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Vaccination: Cornerstone of Influenza Control

Current inactivated influenza vaccines

Vaccine formulations

Initial inactivated influenza vaccine formulations invariably consisted of whole inactivated virus formulations. 2, x JM Wood, MS Williams. History of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (317 - 323) 4 x IGS Furminger. Vaccine production. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (324 - 332) Whole inactivated virus vaccines are generally quite immunogenic. However, despite the introduction of improved techniques for virus purification, local reactogenicity and systemic side effects remain a problem associated with the use of these vaccines, particularly in small children. 17 x FL Ruben. Prevention and control of influenza. Role of vaccine. Am J Med 82 (Suppl 6a) (1987) (31 - 34) Crossref. This has led to the development of vaccine formulations consisting of disrupted virus particles, which turned out to be almost equally immunogenic in primed individuals, yet causing significantly fewer side effects. 2 x JM Wood, MS Williams. History of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (317 - 323) These split-virus vaccines, first licensed in the USA in 1968, are among the most widely used formulations to date. While ether was the original splitting agent of choice, currently detergents such as Tween 80, Triton N101, cetyl trimethyl ammonium bromide (CTAB) and sodium deoxycholate are used in addition to ether to disrupt the virus particles. 4 x IGS Furminger. Vaccine production. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (324 - 332) A disadvantage of split vaccines, relative to whole inactivated virus, is their comparatively low immunogenicity in unprimed individuals, such as young children without prior exposure to flu virus or vaccine, requiring a booster immunization for adequate protection. 18 x KG Nicholson, DAJ Tyrrell, P Harrison, et al.. Clinical studies of monovalent inactivated whole virus and subunit A/USSR/77 (H1N1) vaccine: serological responses and clinical reactions. J Biol Stand 7 (1979) (123 - 136) Crossref.

Relative to split-virus vaccines, subunit preparations represent a further refinement and improvement of the vaccine formulation. Subunit vaccines contain the HA and NA surface glycoproteins purified from other viral components. 4 x IGS Furminger. Vaccine production. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (324 - 332) Because of their high purity, subunit vaccines have a favourable profile in terms of local and systemic side effects, compared to whole-virus and split vaccines. 19 x WEP Beyer, AM Palache, ADME Osterhaus. Comparison of serology and reactogenicity between influenza subunit vaccines and whole or split vaccines. A review and meta-analysis of the literature. Clin Drug Invest 15 (1998) (1 - 12) Crossref. Yet, subunit vaccines are equally immunogenic in primed individuals. The concept of using just the isolated viral HA and NA antigens is based on the notion that the primary correlate of protection against influenza is an adequate level of circulating antibodies against the surface glycoproteins of the virus, especially HA (see Chapter 4). Subunit antigens are isolated by detergent solubilization of the viral envelope, followed by sedimentation of the nucleocapsid through ultracentrifugation. Removal of the detergent from the supernatant by adsorption onto a hydrophobic resin, such as Amberlite, results in the formation of rosettes of HA and NA, with only small amounts of contaminating core proteins, such as NP or M1, and viral membrane lipid. 4 x IGS Furminger. Vaccine production. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (324 - 332) Influenza subunit vaccines were first licensed in UK in 1980 and are now used in many countries worldwide.

Selection of vaccine strains

To be effective, the vaccine components need to match those of the circulating influenza virus strains in the target season (see Chapter 3). Current influenza vaccines contain three virus strains, two A strains (an H3N2 and an H1N1 strain) and one B strain. These strains are included in the vaccines on recommendation of the WHO. 8, x Y Ghendon. Influenza surveillance. Bull World Health Org 61 (1991) (509 - 515) 9 x World Health Organization. Influenza vaccines. Wkly Epidemiol Rec 75 (2000) (281 - 288) This recommendation is based on an extensive review of epidemiological data and antigenic and genetic analyses of virus isolates by the four WHO Collaborating Centres. Recently, a mathematical modeling approach for mapping of the antigenic distance between virus strains has been included in the strain selection process. 20 x DJ Smith, AS Lapedes, JC de Jong, et al.. Mapping the antigenic and genetic evolution of influenza virus. Science 305 (2004) (371 - 376) Crossref. In order to allow vaccine manufacturers sufficient time for production, in February of each year the WHO issues its recommendation about which viral strains should be included in the next winter's vaccine for the northern hemisphere. A second review follows in September to consider adjustments of the vaccine composition for the southern hemisphere.

That this system of surveillance and recommendation works quite well is demonstrated by the good match achieved in, for example, the influenza seasons from 1987 to 1997. 5 x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345) Within this period, 23 vaccine strains recommended by the WHO matched with the subsequently circulating total of 30 virus strains ( Table 15 ). A complete match of all three strains was achieved in five out of 10 seasons. Nevertheless, an intrinsic uncertainty remains and sometimes there is not a perfect match between vaccine strains and circulating viruses, in which case the vaccine may have reduced efficacy. However, these occasional mismatches should by no means be regarded as a general justification for not providing or taking the vaccination.

