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Influenza Epidemics and Pandemics

Annual influenza epidemics

Nature of antigenic drift

The replication of viral RNA in an infected host cell is an error-prone process, much more so than the replication of DNA. One reason for this is the lack of so-called proofreading mechanisms in the replication of RNA. As a result of the infidelity of RNA replication, the mutation frequency in the influenza virus RNA is approximately one in 100,000 nucleotides. 8 x J Stech, X Xiong, V Scholtissek, RG Webster. Independence of evolutionary and mutational rates after transmission of avian influenza viruses to swine. J Virol 73 (1999) (1878 - 1884) Considering that the size of the entire influenza virus genome is about 14,000 nucleotides, this implies that many new viral RNA genome copies will contain one or more mutations. While the majority of these mutations will be silent or generate stop codons, others will result in amino acid substitutions in the translated proteins, which may give rise to new variants with an advantage over the parent virus. Antigenic drift of HA occurs as a result of accumulation of point mutations in the antigenic domains (epitopes) of HA1 (see Figure 7). Selective advantage for the new variants in this case arises because these variants are no longer neutralized by pre-existing antibodies of the host.

Key Messages

  • Influenza viruses continuously change their antigenic properties through “antigenic drift” and “antigenic shift”.
  • Antigenic drift is due to accumulation of mutations in antigenic epitopes of viral antigens. As a result, pre-existing antibodies against the viral HA neutralize newer drift variants of the virus less efficiently.
  • Antigenic drift of HA is the cause of recurrent annual influenza epidemics. It necessitates repeated vaccination of target groups and regular updates of the vaccine composition.
  • The natural reservoir of influenza A viruses is among wild aquatic birds. All 16 subtypes of HA and all nine subtypes of NA have been identified in waterfowl.
  • Antigenic shift implies that an influenza A virus with a new HA subtype is introduced into the human population. This may occur by (i) direct transmission of an avian virus from birds to humans, (ii) genetic reassortment between an avian and a human virus, or (iii) reintroduction of an “old” strain into the population.
  • Antigenic shift is the cause of occasional global outbreaks of influenza (pandemics). These arise primarily because of a total lack of immunity against the new virus subtype in the population.
  • Since the reservoir of influenza A viruses is among wild birds and avian viruses do occasionally cross the species barrier to humans, influenza is a non-eradicable disease and pandemics will continue to occur.
  • Intensive surveillance of influenza activity among birds (and other species, including humans) is required for optimal pandemic preparedness.
  • To improve the global level of pandemic preparedness, the WHO is encouraging individual countries to institute pandemic preparedness plans and to stimulate annual influenza vaccine uptake.

Antigenic drift is a gradual process. Mutations may arise in one epitope of HA with other epitopes remaining unchanged. Thus, depending on the nature of the mutation, the new strain may still be partially recognized by the immune defence of the host. This gradual change is illustrated in Table 3 , which shows that drift variants of the 1968 Hong Kong pandemic virus gradually lost the ability to cross-react with an antiserum against the original virus, while antisera against increasingly distant drift viruses no longer cross-react with the 1968 strain. 1 x PF Wright, RG Webster. Orthomyxoviruses. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1533 - 1579)

Table 3 Antigenic drift of influenza H3N2 virus from 1968 to 1997. The table provides haemagglutination–inhibition titres (see Chapter 8) of ferret antisera against drift variants of the H3N2 virus. source: Reproduced from Wright PF, Webster RG. Orthomyxoviruses. In: Knipe DM, Howley PM, Griffin DE et al., editors. Fields Virology, 4th edn. Lippincott Williams & Wilkins, 2001; pp. 1533–1579 1 x PF Wright, RG Webster. Orthomyxoviruses. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1533 - 1579) with permission from Lippincott Williams & Wilkins.

