Association of respiratory infections and the impact of vaccinations on cardiovascular diseases

Abstract

Influenza, pneumococcal, severe acute respiratory syndrome coronavirus 2, and respiratory syncytial virus infections are important causes of high morbidity and mortality in the elderly. Beyond the burden of infectious diseases, they are also associated with several non-infectious complications like cardiovascular events. A growing body of evidence in prospective studies and meta-analyses has shown the impact of influenza and pneumococcal vaccines on types of cardiovascular outcomes in the general population. Influenza vaccination showed a potential benefit for primary and secondary prevention of cardiovascular diseases across all ages. A reduced risk of cardiovascular events for individuals aged 65 years and older was associated with pneumococcal vaccination. Despite scientific evidence on the effectiveness, safety, and benefits of the vaccines and recommendations to vaccinate elderly patients and those with risk factors, vaccination rates remain sub-optimal in this population. Doubts about vaccine necessity or efficacy and concerns about possible adverse events in patients and physicians refer to delayed acceptance. Vaccination campaigns targeting increasing professional recommendations and public perceptions should be implemented in the coming years. The aim of this review paper is to summarize the effect of vaccination in the field of cardiovascular disease to achieve a higher vaccination rate in this patient population.

Graphical Abstract

Open in new tabDownload slide

Introduction

Coronary artery disease remains a leading cause of death worldwide.¹ The hypothesis that influenza may trigger acute cardiovascular events and death was advanced early, when the association between seasonal influenza activity and cardiovascular mortality was first noted.² Subsequent studies revealed a significant association between influenza infection and adverse cardiovascular events, especially in the first 2 weeks after infection.^3–6 Conversely, patients with manifest cardiovascular disease are at increased risk of influenza infection.⁷ Vaccinations against bacterial and viral infections such as pneumococcus, influenza, severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), and, in the near future, respiratory syncytial virus (RSV) are important preventive health care measures in the general population and in patients with cardiovascular diseases. Inflammation plays a central role in atherosclerotic progression from initiation to rupture of atherosclerotic plaques. Although the inflammatory process is multi-factorial, exogenous pathogens, including influenza virus and pneumococcus, may modulate the inflammatory response.⁸ Not least due to the vaccine development during the corona pandemic, research in this area has increased significantly. This review discusses the association of infections with cardiovascular disease and the most relevant immunization strategies that are already available or will come soon.

Mechanisms for adverse cardiovascular events associated with viral respiratory infections

Respiratory infections are often accompanied by fever, hypoxia, and adrenergic activation. In this way, they disrupt homoeostasis and cause an imbalance between oxygen supply and demand, thus indirectly provoking adverse cardiovascular events like type 2 myocardial infarctions (MIs).⁹ Additionally, exuberant pro-inflammatory cytokine release and hypercoagulability may lead to endothelial dysfunction and thromboembolism, and many of the cytokines such as IL-1b, IL-6, or TNFa have been shown to play a pro-atherogenic role.¹⁰ In this pro-inflammatory milieu, infiltration of neutrophils and monocytes into atherosclerotic plaques is enhanced and favours lesion progression, plaque rupture, and consecutive type 1 MI.^11,12 Another important mechanism for cardiovascular complications in patients with viral infections is the direct impact of the pathogen on the myocardium. After myocardial infiltration, viral replication even occurs in cardiomyocytes¹³ and thereby provokes myocarditis, ventricular arrhythmia, and heart failure (HF).^14,15

The relation between viral infections and cardiovascular disease also applies vice versa, as macrophages from patients with pre-existent cardiovascular disease actively suppress the induction of helper T cells and thereby attenuate anti-viral immunity.¹⁶ By preventing deleterious and pro-inflammatory complications, the above-mentioned vaccinations are at least indirectly cardioprotective. Interestingly, there is evidence that the influenza vaccine may exert pleiotropic effects by direct atherosclerotic plaque stabilization. In the atherosclerosis ApoE knockout mouse model, influenza-vaccinated mice developed smaller and more stable plaque lesions compared with unvaccinated mice.¹⁷ Additionally, vaccine-induced antibodies were shown to induce vasodilation and natriuresis via activation of the bradykinin 2 receptor.¹⁸Figure 1 summarizes the potential mechanism for adverse cardiovascular events associated with respiratory infections. Further research is needed to explore the direct cardioprotective effects of vaccinations.

