Effectiveness of MF59™-adjuvanted subunit influenza vaccine in preventing hospitalisations for cardiovascular disease, cerebrovascular disease and pneumonia in the elderly

doi:10.1016/j.vaccine.2007.08.039

Vaccine

Volume 25, Issue 42, 16 October 2007, Pages 7313-7321

https://doi.org/10.1016/j.vaccine.2007.08.039 Get rights and content

Abstract

Annual circulation of influenza virus coincides with a peak in cardiovascular and pneumonia mortality/morbidity. This study aimed to determine the effectiveness of MF59™-adjuvanted subunit influenza vaccine in preventing hospitalisation due to acute coronary syndrome (ACS), cerebrovascular accident (CVA) and pneumonia in the elderly. Three case–control studies were performed during the 2004–2005 influenza season in three health districts in Valencia, Spain (total elderly [>64 years of age] population: n = 105,454). Controls were patients admitted for an acute surgical process or trauma within 10 days of case admission. In total, 159 patients were hospitalised for ACS, 148 for CVA and 242 for pneumonia. The risk of hospitalisation after the start of the influenza season was significantly lower in vaccinated patients compared with non-vaccinated patients (adjusted odds ratios: 0.13 [P = 0.013] for ACS; 0.07 [P = 0.007] for CVA; 0.31 [P = 0.005] for pneumonia). During peak virus circulation, vaccination with MF59™-adjuvanted subunit influenza vaccine was associated with an 87% relative risk reduction in hospitalisation for ACS, 93% for CVA, and 69% for pneumonia.

Introduction

Annual circulation of the influenza virus coincides with a significant seasonal increase in morbidity and mortality, resulting from both the symptoms of influenza itself and from other associated illnesses. For example, one study has estimated a rate of 115 hospitalisations per 100,000 person-years for circulatory and respiratory illness associated with influenza [1]. This rate rose dramatically with age, ranging from 230 in patients aged 65–69 years to 1669 in the ≥85 years of age group. Other studies have shown that mortality from ischaemic heart disease, acute myocardial infarction, cerebrovascular disease, diabetes, cardiorespiratory disease and chronic obstructive pulmonary disease (COPD) was associated with influenza [2], [3], [4]. Again, mortality was substantially higher in the elderly [2], [4]. Such observations have led some authors to suggest that influenza is the singular cause of the increase in seasonal morbidity and mortality [2].

Despite the elderly being at increased risk of developing influenza-related complications, a considerable percentage remains unvaccinated [5], and the effectiveness of conventional influenza vaccines is substantially lower in this age group compared with young adults [6]. Furthermore, the ability to mount an effective immune response against infection gradually wanes with age [7]. Adjuvanted influenza vaccines are currently being developed, which aim to improve the effectiveness of influenza vaccines in the elderly.

MF59™, a novel adjuvant, was first approved for human use in 1997 [8]; the MF59™ adjuvant is an oil-in-water emulsion containing the naturally occurring squalene oil, and as such, is a biodegradable and biocompatible adjuvant [8]. It is thought to act by recruiting and activating antigen-presenting cells at the injection site, thus increasing their capacity to capture, transport and process the co-administered antigens [9]. To date, more than 23 million doses of the MF59™-adjuvanted subunit influenza vaccine have been distributed [9].

Vaccination with MF59™-adjuvanted subunit influenza vaccine results in an enhanced immune response in the elderly and in subjects with underlying chronic disease, compared with a non-adjuvanted vaccine [10], [11]. Furthermore, a heterotypic immune response is observed, demonstrating the vaccine's ability to confer protection against a broader range of influenza virus strains [12], [13], [14]. The MF59™-adjuvanted subunit influenza vaccine has shown higher clinical efficacy compared with conventional vaccines [15] and has been associated with a reduced risk of hospitalisation for pneumonia in non-institutionalised elderly subjects [16].