Table 15 Match between WHO vaccine recommendations and epidemic virus strains circulating in subsequent winter season. source: Adapted from Wood JM. Standardization of inactivated influenza vaccines. In: Nicholson KG, Webster RG, Hay AJ, editors. Textbook of Influenza. Blackwell Science, 1998; pp. 333–345 5 x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345) with permission from Blackwell Publishing.

Match between vaccine recommendations and concurrent epidemic influenza virus strains
Season A/H1N1 A/H3N2 B
1987–1988 +
1988–1989 + + +
1989–1990 + + +
1990–1991 + +
1991–1992 + + +
1992–1993 + +
1993–1994 + +
1994–1995 +
1995–1996 + + +
1996–1997 + + +

References in context

  • That this system of surveillance and recommendation works quite well is demonstrated by the good match achieved in, for example, the influenza seasons from 1987 to 1997.5 Within this period, 23 vaccine strains recommended by the WHO matched with the subsequently circulating total of 30 virus strains (Table 15).
    Go to context

Dose standardization

The development of the single radial immunodiffusion (SRD) test has allowed the implementation of a stringent standardization of vaccine dosaging. 5 x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345) The SRD test determines the content of HA antigen in influenza vaccines on the basis of the immunological activity of the antigen against a reference sheep antiserum ( Figure 24 ). 5 x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345) The application of this assay and the use of standardized reagents, supplied by one of the WHO Collaborating Centres to influenza vaccine manufacturers, thus guarantee optimal uniformity among different influenza vaccine formulations in terms of potency. 5 x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345)

Figure 24 Single radial immunodiffusion (SRD) test of influenza vaccine potency. 5 x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345) Serial dilutions of detergent-treated vaccine, and a reference antigen (Ref), are added to wells in an agarose gel containing a sheep antiserum against the relevant HA. The surface area of the precipitation rings formed (top) is subsequently plotted as a function of the dilution of the vaccine (bottom). The slope of the resulting curves is a direct measure of the HA concentration in the vaccine, and is compared with that of the reference curve. In the graph, data for vaccine samples A and D and the reference antigen shown in the top gel are plotted. source: Courtesy of Jeroen Medema, Solvay Pharmaceuticals, Weesp, the Netherlands.

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References in context

Several studies have shown that a vaccine dose of ≥10 µg HA per strain induces an adequate immune response in primed individuals. 21, x AM Palache, WEP Beyer, G Lüchters, et al.. Influenza vaccines: the effect of vaccine dose on antibody response in primed populations during the ongoing interpandemic period. A review of the literature. Vaccine 11 (1993) (892 - 908) Crossref. 22 x J Treanor, W Keitel, R Belshe, et al.. Evaluation of a single dose of half strength inactivated influenza vaccine in healthy adults. Vaccine 20 (2002) (1099 - 1105) Crossref. Current trivalent inactivated influenza vaccines contain 15 µg of HA per strain as assessed by the SRD assay. This dose scheme has been formally standardized. 5, x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345) 23, x European Medicines Agency (EMEA). Note for guidance on harmonization of requirements for influenza vaccines. CPMP/BWP/214/96. (www.emea.eu.int/pdfs/human/bwp/021496en.pdf) (1997) 24 x JM Wood, RA Levandowski. The influenza vaccine licensing process. Vaccine 21 (2003) (1786 - 1788) Crossref. The trivalent inactivated influenza vaccine is administered by intramuscular or deep subcutaneous injection.

Evaluation of vaccine immunogenicity

Not only has the composition of influenza vaccines been standardized in many countries, in the EU, criteria for vaccine immunogenicity have also been implemented. 5, x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345) 22, x J Treanor, W Keitel, R Belshe, et al.. Evaluation of a single dose of half strength inactivated influenza vaccine in healthy adults. Vaccine 20 (2002) (1099 - 1105) Crossref. 23 x European Medicines Agency (EMEA). Note for guidance on harmonization of requirements for influenza vaccines. CPMP/BWP/214/96. (www.emea.eu.int/pdfs/human/bwp/021496en.pdf) (1997) As indicated above, current inactivated influenza vaccines aim at induction of an efficient systemic antibody response against the viral surface antigens. Accordingly, vaccine efficacy is evaluated on the basis of serological data, in particular antibody titres and seroprotection rates.

