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  1. IMPACT OF REPEATED INFLUENZA VACCINATION AMONG CHILDREN AND ADULTS Universal Vaccination Against Influenza- Are We Ready? Wendy A. Keitel, M.D. October 24, 2005

  2. REPEATED IMMUNIZATION WITH INFLUENZA VIRUS VACCINES • QUESTIONS • What is the risk that annual vaccination could adversely affect future immune responses following influenza infection or vaccination? • What is the potential for other adverse effects among persons who are repeatedly vaccinated against influenza? • OBJECTIVE • Review published data regarding immunogenicity, efficacy, and safety of repeated vaccination Consider live and inactivated vaccines

  3. BACKGROUND Original Antigenic Sin: Preferential orientation of secondary antibodies toward priming epitopes (Francis T, et al. Trans Assn Am Phys 66:231, 1953) Hoskins’ Hypothesis: Annual vaccination of school children with inactivated influenza A vaccine confers no long-term advantage (Hoskins TW, et al. Lancet i: 33, 1979)

  4. REPEATED IMMUNIZATION AGAINST INFLUENZAOptimal Study Design Available Data • Randomized, double-blind, placebo-controlled • Enrollment prior to first exposure to influenza antigens • Longitudinal assessment of clinical and immunological responses • Direct comparison of live & inactivated vaccines • Optimal doses / regimens used • Non-randomized; relevant study groups not compared • Primed/heterogeneous populations; variable exposure to influenza • Short duration of follow-up; incomplete assessment of immune responses after vaccination or infection

  5. ‘THE HOSKINS’ PARADOX’Study Design • Clinical trials conducted among boarders 11-19 y.o. at Christ’s Hospital boys’ school starting in 1970 • Subjects randomized to receive sequential variants of influenza A/H3N2 (HK, Eng, PC) or B vaccine (WV) • Throat swab and paired blood samples were collected from boys with febrile ARD during flu epidemics • Infection = Virus isolation and/or 4-fold or greater increase in serum HAI antibody level vs. epidemic strains

  6. ‘THE HOSKINS’ PARADOX’Summary and conclusions based on 375 boys present during 3 sequential influenza A/H3N2 epidemics • Overall, 40-50% of boys in each group were infected • Boys vaccinated for the first time were partially protected against the next outbreak variant • Revaccination with updated strains was less effective than first time vaccination The practice of offering annual revaccination to adults seems open to question.

  7. Beyer Reanalysis Most subjects were not vaccinated each year ‘First Vac’ group not present in all epidemics Incomplete vaccination strategies preclude our ability to interpret data from 1975/6 epidemic Additional Concerns Vaccine potency unclear Cohort effect possible Authors excluded infected subjects from vaccinated groups Effects of vaccination on illness severity not described ‘THE HOSKIN’S PARADOX’Criticisms of Study Design Beyer WEP et al. Vaccine 16:1929, 1998.


  9. REPEATED ANNUAL IMMUNIZATION WITH INFLUENZA VACCINESHouston Family Study (HFS): Healthy Children • Up to 197 children (3-19 y.o.) followed up to 4 yrs (1985-89) • Randomized to receive TIV, bivalent CR-A, or P annually for up to 3 yrs; no vaccines given year 4 • Blood samples collected before & after immunization, and after the end of the epidemic period • Illness assessments with virus cultures performed during influenza epidemic periods From Gruber WC, et al. Am J Dis Child 144:595, 1990; Clover RD, et al. J Infect Dis 163:300, 1991; and Piedra PA and Glezen WP. Semin Pediatr Infect Dis 2(2):140, 1991.

  10. REPEATED ANNUAL IMMUNIZATION WITH INFLUENZA VACCINESHFS:Healthy Children (2) Year 3: H3N2 Infection Rates • Yr 1: TIV protected against influenza B infections • Yr 2: CR & TIV protected against H1N1 infections (CR-younger; TIV-older) • Yr 3: TIV protected against H3N2 infection and illness; CR protected against illness • Yr 4: CR protected against H1N1 infection (CR protection longer-lived than TIV) Adapted from Piedra PA and Glezen WP. Semin Pediatr Infect Dis 2(2):140, 1991. Vaccine Group (N=52-82/group)

  11. REPEATED ANNUAL IMMUNIZATION WITH INFLUENZA VACCINESChildren with CF and Family Members HAI Titer (log2) vs. A/Taiwan (H1N1) • 41 CF patients and their family members were given CR or TIV for up to 3 years (most were previously immunized with TIV) • Serologic responses for subjects in study for all 3 years are shown (N=21 for TIV and 13 for CR) Adapted from Gruber W, et al. J Infect Dis 169:241-7, 1994.