Influenza vaccine

Influenza is a widespread virus known for its seasonal infection outbreak and its continuous generation of novel strains by antigen drift and antigen shift with the need to adapt vaccines.²⁰ The severity of infection varies from asymptomatic courses, upper respiratory tract infections associated with fever, and general infectious symptoms to life-threatening respiratory failure, especially in compromised patients.²¹ Actually, there are inactivated, live attenuated, and recombinant haemagglutinin vaccines licensed for disease prevention in trivalent or quadrivalent composition whose approval differs between patient groups and countries.²¹

Recently, Fröbert et al.²² called the influenza vaccination as ideal to prevent cardiovascular disease. Infection with influenza is associated with increased risk for patients with acute and chronic heart diseases, from which strong recommendations for vaccination were generated.²³

Influenza vaccination in heart failure

Data from the PARADIGM-HF trial suggest a lower risk for death in patients with a left ventricular ejection fraction ≤ 40%,²⁴ according to results from a large cohort of patients with acute HF.²⁵ Two recently published observational studies focusing on HF patients during influenza season revealed reduced all-cause mortality in vaccinated individuals [hazard ratio (HR) 0.66 and 0.77, respectively],^26,27 which was in agreement with the results of a large meta-analysis from six cohort studies evaluating 179 158 patients with HF published in 2020²⁸ and again in a meta-analysis of clinical trial studies including on a total of 9059 patients.²⁹ In the prospective, observational cohort study of Mefford et al.²⁶ 74 840 patients were included and 1:1 matched on age, sex, and ejection fraction at vaccination date. Amongst vaccinated patients with HF, the average rate of all-cause mortality during all influenza season was 119.1/1000 person-years, whereas rates amongst unvaccinated patients with HF were consistently higher with an average rate of all-cause mortality of 177.8/1000 person-years. However, no clear evidence was observed for the benefit of preventing mortality due to cardiovascular events and hospitalization.

Influenza vaccination effect on myocardial infarction

The impact of influenza vaccination as a primary and secondary prophylaxis on MI has been evaluated in randomized controlled trials and case-control studies. Data from a case-control study based on a Spanish database were investigated for influenza vaccination as a primary prevention for acute MI. An association between influenza vaccination and reduced incidence of acute MI was detected independently of epidemic periods with a risk reduction between 10% and 15%.³⁰ Results from a case-control study based on the United Kingdom General Practice Research Database generated a risk reduction of 19% for acute MI. However, in this study, vaccination pre-emptively to the winter influenza epidemic showed a greater risk reduction than in the previously mentioned study.³¹ The Influenza Vaccination After Myocardial Infarction (IAMI) trial examined influenza vaccine vs. placebo directly administered after MI (up to 72 h) in a randomized controlled trial focussing on a composite of all-cause death, MI, or stent thrombosis 12 months afterwards as the primary endpoint. Herein, a 28% risk reduction was detected [HR 0.72 (0.52–0.99)] for a primary composite endpoint with an additional 41% risk reduction of all-cause and cardiovascular death but without reduction for MI as key secondary endpoints.³² A consecutively performed comparison between ST-segment elevation MI (STEMI) and non-ST-segment elevation MI (NSTEMI) in the same cohort revealed a reduced all-cause death rate in patient after NSTEMI (HR 0.47 vs. HR 0.86).³² Already in the late 1990s, a case-control study showed a negative association of reoccurring MI (OR 0.33) in the same epidemic season after influenza vaccination.³³ Few years later, the Flu Vaccination Acute Coronary Syndrome (FLUVACS) study conducted as a single-blind randomized control trial compared influenza vaccination vs. placebo in patients with MI or stable coronary artery disease planned for percutaneous coronary intervention. At 6-month and 1-year follow-up, a reduced relative risk (RR) of cardiovascular death (RR 0.25 and 0.34, respectively) and the composite outcome of cardiovascular death, MI, or rehospitalization for ischaemia (RR 0.50 and 0.59, respectively) in influenza vaccinated patients were observed.^34,35 Contradictory, a Polish single-centre, randomized, double-blind, placebo-controlled study only detected beneficial effects against coronary ischaemic event as a secondary endpoint but not cardiovascular death as a primary endpoint. In contrast, not all included patients suffered from an acute myocardial ischaemia but merely a known coronary artery disease.³⁶ In acute coronary syndrome (ACS) patients, influenza vaccination reduced the risk for major adverse cardiovascular events (MACEs), defined as death, hospitalization for ACS or hospitalization for HF (HR 0.70) but not for the incidence of cardiovascular death.³⁷