Antibody titres are generally determined on the basis of haemagglutination–inhibition (HI) activity 5, x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345) 6 x D Hobson, RL Curry, AS Beare, A Ward-Gardner. The role of serum haemagglutination-inhibiting antibody in protection against challenge virus infection with A2 and B viruses. J Hyg (Lond) 70 (1972) (767 - 777) Crossref. or, occasionally, by single radial haemolysis (SRH). 5 x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345) In the HI assay, serum samples of vaccinated individuals are tested for their ability to inhibit agglutination of erythrocytes, induced by influenza virus through interaction of the viral HA with sialic acid on the red cell surface. Antibodies directed against HA interfere with this interaction, thus inhibiting the agglutination process. In practice, serial dilutions of serum are incubated with a standardized amount of influenza virus, after which a fixed concentration of erythrocytes, generally from guinea-pigs or turkeys, is added and the extent of haemagglutination determined. The highest serum dilution at which agglutination still occurs is defined as the HI titre ( Figure 25 ). The SRH test evaluates the capacity of serial dilutions of antibodies against HA to lyse erythrocytes in the presence of guinea-pig complement. 5 x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345)

Figure 25 Haemagglutination–inhibition (HI) titration of an antiserum against influenza. Turkey or guinea pig erythrocytes are incubated with a standard amount of influenza virus and two-fold dilutions of the serum to be evaluated. The reciprocal of the highest dilution at which haemagglutination is completely inhibited (haemagglutination inhibition is observed as the formation of a small concentrated dot of red cells in the bottom of the well) is defined as the HI titre of the sample. For example, the HI titre of serum C is 320, that of serum F is 2560. source: Courtesy of René Benne, Laboratory of Infectious Diseases, Groningen, the Netherlands.

f08-25-9780723434337

References in context

  • The highest serum dilution at which agglutination still occurs is defined as the HI titre (Figure 25).
    Go to context

The European Medicines Agency (EMEA) has formally standardized the EU requirements for annual evaluation of influenza vaccine efficacy ( Table 16 ). 23, x European Medicines Agency (EMEA). Note for guidance on harmonization of requirements for influenza vaccines. CPMP/BWP/214/96. (www.emea.eu.int/pdfs/human/bwp/021496en.pdf) (1997) 24 x JM Wood, RA Levandowski. The influenza vaccine licensing process. Vaccine 21 (2003) (1786 - 1788) Crossref. These requirements include specified numbers of seroconversions and/or numbers of individuals achieving a certain antibody titre upon vaccination within a study population of a specified age range. In addition, there is a requirement for an annual clinical study among 50 volunteers of 18–60 years old and 50 volunteers of age >60 years. However, after evaluation of the long-term experience with the EU-specific registration process, the value and need for these annual serological studies for relicensure of influenza vaccines have recently been questioned. 25 x Voordouw B. Influenza Vaccination in Community Dwelling Elderly Persons. PhD thesis, Erasmus University, Rotterdam, 2005. ISBN 90-8559-103-1.

Table 16 Criteria of the European Medicines Agency (EMEA) of the EU for the evaluation of influenza vaccine efficacy. Issued by the Committee on Proprietary Medicinal Products (CPMP). Note for guidance on harmonization of requirements for influenza vaccines. CHMP/BWP/214/96, 1997 ( www.emea.eu.int/pdfs/human/bwp/021496en.pdf ) 23 x European Medicines Agency (EMEA). Note for guidance on harmonization of requirements for influenza vaccines. CPMP/BWP/214/96. (www.emea.eu.int/pdfs/human/bwp/021496en.pdf) (1997) source: © EMEA 1997 Reproduction and/or distribution of this document is authorized for non-commercial purposes only provided the EMEA is acknowledged.

European Union criteria for the assessment of vaccines
Criterion 18–60 years >60 years
Seroconversions or significant rises in anti-HA antibody titre >40% >30%
Mean geometric increase in titre >2.5 >2.0
Patients achieving HI titre ≥ 40 or SRH titre >25 mm2 >70% >60%

References in context

  • The European Medicines Agency (EMEA) has formally standardized the EU requirements for annual evaluation of influenza vaccine efficacy (Table 16).23,24 These requirements include specified numbers of seroconversions and/or numbers of individuals achieving a certain antibody titre upon vaccination within a study population of a specified age range.
    Go to context

