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ObjectiveINGR1D (INvestigating Genetic Risk for type 1 Diabetes) was a type 1 diabetes (T1D) genetic screening study established to identify participants for a primary prevention trial (POInT, Primary Oral Insulin Trial).MethodsThe majority of participants were recruited by research midwives in antenatal clinics from 18 weeks’ gestation. Using the NHS Newborn Bloodspot Screening Programme (NBSP) infrastructure, participants enrolled in INGR1D had an extra sample taken from their day 5 bloodspot card sent for T1D genetic screening. Those at an increased risk of T1D were informed of the result, given education about T1D and the opportunity to take part in POInT.ResultsBetween April 2018 and November 2020, 66% of women approached about INGR1D chose to participate. 15 660 babies were enrolled into INGR1D and 14 731 blood samples were processed. Of the processed samples, 157 (1%) had confirmed positive results, indicating an increased risk of T1D, of whom a third (n=49) enrolled into POInT (20 families were unable to participate in POInT due to COVID-19 lockdown restrictions).ConclusionThe use of prospective consent to perform personalised genetic testing on samples obtained through the routine NBSP represents a novel mechanism for clinical genetic research in the UK and provides a model for further population-based genetic studies in the newborn.

ObjectivesTo describe rates and variation in uptake of pneumococcal and measles, mumps and rubella (MMR) vaccines in children and associated change in vaccine-preventable diseases (VPDs) across the first and second waves of the COVID-19 pandemic.MethodsRetrospective database study of all children aged ResultsCoverage of booster dose of pneumococcal vaccine decreased from 94.5% (95% CI 94.3% to 94.7%) at its height on International Organization for Standardization (ISO) week 47 (2020) to 93.6% (95% CI 93.4% to 93.8%) by the end of the study. Coverage of second dose of MMR decreased from 85.0% (95% CI 84.7% to 85.3%) at its height on ISO week 37 (2020) to 84.1% (95% CI 83.8% to 84.4%) by the end of the study. The break point in trends for MMR was at ISO week 34 (2020) (95% CI weeks 32–37 (2020)), while for pneumococcal vaccine the break point was later at ISO week 3 (2021) (95% CI week 53 (2020) to week 8 (2021)). Vaccination coverage for children of white ethnicity was less likely to decrease than other ethnicities. Rates of consultation for VPDs fell and remained low since August 2020.ConclusionChildhood vaccination rates started to fall ahead of the onset of the second wave; this fall is accentuating ethnic, socioeconomic and geographical disparities in vaccine uptake and risks widening health disparities. Social distancing and school closures may have contributed to lower rates of associated VPDs, but there may be increased risk as these measures are removed.

Three hexavalent (DTaP-IPV-Hib-HepB) vaccines are licensed in Europe, only one of which (Vaxelis, Hex-V), uses a meningococcal outer membrane protein complex as a carrier protein for Hemophilus influenza type b (Hib), creating potential interactions with the meningococcal vaccine 4CMenB.In this single-center open-label randomized trial, infants were randomized in a 1:1 ratio to receive Hex-V or an alternative hexavalent vaccine (Infanrix-Hexa, Hex-IH) at 2, 3, and 4 months with 4CMenB (2, 4, and 12 months) in the UK routine immunization schedule. The primary outcome was noninferiority of geometric mean concentrations (GMCs) of anti-PRP (Hib) IgG at 5 months of age. Secondary outcomes included safety, reactogenicity, and immunogenicity of other administered vaccines measured at 5 and 13 months of age.Of the 194 participants enrolled, 96 received Hex-V and 98 Hex-IH. Noninferiority of anti-PRP IgG GMCs at 5 months of age in participants receiving Hex-V was established; GMCs were 23-times higher following three doses of Hex-V than three doses of Hex-IH (geometric mean ratio (GMR) 23.25; one-sided 95% CI 16.21, -). 78/85 (92%) of Hex-V recipients and 43/87 (49%) of Hex-IH recipients had anti-PRP antibodies ≥1.0 µg/mL. At 5 months of age serum, bactericidal activity titers against MenB strain 5/99 were higher following Hex-V than Hex-IH (GMR 1.56; 95% CI, 1.13-2.14). The reactogenicity profile was similar in both groups.These data support flexibility in the use of either Hex-IH or Hex-V in infant immunization schedules containing 4CMenB, with the possibility that Hex-V may enhance protection against Hib.