The MF59™-adjuvanted subunit influenza vaccine was used by the public health service of the Valencia Autonomous Region to vaccinate the elderly during the 2004–2005 influenza season. In this study, we have estimated the vaccine's effectiveness in reducing the risk of hospitalisation for acute coronary syndrome (ACS), cerebrovascular accident (CVA) and pneumonia associated with the seasonal increase in influenza virus circulation.

Section snippets

Methods

Three case–control studies were performed in the elderly (>64 years of age) population from three health districts in the Valencia Autonomous Region, Spain (total number of elderly residents in these districts: n = 105,454 at 31 December 2004), where MF59™-adjuvanted subunit influenza vaccine was used. Subjects not using the public health service may have been vaccinated with a different influenza vaccine. The risk of hospitalisation for ACS, CVA or pneumonia was evaluated for patients who had

Patients included

During the study period there were 159 hospitalisations for ACS, 148 for CVA and 242 for pneumonia that met the inclusion criteria. After consideration of the exclusion criteria, 144 (90.6%) cases admitted for ACS, 134 (90.5%) for CVA, and 198 (81.8%) for pneumonia were included in the study. The main reasons for exclusion were a lack of consent or suitable controls. Cases were unique for each study.

A total of 75.2% and 78.1% of vaccinated cases and controls, respectively (P = 0.314), were

Discussion

In these case–control studies, receipt of an MF59™-adjuvanted subunit influenza vaccine was associated with a reduced risk of emergency admission for ACS, CVA or pneumonia in the elderly (>64 years of age).

The findings of this study are consistent with other recently published studies regarding influenza vaccine effectiveness in preventing episodes of cardiac arrest, acute myocardial infarction and cerebrovascular accident [25], [26], [27], [28], [29], [30]. Inconclusive results of other

Conclusions

These results suggest that MF59™-adjuvanted influenza vaccination is associated with a significant reduction in the risk of hospitalisation for ACS, CVA and pneumonia during the period of influenza virus circulation. Such results are consistent with the findings of other studies in different populations and influenza seasons. The results are both epidemiologically and biologically plausible, and confirm reports that a relationship may exist between influenza virus infection and the development

References (39)

K.G. Nicholson et al.
Influenza
Lancet
(2003)
G. Gavazzi et al.
Ageing and infection
Lancet Infect Dis
(2002)
A. Podda et al.
MF59: a safe and potent adjuvant for human use
V. Baldo et al.
MF59-adjuvanted influenza vaccine confers superior immunogenicity in adult subjects (18–60 years of age) with chronic diseases who are at risk of post-influenza complications
Vaccine
(2007)
S. De Donato et al.
Safety and immunogenicity of MF59-adjuvanted influenza vaccine in the elderly
Vaccine
(1999)
J. Puig-Barberà et al.
Effectiveness of the MF59-adjuvanted influenza vaccine in preventing emergency admissions for pneumonia in the elderly over 64 years of age
Vaccine
(2004)
O.S. Miettinen
The “case–control” study: valid selection of subjects
J Chronic Dis
(1985)
D.H. Spodick et al.
Association of acute respiratory symptoms with onset of acute myocardial infarction: prospective investigation of 150 consecutive patients and matched control patients
Am J Cardiol
(1984)
W.W. Thompson et al.
Influenza-associated hospitalizations in the United States
JAMA
(2004)
T.A. Reichert et al.
Influenza and the winter increase in mortality in the United States, 1959–1999
Am J Epidemiol
(2004)

M. Madjid et al.

Influenza epidemics and acute respiratory disease activity are associated with a surge in autopsy-confirmed coronary heart disease death: results from 8 years of autopsies in 34892 subjects

Eur Heart J

(2007)

C.-M. Wong et al.

Influenza-associated mortality in Hong Kong

CID

(2004)

M. Kroneman et al.

Influenza vaccination in Europe: an inventory of strategies to reach target populations and optimise vaccination uptake

Euro Surveill

(2003)

O’Hagan DT. New generation vaccine adjuvants. Encyclopedia of Life Science 2007. Available from...

