Publications by authors named "Ray Borrow"

316 Publications

Seroprevalence of SARS-CoV-2 Antibodies in University Students: cross-sectional study, December 2020, England.

J Infect 2021 Apr 29. Epub 2021 Apr 29.

Public Health England, 61 Colindale Avenue, London NW9 5EQ, UK.

Background: In England, the reopening of universities in September 2020 coincided with a rapid increase in SARS-CoV-2 infection rates in university aged young adults. This study aimed to estimate SARS-CoV-2 antibody prevalence in students attending universities that had experienced a COVID-19 outbreak after reopening for the autumn term in September 2020.

Methods: A cross-sectional serosurvey was conducted during 02-11 December 2020 in students aged ≤ 25 years across five universities in England. Blood samples for SARS-CoV-2 antibody testing were obtained using a self-sampling kit and analysed using the Abbott SARS-CoV-2 N antibody and/or an in-house receptor binding domain (RBD) assay.

Findings: SARS-CoV-2 seroprevalence in 2,905 university students was 17.8% (95%CI, 16.5-19.3), ranging between 7.6%-29.7% across the five universities. Seropositivity was associated with being younger likely to represent first year undergraduates (aOR 3.2, 95% CI 2.0-4.9), living in halls of residence (aOR 2.1, 95% CI 1.7-2.7) and sharing a kitchen with an increasing number of students (shared with 4-7 individuals, aOR 1.43, 95%CI 1.12-1.82; shared with 8 or more individuals, aOR 1.53, 95% CI 1.04-2.24). Seropositivity was 49% in students living in halls of residence that reported high SARS-CoV-2 infection rates (>8%) during the autumn term.

Interpretation: Despite large numbers of cases and outbreaks in universities, less than one in five students (17.8%) overall had SARS-CoV-2 antibodies at the end of the autumn term in England. In university halls of residence affected by a COVID-19 outbreak, however, nearly half the resident students became infected and developed SARS-CoV-2 antibodies.
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http://dx.doi.org/10.1016/j.jinf.2021.04.028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8081745PMC
April 2021

Increase in penicillin-resistant invasive meningococcal serogroup W ST-11 complex isolates in England.

Vaccine 2021 May 13;39(19):2719-2729. Epub 2021 Apr 13.

Meningococcal Reference Unit, Public Health England, Manchester Royal Infirmary, Manchester, United Kingdom.

Introduction: Invasive meningococcal disease (IMD) caused by serogroup W meningococci belonging to the ST-11 complex (MenW:cc11) has been increasing globally since the early 2000s. Penicillin resistance among meningococci due to the production of beta-lactamase remains relatively rare. Isolates displaying resistance and reduced susceptibility to penicillin due to alterations in the penA gene (encoding Penicillin Binding Protein 2) are increasingly reported. In 2016, a penicillin-resistant clade of MenW:cc11 isolates with altered penA genes was identified in Australia. More recently, an increase in penicillin-resistant invasive MenW:cc11 isolates was observed in England. Here, we investigate the distribution of penicillin resistance among English invasive MenW:cc11 isolates.

Methods: Isolates from IMD cases in England from July 2010 to August 2019 underwent whole genome sequencing and antibiotic susceptibility testing as part of routine surveillance. The PubMLST Neisseria database was used to determine the distribution of penicillin resistance among English MenW:cc11 isolates and to identify other closely related isolates.

Results: Twenty-five out of 897 English invasive MenW:cc11 isolates were resistant to penicillin; identified among six distinct sublineages and a singleton. Expansion of the Australian penicillin-resistant clade included isolates from several new countries as well as 20 English isolates. A newly identified penicillin resistance-associated lineage was also identified among several countries.

Conclusion: Penicillin resistance among diverse MenW:cc11 isolates is increasing. Surveillance of antibiotic resistance among meningococci is essential to ensure continued effective use.
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http://dx.doi.org/10.1016/j.vaccine.2021.03.002DOI Listing
May 2021

High coverage of diverse invasive meningococcal serogroup B strains by the 4-component vaccine 4CMenB in Australia, 2007-2011: Concordant predictions between MATS and genetic MATS.

Hum Vaccin Immunother 2021 Apr 13:1-9. Epub 2021 Apr 13.

Queensland Paediatric Infectious Disease Laboratory, Children's Health Queensland Hospitals and Health Service, Queensland Children's Hospital, Brisbane, Australia.

Meningococcal serogroup B (MenB) accounts for an important proportion of invasive meningococcal disease (IMD). The 4-component vaccine against MenB (4CMenB) is composed of factor H binding protein (fHbp), neisserial heparin-binding antigen (NHBA), adhesin A (NadA), and outer membrane vesicles of the New Zealand strain with Porin 1.4. A meningococcal antigen typing system (MATS) and a fully genomic approach, genetic MATS (gMATS), were developed to predict coverage of MenB strains by 4CMenB. We characterized 520 MenB invasive disease isolates collected over a 5-year period (January 2007-December 2011) from all Australian states/territories by multilocus sequence typing and estimated strain coverage by 4CMenB. The clonal complexes most frequently identified were ST-41/44 CC/Lineage 3 (39.4%) and ST-32 CC/ET-5 CC (23.7%). The overall MATS predicted coverage was 74.6% (95% coverage interval: 61.1%-85.6%). The overall gMATS prediction was 81.0% (lower-upper limit: 75.0-86.9%), showing 91.5% accuracy compared with MATS. Overall, 23.7% and 13.1% (MATS) and 26.0% and 14.0% (gMATS) of isolates were covered by at least 2 and 3 vaccine antigens, respectively, with fHbp and NHBA contributing the most to coverage. When stratified by year of isolate collection, state/territory and age group, MATS and gMATS strain coverage predictions were consistent across all strata. The high coverage predicted by MATS and gMATS indicates that 4CMenB vaccination may have an impact on the burden of MenB-caused IMD in Australia. gMATS can be used in the future to monitor variations in 4CMenB strain coverage over time and geographical areas even for non-culture confirmed IMD cases.
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http://dx.doi.org/10.1080/21645515.2021.1904758DOI Listing
April 2021

Self-Reported Real-World Safety and Reactogenicity of COVID-19 Vaccines: A Vaccine Recipient Survey.

Life (Basel) 2021 Mar 17;11(3). Epub 2021 Mar 17.

Department of Respiratory Medicine, Salford Royal Hospital NHS Foundation Trust, Manchester M6 8HD, UK.

