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

Date Published: June 19, 2007

Publisher: Public Library of Science

Author(s): Steven Riley, Joseph T Wu, Gabriel M Leung, Marc Lipsitch

Abstract: BackgroundThe 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 FindingsWe 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.ConclusionsIn 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.

Partial Text: The recent spread of H5N1 highly pathogenic avian influenza (HPAI) in wild birds and poultry may be a precursor to the emergence of a 1918-like human pandemic [1,2]. Therefore, stockpiles of human pre-pandemic vaccine (targeted at avian HPAI strains) are being considered by many countries. For example, the US intends to provide enough pre-pandemic vaccine to protect 20 million people [3]. Data from Phase II clinical trials are available for three candidate vaccines [4–6]. Two of the candidates are adjuvant inactivated whole-virion vaccines for which immunological responses for doses in the ranges 1.25–10 μg [5] and 7.5–30 μg [4] have been reported. The third candidate is a nonadjuvant inactivated split-virion vaccine [6] for which immunological responses for doses in the range 7.5–90 μg have been reported. All three trials found that during haemagglutinin inhibition (HI) tests, sera from at least 50% of individuals who received two inoculations at the maximum dose were able to neutralize target antigens at concentrations of 1:40. It should be noted that pre-pandemic vaccine stockpiles would most likely be used as part of a globally reactive strategy; i.e., countries would plan to initiate vaccination programs when a nascent pandemic is confirmed in a remote region, rather than routinely vaccinating against avian strains. However, it would not be possible to use vaccines in a truly reactive way, i.e., vaccinating contacts of individual cases, because the time lag between vaccination and protection is long compared with the likely speed of progression of individual national epidemics.

Initially, we considered a homogeneous population without different risk groups. For all three vaccine candidates [4–6], increasing the population coverage by lowering the dose led to substantially lower infection attack rates (see Figure 2A–2C). However, the specific shape of the response curves for the different vaccines (Figure 1) influenced the expected degree of reduction for a given change in dose. For example, halving the dose from the maximum (therefore doubling the coverage) had a large impact on the infection attack rate for the vaccine reported by Treanor et al. [6] (hereafter, the Treanor vaccine), a less substantial effect for the vaccine reported by Lin et al. [5] (Lin vaccine), and very little change for the vaccine reported by Bresson et al. [4] (Bresson vaccine). If the optimal dose gave an attack rate within 1% of that of the minimum dose, we set the optimal dose to be the minimum. Under this criterion, for stockpile sizes too small to provide a minimum dose for all, the optimal dose for all three vaccine candidates (black lines, Figure 2A–2C) was equal to the minimum dose tested. For these small stockpiles, optimal coverage was less than 100% (green lines, Figure 2D–2F). For larger stockpile sizes, the optimal dose corresponded to an equal division of antigen among all members of the population.

For a stockpile of pandemic influenza vaccine that is constrained by total mass of antigen, we have shown that for the three candidates for which data are available [4–6], wider coverage at lower doses would likely result in substantially lower infection attack rates. A reduction in attack rate of 8.9% (see Table 1) in a population the size of the US (300 million) corresponds to 27 million fewer influenza infections in a period of less than a year. Even if 45% of the stockpile were reserved to be used at maximum dose for health care workers, a reduction in attack rate of 4.8% implies that 14 million infections could be averted. Although these results are sensitive to some uncertainties (see below), the general pattern of lower doses being substantially more efficient at the population level is consistent across all three vaccines candidates and over a number of alternatives for key assumptions (Table 1).



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