Influenza vaccination effect on major adverse cardiovascular events

A recently updated meta-analysis included 14 420 patients to compare influenza vaccine vs. placebo. In vaccinated patients, 25% lower-risk MACEs at follow-up (RR 0.75) but no significant difference between concerning all-cause mortality, cardiovascular mortality, or MI were detected.³⁸ Of note, high-dose trivalent inactivated vaccine compared with standard-dose quadrivalent inactivated vaccine did not provide a significant reduction of all-cause mortality or cardiopulmonary hospitalizations in patients after MI or HF.³⁹ Davidson et al.⁴⁰ recently performed a study investigating the effect of influenza vaccination on acute cardiovascular event risk. Individuals aged 40–84 years with a first acute cardiovascular event and influenza vaccination occurring within 12 months of each September were selected from the Clinical Practice Research Datalink. In self-controlled case series analysis, season-adjusted cardiovascular risk stratified incidence ratios for cardiovascular events after vaccination were compared with baseline time before and >120 days after vaccination. In the main analysis, reduced cardiovascular events were seen after vaccination amongst individuals of all age groups and with raised and low cardiovascular risk. Detailed information about the vaccine efficacy (VE) on the occurrence on different cardiovascular events is summarized in Table 1.

The totality of evidence generated by the discussed studies supports the recommendations of the Center of Disease Control and the American College of Cardiology, which clearly recommend vaccination for the prevention of influenza.^59,60 Already in the context of the follow-up of a cardiac event as well as in patients with previous cardiac disease, attention should be paid to adequate vaccination protection, especially at the beginning of the winter epidemic. Improved vaccine uptake could help to reduce the risk of first acute cardiovascular events amongst those already eligible to receive the seasonal influenza vaccine.

Pneumococcal vaccine

Streptococcus pneumoniae has been the leading morbidity and mortality cause in lower respiratory tract infection (LRTI) and responsible for more death cases than all other pathogens.⁶¹ There seems to exist a bidirectional relationship between pneumonia and cardiovascular disease.⁶² On one hand, cardiovascular disease increases the risk of hospitalization for pneumonia,^62,63 but the opposite could also be true. Pneumonia may raise the risk of ACS, stroke, HF, arrhythmias, and even death, acutely or even years after that.^62,64,65 A recent systematic review and meta-analysis showed that community-acquired pneumonia (CAP) significantly increases the odds of developing ACS (OR 3.02), stroke (OR 2.88), mortality (OR 3.22), and all cardiovascular disease events.⁶⁶ The authors concluded that pneumonia should be considered as a new risk factor for cardiovascular complications.

Pneumococcal vaccine types

Two different vaccine types are licensed. The 23-valent polysaccharide-based vaccine (PPSV23) is recommended to prevent pneumococcal disease by many public health agencies for adults ≥ 65 years of age and other high-risk groups. The PPSV23 covers the most common pneumococcal serotypes (1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F), but the immunoresponse is limited to B-cell stimulation and antibody production.⁶⁷ Due to the absence of memory B-cell training, the immunity decreased over the years, especially in the elderly. The second vaccine type, pneumococcal conjugate vaccine (PCV), is more immunogenic and increases the immune response by inducing a memory immunoresponse. Pneumococcal conjugate vaccines contain pneumococcal polysaccharide antigens covalently linked to immunogenic carrier proteins that induce T-cell-dependent humoral immunoresponse and stimulate T cells to help B cells in producing antibodies to vaccine for a better immune memory.⁶⁸ Three types of PCVs are licensed for adults (PCV13, PCV15, and PCV20).