An online survey was conducted to compare the safety, tolerability and reactogenicity of available COVID-19 vaccines in different recipient groups. This survey was launched in February 2021 and ran for 11 days. Recipients of a first COVID-19 vaccine dose ≥7 days prior to survey completion were eligible. The incidence and severity of vaccination side effects were assessed. The survey was completed by 2002 respondents of whom 26.6% had a prior COVID-19 infection. A prior COVID-19 infection was associated with an increased risk of any side effect (risk ratio 1.08, 95% confidence intervals (1.05-1.11)), fever (2.24 (1.86-2.70)), breathlessness (2.05 (1.28-3.29)), flu-like illness (1.78 (1.51-2.10)), fatigue (1.34 (1.20-1.49)) and local reactions (1.10 (1.06-1.15)). It was also associated with an increased risk of severe side effects leading to hospital care (1.56 (1.14-2.12)). While mRNA vaccines were associated with a higher incidence of any side effect (1.06 (1.01-1.11)) compared with viral vector-based vaccines, these were generally milder ( < 0.001), mostly local reactions. Importantly, mRNA vaccine recipients reported a considerably lower incidence of systemic reactions (RR < 0.6) including anaphylaxis, swelling, flu-like illness, breathlessness and fatigue and of side effects requiring hospital care (0.42 (0.31-0.58)). Our study confirms the findings of recent randomised controlled trials (RCTs) demonstrating that COVID-19 vaccines are generally safe with limited severe side effects. For the first time, our study links prior COVID-19 illness with an increased incidence of vaccination side effects and demonstrates that mRNA vaccines cause milder, less frequent systemic side effects but more local reactions.
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http://dx.doi.org/10.3390/life11030249DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8002738PMC
March 2021

Association between self-reported signs and symptoms and SARS-CoV-2 antibody detection in UK key workers.

J Infect 2021 05 26;82(5):151-161. Epub 2021 Mar 26.

Field Service, East of England, National Infection Service, Public Health England, Cambridge, United Kingdom; NIHR Health Protection Research Unit (HPRU) in Genomics and Data Enabling, University of Warwick, Warwick, United Kingdom. Electronic address:

Background: Screening for SARS-CoV-2 antibodies is under way in some key worker groups; how this adds to self-reported COVID-19 illness is unclear. In this study, we investigate the association between self-reported belief of COVID-19 illness and seropositivity.

Methods: Cross-sectional study of three key worker streams comprising (A) Police and Fire & Rescue (2 sites) (B) healthcare workers (1 site) and (C) healthcare workers with previously positive PCR result (5 sites). We collected self-reported signs and symptoms of COVID-19 and compared this with serology results from two SARS-CoV-2 immunoassays (Roche Elecsys® and EUROIMMUN).

Results: Between 01 and 26 June, we recruited 2847 individuals (Stream A: 1,247, Stream B: 1,546 and Stream C: 154). Amongst those without previous positive PCR tests, 687/2,579 (26%) reported belief they had COVID-19, having experienced compatible symptoms; however, only 208 (30.3%) of these were seropositive on both immunoassays. Both immunoassays had high sensitivities relative to previous PCR positivity (>93%); there was also limited decline in antibody titres up to 110 days post symptom onset. Symptomatic but seronegative individuals had differing symptom profiles and shorter illnesses than seropositive individuals.

Conclusion: Non-COVID-19 respiratory illness may have been mistaken for COVID-19 during the outbreak; laboratory testing is more specific than self-reported key worker beliefs in ascertaining past COVID-19 disease.
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http://dx.doi.org/10.1016/j.jinf.2021.03.019DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7997203PMC
May 2021

UK guidelines and testing for invasive meningococcal disease.

Lancet Infect Dis 2021 04;21(4):455-456

Immunisation and Countermeasures Division, Public Health England, Colindale, London NW9 5EQ, UK.

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http://dx.doi.org/10.1016/S1473-3099(21)00092-XDOI Listing
April 2021

Serological surveillance of SARS-CoV-2: Six-month trends and antibody response in a cohort of public health workers.

J Infect 2021 05 22;82(5):162-169. Epub 2021 Mar 22.

Immunisation and Countermeasures Division, PHE Colindale, National Infection Service, 61 Colindale Avenue, London NW9 5EQ, UK; Paediatric Infectious Diseases Research Group (PIDRG), St. Georges University of London (SGUL), London, UK. Electronic address:

Background: Antibody waning after SARS-CoV-2 infection may result in reduction in long-term immunity following natural infection and vaccination, and is therefore a major public health issue. We undertook prospective serosurveillance in a large cohort of healthy adults from the start of the epidemic in England.

Methods: Clinical and non-clinical healthcare workers were recruited across three English regions and tested monthly from March to November 2020 for SARS-CoV-2 spike (S) protein and nucleoprotein (N) antibodies using five different immunoassays. In positive individuals, antibody responses and long-term trends were modelled using mixed effects regression.

Findings: In total, 2246 individuals attended 12,247 visits and 264 were seropositive in ≥ 2 assays. Most seroconversions occurred between March and April 2020. The assays showed > 85% agreement for ever-positivity, although this changed markedly over time. Antibodies were detected earlier with Abbott (N) but declined rapidly thereafter. With the EuroImmun (S) and receptor-binding domain (RBD) assays, responses increased for 4 weeks then fell until week 12-16 before stabilising. For Roche (N), responses increased until 8 weeks, stabilised, then declined, but most remained above the positive threshold. For Roche (S), responses continued to climb over the full 24 weeks, with no sero-reversions. Predicted proportions sero-reverting after 52 weeks were 100% for Abbott, 59% (95% credible interval 50-68%) Euroimmun, 41% (30-52%) RBD, 10% (8-14%) Roche (N) < 2% Roche (S).

Interpretation: Trends in SARS-CoV-2 antibodies following infection are highly dependent on the assay used. Ongoing serosurveillance using multiple assays is critical for monitoring the course and long-term progression of SARS-CoV-2 antibodies.
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http://dx.doi.org/10.1016/j.jinf.2021.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7982645PMC
May 2021

SARS-CoV-2 infection and transmission in primary schools in England in June-December, 2020 (sKIDs): an active, prospective surveillance study.

Lancet Child Adolesc Health 2021 Mar 16. Epub 2021 Mar 16.

National Infection Service, Public Health England, London, UK.

Background: Little is known about the risk of SARS-CoV-2 infection and transmission in educational settings. Public Health England initiated a study, COVID-19 Surveillance in School KIDs (sKIDs), in primary schools when they partially reopened from June 1, 2020, after the first national lockdown in England to estimate the incidence of symptomatic and asymptomatic SARS-CoV-2 infection, seroprevalence, and seroconversion in staff and students.

Methods: sKIDs, an active, prospective, surveillance study, included two groups: the weekly swabbing group and the blood sampling group. The swabbing group underwent weekly nasal swabs for at least 4 weeks after partial school reopening during the summer half-term (June to mid-July, 2020). The blood sampling group additionally underwent blood sampling for serum SARS-CoV-2 antibodies to measure previous infection at the beginning (June 1-19, 2020) and end (July 3-23, 2020) of the summer half-term, and, after full reopening in September, 2020, and at the end of the autumn term (Nov 23-Dec 18, 2020). We tested for predictors of SARS-CoV-2 antibody positivity using logistic regression. We calculated antibody seroconversion rates for participants who were seronegative in the first round and were tested in at least two rounds.

