Vaccination Gives Protection From the Flu And Improves Heart Attack Mortality Risk
Overview
The ongoing debate about the survival benefits of influenza vaccination and the duration of its protective effects is addressed by this study, which employed a self-controlled case series (SCCS) and a matched case-control design. Utilizing data from the National Health Interview Survey (NHIS) and public-use mortality records from 2005 to 2018 in the United States, the research analyzed the impact of influenza vaccination on mortality. The SCCS included participants who received the influenza vaccine within 12 months before the survey and subsequently died within one year post-vaccination. The matched case-control study paired individuals who died during the influenza season with four survivors.
Introduction
Influenza, traditionally recognized as an acute, self-limiting illness, has a significant potential for severe outcomes, including death. Each year, seasonal influenza is associated with a considerable global health burden, resulting in an estimated 294,000 to 518,000 respiratory-related deaths. However, the impact of influenza extends beyond the respiratory system, affecting various extrapulmonary organs and tissues, particularly the cardiovascular system. This connection increases the risk of mortality, especially in vulnerable populations like the elderly. In older adults, influenza often triggers dysregulated immune responses and heightened systemic inflammation, leading to a higher susceptibility to severe complications. It has been reported that around 12% of laboratory-confirmed influenza cases in older adults are linked to significant cardiovascular events, highlighting the substantial risk posed by cardiovascular complications associated with influenza.
Vaccination against influenza has emerged as a key preventive measure, significantly reducing the risk of influenza-related deaths. The benefits of vaccination extend beyond the prevention of influenza virus infection, also reducing the risk of complications involving multiple organ systems. Research has demonstrated a substantial survival benefit associated with influenza vaccination, showing a 39% reduction in all-cause mortality among the general population and a 25% reduction among those with pre-existing cardiovascular conditions. The Centers for Disease Control and Prevention (CDC) in the United States has estimated that influenza vaccination prevents thousands of deaths during influenza seasons, further emphasizing its critical role in public health.
Despite the well-documented advantages, the survival benefit of influenza vaccination remains a topic of debate. The protective effects reported in studies vary, contributing to ongoing skepticism. This skepticism stems from potential biases in observational studies and the selective nature of populations included in clinical trials, particularly concerning all-cause and cardiovascular-related mortality. Additionally, while extensive research has focused on vaccine-induced protection against hospitalization, there is limited evidence on how these survival benefits evolve over time, especially concerning long-term outcomes.
To address these knowledge gaps, this study employs a rigorous research methodology, including the self-controlled case series (SCCS) and matched case-control designs. By leveraging extensive data from the National Health Interview Survey (NHIS) and linked mortality records, the study aims to provide a comprehensive analysis of the survival benefits conferred by influenza vaccination. Specifically, it investigates the impact of vaccination on all-cause and cardiovascular mortality, as well as the temporal changes in these benefits over a one-year period. This approach not only offers insights into the immediate effects of vaccination but also sheds light on its longer-term protective effects, contributing to a more nuanced understanding of the role of influenza vaccination in reducing mortality.
Also read Influenza surveillance: A Review of Data Sources
Methods
Inclusion Criteria:
- Recent Influenza Vaccination: Participants must have received an influenza vaccination within the past 12 months.
- Eligibility for Linked Mortality Data: Individuals included in the study were required to be eligible for the publicly available, linked mortality data.
- Mortality within One Year Post-Vaccination: Participants were included if they died within one year following their influenza vaccination.
Exclusion Criteria:
- Incomplete Vaccination Information: Participants were excluded if they had missing information regarding the year or month of their influenza vaccination.
- Missing Death Data: Participants with incomplete data on the specific quarter of death were also excluded from the analysis.
This rigorous selection process ensured that the study population was well-defined and that the data used for analysis was accurate and reliable.
Analysis
In the SCCS study, a 168-day risk interval was identified, commencing on the 29th day post-influenza vaccination. This interval was divided into six distinct risk periods: Days 29–56 (Weeks 5–8), Days 57–84 (Weeks 9–12), Days 85–112 (Weeks 13–16), Days 113–140 (Weeks 17–20), Days 141–168 (Weeks 21–24), and Days 169–196 (Weeks 25–28). The rationale for selecting Day 29 as the starting point was grounded in the typical timeline for antibody production, which generally occurs 2 to 4 weeks following vaccination. Additionally, this timeframe aligns with the expected duration of influenza vaccine efficacy, typically lasting 6 to 8 months. The control period encompassed the remaining time within the year, excluding the defined risk interval. This time segmentation approach mirrors previous research.
