title: Optimizing the dose of pre-pandemic influenza vaccines to reduce the infection attack rate.
abstract: BACKGROUND
  The recent spread of avian influenza in wild birds and poultry may be a precursor to the emergence of a 1918-like human pandemic. Therefore, stockpiles of human pre-pandemic vaccine (targeted at avian strains) are being considered. For many countries, the principal constraint for these vaccine stockpiles will be the total mass of antigen maintained. We tested the hypothesis that lower individual doses (i.e., less than the recommended dose for maximum protection) may provide substantial extra community-level benefits because they would permit wider vaccine coverage for a given total size of antigen stockpile.
  
  
  RESULTS
  We used a mathematical model to predict infection attack rates under different policies. The model incorporated both an individual's response to vaccination at different doses and the process of person-to-person transmission of pandemic influenza. We found that substantial reductions in the attack rate are likely if vaccines are given to more people at lower doses. These results are applicable to all three vaccine candidates for which data are available. As a guide to the magnitude of the effect, we simulated epidemics based on historical studies of immunogenicity. For example, for one of the vaccines for which data are available, the attack rate would drop from 67.6% to 58.7% if 160 out of the total US population of 300 million were given an optimal dose rather than 20 out of 300 million given the maximally protective dose (as promulgated in the US National Pandemic Preparedness Plan). Our results are conservative with respect to a number of alternative assumptions about the precise nature of vaccine protection. We also considered a model variant that includes a single high-risk subgroup representing children. For smaller stockpile sizes that allow vaccine to be offered only to the high-risk group at the optimal dose, the predicted benefits of using the homogenous model formed a lower bound in the presence of a risk group, even when the high-risk group was twice as infective and twice as susceptible.
  
  
  CONCLUSIONS
  In addition to individual-level protection (i.e., vaccine efficacy), the population-level implications of pre-pandemic vaccine programs should be considered when deciding on stockpile size and dose. Our results suggest that a lower vaccine dose may be justified in order to increase population coverage, thereby reducing the infection attack rate overall.
authors.affiliation: Department of Community Medicine and School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Hong Kong Special Administrative Region, China. steven.riley@hku.hk
authors.forename: Steven
authors.initials: S
authors.lastname: Riley
authors.forename: Joseph T
authors.initials: JT
authors.lastname: Wu
authors.forename: Gabriel M
authors.initials: GM
authors.lastname: Leung
mesh_terms: D000465:Algorithms; D000818:Animals; D001717:Birds; D003140:Communicable Disease Control / Q000379:methods; D004196:Disease Outbreaks / Q000517:prevention & control*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D005585:Influenza in Birds / Q000276:immunology*; D007251:Influenza, Human / Q000276:immunology*; D032541:Mass Vaccination / Q000379:methods
chemical_list: D007252:Influenza Vaccines