Immunogenicity, safety, and reactogenicity of heterologous COVID-19 primary vaccination incorporating mRNA, viral-vector, and protein-adjuvant vaccines in the UK (Com-COV2): a single-blind, randomised, phase 2, non-inferiority trial.

BACKGROUND: Given the importance of flexible use of different COVID-19 vaccines within the same schedule to facilitate rapid deployment, we studied mixed priming schedules incorporating an adenoviral-vectored vaccine (ChAdOx1 nCoV-19 [ChAd], AstraZeneca), two mRNA vaccines (BNT162b2 [BNT], Pfizer-BioNTech, and mRNA-1273 [m1273], Moderna) and a nanoparticle vaccine containing SARS-CoV-2 spike glycoprotein and Matrix-M adjuvant (NVX-CoV2373 [NVX], Novavax). METHODS: Com-COV2 is a single-blind, randomised, non-inferiority trial in which adults aged 50 years and older, previously immunised with a single dose of ChAd or BNT in the community, were randomly assigned (in random blocks of three and six) within these cohorts in a 1:1:1 ratio to receive a second dose intramuscularly (8-12 weeks after the first dose) with the homologous vaccine, m1273, or NVX. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentrations measured by ELISA in heterologous versus homologous schedules at 28 days after the second dose, with a non-inferiority criterion of the GMR above 0·63 for the one-sided 98·75% CI. The primary analysis was on the per-protocol population, who were seronegative at baseline. Safety analyses were done for all participants who received a dose of study vaccine. The trial is registered with ISRCTN, number 27841311. FINDINGS: Between April 19 and May 14, 2021, 1072 participants were enrolled at a median of 9·4 weeks after receipt of a single dose of ChAd (n=540, 47% female) or BNT (n=532, 40% female). In ChAd-primed participants, geometric mean concentration (GMC) 28 days after a boost of SARS-CoV-2 anti-spike IgG in recipients of ChAd/m1273 (20 114 ELISA laboratory units [ELU]/mL [95% CI 18 160 to 22 279]) and ChAd/NVX (5597 ELU/mL [4756 to 6586]) was non-inferior to that of ChAd/ChAd recipients (1971 ELU/mL [1718 to 2262]) with a GMR of 10·2 (one-sided 98·75% CI 8·4 to ∞) for ChAd/m1273 and 2·8 (2·2 to ∞) for ChAd/NVX, compared with ChAd/ChAd. In BNT-primed participants, non-inferiority was shown for BNT/m1273 (GMC 22 978 ELU/mL [95% CI 20 597 to 25 636]) but not for BNT/NVX (8874 ELU/mL [7391 to 10 654]), compared with BNT/BNT (16 929 ELU/mL [15 025 to 19 075]) with a GMR of 1·3 (one-sided 98·75% CI 1·1 to ∞) for BNT/m1273 and 0·5 (0·4 to ∞) for BNT/NVX, compared with BNT/BNT; however, NVX still induced an 18-fold rise in GMC 28 days after vaccination. There were 15 serious adverse events, none considered related to immunisation. INTERPRETATION: Heterologous second dosing with m1273, but not NVX, increased transient systemic reactogenicity compared with homologous schedules. Multiple vaccines are appropriate to complete primary immunisation following priming with BNT or ChAd, facilitating rapid vaccine deployment globally and supporting recognition of such schedules for vaccine certification. FUNDING: UK Vaccine Task Force, Coalition for Epidemic Preparedness Innovations (CEPI), and National Institute for Health Research. NVX vaccine was supplied for use in the trial by Novavax.

Sustained Declines in Age Group-Specific Rotavirus Infection and Acute Gastroenteritis in Vaccinated and Unvaccinated Individuals During the 5 Years Since Rotavirus Vaccine Introduction in England.

BACKGROUND: The introduction of an oral live-attenuated monovalent rotavirus vaccine (Rotarix®) into the UK infant immunization program in July 2013 was associated with large reductions in laboratory-confirmed rotavirus infections and hospitalizations due to acute gastroenteritis (AGE) within 12 months. Here we report the 5-year impact of the program in England. METHODS: Individuals with laboratory-confirmed rotavirus infections during 2000-2018 and all-cause hospitalizations for AGE during 2007-2018 were identified using national electronic records. Age-specific incidence rate ratios (IRR) and estimated numbers of cases averted in each of the 5 postvaccination years were calculated. RESULTS: There were 206 389 laboratory-confirmed rotavirus infections and 3 657 651 hospitalizations for all-cause AGE. Reductions of 69-83% in laboratory-confirmed rotavirus infections in all age groups and 77-88% in infants aged <1 year in each of the 5 postvaccine years are reported, with 11 386-11 633 cases averted annually. All-cause AGE hospitalizations were reduced by 12-35% across all age-groups and by 25-48% in <1 year-olds in the 5 postvaccine years, with 24 474-49 278 hospitalizations averted annually. There was strong evidence of indirect (herd) protection, with at least 50% and up to 80% of the non-specific end point of all-cause gastroenteritis (AGE) hospitalizations averted being in unvaccinated age-groups, primarily older adults. Seasonal changes include a possible shift from annual to biennial peaks with lower peak incidence and longer seasons. CONCLUSIONS: There were large and sustained declines in both laboratory-confirmed rotavirus infections and AGE hospitalizations across all age groups in each of the 5 years since the introduction of the UK rotavirus program.

