultry production ventures
and proximity of humans and animals in many markets create potential for
virus recombination and conditions conducive for the spread of the influenza
virus and mass influenza outbreaks |
• |
Rearing of pigs, birds (pet) and poultry together |
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Increase in intercontinental travel within hours rather than months as
in olden days and is in millions rather than hundreds |
Animals, birds and humans living in close proximity places could create epicenters for influenza viruses. Ducks/chickens with pigs sharing ponds can very well contribute to the development of a reassortant virus. Pigs are known to be an intermediate host for the genesis of pandemic influenza viruses. Past pandemics reflect the role of birds in the generation of novel influenza virus reassortants. DISEASE
In pigs: Swine influenza is a highly contagious and an economically
important disease of pigs (Heinen, 2003; Pawaiya
et al., 2009). Swine flu H1N1 is common among pigs as 25% of animals
were found to carry antibodies by sero-surveillance. Among pigs the disease
spreads by aerosols during close contact and also by contaminated objects/fomites
moving between infected and uninfected pig sheds. If the virus is introduced
for the first time into susceptible herds, then acute infections occur and may
result in severe outbreaks. In the epidemic form, the virus quickly moves through
the swine population followed by rapid recovery provided there are not complicating
factors like secondary bacterial infections. In the endemic form, clinical signs
may be less observed. Mortality rates are generally low in SIV infections, though
morbidity can be up to 100%. Clinical signs occurs suddenly and the affected
pigs exhibits signs like coughing, sneezing, nasal discharge, tachypnoea, dyspnea,
pyrexia, anorexia and lethargy and some may occasionally show signs of fatal
bronchopneumonia (Van Reeth, 2007; Simon-Grife
et al., 2012), rarely pregnant sows may abort. Clinical signs usually
persist for about seven days followed by quick and complete recovery unless
complicated by secondary bacterial infections which can exacerbate the clinical
manifestations (Easterday and Van Reeth, 1999; Pawaiya
et al., 2009). The disease causes high morbidity (as high as 100%)
but low mortality if secondary bacterial infections are avoided.
There may be chance of sporadic disease with little or no any symptom, especially in herds where infections become a continuous problem or all the animals have been vaccinated.
In humans: Humans get infected by inhalation during close contact with
infected pigs due to direct occupational exposure or in livestock exhibits housing
pigs at fairs. Airborne human-to-human transmission can also occur. The affected
individuals exhibits signs similar to that of human seasonal flu like fever,
lethargy, loss of appetite, coughing, sneezing, sore throat, runny nose, difficulty
in breathing, myalgia, headache, chills, fatigue vomiting and diarrhea (Pawaiya
et al., 2009). In children neurological symptoms like seizures and
changes in mental status like confusion or behavioral changes can also occur.
Few such cases can be very severe and often fatal. The infected individuals
could remain potentially contagious as long as they become symptomatic following
onset of illness; childrens could remain infective for longer periods
(Iannelli, 2013). Young people below the age of 25 are
more susceptible/affected (Simonsen et al., 2004;
Pawaiya et al., 2009; Chowell
et al., 2011; Rifkin and Schaal, 2012).
The H1N1 swine flu viruses are antigenically very different from human H1N1
(human influenza) viruses (Pawaiya et al., 2009).
Therefore, human seasonal flu vaccines are not effective in cases of H1N1 Swine
Flu viruses.
DIAGNOSIS
Presumptive diagnosis can be made based on clinical and pathological findings
but confirmatory diagnosis requires detection of the particular influenza virus
subtype in the affected host (birds, pigs or humans). Swine flu H1N1 virus can
be detected by viral nucleic acid detection (Bertran
et al., 2012; Read et al., 2012; Simon-Grife
et al., 2012; Jackowska et al., 2013;
Romanowska et al., 2013) or by serologic assays
(Simon-Grife et al., 2012; Skowronski
et al., 2012). Virus isolation can be performed in MDCK cell lines
or primary swine kidney cell lines or in embryonated chicken eggs. Serological
test like ELISA and molecular tools like RT-PCR, Real-time PCR are also used
in the diagnosis of swine influenza (Yang et al.,
2013). Respiratory specimen like nasal swabs, lung tissues should be collected
within the first 4-5 days of illness when an infected person is most likely
to be shedding virus (Alexander, 2008). Serum from acute
and convalescent phase of infection can also be collected.
Bird flu and swine influenza viruses are zoonotic in nature and therefore the
samples for diagnosis should be handled carefully to avoid transmission to humans.
Precise and timely diagnosis needs appropriate samples to be sent to referral
laboratories (choice and quality of specimens and the conditions for their transport
and storage), having appropriate biosafety levels (BSL3/4) designated worldwide
(Kumar and Henrickson, 2012). Respiratory samples viz.,
nasal swabs and lung tissues are to be collected within initial period of symptoms,
preferably within first 5 days, as during this time only infected person most
likely sheds virus (Alexander, 2008). Serum from acute
and convalescent phase of infection can also be collected.
TREATMENT
Neuraminidase plays role in the release and spread of progeny viruses from
infected cells and is the main target in the development of drugs against influenza
viruses (Wang et al., 2009). Neuraminidase inhibitors
like Oseltamivir (Tamiflu and Fluvir) and Zanamivir (Relenza) are widely used
as anti-flu drugs in the treatment of swine flu cases in humans (Parmar
et al., 2011; Hsu et al., 2012; Vijayan
et al., 2012) but not in swine. Oseltamivir is the drug of choice.