Findings: During the summer half-term, 11 966 participants (6727 students, 4628 staff, and 611 with unknown staff or student status) in 131 schools had 40 501 swabs taken. Weekly SARS-CoV-2 infection rates were 4·1 (one of 24 463; 95% CI 0·1-21·8) per 100 000 students and 12·5 (two of 16 038; 1·5-45·0) per 100 000 staff. At recruitment, in 45 schools, 91 (11·2%; 95% CI 7·9-15·1) of 816 students and 209 (15·1%; 11·9-18·9) of 1381 staff members were positive for SARS-CoV-2 antibodies, similar to local community seroprevalence. Seropositivity was not associated with school attendance during lockdown (p=0·13 for students and p=0·20 for staff) or staff contact with students (p=0·37). At the end of the summer half-term, 603 (73·9%) of 816 students and 1015 (73·5%) of 1381 staff members were still participating in the surveillance, and five (four students, one staff member) seroconverted. By December, 2020, 55 (5·1%; 95% CI 3·8-6·5) of 1085 participants who were seronegative at recruitment (in June, 2020) had seroconverted, including 19 (5·6%; 3·4-8·6) of 340 students and 36 (4·8%; 3·4-6·6) of 745 staff members (p=0·60).

Interpretation: In England, SARS-CoV-2 infection rates were low in primary schools following their partial and full reopening in June and September, 2020.

Funding: UK Department of Health and Social Care.
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http://dx.doi.org/10.1016/S2352-4642(21)00061-4DOI Listing
March 2021

Robust SARS-CoV-2-specific T cell immunity is maintained at 6 months following primary infection.

Nat Immunol 2021 05 5;22(5):620-626. Epub 2021 Mar 5.

Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham, UK.

The immune response to SARS-CoV-2 is critical in controlling disease, but there is concern that waning immunity may predispose to reinfection. We analyzed the magnitude and phenotype of the SARS-CoV-2-specific T cell response in 100 donors at 6 months following infection. T cell responses were present by ELISPOT and/or intracellular cytokine staining analysis in all donors and characterized by predominant CD4 T cell responses with strong interleukin (IL)-2 cytokine expression. Median T cell responses were 50% higher in donors who had experienced a symptomatic infection, indicating that the severity of primary infection establishes a 'set point' for cellular immunity. T cell responses to spike and nucleoprotein/membrane proteins were correlated with peak antibody levels. Furthermore, higher levels of nucleoprotein-specific T cells were associated with preservation of nucleoprotein-specific antibody level although no such correlation was observed in relation to spike-specific responses. In conclusion, our data are reassuring that functional SARS-CoV-2-specific T cell responses are retained at 6 months following infection.
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http://dx.doi.org/10.1038/s41590-021-00902-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610739PMC
May 2021

Use of dried blood spot samples for SARS-CoV-2 antibody detection using the Roche Elecsys ® high throughput immunoassay.

J Clin Virol 2021 03 19;136:104739. Epub 2021 Jan 19.

Field Service, Public Health England, United Kingdom.

Dried blood spot samples (DBS) provide an alternative sample type to venous blood samples for antibody testing. DBS are used by NHS for diagnosing Hepatitis C and by Public Health England for large scale HIV and Hepatitis C serosurveillance; the applicability of DBS based approaches for SARS-CoV-2 antibody detection is uncertain. The study aimed to compare antibody detection in DBS eluates using the Roche Elecsys ® immunoassay with antibody detection in paired plasma samples, using the same assay. The study was in one Police and one Fire & Rescue facility in England; it comprised of 195 participants within a larger sample COVID-19 serodiagnostics study of keyworkers, EDSAB-HOME. Outcome measures were sensitivity and specificity of DBS (the index test) relative to plasma (the reference test), at an experimental cut-off; quality of DBS sample collected; estimates of relative sensitivity of DBS vs. plasma immunoassay in a larger population. 18/195 (9.2%) participants tested positive using plasma samples. DBS sample quality varied markedly by phlebotomist, and low sample volume significantly reduced immunoassay signals. Using an experimental cut-off, sensitivity and specificity of DBS were 89.0% (95% CI 67.2, 96.9%) and 100.0% (95% CI 97.9, 100%) respectively compared with using plasma. The limit of detection for DBS is about 30 times higher than for plasma. DBS use for SARS-CoV-2 serology, though feasible, is insensitive relative to immunoassays on plasma. Sample quality impacts on assay performance. Alternatives, including the collection of capillary blood samples, should be considered for screening programs.
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http://dx.doi.org/10.1016/j.jcv.2021.104739DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7817498PMC
March 2021

Rapid community point-of-care testing for COVID-19 (RAPTOR-C19): protocol for a platform diagnostic study.

Diagn Progn Res 2021 Feb 8;5(1). Epub 2021 Feb 8.

Nuffield Department of Primary Care Health Sciences, University of Oxford, Radcliffe Observatory Quarter, Woodstock Road, Oxford, OX2 6GG, UK.

Background: The aim of RApid community Point-of-care Testing fOR COVID-19 (RAPTOR-C19) is to assess the diagnostic accuracy of multiple current and emerging point-of-care tests (POCTs) for active and past SARS-CoV2 infection in the community setting. RAPTOR-C19 will provide the community testbed to the COVID-19 National DiagnOstic Research and Evaluation Platform (CONDOR).

Methods: RAPTOR-C19 incorporates a series of prospective observational parallel diagnostic accuracy studies of SARS-CoV2 POCTs against laboratory and composite reference standards in patients with suspected current or past SARS-CoV2 infection attending community settings. Adults and children with suspected current SARS-CoV2 infection who are having an oropharyngeal/nasopharyngeal (OP/NP) swab for laboratory SARS-CoV2 reverse transcriptase Digital/Real-Time Polymerase Chain Reaction (d/rRT-PCR) as part of clinical care or community-based testing will be invited to participate. Adults (≥ 16 years) with suspected past symptomatic infection will also be recruited. Asymptomatic individuals will not be eligible. At the baseline visit, all participants will be asked to submit samples for at least one candidate point-of-care test (POCT) being evaluated (index test/s) as well as an OP/NP swab for laboratory SARS-CoV2 RT-PCR performed by Public Health England (PHE) (reference standard for current infection). Adults will also be asked for a blood sample for laboratory SARS-CoV-2 antibody testing by PHE (reference standard for past infection), where feasible adults will be invited to attend a second visit at 28 days for repeat antibody testing. Additional study data (e.g. demographics, symptoms, observations, household contacts) will be captured electronically. Sensitivity, specificity, positive, and negative predictive values for each POCT will be calculated with exact 95% confidence intervals when compared to the reference standard. POCTs will also be compared to composite reference standards constructed using paired antibody test results, patient reported outcomes, linked electronic health records for outcomes related to COVID-19 such as hospitalisation or death, and other test results.

Discussion: High-performing POCTs for community use could be transformational. Real-time results could lead to personal and public health impacts such as reducing onward household transmission of SARS-CoV2 infection, improving surveillance of health and social care staff, contributing to accurate prevalence estimates, and understanding of SARS-CoV2 transmission dynamics in the population. In contrast, poorly performing POCTs could have negative effects, so it is necessary to undertake community-based diagnostic accuracy evaluations before rolling these out.

Trial Registration: ISRCTN, ISRCTN14226970.
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http://dx.doi.org/10.1186/s41512-021-00093-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868893PMC
February 2021

Immune Response and Safety of Viral Vaccines in Children with Autoimmune Diseases on Immune Modulatory Drug Therapy.

Expert Rev Vaccines 2020 12 28;19(12):1115-1127. Epub 2021 Jan 28.

Royal Manchester Children's Hospital, Lydia Becker Institute of Immunology and Inflammation, University of Manchester , Manchester, UK.

