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BackgroundPaediatric pneumococcal conjugate vaccination (PCV) has reduced adult PCV-serotype disease: PCV7 has greater indirect effects than PCV13. Ongoing surveillance is required to evaluate current vaccine usage and inform future vaccine deployment, particularly with respiratory infection epidemiology changing following SARS-CoV-2 emergence.Methods and FindingsA retrospective cohort study, all adults ≥16 years admitted to three UK hospitals, 2006-2022, with pneumococcal disease. Medical records were reviewed for each clinical episode and serotype data were obtained from the UK Health Security Agency national reference laboratory.We identified 1,501 (40.3%) cases of invasive pneumococcal disease (IPD) with known serotype, 134 (3.6%) IPD cases without serotype data, and 2,084 (56.0%) non-IPD cases, which are typically missed in national surveillance. Disease incidence increased progressively from 2006-2020, followed by a sudden decline after COVID-19 emergence and then a gradual increase to pre-pandemic levels.Paediatric PCV7 introduction reduced adult PCV7 serotype IPD from 29.4% [24.1–35.4] of IPD in 2006-09 to 7.0% [3.7–12.7] in 2021-22. PCV13 introduction also decreased adult vaccine serotype IPD, but considerable residual adult disease remains, causing 34.3% [28.6–40.4] of IPD in 2006-09 and 21.7% [15.5–29.6] 9 in 2021-22, respectively. Serotype replacement diminished the benefits of PCV introduction: PCV20-13 and non-PCV serotypes represented 27.0% [21.9–32.9] and 9.3% [6.3–13.5] of disease in 2006-2009, and 39.5% [31.5–48.2] and 31.8% [24.4–40.2] in 2021-2022, respectively.Serotype shifts have resulted in increasing disease caused by serotype 3 and 8, and the re-emergence of serotype 19F and 19A. These serotype shifts occurred as clinical disease severity changed, and whilst the COVID-19 pandemic disrupted disease severity trends, these have now largely reverted to previous trajectories. Patient age trended upwards and although CURB65 severity decreased there were increased ICU admission rates. Overall, inpatient mortality decreased and hospitalisation duration remained stable.ConclusionsAfter 17 years of PCV use, residual pneumococcal disease due to the vaccine serotypes among hospitalised adults remains. The sharp decline in pneumococcal disease during the COVID-19 pandemic has now reversed, with increasing cases due to vaccine serotypes, especially serotype 3. Around 68.2% of cases in 2022 were potentially covered by the recently licensed 20-valent PCV.

The serial interval of an infectious disease, commonly interpreted as the time between the onset of symptoms in sequentially infected individuals within a chain of transmission, is a key epidemiological quantity involved in estimating the reproduction number. The serial interval is closely related to other key quantities, including the incubation period, the generation interval (the time between sequential infections), and time delays between infection and the observations associated with monitoring an outbreak such as confirmed cases, hospital admissions, and deaths. Estimates of these quantities are often based on small data sets from early contact tracing and are subject to considerable uncertainty, which is especially true for early coronavirus disease 2019 data. In this paper, we estimate these key quantities in the context of coronavirus disease 2019 for the UK, including a meta-analysis of early estimates of the serial interval. We estimate distributions for the serial interval with a mean of 5.9 (95% CI 5.2; 6.7) and SD 4.1 (95% CI 3.8; 4.7) days (empirical distribution), the generation interval with a mean of 4.9 (95% CI 4.2; 5.5) and SD 2.0 (95% CI 0.5; 3.2) days (fitted gamma distribution), and the incubation period with a mean 5.2 (95% CI 4.9; 5.5) and SD 5.5 (95% CI 5.1; 5.9) days (fitted log-normal distribution). We quantify the impact of the uncertainty surrounding the serial interval, generation interval, incubation period, and time delays, on the subsequent estimation of the reproduction number, when pragmatic and more formal approaches are taken. These estimates place empirical bounds on the estimates of most relevant model parameters and are expected to contribute to modeling coronavirus disease 2019 transmission.