A standard SCCS model, with a predefined end of observation, was utilized, considering death as the primary event of interest, with only one exposure and observation starting at the age of vaccination. Relative incidence (RI) and its 95% confidence interval (CI) were calculated using the SCCS model, adjusting for seasonal effects. Seasons were classified into four categories: spring (March 21st–June 21st), summer (June 22nd–September 22nd), autumn (September 23rd–December 21st), and winter (December 22nd–March 20th of the following year). Stratified analyses explored potential variations in the relationship between influenza vaccination and mortality risk, considering factors such as comorbidities and demographics. Given the study’s duration, spanning over a decade, relative incidences of all-cause mortality following influenza vaccination within a year were calculated based on stratifications by influenza season, vaccine match-mismatch, vaccination coverage, and influenza attack rate. Vaccine effectiveness and the percentage of visits for influenza-like illness were used as indicators of vaccine match-mismatch and influenza attack rate, respectively. These data were sourced from the CDC of the United States, covering the 2004–2005 to 2018–2019 influenza seasons. The likelihood ratio test assessed potential interactions between influenza vaccination and these factors. To ensure robustness, several sensitivity analyses were performed, including the combination of the six risk windows into three intervals and the exclusion of the seasonal effect in the SCCS model. Additionally, a meta-analysis aggregated the RI values calculated from 500 randomizations of the month of death within specific quarters, and a separate SCCS model was created for mortality due to accidents.
In the matched case-control study, four controls were randomly matched for each case, based on variables such as age, survey year, sex, region, race, and comorbidity index. The comorbidity index was calculated by summing scores from 10 different diseases, with specific scores assigned to conditions like coronary heart disease, stroke, COPD, arthritis, and others. The scores were categorized into four groups: 0, 1–2, 3–4, and ≥5. Conditional logistic regression models were used to calculate odds ratios for influenza vaccination related to different causes of death. Covariates included various underlying conditions, smoking status, alcohol consumption, emergency room visits in the past year, and self-reported health status, all obtained through a questionnaire.
Data analysis was performed using SAS (version 9.4; SAS Institute Inc., Cary, NC, USA) and RStudio (version 2022.2.1.461; RStudio Team, 2022). The SCCS models were constructed using the “SCCS” R package, with forest plots generated using the “forestplot” and “ggplot2” R packages. Meta-analysis was conducted with the “meta” R package. All statistical tests were two-sided, with a significance threshold of p < 0.05.
Results
In a study involving 1,167 participants who passed away within a year after receiving the influenza vaccination between 2005 and 2018, 362 deaths were attributed to cardiovascular diseases, with 311 related to heart disease and 51 to cerebrovascular conditions. The average age of these participants was 74.09 years, and 52.6% were male, while 47.4% were female. A significant proportion (88.2%) of the participants had chronic conditions, such as heart disease, chronic respiratory diseases, or cancer. The median observation period was 288 days. Additionally, 28 participants succumbed to influenza and pneumonia.
The study found that mortality risk was significantly lower following influenza vaccination, particularly between 29 to 56 days post-vaccination. During this period, the relative incidence of all-cause mortality decreased by 81% and cardiovascular mortality by 72%. The protective effect diminished and returned to baseline by 169 to 196 days. Over the period from 29 to 196 days post-vaccination, the influenza vaccine demonstrated a 46% reduction in all-cause mortality and a 43% reduction in cardiovascular mortality.
Further analysis revealed a consistent reduction in heart disease mortality, similar to cardiovascular disease mortality, but no significant protective effect for cerebrovascular mortality was observed. Due to the small sample size, no protective effect against mortality from influenza and pneumonia was detected. Additionally, stratified analyses by influenza season, vaccine effectiveness, vaccination coverage, and influenza-like illness visits showed no significant differences.
Demographics and comorbidities, including prior cardiovascular diseases, did not significantly modify the effect of the vaccine on mortality outcomes. Sensitivity analyses, including removing seasonal effects, dividing the risk interval, and meta-analysis, confirmed the robustness of the primary findings. No association was found between influenza vaccination and mortality due to accidents.
Conclusion
This study highlighted the survival benefits associated with influenza vaccination, particularly emphasizing the duration of its protective effects. Within 29 to 196 days post-vaccination, there was a 46% relative reduction in all-cause mortality and a 43% reduction in cardiovascular mortality, regardless of pre-existing cardiovascular conditions. The most pronounced protection was observed between days 29 to 56 following vaccination, with the protective effect gradually diminishing and returning to baseline by days 169 to 196.
Additionally, the study confirmed the survival advantages during the influenza seasons in which the vaccine was administered, with vaccinated individuals being 26% less likely to die from any cause and 36% less likely to die from cardiovascular diseases compared to those who were not vaccinated.
The evidence supporting the survival benefits of influenza vaccination continues to grow, despite variability in the estimates of its protective impact. For instance, a meta-analysis linked influenza vaccination to a 25% reduction in all-cause mortality and an 18% reduction in cardiovascular mortality among those with pre-existing cardiovascular conditions. In contrast, some studies have reported more significant risk reductions, with up to a 39% decrease in all-cause mortality and a 55% decrease in cardiovascular mortality. However, other studies have not demonstrated a significant protective effect against mortality. For example, a regression discontinuity analysis conducted in England and Wales found no significant difference in hospitalization or mortality risk among individuals with different vaccination statuses at the age of 65.
These differences in outcomes can likely be attributed to variations in study settings, methodologies, and how outcomes were measured across different studies.
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