An antenatal pertussis vaccination programme was introduced in 2012 in the UK in the context of a national outbreak of pertussis. It has been shown that a lower antibody response to primary immunisation can be seen for certain pertussis antigens in infants born to women who received pertussis-containing antenatal vaccines, a phenomenon known as blunting. The longer-term impact of this has not been documented previously, and accordingly was evaluated in this study. Children were predominantly recruited from a previous study in which their mothers had received acellular pertussis-containing antenatal vaccines (dTaP 3-IPV [diphtheria toxoid, tetanus toxoid, three antigen acellular pertussis and inactivated polio] or dTaP 5-IPV [diphtheria toxoid, tetanus toxoid, five antigen acellular pertussis and inactivated polio]), or no pertussis-containing vaccine. Blood samples were obtained prior to and one month after the acellular pertussis-containing preschool booster (dTaP 5-IPV) was given at around age 3 years 4 months. Pre- and post-booster immunoglobulin G (IgG) geometric mean concentrations (GMCs) against pertussis toxin, filamentous haemagglutinin, fimbriae 2 & 3, and pertactin, were compared. Prior to the receipt of the preschool booster, there was no difference in the IgG GMCs against pertussis-specific antigens between children born to women vaccinated with dTaP 3-IPV and dTaP 5-IPV; however, IgG GMCs against pertussis toxin were significantly lower in children born to women vaccinated with dTaP 3-IPV compared with children born to unvaccinated women (geometric mean ratio 0.42 [95 % CI 0.22–0.78], p = 0.03). One month after the receipt of the preschool booster there was no differences between the groups. The blunting effect of antenatal pertussis vaccine on pertussis responses in children can persist until preschool age, although it is overcome by the administration of a booster dose. ClinicalTrials.gov registration number: NCT03578120

Background Priming COVID-19 vaccine schedules have been deployed at variable intervals globally, which might influence immune persistence and the relative importance of third-dose booster programmes. Here, we report exploratory analyses from the Com-COV trial, assessing the effect of 4-week versus 12-week priming intervals on reactogenicity and the persistence of immune response up to 6 months after homologous and heterologous priming schedules using the vaccines BNT162b2 (tozinameran, Pfizer/BioNTech) and ChAdOx1 nCoV-19 (AstraZeneca). Methods Com-COV was a participant-masked, randomised immunogenicity trial. For these exploratory analyses, we used the trial's general cohort, in which adults aged 50 years or older were randomly assigned to four homologous and four heterologous vaccine schedules using BNT162b2 and ChAdOx1 nCoV-19 with 4-week or 12-week priming intervals (eight groups in total). Immunogenicity analyses were done on the intention-to-treat (ITT) population, comprising participants with no evidence of SARS-CoV-2 infection at baseline or for the trial duration, to assess the effect of priming interval on humoral and cellular immune response 28 days and 6 months post-second dose, in addition to the effects on reactogenicity and safety. The Com-COV trial is registered with the ISRCTN registry, 69254139 (EudraCT 2020–005085–33). Findings Between Feb 11 and 26, 2021, 730 participants were randomly assigned in the general cohort, with 77–89 per group in the ITT analysis. At 28 days and 6 months post-second dose, the geometric mean concentration of anti-SARS-CoV-2 spike IgG was significantly higher in the 12-week interval groups than in the 4-week groups for homologous schedules. In heterologous schedule groups, we observed a significant difference between intervals only for the BNT162b2–ChAdOx1 nCoV-19 group at 28 days. Pseudotyped virus neutralisation titres were significantly higher in all 12-week interval groups versus 4-week groups, 28 days post-second dose, with geometric mean ratios of 1·4 (95% CI 1·1–1·8) for homologous BNT162b2, 1·5 (1·2–1·9) for ChAdOx1 nCoV-19–BNT162b2, 1·6 (1·3–2·1) for BNT162b2–ChAdOx1 nCoV-19, and 2·4 (1·7–3·2) for homologous ChAdOx1 nCoV-19. At 6 months post-second dose, anti-spike IgG geometric mean concentrations fell to 0·17–0·24 of the 28-day post-second dose value across all eight study groups, with only homologous BNT162b2 showing a slightly slower decay for the 12-week versus 4-week interval in the adjusted analysis. The rank order of schedules by humoral response was unaffected by interval, with homologous BNT162b2 remaining the most immunogenic by antibody response. T-cell responses were reduced in all 12-week priming intervals compared with their 4-week counterparts. 12-week schedules for homologous BNT162b2 and ChAdOx1 nCoV-19–BNT162b2 were up to 80% less reactogenic than 4-week schedules. Interpretation These data support flexibility in priming interval in all studied COVID-19 vaccine schedules. Longer priming intervals might result in lower reactogenicity in schedules with BNT162b2 as a second dose and higher humoral immunogenicity in homologous schedules, but overall lower T-cell responses across all schedules. Future vaccines using these novel platforms might benefit from schedules with long intervals. Funding UK Vaccine Taskforce and National Institute for Health and Care Research.

