Pharma Focus Asia

Optimizing the Dose of Pre-Pandemic Influenza Vaccines to Reduce the Infection Attack Rate

Steven Riley 1, Joseph T. Wu1 1, Gabriel M. Leung1

Steven Riley 1, Joseph T. Wu1 1, Gabriel M. Leung1


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.

Methods and Findings

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.


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.

Funding: This work was supported by grants from the Research Fund for the Control of Infectious Diseases of the Health, Welfare and Food Bureau of the Hong Kong SAR Government (JTW, SR, GML); and The University of Hong Kong SARS Research Fund (SR, GML).The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

Competing Interests: The authors have declared that no competing interests exist.

Academic Editor: Marc Lipsitch, Harvard School of Public Health, United States of America

Citation: Riley S, Wu JT, Leung GM (2007) Optimizing the Dose of Pre-Pandemic Influenza Vaccines to Reduce the Infection Attack Rate. PLoS Med 4(6): e218 doi:10.1371/journal.pmed.0040218

Received: November 1, 2006; Accepted: June 11, 2007; Published: June 19, 2007

Copyright: © 2007 Riley et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abbreviations: HI, haemagglutinin inhibition; HPAI, highly pathogenic avian influenza

* To whom correspondence should be addressed. E-mail:

1These authors contributed equally to this work.

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