A. Banzhoff et al.

A new MF59-adjuvanted influenza vaccine enhances the immune response in the elderly with chronic diseases: results from an immunogenicity meta-analysis

Gerontology

(2003)

G. Del Giudice et al.

An MF59-adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine

Vaccine

(2006)

Baldo V, Baldovin T, Floreani A, Fragapane E, Trivello R, The Family Medicine Group. Response of influenza vaccines...

A. Iob et al.

Evidence of increased clinical protection of an MF59-adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in Italy

Epidemiol Infect

(2005)

Direcció General de Salut Pública. Conselleria de Sanitat de la Comunidad Valenciana. Red Centinela Sanitaria. Analysis...

Cited by (76)

Evaluating risk of bias using ROBINS-I tool in nonrandomized studies of adjuvanted influenza vaccine
2023, Vaccine
Seasonal variation in influenza vaccine effectiveness (VE) makes real-world evidence (RWE) useful in supplementing the clinical-evidence base from randomized clinical trials. Adjuvanted inactivated influenza vaccine (aIIV) VE has been evaluated in multiple nonrandomized RWE studies. A systematic literature review of RWE studies evaluating the absolute or relative VE of aIIV was conducted. Identified studies were assessed by evaluators for risk of bias (RoB) by means of the ROBINS-I (Reduction of Bias In Non-randomized Studies of Interventions) tool to inform evidence-based medicine deliberations. Differences in evaluator assessments were resolved by consensus. The literature review yielded 14 follow-up studies, seven test-negative case-control (TNCC) studies, five traditional case-control studies, and one cluster-randomized clinical trial. Most follow-up studies and three TNCC studies were judged at low RoB. Issues increasing RoB included inadequate control of confounding, selection of controls, and reliance on recall of vaccination. The concerns identified in any of the designs could be mitigated with straightforward revisions to design or implementation. 17 of 27 nonrandomized studies of adjuvanted influenza-vaccine effectiveness, some from each of four study designs, were judged at low risk of material bias. These studies merit credence in assessing aIIV effectiveness relative to other influenza vaccines.
Association between influenza vaccination and risk of stroke in Alberta, Canada: a population-based study
2022, The Lancet Public Health
Respiratory infection can be an immediate precursor to stroke and myocardial infarction. Influenza vaccination is associated with reduced risk of myocardial infarction and hospitalisation for cardiac disease, and influenza vaccination is strongly recommended for patients with heart disease. Evidence on whether the same protective association exists for stroke, and whether this potential effect is consistent across age and risk groups, is conflicting. We aimed to assess the risk of stroke after influenza vaccination in adults.
We obtained administrative data from the Alberta Health Care Insurance Plan (which covers all residents of Alberta, Canada) beginning on Sept 30, 2009, or May 15 of the year in which residents were recorded as being 18 years of age. Individuals were censored at the earliest of three events: death, recorded outmigration, or Dec 31, 2018. The outcome of interest was any stroke event, comprising acute ischaemic stroke, intracerebral haemorrhage, subarachnoid haemorrhage, and transient ischaemic attack. We used Andersen-Gill Cox models to analyse the hazard of any stroke event for individuals with recent (<182 days) influenza vaccination compared with those without recent influenza vaccination, with adjustment for age, sex, anticoagulant use, atrial fibrillation, chronic obstructive pulmonary disease, diabetes, hypertension, income quintile, and rural or urban home location. Two-way interaction terms between each individual covariate and vaccination status were used to assess for effect modification by risk factor. The association between vaccination and risk of each type of stroke was also modelled, adjusting for baseline covariates.
The study sample consisted of 4 141 209 adults (29 687 899 person-years of observation time) registered under the provincial health-care system between Sept 30, 2009, and Dec 31, 2018. 1 769 565 (42·73%) individuals received at least one vaccination during the study period, and 38 126 stroke events were recorded. Adjusted for demographics and comorbidities, recent influenza vaccination significantly reduced the hazard of stroke (hazard ratio 0·775 [95% CI 0·757–0·793]). This association persisted across all stroke types. We found effect modification by each covariate examined except for home location; however, vaccination was associated with a reduced risk of stroke overall across all ages and risk profiles with the exception of individuals without hypertension.
The risk of stroke is reduced among people who have recently been vaccinated against influenza compared with those who have not. This association extended to the entire adult population and was not limited to individuals with a baseline high risk of stroke. Further studies in a variety of settings are needed to evaluate whether influenza vaccination could be used as a public health strategy to prevent stroke.
None.
Safety of vaccines used for routine immunization in the United States: An updated systematic review and meta-analysis
2021, Vaccine
Understanding the safety of vaccines is critical to inform decisions about vaccination. Our objective was to conduct a systematic review of the safety of vaccines recommended for children, adults, and pregnant women in the United States.
We searched the literature in November 2020 to update a 2014 Agency for Healthcare Research and Quality review by integrating newly available data. Studies of vaccines that used a comparator and reported the presence or absence of key adverse events were eligible. Adhering to Evidence-based Practice Center methodology, we assessed the strength of evidence (SoE) for all evidence statements. The systematic review is registered in PROSPERO (CRD42020180089).
