Hypothetic Scenario of a Influenza (H5N1) Pandemic
What would happen if the current H5N1 virus, causal agent of the avian influenza, would mutate into a
pandemic form? How can we prepare ourselves for an unpredictable but potential y devastating event?
How can we give priority to such a hypothetical situation when at the moment there are existing more
urgent needs in healthcare. This report intents to answer these questions under best assumptions how
the numerous individual factors would perform and interfere. However nobody knows the exact
dimension of a upcoming pandemic, but preparing and organizing efforts regarding pandemic
preparedness are much less intense than pandemic consequences without preventing measures.
Point in time
Next pandemic can not be prevented, it is just a matter of time and no one can predict the moment.
There is a documented history of pandemic influenza:
(2003 SARS, no influenza virus but corona virus) H5N1
1878 researchers noticed a disease of poultry for the first time. Since then the avian influenza virus
mutated to a highly pathogenic virus with different strains and genetic diversity. Since 2003 the H5N1
virus has differentiate into 10 strains of which only 4 have been isolated in humans. In the period 1995 to
2008 over 60 countries were affected counting hundreds of mil ions of dead birds.
There are some general characteristics of an influenza pandemic: • Virus transmission mainly through air (droplets).
• Incubation period: 1-4 days, infectious 4-5 days from the beginning of symptoms.
Manifestation in waves lasting 6-8 weeks, uncertain time intervals between waves.
• Maximum case fatality rate of 2.5%.
Avian influenza has slightly different features: • Contagion through life or dead infected poultry of infected environment.
• Incubation period of 2-8 days, WHO recommend to use an incubation period of 7 days regarding monitoring patient contacts.
• Case fatality rate is much higher compared to other influenza types: 60% With normal influenza, pneumonia, mostly caused by secondary bacterial infection and therefore curable with antibiotics, is less threatening whereas the avian influenza virus induces viral pneumonia directly, which doesn’t respond to antibiotics or any medication.
• Probably no virus of the H5 subtype has ever circulated among humans which means there is no immunity worldwide against a potential y mutated pandemic form.
In January 2004 there was a severe H5N1 outbreak among poultry in Asia and several human fatal cases were reported, which rose the fear of a severe avian influenza pandemic involving the entire global population. This new dimension of transmission from animal to human could be one of the first alterations within the adjustment of a potential avian influenza pandemic threat. Should the virus develop its transmissibility further so that it can easily spread between humans, then al the requirements for the start of a pandemic are present, namely: New kind of virus to which no one is immune The new virus must have the ability to replicate in humans and cause severe il nesses The first two points were fulfil ed, the only point missing was infections between humans. A subject which recently has been achieved in a laboratory by researcher Fouchier, who modified H5N1 with a few mutations on its genome so it is supposed to easily spread via droplets from human to human.
New evolving feature of the avian virus since 2004 : Virus is more deadly in poultry and capable of survive longer in the environment.
New animals (cats and tigers) can be infected, which means the avian influenza virus has enhanced its range of hosts.
Domestic ducks excrete high viral load without showing any symptoms and therefore make it hard to give local residents useful advices on how to recognize sick animals.
For the first time migratory birds have been infected.
Infection of humans of a non-traditional y group, namely young healthy people.
Hypothetical Outbreak of an avian influenza pandemic
The Global Influenza Surveil ance and Report System (GISRS) of WHO would detect an early beginning
of a rising pandemic. In May 2011 the Pandemic Influenza Preparedness (PIP) Framework was started
to improving the GISRS by linking al the relevant worldwide laboratories for a better exchange of
knowledge/reports and an increased access to vaccination for countries with less resources.
In case of such news of detection WHO would at first put the local partner (Healthcare systems,
laboratories, intervention teams) in the Global Outbreak Alert and Response Network (GOARN) on
stand-by and prepare an investigation. First GOARN-team arriving would identify and confirm the
Three main targets wil be declared by WHO: • to avoid the pandemic • to control the outbreak in humans and • to initiate monitoring and research, including immediate developing of corresponding vaccine.
Control ing the outbreak would mainly mean prevent humans from beeing infected by poultry with measures of kil ing infected or exposed birds. Poultry slaughterer would have to wear protective gear and take antivirals in a prophylactic sense. Additional y the application of vaccination against normal influenza virus would be recommended to reduce the chance that the avian influenza virus could exchange genes with a co-infecting normal influenza virus in humans.