Pneumococcal vaccine development and vaccine efficacy

Amongst participants ≥ 65 years, PCV13 (covering serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) was effective in preventing vaccine-type pneumococcal, bacteraemic, and non-bactaeremic CAP and vaccine-type invasive pneumococcal disease in a large prospective randomized placebo-controlled trial.⁶⁹ Recently published data showed a reduction of invasive pneumococcal disease in elderly and high-risk populations with a lower efficacy of PPSV23 compared with PCV13.⁷⁰ In a prospective multi-centre study conducted in adults aged ≥65 years hospitalized with CAP, the authors evaluated the field effectiveness of PCV13, PPSV23, and sequential vaccination against pneumococcal pneumonia in older adults.⁷¹ A case-control test-negative design was used to estimate VE. Of 1525 cases with CAP hospitalization, 11% were identified as pneumococcal CAP. In the elderly aged patients (>75 years), the adjusted VE was statistically insignificant with 40% for PCV13 and 11% for PPSV23 with high confidence intervals (CIs). However, in the younger subgroup (65–74 years), sequential PCV13/PPSV23 vaccination showed the highest adjusted VE of 80%, followed by single-dose PCV13 with 66% and PPSV23 with 19%. Sequential PCV13/PPSV23 vaccination was most effective for preventing pneumococcal CAP amongst patients aged 65–74 years.

Data collected over the past decade suggest that serotype replacement has reoccurred and that new vaccines will be necessary to prevent pneumococcal disease caused by emergent serotypes, such as 8, 12F, and 22F.^72,73 In light of this increase in the prevalence of non-vaccinal serotypes, the new PCV15 (covering the additional serotypes: 22F and 33F) and PCV20 (covering the additional serotypes: 8, 10A, 11A, 12F, 15B, 22F, and 33F) were developed and have recently been approved for prevention of pneumococcal disease in individuals aged 18 years old and above in Europe and the USA.⁷⁴ The immunogenicity of PCV20 in adults has been established over a number of double-blind^75,76 and open-label⁷⁷ randomized controlled clinical trials. A single dose by intramuscular injection induced robust immune response to all S. pneumoniae serotypes covered by the vaccine.^75,77 The latest Advisory Committee on Immunization Practices recommendations included either PCV20 alone or a sequential vaccination with PCV15 and PPSV23 in selected adults (based on age and risk factors). A 24-valent PCV including four more serotypes and V114 and a 15-valent PCV containing all 13 serotypes of PCV13 and additional serotypes 22F and 33F are under development.

Pneumococcal vaccination effect on cardiovascular disease

The impact of pneumococcal vaccine on cardiovascular disease was evaluated in one meta-analysis and one study.^41,50 Marra et al.⁴⁵ evaluated the efficacy of the polysaccharide vaccine PPSV23 in cardiovascular disease across all ages in a meta-analysis from 18 studies with a total of 716 108 participants. The PPSV23 significantly decreased the risk of cardiovascular disease events for individuals aged 65 years and older. During seasons with good influenza effectiveness, PPSV23 prevented acute exacerbations of chronic heart disease. Focused on MI, Marra et al. showed a modest risk reduction in MI following pneumococcal vaccination in patients ≥ 65 years.

