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Background The 4-component capsular group B meningococcal vaccine (4CMenB) was licensed as a 4-dose infant schedule but introduced into the United Kingdom as 3 doses at 2, 4, and 12 months of age. We describe the immunogenicity and reactogenicity of the 2 + 1 schedule in infants. Methods Infants were randomized to receive 4CMenB with routine immunizations (test group) at 2, 4, and 12 months or 4CMenB alone at 6, 8, and 13 months of age (control group). Serum bactericidal antibody (SBA) assay against a serogroup B meningococcal reference strain (44/76-SL), memory B-cell responses to factor H binding protein, Neisseria adhesion protein A, Neisseria heparin binding antigen, Porin A (PorA), and reactogenicity was measured. Results One hundred eighty-seven infants were randomized (test group: 94; control group: 93). In the test group, 4CMenB induced SBA titers above the putative protective threshold (1:4) after primary and booster doses in 97% of participants. Postbooster, the SBA GMT (72.1; 95% confidence interval [CI], 51.7–100.4) was numerically higher than the serum bactericidal antibody geometric mean titre (SBA GMT) determined post–primary vaccination (48.6; 95% CI, 37.2–63.4). After primary immunizations, memory B-cell responses did not change when compared with baseline controls, but frequencies significantly increased after booster. Higher frequency of local and systemic adverse reactions was associated with 4CMenB. Conclusions A reduced schedule of 4CMenB was immunogenic and established immunological memory after booster.

Background Pertussis can lead to serious disease and even death in infants. Older adults are more vulnerable to complications as well. In high-income countries, acellular pertussis vaccines are used for priming vaccination. In the administration of booster vaccinations to different age groups and target populations there is a substantial between-country variation. We investigated the effect of age on the response to acellular pertussis booster vaccination in three European countries. Methods This phase IV longitudinal intervention study performed in Finland, the Netherlands and the United Kingdom between October 2017 and January 2019 compared the vaccine responses between healthy participants of four age groups: children (7–10y), adolescents (11–15y), young adults (20–34y), and older adults (60–70y). All participants received a three-component acellular pertussis vaccine. Serum IgG and IgA antibody concentrations to pertussis antigens at day 0, 28, and 1 year were measured with a multiplex immunoassay, using pertussis toxin concentrations at day 28 as primary outcome. This trial is registered with ClinicalTrialsRegister.eu (2016–003,678–42). Findings Children (n = 109), adolescents (n = 121), young adults (n = 74), and older adults (n = 75) showed high IgG antibody concentrations to pertussis toxin at day 28 with GMCs of 147 (95% CI 120–181), 161 (95% CI 132–196), 103 (95% CI 80–133), and 121 IU/ml (95% CI 94–155), respectively. A significant increase in GMCs for vaccine antigens in all age groups by 28 days was found which had decreased by 1 year. Differences in patterns of IgG GMCs at 28 days and 1 year post-vaccination did not have a consistent relationship to age. In contrast, IgA antibodies for all antigens increased with age at all timepoints. Interpretation Acellular pertussis booster vaccination induces significant serum IgG responses to pertussis antigens across the age range which are not uniformly less in older adults. Acellular boosters could be considered for older adults to reduce the health and economic burden of pertussis.

Neisseria meningitidis is a major cause of meningitis and septicaemia. A MenB vaccine (4CMenB) was licensed by the European Medicines Agency in January 2013. Here we describe the blood transcriptome and proteome following infant immunisations with or without concomitant 4CMenB, to gain insight into the molecular mechanisms underlying post‐vaccination reactogenicity and immunogenicity. Infants were randomised to receive control immunisations (PCV13 and DTaP‐IPV‐Hib) with or without 4CMenB at 2 and 4 months of age. Blood gene expression and plasma proteins were measured prior to, then 4 h, 24 h, 3 days or 7 days post‐vaccination. 4CMenB vaccination was associated with increased expression of ENTPD7 and increased concentrations of 4 plasma proteins: CRP, G‐CSF, IL‐1RA and IL‐6. Post‐vaccination fever was associated with increased expression of SELL, involved in neutrophil recruitment. A murine model dissecting the vaccine components found the concomitant regimen to be associated with increased gene perturbation compared with 4CMenB vaccine alone with enhancement of pathways such as interleukin‐3, ‐5 and GM‐CSF signalling. Finally, we present transcriptomic profiles predictive of immunological and febrile responses following 4CMenB vaccine., A randomised clinical trial evaluates transcriptomic and proteomic profiles following infant concomitant 4CMenB vaccination, compared with control vaccines alone. A novel framework is provided for both understanding and predicting vaccine immunogenicity and reactogenicity.

