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Vaccination: Cornerstone of Influenza Control

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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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.

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  • The highest serum dilution at which agglutination still occurs is defined as the HI titre (Figure 25).
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Figure 26 Production of influenza vaccine virus on embryonated chicken eggs. source: Courtesy of Solvay Pharmaceuticals, Weesp, the Netherlands.

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  • 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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Figure 27 Use of influenza vaccine in 56 developed and developing countries in the period 1997–2003. source: Reproduced from The Macroepidemiology of Influenza Vaccination (MIV) Study Group. The macroepidemiology of influenza vaccination in 56 countries, 1997–2003. Vaccine 2005; 23: 5133–5143 10 x The Macroepidemiology of Influenza Vaccination (MIV) Study Group. The macroepidemiology of influenza vaccination in 56 countries, 1997–2003. Vaccine 23 (2005) (5133 - 5143) with permission from Elsevier.

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  • The most dramatic changes in this respect have occurred in Korea, Latin America, Japan and some central and eastern European countries.10 Figure 27 presents a survey of influenza vaccine distribution in 56 developed and rapidly developing countries in 1997 and 2003.
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Figure 28 Relationship between influenza vaccine efficacy and clinical effectiveness of influenza vaccination. The figure shows a hypothetical example in which vaccination is associated with a 35% reduction in all outcomes evaluated (such as hospitalizations for pneumonia). However, not all outcomes are due to influenza. If only 40% of the outcomes represented complications of influenza, the underlying efficacy of the vaccine preventing direct influenza-associated outcomes would be 35%/0.4 = 87.5%. source: Adapted from Nichol KL. Efficacy/clinical effectiveness of inactivated influenza virus vaccines in adults. In: Nicholson KG, Webster RG, Hay AJ, editors. Textbook of Influenza. Blackwell Science, 1998; pp. 358–372 13 x KL Nichol. Efficacy/clinical effectiveness of inactivated influenza virus vaccines in adults. KG Nicholson, RG Webster, AJ Hay (Eds.) Textbook of Influenza (Blackwell Science, 1998) (358 - 372) with permission from Blackwell Publishing.

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  • It is defined as the reduction of clinically relevant, but not necessarily influenza-specific, disease in a “real-life” situation, including all influenza-like illness (ILI), hospitalizations due to pneumonia from all causes or death from all causes.12,13,40 As this parameter includes – by definition – disease that is not caused by the influenza virus, clinical effectiveness of vaccination is generally estimated to be lower than the actual vaccine efficacy, as illustrated by the hypothetical example presented in Figure 28.13 Therefore, clinical effectiveness should not be confused for vaccine efficacy, as this may result in a substantial underestimation of the actual performance of the vaccine.
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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 + + +

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  • 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).
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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%

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

Table 17 Recommendations for influenza vaccination of specific target groups adopted in most European countries. source: Source: The Macroepidemiology of Influenza Vaccination (MIV) Study Group. The macroepidemiology of influenza vaccination in 56 countries, 1997–2003. Vaccine 2005; 23: 5133–5143. 10 x The Macroepidemiology of Influenza Vaccination (MIV) Study Group. The macroepidemiology of influenza vaccination in 56 countries, 1997–2003. Vaccine 23 (2005) (5133 - 5143)

Influenza vaccination recommendations in European countries
  • People aged >65 years.
  • Residents of nursing homes and other long-term care facilities.
  • Adults and children with chronic pulmonary disorders.
  • Adults and children with chronic cardiovascular disorders.
  • Those who have required regular medical follow-up or hospitalization during the preceding year because of
    • chronic metabolic diseases (including diabetes mellitus),
    • renal dysfunction,
    • haemoglobinopathies, or
    • immunosuppression (including immunosuppression caused by medications or by human immunodeficiency virus).
  • Children and teenagers (aged 6 months to 18 years) who are receiving long-term aspirin therapy and therefore might be at risk for developing influenza infection.
  • Vaccination of health-care workers and others in close contact with persons at high risk, including household members, is recommended.

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  • Table 17 presents the recommendations for influenza vaccination adopted in most countries.
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Table 18 Clinical effectiveness of influenza vaccination of the elderly. source: Adapted from Nichol KL. The efficacy, effectiveness and cost-effectiveness of inactivated influenza virus vaccines. Vaccine 2003; 21: 1769–1775 12 x KL Nichol. The efficacy, effectiveness and cost-effectiveness of inactivated influenza virus vaccines. Vaccine 21 (2003) (1769 - 1775) Crossref. with permission from Elsevier.