For each virus strain, at least one of the above criteria should be met

Annual timetable for vaccine production and licensing

As almost all current influenza vaccines are prepared from egg-grown virus ( Figure 26 ), the annual vaccine production cycle begins with the estimation and ordering of the required numbers of embryonated chicken eggs well before actual vaccine production starts. 26 x C Gerdil. The annual production cycle for influenza vaccine. Vaccine 21 (2003) (1776 - 1779) Crossref. Then, after the WHO has issued its recommendation, seed viruses are generated and characterized for approval by the WHO Collaborating Centres. These seed viruses are high-growth reassortants (see Chapter 3), carrying the HA and NA of the recommended vaccine virus on the background of a virus that replicates well in embryonated eggs. Generally, 1–2 months after the WHO recommendation, seed virus lots are released to the manufacturers. Vaccine production then continues for several months. In this process, quantification of the potency of monovalent vaccine bulks is a critical step, requiring the availability of specific reagents for SRD determination. Finally, the ultimate trivalent vaccine can be formulated and the syringes or vials filled. Immediately after the first batches of trivalent vaccine have been released for use, two serological clinical studies (in people aged 18–60 and >60 years) are performed to satisfy the licensing criteria of the European regulatory authorities, 23, x European Medicines Agency (EMEA). Note for guidance on harmonization of requirements for influenza vaccines. CPMP/BWP/214/96. (www.emea.eu.int/pdfs/human/bwp/021496en.pdf) (1997) 24 x JM Wood, RA Levandowski. The influenza vaccine licensing process. Vaccine 21 (2003) (1786 - 1788) Crossref. as discussed above. Results of these clinical studies form part of the annual registration dossier for market authorization in the member states of the EU.

Figure 26 Production of influenza vaccine virus on embryonated chicken eggs. source: Courtesy of Solvay Pharmaceuticals, Weesp, the Netherlands.

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References in context

  • As almost all current influenza vaccines are prepared from egg-grown virus (Figure 26), the annual vaccine production cycle begins with the estimation and ordering of the required numbers of embryonated chicken eggs well before actual vaccine production starts.26 Then, after the WHO has issued its recommendation, seed viruses are generated and characterized for approval by the WHO Collaborating Centres.
    Go to context

From the time of recommendation by the WHO of virus strains to be included in the vaccine, it takes approximately 6 months to bring the vaccine to the market. Within two campaigns for the northern and southern hemispheres, a total of about 300 million doses of influenza vaccine are currently being produced each year.

 
x

Figure 24 Single radial immunodiffusion (SRD) test of influenza vaccine potency. 5 x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345) Serial dilutions of detergent-treated vaccine, and a reference antigen (Ref), are added to wells in an agarose gel containing a sheep antiserum against the relevant HA. The surface area of the precipitation rings formed (top) is subsequently plotted as a function of the dilution of the vaccine (bottom). The slope of the resulting curves is a direct measure of the HA concentration in the vaccine, and is compared with that of the reference curve. In the graph, data for vaccine samples A and D and the reference antigen shown in the top gel are plotted. source: Courtesy of Jeroen Medema, Solvay Pharmaceuticals, Weesp, the Netherlands.

f08-24-9780723434337

References in context

Figure 25 Haemagglutination–inhibition (HI) titration of an antiserum against influenza. Turkey or guinea pig erythrocytes are incubated with a standard amount of influenza virus and two-fold dilutions of the serum to be evaluated. The reciprocal of the highest dilution at which haemagglutination is completely inhibited (haemagglutination inhibition is observed as the formation of a small concentrated dot of red cells in the bottom of the well) is defined as the HI titre of the sample. For example, the HI titre of serum C is 320, that of serum F is 2560. source: Courtesy of René Benne, Laboratory of Infectious Diseases, Groningen, the Netherlands.

f08-25-9780723434337

References in context

  • The highest serum dilution at which agglutination still occurs is defined as the HI titre (Figure 25).
    Go to context

Figure 26 Production of influenza vaccine virus on embryonated chicken eggs. source: Courtesy of Solvay Pharmaceuticals, Weesp, the Netherlands.

f08-26-9780723434337

References in context

  • As almost all current influenza vaccines are prepared from egg-grown virus (Figure 26), the annual vaccine production cycle begins with the estimation and ordering of the required numbers of embryonated chicken eggs well before actual vaccine production starts.26 Then, after the WHO has issued its recommendation, seed viruses are generated and characterized for approval by the WHO Collaborating Centres.
    Go to context

Table 15 Match between WHO vaccine recommendations and epidemic virus strains circulating in subsequent winter season. source: Adapted from Wood JM. Standardization of inactivated influenza vaccines. In: Nicholson KG, Webster RG, Hay AJ, editors. Textbook of Influenza. Blackwell Science, 1998; pp. 333–345 5 x JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345) with permission from Blackwell Publishing.