Of 56,603 reviewed citations, 338 studies reported in 518 publications met inclusion criteria. For children, SoE was high for no increased risk of autism following measles, mumps, and rubella (MMR) vaccine. SoE was high for increased risk of febrile seizures with MMR. There was no evidence of increased risk of intussusception with rotavirus vaccine at the latest follow-up (moderate SoE), nor of diabetes (high SoE). There was no evidence of increased risk or insufficient evidence for key adverse events for newer vaccines such as 9-valent human papillomavirus and meningococcal B vaccines. For adults, there was no evidence of increased risk (varied SoE) or insufficient evidence for key adverse events for the new adjuvanted inactivated influenza vaccine and recombinant adjuvanted zoster vaccine. We found no evidence of increased risk (varied SoE) for key adverse events among pregnant women following tetanus, diphtheria, and acellular pertussis vaccine, including stillbirth (moderate SoE).
Across a large body of research we found few associations of vaccines and serious key adverse events; however, rare events are challenging to study. Any adverse events should be weighed against the protective benefits that vaccines provide.
Commonly Used Adjuvant Human Vaccines: Advantages and Side Effects
2020, Journal of Allergy and Clinical Immunology: In Practice
Vaccines are a cost-effective and successful means for preventing disease. Routine health vaccine administration begins in early childhood and extends into the elderly; however, there is evidence to suggest that the immunologic and protective response to vaccination is less potent in older individuals. In recent years, newer adjuvant vaccines have been developed to improve humoral and cell-mediated immune response after vaccination. Despite the use of adjuvants in vaccines for many decades, there is limited teaching in postgraduate medical education regarding the adjuvants found in human vaccines. We summarize the current literature cited in PubMed from January 1980 to December 2019. Studies examined included those supporting the use of adjuvants in human vaccines, the mechanisms via which they enhance the immunologic response, and the reported side effects that are associated with the use of adjuvant vaccines. Overall, the data show that newer adjuvant vaccines lead to improved humoral and cell-mediated immunity against infections in populations, including those with decreased response to typical vaccines without adjuvants. Side effects related to adjuvants in vaccines were reported. Research aimed at improving vaccine effectiveness and minimizing side effects continues to be underway.
Effects of influenza vaccination on the risk of cardiovascular and respiratory diseases and all-cause mortality
2020, Ageing Research Reviews
Influenza vaccination is a simple strategy recommended for the prevention of influenza infection and its complications. This meta-analysis aimed to provide current supportive evidence for the breadth and validity of the observed protective effects of influenza vaccination on cardiovascular and respiratory adverse outcomes and all-cause mortality in older adults and in general adult population.
We searched PubMed, Embase, Web of Science, and the Cochrane Library to identify all published studies comparing influenza vaccination with placebo from the database inception to November 11, 2018. These included studies reporting the associations of influenza vaccination with the risk of aforementioned adverse outcomes.
The pooled adjusted relative risks among influenza-vaccinated people relative to unvaccinated people for the outcomes of interest were 0.74 (95 % confidence interval [CI] = 0.70−0.78) for cardiovascular diseases (63 studies), 0.82 (95 % CI = 0.75−0.91) for respiratory diseases (29 studies), and 0.57 (95 % CI = 0.51−0.63) for all-cause mortality (43 studies). We performed subgroup analysis of age, sex, and region/country and found that these protective effects were evident in the general adult population and particularly robust in older adults and in those with pre-existing specific diseases.
Influenza vaccine is associated with a significant risk reduction of cardiovascular and respiratory adverse outcomes as well as all-cause mortality. Such a preventative measure can benefit the general population as well as those in old age and with pre-existing specific diseases.
Influenza vaccination as a novel means of preventing coronary heart disease: Effectiveness in older adults
2020, Vaccine
Atherosclerosis can have various etiologies, including several newly recognized immunoinflammatory mechanisms. A growing body of evidence suggests that influenza infection is chronologically linked to acute myocardial infarction (AMI), and thus that the virus is a novel cardiovascular disease (CVD) risk factor. Morbidity and mortality rates for both influenza infection and AMI rise markedly with age. Epidemiological studies have demonstrated that influenza vaccination (IV) has a cardioprotective effect, especially in people aged 65 and over; hence, IV may be of value in the management of CVD. These observations justify efforts to better understand the underlying mechanisms and to identify therapeutic targets in older adults.
In view of the above, the objective of the present study was to review the literature data on the cellular mechanisms that link IV to the prevention of atherosclerotic complications. Given the greater burden of CVD in older subjects, we also questioned the impact of aging on this association.
The most widely recognized benefit of IV is the prevention of influenza infection and the latter’s cardiovascular complications. In a new hypothesis, however, an influenza-independent effect is driven by vaccine immunity and modulation of the ongoing immunoinflammatory response in individuals with CVD. Although influenza infection and IV both induce a proinflammatory response, they have opposite effects on the progression of atherosclerosis – suggesting a hormetic phenomenon.
Aging is characterized by chronic inflammation (sometimes referred to as “inflammaging”) that progresses insidiously during the course of aging-related diseases, including CVD. It remains to be determined whether vaccination has an effect on aging-related diseases other than CVD.
Although the studies of this topic had various limitations, the results highlight the potential benefits of vaccination in protecting the health of older adults, and should drive research on the molecular immunology of the response to IV and its correlation with atheroprotective processes.

