A review of evidence for pneumococcal vaccination in adults at increased risk of pneumococcal disease: risk group definitions and optimization of vaccination coverage in the United Kingdom.

INTRODUCTION: Pneumococcal disease (PD) significantly contributes to morbidity and mortality, carrying substantial economic and public health burden. This article is a targeted review of evidence for pneumococcal vaccination in the UK, the definitions of groups at particular risk of PD and vaccine effectiveness. AREAS COVERED: Relevant evidence focusing on UK data from surveillance systems, randomized controlled trials, observational studies and publicly available government documents is collated and reviewed. Selected global data are included where appropriate. EXPERT OPINION: National vaccination programs have reduced the incidence of vaccine-type PD, despite the rising prominence of non-vaccine serotypes in the UK. The introduction of higher-valency conjugate vaccines provides an opportunity to improve protection against PD for adults in risk groups. Several incentives are in place to encourage general practitioners to vaccinate risk groups, but uptake is low-suboptimal particularly among at-risk individuals. Wider awareness and understanding among the public and healthcare professionals may increase vaccination uptake and coverage. National strategies targeting organizational factors are urgently needed to achieve optimal access to vaccines. Finally, identifying new risk factors and approaches to risk assessment for PD are crucial to ensure those at risk of PD can benefit from pneumococcal vaccination.

Estimating the Cost-Effectiveness of Switching to Higher-Valency Pediatric Pneumococcal Conjugate Vaccines in the United Kingdom.

Currently, the 13-valent pneumococcal conjugate vaccine (PCV13) is administered under a 1+1 (1 primary dose) pediatric schedule in the United Kingdom (UK). Higher-valency PCVs, 15-valent PCV (PCV15), or 20-valent PCV (PCV20) might be considered to expand serotype coverage. We evaluated the cost-effectiveness of PCV20 or PCV15 using either a 2+1 (2 primary doses) or 1+1 schedule for pediatric immunization in the UK. Using a dynamic transmission model, we simulated future disease incidence and costs under PCV13 1+1, PCV20 2+1, PCV20 1+1, PCV15 2+1, and PCV15 1+1 schedules from the UK National Health Service perspective. We prospectively estimated disease cases, direct costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratio. Scenario analyses were performed to estimate the impact of model assumptions and parameter uncertainty. Over a five-year period, PCV20 2+1 averted the most disease cases and gained the most additional QALYs. PCV20 2+1 and 1+1 were dominant (cost-saving and more QALYs gained) compared with PCV15 (2+1 or 1+1) and PCV13 1+1. PCV20 2+1 was cost-effective (GBP 8110/QALY) compared with PCV20 1+1. PCV20 was found cost-saving compared with PCV13 1+1, and PCV20 2+1 was cost-effective compared with PCV20 1+1. Policymakers should consider the reduction in disease cases with PCV20, which may offset vaccination costs.

Impact of SARS-CoV-2 infective exacerbation of chronic obstructive pulmonary disease on clinical outcomes in a prospective cohort study of hospitalised adults.

OBJECTIVES: To determine whether acute exacerbations of chronic obstructive pulmonary disease (AECOPD) triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), have worse outcomes than AECOPD caused by other infectious agents or non-infective AECOPD (NI-COPD). DESIGN: A two-hospital prospective cohort study of adults hospitalised with acute respiratory disease. We compared outcomes with AECOPD and a positive test for SARS-CoV-2 (n = 816), AECOPD triggered by other infections (n = 3038) and NI-COPD (n = 994). We used multivariable modelling to adjust for potential confounders and assessed variation by seasons associated with different SARS-CoV-2 variants. SETTING: Bristol UK, August 2020-May 2022. PARTICIPANTS: Adults (≥18 y) hospitalised with AECOPD. MAIN OUTCOME MEASURES: We determined the risk of positive pressure support, longer hospital admission and mortality following hospitalisation with AECOPD due to non-SARS-CoV-2 infection compared with SARS-CoV-2 AECOPD and NI-COPD. RESULTS: Patients with SARS-CoV-2 AECOPD, in comparison to non-SARS-CoV-2 infective AECOPD or NI-COPD, more frequently required positive pressure support (18.5% and 7.5% vs. 11.7%, respectively), longer hospital stays (median [interquartile range, IQR]: 7 [3-15] and 5 [2-10] vs. 4 [2-9] days, respectively) and had higher 30-day mortality (16.9% and 11.1% vs. 5.9%, respectively) (all p < 0.001). In adjusted analyses, SARS-CoV-2 AECOPD was associated with a 55% (95% confidence interval [95% CI]: 24-93), 26% (95% CI: 15-37) and 35% (95% CI: 10-65) increase in the risk of positive pressure support, hospitalisation length and 30-day mortality, respectively, relative to non-SARS-CoV-2 infective AECOPD. The difference in risk remained similar during periods of wild-type, Alpha and Delta SARS-CoV-2 strain dominance, but diminished during Omicron dominance. CONCLUSIONS: SARS-CoV-2-related AECOPD had worse patient outcomes compared with non-SARS-CoV-2 AECOPD or NI-AECOPD, although the difference in risks was less pronounced during Omicron dominance.