Safety and immunogenicity of heterologous versus homologous prime-boost schedules with an adenoviral vectored and mRNA COVID-19 vaccine (Com-COV): a single-blind, randomised, non-inferiority trial.

BACKGROUND: Use of heterologous prime-boost COVID-19 vaccine schedules could facilitate mass COVID-19 immunisation. However, we have previously reported that heterologous schedules incorporating an adenoviral vectored vaccine (ChAdOx1 nCoV-19, AstraZeneca; hereafter referred to as ChAd) and an mRNA vaccine (BNT162b2, Pfizer-BioNTech; hereafter referred to as BNT) at a 4-week interval are more reactogenic than homologous schedules. Here, we report the safety and immunogenicity of heterologous schedules with the ChAd and BNT vaccines. METHODS: Com-COV is a participant-blinded, randomised, non-inferiority trial evaluating vaccine safety, reactogenicity, and immunogenicity. Adults aged 50 years and older with no or well controlled comorbidities and no previous SARS-CoV-2 infection by laboratory confirmation were eligible and were recruited at eight sites across the UK. The majority of eligible participants were enrolled into the general cohort (28-day or 84-day prime-boost intervals), who were randomly assigned (1:1:1:1:1:1:1:1) to receive ChAd/ChAd, ChAd/BNT, BNT/BNT, or BNT/ChAd, administered at either 28-day or 84-day prime-boost intervals. A small subset of eligible participants (n=100) were enrolled into an immunology cohort, who had additional blood tests to evaluate immune responses; these participants were randomly assigned (1:1:1:1) to the four schedules (28-day interval only). Participants were masked to the vaccine received but not to the prime-boost interval. The primary endpoint was the geometric mean ratio (GMR) of serum SARS-CoV-2 anti-spike IgG concentration (measured by ELISA) at 28 days after boost, when comparing ChAd/BNT with ChAd/ChAd, and BNT/ChAd with BNT/BNT. The heterologous schedules were considered non-inferior to the approved homologous schedules if the lower limit of the one-sided 97·5% CI of the GMR of these comparisons was greater than 0·63. The primary analysis was done in the per-protocol population, who were seronegative at baseline. Safety analyses were done among participants receiving at least one dose of a study vaccine. The trial is registered with ISRCTN, 69254139. FINDINGS: Between Feb 11 and Feb 26, 2021, 830 participants were enrolled and randomised, including 463 participants with a 28-day prime-boost interval, for whom results are reported here. The mean age of participants was 57·8 years (SD 4·7), with 212 (46%) female participants and 117 (25%) from ethnic minorities. At day 28 post boost, the geometric mean concentration of SARS-CoV-2 anti-spike IgG in ChAd/BNT recipients (12 906 ELU/mL) was non-inferior to that in ChAd/ChAd recipients (1392 ELU/mL), with a GMR of 9·2 (one-sided 97·5% CI 7·5 to ∞). In participants primed with BNT, we did not show non-inferiority of the heterologous schedule (BNT/ChAd, 7133 ELU/mL) against the homologous schedule (BNT/BNT, 14 080 ELU/mL), with a GMR of 0·51 (one-sided 97·5% CI 0·43 to ∞). Four serious adverse events occurred across all groups, none of which were considered to be related to immunisation. INTERPRETATION: Despite the BNT/ChAd regimen not meeting non-inferiority criteria, the SARS-CoV-2 anti-spike IgG concentrations of both heterologous schedules were higher than that of a licensed vaccine schedule (ChAd/ChAd) with proven efficacy against COVID-19 disease and hospitalisation. Along with the higher immunogenicity of ChAd/BNT compared with ChAD/ChAd, these data support flexibility in the use of heterologous prime-boost vaccination using ChAd and BNT COVID-19 vaccines. FUNDING: UK Vaccine Task Force and National Institute for Health Research.

Seasonal Influenza Vaccination During Pregnancy and the Risk of Major Congenital Malformations in Live-born Infants: A 2010-2016 Historical Cohort Study.

