Influenza vaccine outcomes: a meta-analysis revealing morbidity benefits amid low infection prevention

Abstract

Background: The morbidity and mortality associated with influenza viruses are a significant public health challenge. Annual vaccination against circulating influenza strains reduces hospitalisations and increases survival rates but requires a yearly redesign of vaccines against prevalent subtypes. The complex genetics of influenza viruses with high antigenic drift create an ongoing challenge in vaccine development to address dynamic influenza epidemiology. Understanding the evolution of influenza viruses and the vaccine's effectiveness against different types and subtypes is pivotal to designing public health measures against influenza.

Methods: We conducted a systematic review and meta-analysis of 192 705 patients, collecting information on the incidence and severity of the disease. The results of this meta-analysis were further validated using data from 6 594 765 patients from TriNetX. We analysed the prevalence of the most common influenza A virus (IAV) subtypes (H1N1 and H3N2) and influenza B virus (IBV), as well as vaccination effectiveness against them in three age groups, given that age is associated with influenza disease severity.

Results: Our analysis reflects that overall vaccination against H1N1 IAV and IBV is effective in reducing infection and influenza-related complications in children aged <5 years old, individuals between 5 and 65 years old and older adults aged >65 years old. By contrast, while vaccination against H3N2 IAV is effective in protecting against infection in infants <5 years old, it provides reduced protection against infection in older individuals.

Conclusions: Despite higher infection rates, vaccination against H3N2 remains as highly effective as vaccination against H1N1 and IBV in reducing influenza-related morbidity and mortality in all age groups. Detailing vaccine effectiveness in terms of infection protection and disease burden across different age groups is necessary for understanding vaccine impacts in terms of other outcomes, e.g. hospitalisations, mortality and disease severity; for improving vaccine formulations and public awareness; and for enhancing vaccination campaigns to improve coverage and public acceptance.

FIGURE 1

The selection process of the studies included in the meta-analysis and primary data analysis. a) Schematic representation of the selection process, with 119 studies included in the meta-analysis. b) The total number of patients included in this study (n=192 705) and a pie chart of the percentage of studies from each country. c) Number of cases for each virus. These data were used to build the literature dataset. IAV: influenza A virus; IBV: influenza B virus.

FIGURE 2

Prevalence of influenza subtypes and odds ratio (OR) of infection in three age groups. a) Prevalence of influenza A virus subtypes H1N1 and H3N2 and influenza B virus (IBV) in patients <5 years old versus >5 years old, and >65 years old versus <65 years old. Results were obtained by random forest meta-analysis, and each point represents a single study. This analysis was performed using the literature dataset. b) Ln(OR) of infection was calculated for each influenza virus type or subtype. In the top panels, patients >5 years old were used as controls, whereas in the bottom panels, patients <65 years old were used as controls (shaded in panel a). This analysis was performed using the literature dataset. c) Infection Ln(OR) of patients <5 years old versus >5 years old, and patients >65 years old versus <65 years old, both obtained using the TriNetX online tool. The dotted line represents the reference Ln(OR) corresponding to the patients >5 years old (left panel) and <65 years old (right panel). This analysis was performed using the TriNetX dataset. yo: years old.

FIGURE 3

Vaccine effectiveness in preventing infections diagnosed by reverse transcription-PCR. a) Violin plots showing the prevalence (ratio) of influenza A virus (IAV) subtypes H1N1 and H3N2 and influenza B virus (IBV) in vaccinated versus unvaccinated cohorts from the total number of individuals included in the studies used in the meta-analysis cohort across all ages. Each point represents a study. The median (solid lines) and the quartiles (dotted lines) are shown. This analysis was performed using the literature dataset. b) Ln odds ratio (OR) of vaccinated versus unvaccinated cohorts, comparing vaccine effectiveness depending on the three influenza viruses under analysis. This analysis was performed using the literature dataset. c) Ln(OR) of IAV subtypes H1N1 and H3N2 and IBV in vaccinated versus unvaccinated patients in hospitalised cohorts obtained from the TriNetX online tool and the TriNetX dataset. Patients were subdivided into the three indicated ages groups. *: p<0.05; **: p<0.01; ***: p<0.001.

FIGURE 4

Vaccine effectiveness to prevent influenza virus infection-associated mortality obtained from the TriNetX dataset. a) Cumulative odds ratio (OR) of mortality after influenza virus infection (left panel) and cumulative OR of secondary bacterial infection as an outcome in infected patients after vaccination (right panel) versus time post infection. b) Mortality risk ratio (%) in the whole population (left panel) of the TriNetX dataset at different months after infection by different influenza viruses. c) Cumulative risk ratio (%) of mortality during the first year after influenza infection in patients <5 years old. d) Cumulative OR of mortality in influenza A virus (IAV) subtypes H1N1 and H3N2 and influenza B virus (IBV) infected patients after vaccination or no vaccination at different times post infection. e) Cumulative OR of mortality in patients infected with IAV subtypes H1N1 (red) and H3N2 (blue) and IBV (green), comparing subgroups of ages 5–65 years old and >65 years old, comparing mortality OR in vaccinated versus unvaccinated individuals at different times post infection. *: p<0.05; **: p<0.01; ***: p<0.001.

FIGURE 5

Odds ratio of mortality-associated risk factors of patients within the first 3 months after influenza diagnosis divided by influenza A virus (IAV) H1N1 and H3N2 and influenza B virus (IBV) and vaccine effectiveness (%). a) Odds ratio of mortality in unvaccinated and vaccinated patients with influenza who had previously had a certain condition within the indicated group of diseases. Analysis performed using the TriNetX dataset. b) Vaccine effectiveness per influenza type or subtype according to the capacity to prevent mortality in the risk groups mentioned in a. Each dot represents the vaccine effectiveness for each risk group mentioned in a. Error bars represent the 95% CI. *: p<0.05; **: p<0.01; ***: p<0.001.