Match between vaccine recommendations and concurrent epidemic influenza virus strains
Season A/H1N1 A/H3N2 B
1987–1988 +
1988–1989 + + +
1989–1990 + + +
1990–1991 + +
1991–1992 + + +
1992–1993 + +
1993–1994 + +
1994–1995 +
1995–1996 + + +
1996–1997 + + +

References in context

  • That this system of surveillance and recommendation works quite well is demonstrated by the good match achieved in, for example, the influenza seasons from 1987 to 1997.5 Within this period, 23 vaccine strains recommended by the WHO matched with the subsequently circulating total of 30 virus strains (Table 15).
    Go to context

Table 16 Criteria of the European Medicines Agency (EMEA) of the EU for the evaluation of influenza vaccine efficacy. Issued by the Committee on Proprietary Medicinal Products (CPMP). Note for guidance on harmonization of requirements for influenza vaccines. CHMP/BWP/214/96, 1997 ( www.emea.eu.int/pdfs/human/bwp/021496en.pdf ) 23 x European Medicines Agency (EMEA). Note for guidance on harmonization of requirements for influenza vaccines. CPMP/BWP/214/96. (www.emea.eu.int/pdfs/human/bwp/021496en.pdf) (1997) source: © EMEA 1997 Reproduction and/or distribution of this document is authorized for non-commercial purposes only provided the EMEA is acknowledged.

European Union criteria for the assessment of vaccines
Criterion 18–60 years >60 years
Seroconversions or significant rises in anti-HA antibody titre >40% >30%
Mean geometric increase in titre >2.5 >2.0
Patients achieving HI titre ≥ 40 or SRH titre >25 mm2 >70% >60%

References in context

  • The European Medicines Agency (EMEA) has formally standardized the EU requirements for annual evaluation of influenza vaccine efficacy (Table 16).23,24 These requirements include specified numbers of seroconversions and/or numbers of individuals achieving a certain antibody titre upon vaccination within a study population of a specified age range.
    Go to context

For each virus strain, at least one of the above criteria should be met

References

Label Authors Title Source Year
2

References in context

  • Flu vaccine development began just a few years after the first isolation of the influenza virus in 1933.1,2 Pioneering studies demonstrated that influenza A/PR/8/34 (H1N1) virus would infect humans upon subcutaneous administration, inducing virus-neutralizing antibodies.2,3 Soon after these initial observations, studies using formalin-inactivated whole-virus preparations were conducted, the first inactivated influenza vaccines being introduced in the 1940s.2 Most current influenza vaccines are also inactivated formulations, consisting of either split virus or subunit preparations, the latter containing just the isolated viral haemagglutinin (HA) and neuraminidase (NA).2,4,5 These vaccines are generally produced from virus grown on embryonated chicken eggs.
    Go to context

  • Flu vaccine development began just a few years after the first isolation of the influenza virus in 1933.1,2 Pioneering studies demonstrated that influenza A/PR/8/34 (H1N1) virus would infect humans upon subcutaneous administration, inducing virus-neutralizing antibodies.2,3 Soon after these initial observations, studies using formalin-inactivated whole-virus preparations were conducted, the first inactivated influenza vaccines being introduced in the 1940s.2 Most current influenza vaccines are also inactivated formulations, consisting of either split virus or subunit preparations, the latter containing just the isolated viral haemagglutinin (HA) and neuraminidase (NA).2,4,5 These vaccines are generally produced from virus grown on embryonated chicken eggs.
    Go to context

  • Flu vaccine development began just a few years after the first isolation of the influenza virus in 1933.1,2 Pioneering studies demonstrated that influenza A/PR/8/34 (H1N1) virus would infect humans upon subcutaneous administration, inducing virus-neutralizing antibodies.2,3 Soon after these initial observations, studies using formalin-inactivated whole-virus preparations were conducted, the first inactivated influenza vaccines being introduced in the 1940s.2 Most current influenza vaccines are also inactivated formulations, consisting of either split virus or subunit preparations, the latter containing just the isolated viral haemagglutinin (HA) and neuraminidase (NA).2,4,5 These vaccines are generally produced from virus grown on embryonated chicken eggs.
    Go to context

  • Flu vaccine development began just a few years after the first isolation of the influenza virus in 1933.1,2 Pioneering studies demonstrated that influenza A/PR/8/34 (H1N1) virus would infect humans upon subcutaneous administration, inducing virus-neutralizing antibodies.2,3 Soon after these initial observations, studies using formalin-inactivated whole-virus preparations were conducted, the first inactivated influenza vaccines being introduced in the 1940s.2 Most current influenza vaccines are also inactivated formulations, consisting of either split virus or subunit preparations, the latter containing just the isolated viral haemagglutinin (HA) and neuraminidase (NA).2,4,5 These vaccines are generally produced from virus grown on embryonated chicken eggs.
    Go to context

  • However, despite the introduction of improved techniques for virus purification, local reactogenicity and systemic side effects remain a problem associated with the use of these vaccines, particularly in small children.17 This has led to the development of vaccine formulations consisting of disrupted virus particles, which turned out to be almost equally immunogenic in primed individuals, yet causing significantly fewer side effects.2 These split-virus vaccines, first licensed in the USA in 1968, are among the most widely used formulations to date.
    Go to context