Severity of Omicron (B.1.1.529) and Delta (B.1.617.2) SARS-CoV-2 infection among hospitalised adults: A prospective cohort study in Bristol, United Kingdom.

Background: There is an urgent public health need to evaluate disease severity in adults hospitalised with Delta and Omicron SARS-CoV-2 variant infections. However, limited data exist assessing severity of disease in adults hospitalised with Omicron SARS-CoV-2 infections, and to what extent patient-factors, including vaccination, age, frailty and pre-existing disease, affect variant-dependent disease severity. Methods: A prospective cohort study of adults (≥18 years of age) hospitalised with acute lower respiratory tract disease at acute care hospitals in Bristol, UK conducted over 10-months. Delta or Omicron SARS-CoV-2 infection was defined by positive SARS-CoV-2 PCR and variant identification or inferred by dominant circulating variant. We constructed adjusted regression analyses to assess disease severity using three different measures: FiO2 >28% (fraction inspired oxygen), World Health Organization (WHO) outcome score >5 (assessing need for ventilatory support), and hospital length of stay (LOS) >3 days following admission for Omicron or Delta infection. Findings: Independent of other variables, including vaccination, Omicron variant infection in hospitalised adults was associated with lower severity than Delta. Risk reductions were 58%, 67%, and 16% for supplementary oxygen with >28% FiO2 [Relative Risk (RR) = 0.42 (95%CI: 0.34-0.52), P < 0.001], WHO outcome score >5 [RR = 0.33 (95%CI: 0.21-0.50), P < 0.001], and to have had a LOS > 3 days [RR = 0.84 (95%CI: 0.76-0.92), P < 0.001]. Younger age and vaccination with two or three doses were also independently associated with lower COVID-19 severity. Interpretation: We provide reassuring evidence that Omicron infection results in less serious adverse outcomes than Delta in hospitalised patients. Despite lower severity relative to Delta, Omicron infection still resulted in substantial patient and public health burden and an increased admission rate of older patients with Omicron which counteracts some of the benefit arising from less severe disease. Funding: AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.

Cost-effectiveness of using a 20-valent pneumococcal conjugate vaccine to directly protect adults in England at elevated risk of pneumococcal disease.

OBJECTIVES: Despite the current pneumococcal vaccination program in England for older adults and adults with underlying conditions, disease burden remains high. We evaluated cost-effectiveness of 20-valent pneumococcal conjugate vaccine (PCV20) compared to current pneumococcal recommendations for adults in England. METHODS: Lifetime outcomes/costs of invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP) among adults aged 65-99 years and adults aged 18-64 years with underlying conditions in England were projected using a deterministic cohort model. Vaccination with PCV20 was compared with 23-valent pneumococcal polysaccharide vaccine (PPV23) from the National Health Service perspective. RESULTS: PCV20 was cost saving compared with PPV23 in base case and most sensitivity analyses. In the base case, replacing PPV23 with PCV20 prevented 7,789 and 140,046 cases of IPD and hospitalized CAP, respectively, and 22,199 associated deaths, resulting in incremental gain of 91,375 quality-adjusted life-years (QALYs) and incremental savings of £160M. In probabilistic sensitivity analyses, PCV20 (vs. PPV23) was cost saving in 85% of simulations; incremental cost per QALY was below £30,000 in 99% of simulations. CONCLUSIONS: PCV20 vaccination in adults aged 65-99 years and those aged 18-64 years with underlying comorbidities in England is expected to prevent more hospitalizations, save more lives, and yield lower overall costs than current recommendations for PPV23.

Public health and budgetary impact of 20-valent pneumococcal conjugate vaccine for adults in England.

