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Background: The Invasive Respiratory Infection Surveillance (IRIS) Consortium was established to assess the impact of the COVID-19 pandemic on invasive diseases caused by Streptococcus pneumoniae, Haemophilus influenzae, Neisseria meningitidis, and Streptococcus agalactiae. We aimed to analyse the incidence and distribution of these diseases during the first 2 years of the COVID-19 pandemic compared to the 2 years preceding the pandemic., Methods: For this prospective analysis, laboratories in 30 countries and territories representing five continents submitted surveillance data from Jan 1, 2018, to Jan 2, 2022, to private projects within databases in PubMLST. The impact of COVID-19 containment measures on the overall number of cases was analysed, and changes in disease distributions by patient age and serotype or group were examined. Interrupted time-series analyses were done to quantify the impact of pandemic response measures and their relaxation on disease rates, and autoregressive integrated moving average models were used to estimate effect sizes and forecast counterfactual trends by hemisphere., Findings: Overall, 116 841 cases were analysed: 76 481 in 2018-19, before the pandemic, and 40 360 in 2020-21, during the pandemic. During the pandemic there was a significant reduction in the risk of disease caused by S pneumoniae (risk ratio 0·47; 95% CI 0·40-0·55), H influenzae (0·51; 0·40-0·66) and N meningitidis (0·26; 0·21-0·31), while no significant changes were observed for S agalactiae (1·02; 0·75-1·40), which is not transmitted via the respiratory route. No major changes in the distribution of cases were observed when stratified by patient age or serotype or group. An estimated 36 289 (95% prediction interval 17 145-55 434) cases of invasive bacterial disease were averted during the first 2 years of the pandemic among IRIS-participating countries and territories., Interpretation: COVID-19 containment measures were associated with a sustained decrease in the incidence of invasive disease caused by S pneumoniae, H influenzae, and N meningitidis during the first 2 years of the pandemic, but cases began to increase in some countries towards the end of 2021 as pandemic restrictions were lifted. These IRIS data provide a better understanding of microbial transmission, will inform vaccine development and implementation, and can contribute to health-care service planning and provision of policies., Funding: Wellcome Trust, NIHR Oxford Biomedical Research Centre, Spanish Ministry of Science and Innovation, Korea Disease Control and Prevention Agency, Torsten Söderberg Foundation, Stockholm County Council, Swedish Research Council, German Federal Ministry of Health, Robert Koch Institute, Pfizer, Merck, and the Greek National Public Health Organization., Competing Interests: Declaration of interests The UK Health Security Agency's Immunisation and Vaccine Preventable Diseases Division has provided vaccine manufacturers (GSK, Pfizer, and Sanofi) with post-marketing surveillance reports, which the Marketing Authorization Holders are required to submit to the UK Licensing authority in compliance with their Risk Management Strategy. A cost recovery charge is made for these reports. The UK Health Security Agency's Respiratory and Vaccine Preventable Bacteria Reference Unit has received unrestricted research grants from Pfizer to participate in pneumococcal surveillance projects. CHI de Créteil (France) received research grants from the French Public Health Agency, Pfizer, and MSD. University Hospitals Leuven (Belgium) received research grants from Merck-MSD and Pfizer, and consulting fees from Merck-MSD. SD received personal payments or honoraria from Pfizer. The Swiss National Reference Center for Invasive Pneumococci received funding from the Federal Office of Public Health. MH has received grants from Pfizer and personal fees (for being on an advisory board) from Pfizer and Merck Sharp & Dohme. The National Medicines Institute (Warsaw, Poland) received funding from the Polish Ministry of Health, the Polish Ministry of Science and Higher Education, Pfizer, and MSD. AS received payments from MSD and Pfizer for lectures, and from MSD, Pfizer, and Sanofi Pasteur for participation in advisory boards. AS is the unpaid