Research would include identification of molecular viral structure, tracking its evolution in birds, defining pathogenicity in humans and pandemic potential as wel as evaluate resistance towards antivirals and prepare/initiate vaccine production.
Public health interventions which were applied when SARS and Influenza A(H1N1) threatened the world and partial y were successful won’t control a pandemic virus, which is far more contagious, has a very short incubation period and which can be transmitted before the beginning of symptoms. Besides that, pandemics manifest in waves which not always affect the same geographic region and the same age groups, the second wave normal y tends to be more severe than the first one. A World Bank report assumes as a worst-case scenario that a severe pandemic would kil about 71 mil ion people worldwide. A few experts cited in the report estimated death tol of 180-250 mil ion people. Prognosis of a mild pandemic speaks of 1.4 mil ion deaths (decrease of GDP 0.7%), a moderate pandemic of 14.2 mil ion deaths (GDP -2%). The WHO estimates a mild pandemic to cause 2-7.4 mil ion deaths . Looking at this numbers shows clearly how hypothetic and uncertain such estimations are and that a reliable prognosis is absolutely impossible.
Economical impact
The report of the World Bank estimated costs of a severe influenza pandemic at more than $3 tril ion,
reducing the global GDP by 4.8%. Researchers at Australian National University are assuming a GDP
drop of 5.5%. Other reports assumes only in the US to face costs of $167 bil ion in case of a severe
This tremendous deficit is composed of different economic losses in tourism, traveling, trade and
productivity. The biggest part (60%) would be caused of individual avoiding behavior (travel, restaurants,
mass gatherings). Only 30% of the costs would come from the il ness directly, while mortality is
responsible for little 10%.
Companies are confronted with three main threats in case of pandemic: Staff being absent (sick, caring for other persons, refusing to leave their house); Therefore enterprises which are able to provide their personnel vaccination have a big advantage. Possibility of working at home or in remote locations keeps up functioning a company. Identifying key staff and time-related vulnerabilities must be part of a wel elaborated pandemic plan.
• Interruptions of production and services as wel as in supply chain.
• Loss of market and customers: decreasing confidence and distribution systems .
Non-medical interventions
These kind of measures (personal hygiene, facial masks, contact tracing, screening of travelers,
cancel ation of gatherings/mass events, isolation of patients) reduces transmission especial y at the
beginning of a pandemic and slows down international spread. In countries with low resources this non-
medical interventions wil be the principal strategy against a pandemic. Once the pandemic has spread
in a large way priorities need to be changed, focusing more on reduction of morbidity and mortality than
on reduction of transmission and international spread.
Currently there are two groups of antivirals: the adamantane derivates (amantadine and rimantadine)
and neuraminidase inhibitors (zanamivir and oseltamivir).
Purpose of antivirals is to diminish the length of il ness and thus length of contagious period, it reduces
symptom severity as wel as complications . It may slow down the spread and buy some time for
developing vaccines. Antivirals must be taken within the first 48h from onset of symptoms.
A second purpose of antivirals is the prophylactic intake, but it has to be examined if prophylaxis makes
medical y sense (viral response, resistance, pandemic severety).
The importance of antivirals is especial y high during the first wave, when vaccination is not available
yet. The biggest fear in relying on and using antivirals is the virus ability to adapt and mutate and thus
aquire medication resistance. Most of the H5N1-strains show already resistance towards adamantanes .
Recently arising reports, having documented resistance against neuraminidase inhibitors as wel ,
provoked serious concerns since oseltamivir has been the drug of choice for storing as part of
preparedness in many countries.
New kind of antivirals such as monoclonal antibodies against conserved haemagglutinin epitopes show
a reduced risk for drug-resistance and ability to provide fast and broad protection. However, selection
pressure may provoke influenza virus to mutate and escape from antibodies as wel .
Vaccination is the most effective mean in combat against a pandemic virus, but it is impossible to
produce vaccines in advance if we don’t know exactly the genetic profile of the pandemic virus. It takes
several months to develop an appropriate vaccine, which won’t be available for the first pandemic wave.
In case of pandemic pharmaceutical industry wil face an overwhelming demand which could not be
satisfied. In the beginning population of the manufacture country wil have first access to vaccine, making Europe, Australia, North America and Japan to privileged countries. Maybe production capacity al ows, after having had enough time to produce to prevent a high amount of deaths during the second wave which normal y causes a more severe form of influenza. Nevertheless countries wil have to make the hard decision which group of the population wil be vaccinated with priority.