BACKGROUND: Despite use of 23-valent pneumococcal polysaccharide vaccine (PPV23) in England, disease burden among at-risk adults remains high. We evaluated the public health and budgetary impact of 20-valent pneumococcal conjugate vaccine (PCV20) compared to the current adult pneumococcal vaccination program. METHODS: Five-year outcomes and costs of invasive pneumococcal disease (IPD) and community-acquired pneumonia (CAP) among adults aged 65-99 years and adults aged 18-64 years with underlying conditions in England were projected using a deterministic cohort model. Hypothetical vaccination with PCV20 versus PPV23 was compared from the National Health Service (NHS) perspective. RESULTS: Replacing PPV23 with PCV20 would prevent 785 IPD hospitalizations, 11,751 CAP hospitalizations, and 1,414 deaths over 5 years, and would reduce medical care costs by £48.5 M. With vaccination costs higher by £107.2 M, projected net budgetary impact is £58.7 M. The budgetary impact would be greatest in year 1 (£26.3 M), and would decrease over time (to £1.6 M by year 5). The average budget increase (£11.7 M/year) represents <0.01% of the Department of Health and Social Care total budget and <3% of the vaccine budget. CONCLUSIONS: Use of PCV20 among adults currently eligible for PPV23 in England would substantially reduce the burden of pneumococcal disease, with modest budgetary impact.

Incidence of community acquired lower respiratory tract disease in Bristol, UK during the COVID-19 pandemic: A prospective cohort study.

Background: The emergence of COVID-19 and public health measures implemented to reduce SARS-CoV-2 infections have both affected acute lower respiratory tract disease (aLRTD) epidemiology and incidence trends. The severity of COVID-19 and non-SARS-CoV-2 aLRTD during this period have not been compared in detail. Methods: We conducted a prospective cohort study of adults age ≥18 years admitted to either of two acute care hospitals in Bristol, UK, from August 2020 to November 2021. Patients were included if they presented with signs or symptoms of aLRTD (e.g., cough, pleurisy), or a clinical or radiological aLRTD diagnosis. Findings: 12,557 adult aLRTD hospitalisations occurred: 10,087 were associated with infection (pneumonia or non-pneumonic lower respiratory tract infection [NP-LRTI]), 2161 with no infective cause, with 306 providing a minimal surveillance dataset. Confirmed SARS-CoV-2 infection accounted for 32% (3178/10,087) of respiratory infections. Annual incidences of overall, COVID-19, and non- SARS-CoV-2 pneumonia were 714.1, 264.2, and 449.9, and NP-LRTI were 346.2, 43.8, and 302.4 per 100,000 adults, respectively. Weekly incidence trends in COVID-19 aLRTD showed large surges (median 6.5 [IQR 0.7-10.2] admissions per 100,000 adults per week), while other infective aLRTD events were more stable (median 14.3 [IQR 12.8-16.4] admissions per 100,000 adults per week) as were non-infective aLRTD events (median 4.4 [IQR 3.5-5.5] admissions per 100,000 adults per week). Interpretation: While COVID-19 disease was a large component of total aLRTD during this pandemic period, non- SARS-CoV-2 infection still caused the majority of respiratory infection hospitalisations. COVID-19 disease showed significant temporal fluctuations in frequency, which were less apparent in non-SARS-CoV-2 infection. Despite public health interventions to reduce respiratory infection, disease incidence remains high. Funding: AvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.

A novel approach to estimate the local population denominator to calculate disease incidence for hospital-based health events in England.

While incidence studies based on hospitalisation counts are commonly used for public health decision-making, no standard methodology to define hospitals' catchment population exists. We conducted a review of all published community-acquired pneumonia studies in England indexed in PubMed and assessed methods for determining denominators when calculating incidence in hospital-based surveillance studies. Denominators primarily were derived from census-based population estimates of local geographic boundaries and none attempted to determine denominators based on actual hospital access patterns in the community. We describe a new approach to accurately define population denominators based on historical patient healthcare utilisation data. This offers benefits over the more established methodologies which are dependent on assumptions regarding healthcare-seeking behaviour. Our new approach may be applicable to a wide range of health conditions and provides a framework to more accurately determine hospital catchment. This should increase the accuracy of disease incidence estimates based on hospitalised events, improving information available for public health decision making and service delivery planning.

Hospitalization costs of adult community-acquired pneumonia in England.