  • However, despite the introduction of improved techniques for virus purification, local reactogenicity and systemic side effects remain a problem associated with the use of these vaccines, particularly in small children.17 This has led to the development of vaccine formulations consisting of disrupted virus particles, which turned out to be almost equally immunogenic in primed individuals, yet causing significantly fewer side effects.2 These split-virus vaccines, first licensed in the USA in 1968, are among the most widely used formulations to date.
    Go to context

JM Wood, MS Williams. History of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (317 - 323) 1998
4

References in context

  • Flu vaccine development began just a few years after the first isolation of the influenza virus in 1933.1,2 Pioneering studies demonstrated that influenza A/PR/8/34 (H1N1) virus would infect humans upon subcutaneous administration, inducing virus-neutralizing antibodies.2,3 Soon after these initial observations, studies using formalin-inactivated whole-virus preparations were conducted, the first inactivated influenza vaccines being introduced in the 1940s.2 Most current influenza vaccines are also inactivated formulations, consisting of either split virus or subunit preparations, the latter containing just the isolated viral haemagglutinin (HA) and neuraminidase (NA).2,4,5 These vaccines are generally produced from virus grown on embryonated chicken eggs.
    Go to context

  • Initial inactivated influenza vaccine formulations invariably consisted of whole inactivated virus formulations.2,4 Whole inactivated virus vaccines are generally quite immunogenic.
    Go to context

  • Initial inactivated influenza vaccine formulations invariably consisted of whole inactivated virus formulations.2,4 Whole inactivated virus vaccines are generally quite immunogenic.
    Go to context

  • Removal of the detergent from the supernatant by adsorption onto a hydrophobic resin, such as Amberlite, results in the formation of rosettes of HA and NA, with only small amounts of contaminating core proteins, such as NP or M1, and viral membrane lipid.4 Influenza subunit vaccines were first licensed in UK in 1980 and are now used in many countries worldwide.
    Go to context

  • Removal of the detergent from the supernatant by adsorption onto a hydrophobic resin, such as Amberlite, results in the formation of rosettes of HA and NA, with only small amounts of contaminating core proteins, such as NP or M1, and viral membrane lipid.4 Influenza subunit vaccines were first licensed in UK in 1980 and are now used in many countries worldwide.
    Go to context

IGS Furminger. Vaccine production. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (324 - 332) 1998
5

References in context

  • Single radial immunodiffusion (SRD) test of influenza vaccine potency.5 Serial dilutions of detergent-treated vaccine, and a reference antigen (Ref), are added to wells in an agarose gel containing a sheep antiserum against the relevant HA.
    Go to context


  • Go to context

  • Flu vaccine development began just a few years after the first isolation of the influenza virus in 1933.1,2 Pioneering studies demonstrated that influenza A/PR/8/34 (H1N1) virus would infect humans upon subcutaneous administration, inducing virus-neutralizing antibodies.2,3 Soon after these initial observations, studies using formalin-inactivated whole-virus preparations were conducted, the first inactivated influenza vaccines being introduced in the 1940s.2 Most current influenza vaccines are also inactivated formulations, consisting of either split virus or subunit preparations, the latter containing just the isolated viral haemagglutinin (HA) and neuraminidase (NA).2,4,5 These vaccines are generally produced from virus grown on embryonated chicken eggs.
    Go to context

  • Thus far, the hallmark for influenza vaccine efficacy has been the induction of an adequate level of virus-neutralizing antibodies in the serum.5–7 These antibodies are primarily directed against the envelope glycoproteins of the virus, HA and NA, HA being the major target for virus-neutralizing antibodies (see Chapter 4).
    Go to context

  • That this system of surveillance and recommendation works quite well is demonstrated by the good match achieved in, for example, the influenza seasons from 1987 to 1997.5 Within this period, 23 vaccine strains recommended by the WHO matched with the subsequently circulating total of 30 virus strains (Table 15).
    Go to context


  • Go to context


  • Go to context


  • Go to context

  • This dose scheme has been formally standardized.5,23,24 The trivalent inactivated influenza vaccine is administered by intramuscular or deep subcutaneous injection.
    Go to context

  • Not only has the composition of influenza vaccines been standardized in many countries, in the EU, criteria for vaccine immunogenicity have also been implemented.5,22,23 As indicated above, current inactivated influenza vaccines aim at induction of an efficient systemic antibody response against the viral surface antigens.
    Go to context

  • Antibody titres are generally determined on the basis of haemagglutination–inhibition (HI) activity5,6 or, occasionally, by single radial haemolysis (SRH).5 In the HI assay, serum samples of vaccinated individuals are tested for their ability to inhibit agglutination of erythrocytes, induced by influenza virus through interaction of the viral HA with sialic acid on the red cell surface.
    Go to context