: Children with autoimmune diseases often require treatment with systemic immunosuppressives. Efficacy and safety of vaccination, particularly live-attenuated viral vaccines in these patients remain a concern. : To evaluate the immunogenicity and safety of viral vaccines in children and young people treated with systemic immunosuppressive drugs for autoimmune diseases. A systemic literature review was performed using Pubmed including English papers in subjects less than 21 years old. Viral vaccines were generally immunogenic and safe in children receiving immunosuppressive drugs, including biologics. Use of low-dose prednisolone or disease-modifying antirheumatic drugs did not significantly impact on vaccine immunogenicity, although there was anecdotal evidence of reduced immunogenicity in patients receiving high-dose prednisolone/methylprednisolone and pulse cyclophosphamide. Patients on biologics mounted adequate seroprotective responses, but antibody titers tended to be lower. Both live-attenuated and inactivated vaccines were well tolerated with no serious adverse events. Autoimmune disease activity was not adversely affected by vaccination. : Current evidence indicates that administration of viral vaccines to children with autoimmune diseases receiving most systemic immunosuppressive drugs is immunogenic and safe. MMR can safely be given to most patients receiving biologics, but patients on high-dose prednisolone and pulse cyclophosphamide should avoid MMR and other live viral vaccines.
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http://dx.doi.org/10.1080/14760584.2021.1875825DOI Listing
December 2020

Immunogenicity of the UK group B meningococcal vaccine (4CMenB) schedule against groups B and C meningococcal strains (Sched3): outcomes of a multicentre, open-label, randomised controlled trial.

Lancet Infect Dis 2021 05 8;21(5):688-696. Epub 2021 Jan 8.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, UK; National Institute for Health Research Oxford Biomedical Research Centre, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, UK. Electronic address:

Background: The use of the multicomponent meningococcal vaccine 4CMenB in the UK schedule at 2, 4, and 12 months of age has been shown to be 59·1% effective at preventing invasive group B meningococcal disease. Here, we report the first data on the immunogenicity of this reduced-dose schedule to help to interpret this effectiveness estimate.

Methods: In this multicentre, parallel-group, open-label, randomised clinical trial, infants aged up to 13 weeks due to receive their primary immunisations were recruited via child health database mailouts in Oxfordshire and via general practice surgeries in Gloucestershire and Hertfordshire. Infants were randomly assigned (1:1) with permuted block randomisation to receive a 2 + 1 (2, 4, and 12 months; group 1) or 1 + 1 (3 and 12 months; group 2) schedule of the 13-valent pneumococcal conjugate vaccine (PCV13). All infants also received 4CMenB at 2, 4, and 12 months of age, and had blood samples taken at 5 and 13 months. Participants and clinical trial staff were not masked to treatment allocation. Proportions of participants with human complement serum bactericidal antibody (hSBA) titres of at least 4 were determined for group B meningococcus (MenB) reference strains 5/99 (Neisserial Adhesin A [NadA]), NZ98/254 (porin A), and 44/76-SL (factor H binding protein [fHbp]). Geometric mean titres (GMTs) with 95% CIs were also calculated, and concomitant vaccine responses (group C meningococcus [MenC], Haemophilus influenzae b [Hib], tetanus, diphtheria, and pertussis) were compared between groups. The primary outcome was PCV13 immunogenicity, with 4CMenB immunogenicity and reactogenicity as secondary outcomes. All individuals by randomised group with a laboratory result were included in the analysis. The study is registered on the EudraCT clinical trials database, 2015-000817-32, and ClinicalTrials.gov, NCT02482636, and is complete.

Findings: Between Sept 22, 2015, and Nov 1, 2017, of 376 infants screened, 213 were enrolled (106 in group 1 and 107 in group 2). 204 samples post-primary immunisation and 180 post-boost were available for analysis. The proportion of participants with hSBA of at least 4 was similar in the two study groups. For strain 5/99, all participants developed hSBA titres above 4 in both groups and at both timepoints. For strain 44/76-SL, these proportions were 95·3% (95% CI 88·5-98·7) or above post-priming (82 of 86 participants in group 1), and 92·4% (84·2-97·2) or above post-boost (73 of 79 participants in group 1). For strain NZ98/254, these proportions were 86·5% (78·0-92·6) or above post-priming (83 of 96 participants in group 2) and 88·6% (79·5-94·7) or above post-boost (70 of 79 participants in group 1). The MenC rabbit complement serum bactericidal antibody (rSBA) titre in group 1 was significantly higher than in group 2 (888·3 vs 540·4; p=0·025). There was no significant difference in geometric mean concentrations between groups 1 and 2 for diphtheria, tetanus, Hib, and pertussis post-boost. A very small number of children did not have a protective response against 44/76-SL and NZ98/254. Local and systemic reactions were similar between the two groups, apart from the 3 month timepoint when one group received an extra dose of PCV13 and recorded more systemic reactions.

Interpretation: These data support the recent change to the licensed European schedule for 4CMenB to add an infant 2 + 1 schedule, as used in the routine UK vaccine programme with an effectiveness of 59·1%. When compared with historical data, our data do not suggest that effectiveness would be higher with a 3 + 1 schedule, however a suboptimal boost response for bactericidal antibodies against vaccine antigen fHbp suggests a need for ongoing surveillance for vaccine breakthroughs due to fHbp-matched strains. Changing from a 2 + 1 to a 1 + 1 schedule for PCV13 for the UK is unlikely to affect protection against diphtheria, tetanus, and Hib, however an unexpected reduction in bactericidal antibodies against MenC seen with the new schedule suggests that ongoing surveillance for re-emergent MenC disease is important.

Funding: Bill & Melinda Gates Foundation and the National Institute for Health Research.
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http://dx.doi.org/10.1016/S1473-3099(20)30600-9DOI Listing
May 2021

HPV16 and HPV18 seropositivity and DNA detection among men who have sex with men: a cross-sectional study conducted in a sexual health clinic in London.

Sex Transm Infect 2020 Dec 23. Epub 2020 Dec 23.

Institute for Global Health, University College London, London, UK

Objectives: Men who have sex with men (MSM) have an increased risk of human papillomavirus (HPV) infection and related diseases compared with men who have sex exclusively with women. From April 2018, there has been a phased roll-out of HPV vaccination offered to MSM aged up to 45 years old who are attending sexual health clinics and HIV clinics in England. The vaccine is most effective if delivered prior to HPV infection. We estimated the proportion of MSM with no current vaccine-type infection and no serological evidence of prior infection, in a study undertaken prior to vaccine introduction.

Methods: We conducted a cross-sectional study among 484 MSM aged 18-40 years old who attended a sexual health clinic in London between 2010 and 2012. We estimated the prevalence of current and past infection by testing for HPV DNA in anogenital samples and for serum antibodies to HPV16 and HPV18.

Results: The median age was 30 years (IQR 25-35). The prevalence of HPV16 and HPV18 DNA was 13.2% and 6.2%, respectively. Seropositivity for HPV16 and HPV18 was 28.5% and 17.1%, respectively, with 11.4% seropositive for both types. Seropositivity for the same HPV type was strongly associated with anogenital DNA detection. 279 MSM (57.6%) tested negative for both HPV16 and HPV18 serology and were DNA negative for these two types; only 5 MSM (1.0%) were seropositive and DNA positive for both HPV types.

