Our study did not show a statistically significant association between vaccination coverage and nosocomial influenza incidence rate, although the results suggest a protective effect – a 10% increase in vaccination coverage was estimated to correspond to 11% decrease in nosocomial influenza incidence rate (p=0.37). It was also observed that influenza activity in Singapore predominantly followed the Southern Hemisphere influenza seasonal pattern between 2013 and 2018.
Similar studies, interestingly few, show that HCW vaccination coverage is associated with reduced nosocomial influenza incidence(4,5). Our study observed a similar trend, but statistical significance was not reached despite a relatively large number of nosocomial influenza cases. The effect size observed in this study, when measured by proportion of nosocomial influenza (not shown) is similar to that of a study performed in cancer patients(4).
A mismatch in the Northern Hemisphere timing of HCW vaccination and predominantly Southern Hemisphere seasonal peaks in influenza activity in our study may have reduced the effect size observed and contributed to the lack of statistical significance. Furthermore, virulence, vaccine efficacy and the match of vaccine strains vary between influenza seasons and may contribute to significant variation.
Notwithstanding this, the results are encouraging. Firstly, the observed effect size is clinically significant. Secondly, dose-effect relationships were observed in the sensitivity analyses. When non-clinical staff were included in the calculation of vaccine coverage, the association observed was weakened. Decreasing the diagnostic specificity of nosocomial influenza by using less stringent classification thresholds (days from admission to laboratory diagnosis) resulted in a weaker association. This is consistent with a protective effect expected of HCW influenza vaccination on nosocomial influenza.
Singapore is located 1.3˚N and was deemed to have year-round influenza activity and varying peak periods(6,9). WHO had also recommended Singapore to adopt the Northern Hemisphere influenza vaccine formulation(10). In contrast, our hospital-based data from 2013 to 2018 indicated that influenza activity, both nosocomial and community-acquired, predominantly shows southern hemisphere seasonal peaks. A local study concurs, reporting that “severe epidemics were more commonly observed around middle of the year.(9)”
In view of the findings, a Southern Hemisphere vaccination timing should be considered in our hospital, if not nationally. Nevertheless, the seasonal profile of influenza activity may not be stable in the tropics and continued influenza surveillance is needed. Given that tropical countries face year-round influenza activity, selection of vaccine formulation should also be guided by strain coverage. This requires evaluation if differences in vaccine strains are significant enough to prefer one over another. To achieve good coverage of circulating strains, there may even be years where at-risk populations are recommended to be vaccinated with both the Southern and Northern Hemisphere vaccines in the same year, as was the case in 2019(11). Such considerations may influence vaccination timing in some years. However, where there is no such preference between vaccine formulations in a year, our data suggests that a Southern Hemisphere vaccination timing may better match with influenza activity peaks.
The ecological study design has limitations. Potential unmeasured confounders such as improved infection control measures coinciding with improved vaccination uptake may give rise to false associations. Nevertheless, an ecological study is practical and feasible compared to other study designs in assessing the effectiveness of an institutional influenza vaccination program. Particularly, it is challenging to determine an individual patient’s exposure to unvaccinated HCWs.
The study likely underestimates the true incidence of nosocomial incidence. The definition of nosocomial influenza of laboratory diagnosis at seven days or more from admission yields specificity but may underestimate the incidence given that the incubation period is between one to four days. Underestimation may also arise from passive surveillance of laboratory data rather than active sampling of inpatients for influenza. As there was no post-discharge surveillance, infected cases who became symptomatic after discharge may not be detected and contributes to underestimation.
Nevertheless, our study is well-sized with 256 cases over 2,480,010 patient-days. We also analyze monthly nosocomial influenza incidence rates, while other studies often use the annual proportions of nosocomial influenza amongst all influenza diagnosed which may be difficult to interpret and compare(4,5). This study also presents evidence and a perspective from a tropical country with differing influenza seasonal patterns and less certain vaccination timings to match peak influenza activity.