BACKGROUND: Available evidence indicates that seasonal inactivated influenza vaccination during pregnancy protects both the mother and her newborn and is safe. Nevertheless, ongoing safety assessments are important in sustaining vaccine uptake. Few studies have explored safety in relation to major congenital malformations (MCMs), particularly in the first trimester when most organogenesis occurs. METHODS: Anonymized UK primary care data (the Clinical Practice Research Datalink), including a recently developed Pregnancy Register, were used to identify live-born singletons delivered between 2010 and 2016. Maternal influenza vaccination was determined using primary care records and stratified by trimester. Ascertainment of MCMs from infant primary care records was maximized by linkage to hospitalization data and death certificates. The relationship between vaccination and MCMs recorded in the year after delivery and in early childhood was then assessed using multivariable Cox regression. RESULTS: A total of 78 150 live-birth pregnancies were identified: 6872 (8.8%) were vaccinated in the first trimester, 11 678 (14.9%) in the second, and 12 931 (16.5%) in the third. Overall, 5707 live births resulted in an infant with an MCM recorded in the year after delivery and the adjusted hazard ratio when comparing first-trimester vaccination to no vaccination was 1.06 (99% CI, .94-1.19; P = .2). Results were similar for second- and third-trimester vaccination and for analyses considering MCMs recorded beyond the first birthday. CONCLUSIONS: In this large, population-based historical cohort study there was no evidence to suggest that seasonal influenza vaccine was associated with MCMs when given in the first trimester or subsequently in pregnancy.

Seroprevalence of SARS-CoV-2 among Blood Donors and Changes after Introduction of Public Health and Social Measures, London, UK.

We describe results of testing blood donors in London, UK, for severe acute respiratory disease coronavirus 2 (SARS-CoV-2) IgG before and after lockdown measures. Anonymized samples from donors 17-69 years of age were tested using 3 assays: Euroimmun IgG, Abbott IgG, and an immunoglobulin receptor-binding domain assay developed by Public Health England. Seroprevalence increased from 3.0% prelockdown (week 13, beginning March 23, 2020) to 10.4% during lockdown (weeks 15-16) and 12.3% postlockdown (week 18) by the Abbott assay. Estimates were 2.9% prelockdown, 9.9% during lockdown, and 13.0% postlockdown by the Euroimmun assay and 3.5% prelockdown, 11.8% during lockdown, and 14.1% postlockdown by the receptor-binding domain assay. By early May 2020, nearly 1 in 7 donors had evidence of past SARS-CoV-2 infection. Combining results from the Abbott and Euroimmun assays increased seroprevalence by 1.6%, 2.3%, and 0.6% at the 3 timepoints compared with Euroimmun alone, demonstrating the value of using multiple assays.

Safety of live attenuated influenza vaccine (LAIV) in children with moderate to severe asthma.

BACKGROUND: Live attenuated influenza vaccine (LAIV) is recommended for annual influenza vaccination in children from age 2 years. However, some guidelines recommend against its use in children with asthma or recurrent wheeze due to concerns over its potential to induce wheezing. OBJECTIVE: We sought to assess the safety of LAIV in children with moderate to severe asthma, and in preschool children with recurrent wheeze. METHODS: Prospective, multicenter, open-label, phase IV intervention study in 14 specialist UK clinics. LAIV was administered under medical supervision, with follow-up of asthma symptoms 72 hours and 4 weeks late, using validated questionnaires. RESULTS: A total of 478 young people (median, 9.3; range, 2-18 years) with physician-diagnosed asthma or recurrent wheeze were recruited, including 208 (44%) prescribed high-dose inhaled corticosteroids and 122 (31%) with severe asthma. There was no significant change in asthma symptoms in the 4 weeks after administration (median change, 0; P = .26, McNemar test), with no impact of level of baseline asthma control/symptoms in predicting either a worsening of asthma or exacerbation after LAIV using a regression model. A total of 47 subjects (14.7%; 95% CI, 11%-19.1%) reported a severe asthma exacerbation in the 4 weeks after immunization, requiring a short course of systemic corticosteroids; in 4 cases, this occurred within 72 hours of vaccination. No association with asthma severity, baseline lung function, or asthma control was identified. CONCLUSIONS: LAIV appears to be well tolerated in the vast majority of children with asthma or recurrent wheeze, including those whose asthma is categorized as severe or poorly controlled.

Effect of Pneumococcal Conjugate Vaccines on Pneumococcal Meningitis, England and Wales, July 1, 2000-June 30, 2016.