Antigenic drift of influenza H3N2 virus from 1968 to 1997
Reference ferret antisera
HK/68 ENG/72 VIC/75 TEX/77 BANG/79 PHIL/82 MISS/85 SHN/87 BEI/89 BEI/92
Strain designation 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
1. A/Hong Kong/01/68 2560 1280 40 5 5 5 10 10 5 5
2. A/England/42/72 320 1280 80 20 5 5 5 5 5 5
3. A/Victoria/03/75 5 80 320 40 10 20 10 5 5 5
4. A/Texas/01/77 5 80 160 1280 160 320 320 10 10 5
5. A/Bangkok/01/79 5 5 80 640 640 640 640 20 10 5
6. A/Philippines/02/82 5 5 10 40 40 320 160 10 10 5
7. A/Mississippi/01/85 5 5 40 160 80 640 640 40 20 20
8. A/Shanghai/11/87 5 5 5 5 5 5 80 320 160 20
9. A/Beijing/353/89 5 5 5 5 5 5 5 160 320 40
10. A/Beijing/32/92 5 5 5 5 5 5 10 20 80 640
11. A/Johannesburg/33/94 5 5 5 5 5 5 5 10 20 160
12. A/Nanchang/933/95 5 5 5 5 5 5 5 5 10 20
13. A/Sydney05/97 5 5 5 5 5 5 5 5 5 5

References in context

Seasonality of influenza outbreaks

While in tropical countries influenza may be present all year round, epidemics in temperate regions occur almost exclusively in the winter months, from October to April in the northern hemisphere and from April to October in the southern hemisphere. It is not clear why there is this seasonal regularity in the occurrence of influenza outbreaks. One reason is thought to be crowding of people in closed spaces with poor ventilation. For example, spreading of the virus may be facilitated in schools – there is evidence that school children in particular play a prominent role in the transmission of influenza. 9 x JP Fox, MK Cooney, CE Hall, HM Foy. Influenza virus infections in Seattle families, 1975–1979. II. Pattern of infection in invaded households and relation of age and prior antibody to occurrence of infection and related illness. Am J Epidemiol 116 (1982) (228 - 242)

Despite their annual seasonal character, influenza epidemics are unpredictable. 4, x ED Kilbourne. Influenza pandemics of the 20th century. Emerg Inf Dis 12 (2006) (9 - 14) 7 x KG Nicholson, JM Wood, M Zambon. Influenza. Lancet 362 (2003) (1733 - 1745) When precisely they will start and how long they will last are questions that are difficult to answer in advance. Figure 11 illustrates the variation in the onset and duration of influenza epidemics recorded in the Netherlands in the last three decades of the previous century. It is also impossible to predict how virulent a winter epidemic will be. The severity of an epidemic in any given year is a subtle interplay between the waning immunity in the population, the extent of antigenic drift of the virus and the intrinsic virulence of the new virus variant.

Figure 11 Onset and duration of influenza epidemics in the Netherlands, 1971–1999. source: Courtesy of Solvay Pharmaceuticals, Weesp, the Netherlands.

f03-11-9780723434337

References in context

  • Despite their annual seasonal character, influenza epidemics are unpredictable.4,7 When precisely they will start and how long they will last are questions that are difficult to answer in advance. Figure 11 illustrates the variation in the onset and duration of influenza epidemics recorded in the Netherlands in the last three decades of the previous century.
    Go to context

Regular update of vaccine composition and influenza surveillance

The antigenic drift of influenza virus necessitates regular updates of the composition of the influenza vaccine (see Chapter 8). Obviously, a close match of the virus strains in the vaccine and the strains subsequently circulating in the winter season is of key importance for the protective efficacy of the vaccine. Current inactivated influenza vaccines contain three virus strains (two A strains and one B strain), the specific composition of the vaccine being recommended annually by the WHO.

In 1947, the WHO established an international Influenza Surveillance Network of laboratories to monitor the emergence and spread of new influenza strains around the world and thus to predict the circulating strains to be represented in the vaccine. This activity is co-ordinated by the WHO Collaborating Centres based in Atlanta, London, Melbourne and Tokyo. In general, despite the inherent uncertainty of this approach, the selection of vaccine virus strains has worked quite well thus far (see Chapter 8). In addition, the uncertainty in predicting epidemic virus strains has been further reduced by mathematical modeling of the antigenic distance between different viruses, allowing a more accurate selection of the strains that need to be included in the vaccine. 10 x DJ Smith, AS Lapedes, JC de Jong, et al.. Mapping the antigenic and genetic evolution of influenza virus. Science 305 (2004) (371 - 376) However, when occasional mismatches do occur, people in target groups should nonetheless be encouraged to be vaccinated, as there is still benefit in spite of the reduced efficacy of the vaccine under these conditions.