Pneumococcal vaccination effect on ischaemic heart disease

The impact of pneumococcal vaccines on the occurrence of ischaemic heart disease was evaluated in one prospective study.⁵⁰ Patients vaccinated by PPSV23 and influenza experienced fewer deaths (HR 0.65; 95% CI 0.55–0.77; P < 0.001) and fewer cases of pneumonia (HR 0.57; 95% CI 0.51–0.64; P < 0.001), ischaemic stroke (HR 0.67; 95% CI 0.54–0.83; P < 0.001), and acute MI (HR 0.52; 95% CI 0.38–0.71; P < 0.001), compared with unvaccinated subjects. A significant reduction of ischaemic heart disease in patients who received PPSV23 alone compared with the unvaccinated group was not seen.

Pneumococcal vaccination effect on congestive heart failure

The impact of pneumococcal vaccination in preventing from hospitalization for congestive HF (CHF) was evaluated in three studies.^50,55,57 In a study from Taiwan, patients who received a combination vaccination with PPSV and influenza vaccine had a significant risk decrease of CHF compared with the patients receiving the influenza vaccine alone.⁵⁵ Each study group contained 8142 subjects. The results indicated that an additive effect of receiving both vaccines was associated with a significantly lower all-cause mortality (RR 0.74; 95% CI 0.57–0.96); hospitalization of all diseases including pneumonia, influenza, chronic obstructive pulmonary disease, respiratory diseases, and congestive heart disease (RR 0.77; 95% CI 0.67–0.90); and a 13% reduction (95% CI 0.81–0.94) in inpatient expenditures of all diseases when compared with receiving influenza vaccine alone. In contrast, no difference in the incidence of hospital admissions was found in the study of Hedlund et al.⁵⁷ Furthermore, in Hung et al.,⁵⁰ subjects who received pneumococcal vaccination alone had no significant CHF reduction compared with the unvaccinated group. The PPSV23 vaccination showed no significant reduction in the risk of having cerebrovascular disease following vaccination.⁴⁵

The impact of PCV13 on cardiovascular events has not been studied nor has sequential vaccination with PCV13 and PPSV23. Some studies showed that pneumococcal vaccination alone had no significant impact on cardiovascular outcomes.⁵⁰ Receiving the combination of influenza and pneumococcal vaccinations was often associated with positive effects on cardiovascular disease.⁵⁷ This is an important outcome to promote sustainable vaccination programmes. Due to the upcoming new vaccines with more serotypes, further studies on the impact of pneumococcal vaccination on cardiovascular disease are awaited.

Severe acute respiratory syndrome coronavirus 2 vaccine

Cardiovascular involvement after SARS-CoV2 infection was found to be frequent amongst the general population, especially in the pre-vaccination era, and particularly for hospitalized patients or those who experienced a more severe course of the disease. Around 20% of those with hospitalized COVID-19 have biochemical evidence of cardiac injury.⁷⁸ Patients with myocardial injury as a complication of COVID-19 have an increase in mortality.⁷⁹ The exact prevalence of cardiac involvement in SARS-CoV-2 infection is difficult to estimate, owing in part to the heterogeneity of clinical severity of this disease. Figure 2 shows the possible extent on cardiac alteration due to severe COVID-19.

COVID-19 vaccines

By the end of the year 2020, the first COVID-19 vaccines were internationally available. Recommendations vary for immunocompetent and immunocompromised or patients at risk for a severe illness regarding the number of boosters.^81,82 Vaccination coverage varies across the world and even within one continent. A total of nearly 70% of the US population has a complete primary series of three doses.⁸³ The association of vaccination on cardiovascular outcomes following infection has rarely been elucidated.

COVID-19 vaccination effect on major adverse cardiovascular events

Taken from the largest US cohort of patients with SARS-CoV2, Jiang et al.⁸⁴ investigated the association between vaccination and MACE amongst patients with prior SARS-CoV2 infection. The Cox proportional hazards model showed full (adjusted HR 0.59; 95% CI 0.55–0.63) and partial (adjusted HR 0.76; 95% CI 0.65–0.89) vaccination were associated with reduced risk of MACE. The results were concordant with data from the Korean registry⁸⁵ and found out that full vaccination was associated with a decreased risk of MI and ischaemic stroke after COVID-19.