In pigs, usually supportive therapy and antibiotics treatment is carried out
to control secondary bacterial infection.
PREVENTION AND CONTROL
Adequate prevention and control measures include strict biosecurity measures
along with regular disease surveillance and monitoring programmes. Applying
advanced diagnostics, stockpiling drugs like Tamiflu and development of novel
vaccines utilizing recent tools and techniques and judicious vaccination strategies
are of paramount importance in preventing the disease. These measures also limit
epidemic potential and help avoid an imminent human pandemic (Pawaiya
et al., 2009; Mak et al., 2012;
Moukarram et al., 2012).
Adopt proper farm management practices along with good sanitation and hygienic
measures like washing hands, following appropriate disinfection (sodium hypochlorite)
and sanitary practices. Follow basic preventive measures, with strict vigil/
case identification and quick detection, isolation, quarantine, treatment of
infected animals. Close contact with infected pigs should be avoided. People
suffering from swine flu should take proper rest and must stay away from going
to public places where numerous people gather. Safety measures such as wearing
protective clothing, gloves, goggles, gown, rubber boots etc. must be taken
care of during bird flu and swine flu disease outbreaks.
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Fig. 2: |
Swine flu-Methods for diagnosing, treating, preventing and
controlling it in human |
Personal hygiene and biosafety measures should be adopted/upgraded like use
of face mask, covering mouth and nostrils with tissue paper or handkerchief
while sneezing or coughing and wash hands properly. Better wear surgical mask.
Frequent hand washing helps reduce the chance of getting contamination from
infected sources/fomites. Spread of infection can also be checked by avoiding
touching of eyes, nose and mouth in the SIV contaminated environment. Drop the
used tissue papers etc. in the dust-bin/trash during swine flu epidemics/pandemics.
The virus is not transmitted by ingestion of pork so ingestion of properly handled
and cooked pork is safe for humans.
Heightened vigilance and regular monitoring for identifying the influenza/flu
cases is of paramount importance to prevent and control spread of bird flu and
swine flu viruses and the flu pandemics. Regular and timely surveillance and
tracking of influenza viruses at global level are the key factors for this purpose
(Mak et al., 2012; Rebmann
et al., 2012; Seetoh et al., 2012).
International flights, train and surface transport should also come under strict
surveillance. Wide public awareness on the prevention and control strategies
as well as the zoonotic impact of bird flu and swine flu should be created using
mass media (Pawaiya et al., 2009; Verma
et al., 2012; Viveki et al., 2012).
Along with it education and training programmes should be organized for para-veterinary
professionals, animal and poultry farmers, animal transporters, etc (Ear,
2012). There should be some policy for filling the gaps in the knowledge
of these influenza pandemic especially in developing countries (Kouassi
et al., 2012; Cantey et al., 2013).
Methods involved in diagnosis, treatment, prevention and control of swine flu in human as discussed above is depicted schematically in Fig. 2.
Vaccines: For the prevention of swine influenza in pigs vaccines are
available but are not proven to be 100% effective. The recombinant equine herpes
virus-1 (EHV-1) encoding H1 of A(H1N1) pdm09 can protect the pigs against itself
or any other influenza virus (Said et al., 2013).
Only recently, for the current pandemic H1N1 strain the vaccine has been developed
and approved by FDA and European medicines agency for use in US and UK, respectively.
These include the chicken egg cultured swine flu viruses used as killed vaccine
or as sub unit vaccine after digestion with detergent or cell culture vaccine
(Vero or MDCK) and the cold adopted influenza virus. Vaccine for human influenza
does not protect people against avian influenza infection and may lead to adverse
effects following immunization with classical influenza vaccines (Wiwanitkit,
2009).
Two types of influenza vaccines are available namely:
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Trivalent Inactivated Influenza Vaccine (TIV), administered
via injection |
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Live Attenuated Influenza Vaccine (LAIV), administered via nasal spray |
LAIV is not recommended for individuals under age 2 and over 49 years age. Effective vaccines for protecting birds as well as humans against the novel reassortant H1N1 and H5N1 subtype virus are the need of hour. CONCLUSION Disease outbreaks of bird flu and the recent swine flu pandemic and their public health impacts with probable potential of a deadly human pandemic have created an alarming situation worldwide. Fortunately, swine flu did not acquire the lethality like that of bird flu virus having nearly 60% case fatality rates, in which case a deadly pandemic would begin threatening human survivability. Continuous global efforts are on the way so as to gain better understanding about the virus, focusing on its pathogenesis, genetic versatility, zoonosis, pandemic potential, treatment and control. Prevention and control strategies focus on strict biosecurity, adequate disease surveillance, timely diagnosis, appropriate culling measures and judicious vaccination measures along with adequate public health and biosafety measures. Since the appearance of this disease is unpredictable, these responses must be prompt, well planned and complete. SIVs do not normally infect humans and had been only responsible for sporadic zoonotic infections. However, the current novel influenza A (H1N1) swine flu virus has caused pandemic situation in several countries due to gene swapping amongst between avian, swine and human viruses. Swine flu viruses does not cause any illness in pigs but change constantly like the other Type A influenza viruses which poses difficulty in developing a permanent, long-lasting and effective vaccine. Though the recent/current swine flu pandemic is looking moderately severe at present but if the virus acquires the deadly lethality like that of bird flu virus then situation would be worst for the survivability of mankind. Possible pandemic threat posed by the highly pathogenic H5N1 bird flu virus and the H1N1 swine flu subtype or with an emerging new subtype, if happens could be catastrophic for humans considering its past lethality rate.
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