Summary Viral variants of concern may emerge with dangerous resistance to the immunity generated by the current vaccines to prevent coronavirus disease 2019 (Covid-19). Moreover, if some variants of concern have increased transmissibility or virulence, the importance of efficient public health measures and vaccination programs will increase. The global response must be both timely and science based.

Objective:Serogroup W and Y invasive meningococcal disease increased globally from 2000 onwards. Responding to a rapid increase in serogroup W clonal complex 11 (W:cc11) invasive meningococcal disease, the UK replaced an adolescent booster dose of meningococcal C conjugate vaccine with quadrivalent MenACWY conjugate vaccine in 2015. By 2018, the vaccine coverage in the eligible school cohorts aged 14 to 19years was 84%. We assessed the impact of the MenACWY vaccination programme on meningococcal carriage. Methods:An observational study of culture-defined oropharyngeal meningococcal carriage prevalence before and after the start of the MenACWY vaccination programme in UK school students, aged 15 to 19years, using two cross-sectional studies: 2014 to 2015 “UKMenCar4” and 2018 “Be on the TEAM” (ISRCTN75858406). Results:A total of 10625 participants preimplementation and 13438 postimplementation were included. Carriage of genogroups C, W, and Y (combined) decreased from 2.03 to 0.71% (OR 0.34 [95% CI 0.27–0.44], p.those expressing capsule) decreased for genogroup W by 53.8% (95% CI -5.0 – 79.8, p=0.016) and for genogroup Y by 30.1% (95% CI 8.946·3, p=0.0025). Discussion:The UK MenACWY vaccination programme reduced carriage acquisition of genogroup and serogroup Y and W meningococci and sustained low levels of genogroup C carriage. These data support the use of quadrivalent MenACWY conjugate vaccine for indirect (herd) protection.