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

Background: Pertussis can lead to serious disease and even death in infants. In addition older adults and patients with chronic diseases are more vulnerable to complications. In high-income countries, priming vaccination in infancy is usually undertaken using acellular pertussis vaccines. There is a significant between-country variation in the use of booster vaccinations which are administered at different ages and to different target populations. We investigated the effect of age on the response to acellular pertussis booster vaccination in three European countries. Methods: In total 379 participants, divided between four age groups - children (7-10y), adolescents (11-15y), young adults (20-34y), and older adults (60-70y) - received a pertussis toxoid, filamentous haemagglutinin, and pertactin containing booster vaccine. Serum IgG and IgA antibody concentrations to pertussis vaccine antigens at day 0, day 28, and one year were measured with a multiplex immunoassay. Findings: Participants from all four age groups showed high IgG antibodies to pertussis toxin at day 28. IgG antibody concentrations at 28 days and one year postvaccination were comparable between the age groups, but IgA concentrations showed an increase of antibody concentrations with age at all timepoints. Interpretation: Acellular pertussis booster vaccination induces comparable serological responses in older adults as younger age groups and could be considered for older adults in order to increase their protection. Trial Registration: The trial was registered at the EU Clinical Trial database (EudraCT number 2016-003678-42). Funding: PERISCOPE has received funding from the Innovative Medicines Initiative2 Joint Undertaking under grant agreement No 115910. This Joint Undertaking receives support from the European Union’s Horizon 2020 research and innovation programme, EFPIA and BMGF. Declaration of Interests: None of the authors received payment or service from a third part at any time, nor does anyone have a financial relationship with entities in the bio-medical arena. None of the authors have any patents relevant to the work. MVP is a member of the Portuguese National Immunisation Technical Advisory Group (Comissao Tecnica de Vacinacao da Direccao Geral de Saude). Ethics Approval Statement: The trial was approved by the Medical Research Ethics Committees United (MEC-U, NL60807.100.17-R17.039) in the Netherlands, the South Central - Hampshire B Research Ethics Committee (REC, 19/SC/0368) in the UK, and the MREC UTU (ETMK Dnro: 129/1800/2017) in Finland. Written informed consent was obtained from all adult participants, and parents or legal guardian of minors, at the start of the study.

Summary 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.

Immunocompromised children have a higher risk of developing infections and associated higher rates of mortality and morbidity. Although this group could benefit the most from vaccine administration, specific considerations regarding immunisations are required. This review is a summary of the vaccines that are relevant to the immunocompromised host, covering both live and non-live vaccines. The burden of disease, safety, immunogenicity/effectiveness and specific recommendations for each vaccine are described as well as specific guidelines from different organisations.

The prognosis of the association between Breast Cancer (BC) and Meningioma (M) is unknown. To evaluate the survival impact of tumor exposure sequence in patients with both tumors. Patients were divided in groups according to the tumors sequence: BC before M (group 1), synchronous BC + M (group 2) and BC after M (group 3). The SEER database was used. Demographics, meningioma and breast cancer variables were analyzed. The primary outcome was oncological survival. A total of 1715 patients were included (median follow-up:84 months). Group 2 had the shortest survival (median:32 months) and group 1 the longest (median:110 months). On the unadjusted analysis, group 2 had the shortest survival (HR:3.13, 95% CI 1.62-6.04) and adjusted analysis confirmed this finding (HR 3.11, 95% CI 1.58-6.19), with no statistical difference between the metachronous tumors groups. Increasing age (HR:1.13, 95% CI 1.11-1.15, p 0.05). The association between surgery and radiotherapy in BC treatment improved the outcome (HR 0.37, 95% CI 0.23-0.93, p 0.05) on stratified analysis. Synchronous tumors were associated with lower survival. Increasing age had a negative influence on patient survival. Although surgery and radiotherapy for breast cancer had a positive influence in the outcome, meningioma treatment was not related with survival. Grade III meningioma and hormonal receptor status only influenced synchronous tumors patient survival. info:eu-repo/semantics/publishedVersion

