Reducing Hospital Capacity Needs for Seasonal Respiratory Infections: the case of switching to High-Dose influenza vaccine for Dutch older adults

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Optimal protection against influenza is more important than ever, since, with COVID-19 restrictions being lifted, severe seasonal influenza epidemics are to be expected. Indeed, immunity in the population has lacked regular boosting due to social distancing and other restrictions resulting in increased risks for seasonal influenza epidemics 1 . Such epidemics will come with additional pressure on hospital and intensive-care unit capacity and corresponding societal costs, especially among adults 60 years and older (60+). For this risk group, the quadrivalent influenza vaccine (QIV) has been in use since 2019/2020 in the Netherlands.
However, the vaccine effectiveness of QIV remains suboptimal in elderly individuals. Notably, we demonstrated that even if the 60+ group in the Netherlands had been vaccinated with QIV during the 2010/11 through 2017/18 seasons, on average still hundreds of influenza-associated respiratory disease hospitalizations would have occurred among these senior individuals on an annual basis 2 . Ergo, despite vaccination with QIV, there remains a considerable burden of influenza among older adults with a corresponding need for healthcare capacity. With ongoing developments in the area of influenza vaccines, further improvements in vaccination programmes might therefore be considered. Potential improvements include, for example, a switch from the standard-dose (SD) to a high-dose (HD) vaccine formulation for the 60+ population. Current SD inactivated influenza vaccines contain 15 g of the hemagglutinin (HA) antigen per virus strain included in the vaccine. By contrast, the HD vaccine contains 60 g HA per strain. HD influenza vaccine has been shown to be superior compared to SD in various studies [3][4][5] with improved vaccine effectiveness and no increase in serious adverse events. QIV-HD is available for older adults in the United States (US) since 2020, and its use has been recommended in countries like Canada, Germany, Italy, and the UK [6][7][8][9][10] . Recently, the potential benefit of a switch from SD to HD to further reduce hospitalizations has been demonstrated in retrospective database analyses in the US [11][12][13] . Here, we estimated the potential impactspecifically in terms of hospital admissions and related costs -of a switch from QIV-SD to QIV-HD in the Netherlands. Hospital capacity has emerged as a crucial factor in infectious disease control during the COVID-19 pandemic, justifying the focus of our study.
The remaining burden of influenza in the Netherlands among the 60+ group can be estimated at approximately 61,500 influenza cases annually, over the period of 2010/11-2017/18 (with assumed QIV-SD coverage rates of 50% and 70% among 60-65-olds and 65+, respectively) 2 . This remaining burden is largely due to immunosenescence contributing to the modest vaccine effectiveness of QIV-SD in this specific group. As indicated above, QIV-HD, due to its four times higher dose of antigen compared to QIV-SD, induces a stronger immune J o u r n a l P r e -p r o o f response and, therefore, overcomes part of the immunosenescence effects and provides older adults with improved protection against influenza. Specifically, the HD-vaccine has been shown to provide superior protection against cardiovascular complications of influenza and corresponding hospitalizations 4 . Cardiovascular complications have been found to occur from days up to months after the actual influenza infection [14][15][16] .
We estimated the number of hospitalizations in the 60+ population that could have been   As exemplified by the COVID-19 pandemic, outbreaks of respiratory infections pose a significant pressure on hospital capacity in the Netherlands as well as elsewhere. However, this pressure is by no means restricted to the current COVID-19 crisis. For example, influenza regularly poses strains on hospital capacity during annual winter epidemics. In addition, increased influenza-related cardiovascular events may put an even higher pressure on hospital capacity. For the coming years, it is to be anticipated that epidemics of respiratory infections, influenza-and coronavirus alike, will coincide during winter seasons 25 . Therefore, maximal control of these seasonal epidemics is crucial to avoid hospital capacity overload. Optimization of influenza vaccination represents one measure to achieve such maximal control. In the present study, we demonstrate that a relevant improvement of influenza vaccination among older adults in the Netherlands can be achieved by switching from the current QIV-SD to QIV-HD. Indeed, based on the 2019/20 influenza season, we estimate that such a switch could avert an additional 220 cardio-respiratory hospitalizations annually, corresponding to almost €1.22 million in terms of cost savings in hospitals. This demonstrates that not only a significant reduction in pressure on hospital capacity can be achieved, but that a switch from QIV-SD to QIV-HD comes with notable cost savings as well. The significance of our results is further illustrated by comparing the 71 respiratory hospitalizations avoided in this analysis with previously published results 2 , where it was estimated that switching from TIV to QIV (i.e. SD) could result in 84 avoided respiratory-related hospitalizations. These published results were based on a slightly broader population of those aged 60+ as well as high-risk individuals below 60 years. Notably, these earlier findings gave rise to the switch from TIV to QIV (i.e. SD) in the Netherlands.
As indicated above, the major share of the benefits of the switch from QIV-SD to QIV-HD come from cardiovascular-related hospital admissions (68% of hospitalizations avoided).
This logically derives from our assumption that for every respiratory hospitalization almost two cardiovascular hospitalizations occur 19 . In general, it can be concluded that including J o u r n a l P r e -p r o o f cardiovascular-related hospitalizations in a cost-effectiveness analysis may have a major impact on the favourability of the result than if respiratory-related hospitalizations alone are included.
Against the perspective of a potential resurge of influenza now that COVID-19 control measures are relaxed after two years of lockdowns and social distancing and in view of the recurrent pressure on hospital capacity within the broader context of winter peaks in respiratory infections, including not only influenza but also coronavirus, respiratory syncytial virus and pneumococcal infections, further improvement of the Dutch influenza vaccination programme by a switch to QIV-HD appears not only timely but urgent.