Influenza Virus

Influenza is an acute, febrile, self-limiting illness caused by Influenza viruses A, B and C. The worldwide morbidity and mortality caused by influenza has been increasing over the years due to the emergence of virulent strains eliciting pandemics. The infection rate during outbreaks of influenza can be as high as40% over a period of 5 to 6 weeks. This feature causes an epidemic of influenza to convert into a pandemic within few week. Mortality is primarily related to superadded bacterial infections, especially Haemophilus influenzae, which can result in pulmonary complications in the very young and elderly age groups.

About the virus

The influenza virus belongs to the Orthomyxoviridae family of enveloped viruses and is classified, based on distinct antigenic properties, into types A, B and C. The genome of these viruses is unique, having 7 to 8 segments of single stranded RNA, which has the advantage of re-assortment of genetic material between the different types of viruses. Influenza is not unique to humans but can cause epidemics among swine, horses, birds and marine mammals as well. While Influenza A virus can cause disease among all of the above, Influenza B causes disease only in humans and type C causes disease in humans and swine only. Type A has been responsible for the majority of pandemics having significant mortality. Type B is causes severe disease only in individuals with high risk factors such as the elderly or immunocompromised patients. Type C is associated with mild disease and possesses no seasonal trends.

The type A virus possesses 8 structural proteins, of which the surface glycoproteins with Neuraminidase (NA) and Hemagglutinin (HA) activity are critical in pathogenesis and the classification of the virus into subtypes. While the HA spike is a trimer, the NA is a mushroom shaped rod. The viral Hemagglutinin is a monomer (HA 0) which is cleaved by the host cell proteases into two parts HA1 and HA2.  A minimum of 15 antigenically different HA subtypes have been described (H 1 to H 15).  The viral NA enzyme catalyzes the removal of the terminal sialic acid residues from sialic acid containing glycoproteins. There are 9 different subtypes for neuraminidase (N1 to N9).

Antigenic Variation

The segmented genome of the Influenza virus confers the property of antigenic variation. This is of great significance in the epidemiology of the disease. Variability is the highest of the type A virus, which is also responsible for the major pandemics of influenza. The variability is primarily expressed as instability of the surface proteins hemagglutinin and neuraminidase. Two types of independent antigenic variations have been observed:

  • Antigenic drift: This is a gradual, sequential change in the antigenic structure which occurs at regular and frequent intervals. Though the antigens are different, they continue to react with the sera against previous antigens to varying degrees. Antigenic drift occurs due to mutation and selection. This process is influenced by the presence of antibodies to previous strains in a given population. The drift is responsible for the frequent outbreaks and epidemics caused by the virus in particular geographic regions.
  • Antigenic Shift:  This is an abrupt, sudden change in the antigenic structure of the surface glycoproteins resulting in a novel strain which is completely different from its predecessor strain. An antigenic shift with a new variant virus causes major epidemics which are likely to spread over a large geographic area leading to a pandemic.

History of Influenza

Commonly known as ?the flu?, the first instances of influenza-like disease were recorded as early as 400 years ago. The first recorded pandemic of influenza was in 1580 after which there have been a minimum of 31 recorded pandemics. The largest one occurred between1918 and 1919 with approximately 21 million deaths worldwide.

Designating the virus:  The referenced strains involved in pandemics have been classified as well as designated to signify the type, area of origin, year, the subtype of the neuraminidase and hemagglutinin possessed by them. e.g A/Hong Kong/1/68 (H3N2)


Calendar of Influenza Events

  • 1889 ? 1900 -  outbreak caused by H2N8 strain
  • 1900 ? 1910 -  extensive epidemics caused by H3N8
  • 1918 ? 1933 - The most severe pandemic, also called ?Spanish Flu? caused by the H1N1 strain. About 200 million people were affected worldwide while about 20 million people perished. An unusual feature of this pandemic was the high mortality among young adults.
  • 1933 ? 1946 - epidemics of H1N1 strains and the discovery of the Influenza virus.
  • 1946 ? 1957 - Epidemics caused by H1N1 strains
  • 1957 ? 1968 - pandemic of ?Asian Flu? with widespread morbidity but low mortality. This pandemic was caused by the H2N2 strain.
  • 1968 to present - pandemic of ?Hong Kong flu? with very low mortality caused by the H3N2 strain
  • 1977 to present ? Re-emergence of the H1N1 strains in Russia and China with low mortality.
  • 2004 to present ? Avian Influenza epizootic in Thailand followed by sporadic outbreaks in humans primarily those in direct contact with diseased poultry.

Vaccines

The property of genetic re-assortment by the Influenza virus is a critical barrier in the development of a vaccine for influenza. In order for a vaccine to be effective, it must be active against strains that exist in the population in a given geographic region.  Strain typing is crucial in the identification of trends in antigenic variation and accordingly development of vaccines to prevent morbidity and mortality during outbreaks.  Early Influenza vaccines were prepared from inactivated virus grown in egg cultures. These often led to anaphylactic reactions among the recipients due to the egg proteins. Subunit vaccines were then introduced to minimize the toxic reactions of the inactivated vaccine. The disadvantage of the parenteral vaccines is that they induce formation of circulating antibodies but do not induce local immunity.

Live attenuated (cold adapted) Influenza Vaccine (CAIV - T): This is an intranasal vaccine, licensed by the US FDA for use in individuals between the ages of 5 and 49. The strains utilized are cold adapted Influenza A/AnnArbor/6/60(H2N2) and B/Ann Arbor/1/66. Live virus vaccines have the advantage of the principle of re-assortment in the development of new antigenic variants. This vaccine is well tolerated by adults with mild upper respiratory symptoms being runny nose or sore throat. In children, the symptoms persist up to 8 days after the vaccine. The principle of using a live virus vaccine is primarily to replace the wild strains present in the population with the attenuated vaccine strain. Thus, the live virus vaccine induces local immunity in the respiratory tract. An annual vaccination program must be considered for high risk groups such as children and the elderly in which the likelihood of complications and mortality is the greatest. The live intranasal vaccine is preferred over the parenteral vaccine by people.

The recent pandemic by Avian influenza A virus

A highly pathogenic strain of Avian Influenza A virus (H5N1) caused an epizootic outbreak (animal outbreak) among birds in Asia, Europe, Africa and the near East in 2004. This strain is likely to have become endemic among the poultry and wild birds in some of these areas. Sporadic infections in humans who come in direct contact with infected poultry have been observed. Though there has been limited evidence of direct human to human transmission, the epizootic nature of this strain is a cause of major public health concern. The immunity among the human population to the H5N1 strain is virtually absent and the morbidity and mortality rates in cases of human outbreaks is likely to be high.

Molecular sequencing of the Avian flu virus from Thailand, Vietnam and Indonesia has already shown the virus to be resistant to amantidine and rimantidine, the commonly used antiviral agents for influenza. Two other drugs, oseltamivir and zanamivir, are active against this virus, though some oseltamivir resistant strains have also emerged. Currently no vaccines are available of the H5N1 strain for human use.