We describe the effects of the 7-valent (PCV7) and 13-valent (PCV13) pneumococcal conjugate vaccines on pneumococcal meningitis in England and Wales during July 1, 2000-June 30, 2016. Overall, 84,473 laboratory-confirmed invasive pneumococcal disease cases, including 4,160 (4.9%) cases with meningitis, occurred. PCV7 implementation in 2006 did not lower overall pneumococcal meningitis incidence because of replacement with non-PCV7-type meningitis incidence. Replacement with PCV13 in 2010, however, led to a 48% reduction in pneumococcal meningitis incidence by 2015-16. The overall case-fatality rate was 17.5%: 10.7% among patients <5 years of age, 17.3% among patients 5-64 years of age, and 31.9% among patients >65 years of age. Serotype 8 was associated with increased odds of death (adjusted odds ratio 2.9, 95% CI 1.8-4.7). In England and Wales, an effect on pneumococcal meningitis was observed only after PCV13 implementation. Further studies are needed to assess pneumococcal meningitis caused by the replacing serotypes.

Do delays in data availability limit the implementation of near real-time vaccine safety surveillance using the Clinical Practice Research Datalink?

PURPOSE: Near real-time vaccine safety surveillance (NRTVSS) using electronic health records has been used to detect timely vaccine safety signals. Trial implementation of NRTVSS using the Clinical Practice Research Datalink (CPRD) has shown that there is limited power to detect safety signals for rare events. Delays in recording outcomes and receiving data influence the power and timeliness to identify a signal. Our work aimed to compare how different sources of delays influence power and expected time to signal to implement NRTVSS using CPRD. METHODS: We studied seasonal influenza vaccine/Guillain-Barré syndrome and performed power and expected time to signal calculations for the 2013-2014/2014-2015 seasons. We used the Poisson-based maximised sequential probability ratio test, which compares observed-to-expected events. For each study season, we obtained an average Guillain-Barré syndrome/seizures age-sex-adjusted rate from the 5 previous seasons and then used this rate to calculate the expected number of events, assuming a 42-day risk-window. Calculations were performed for detecting rate ratios of 1.5 to 10. We compared power and timeliness considering combinations of the presence/absence of delays in recording outcomes and in receiving data. The R-package Sequential was used. RESULTS: In general, there was ≥80% power to detect increases in risk of ≥4 at the end of the season. Assuming absence of delays slightly improved power (a maximum increase of 4%) but did not noticeably reduce time to detect a signal. CONCLUSION: Removing delays in data availability is insufficient to significantly improve the performance of a NRTVSS system using CPRD. Expansion of CPRD data is required. KEY POINTS The Clinical Practice Research Datalink (CPRD) can be used to implement near real-time vaccine safety surveillance, but there is limited power to detect signals for rare outcomes. Delays in recording outcomes and in receiving data might limit power and timeliness of a system. We assessed the influence of these sources of delays to inform data providers of the steps required to improve a system using CPRD data. Removing delays in recording outcomes and receiving data is unlikely to significantly improve the performance of a system using CPRD data. Expansion of the data available is needed.

Effectiveness and impact of a reduced infant schedule of 4CMenB vaccine against group B meningococcal disease in England: a national observational cohort study.

BACKGROUND: In September, 2015, the UK became the first country to introduce the multicomponent group B meningococcal (MenB) vaccine (4CMenB, Bexsero) into a publicly funded national immunisation programme. A reduced two-dose priming schedule was offered to infants at 2 months and 4 months, alongside an opportunistic catch-up for 3 month and 4 month olds. 4CMenB was predicted to protect against 73-88% of MenB strains. We aimed to assess the effectiveness and impact of 4CMenB in vaccine-eligible infants in England. METHODS: Public Health England (PHE) undertakes enhanced surveillance of meningococcal disease through a combination of clinical, public health, and laboratory reporting. Laboratory-confirmed cases of meningococcal disease are followed up with PHE local health protection teams, general practitioners, and hospital clinicians to collect demographic data, vaccination history, clinical presentation, and outcome. For cases diagnosed between Sept 1, 2015, and June 30, 2016, vaccine effectiveness was assessed using the screening method. Impact was assessed by comparing numbers of cases of MenB in vaccine-eligible children to equivalent cohorts in the previous 4 years and to cases in vaccine-ineligible children. FINDINGS: Coverage of 4CMenB in infants eligible for routine vaccination was high, achieving 95·5% for one dose and 88·6% for two doses by 6 months of age. Two-dose vaccine effectiveness was 82·9% (95% CI 24·1-95·2) against all MenB cases, equivalent to a vaccine effectiveness of 94·2% against the highest predicted MenB strain coverage of 88%. Compared with the prevaccine period, there was a 50% incidence rate ratio (IRR) reduction in MenB cases in the vaccine-eligible cohort (37 cases vs average 74 cases; IRR 0·50 [95% CI 0·36-0·71]; p=0·0001), irrespective of the infants' vaccination status or predicted MenB strain coverage. Similar reductions were observed even after adjustment for disease trends in vaccine-eligible and vaccine-ineligible children. INTERPRETATION: The two-dose 4CMenB priming schedule was highly effective in preventing MenB disease in infants. Cases in vaccine-eligible infants halved in the first 10 months of the programme. While ongoing national surveillance will continue to monitor the longer-term impact of the programme, these findings represent a step forward in the battle against meningococcal disease and will help reassure that the vaccine protects against this deadly infection. FUNDING: Public Health England.