In comparison with the cardiac injury that results from natural infection by SARS-COV2, cardiovascular manifestations after SARS-COV2 vaccination (myocarditis, pericarditis, and unusual thrombotic events) are exceedingly rare events. A syndrome of unusual thrombosis in combination with severe thrombocytopenia, termed vaccine-induced immune thrombotic thrombocytopenia, has been reported after ChAdOx1 nCoV-19 vaccination.⁸⁶ Myocarditis and pericarditis after immunization lead to hospitalizations that are frequently brief and symptoms that often resolve, treated with standard anti-inflammatory therapies. Myocarditis is more often reported after mRNA vaccination.⁸⁷ Overall, the incidence of the reported cardiovascular events is very rare, and the benefits of vaccination far outweigh the risk.

Respiratory syncytial virus

Respiratory syncytial virus is known for causing a wide range of illnesses varying from mild upper respiratory tract infections to severe bronchiolitis and pneumonia in young children, but the appreciation of its impact on older adults is growing. Infection with RSV is under-recognized by health care providers that treat adults. Most studies of respiratory viral illness in adults with cardiovascular disease have focused on influenza, but there is growing evidence that other respiratory viruses, particularly RSV, are also significant.⁸⁸ A meta-analysis evaluating the disease burden of RSV-acute respiratory infections (ARIs) worldwide found a global hospital admissions rate of 336 000 hospitalizations (uncertainty range 186 000–614 000) and estimated about 14 000 in-hospital deaths related to RSV-ARI.⁸⁹ With an annual incidence between 44.2 and 58.9/100 000, in a prospective, population-based, surveillance study to estimate the incidence of RSV hospitalization, RSV-ARI is not a rare viral disease.⁹⁰

Respiratory syncytial virus in patients with cardiopulmonary disease

Patients with underlying cardiopulmonary disease appear to be at increased risk of symptomatic RSV infection with increased morbidity.⁹¹ Modelling studies of older adults with high-risk cardiac and pulmonary conditions have shown greater hospitalization rates for circulatory and respiratory diagnosis due to RSV compared to those with no risk factors.^92,93 Studies suggest that there is an increased risk of symptomatic illness and hospitalization due to RSV in adults with pre-existing cardiac disease.^94,95 In addition to cardiovascular disease in general, underlying coronary artery disease and development of coronary HF affected by RSV were also reported.⁹⁶ Preceding respiratory viral infections have been reported to predispose to myocardial injury for many years. A case series in the UK demonstrated the higher risk of first and recurrent MI and stroke in patients after recent symptoms of respiratory tract infection when compared with asymptomatic periods.⁹⁷ Like other viral and bacterial pathogens, RSV infection has been proposed to be associated with the development of atherosclerosis and increased risk of MI.

Respiratory syncytial virus vaccination

Given that an increased risk of cardiovascular outcomes has been seen with RSV, the application of an effective vaccine against RSV could potentially have similar implications for reducing the risk of cardiovascular complications in older or at-risk individuals. The urgent need for safe and effective preventive therapies has led to the development of several vaccine candidates. The RSV genome encodes 11 proteins; two play a key role for pathogenesis and are important antigens for generating protective immunity. Glycoprotein G is responsible for viral attachment, and the fusion protein F mediates for viral penetration and syncytium formation. Two different subtypes of RSV A and B are circulating concurrently. They are distinguished mainly by the variations in the G protein.⁹⁸ Most RSV vaccine candidates target the RSV F glycoprotein, which mediates viral fusion and host-cell entry, elicits neutralizing antibodies, and is highly conserved across the two RSV subtypes (A and B).^99,100