OBJECTIVE: Accurate and up-to-date figures of the cost of community-acquired pneumonia (CAP) hospitalization are needed to understand the associated economic burden for public health decision-makers. Recent estimates are lacking, and previously published estimates differ markedly. Our objective was to estimate the current mean cost to the UK National Health Service (NHS) for adult hospitalized CAP. METHODS: All CAP hospitalizations in 2019 for those aged ≥18 years were identified from English Hospital Episode Statistics (HES). Each hospitalization was mapped to the tariff cost paid to the care provider within the NHS, including critical care costs and accounting for length of stay and complexity of the case. Mean hospitalization costs were estimated in total and in individuals with defined underlying comorbidities. RESULTS: A mean cost of £3,904 was estimated for 187,251 CAP admissions providing a total cost of approximately £731 million per annum. The mean cost was £3,402, excluding critical care costs, and £11,654 for critical care episodes in the 4.4% of admissions receiving this care. Groups at high risk of CAP had higher mean costs, ranging from £4,458 for people with diabetes to £5,215 for those with heart disease aged <65 years and £4,356 for those with heart disease to £4,751 for those with liver disease aged >65 years who comprised 74.3% of admissions overall. CONCLUSION: This estimate of the cost of hospitalization for CAP from the total population and in those with certain underlying comorbidities will allow a valid understanding of the cost-benefit of vaccination and evidence-based prioritization of pneumococcal vaccination to those at highest risk.

Community-acquired pneumonia (CAP) is a disease that is most commonly caused in England by the bacterium Streptococcus pneumoniae, which infects patients outside of a hospital. Patients who suffer from CAP often require hospitalization, which incurs a cost to the UK National Health Service (NHS). The goal of this study was to establish the annual cost of hospitalized CAP.The researchers used England's national healthcare database, known as Hospital Episodes Statistics (HES), to select all adults in England who were hospitalized for CAP in 2019. For the 187,251 patients hospitalized, an average cost of £3,904 per person was estimated, amounting to a total cost of £731 million per year to the NHS. Most people admitted to hospital with CAP were at risk for the disease (due to factors such as increased age or presence of another disease) and the cost of treatment for this subgroup was disproportionately larger than that for treatment of patients not at risk. Furthermore, while approximately 5% of patients admitted for CAP received critical care during treatment, the average cost for these patients was over £8,000 higher than for those outside this subsection.The costs of hospitalization reported in this analysis were higher than previously estimated. The researchers highlighted weaknesses in other studies and limitations of the current study which could explain the difference. This work provides up-to-date figures for the cost of treating CAP in hospital in England. Public health decision-makers can use these estimates to determine the cost-benefit of vaccines that can help protect against important causes of CAP, particularly vaccines that target S. pneumoniae.

A review of current data to support decision making for introduction of next generation higher valency pneumococcal conjugate vaccination of immunocompetent older adults in the UK.

INTRODUCTION: The burden of pneumococcal disease in older UK adults remains substantial. Higher valency pneumococcal conjugate vaccines (PCVs) are currently in development with adult formulations for two of these anticipated to become available in 2022. This article collates and reviews relevant candidate data now available that may be used to support cost effectiveness assessments of vaccinating immunocompetent UK adults aged ≥65-years with PCVs. AREAS COVERED: This article uses published data from surveillance systems, randomized controlled trials and observational studies. It focuses on local data from the UK but where these are either limited or not available relevant global data are considered. EXPERT OPINION: The body of relevant data now available suggests the UK is well placed to assess the cost effectiveness of vaccinating immunocompetent ≥65-year olds with new generation higher valency PCVs. Recent contemporary data provide important new and robust insights into the epidemiology of pneumococcal disease in older UK adults and help to address much of the uncertainty and data gaps associated with previous analyses. Using these data to make informed decisions about use of new higher valency PCVs for routine use in older adults will be important for public health in the UK.

Identifying UK travellers at increased risk of developing pneumococcal infection: a novel algorithm.

BACKGROUND: In 2016, the travel subcommittee of the UK Joint Committee on Vaccination and Immunisation (JCVI) recommended that 13-valent PCV (PCV13) could be offered to travellers aged over 65 years, visiting countries without infant PCV immunization programmes. This study aimed to identify, collate and review the available evidence to identify specific countries where UK travellers might be at an increased risk of developing pneumococcal infection. The data were then used to develop an algorithm, which could be used to facilitate implementation of the JCVI recommendation. METHODS: We conducted a systematic search of the published data available for pneumococcal disease, PCV vaccine implementation, coverage data and programme duration by country. The primary data sources used were World Health Organization databases and the International Vaccine Access Centre Vaccine Information and Epidemiology Window-hub database. Based on the algorithm, the countries were classified into 'high overall risk', 'intermediate overall risk' and 'low overall risk' from an adult traveller perspective. This could determine whether PCV13 should be recommended for UK adult travellers. RESULTS: A data search for a total of 228 countries was performed, with risk scores calculated for 188 countries. Overall, 45 countries were classified as 'high overall risk', 86 countries as 'intermediate overall risk', 57 countries as 'low overall risk' and 40 countries as 'unknown'. CONCLUSION: To our knowledge this is the first attempt to categorize the risk to UK adult travellers of contracting pneumococcal infection in each country, globally. These findings could be used by national travel advisory bodies and providers of travel vaccines to identify travellers at increased risk of pneumococcal infection, who could be offered PCV immunization.