Assessing recording delays in general practice records to inform near real-time vaccine safety surveillance using the Clinical Practice Research Datalink (CPRD).

PURPOSE: Near real-time vaccine safety surveillance (NRTVSS) is an option for post-licensure vaccine safety assessment. NRTVSS requires timely recording of outcomes in the database used. Our main objective was to examine recording delays in the Clinical Practice Research Datalink (CPRD) for outcomes of interest for vaccine safety to inform the feasibility of NRTVSS using these data. We also evaluated completeness of recording and further assessed reporting delays for hospitalized events in CPRD. METHODS: We selected Guillain-Barré syndrome (GBS), Bell's palsy (BP), optic neuritis (ON) and febrile seizures (FS), from January 2005 to June 2014. We assessed recording delays (e.g. due to feedback from specialist referral) in stand-alone CPRD by comparing the event and system dates and excluding delays >1 year. We used linked CPRD-hospitalization data to further evaluate delays and completeness of recording in CPRD. RESULTS: Among 51 220 patients for the stand-alone CPRD analysis (GBS: n = 830; BP: n = 12 602; ON: n = 1720; and FS: n = 36 236), most had a record entered within 1 month of the event date (GBS: 73.6%; BP: 93.4%; ON: 76.2%; and FS: 85.6%). A total of 13 482 patients, with a first record in hospital, were included for the analysis of linked data (GBS: n = 678; BP: n = 4060; ON: n = 485; and FS: n = 8321). Of these, <50% had a record in CPRD after 1 year (GBS: 41.3%; BP: 22.1%; ON: 22.4%; and FS: 41.8%). CONCLUSION: This work shows that most diagnoses in CPRD for the conditions examined were recorded with delays of ≤30 days, making NRTVSS possible. The pattern of delays was condition-specific and could be used to adjust for delays in the NRTVSS analysis. Despite low sensitivity of recording, implementing NRTVSS in CPRD is worthwhile and could be carried out, at least on a trial basis, for events of interest. © 2017 The Authors. Pharmacoepidemiology & Drug Safety Published by John Wiley & Sons Ltd.

Near real-time vaccine safety surveillance using electronic health records-a systematic review of the application of statistical methods.

PURPOSE: Pre-licensure studies have limited ability to detect rare adverse events (AEs) to vaccines, requiring timely post-licensure studies. With the increasing availability of electronic health records (EHR) near real-time vaccine safety surveillance using these data has emerged as an option. We reviewed methods currently used to inform development of similar systems for countries considering their introduction. METHODS: Medline, EMBASE and Web of Science were searched, with additional searches of conference abstract books. Questionnaires were sent to organizations worldwide to ascertain unpublished studies. Eligible studies used EHR and regularly assessed pre-specified AE to vaccine(s). Key features of studies were compared descriptively. RESULTS: From 2779 studies, 31 were included from the USA (23), UK (6), and Taiwan and New Zealand (1 each). These were published/conducted between May 2005 and April 2015. Thirty-eight different vaccines were studied, focusing mainly on influenza (47.4%), especially 2009 H1N1 vaccines. Forty-six analytic approaches were used, reflecting frequency of EHR updates and the AE studied. Poisson-based maximized sequential probability ratio test was the most common (43.5%), followed by its binomial (23.9%) and conditional versions (10.9%). Thirty-seven of 49 analyses (75.5%) mentioned control for confounding, using an adjusted expected rate (51.4% of those adjusting), stratification (16.2%) or a combination of a self-controlled design and stratification (13.5%). Guillain-Barré syndrome (11.9%), meningitis/encephalitis/myelitis (11.9%) and seizures (10.8%) were studied most often. CONCLUSIONS: Near real-time vaccine safety surveillance using EHR has developed over the past decade but is not yet widely used. As more countries have access to EHR, it will be important that appropriate methods are selected, considering the data available and AE of interest.

Safety of live attenuated influenza vaccine in atopic children with egg allergy.