Conclusions: This is the first study to determine both the prevalence of HPV DNA in anogenital samples and HPV seroprevalence among MSM attending a sexual health clinic in the UK. Over half of MSM in this study had no evidence of a previous or current infection with either of the high-risk HPV types included in the quadrivalent vaccine, which supports the rationale for opportunistic HPV vaccination of MSM attending sexual health clinics.
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http://dx.doi.org/10.1136/sextrans-2020-054726DOI Listing
December 2020

Killing 2 Cocci With 1 Vaccine: Unleashing the Full Potential of an Adolescent Meningococcal B Immunization Program.

Clin Infect Dis 2020 Dec 19. Epub 2020 Dec 19.

Immunisation and Countermeasures Division, Public Health England, London, United Kingdom.

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http://dx.doi.org/10.1093/cid/ciaa1644DOI Listing
December 2020

Genomic analysis of the meningococcal ST-4821 complex-Western clade, potential sexual transmission and predicted antibiotic susceptibility and vaccine coverage.

PLoS One 2020 10;15(12):e0243426. Epub 2020 Dec 10.

National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, PR China.

Introduction: The ST-4821 complex (cc4821) is a leading cause of serogroup C and serogroup B invasive meningococcal disease in China where diverse strains in two phylogenetic groups (groups 1 and 2) have acquired fluoroquinolone resistance. cc4821 was recently prevalent among carriage isolates in men who have sex with men in New York City (USA). Genome-level population studies have thus far been limited to Chinese isolates. The aim of the present study was to build upon these with an extended panel of international cc4821 isolates.

Methods: Genomes of isolates from Asia (1972 to 2017), Europe (2011 to 2018), North America (2007), and South America (2014) were sequenced or obtained from the PubMLST Neisseria database. Core genome comparisons were performed in PubMLST.

Results: Four lineages were identified. Western isolates formed a distinct, mainly serogroup B sublineage with alleles associated with fluoroquinolone susceptibility (MIC <0.03 mg/L) and reduced penicillin susceptibility (MIC 0.094 to 1 mg/L). A third of these were from anogenital sites in men who have sex with men and had unique denitrification gene alleles. Generally 4CMenB vaccine strain coverage was reliant on strain-specific NHBA peptides.

Discussion: The previously identified cc4821 group 2 was resolved into three separate lineages. Clustering of western isolates was surprising given the overall diversity of cc4821. Possible association of this cluster with the anogenital niche is worthy of monitoring given concerns surrounding antibiotic resistance and potential subcapsular vaccine escape.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0243426PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7728179PMC
January 2021

4CMenB Immunization Induces Serum Bactericidal Antibodies Against Non-Serogroup B Meningococcal Strains in Adolescents.

Infect Dis Ther 2021 Mar 13;10(1):307-316. Epub 2020 Nov 13.

GSK, Siena, Italy.

Introduction: Invasive meningococcal disease (IMD) is an important public health concern. In developed countries, most IMD is caused by meningococcal serogroup B (MenB) and two protein-based MenB vaccines are currently available: the four-component vaccine 4CMenB (Bexsero, GSK) and the bivalent vaccine MenB-FHbp (Trumenba, Pfizer). Genes encoding the 4CMenB vaccine antigens are also present in strains belonging to other meningococcal serogroups.

Methods: To evaluate the potential of 4CMenB vaccination to protect adolescents against non-MenB IMD, we tested the bactericidal activity of sera from immunized adolescents on 147 (127 European and 20 Brazilian) non-MenB IMD isolates, with a serum bactericidal antibody assay using human complement (hSBA). Serum pools were prepared using samples from randomly selected participants in various clinical trials, pre- and post-vaccination: 12 adolescents who received two doses of 4CMenB 2 months apart, and 10 adolescents who received a single dose of a MenACWY conjugate vaccine (as positive control).

Results: 4CMenB pre-immune sera killed 7.5% of the 147 non-MenB isolates at hSBA titers ≥ 1:4. In total, 91 (61.9%) tested isolates were killed by post-dose 2 pooled sera at hSBA titers ≥ 1:4, corresponding to 44/80 (55.0%) MenC, 26/35 (74.3%) MenW, and 21/32 (65.6%) MenY isolates killed.

Conclusion: 4CMenB vaccination in adolescents induces bactericidal killing of non-MenB isolates, suggesting that mass vaccination could impact IMD due to serogroups other than MenB.
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http://dx.doi.org/10.1007/s40121-020-00370-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7954916PMC
March 2021

Herd Protection against Meningococcal Disease through Vaccination.

Microorganisms 2020 Oct 28;8(11). Epub 2020 Oct 28.

Meningococcal Reference Unit, National Infection Service, Public Health England, Manchester M13 9WL, UK.

Reduction in the transmission of within a population results in fewer invasive disease cases. Vaccination with meningococcal vaccines composed of high weight capsular polysaccharide without carrier proteins has minimal effect against carriage or the acquisition of carriage. Conjugate vaccines, however, elicit an enhanced immune response which serves to reduce carriage acquisition and hinder onwards transmission. Since the 1990s, several meningococcal conjugate vaccines have been developed and, when used in age groups associated with higher carriage, they have been shown to provide indirect protection to unvaccinated cohorts. This herd protective effect is important in enhancing the efficiency and impact of vaccination. Studies are ongoing to assess the effect of protein-based group B vaccines on carriage; however, current data cast doubt on their ability to reduce transmission.
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http://dx.doi.org/10.3390/microorganisms8111675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7693901PMC
October 2020

Understanding the reactogenicity of 4CMenB vaccine: Comparison of a novel and conventional method of assessing post-immunisation fever and correlation with pre-release in vitro pyrogen testing.

Vaccine 2020 11 24;38(49):7834-7841. Epub 2020 Oct 24.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, NIHR Oxford Biomedical Research Centre, United Kingdom.

Background: Better understanding of vaccine reactogenicity is crucial given its potential impact upon vaccine safety and acceptance. Here we report a comparison between conventional and novel (continuous) methods of monitoring temperature and evaluate any association between reactogenicity and the monocyte activation test (MAT) employed for testing four-component capsular group B meningococcal vaccine (4CMenB) batches prior to release for clinical use in Europe.

Methods: Healthy 7-12-week-old infants were randomised in two groups: group PCV13 2 + 1 (received pneumococcal conjugate vaccine 13 valent (PCV13) at 2, 4 and 12 months) and group PCV13 1 + 1 (received reduced schedule at 3 and 12 months). In both, infants received the remaining immunisations as per UK national schedule (including 4CMenB at 2, 4 and 12 months of age). Fever was measured for the first 24 h after immunisations using an axillary thermometer and with a wireless continuous temperature monitoring device (iButton®). To measure the relative pyrogenicity of individual 4CMenB batches, MAT was performed according to Ph. Eu. chapter 2.6.30 method C using PBMCs with IL-6 readout.