View all citing articles on Scopus

View full text

Effectiveness of MF59™-adjuvanted subunit influenza vaccine in preventing hospitalisations for cardiovascular disease, cerebrovascular disease and pneumonia in the elderly

Abstract

Introduction

Section snippets

Methods

Patients included

Discussion

Conclusions

Lancet

Lancet Infect Dis

Vaccine

Vaccine

Vaccine

J Chronic Dis

Am J Cardiol

Influenza-associated hospitalizations in the United States

JAMA

Influenza and the winter increase in mortality in the United States, 1959–1999

Am J Epidemiol

Influenza epidemics and acute respiratory disease activity are associated with a surge in autopsy-confirmed coronary heart disease death: results from 8 years of autopsies in 34892 subjects

Eur Heart J

Influenza-associated mortality in Hong Kong

CID

Influenza vaccination in Europe: an inventory of strategies to reach target populations and optimise vaccination uptake

Euro Surveill

A new MF59-adjuvanted influenza vaccine enhances the immune response in the elderly with chronic diseases: results from an immunogenicity meta-analysis

Gerontology

An MF59-adjuvanted inactivated influenza vaccine containing A/Panama/1999 (H3N2) induced broader serological protection against heterovariant influenza virus strain A/Fujian/2002 than a subunit and a split influenza vaccine

Vaccine

Evidence of increased clinical protection of an MF59-adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in Italy

Epidemiol Infect