Clinical and financial burden of hospitalised community-acquired pneumonia in patients with selected underlying comorbidities in England.

BACKGROUND: Hospitalised pneumonia may have long-term clinical and financial impact in adult patients with underlying comorbidities. METHODS: We conducted a retrospective cohort study using the Hospital Episode Statistics (HES) database to determine the clinical and financial burden over 3 years of hospitalised community-acquired pneumonia (CAP) to England's National Health Service (NHS). Subjects were adults with six underlying comorbidities (chronic heart disease (CHD); chronic kidney disease (CKD); chronic liver disease (CLD); chronic respiratory disease (CRD); diabetes mellitus (DM) and post bone marrow transplant (post-BMT)) with an inpatient admission in 2012/2013. Patients with CAP in 2013/2014 were followed for 3 years and compared with similarly aged, propensity score-matched adults with the same comorbidity without CAP. FINDINGS: The RR of hospital admissions increased after CAP, ranging from 1.08 (95% CI 1.04 to 1.12) for CKD to 1.38 (95% CI 1.35 to 1.40) for CRD. This increase was maintained for at least 2 years. Mean difference in hospital healthcare costs (£) was higher for CAP patients in 2013/2014; ranging from £1115 for DM to £8444 for BMT, and remained higher for 4/6 groups for 2 more years, ranging from £1907 (95% CI £1573 to £2240) for DM to £11 167 (95% CI £10 847 to £11 486) for CRD.) The OR for mortality was significantly higher for at least 3 years after CAP, ranging from 4.76 (95% CI 4.12 to 5.51, p<0.0001) for CLD to 7.50 (95%CI 4.71 to 11.92, p<0.0001) for BMT. INTERPRETATION: For patients with selected underlying comorbidities, healthcare utilisation, costs and mortality increase for at least 3 years after being hospitalised CAP.

Protecting UK adolescents and adults against meningococcal serogroup B disease.

INTRODUCTION: Meningococcal serogroup B disease (MenB) is endemic in the UK and continues to cause the majority of invasive meningococcal disease. Two broadly protective protein-based MenB vaccines are now licensed and available, both with wide age indications. Whilst the UK recently became the first country to routinely vaccinate infants against MenB, a recommendation has not yet been extended to older age groups who can also now benefit from these vaccines. AREAS COVERED: This review summarizes the evidence supporting the rationale for adolescents and adults in the UK to consider MenB vaccination. EXPERT COMMENTARY: Although MenB disease is rare, the UK reports one of the highest annual incidence rates within the European region, with over a third of cases occurring in those aged 10+ years. Overall, the case fatality rate following MenB disease in the UK is 4.2% but can be more than twice as high in teenagers and adults than in infants, and survivors are often left with life-changing disabling sequelae. MenB outbreaks are unpredictable and continue to occur in regions where it is endemic. These outbreaks often affect students attending school or university, with living on a campus being an important risk factor. Concerned individuals in this age group should consider MenB vaccination.

Community-acquired pneumonia in the United Kingdom: a call to action.

Pneumococcal disease has a high burden in adults in the United Kingdom (UK); however, the total burden is underestimated, principally because most cases of community-acquired pneumonia (CAP) are non-invasive. Research into pneumonia receives poor funding relative to its disease burden (global mortality, disability-adjusted life years, and years lived with disability), ranking just 20 out of 25 for investment in infectious diseases in the UK. The current accuracy of data for establishing incidence rates is questionable, and it is a reflection of the paucity of research that much of the background information available derives from nearly 30 years ago. Given the relationship between CAP and mortality (pneumonia accounts for 29,000 deaths per annum in the UK, and 5-15% of patients hospitalised with CAP die within 30 days of admission), and the increasing threat of antimicrobial resistance associated with inappropriate antibiotic prescribing, such neglect of a highly prevalent problem is concerning. In this Call to Action, we explore the poorly understood burden of CAP in the UK, discuss the importance of an accurate diagnosis and appropriate treatment, and suggest how national collaboration could improve the management of an often life-threatening, yet potentially preventable disease.