BACKGROUND: Live attenuated influenza vaccine (LAIV) is an intranasal vaccine recently incorporated into the United Kingdom immunization schedule. However, it contains egg protein and, in the absence of safety data, is contraindicated in patients with egg allergy. Furthermore, North American guidelines recommend against its use in asthmatic children. OBJECTIVE: We sought to assess the safety of LAIV in children with egg allergy. METHODS: We performed a prospective, multicenter, open-label, phase IV intervention study involving 11 secondary/tertiary centers in the United Kingdom. Children with egg allergy (defined as a convincing clinical reaction to egg within the past 12 months and/or >95% likelihood of clinical egg allergy as per published criteria) were recruited. LAIV was administered under medical supervision, with observation for 1 hour and telephone follow-up 72 hours later. RESULTS: Four hundred thirty-three doses were administered to 282 children with egg allergy (median, 4.9 years; range, 2-17 years); 115 (41%) had experienced prior anaphylaxis to egg. A physician's diagnosis of asthma/recurrent wheezing was noted in 67%, and 51% were receiving regular preventer therapy. There were no systemic allergic reactions (upper 95% CI for population, 1.3%). Eight children experienced mild self-limiting symptoms, which might have been due an IgE-mediated allergic reaction. Twenty-six (9.4%; 95% CI for population, 6.2% to 13.4%) children experienced lower respiratory tract symptoms within 72 hours, including 13 with parent-reported wheeze. None of these episodes required medical intervention beyond routine treatment. CONCLUSIONS: In contrast to current recommendations, LAIV appears to be safe for use in children with egg allergy. Furthermore, the vaccine appears to be well tolerated in children with a diagnosis of asthma or recurrent wheeze.

Antibody responses after primary immunization in infants born to women receiving a pertussis-containing vaccine during pregnancy: single arm observational study with a historical comparator.

INTRODUCTION: In England, antenatal pertussis immunization using a tetanus/low-dose diphtheria/5-component acellular-pertussis/inactivated-polio (TdaP5/IPV) vaccine was introduced in October 2012. We assessed infant responses to antigens in the maternal vaccine and to those conjugated to tetanus (TT) or the diphtheria toxin variant, CRM. METHODS: Infants of 141 TdaP5/IPV-vaccinated mothers in Southern England immunized with DTaP5/IPV/Haemophilus influenzae b (Hib-TT) vaccine at 2-3-4 months, 13-valent pneumococcal vaccine (PCV13, CRM-conjugated) at 2-4 months and 1 or 2 meningococcal C vaccine (MCC-CRM- or MCC-TT) doses at 3-4 months had blood samples taken at 2 and/or 5 months of age. RESULTS: Antibody responses to pertussis toxin (PT), filamentous hemagglutinin (FHA), fimbriae 2 + 3 (FIMs), diphtheria, tetanus, Hib, MCC and PCV13 serotypes were compared to responses in a historical cohort of 246 infants born to mothers not vaccinated in pregnancy. Infants had high pertussis antibody concentrations pre-immunization but only PT antibodies increased post-immunization (fold-change, 2.64; 95% confidence interval [CI], 2.12-3.30; P < .001), whereas FHA antibodies fell (fold-change, 0.56; 95% CI, .48-.65; P < .001). Compared with infants of unvaccinated mothers, PT, FHA, and FIMs antibodies were lower post-vaccination, with fold-differences of 0.67 (0.58-0.77; P < .001), 0.62 (0.54-0.71; P < .001) and 0.51 (0.42-0.62; P < .001), respectively. Antibodies to diphtheria and some CRM-conjugated antigens were also lower, although most infants achieved protective thresholds; antibodies to tetanus and Hib were higher. CONCLUSIONS: Antenatal pertussis immunization results in high infant pre-immunization antibody concentrations, but blunts subsequent responses to pertussis vaccine and some CRM-conjugated antigens. In countries with no pertussis booster until school age, continued monitoring of protection against pertussis is essential.

Invasive pneumococcal disease, comorbidities, and polysaccharide vaccine use in children aged 5-15 years in England and Wales.

BACKGROUND: In the United Kingdom, the 23-valent pneumococcal polysaccharide vaccine (PPV23) is recommended in addition to routine pneumococcal conjugate vaccination for at-risk children aged ≥2 years. This study describes the epidemiology, serotype distribution, clinical characteristics, vaccination status, and reasons for nonvaccination in children aged 5-15 years with invasive pneumococcal disease (IPD). METHODS: Public Health England conducts enhanced national surveillance of IPD in England and Wales. In 2012, general practitioners (GPs) were contacted to complete a questionnaire for children aged 5-15 years with laboratory-confirmed IPD diagnosed during 2 epidemiological years, July 2009-June 2011. RESULTS: During 2009-2011, 447 IPD episodes occurred in 439 children (incidence, 2.2/100 000), and GPs of 423 of the 439 (96.4%) children completed the questionnaire. Comorbidity was reported in 124 (29.3%); a third each were immunocompromised or had chronic respiratory disease or other comorbidities. Pneumonia was the most common presentation (332/439 [75.6%]), and IPD-related case fatality was 1.8% (8/439). Only 26.6% (33/124) of children with comorbidities had received PPV23, and development of PPV23-type IPD was not associated with prior PPV23 vaccination (adjusted odds ratio [AOR], 1.09; 95% confidence interval [CI], .36-3.32; P = .88), even when analysis was restricted to the extra 11 PPV23 serotypes not contained in the 13-valent pneumococcal conjugate vaccine (AOR, 1.70; 95% CI, .30-9.76; P = .55). GPs of eligible but unvaccinated cases with comorbidities were mostly unaware that the child required PPV23 and/or expected pediatricians to inform them to administer the vaccine. CONCLUSIONS: Only a quarter of children with comorbidities who developed IPD had received PPV23 prior to infection. Among PPV23-vaccinated children with comorbidities, however, there was no evidence of protection against PPV23 serotypes.

