We used a mathematical model to evaluate optimal pH1N1 vaccination strategies, focusing our analysis on the Canadian population and considering the effect of targeting different age groups for prioritization of vaccine allocation on projected hospitalizations and mortality. Depending on the outcome assessed and the assumptions used, both attack rate- and outcome-based strategies were effective in reducing morbidity and mortality, but in most scenarios, delaying vaccine distribution by one week to preferentially immunize individuals with underlying high-risk conditions was the optimal strategy. We observed that the dynamics of pH1N1 transmission is a critical area of uncertainty, with all vaccination strategies having limited impact if the epidemic peak occurs prior to or concomitantly with vaccine availability (projected for mid-November).
Our analysis focused on the occurrence of severe outcomes and did not directly consider the effect of vaccination on reducing disease transmission and the resultant downstream effects, such as reduced societal disruption and economic costs (such as those associated with time lost from work or school). Additionally, when assessing severe outcomes, there is a need to consider how these outcomes may interact; for instance, a strategy that focuses on reducing mortality at the expense of higher attack rates could lead to the saturation of ICU capacity, resulting in higher mortality in younger age groups than has been observed to date.
The epidemiology of pH1N1 appears distinct from that of seasonal influenza (but similar to that of prior pandemics ,
) in that younger age is associated with the highest attack rates, a phenomenon that has resulted in a higher absolute burden of morbidity and mortality in this age group than is typically observed with seasonal influenza, even though per-case risks of poor outcome may not differ from those seen with seasonal influenza. However, although older age groups are less likely to be infected with the pandemic strain than younger individuals, infections in individuals aged > 50 years documented in Ontario have been associated with increased ICU admissions and death 
Our model assumes that two doses of pH1N1 vaccine will be required to elicit a protective response, but emerging data have demonstrated that a single dose may be sufficiently immunogenic in healthy adults ,
. Whether these results extend to children, the elderly, or individuals with underlying medical conditions remains to be seen. The implications of a single dose vaccine are similar to shifting the epidemic peak to later in the winter, resulting in enhanced effectiveness for any vaccination strategy adopted, relative to a two-dose schedule. The preference for an attack rate-based strategy using a single vaccine dose when vaccination coverage is high agrees with a recent study suggesting that targeting age groups at the highest risk of infection may be the optimal solution 
, but in our model, this is only the case when vaccine is available well before the epidemic peak. Finally, we evaluated the impact of poor vaccine effectiveness in older individuals on preferred strategies, as this has been a concern with seasonal vaccine 
; we found limited impact of decreased effectiveness on the rank-ordering of preferred strategies except when older individuals were highly likely (70%) to be immune to infection in the absence of vaccination, and were effectively “pre-vacccinated” by early life influenza exposures.
Our analysis is subject to several important limitations. As with all mathematic models, this model includes simplifyingassumptions and incorporates parameter values that are subjectto some uncertainty. Model calibration to existing data was used to derive estimates of key epidemiologic parameters and these values are in agreement with estimates from other settings ,
. We incorporated non-homogeneous mixing patterns between age groups, but did not consider the effect of spatial heterogeneity. However, other studies have demonstrated that estimates of R0 appear to be consistent across locations and spatial scales ,
. Some other simplifying assumptions included non-differential transmissibility of influenza by symptomatic and asymptomatic cases and non-incorporation of other concurrent mitigation strategies on influenza transmission, including antivirals and social distancing measures, on influenza transmission. We also did not consider the impact of co-circulating seasonal influenza strains, although recent data suggest that reduced circulation of seasonal strains may be observed in the upcoming influenza season ,
. To address the uncertainty in our estimates of mortality and hospitalization rates, due to both the low frequency of occurrence of these outcomes and reporting biases and other limitations inherent in surveillance data, we have focused our analysis on qualitative results.
In summary, we have developed an age-structured mathematical model to evaluate optimal vaccination strategies for pH1N1. This model demonstrates the importance of the interaction between pH1N1 transmission dynamics and the demographic characteristics of population at risk of pH1N1 infection on the potential effectiveness of vaccination strategies. It also highlights the value of moving away from strictly age-based vaccination prioritization schemes toward strategies that target high-risk groups, regardless of age.
We thank Michael Campitelli and Ruth Sanderson for providing data, and Barbara Law and Susan Tamblyn for helpful discussions related to plausible vaccination strategies.
The opinions, results and conclusions reported in this paper are those of the authors and are independent from the funding sources. No endorsement by the Institute for Clinical Evaluative Sciences or the Ontario Ministry of Health and Long-Term Care is intended or should be inferred.