Variable seasonal influenza vaccine effectiveness across geographical regions, age groups and levels of vaccine antigenic similarity with circulating virus strains: A systematic review and meta-analysis of the evidence from test-negative design studies after the 2009/10 influenza pandemic

Highlights

• Vaccine performed best against A(H1N1)pdm09 & worst against A(H3N2) in all regions.

• Overall, point pooled VE increased from Asia, to Europe, North America, & Oceania.

• Overall, point pooled VE declined with age in the Northern hemisphere.

• Considerably higher pooled VE with antigenically similar versus dissimilar vaccine.

• Consistent patterns in VE across regions, age groups, vaccine antigenic similarity.

Abstract

Background

We examined the influence of some factors on seasonal influenza vaccine effectiveness (VE) from test-negative design (TND) studies.

Methods

We systematically searched for full-text publications of VE against laboratory-confirmed influenza from TND studies in outpatient settings after the 2009/10 influenza pandemic. Two reviewers independently selected and extracted data from the included studies. We calculated pooled adjusted VE across geographical regions, age groups and levels of vaccine antigenic similarity with circulating virus strains, using an inverse variance, random-effects model.

Results

We included 76 full-text articles from 11,931 citations. VE estimates against A(H1N1)pdm09, A(H3N2), influenza B, and all influenza were homogenous and point pooled VE higher in the Southern hemisphere compared with the Northern hemisphere. The difference in pooled VE between the Southern and Northern hemispheres was statistically significant for A(H3N2), influenza B, and all influenza. A consistent pattern was observed in pooled VE across both hemispheres and continents, with the highest point pooled VE being against A(H1N1)pdm09, followed by influenza B, and lowest against A(H3N2). A nearly consistent pattern was observed in pooled VE across age groups in the Northern hemisphere, with pooled VE mostly decreasing with age. Point pooled VE against A(H3N2), influenza B, and all influenza were statistically significantly higher when vaccine was antigenically similar to circulating virus strains compared with when antigenically dissimilar. Similar pattern was observed in the Northern hemisphere, but there was a lack of data from the Southern hemisphere.

Conclusion

Consistent patterns appear to exist in seasonal influenza VE across regions, age groups, and levels of vaccine antigenic similarity with circulating virus strains, with best vaccine performance against A(H1N1)pdm09 and worst against A(H3N2). The evidence highlights the need to consider geographical location, age, and vaccine antigenic similarity with circulating virus strains when designing and evaluating influenza VE studies.

Introduction

Seasonal influenza is characterized by epidemics occurring from around April to September in the Southern hemisphere, and from around October to March in the Northern hemisphere. Vaccination has been an effective strategy for influenza prevention. However, following widespread mitigation measures during the coronavirus disease 2019 (COVID-19) pandemic such as social/physical distancing, influenza activities appeared to be less in the United States of America (USA) and in various countries in the Southern hemisphere [1], although historical data from the USA generally suggests that influenza circulation has been low during the COVID-19 pandemic. It may however mean that a combination of these strategies may be as effective as vaccination. Nevertheless, in terms of practicality of strategies for influenza prevention, vaccination remains the most practical of the strategies and is very effective.

Continuous changes that occur in influenza viruses over time (antigenic drift) [2], however, mean that influenza vaccines have to be re-formulated each influenza season, and can be mismatched with the virus strains in circulation [3]. Similarly, seasonal influenza vaccine effectiveness (VE) may differ across geographical regions depending on the circulating strains. Characteristics of vaccine recipients, such as age, may also impact VE [4]. As such, influenza VE is evaluated each influenza season to assess vaccine performance and forecast the virus strains that are likely to be in circulation in the immediate subsequent season; then, this knowledge is used to inform vaccine development [3], vaccination policy and public health planning.

Due to feasibility and ethical considerations, observational studies are used instead of randomized controlled trials to assess influenza VE. The test-negative design (TND) has become an increasingly popular observational study design for estimating influenza VE [5]. In TND, individuals presenting with acute respiratory or influenza-like illness are tested for influenza; those who test positive become the cases and those who test negative become the controls [6]. VE is then calculated as one minus the adjusted ratio of the odds of vaccination in those that tested positive, to the odds of vaccination in those that tested negative, multiplied by 100. It is suggested that the TND helps to reduce biases due to differential healthcare-seeking behaviour between vaccinated and unvaccinated persons, and differential misclassification of influenza infection status [5]. However, the TND may fail to correct for differential healthcare-seeking behaviour among vaccinated and unvaccinated individuals if stringent methods for study participants’ enrollment and influenza testing are not applied [7].

We undertook a systematic review and meta-analysis to identify, critically appraise and summarize the findings of published TND studies that examined seasonal influenza VE in outpatient (primary care) settings after the 2009/10 influenza pandemic.