Administration of AS03B-adjuvanted A(H1N1)pdm09 vaccine in children aged <3 years enhances antibody response to H3 and B viruses following a single dose of trivalent vaccine one year later.

BACKGROUND: We report on a follow-up clinical and serological investigation of 274 children who received seasonal influenza vaccine (trivalent inactivated vaccine [TIV]) 1 year after receipt of either AS03(B)-adjuvanted subunit or whole virus monovalent A(H1N1)pdm09 vaccine and describe the antibody responses to the H3N2 A/Perth/16/2009 and B/Brisbane/60/2008 components of TIV. METHODS: Vaccine responses were analyzed using hemagglutination inhibition (HAI) assays. In children aged <3 years, previous receipt of adjuvanted vaccine resulted in higher HAI antibody responses to H3N2 and B strains compared with nonadjuvanted vaccine (fold change 16.8 vs 4.3 for H3N2 and 7.0 vs 1.6 for B). In children aged >3 years, responses to the H3 and B components of TIV were similar between vaccine groups. Sera taken before and after the pandemic vaccine were also analyzed by HAI using A/Perth/16/2009 virus. This analysis showed that 11.1% of children receiving the AS03(B)-adjuvanted vaccine but only 1.4% in the nonadjuvanted group had a 4-fold rise to A/Perth/16/2009. CONCLUSION: AS03B-adjuvanted A(H1N1)pdm09 influenza vaccine generates a cross-reactive antibody response to H3N2 in children and enhances responses to heterologous subtypes in children aged <3 years 1 year later.

Erratum to "Risk of cardiac arrhythmia and cardiac arrest after primary and booster COVID-19 vaccination in England: A self-controlled case series analysis" [Vaccine: X 15 (2023) 100418].

[This corrects the article DOI: 10.1016/j.jvacx.2023.100418.].

Invasive pneumococcal disease 3 years after introduction of a reduced 1 + 1 infant 13-valent pneumococcal conjugate vaccine immunisation schedule in England: a prospective national observational surveillance study.

BACKGROUND: The UK transition from a 2 + 1 to a 1 + 1 infant immunisation schedule with the 13-valent pneumococcal conjugate vaccine (PCV13) on Jan 1, 2020, coincided with the start of the COVID-19 pandemic. We describe the epidemiology of invasive pneumococcal disease (IPD) in England over 6 financial years (April 1 to March 31) between 2017-18 and 2022-23. METHODS: We used prospective national surveillance data, including serotyping and whole-genome sequencing of invasive isolates, to analyse IPD trends in England by age and financial year. We compared breakthrough infections and vaccine failure rates in 2022-23 among children eligible for the 1 + 1 schedule with rates in cohorts of children eligible for the 2 + 1 schedule between 2017-18 and 2019-20. We assessed genomic changes over time by comparing Global Pneumococcal Sequencing Clusters and multilocus sequence types among PCV13 serotypes causing IPD. FINDINGS: There were 4598 laboratory-confirmed IPD cases in 2022-23, 3025 in 2021-22, 1240 in 2020-21, and 5316 in 2019-20. IPD incidence in 2022-23 was 14% lower than in 2019-20 (incidence rate ratio [IRR] 0·86, 95% CI 0·81-0·91; p<0·001). IPD incidence in 2022-23 compared with 2019-20 was 34% higher in children (aged <15 years) (378 cases vs 292 cases; IRR 1·34, 95% CI 1·08-1·68; p=0·009) and 17% lower in adults (aged 15 years and older; 4220 vs 5024; 0·83, 0·78-0·88; p<0·001). The proportion of PCV13-type IPD increased from 19·4% (95% CI 18·2-20·4; 957 of 4947) in 2019-20 to 29·7% (28·3-31·0; 1283 of 4326) in 2022-23, mainly due to serotype 3, but also serotypes 19F, 19A, and 4, alongside a decrease in non-PCV13 serotypes 8, 12F, and 9N. The increase in IPD incidence due to serotypes 3, 19A, and 19F was driven by clonal expansion of previously circulating strains, whereas serotype 4 expansion was driven by newer strains (ie, sequence types 801 and 15603). Breakthrough infections and vaccine failure rates were similar in children eligible for the 1 + 1 (1·08 per 100 000 person-years) and 2 + 1 (0·76 per 100 000 person-years; IRR 1·42, 95% CI 0·78-2·49; p=0·20) PCV13 schedules. INTERPRETATION: Overall, IPD incidence in England was lower in 2022-23, 2 years after removal of pandemic restrictions, than in 2019-20. Breakthrough and vaccine failure rates were not significantly different between children who received the 1 + 1 compared with the 2 + 1 PCV13 immunisation schedule. The post-pandemic increase in childhood IPD incidence and especially PCV13-type IPD will require close monitoring. FUNDING: None.