Results: Fever rates detected by the iButton® ranged from 28.7% to 76.5% and from 46.6% to 71.1% in group PCV13 2 + 1 and PCV13 1 + 1 respectively, across all study visits. The iButton® recorded a higher number of fever episodes when compared with axillary measurements in both groups (range of axillary temperature fevers; group PCV13 2 + 1: 6.7%-38%; group PCV13 1 + 1: 11.4%-37.1%). An agreement between the two methods was between 0.39 and 0.36 (p < 0.001) at 8 h' time-point post primary immunisations. No correlation was found between MAT scores and fever rates, or other reported adverse events.

Conclusions: It is likely that conventional, intermittent, fever measurements underestimates fever rates following immunisation. 4CMenB MAT scores didn't predict reactogenicity, providing reassurance that vaccine batches with the highest acceptable pyrogen level are not associated with an increase in adverse events. Clinicaltrials.gov identifier: NCT02482636.
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http://dx.doi.org/10.1016/j.vaccine.2020.10.023DOI Listing
November 2020

'Be on the TEAM' Study (Teenagers Against Meningitis): protocol for a controlled clinical trial evaluating the impact of 4CMenB or MenB-fHbp vaccination on the pharyngeal carriage of meningococci in adolescents.

BMJ Open 2020 10 22;10(10):e037358. Epub 2020 Oct 22.

Oxford Vaccine Group, Department of Paediatrics, University of Oxford, Oxford, UK.

Introduction: Capsular group B (MenB) is the most common cause of invasive meningococcal disease (IMD) in many parts of the world. A MenB vaccine directed against the polysaccharide capsule remains elusive due to poor immunogenicity and safety concerns. The vaccines licensed for the prevention of MenB disease, 4CMenB (Bexsero) and MenB-fHbp (Trumenba), are serogroup B 'substitute' vaccines, comprised of subcapsular proteins and are designed to provide protection against most MenB disease-causing strains. In many high-income countries, such as the UK, adolescents are at increased risk of IMD and have the highest rates of meningococcal carriage. Beginning in the late 1990s, immunisation of this age group with the meningococcal group C conjugate vaccine reduced asymptomatic carriage and disrupted transmission of this organism, resulting in lower group C IMD incidence across all age groups. Whether vaccinating teenagers with the novel 'MenB' protein-based vaccines will prevent acquisition or reduce duration of carriage and generate herd protection was unknown at the time of vaccine introduction and could not be inferred from the effects of the conjugate vaccines. 4CMenB and MenB-fHbp may also impact on non-MenB disease-causing capsular groups as well as commensal spp. This study will evaluate the impact of vaccination with 4CMenB or MenB-fHbp on oropharyngeal carriage of pathogenic meningococci in teenagers, and consequently the potential for these vaccines to provide broad community protection against MenB disease.

Methods And Analysis: The 'Be on the TEAM' (Teenagers Against Meningitis) Study is a pragmatic, partially randomised controlled trial of 24 000 students aged 16-19 years in their penultimate year of secondary school across the UK with regional allocation to a 0+6 month schedule of 4CMenB or MenB-fHbp or to a control group. Culture-confirmed oropharyngeal carriage will be assessed at baseline and at 12 months, following which the control group will be eligible for 4CMenB vaccination. The primary outcome is the carriage prevalence of potentially pathogenic meningococci (defined as those with genogroups B, C, W, Y or X), in each vaccine group compared separately to the control group at 12 months post-enrolment, that is, 12 months after the first vaccine dose and 6 months after the second vaccine dose. Secondary outcomes include impact on carriage of: genogroup B meningococci; hyperinvasive meningococci; all meningococci; those meningococci expressing vaccine antigens and; other spp. A sample size of 8000 in each arm will provide 80% power to detect a 30% reduction in meningococcal carriage, assuming genogroup B, C, W, Y or X meningococci carriage of 3.43%, a design effect of 1.5, a retention rate of 80% and a significance level of 0.05. Study results will be available in 2021 and will inform the UK and international immunisation policy and future vaccine development.

Ethics And Dissemination: This study is approved by the National Health Service South Central Research Ethics Committee (18/SC/0055); the UK Health Research Authority (IRAS ID 239091) and the UK Medicines and Healthcare products Regulatory Agency. Publications arising from this study will be submitted to peer-reviewed journals. Study results will be disseminated in public forums, online, presented at local and international conferences and made available to the participating schools.

Trial Registration Numbers: ISRCTN75858406; Pre-results, EudraCT 2017-004609-42.
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http://dx.doi.org/10.1136/bmjopen-2020-037358DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7583083PMC
October 2020

Multicomponent meningococcal serogroup B vaccination elicits cross-reactive immunity in infants against genetically diverse serogroup C, W and Y invasive disease isolates.

Vaccine 2020 11 7;38(47):7542-7550. Epub 2020 Oct 7.

PRA Health Sciences c/o GSK, Fort Washington, PA, USA. Electronic address:

Background: The multicomponent meningococcal serogroup B vaccine (4CMenB) is currently indicated for active immunization against invasive meningococcal disease caused by Neisseria meningitidis serogroup B (MenB). However, genes encoding the 4CMenB antigens are also variably present and expressed in strains belonging to other meningococcal serogroups. In this study, we evaluated the ability of antibodies raised by 4CMenB immunisation to induce complement-mediated bactericidal killing of non-MenB strains.

Methods: A total of 227 invasive non-MenB disease isolates were collected between 1 July 2007 and 30 June 2008 from England and Wales, France, and Germany; 41 isolates were collected during 2012 from Brazil. The isolates were subjected to genotypic analyses. A subset of 147 isolates (MenC, MenW and MenY) representative of the meningococcal genetic diversity of the total sample were tested in the human complement serum bactericidal antibody assay (hSBA) using sera from infants immunised with 4CMenB.

Results: Serogroup and clonal complex repertoires of non-MenB isolates were different for each country. For the European panel, MenC, MenW and MenY isolates belonged mainly to ST-11, ST-22 and ST-23 complexes, respectively. For the Brazilian panel, most MenC and MenW isolates belonged to the ST-103 and ST-11 complexes, respectively, and most MenY isolates were not assigned to clonal complexes. Of the 147 non-MenB isolates, 109 were killed in hSBA, resulting in an overall coverage of 74%.

Conclusion: This is the first study in which 147 non-MenB serogroup isolates have been analysed in hSBA to evaluate the potential of a MenB vaccine to cover strains belonging to other serogroups. These data demonstrate that antibodies raised by 4CMenB are able to induce bactericidal killing of 109 non-MenB isolates, representative of non-MenB genetic and geographic diversity. These findings support previous evidence that 4CMenB immunisation can provide cross-protection against non-MenB strains in infants, which represents an added benefit of 4CMenB vaccination.
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http://dx.doi.org/10.1016/j.vaccine.2020.09.050DOI Listing
November 2020

Antibody persistence following meningococcal ACWY conjugate vaccine licensed in the European Union by age group and vaccine.

Expert Rev Vaccines 2020 08 8;19(8):745-754. Epub 2020 Sep 8.

Vaccine Evaluation Unit, Public Health England, Manchester Royal Infirmary , Manchester, UK.