Background Vaccination of children and young people against SARS-CoV-2 is recommended in some countries. Scarce data have been published on immune responses induced by COVID-19 vaccines in people younger than 18 years compared with the same data that are available in adults. Methods COV006 is a phase 2, single-blind, randomised, controlled trial of ChAdOx1 nCoV-19 (AZD1222) in children and adolescents at four trial sites in the UK. Healthy participants aged 6–17 years, who did not have a history of chronic respiratory conditions, laboratory-confirmed COVID-19, or previously received capsular group B meningococcal vaccine (the control), were randomly assigned to four groups (4:1:4:1) to receive two intramuscular doses of 5 × 1010 viral particles of ChAdOx1 nCoV-19 or control, 28 days or 84 days apart. Participants, clinical investigators, and the laboratory team were masked to treatment allocation. Study groups were stratified by age, and participants aged 12–17 years were enrolled before those aged 6–11 years. Due to the restrictions in the use of ChAdOx1 nCoV-19 in people younger than 30 years that were introduced during the study, only participants aged 12–17 years who were randomly assigned to the 28-day interval group had received their vaccinations at the intended interval (day 28). The remaining participants received their second dose at day 112. The primary outcome was assessment of safety and tolerability in the safety population, which included all participants who received at least one dose of the study drug. The secondary outcome was immunogenicity, which was assessed in participants who were seronegative to the nucleocapsid protein at baseline and received both prime and boost vaccine. This study is registered with ISRCTN (15638344). Findings Between Feb 15 and April 2, 2021, 262 participants (150 [57%] participants aged 12–17 years and 112 [43%] aged 6–11 years; due to the change in the UK vaccination policy, the study terminated recruitment of the younger age group before the planned number of participants had been enrolled) were randomly assigned to receive vaccination with two doses of either ChAdOx1 nCoV-19 (n=211 [n=105 at day 28 and n=106 at day 84]) or control (n=51 [n=26 at day 28 and n=25 at day 84]). One participant in the ChAdOx1 nCoV-19 day 28 group in the younger age bracket withdrew their consent before receiving a first dose. Of the participants who received ChAdOx1 nCoV-19, 169 (80%) of 210 participants reported at least one solicited local or systemic adverse event up to 7 days following the first dose, and 146 (76%) of 193 participants following the second dose. No serious adverse events related to ChAdOx1 nCoV-19 administration were recorded by the data cutoff date on Oct 28, 2021. Of the participants who received at least one dose of ChAdOx1 nCoV-19, there were 128 unsolicited adverse events up to 28 days after vaccination reported by 83 (40%) of 210 participants. One participant aged 6–11 years receiving ChAdOx1 nCoV-19 reported a grade 4 fever of 40·2°C on day 1 following first vaccination, which resolved within 24 h. Pain and tenderness were the most common local solicited adverse events for all the ChAdOx1 nCoV-19 and capsular group B meningococcal groups following both doses. Of the 242 participants with available serostatus data, 14 (6%) were seropositive at baseline. Serostatus data were not available for 20 (8%) of 262 participants. Among seronegative participants who received ChAdOx1 nCoV-19, anti-SARS-CoV-2 IgG and pseudoneutralising antibody titres at day 28 after the second dose were higher in participants aged 12–17 years with a longer interval between doses (geometric means of 73 371 arbitrary units [AU]/mL [95% CI 58 685–91 733] and 299 half-maximal inhibitory concentration [IC50; 95% CI 230–390]) compared with those aged 12–17 years who received their vaccines 28 days apart (43 280 AU/mL [95% CI 35 852–52 246] and 150 IC50 [95% CI 116–194]). Humoral responses were higher in those aged 6–11 years than in those aged 12–17 years receiving their second dose at the same 112-day interval (geometric mean ratios 1·48 [95% CI 1·07–2·07] for anti-SARS-CoV-2 IgG and 2·96 [1·89–4·62] for pseudoneutralising antibody titres). Cellular responses peaked after a first dose of ChAdOx1 nCoV-19 across all age and interval groups and remained above baseline after a second vaccination. Interpretation ChAdOx1 nCoV-19 is well tolerated and immunogenic in children aged 6–17 years, inducing concentrations of antibody that are similar to those associated with high efficacy in phase 3 studies in adults. No safety concerns were raised in this trial. Funding AstraZeneca and the UK Department of Health and Social Care through the UK National Institute for Health and Care Research.