RSVPreF3-adjuvanted protein-based vaccine

The recently approved vaccine candidate RSVPreF3 contains recombinant glycoprotein F stabilized in the prefusion conformation. RSVPreF3 was approved by the US Food and Drug Administration (FDA) in May 2023 for the prevention of LRTI caused by RSV in individuals 60 years of age and older. In June 2023, the European Commission authorized the vaccine for active immunization for the prevention of LRTD caused by RSV in adults aged 60 years and older. A randomized, placebo-controlled, phase III trial (AReSVi-006 trial) investigates the efficacy of a single dose of RSVPreF3-adjuvanted vaccine over 3 years and following an annual revaccination schedule in adults aged 60 years and above.¹⁰¹ The study is ongoing and approximately 25 000 participants from 17 countries were enrolled. RSVPreF3 showed consistently high VE, also observed across a range of pre-specified secondary endpoints, highlighting the impact the vaccine candidate could have on the populations most at risk of the severe outcomes of RSV. In the trial, the vaccine showed a statistically significant overall efficacy of 82.6% against RSV-LRTD in adults aged 60 years and older, meeting the primary endpoint. In participants with pre-existing comorbidities, such as underlying cardiorespiratory conditions, VE was 94.6% with 93.8% efficacy observed in adults aged 70–79 years. After the first season, 12 469 participants in the vaccine arm were re-randomized to receive either the RSV vaccine or placebo and were followed up for the occurrence of RSV-LRTD. Vaccine efficacy of a single dose is efficacious against RSV-LRTD and severe LRTD over two full RSV seasons.¹⁰²

RSV.preF protein-based vaccine

A second vaccine candidate, recently approved by the European Commission, is RSV.preF. It has the same technology as RSV.preF3 without an adjuvant and is licensed in the USA for people of older age and pregnant woman. The RENOIR pivotal trial for the vaccination of older adults was able to enrol 45 000 people from seven countries. Both primary endpoints were also met for this vaccine.¹⁰³ Patients with ≥2 symptoms in the RSV-LRTI had an efficacy of 66.7%, and with ≥3 symptoms, the efficacy was increased to 85.7%. This good result was seen across all age groups. Most local reactions and systemic events were mild to moderate. Co-administration with a quadrivalent influenza vaccine is possible in both RSV vaccine types.

All RSV ongoing vaccine candidates and study results are shown in Table 2.

Position in the cardiovascular guidelines

Despite evident associations between infectious disease and cardiovascular mortality, the representation and recommendations for vaccinations in the guidelines of the European Society of Cardiology vary considerably (Table 3). For pulmonary hypertension, HF, and acute and chronic coronary syndromes as well as hypertrophic cardiomyopathy and congenital heart disease, guideline recommendations are present. This is not the case for the guidelines of peripheral arterial disease, diabetes mellitus, hypertension, and dyslipidaemia. This is understandable, as guidelines can only reflect the evidence that has been generated in controlled clinical trials in the respective conditions. As reflected by guidelines, there is a need for doing studies in populations of a broad spectrum of cardiovascular diseases, where recommendations are lacking. It is clear that in conditions such as peripheral artery disease, arterial hypertension, diabetes mellitus, and dyslipidaemia, the event rate is low and guideline-relevant studies need to incorporate a large number of patients. However, these conditions pave the way to acute complications and more severe conditions, such as ACSs and HF with all associated comorbidities, resulting in a high rate of morbidity and mortality. As the pathophysiological mechanisms are applicable not only in coronary artery disease but also in arterial hypertension, diabetes, and dyslipidaemia with a high rate of invisible vascular diseases, these conditions should be taken into consideration in the future clinical trials. Furthermore, a complete coverage of cardiovascular diseases with data concerning vaccination would allow an increase of visibility and awareness for the need of high vaccination rates in populations with a high morbidity load of cardiovascular disease.