ObjectivesWe aimed to evaluate the safety and optimal dose of a novel inactivated whole-virus adjuvanted vaccine against SARS-CoV-2: VLA2001.MethodsWe conducted an open-label, dose-escalation study followed by a double-blind randomized trial using low, medium and high doses of VLA2001 (1:1:1). The primary safety outcome was the frequency and severity of solicited local and systemic reactions within 7 days after vaccination. The primary immunogenicity outcome was the geometric mean titre (GMT) of neutralizing antibodies against SARS-CoV-2 two weeks after the second vaccination. The study is registered as NCT04671017.ResultsBetween December 16, 2020, and June 3, 2021, 153 healthy adults aged 18–55 years were recruited in the UK. Overall, 81.7% of the participants reported a solicited AE, with injection site tenderness (58.2%) and headache (46.4%) being the most frequent. Only 2 participants reported a severe solicited event. Up to day 106, 131 (85.6%) participants had reported any AE. All observed incidents were transient and non-life threatening in nature. Immunogenicity measured at 2 weeks after completion of the two-dose priming schedule, showed significantly higher GMTs of SARS-CoV-2 neutralizing antibody titres in the highest dose group (GMT 545.6; 95% CI: 428.1, 695.4) which were similar to a panel of convalescent sera (GMT 526.9; 95% CI: 336.5, 825.1). Seroconversion rates of neutralizing antibodies were also significantly higher in the high-dose group (>90%) compared to the other dose groups. In the high dose group, antigen-specific IFN-γ expressing T-cells reactive against the S, M and N proteins were observed in 76, 36 and 49%, respectively.ConclusionsVLA2001 was well tolerated in all tested dose groups, and no safety signal of concern was identified. The highest dose group showed statistically significantly stronger immunogenicity with similar tolerability and safety, and was selected for phase 3 clinical development.

Limited data exist assessing severity of disease in adults hospitalised with Omicron SARS-CoV-2 variant infections, and to what extent patient-factors, including vaccination and pre-existing disease, affect variant-dependent disease severity. This prospective cohort study of all adults (≥18 years of age) hospitalised at acute care hospitals in Bristol, UK assessed disease severity using 3 different measures: FiO2 >28%, World Health Organization (WHO) outcome score >5, and hospital length of stay (LOS) >3 days following admission for Omicron or Delta variant infection. Independent of other variables, including vaccination, Omicron variant infection was associated with a statistically lower severity compared to Delta; risk reductions were 58%, 67%, and 16% for FiO2, WHO score, and LOS, respectively. Younger age and vaccination with two or three doses were also independently associated with lower COVID-19 severity. Despite lower severity relative to Delta, Omicron infection still resulted in substantial patient and public health burden following admission.

BackgroundThere 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.MethodsA 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.FindingsIndependent 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),P5 [RR=0·33 (95%CI: 0·21-0·50),P3 days [RR=0·84 (95%CI: 0·76-0·92),PInterpretationWe 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.FundingAvonCAP is an investigator-led project funded under a collaborative agreement by Pfizer.RESEARCH IN CONTEXTEvidence before this studyThe burden of COVID-19 on hospital services is determined by the prevalence and severity of SARS-CoV-2 variants, and modified by individual factors such as age, frailty and vaccination status. Real world data suggest that vaccine effectiveness is lower and may wane faster over time against symptomatic disease with Omicron (B.1.1.529) than with Delta (B.1.617.2) SARS-CoV-2 variant. However, numbers of hospitalisations as a case proportion during the Omicron wave have been considerably lower than previous waves. Several reports have compared the risk of hospitalisation or severe disease based on SARS-CoV-2 variant, some suggesting that Omicron is probably less severe than Delta in vaccinated and unvaccinated individuals.Added value of this studyThis study provides robust data assessing the relative severity of Delta and Omicron SARS-CoV-2 variants in patients admitted to hospital, including the first analysis assessing risk for any positive pressure ventilatory support, as well as risk of supplementary oxygen requirement and extended hospital admission, that may guide resource planning in hospitals. We found evidence that infection with Omicron was associated with a milder clinical course following hospital admission than that caused by Delta and that vaccination was independently associated with lower in-hospital disease severity using these three separate severity measures. Specifically, compared to Delta, Omicron-related hospitalizations were 58%, 67%, and 16% less likely to require high flow oxygen >28% FiO2, positive pressure ventilatory support or more critical care, and to have a hospital stay lasting more than three days, respectively.This study reports the considerable morbidity resulting from Omicron infection, with 18% of Omicron admissions requiring oxygen supplementation FiO2>28%, 6% requiring positive pressure ventilation, 62% needing hospitalization ≥four days, and 4% in-hospital mortality. In determining the reduced requirement of increased oxygen requirement and total positive pressure requirement, including non-invasive ventilation, this analysis should contribute to future hospital care and service planning assessments.Implications of all the available evidenceThe risk of severe outcomes following SARS-CoV-2 infection is substantially lower for Omicron than for Delta, with greater reductions for more severe disease outcomes. Significant variation in risk occurs with age and vaccination status, with older and unvaccinated individuals remaining at particular risk of adverse outcome. These results highlight the importance of maintaining high levels of vaccine coverage in patient groups at risk of severe disease.The impact of lower severity Omicron-related hospitalization must be balanced against increased transmissibility and overall higher numbers of infections with this variant and there remains a substantial patient and public health burden. The increased admission rate of older patients with Omicron counteracts some of the benefit arising from less severe disease. Despite the risk reduction in high level oxygen supplementation requirement and high dependency care with Omicron compared to earlier variants at the individual level, healthcare systems could still be overwhelmed.