The current vaccine production method with fertilized chicken eggs takes longtime and avoids a fast vaccination response. Therefore efforts have to be taken to find a way to produce vaccines in a alternative and dose-sparing way. Several new technologies (cel -derived whole-virus inactivated vaccines/recombinant-protein-based vaccines/virus-like particle-based vaccines/DNA-vaccines/viral-vector-based vaccines) for producing vaccine egg-independently are being explored at present and are showing encouraging results. Next step wil be to test the new vaccines in a broad way and get official approval for mass production in the near future .
Possible prevention
It is almost impossible to prevent a future pandemic with avian influenza virus H5N1. Control ing and
monitoring circulation of H5N1 in poultry and therefore a good col aboration between animal and public
health authorities is essential. Fundamental changes in poultry farming could be a possible long-term
solution, but it is very hard (ideological y and financial y) to implement such kind of measures in a region
where poultry farming forms the backbone of rural existence and where farmers have been traditional y
practicing this kind of agriculture for decades.
The World has faced several influenza pandemic in the past and drawn appropriate lessons from. The
uncertainty about the moment, the pathogenicity, the transmissibility and lethality of a future pandemic
with avian influenza virus H5N1 remains at present as wel as in the future. But to mitigate the
devastating-looking threat, we have to emphasize that the world never has been better prepared for
such kind of menace. With WHO in a supervisory and executive function, coordination of worldwide
measures is one of the most important tools against a rising pandemic. Global surveil ance programs
observe constantly critical regions and facilitate the exchange of findings, knowledge and experience.
New partnerships between scientific, industrial and government players form a powerful network to have
an organized and directed acting during pandemic-free period as wel as in worst-case scenario. New
milestones in vaccine development promise a potential tool against a future pandemic, although it stil
takes some time for vaccination to be ready and operational. Only time wil tel if we wil be able to deal with a future pandemic and if our current efforts concerning preparedness plan, developed measures and means were not in vain. This report includes inputs from a variety of sources.
Potter, C.W., A history of influenza. Journal of Applied Microbiology, 2001. 91(4): p. 572-579.
Sambhara, S. and G.A. Poland, H5N1 Avian Influenza: Preventive and Therapeutic Strategies Against a Pandemic. Annual Review of Medicine, 2010. 61(1): p. 187-198.
Alexander, D. and I. Brown, History of highly pathogenic avian influenza. Rev Sci Tech, 2008. 28(1): p. 19-38.
Davies, L., Pandemic Potential Insurance Impact. LLOYD’S EMERGING RISKS TEAM, 2008.
WHO, Factsheet Avian Influenza. 2011.
WHO, Cumulative number of confirmed human cases of avian influenza A/(H5N1) reported to WHO, Avian influenza: assessing the pandemic threat. 2005.
WHO, Pandemic Influenza Preparedness Framework for the sharing of influenza viruses and access to vaccines and other benefits. 2011.
Bloomberg, Flu Pandemic May Cost World Economic Up To $3 tril ion. Center for Infectious Disease Research and Policy (CIDRAP) 2008.
Singh, N., A. Pandey, and S.K. Mittal, Avian influenza pandemic preparedness: developing prepandemic and pandemic vaccines against a moving target. Expert Reviews in Molecular
Medicine, 2010. 12: p. nul -nul .
Oxford, J., Antivirals for the treatment and prevention of epidemic and pandemic influenza. Influenza Other Respi Viruses, 2007.
Cheung, C.-L., et al., Distribution of Amantadine-Resistant H5N1 Avian Influenza Variants in Asia. Journal of Infectious Diseases, 2006. 193(12): p. 1626-1629.
de Jong, M.D., et al., Oseltamivir Resistance during Treatment of Influenza A (H5N1) Infection. New England Journal of Medicine, 2005. 353(25): p. 2667-2672.
Le, M., H. Wertheim, and H. Nguyen, Influenza A H5N1 Clade 2.3.4 Virus with a Different Antiviral Susceptibility Profile Replaced Clade 1 Virus in Humans in Northern Vietnam. PLoS
ONE, 2008. 3(10): p. 33-39.
Zharikova, D., et al., Influenza Type A Virus Escape Mutants Emerge In Vivo in the Presence of Antibodies to the Ectodomain of Matrix Protein 2. Journal of Virology, 2005. 79(11): p. 6644-
Chen, M.-W., et al., A consensus–hemagglutinin-based DNA vaccine that protects mice against divergent H5N1 influenza viruses. Proceedings of the National Academy of Sciences, 2008.
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