Vice President of the European Meningococcal and Haemophilus Disease Society. The Finnish Institute for Health and Welfare (Finland) received research funding from Pfizer. ABB is an unpaid adviser to WHO, providing expertise related to vaccines and antimicrobial resistance. ABB is an unpaid General Assembly member (2022 onwards), and has been a board member (2016–22) and Secretary (2018–22), of the International Society of Pneumonia and Pneumococcal Diseases (ISPPD). MD has received financial support from Pfizer to attend national scientific meetings. MdP received grant funding from the National Research Foundation (South Africa) and the Bill & Melinda Gates Foundation to support the International Pathogenic Neisseria Conference (IPNC) 2022 meeting. MdP received personal support from the ISPPD to participate in the ISPPD conference in 2022, and was a member of the organising and scientific committee for the IPNC meeting in 2022. HH and MC received a grant from Pfizer (W1243730) to investigate Irish pneumococcal serotypes by whole-genome sequencing. HH received payment from Scottish Hospitals Enquiry for expert testimony. HH was the President of the Healthcare Infection Society (2018–22). KAJ received personal royalties from GlaxoSmithKline, and personal honoraria from the Wellcome Trust. SL performs contract research on behalf of St George's University of London for pharmaceutical companies (GlaxoSmithKline, Pfizer, and Sanofi), including vaccine manufacturers, but does not receive any personal remuneration. T-TL received consulting fees from the Trond Mohn Foundation. T-TL is an unpaid board member of the European Meningococcal and Haemophilus Disease Society and the German Society for Hygiene and Microbiology, committee for microbial systematics, population genetics and infection epidemiology. SM participated on an unpaid advisory board for Pfizer for the meningococcal type B vaccine in South Africa in 2020. WM received funding from GlaxoSmithKline and Pfizer for investigator-initiated research on meningitis B (MenB) strain vaccine coverage. CS received financial support for flights, accommodation, and registration to attend the 2022 ISPPD meeting in Canada. H-CS received funding from Pfizer for a pneumococcal carriage project. H-CS received funding for participation on a data safety monitoring board or advisory board for MSD. LS received personal support from the European Centre for Disease Prevention and Control for attending the European Scientific Conference on Applied Infectious Disease Epidemiology in 2022. MPGvdL received consulting fees from Pfizer, Merck, and GlaxoSmithKline; payment or honoraria from Pfizer and Merck; and support for attending meetings or travel, or both, from Pfizer. AvG is the chairperson for the National Advisory Group on Immunization of South Africa. NMvS received fees for services and consulting fees from MSD and GlaxoSmithKline, and research funding from the Dutch Health Counsel, US National Institutes of Health, and Amsterdam University Medical Centers, and from MSD and GlaxoSmithKline, which are all directly paid to the institution. NMvS holds a patent (WO 2013/020090 A3) on vaccine development against Streptococcus pyogenes. NMvS is an unpaid scientific adviser to the ItsME foundation, and a scientific adviser to the StrepAotearoa New Zealand project but fees are paid to the University of Amsterdam. NMvS holds personal stocks in Genmab. JY received payments for lectures given at scientific meetings organised by MSD and Pfizer; received support from MSD and Pfizer to attend national and international scientific meetings; and participated in advisory boards for MSD and Pfizer. DS is supported by an Oxford Clarendon Scholarship. All other authors declare no competing interests., (Copyright © 2023 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Introduction. In 2009, the World Health Organization (WHO) established the Global Invasive Bacterial Vaccine Preventable Disease (IB-VPD) Surveillance Network (GISN) to monitor the global burden and aetiology of bacterial meningitis, pneumonia and sepsis caused by Haemophilus influenzae (Hi), Neisseria meningitidis (Nm) and Streptococcus pneumoniae (Sp). Hypothesis/Gap Statement . The GISN established an external quality assessment (EQA) programme for the characterization of Hi, Nm