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. 2011;6(8):e23580.
doi: 10.1371/journal.pone.0023580. Epub 2011 Aug 23.

Can Interactions Between Timing of Vaccine-Altered Influenza Pandemic Waves and Seasonality in Influenza Complications Lead to More Severe Outcomes?

Free PMC article

Can Interactions Between Timing of Vaccine-Altered Influenza Pandemic Waves and Seasonality in Influenza Complications Lead to More Severe Outcomes?

Utkarsh J Dang et al. PLoS One. .
Free PMC article


Vaccination can delay the peak of a pandemic influenza wave by reducing the number of individuals initially susceptible to influenza infection. Emerging evidence indicates that susceptibility to severe secondary bacterial infections following a primary influenza infection may vary seasonally, with peak susceptibility occurring in winter. Taken together, these two observations suggest that vaccinating to prevent a fall pandemic wave might delay it long enough to inadvertently increase influenza infections in winter, when primary influenza infection is more likely to cause severe outcomes. This could potentially cause a net increase in severe outcomes. Most pandemic models implicitly assume that the probability of severe outcomes does not vary seasonally and hence cannot capture this effect. Here we show that the probability of intensive care unit (ICU) admission per influenza infection in the 2009 H1N1 pandemic followed a seasonal pattern. We combine this with an influenza transmission model to investigate conditions under which a vaccination program could inadvertently shift influenza susceptibility to months where the risk of ICU admission due to influenza is higher. We find that vaccination in advance of a fall pandemic wave can actually increase the number of ICU admissions in situations where antigenic drift is sufficiently rapid or where importation of a cross-reactive strain is possible. Moreover, this effect is stronger for vaccination programs that prevent more primary influenza infections. Sensitivity analysis indicates several mechanisms that may cause this effect. We also find that the predicted number of ICU admissions changes dramatically depending on whether the probability of ICU admission varies seasonally, or whether it is held constant. These results suggest that pandemic planning should explore the potential interactions between seasonally varying susceptibility to severe influenza outcomes and the timing of vaccine-altered pandemic influenza waves.

Conflict of interest statement

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


Figure 1
Figure 1. Probability of ICU admission per influenza infection, estimated from the H1N1 pandemic of 2009.
Data from the H1N1 pandemic of 2009 (black line) was fit to our seasonally varying function (Table S2) and extrapolated (solid grey line). Weekly H1N1 positive specimens (dashed grey line) is on the secondary vertical axis.
Figure 2
Figure 2. Example where vaccination increases the number of ICU admissions.
A typical run where the number of ICU admissions increased due to vaccination for Profile C for 40% vaccination rate. (a), infected incidence (black) and number of ICU admissions (grey) over time without vaccination (top panel) and (c), with vaccination (bottom panel). (b), time series of the number of susceptible individuals without (top panel) and (d), with vaccination (bottom panel). Vaccination leads to an increase in the number of ICU admissions by increasing the number of susceptibles available for another wave leading to higher incidence and higher morbidity. Parameter values: formula image years, formula image years, formula image, formula image, formula image, formula image, formula image, formula image and formula image.
Figure 3
Figure 3. ICU admissions averted (top) and infections averted (bottom) for different vaccination profiles.
Boxplots of ICU admissions and infections averted with different vaccination profiles for 40% vaccination rate. Vaccinating a larger proportion of the population in advance can lead leads to a lower number of infections in total but a higher number of ICU admissions. Points are drawn as outliers formula image if they are larger than formula image or smaller than formula image, where q1 and q3 are the 25th and 75th percentiles, respectively.
Figure 4
Figure 4. Scatter plots of realizations where ICU admissions increased or decreased due to vaccination, as a function of various parameters.
Parameters where vaccination caused a higher (black circles) or lower (blue diamonds) number of ICU cases for Profile B for 40% vaccination rate. There is some evidence for clustering near the upper constraint for the entry time parameter. formula image (horizontal axis in all panels) values smaller than approximately 1.7 did not give rise to simulations that passed our filtering criterion, hence the lack of data for these values of formula image. Longer duration of infectiousness (smaller formula image), more rapid antigenic drift (larger formula image), or when the entry time is later in the summer (larger formula image) seem more conducive to resulting in an increase in the number of ICU admissions.

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