Introduction: Meningococcal disease caused by is a major cause of meningitis and septicemia with high rates of morbidity and mortality worldwide. MenACWY-TT and MenACWY-CRM are meningococcal conjugate vaccines approved for use in children and adults in the UK. The aim of this review was to evaluate and compare antibody responses and persistence in different age groups after MenACWY-TT and MenACWY-CRM.

Areas Covered: Randomized trials showed that MenACWY-TT is immunogenic at all ages. MenACWY-CRM is immunogenic for infants and adults, but there is a lack of data for children aged 1 to 2 years. Studies on MenACWY-TT indicated that serum bactericidal antibody (SBA) utilizing baby rabbit complement (rSBA) titers were significantly higher and more stable than SBA using human complement (hSBA) titers, compared with hSBA titers, which were lower and declined more rapidly by 1 year following post-primary MenACWY-TT and MenACWY-CRM vaccination, especially for MenA.

Expert Opinion: MenACWY-TT and MenACWY-CRM are both well tolerated and induce similar antibody persistence and immunogenicity against all four serogroups for individuals more than one year old. rSBA assay is a more robust assay than the hSBA assay when vaccinating with MenACWY-TT, while rSBA and hSBA assays had similar antibody persistence when vaccinating with MenACWY-CRM.
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http://dx.doi.org/10.1080/14760584.2020.1800460DOI Listing
August 2020

Broad vaccine protection against Neisseria meningitidis using factor H binding protein.

Vaccine 2020 11 30;38(49):7716-7727. Epub 2020 Aug 30.

Vaccine Medical Development, Scientific and Clinical Affairs, Pfizer Inc, Collegeville, PA, USA. Electronic address:

Neisseria meningitidis, the causative agent of invasive meningococcal disease (IMD), is classified into different serogroups defined by their polysaccharide capsules. Meningococcal serogroups A, B, C, W, and Y are responsible for most IMD cases, with serogroup B (MenB) causing a substantial percentage of IMD cases in many regions. Vaccines using capsular polysaccharides conjugated to carrier proteins have been successfully developed for serogroups A, C, W, and Y. However, because the MenB capsular polysaccharide is poorly immunogenic, MenB vaccine development has focused on alternative antigens. The 2 currently available MenB vaccines (MenB-4C and MenB-FHbp) both include factor H binding protein (FHbp), a surface-exposed protein harboured by nearly all meningococcal isolates that is important for survival of the bacteria in human blood. MenB-4C contains a nonlipidated FHbp from subfamily B in addition to other antigens, including Neisserial Heparin Binding Antigen, Neisserial adhesin A, and outer membrane vesicles, whereas MenB-FHbp contains a lipidated FHbp from each subfamily (A and B). FHbp is highly immunogenic and a main target of bactericidal activity of antibodies elicited by both licensed MenB vaccines. FHbp is also an important vaccine component, in contrast to some other meningococcal antigens that may have limited cross-protection across strains, as FHbp-specific antibodies can provide broad cross-protection within each subfamily. Limited cross-protection between subfamilies necessitates the inclusion of FHbp variants from both subfamilies to achieve broad FHbp-based vaccine coverage. Additionally, immune responses to the lipidated form of FHbp have a superior cross-reactive profile to those elicited by the nonlipidated form. Taken together, the inclusion of lipidated FHbp variants from both FHbp subfamilies is expected to provide broad protection against the diverse disease-causing meningococcal strains expressing a wide range of FHbp sequence variants. This review describes the development of vaccines for MenB disease prevention, with a focus on the FHbp antigen.
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http://dx.doi.org/10.1016/j.vaccine.2020.08.031DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082720PMC
November 2020

Geographically widespread invasive meningococcal disease caused by a ciprofloxacin resistant non-groupable strain of the ST-175 clonal complex.

J Infect 2020 10 25;81(4):575-584. Epub 2020 Aug 25.

Meningococcal Reference Unit, Public Health England, Manchester, UK.

Introduction: Invasive meningococcal disease (IMD) caused by non-serogroupable (NG) strains mainly affects immunocompromised individuals. Reduced susceptibility to penicillin in meningococci is increasing in Europe but ciprofloxacin resistance remains rare. In 2019, three travel-related meningococcal disease cases caused by a ciprofloxacin-resistant NG strain were identified in England, leading Germany to report four additional IMD cases (2016 to 2019). We describe these and newly identified cases and characterise the strain responsible.

Methods: Cases were identified as part of national surveillance and by analysing available genomes using PubMLST tools.

Results: Of the cases identified in England in 2019, two geographically distinct cases developed conjunctivitis after returning from Mecca (Kingdom of Saudi Arabia) and a third linked case presented with IMD. Of the four cases from Germany, three occurred in asylum seekers - two familial and a further geographically distinct case. Further IMD cases were identified in Italy (n = 2; 2017-2018), Sweden (n = 1; 2016) and England (n = 1; 2015). A single ST-175 clonal complex (cc175) strain with genosubtype P1.22-11,15-25 was responsible. Decreased susceptibility to penicillin was widespread with three ciprofloxacin resistant subclusters. Constituent isolates were potentially covered by subcapsular vaccines.

Conclusion: This disease associated NG cc175 strain exhibits resistance to antibiotics commonly used to prevent IMD but is potentially covered by subcapsular (meningococcal B) vaccines.
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http://dx.doi.org/10.1016/j.jinf.2020.08.030DOI Listing
October 2020

First real world evidence of meningococcal group B vaccine, 4CMenB, protection against meningococcal group W disease; prospective enhanced national surveillance, England.

Clin Infect Dis 2020 Aug 26. Epub 2020 Aug 26.

Immunisation and Countermeasures Division, Public Health England, Colindale, London, UK.

Background: 4CMenB is a protein-based meningococcal group B vaccine but the vaccine antigens may also be present on non-group B meningococci. In September 2015, the UK implemented 4CMenB into the national infant immunisation programme, alongside an emergency adolescent meningococcal ACWY (MenACWY) programme to control a national outbreak of group W (MenW) disease caused by a hypervirulent strain belonging to the ST11 clonal complex. The adolescent programme aimed to provide direct protection for adolescents and, over time, indirect (herd) protection across the population.

Methods: Public Health England conducts meningococcal disease surveillance in England. MenW cases confirmed during four years before and four years after implementation of both vaccines were analysed. Poisson models were constructed to estimate direct protection against MenW disease offered by the infant 4CMenB programme on top of the indirect impact of the adolescent MenACWY programme in children eligible for 4CMenB but not MenACWY.

Results: Model estimates showed 69% (adjusted incidence rate ratio (IRR) 0.31, 95%CI, 0.20-0.67) and 52% (aIRR 0.48, 95%CI 0.28-0.81) fewer MenW cases than predicted among age-cohorts that were fully-eligible and partly-eligible for 4CMenB, respectively. There were 138 MenW cases in &5 year-olds. 4CMenB directly prevented 98 (95%CI, 34-201) cases, while the MenACWY programme indirectly prevented an additional 114 (conservative) to 899 (extreme) cases over four years. Disease severity was similar in 4CMenB-immunised and unimmunised children.

Conclusions: Our results provide the first real-world evidence of the direct protection afforded by 4CMenB against MenW:cc11 disease. 4CMenB has the potential to provide some protection against all meningococcal serogroups.
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http://dx.doi.org/10.1093/cid/ciaa1244DOI Listing
August 2020

Vaccines and routine immunization strategies during the COVID-19 pandemic.