and Sp by culture and diagnostic PCR. Aim. To assess the performance of sentinel site laboratories (SSLs), national laboratories (NLs) and regional reference laboratories (RRLs) between 2014 and 2019 in the EQA programme. Methodology. Test samples consisted of bacterial smears for Gram-staining, viable isolates for identification and serotyping or serogrouping (ST/SG), plus simulated cerebrospinal fluid (CSF) samples for species detection and ST/SG by PCR. SSLs and NLs were only required to analyse the slides for Gram staining and identify the species of the live isolates. RRLs, and any SLs and NLs that had the additional laboratory capacity, were also required to ST/SG the viable isolates and analyse the simulated CSF samples. Results. Across the period, 69-112 SS/NL labs and eight or nine RRLs participated in the EQA exercise. Most participants correctly identified Nm and Sp in Gram-stained smears but were less successful with Hi and other species. SSLs/NLs identified the Hi, Nm and Sp cultures well and also submitted up to 56 % of Hi, 62 % of Nm and 33 % of Sp optional ST/SG results each year. There was an increasing trend in the proportion of correct results submitted over the 6 years for Nm and Sp. Some SSLs/NLs also performed the optional detection and ST/SG of the three organisms by PCR in simulated CSF from 2015 onwards; 89-100 % of the CSF samples were correctly identified and 76-93 % of Hi-, 90-100 % of Nm- and 75-100 % of Sp-positive samples were also correctly ST/SG across the distributions. The RRLs performed all parts of the EQA to a very high standard, with very few errors across all aspects of the EQA. Conclusion. The EQA has been an important tool in maintaining high standards of laboratory testing and building of laboratory capacity in the GISN.

Sepsis and meningitis caused by serogroup B meningococcus are devastating diseases of infants and young adults, which cannot yet be prevented by vaccination. By genome mining, we discovered GNA1870, a new surface-exposed lipoprotein of Neisseria meningitidis that induces high levels of bactericidal antibodies. The antigen is expressed by all strains of N. meningitidis tested. Sequencing of the gene in 71 strains representative of the genetic and geographic diversity of the N. meningitidis population, showed that the protein can be divided into three variants. Conservation within each variant ranges between 91.6 to 100%, while between the variants the conservation can be as low as 62.8%. The level of expression varies between strains, which can be classified as high, intermediate, and low expressors. Antibodies against a recombinant form of the protein elicit complement-mediated killing of the strains that carry the same variant and induce passive protection in the infant rat model. Bactericidal titers are highest against those strains expressing high yields of the protein; however, even the very low expressors are efficiently killed. The novel antigen is a top candidate for the development of a new vaccine against meningococcus.

Homologous recombination was used to generate a number of mutants of serogroup B Neisseria meningitidis B16B6 with the following characteristics: (i) an inability to bind human or porcine transferrin because of loss of both transferrin binding proteins (Tbp) A and B [strain B16B6(Str(r))/tbpA(-)B(-)] and (ii) an ability to bind porcine transferrin but not human transferrin [strain B16B6(Str(r))/tbpA(ap)B(ap)] due to replacement of the meningococcal Tbp with the Tbp of Actinobacillus pleuropneumoniae. During construction of the B16B6(Str(r))/tbpA(ap)B(ap) strain, transformants expressing only TbpA or TbpB of A. pleuropneumoniae were isolated [strains B16B6(Str(r))/tbpA(ap)B(-) and B16B6(Str(r))/tbpA(-)B(ap)]. Expression of the A. pleuropneumoniae Tbp in N. meningitidis B16B6 was iron regulated and expressed under the control of the meningococcal promoter. The relative abilities of the meningococcal transformants to bind porcine transferrin were in the order B16B6(Str(r))/tbpA(ap)B(ap) > B16B6(Str(r))/tbpA(ap)B(-) > B16B6(Str(r))/tbpA(-)B(ap). Of these transformants, only B16B6(Str(r))/tbpA(ap)B(ap) could grow in the presence of porcine transferrin as the sole iron source, achieving a growth rate similar to that of the B16B6 parent strain in the presence of human transferrin.