RationaleStreptococcus pneumoniaeepidemiology is changing in response to vaccination and some data suggest empyema incidence is increasing. However, differences exist between UK and USA studies. We describe trends in the clinical phenotype of adult pneumococcal pleural infection, including simple parapneumonic effusions (SPE) in the pneumococcal conjugate vaccination (PCV) era.ObjectivesTo determine whether there were differences in pneumococcal disease presentation and severity associated with pleural infection.MethodsA retrospective cohort study, all adults ≥16 years admitted to three large UK hospitals, 2006-2018 with pneumococcal disease. 2477 invasive pneumococcal cases were identified: 459 SPE and 100 pleural infection cases. Medical records were reviewed for each clinical episode. Serotype data were obtained from the UK Health Security Agency national reference laboratory.ResultsIncidence increased over time, including non-PCV-serotype disease. PCV7-serotype disease declined following paediatric PCV7 introduction, but the effect of PCV13 was less apparent as disease caused by the additional six serotypes plateaued with serotypes 1 and 3 causing such parapneumonic effusions from 2011 onwards.Patients with pleural infection had a median survival 468 days (95% CI 340-590), versus 286 days (95% CI 274-335) in those with SPE. Pleural infection associated with frank pus had lower 90-day mortality than pleural infection without pus (0% versus 29%,PP=0.049).ConclusionsPneumococcal infection continues to cause severe disease despite the introduction of PCVs. The predominance of serotype 1 and 3 in this adult UK cohort is in keeping with previous studies in paediatric and non-UK studies. Rising non-PCV serotype disease and limited impact of PCV13 on cases caused by serotypes 1 and 3 offset the reductions in adult pneumococcal parapneumonic effusion disease burden observed following introduction of the childhood PCV7 programme.KEY MESSAGESWhat is already known on this topicThe epidemiology of pneumococcal infection is changing in both adults and children following pneumococcal conjugate vaccine (PCV) introduction, as a result of direct and indirect vaccine effects. Other studies have reported that serotypes 1 and 3 disproportionately cause pneumococcal pleural disease; however, the clinical phenotype of parapneumonic effusions associated with pneumococcal infection in adults following PCV introduction is not well described.What this study addsIn this study which presents the largest cohort of patients with a single-organism pleural infection, we demonstrate an increasing incidence of parapneumonic effusions related toStreptococcus pneumoniaein adults, attributable to serotype 1 and 3 disease, despite the introduction of PCV13 in the UK childhood vaccination programme. Interestingly, our data suggest that pneumococcal pleural infection is associated with improved survival up to one-year compared to patients with pneumococcal simple parapneumonic effusions.How this study might affect research, practice or policyCareful assessment of the need for specialist respiratory and thoracic surgical intervention in the context of increasing incidence of adult parapneumonic effusions related toStreptococcus pneumoniaewill be required, in addition to ongoing monitoring of the effect on serotype distribution and clinical phenotype of current and future vaccines against pneumococcus.