Hum Vaccin Immunother 2021 Feb 26;17(2):400-407. Epub 2020 Aug 26.

Departments of Pediatrics and Molecular Virology and Microbiology, Baylor College of Medicine , Houston, TX, USA.

Severe acute respiratory syndrome coronavirus 2 related disease (COVID-19) is now responsible for one of the most challenging and concerning pandemics. By August 2020, there were almost 20 million confirmed cases worldwide and well over half-million deaths. Since there is still no effective treatment or vaccine, non-pharmaceutical interventions have been implemented in an attempt to contain the spread of the virus. During times of quarantine, immunization practices in all age groups, especially routine childhood vaccines, have also been interrupted, delayed, re-organized, or completely suspended. Numerous high-income as well as low- and middle-income countries are now experiencing a rapid decline in childhood immunization coverage rates. We will, inevitably, see serious consequences related to suboptimal control of vaccine-preventable diseases (VPDs) in children concurrent with or following the pandemic. Routine pediatric immunizations of individual children at clinics, mass vaccination campaigns, and surveillance for VPDs must continue as much as possible during pandemic.
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http://dx.doi.org/10.1080/21645515.2020.1804776DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7899627PMC
February 2021

Methods to evaluate serogroup B meningococcal vaccines: From predictions to real-world evidence.

J Infect 2020 12 31;81(6):862-872. Epub 2020 Jul 31.

GSK, Rockville, MD, United States. Electronic address:

Serogroup B meningococci (MenB) remain a prominent cause of invasive meningococcal disease (IMD). The protein-based multicomponent 4CMenB and the bivalent MenB-FHbp are the only currently available vaccines against MenB-caused IMD. Efficacy studies are not possible, due to the low incidence of IMD. Therefore, the vaccines' immunogenicity has been evaluated against several target strains chosen to quantify complement-mediated killing induced by each vaccine component in the serum bactericidal antibody assay. However, due to the wide genetic diversity and different expression levels of vaccine antigens across MenB strains, vaccine performance may differ from one strain to another. Here, we review the methods used to predict MenB strain coverage for 4CMenB and MenB-FHbp. Phenotypic assays such as the meningococcal antigen typing system (MATS, 4CMenB-specific) and the flow cytometric meningococcal antigen surface expression assay (MEASURE; MenB-FHbp-specific) were developed. Genomic approaches are also available, such as genetic MATS (gMATS) and the Bexsero antigen sequence type (BAST) scheme, both 4CMenB-specific. All methods allow tentative predictions of coverage across MenB strains, including that afforded by each vaccine antigen, and are rapid and reproducible. Real-world data on vaccine effectiveness are needed to confirm predictions obtained by these methods.
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http://dx.doi.org/10.1016/j.jinf.2020.07.034DOI Listing
December 2020

Meningococcal disease surveillance in the Asia-Pacific region (2020): The global meningococcal initiative.

J Infect 2020 11 27;81(5):698-711. Epub 2020 Jul 27.

National Institute for Communicable Disease Control and Prevention, Chinese Center for Disease Control and Prevention, Beijing, China. Electronic address:

The degree of surveillance data and control strategies for invasive meningococcal disease (IMD) varies across the Asia-Pacific region. IMD cases are often reported throughout the region, but the disease is not notifiable in some countries, including Myanmar, Bangladesh and Malaysia. Although there remains a paucity of data from many countries, specific nations have introduced additional surveillance measures. The incidence of IMD is low and similar across the represented countries (<0.2 cases per 100,000 persons per year), with the predominant serogroups of Neisseria meningitidis being B, W and Y, although serogroups A and X are present in some areas. Resistance to ciprofloxacin is also of concern, with the close monitoring of antibiotic-resistant clonal complexes (e.g., cc4821) being a priority. Meningococcal vaccination is only included in a few National Immunization Programs, but is recommended for high-risk groups, including travellers (such as pilgrims) and people with complement deficiencies or human immunodeficiency virus (HIV). Both polysaccharide and conjugate vaccines form part of recommendations. However, cost and misconceptions remain limiting factors in vaccine uptake, despite conjugate vaccines preventing the acquisition of carriage.
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http://dx.doi.org/10.1016/j.jinf.2020.07.025DOI Listing
November 2020

Randomized clinical trial of DTaP5-HB-IPV-Hib vaccine administered concomitantly with meningococcal serogroup C conjugate vaccines during the primary infant series.

Vaccine 2020 07 10;38(35):5718-5725. Epub 2020 Jul 10.

Bristol Children's Vaccine Centre, University of Bristol & University Hospitals Bristol NHS Foundation Trust, Bristol, UK. Electronic address:

Background: Concomitant administration of vaccines simplifies delivery. DTaP5-HB-IPV-Hib is a fully liquid, combination vaccine against 6 diseases. This study evaluated the compatibility of DTaP5-HB-IPV-Hib with 2 different meningococcus group C conjugate (MCC) vaccines in infants.

Methods: In a phase 3, open-label study, 284 healthy infants from 11 UK centres received DTaP5-HB-IPV-Hib at age 2, 3, and 4 months; 13-valent pneumococcal conjugate vaccine (PCV13) at 2 and 4 months; a Haemophilus influenzae type b (Hib)-MCC vaccine and a measles/mumps/rubella vaccine at 12 months. Participants were randomised 1:1 to receive either an MCC-detoxified tetanus toxin vaccine (MCC-TT; n = 141) or an MCC-Corynebacterium diphtheriae CRM protein vaccine (MCC-CRM; n = 143) at 3 and 4 months. The primary outcome was seroprotection rate (SPR) to MCC (percent with rabbit complement serum bactericidal antibody titer ≥8).

Results: Per protocol analysis, MCC SPRs were 100 and 96.4 one month after the first dose, 100 and 99.1 after the second dose, and 100 and 97.3 after the third (booster) dose of MCC in the MCC-TT and MCC-CRM groups, respectively. One month after all 3 doses of DTaP5-HB-IPV-Hib, immunoglobulin G anti-polyribosylribitol phosphate SPRs (% ≥0.15 µg/mL) were 97.8 in the MCC-TT group and 100 in the MCC-CRM group; anti-hepatitis B antigen SPRs (% ≥10 mIU/mL) were 96.8 and 96.3 in the MCC-TT and MCC-CRM groups, respectively. All participants were seroprotected against diphtheria and tetanus (≥0.01 IU/mL) and poliovirus types 1, 2, and 3 (≥8 dilution), and seroresponse rates to all pertussis antigens were ≥90.4%. Two vaccine-related serious adverse events (transient severe abdominal pain and crying) occurred concomitantly in 1 participant in the MCC-CRM group. Adverse event rates were similar to other studies of DTaP5-HB-IPV-Hib, with pyrexia ≥38 °C in 10.9% of participants following any dose.

Conclusions: DTaP5-HB-IPV-Hib can be effectively used in a 2-, 3-, and 4-month infant priming schedule when given with 2 doses of MCC.
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http://dx.doi.org/10.1016/j.vaccine.2020.06.015DOI Listing
July 2020