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

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.疫苗接种可通过减少初始对流感易感的个体数量，延缓大流行性流感流行波的峰值。越来越多的证据表明，原发性流感感染后发生重症继发性细菌感染的易感性可能存在季节性差异，冬季为易感高峰。综上，两项发现共同提示：为防控秋季流感大流行波而开展疫苗接种，可能会将疫情推迟足够久，进而无意间增加冬季的流感感染人数——而此时原发性流感感染更易引发重症结局，最终可能导致重症结局的净增加。 现有多数大流行模型默认重症结局的发生概率不存在季节性差异，因此无法捕捉这一效应。本研究证实，2009年H1N1流感大流行期间，每例流感感染者的重症监护病房（Intensive Care Unit, ICU）收治概率呈现季节性规律。我们将这一规律与流感传播模型相结合，旨在探究疫苗接种计划可能无意间将流感易感性转移至流感ICU收治风险更高的月份的条件。 研究发现，当抗原漂移（antigenic drift）足够迅速或存在交叉反应毒株（cross-reactive strain）输入的可能时，秋季大流行波前开展疫苗接种，反而可能增加ICU收治人数。此外，针对预防更多原发性流感感染的疫苗接种计划，这一效应更为显著。敏感性分析揭示了若干可能引发该效应的机制。我们还发现，ICU收治人数的预测值会因重症收治概率是否存在季节性差异，或是否被设定为恒定值而发生显著变化。 上述结果提示，大流行防控规划应探究季节性变化的流感重症结局易感性，与疫苗接种改变的大流行性流感流行波发生时间之间的潜在交互作用。