  • Antibody titres are generally determined on the basis of haemagglutination–inhibition (HI) activity5,6 or, occasionally, by single radial haemolysis (SRH).5 In the HI assay, serum samples of vaccinated individuals are tested for their ability to inhibit agglutination of erythrocytes, induced by influenza virus through interaction of the viral HA with sialic acid on the red cell surface.
    Go to context

  • Antibody titres are generally determined on the basis of haemagglutination–inhibition (HI) activity5,6 or, occasionally, by single radial haemolysis (SRH).5 In the HI assay, serum samples of vaccinated individuals are tested for their ability to inhibit agglutination of erythrocytes, induced by influenza virus through interaction of the viral HA with sialic acid on the red cell surface.
    Go to context

JM Wood. Standardization of inactivated influenza vaccines. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (333 - 345) 1998
6

References in context

  • Thus far, the hallmark for influenza vaccine efficacy has been the induction of an adequate level of virus-neutralizing antibodies in the serum.5–7 These antibodies are primarily directed against the envelope glycoproteins of the virus, HA and NA, HA being the major target for virus-neutralizing antibodies (see Chapter 4).
    Go to context

  • Active immunization against any infectious disease, including influenza, aims at induction of antimicrobial immunity by inoculating the person with an attenuated or inactivated form of the pathogen involved.
    Go to context

  • Antibody titres are generally determined on the basis of haemagglutination–inhibition (HI) activity5,6 or, occasionally, by single radial haemolysis (SRH).5 In the HI assay, serum samples of vaccinated individuals are tested for their ability to inhibit agglutination of erythrocytes, induced by influenza virus through interaction of the viral HA with sialic acid on the red cell surface.
    Go to context

D Hobson, RL Curry, AS Beare, A Ward-Gardner. The role of serum haemagglutination-inhibiting antibody in protection against challenge virus infection with A2 and B viruses. Crossref. J Hyg (Lond) 70 (1972) (767 - 777) 1972
8

References in context


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  • These strains are included in the vaccines on recommendation of the WHO.8,9 This recommendation is based on an extensive review of epidemiological data and antigenic and genetic analyses of virus isolates by the four WHO Collaborating Centres.
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Y Ghendon. Influenza surveillance. Bull World Health Org 61 (1991) (509 - 515) 1991
9

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  • The safety record of inactivated influenza vaccines is excellent.9,14 Hundreds of millions of vaccine doses are distributed worldwide each year, adverse effects being extremely rare.
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  • These strains are included in the vaccines on recommendation of the WHO.8,9 This recommendation is based on an extensive review of epidemiological data and antigenic and genetic analyses of virus isolates by the four WHO Collaborating Centres.
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  • For a long time, doubts and misconceptions about the risk–benefit ratio of influenza vaccination have hampered the implementation of recommended policies for influenza vaccination.
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  • Inactivated influenza vaccines have an excellent safety record.9,14 Currently, about 300 million vaccine doses are being administered annually around the globe,10 and the overall rate of adverse reactions is extremely low.
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World Health Organization. Influenza vaccines. Wkly Epidemiol Rec 75 (2000) (281 - 288) 2000
17

References in context

  • However, despite the introduction of improved techniques for virus purification, local reactogenicity and systemic side effects remain a problem associated with the use of these vaccines, particularly in small children.17 This has led to the development of vaccine formulations consisting of disrupted virus particles, which turned out to be almost equally immunogenic in primed individuals, yet causing significantly fewer side effects.2 These split-virus vaccines, first licensed in the USA in 1968, are among the most widely used formulations to date.
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FL Ruben. Prevention and control of influenza. Role of vaccine. Crossref. Am J Med 82 (Suppl 6a) (1987) (31 - 34) 1987
18

References in context

  • Initial inactivated influenza vaccine formulations invariably consisted of whole inactivated virus formulations.2,4 Whole inactivated virus vaccines are generally quite immunogenic.
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KG Nicholson, DAJ Tyrrell, P Harrison, et al.. Clinical studies of monovalent inactivated whole virus and subunit A/USSR/77 (H1N1) vaccine: serological responses and clinical reactions. Crossref. J Biol Stand 7 (1979) (123 - 136) 1979
19

References in context

  • Subunit vaccines contain the HA and NA surface glycoproteins purified from other viral components.4 Because of their high purity, subunit vaccines have a favourable profile in terms of local and systemic side effects, compared to whole-virus and split vaccines.19 Yet, subunit vaccines are equally immunogenic in primed individuals.
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WEP Beyer, AM Palache, ADME Osterhaus. Comparison of serology and reactogenicity between influenza subunit vaccines and whole or split vaccines. A review and meta-analysis of the literature. Crossref. Clin Drug Invest 15 (1998) (1 - 12) 1998
20