 
x

Figure 11 Onset and duration of influenza epidemics in the Netherlands, 1971–1999. source: Courtesy of Solvay Pharmaceuticals, Weesp, the Netherlands.

f03-11-9780723434337

References in context

  • Despite their annual seasonal character, influenza epidemics are unpredictable.4,7 When precisely they will start and how long they will last are questions that are difficult to answer in advance. Figure 11 illustrates the variation in the onset and duration of influenza epidemics recorded in the Netherlands in the last three decades of the previous century.
    Go to context

Table 3 Antigenic drift of influenza H3N2 virus from 1968 to 1997. The table provides haemagglutination–inhibition titres (see Chapter 8) of ferret antisera against drift variants of the H3N2 virus. source: Reproduced from Wright PF, Webster RG. Orthomyxoviruses. In: Knipe DM, Howley PM, Griffin DE et al., editors. Fields Virology, 4th edn. Lippincott Williams & Wilkins, 2001; pp. 1533–1579 1 x PF Wright, RG Webster. Orthomyxoviruses. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1533 - 1579) with permission from Lippincott Williams & Wilkins.

Antigenic drift of influenza H3N2 virus from 1968 to 1997
Reference ferret antisera
HK/68 ENG/72 VIC/75 TEX/77 BANG/79 PHIL/82 MISS/85 SHN/87 BEI/89 BEI/92
Strain designation 1. 2. 3. 4. 5. 6. 7. 8. 9. 10.
1. A/Hong Kong/01/68 2560 1280 40 5 5 5 10 10 5 5
2. A/England/42/72 320 1280 80 20 5 5 5 5 5 5
3. A/Victoria/03/75 5 80 320 40 10 20 10 5 5 5
4. A/Texas/01/77 5 80 160 1280 160 320 320 10 10 5
5. A/Bangkok/01/79 5 5 80 640 640 640 640 20 10 5
6. A/Philippines/02/82 5 5 10 40 40 320 160 10 10 5
7. A/Mississippi/01/85 5 5 40 160 80 640 640 40 20 20
8. A/Shanghai/11/87 5 5 5 5 5 5 80 320 160 20
9. A/Beijing/353/89 5 5 5 5 5 5 5 160 320 40
10. A/Beijing/32/92 5 5 5 5 5 5 10 20 80 640
11. A/Johannesburg/33/94 5 5 5 5 5 5 5 10 20 160
12. A/Nanchang/933/95 5 5 5 5 5 5 5 5 10 20
13. A/Sydney05/97 5 5 5 5 5 5 5 5 5 5

References in context

References

Label Authors Title Source Year
1

References in context


  • Go to context

  • Influenza viruses continuously undergo antigenic evolution.1 It is this quality that allows them to evade the pre-existing immunity of the host, which implies that immune responses mounted against earlier forms of the virus are less effective or completely ineffective against newer variants.
    Go to context

  • These are commonly referred to as “antigenic drift” and “antigenic shift”.1 Antigenic drift occurs through continuous mutation of the RNA genome of the virus.
    Go to context

  • Occasionally, an entirely new influenza A virus subtype of avian origin emerges in the human population.
    Go to context

  • Antigenic drift is a gradual process.
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

PF Wright, RG Webster. Orthomyxoviruses. DM Knipe, PM Howley, DE Griffin (Eds.) et al. Fields Virology 4th edn. (Lippincott Williams & Wilkins, 2001) (1533 - 1579) 2001
4

References in context

  • By far the most devastating pandemic was the Spanish flu outbreak, which hit at the end of the First World War.3,4 It spread across the globe in three consecutive waves in 1918–19, killing at least 50 million people.5 The subsequent pandemics in 1957 and 1968 were milder,4 but nonetheless also caused a total of approximately 2 million deaths.
    Go to context

  • By far the most devastating pandemic was the Spanish flu outbreak, which hit at the end of the First World War.3,4 It spread across the globe in three consecutive waves in 1918–19, killing at least 50 million people.5 The subsequent pandemics in 1957 and 1968 were milder,4 but nonetheless also caused a total of approximately 2 million deaths.
    Go to context