Background Respiratory syncytial virus (RSV) remains a leading cause of pediatric morbidity, with no approved vaccine. We assessed the safety and immunogenicity of the Ad26.RSV.preF vaccine candidate in adults and children. Methods In this randomized, double-blind, phase 1/2a, placebo-controlled study, 12 adults (18–50 years) and 36 RSV-seropositive children (12–24 months) were randomized 2:1 to Ad26.RSV.preF (1 × 1011 viral particles [vp] for adults, 5 × 1010 vp for children) or placebo, at day 1 and 29, with 6-month immunogenicity and 1-year safety follow-up. Respiratory syncytial virus infection was an exploratory outcome in children. Results In adults, solicited adverse events (AEs) were generally mild to moderate, with no serious AEs. In children, no vaccination-related serious AEs were reported; fever was reported in 14 (58.3%) Ad26.RSV.preF recipients. Baseline pediatric geometric mean titers for RSV A2 neutralization increased from 121 (95% confidence interval [CI], 76–191) to 1608 (95% CI, 730–3544) at day 29, and 2235 (95% CI, 1586–3150) at day 57, remaining elevated over 7 months. Respiratory syncytial virus infection was confirmed in fewer children receiving Ad26.RSV.preF (1, 4.2%) than placebo (5, 41.7%). Conclusions Ad26.RSV.preF demonstrated immunogenicity in healthy adults and toddlers, with no safety concerns raised. Evaluations in RSV-seronegative children are underway.

The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic β cells and promote β cell death. The autoimmunity is considered silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic β cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes. Pre- and postprandial blood glucose decreased between 4 and 18 months of age and gradually increased until the final measurements at 3.6 years of age. Determinants of blood glucose trajectories in the first year of life included sex, body mass index, glucose-related genetic risk scores, and the type 1 diabetes-susceptible INS gene. Children who developed islet autoantibodies had early elevations in blood glucose concentrations. A sharp and sustained rise in postprandial blood glucose was observed at around 2 months prior to autoantibody seroconversion, with further increases in postprandial and, subsequently, preprandial values after seroconversion. These findings show heterogeneity in blood glucose control in infancy and early childhood and suggest that islet autoimmunity is concurrent or subsequent to insults on the pancreatic islets. ispartof: JOURNAL OF CLINICAL INVESTIGATION vol:132 issue:20 ispartof: location:United States status: published

