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

Bauch CT (2011) Can Interactions between Timing of Vaccine-Altered Influenza Pandemic Waves and Seasonality in Influenza Complications Lead to More Severe Outcomes? PLoS ONE 6(8): e23580. doi:10.1371/journal.pone.0023580 Can Interactions between Timing of Vaccine-Altered Influenza Pandemic Waves and Seasonality in Influenza Complications Lead to More Severe Outcomes? Utkarsh J. Dang 0 Chris T. Bauch 0 Alison P. Galvani, Yale University, United States of America 0 1 Department of Mathematics and Statistics, University of Guelph , Guelph, Ontario , Canada , 2 Department of Ecology and Evolutionary Biology, Princeton University , Princeton, New Jersey , United States of America 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. - Funding: This work was supported by the Natural Sciences and Engineering Research Council of Canada and the Canadian Institutes of Health Research. 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. Both seasonal and pandemic influenza are associated with a considerable burden of disease, in the form of absenteeism, hospitalizations, intensive care unit (ICU) admissions, and deaths [1]. Severe complications can occur even in patients without chronic health conditions [2]. Complications are often the result of secondary bacterial infections, and the delay between primary influenza and the diagnosis of subsequent bacterial infections means that the primary influenza infection is not always confirmed [3]. Data from the influenza pandemics of 1918, 1957 and 1968 are consistent with secondary bacterial pneumonia causing the majority of influenza-associated deaths [4]. Pandemic influenza can be associated with a higher burden of disease than seasonal influenza, if only because more individuals become infected during a pandemic due to lower levels of natural immunity in the population, as compared to typical seasonal influenza [5]. As with previous influenza pandemics, the 2009 H1N1 pandemic imposed a significant disease burden [6]. Pulmonary complications were common, with primary influenzal pneumonia and acute respiratory distress syndrome in adults and secondary bacterial pneumonia in children [7]. Secondary pneumococcal infections were often a factor in severe and fatal cases of influenza [8]. However, unlike in previous pandemics, immunization programs may have played a mitigating role, despite late introduction of the vaccine. The use of a vaccine against pandemic influenza for the first time ever suggests that immunization will form a part of mitigation plans for future influenza pandemics. However, as always, it remains necessary to address how best to design and execute large-scale immunization programs in the face of uncertainties. Seasonal influenza is characterized by strong seasonal variation in incidence, generally surging in the winter months in temperate regions [1]. Severe outcomes such as influenza-related hospitalizations and deaths also peak in winter [9,10]. In comparison, although influenza pandemics may be influenced by seasonality, they do not always follow the same pattern: spring, fall and winter waves have all occurred in past pandemics [11]. One possible explanation for this difference is that the widespread host susceptibility that accompanies an antigenically novel strain means an outbreak can occur even when seasonal factors do not support its transmission. The cause of seasonality in seasonal influenza is debated [12]. Suggested contributors include seasonal variation in host health, school attendance, ambient temperature, indoor/outdoor absolute humidity, and ultraviolet (UV) radiation intensity [1215]. Some of these observations have led to a hypothesis that innate host susceptibility varies seasonally, enabling seasonal outbreaks to occur. Impairments of the antimicrobial peptide (AMPs) systems that respond to influenza infection are caused by very low levels of 25-hydroxy-vitamin D [25(OH)D] in the winter months [16]. Vitamin D levels vary with seasonal trends in UV radiation levels and are therefore highest in August and lowest in February (since most Vitamin D is obtained through sun exposure, not diet). This implies heightened host susceptibility in late fall, winter, and early spring [17]. Susceptibility to secondary bacterial infections from influenza also varies seasonally, and exposure to UV-B radiation is known to reduce the risk of invasive pneumococcal disease (pneumonia, bacteremia, and meningitis) [18]. Seasonality in susceptibility to secondary bacterial infections suggests that influenza outcomes might be more severe when peak influenza incidence aligns with peak susceptibility to secondary bacterial infections. Immunization alters the susceptibility of the host population to influenza infection and may thereby affect the timing of pandemic influenza peaks [19]. Therefore, a pandemic immunization program may mitigate a fa (...truncated)