  • Despite their annual seasonal character, influenza epidemics are unpredictable.4,7 When precisely they will start and how long they will last are questions that are difficult to answer in advance. Figure 11 illustrates the variation in the onset and duration of influenza epidemics recorded in the Netherlands in the last three decades of the previous century.
    Go to context

  • While the bird flu outbreak in 1997 was the first documented example of a purely avian virus causing respiratory disease and deaths among humans,18–20 it has since become apparent that the 1918 Spanish flu virus was also an avian virus.3,22–25 Even though the precise origin of the 1918 virus remains enigmatic,3,11,22 based on characterization of genetic material isolated from victims of the 1918 pandemic, it is clear now that the virus was not a human–avian reassortant, but rather an avian-like virus that was introduced in its entirety into the human population and subsequently adapted to the new host.
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

  • A third way by which an antigenic shift may occur and a pandemic arise is reintroduction of an “old” strain into the human population.
    Go to context

  • Figure 14 gives an overview of the influenza pandemics that occurred in the past century.4,29,30 The most terrible outbreak was the Spanish flu in 1918, with an estimated 50 million deaths,5 justifying its description as “the last great plague of mankind”.
    Go to context

ED Kilbourne. Influenza pandemics of the 20th century. Emerg Inf Dis 12 (2006) (9 - 14) 2006
7

References in context


  • Go to context

  • There is no doubt that there will be other pandemics in the future.6,7 Having its reservoir among migratory waterfowl, the influenza virus is non-eradicable and will continue to affect humans.
    Go to context

  • Despite their annual seasonal character, influenza epidemics are unpredictable.4,7 When precisely they will start and how long they will last are questions that are difficult to answer in advance. Figure 11 illustrates the variation in the onset and duration of influenza epidemics recorded in the Netherlands in the last three decades of the previous century.
    Go to context

  • As illustrated in Figure 13, the 1957 Asian H2N2 virus subtype obtained its HA, NA, and PB1 genes from an avian virus and the other fives genes from the circulating H1N1 human strain,1,4,7,14–17 the human H1N1 virus in turn being a distant descendent of the 1918 Spanish flu virus.3 Likewise, the 1968 Hong Kong H3N2 virus acquired its HA and PB1 genes from an avian virus, but retained the NA and remaining five other genes from the then circulating H2N2 human virus.
    Go to context

  • There is no doubt that there will be influenza pandemics in the future.7,11,22 It is not so much a matter of whether they will occur but rather when they will occur.
    Go to context

  • In May 2001, and in February and April 2002, the H5N1 virus subtype was once again detected in Hong Kong's poultry markets,7,33 the specific virus strain differing significantly from the 1997 H5N1 bird flu virus.
    Go to context

KG Nicholson, JM Wood, M Zambon. Influenza. Lancet 362 (2003) (1733 - 1745) 2003
8

References in context

  • As a result of the infidelity of RNA replication, the mutation frequency in the influenza virus RNA is approximately one in 100,000 nucleotides.8 Considering that the size of the entire influenza virus genome is about 14,000 nucleotides, this implies that many new viral RNA genome copies will contain one or more mutations.
    Go to context

J Stech, X Xiong, V Scholtissek, RG Webster. Independence of evolutionary and mutational rates after transmission of avian influenza viruses to swine. J Virol 73 (1999) (1878 - 1884) 1999
9

References in context

  • While in tropical countries influenza may be present all year round, epidemics in temperate regions occur almost exclusively in the winter months, from October to April in the northern hemisphere and from April to October in the southern hemisphere.
    Go to context

JP Fox, MK Cooney, CE Hall, HM Foy. Influenza virus infections in Seattle families, 1975–1979. II. Pattern of infection in invaded households and relation of age and prior antibody to occurrence of infection and related illness. Am J Epidemiol 116 (1982) (228 - 242) 1982
10

References in context

  • In addition, the uncertainty in predicting epidemic virus strains has been further reduced by mathematical modeling of the antigenic distance between different viruses, allowing a more accurate selection of the strains that need to be included in the vaccine.10 However, when occasional mismatches do occur, people in target groups should nonetheless be encouraged to be vaccinated, as there is still benefit in spite of the reduced efficacy of the vaccine under these conditions.
    Go to context

DJ Smith, AS Lapedes, JC de Jong, et al.. Mapping the antigenic and genetic evolution of influenza virus. Science 305 (2004) (371 - 376) 2004

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