Influenza vaccination during the 2021/22 season: A data-linkage test-negative case-control study of effectiveness against influenza requiring emergency care in England and serological analysis of primary care patients.

We present England 2021/22 end-of-season adjusted vaccine effectiveness (aVE) against laboratory confirmed influenza related emergency care use in children aged 1-17 and in adults aged 50+, and serological findings in vaccinated vs unvaccinated adults by hemagglutination inhibition assay. Influenza vaccination has been routinely offered to all children aged 2-10 years and adults aged 65 years + in England. In 2021/22, the offer was extended to children to age 15 years, and adults aged 50-64 years. Influenza activity rose during the latter half of the 2021/22 season, while remaining comparatively low due to COVID-19 pandemic control measures. Influenza A(H3N2) strains predominated. A test negative design was used to estimate aVE by vaccine type. Cases and controls were identified within a sentinel laboratory surveillance system. Vaccine histories were obtained from the National Immunisation Management Service (NIMS), an influenza and COVID-19 vaccine registry. These were linked to emergency department presentations (excluding accidents) with respiratory swabbing ≤ 14 days before or ≤ 7 days after presentation. Amongst adults, 423 positive and 32,917 negative samples were eligible for inclusion, and 145 positive and 6,438 negative samples among children. Those admitted to hospital were further identified. In serology against the circulating A(H3N2) A/Bangladesh/4005/2020-like strain, 61 % of current season adult vaccinees had titres ≥ 1:40 compared to 17 % of those unvaccinated in 2020/21 or 2021/22 (p < 0.001). We found good protection from influenza vaccination against influenza requiring emergency care in children (72.7 % [95 % CI 52.7, 84.3 %]) and modest effectiveness in adults (26.1 % [95 % CI 4.5, 42.8 %]). Adult VE was higher for A(H1N1) (81 % [95 % CI 50, 93 %]) than A(H3N2) (33 % [95 % CI 6, 53 %]). Consistent protection was observable across preschool, primary and secondary school aged children. Imperfect test specificity combined with very low prevalence may have biased estimates towards null. With limited influenza circulation, the study could not determine differences by vaccine types.

Impact of the 7-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in infants younger than 90 days in England and wales.

BACKGROUND: Streptococcus pneumoniae is an uncommon but well-recognized cause of invasive bacterial disease in young infants. This study aimed to determine the impact of the 7-valent pneumococcal conjugate vaccine (PCV7) on invasive pneumococcal disease (IPD) in infants aged <90 days in England and Wales and describe their clinical characteristics following PCV7 introduction. METHODS: Trends in IPD among infants aged <90 days during 1998-1999 through 2009-2010 were analyzed using enhanced national surveillance data. Following PCV7 introduction, clinical information was also obtained for IPD cases in the birth cohorts eligible for vaccination. RESULTS: Prior to PCV7 introduction, IPD incidence in infants aged <90 days was 13.0 (95% confidence interval [CI], 12.0-14.0) per 100 000 live births and PCV7 serotypes accounted for 44% (154/349) of serotyped isolates. PCV7 introduction resulted in 83% (95% CI, 66%-91%, P < .001) reduction in PCV7 IPD and a declining trend in overall IPD by 2009-2010. Of the 256 cases diagnosed after PCV7 introduction, 23% (n = 60) had been born before 37 weeks' gestation. A third of cases (84/256, 33%) developed IPD in the first 48 hours of life, where 42% (35/84) were premature. Meningitis was diagnosed in 94 infants (37%) and its prevalence increased with age. Case fatality was 7% (18/256) and was higher for meningitis than nonmeningitis cases (adjusted odds ratio, 3.8 [95% CI, 1.2-12.0], P = .024). CONCLUSIONS: Young infants have benefited from PCV7 through indirect (herd) protection. Given that a third of cases occurred within 48 hours of birth, further studies should focus on risk factors for IPD in pregnancy and strategies to prevent mother-to-child transmission.