Vaccination rates and strategies to vaccinate

Vaccines are regarded as one of the most effective preventative measures in modern medicine. Vaccination rates in patients with cardiovascular disease are far behind the recommended strategies. In an investigation of the Central Institute for Statutory Health Insurance Physicians in Germany 2020, vaccination rates against influenza of patients with chronic HF were below 40%. One cross-sectional study from the USA showed a slight increase in influenza vaccination during and after the COVID-19 pandemic in the adult population from 41% to 47%.¹¹⁵ Kpozehouen et al.¹¹⁶ investigated the uptake of influenza and pneumococcal vaccine in patients admitted to hospital with HF and atrial fibrillation in Sydney. Low uptake for pneumococcal vaccination (40–45%) was found. Prevalence of influenza vaccination was lower amongst participants younger than 65 (51–72%) than in older ones (78–96%). Participants 65 years or older and those with comorbidities such as hypertension, chronic obstructive pulmonary disease, and chronic renal impairment were more likely to receive the vaccines. In a study from Italy, around 40% were vaccinated against Influenza.¹¹⁷ A lack of awareness of being in a target group correlated significantly with vaccine refusal or delayed acceptance. Other refusal factors included female gender, being aged 45–54, rural residency, absence of higher education, perceived vaccine unsafe, and having vaccine-opposed acquaintances. Influenza vaccination coverage amongst adults aged ≥19 years in the USA with high-risk conditions was 61.0% during the 2017–18 season and was higher compared with those without (40.8%). During 2010–2018, pneumococcal vaccination coverage (≥1 dose) amongst adults aged 19–64 years at increased risk and adults aged ≥65 years ranged from 18.5% to 24.5% and 59.7% to 69.0%, respectively, representing increases in coverage for both age groups (average annual percentage point increase, adults aged 19–64 years at increased risk: 0.7%; average annual percentage point increase, adults aged ≥65 years: 1.3%).¹¹⁸

Patients and resident doctors often complain about a lack of recommendation, knowledge, misunderstandings, and a too high expense. Official recommendation varies from country to country and sometimes from region to region. The periodic assessment of practice performance could help to evaluate the adherence to the recommended vaccines. It has the advantage of measuring adherence to standards of care, identifying barriers to vaccination, developing strategies for improving vaccination adherence, and optimizing vaccine delivery to targeted patients. In order to improve the vaccination coverage, we need easier tools and a better education to inform and motivate treating physicians.

Conclusion

Cardiac disease has been associated with an increased risk of cardiovascular complications following acute infections, which is reduced in patients who are vaccinated. Vaccines are regarded as one of the most effective preventative measures in modern medicine. The combination of pneumococcal and influenza vaccination had an additive effect. All patients with cardiovascular disease should be vaccinated against influenza, pneumococcus, COVID-19, RSV, pertussis, and herpes zoster. Vaccination campaigns targeting increasing professional recommendations and public perceptions should be implemented in the coming years.

Authors’ conclusions and implications for practice

• Infectious disease prevention through immunization is a cornerstone prophylactic measure of cardiovascular events and death.

• Expert opinion: In addition to standard vaccinations, all patients with cardiovascular disease should be vaccinated by the following:

  • High-dose or adjuvanted quadrivalent influenza vaccine yearly

  • A single-dose PCV20

  • Basic immunization and booster against SARS-CoV2 by mRNA vaccines

  • A single-dose protein-based RSV vaccine

• Awareness of vaccinations should be improved in cardiologists and patients with cardiovascular disease.

Acknowledgements

M.B. is supported by the Deutsche Forschungsgemeinschaft (SFB TTR 219, S-01).

Authors contribution

J.R., M.B., and T.W. were responsible for the literature research and the selection of the manuscripts included in the review. J.R., M.B., and T.W. contributed to the conception or design of the work. All authors contributed to the acquisition, analysis, or interpretation of data for the work. J.R., M.T., C.A.H., and F.B. drafted the manuscript and created the graphics and figures. M.B. and T.W. critically revised the manuscript. All authors gave final approval and agree to be accountable for all aspects of work ensuring integrity and accuracy.

Funding

J.R. reports support from GlaxoSmithKline (GSK), Merck Sharp & Dohme (MSD), and Pfizer. M.B. reports support from AstraZeneca, Bayer, Boehringer-Ingelheim, Medtronic, Novartis, ReCor Medical, Servier, and Vifor Pharma. T.W. reports support from Germany Ministry of Research and Education, Bavarian Nordic, Janssen Pharmaceuticals, GSK, MSD, and Pfizer. C.A.H., M.T., and F.B. have nothing to declare.

Data availability

Data available on request from the authors.

References

Author notes