Clinical effectiveness of influenza vaccination of the elderly
Outcome measure Reduction
Community-dwelling senior citizens
Hospitalizations for
 Pneumonia from all causes 33%
 All respiratory conditions 32%
 Congestive heart failure 27%
Death from all causes 50%
Elderly in nursing homes
Respiratory illness 56%
Pneumonia from all causes 53%
Hospitalization in general 48%
Death from all causes 68%

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  • A meta-analysis, including a large number of individual studies among senior citizens living in the community, concluded that vaccination significantly reduces hospitalization and death rates among the elderly (Table 18).50 Another meta-analysis has shown that influenza vaccination is also highly effective among residents of nursing homes (Table 18).51 These findings necessitate a proactive immunization practice by health-care providers in order to allow more elderly people to benefit from existing safe and efficacious influenza vaccines.
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  • A meta-analysis, including a large number of individual studies among senior citizens living in the community, concluded that vaccination significantly reduces hospitalization and death rates among the elderly (Table 18).50 Another meta-analysis has shown that influenza vaccination is also highly effective among residents of nursing homes (Table 18).51 These findings necessitate a proactive immunization practice by health-care providers in order to allow more elderly people to benefit from existing safe and efficacious influenza vaccines.
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Table 19 Possible actions by primary-care physicians to encourage vaccine uptake in target populations. source: Courtesy of Ted van Essen on behalf of the Dutch College of General Practitioners.

Possible actions by primary-care physicians to encourage vaccine uptake in target populations
  • Mark and update the records of people recommended for vaccination.
  • Send invitation letters together with information leaflets to people recommended for vaccination.
  • Organize vaccination clinics to administer vaccine to as many target subjects as possible in a time-efficient way.
  • Promote vaccination of family members of at-risk patients and health-care personnel.
  • Display appropriate information in your patients' waiting room and in your office.

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  • Indeed, they are in the best position to educate and motivate patients to be vaccinated. Table 19 lists a number of recommendations in this respect.
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Table 20 Benefits of influenza vaccination of healthy adults and children. ILI, influenza-like illness; URI, upper respiratory illness. source: Adapted from Nichol KL. The efficacy, effectiveness and cost-effectiveness of inactivated influenza virus vaccines. Vaccine 2003; 21: 1769–1775 12 x KL Nichol. The efficacy, effectiveness and cost-effectiveness of inactivated influenza virus vaccines. Vaccine 21 (2003) (1769 - 1775) Crossref. with permission from Elsevier.

Benefits of influenza vaccination of healthy adults and children
Outcome measure Reduction (%)
Healthy adults <65 years of age
Laboratory-confirmed influenza 70–90
URI/ILI (all causes) 25–34
Work loss due to URI/ILI 32–43
Physician visits due to URI/ILI 42–44
Children
Laboratory-confirmed influenza 60–90
Acute otitis media (all causes) 30–36

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  • Initial trials, conducted among military recruits several decades ago,57 showed that the vaccine was 70–90% efficacious in preventing laboratory-confirmed influenza, provided there was a good antigenic match between vaccine and circulating virus.58 A review of more recent clinical studies shows that the efficacy of inactivated influenza vaccines varied from 65% for all influenza seasons to 72% for those seasons where there was a good match between vaccine and circulating virus.31 Additional studies have reported vaccine efficacies in terms of prevention of confirmed influenza in the range of 80–90% in cases where there was a good match.59,60 Clearly, current inactivated influenza vaccines attain very high efficacy values among healthy younger adults (Table 20).
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  • As demonstrated by a number of studies, conducted in different countries, vaccination significantly reduces illness, absenteeism and influenza-related costs for healthy adults in the work place.12,13 Indeed, vaccination reduces upper respiratory tract and influenza-like illnesses from all causes by approximately 30%, related physician visits by >40% and work loss by >35% (Table 20).60,61 Accordingly, cost–benefit analyses, based on clinical trials or on modelling, have shown that vaccination of healthy working adults is cost-effective and in many cases cost-saving, provided that indirect costs associated with work absenteeism (see Chapter 6) are explicitly taken into account.62 For example, trials conducted in the USA have shown that – with an average cost for vaccine production and administration of $20 – the net saving would be $23 per person vaccinated.63 In another study comparing 131 vaccinated employees from six textile plants in North Carolina, USA, with 131 age- and gender-matched non-vaccinated controls from different plants, the “cost per saved lost work day” was $22.36, resulting in an overall saving of $2.58 per dollar invested in the vaccination programme.64 Other, model-based, studies also indicate that vaccinating working adults would be cost-saving.12 While recent international guidelines for pharmacoeconomic analyses do explicitly recommend the inclusion of production gains and losses,62 also when such indirect costs are not taken into account, vaccination of adults below the age of 65 turns out to be highly cost-effective.
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  • The efficacy of influenza vaccination among children has been evaluated in a number of randomized, controlled trials, involving the use of either trivalent inactivated or experimental live-attenuated vaccines.68–70 From these studies, it appears that vaccination is highly efficacious in terms of preventing laboratory-confirmed influenza for children in their teens (∼90%), whereas a lower efficacy is seen with younger children (Table 20).
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  • A common complication of influenza among young children is acute otitis media (see Chapter 5).
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