Background: Infants in the UK were first offered a pneumococcal conjugate vaccine (PCV7) in 2006, given at 2 and 4 months of age and a booster dose at 13 months (2 + 1 schedule). A 13-valent vaccine (PCV13) replaced PCV7 in 2010. We aimed to compare the post-booster antibody response in UK infants given a reduced priming schedule of PCV13 (ie, a 1 + 1 schedule) versus the current 2 + 1 schedule and to assess the potential effect on population protection. Methods: In this multicentre, parallel group, randomised controlled trial, we recuited infants due to receive their primary immunisations aged up to 13 weeks on first vaccinations by information booklets mailed out via the NHS Child Health Information Service and the UK National Health Application and Infrastructure Services. Eligible infants were randomly assigned (1:1) to receive PCV13 at 2, 4, and 12 months (2 + 1 schedule) or 3 and 12 months of age (1 + 1 schedule) delivered with other routine vaccinations. Randomisation was done by computer-generated permuted block randomisation, with a block size of six. Participants and clinical trial staff were not masked to treatment allocation. The primary endpoint was serotype-specific immunoglobulin G concentrations values (geometric mean concentrations [GMC] in μg/mL) measured in blood samples collected at 13 months of age. Analysis was by modified intention to treat with all individuals included by randomised group if they had a laboratory result. This trial is registered on the EudraCT clinical trial database, number 2015-000817-32, and ClinicalTrials.gov, number NCT02482636. Findings: Between September, 2015, and June, 2016, 376 infants were assessed for eligibility. 81 infants were excluded for not meeting the inclusion criteria (n=50) or for other reasons (n=31). 213 eligible infants were enrolled and randomly allocated to group 1 (n=106; 2 + 1 schedule) or to group 2 (n=107; 1 + 1 schedule). In group 1, 91 serum samples were available for analysis 1 month after booster immunisation versus 86 in group 2. At month 13, post-booster, GMCs were equivalent between schedules for serotypes 3 (0·61 μg/mL in group 1 vs 0·62 μg/mL in group 2), 5 (1·74 μg/mL vs 2·11 μg/mL), 7F (3·98 μg/mL vs 3·36 μg/mL), 9V (2·34 μg/mL vs 2·50 μg/mL), and 19A (8·38 μg/mL vs 8·83 μg/mL). Infants given the 1 + 1 schedule had significantly greater immunogenicity post-booster than those given the 2 + 1 schedule for serotypes 1 (8·92 μg/mL vs 3·07 μg/mL), 4 (3·43 μg/mL vs 2·55 μg/mL), 14 (16·9 μg/mL vs 10·49 μg/mL), and 19F (14·76 μg/mL vs 11·12 μg/mL; adjusted p value range Interpretation: Our findings show that for nine of the 13 serotypes in PCV13, post-booster responses in infants primed with a single dose are equivalent or superior to those seen following the standard UK 2 + 1 schedule. Introducing a 1 + 1 schedule in countries with a mature PCV programme and established herd immunity is likely to maintain population control of vaccine-type pneumococcal disease.

Whooping cough is a highly contagious, acute respiratory disease, caused by the Gram-negative bacterium Bordetella pertussis (Bp). Despite the introduction and widespread use of vaccines starting in the 1950s pertussis cases continue to be reported, with a significant global impact. The role of specific virulence factors in disease and the immune mechanisms associated with protection following natural infection or vaccination are still not completely understood. The recently-developed baboon model of clinical pertussis provides a valuable tool for the study of pertussis. Baboons infected with B. pertussis exhibit all of the manifestations of human pertussis including paroxysmal coughing, mucus production, leukocytosis and transmission. The establishment of this model provides the opportunity to address unanswered questions about the natural progression of this disease and host responses to infection and vaccination in a very relevant model. In this review, we present an overview of our knowledge of pertussis along with recent advances resulting from use of the baboon model. Remaining questions and future research directions are discussed. We hope that the knowledge gained through use of the baboon model of pertussis and clinical studies will allow the development of more efficacious vaccines, conferring long lasting protection against disease and transmission.

A 14-year-old adolescent presented with a prolonged fever, abnormal liver function, anaemia, thrombocytopaenia, but a good general status. Diagnosis of hemophagocytic lymphohistiocytosis (HLH) was suspected, in spite of the initial indolent course. Secondary causes were excluded, but no specific mutation indicative of primary HLH was found. The patient started with specific therapy, but progressed with reactivations and later with persistently active disease. Haematopoietic stem cell transplantation was not successful and the adolescent died 7 months after diagnosis.