  12. ANNUAL IMMUNIZATION OF CHILDREN WITH INACTIVATED VACCINE Immunogenicity in CF Patients (1982-91) Percent with 1:40 Post (A/H3N2) • Effect of repeated annual immunization on serum antibody responses assessed in 38 CF patients over 10 yrs • No significant upward or downward trends in GMTs or % with ‘protective titers’ noted over the 10 year period Note: Vaccine antigens differed from year to year Year of Study Adapted from Gross PA, et al. Vaccine 14:1280, 1996.

  13. REPEATED IMMUNIZATION OF CHILDREN WITH LIVE OR INACTIVATED VACCINESVanderbilt Community Trial (1985-90) Percent Protection • 791 subjects <16 y.o. received 1,809 doses of vaccine or placebo: 277 received 635 doses of TIV • Both vaccines were well tolerated • Immunogenicity related to age, vaccine, pretiter, virus Cannot ascertain effects of repeated vaccination from the data presented Adapted from Neuzil K, et al. Pediatr Infect Dis J 20:733, 2001.

  14. REPEATED IMMUNIZATION OF CHILDREN WITH LIVE ATTENUATED VACCINES Efficacy Against Culture-Confirmed Illness (1996-98) Percent Culture-Positive • 1602 healthy 15-71 m.o. children (1358 in yr. 2) • Active surveillance for influenza conducted during epidemic periods (2-A/H3N2, 1 Flu B) Note: Influenza illnesses were milder in vaccinated children, and significant reductions in OM and LRD were noted Adapted from Belshe RB, et al. NEJM 338:1405, 1998; Belshe RB, et al. J Pediatr 136:168, 2000; and Longini IM, et al. Vaccine 18:1902, 2000.

  15. ANNUAL VACCINATION WITH CR VACCINESEffect On Antibody Responses Geometric Mean Titer • Ab responses among healthy children given CR X 4 years (MV; N=109) compared with children given CR for the first time (FV-new cohort; N=156) • Antibody responses were greater among children given vaccine for the first time Did local immune responses inhibit vaccine virus replication? Adapted from Bernstein DI, et al. Pediatr Infect Dis J 22:28, 2003.

  16. REPEATED VACCINATION OF CHILDREN WITH CR VACCINES Safety • Study Design: Open label, non-randomized, community-based trial of CR vaccine given to children between the ages of 1.5 and 18yrs (1998-2002; N=1571-2225/year). • Risk of medically-attended acute respiratory illness and asthma was assessed during the 6-week period after vaccination and compared to prevaccination rates. • No significant increase in the risk of health care utilization seen in children who received 1, 2, 3, or 4 annual sequential doses. See Piedra P et al. Pediatrics 116: e397, 2005.

  17. REPEATED IMMUNIZATION OF CHILDREN WITH INFLUENZA VIRUS VACCINESOther Significant Experiences • Japan: 3-15 y.o. children were immunized annually with inactivated vaccines. Between 1976-1987, vaccination was obligatory, and 50-85% of children were immunized each year (Reichert T, et al. NEJM 344:889, 2001) • Russia: In one study, healthy 7-14 y.o. children were immunized with inactivated (N up to 4402) or CR (N up to 4870) vaccines once or twice over 2 years. (Rudenko LG, et al. J Infect Dis 168:881, 1993)

  18. REPEATED ANNUAL IMMUNIZATION OF ADULTS AGAINST INFLUENZABCM Longitudinal Trial (1983-88) • 5 yr. trial; healthy adults • P group randomized to TIV or P each year • Blood Samples: Pre/Post; A/C; Spring • Illness assessments during each epidemic • Infection=Isolate and/or antibody rise In most cases, infection rates were similar in FV and MV Percent Protection vs. Placebo Adapted from Keitel WA, et al. Am J Epidemiol 127:353, 1988; Vaccine 15:1114, 1997.

  19. REPEATED VACCINATION WITH LIVE OR INACTIVATED FLU VACCINESVanderbilt Community Trial (1985-90): Effect on Antibody Responses Percent of Subjects with Indicated Response Adapted from Edwards KM, et al. J Infect Dis 169:68, 1994.