BackgroundThe Omicron variant of SARS-CoV-2 infection poses substantial challenges to public health. In England, “plan B” mitigation measures were introduced in December 2021 including increased home working and face coverings in shops, but stopped short of restrictions on social contacts. The impact of voluntary risk mitigation behaviours on future SARS-CoV-2 burden is unknown.MethodsWe developed a rapid online survey of risk mitigation behaviours during the winter 2021 festive period and deployed in two longitudinal cohort studies in the UK (Avon Longitudinal Study of Parents and Children (ALSPAC) and TwinsUK/Covid Symptom Study (CSS) Biobank) in December 2021. Using an individual-based, probabilistic model of COVID-19 transmission between social contacts with SARS-CoV-2 Omicron variant parameters and realistic vaccine coverage in England, we describe the potential impact of the SARS-CoV-2 Omicron wave in England in terms of the effective reproduction number and cumulative infections, hospital admissions and deaths. Using survey results, we estimated in real-time the impact of voluntary risk mitigation behaviours on the Omicron wave in England, if implemented for the entire epidemic wave.ResultsOver 95% of survey respondents (NALSPAC=2,686 and NTwins=6,155) reported some risk mitigation behaviours, with vaccination and using home testing kits reported most frequently. Less than half of those respondents reported that their behaviour was due to “plan B”. We estimate that without risk mitigation behaviours, the Omicron variant is consistent with an effective reproduction number between 2.5 and 3.5. Due to the reduced vaccine effectiveness against infection with the Omicron variant, our modelled estimates suggest that between 55% and 60% of the English population could be infected during the current wave, translating into between 15,000 and 46,000 cumulative deaths, depending on assumptions about vaccine effectiveness. We estimate that voluntary risk reduction measures could reduce the effective reproduction number to between 1.8 and 2.2 and reduce the cumulative number of deaths by up to 24%.ConclusionsWe conclude that voluntary measures substantially reduce the projected impact of the SARS-CoV-2 Omicron variant, but that voluntary measures alone would be unlikely to completely control transmission.

Throughout the ongoing COVID-19 pandemic, the worldwide transmission and replication of SARS-COV-2, the causative agent of COVID-19 disease, has resulted in the opportunity for multiple mutations to occur that may alter the virus transmission characteristics, the effectiveness of vaccines and the severity of disease upon infection. The Omicron variant (B.1.1.529) was first reported to the WHO by South Africa on 24 November 2021 and was declared a variant of concern by the WHO on 26 November 2021. The variant was first detected in the UK on 27 November 2021 and has since been reported in a number of countries globally where it is frequently associated with rapid increase in cases. Here we present analyses of UK data showing the earliest signatures of the Omicron variant and mathematical modelling that uses the UK data to simulate the potential impact of this variant in the UK. In order to account for the uncertainty in transmission advantage, vaccine escape and severity at the time of writing, we carry out a sensitivity analysis to assess the impact of these variant characteristics on future risk.

Accurate surveillance of the COVID-19 pandemic can be weakened by under-reporting of cases, particularly due to asymptomatic or pre-symptomatic infections, resulting in bias. Quantification of SARS-CoV-2 RNA in wastewater (WW) can be used to infer infection prevalence, but uncertainty in sensitivity and considerable variability has meant that accurate measurement remains elusive. Data from 44 sewage sites in England, covering 31% of the population, shows that SARS-CoV-2 prevalence is estimated to within 1.1% of estimates from representative prevalence surveys (with 95% confidence). Using machine learning and phenomenological models, differences between sampled sites, particularly the WW flow rate, influence prevalence estimation and require careful interpretation. SARS-CoV-2 signals in WW appear 4–5 days earlier in comparison to clinical testing data but are coincident with prevalence surveys suggesting that WW surveillance can be a leading indicator for asymptomatic viral infections. Wastewater-based epidemiology complements and strengthens traditional surveillance, with significant implications for public health.