References in context

  • Recently, a mathematical modeling approach for mapping of the antigenic distance between virus strains has been included in the strain selection process.20 In order to allow vaccine manufacturers sufficient time for production, in February of each year the WHO issues its recommendation about which viral strains should be included in the next winter's vaccine for the northern hemisphere.
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DJ Smith, AS Lapedes, JC de Jong, et al.. Mapping the antigenic and genetic evolution of influenza virus. Crossref. Science 305 (2004) (371 - 376) 2004
21

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  • Several studies have shown that a vaccine dose of ≥10 µg HA per strain induces an adequate immune response in primed individuals.21,22 Current trivalent inactivated influenza vaccines contain 15 µg of HA per strain as assessed by the SRD assay.
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AM Palache, WEP Beyer, G Lüchters, et al.. Influenza vaccines: the effect of vaccine dose on antibody response in primed populations during the ongoing interpandemic period. A review of the literature. Crossref. Vaccine 11 (1993) (892 - 908) 1993
22

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  • Several studies have shown that a vaccine dose of ≥10 µg HA per strain induces an adequate immune response in primed individuals.21,22 Current trivalent inactivated influenza vaccines contain 15 µg of HA per strain as assessed by the SRD assay.
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  • Not only has the composition of influenza vaccines been standardized in many countries, in the EU, criteria for vaccine immunogenicity have also been implemented.5,22,23 As indicated above, current inactivated influenza vaccines aim at induction of an efficient systemic antibody response against the viral surface antigens.
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J Treanor, W Keitel, R Belshe, et al.. Evaluation of a single dose of half strength inactivated influenza vaccine in healthy adults. Crossref. Vaccine 20 (2002) (1099 - 1105) 2002
23

References in context

  • Criteria of the European Medicines Agency (EMEA) of the EU for the evaluation of influenza vaccine efficacy.
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  • This dose scheme has been formally standardized.5,23,24 The trivalent inactivated influenza vaccine is administered by intramuscular or deep subcutaneous injection.
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  • Not only has the composition of influenza vaccines been standardized in many countries, in the EU, criteria for vaccine immunogenicity have also been implemented.5,22,23 As indicated above, current inactivated influenza vaccines aim at induction of an efficient systemic antibody response against the viral surface antigens.
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  • The European Medicines Agency (EMEA) has formally standardized the EU requirements for annual evaluation of influenza vaccine efficacy (Table 16).23,24 These requirements include specified numbers of seroconversions and/or numbers of individuals achieving a certain antibody titre upon vaccination within a study population of a specified age range.
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  • Immediately after the first batches of trivalent vaccine have been released for use, two serological clinical studies (in people aged 18–60 and >60 years) are performed to satisfy the licensing criteria of the European regulatory authorities,23,24 as discussed above.
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European Medicines Agency (EMEA). Note for guidance on harmonization of requirements for influenza vaccines. CPMP/BWP/214/96. (www.emea.eu.int/pdfs/human/bwp/021496en.pdf) (1997) 1997
24

References in context

  • This dose scheme has been formally standardized.5,23,24 The trivalent inactivated influenza vaccine is administered by intramuscular or deep subcutaneous injection.
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  • The European Medicines Agency (EMEA) has formally standardized the EU requirements for annual evaluation of influenza vaccine efficacy (Table 16).23,24 These requirements include specified numbers of seroconversions and/or numbers of individuals achieving a certain antibody titre upon vaccination within a study population of a specified age range.
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  • Immediately after the first batches of trivalent vaccine have been released for use, two serological clinical studies (in people aged 18–60 and >60 years) are performed to satisfy the licensing criteria of the European regulatory authorities,23,24 as discussed above.
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JM Wood, RA Levandowski. The influenza vaccine licensing process. Crossref. Vaccine 21 (2003) (1786 - 1788) 2003
25

References in context

  • The European Medicines Agency (EMEA) has formally standardized the EU requirements for annual evaluation of influenza vaccine efficacy (Table 16).23,24 These requirements include specified numbers of seroconversions and/or numbers of individuals achieving a certain antibody titre upon vaccination within a study population of a specified age range.
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Voordouw B. Influenza Vaccination in Community Dwelling Elderly Persons. PhD thesis, Erasmus University, Rotterdam, 2005. ISBN 90-8559-103-1.
26

References in context

  • As almost all current influenza vaccines are prepared from egg-grown virus (Figure 26), the annual vaccine production cycle begins with the estimation and ordering of the required numbers of embryonated chicken eggs well before actual vaccine production starts.26 Then, after the WHO has issued its recommendation, seed viruses are generated and characterized for approval by the WHO Collaborating Centres.
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C Gerdil. The annual production cycle for influenza vaccine. Crossref. Vaccine 21 (2003) (1776 - 1779) 2003

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