  20. IMMUNIZATION AGAINST INFLUENZAEffect on Illness Rates: Elderly Relative Risk vs. Placebo (tan) Logistic regression; OR (blue) • 1838 subjects who were at least 60 years old • Randomized to receive TIV or placebo (1991-2) • Outcomes: ILI and/or serologic influenza within 5 months after vaccination • RISK OF SERO. FLU 0.9% AND 5.1% IN THOSE WITH AND WITHOUT PRIOR VACCINATION; p=0.04 (p=0.07 in logistic regression analysis) Adapted from Govaert TME, et al. JAMA 272:1661, 1994

  21. ANNUAL IMMUNIZATION AGAINST INFLUENZAEffect on Death: Community-Dwelling Elderly % Reduction in Annual Mortality • Population-based cohort of 26,071 subjects >65 followed 1996-2002; death rates in vaccinated compared with rates in unvaccinated • Annual vaccination with TIV reduced risk of death • Interruption of vaccination associated with increased mortality • 1 death prevented/302 doses (or per 195 revaccinations) Adapted from Voordouw ACG, et al. JAMA 292:2089, 2004.

  22. REPEATED IMMUNIZATION WITH INACTIVATED VACCINESMeta-Analysis of Adult Trials • No consistent differences in postvaccination titers or percent ‘protected’ among revaccinated subjects when compared with subjects immunized for the first time • No consistent loss of protection against influenza when multiple vaccination groups are compared with single vaccination groups (Beyer WEP, et al. Arch Int Med 159:182, 1999) Note: Several studies have shown that immune responses among elderly persons who were previously vaccinated were inferior to those immunized for the first time; however, groups were not randomized. (Beyer WEP, et al. Vaccine 14:1331. 1996; Goodwin K, et al. Vaccine, Oct. 3 Epub; Keitel WA, et al. Manuscript in preparation).

  23. REPEATED VACCINATION AGAINST INFLUENZASafety • No reports of enhanced vaccine reactogenicity or other adverse clinical outcomes following vaccination or infection with influenza viruses • For CR Vaccine: Reactogenicity decreases after first vaccination

  24. SUMMARY & CONCLUSIONS • Annual immunization appears safe and well-tolerated (TIV and CR; Young and older) • Although frequencies of 4-fold rise in titer decline following repeated immunization, GMTs and % with putative protective titers are usually similar when compared with first time vaccination • No consistent changes in vaccine efficacy have been noted following repeated immunization • Repeated annual immunization may confer enhanced protection against death during epidemic periods among elderly persons

  25. THEORETICAL CONSIDERATION • Hypothesis: ‘Variation in repeat vaccine efficacy is due to differences in antigenic distances among vaccine strains and between vaccine strains and the epidemic strain.’ Smith DJ et al. Proc Nat Acad Sci 96:14001, 1999 Munoz ET and Deem MW. Vaccine 23:1144, 2005.

  26. INFORMATION GAPS Additional data are needed, including: • Assessment of humoral and cell-mediated immune responses following priming and repeated immunization of infants with live and inactivated vaccines • Expanded analyses of existing databases with particular attention to vaccine safety and effectiveness among repeatedly vaccinated subjects • Improved understanding of the nature of the immune response to influenza to help guide strain selection for optimal responses


  28. ORIGINAL ANTIGENIC SIN • Concept based on patterns of serum antibody responses among persons with varying histories of influenza virus infection or vaccination • Human and other animal model data indicate that the fine specificity of the antibody response is affected by previous antigenic exposure • Results in the production of predominantly cross-reactive antibodies to influenza virus HA following immunological priming

  29. ‘THE HOSKINS’ PARADOX’Vaccine Efficacy During Sequential Influenza A/H3N2 Epidemics • 1972/3: Significant protection conferred by prior H3N2 infection and by vaccination. No differences among boys given 1, 2, or 3 annual doses. (Hoskins TW, et al. Lancet 1973; ii, 116) • 1973/4: As above; attack rate lower in those vaccinated for the first time, but not significantly. (Hoskins TW, et al. Lancet 1976; i, 105)

  30. ‘THE HOSKIN’S PARADOX’Vaccine Efficacy During Sequential Influenza A/H3N2 Epidemics • 1975/6: Infection rates during the epidemic and the cumulative case-rates for 375 boys present during all 3 outbreaks were reported. (Hoskins TW, et al. Lancet 1979; i, 33 No single vaccination group was included, and not all subjects in vaccinated groups were vaccinated just prior to the epidemic.

  31. REPEATED IMMUNIZATION OF CHILDREN WITH LIVE ATTENUATED VACCINES Immunogenicity Over a Two-Year Period • Serum HAI titers vs. vaccine strains assessed in a subset each year (136-CR; 67-P) Virus Year 1 Year 2___ H1N1 A/Texas A/Shenzhen H3N2 A/Wuhan A/Wuhan B B/Harbin B/Harbin Geometric Mean Titer Post Adapted from Belshe RB, et al. NEJM 338:1405, 1998; Belshe RB, et al. J Pediatr 136:168, 2000.