Background: \ud Few data exist on the comparative safety and immunogenicity of different COVID-19 vaccines given as a third (booster) dose. To generate data to optimise selection of booster vaccines, we investigated the reactogenicity and immunogenicity of seven different COVID-19 vaccines as a third dose after two doses of ChAdOx1 nCov-19 (Oxford–AstraZeneca; hereafter referred to as ChAd) or BNT162b2 (Pfizer–BioNtech, hearafter referred to as BNT).\ud \ud Methods: \ud COV-BOOST is a multicentre, randomised, controlled, phase 2 trial of third dose booster vaccination against COVID-19. Participants were aged older than 30 years, and were at least 70 days post two doses of ChAd or at least 84 days post two doses of BNT primary COVID-19 immunisation course, with no history of laboratory-confirmed SARS-CoV-2 infection. 18 sites were split into three groups (A, B, and C). Within each site group (A, B, or C), participants were randomly assigned to an experimental vaccine or control. Group A received NVX-CoV2373 (Novavax; hereafter referred to as NVX), a half dose of NVX, ChAd, or quadrivalent meningococcal conjugate vaccine (MenACWY) control (1:1:1:1). Group B received BNT, VLA2001 (Valneva; hereafter referred to as VLA), a half dose of VLA, Ad26.COV2.S (Janssen; hereafter referred to as Ad26) or MenACWY (1:1:1:1:1). Group C received mRNA1273 (Moderna; hereafter referred to as m1273), CVnCov (CureVac; hereafter referred to as CVn), a half dose of BNT, or MenACWY (1:1:1:1). Participants and all investigatory staff were blinded to treatment allocation. Coprimary outcomes were safety and reactogenicity and immunogenicity of anti-spike IgG measured by ELISA. The primary analysis for immunogenicity was on a modified intention-to-treat basis; safety and reactogenicity were assessed in the intention-to-treat population. Secondary outcomes included assessment of viral neutralisation and cellular responses. This trial is registered with ISRCTN, number 73765130.\ud \ud Findings: \ud Between June 1 and June 30, 2021, 3498 people were screened. 2878 participants met eligibility criteria and received COVID-19 vaccine or control. The median ages of ChAd/ChAd-primed participants were 53 years (IQR 44–61) in the younger age group and 76 years (73–78) in the older age group. In the BNT/BNT-primed participants, the median ages were 51 years (41–59) in the younger age group and 78 years (75–82) in the older age group. In the ChAd/ChAD-primed group, 676 (46·7%) participants were female and 1380 (95·4%) were White, and in the BNT/BNT-primed group 770 (53·6%) participants were female and 1321 (91·9%) were White. Three vaccines showed overall increased reactogenicity: m1273 after ChAd/ChAd or BNT/BNT; and ChAd and Ad26 after BNT/BNT. For ChAd/ChAd-primed individuals, spike IgG geometric mean ratios (GMRs) between study vaccines and controls ranged from 1·8 (99% CI 1·5–2·3) in the half VLA group to 32·3 (24·8–42·0) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·1 (95% CI 0·7–1·6) for ChAd to 3·6 (2·4–5·5) for m1273. For BNT/BNT-primed individuals, spike IgG GMRs ranged from 1·3 (99% CI 1·0–1·5) in the half VLA group to 11·5 (9·4–14·1) in the m1273 group. GMRs for wild-type cellular responses compared with controls ranged from 1·0 (95% CI 0·7–1·6) for half VLA to 4·7 (3·1–7·1) for m1273. The results were similar between those aged 30–69 years and those aged 70 years and older. Fatigue and pain were the most common solicited local and systemic adverse events, experienced more in people aged 30–69 years than those aged 70 years or older. Serious adverse events were uncommon, similar in active vaccine and control groups. In total, there were 24 serious adverse events: five in the control group (two in control group A, three in control group B, and zero in control group C), two in Ad26, five in VLA, one in VLA-half, one in BNT, two in BNT-half, two in ChAd, one in CVn, two in NVX, two in NVX-half, and one in m1273.\ud \ud Interpretation: \ud All study vaccines boosted antibody and neutralising responses after ChAd/ChAd initial course and all except one after BNT/BNT, with no safety concerns. Substantial differences in humoral and cellular responses, and vaccine availability will influence policy choices for booster vaccination.\ud \ud Funding: \ud UK Vaccine Taskforce and National Institute for Health Research.

Human respiratory syncytial virus (RSV) is a major cause of lower respiratory tract infection in young children globally, but little is known about within-host RSV diversity. Here, we characterised within-host RSV populations using deep-sequencing data from 319 nasopharyngeal swabs collected during 2017-2020. RSV-B had lower consensus diversity than RSV-A at the population level, while exhibiting greater within-host diversity. Two RSV-B consensus sequences had an amino acid alteration (K68N) in the fusion (F) protein, which has been associated with reduced susceptibility to nirsevimab (MEDI8897), a novel RSV monoclonal antibody under development. In addition, several minor variants were identified in the antigenic sites of the F protein, one of which may confer resistance to palivizumab, the only licensed RSV monoclonal antibody. The differences in within-host virus populations emphasise the importance of monitoring for vaccine efficacy and may help to explain the different prevalences of monoclonal antibody-escape mutants between the two subgroups.

Background Antibody Fc-mediated functions, such as antibody-dependent cellular cytotoxicity, contribute to vaccine-induced protection against viral infections. Fc-mediated function of anti-Ebola glycoprotein (GP) antibodies suggest that Fc-dependent activation of effector cells, including natural killer (NK) cells, could play a role in vaccination against Ebola virus disease. Methods We analyzed the effect on primary human NK cell activation of anti-Ebola GP antibody in the serum of United Kingdom–based volunteers vaccinated with the novel 2-dose heterologous adenovirus type 26.ZEBOV, modified vaccinia Ankara–BN-Filo vaccine regimen. Results We demonstrate primary human NK cell CD107a and interferon γ expression, combined with down-regulation of CD16, in response to recombinant Ebola virus GP and post-vaccine dose 1 and dose 2 serum samples. These responses varied significantly with vaccine regimen, and NK cell activation was found to correlate with anti-GP antibody concentration. We also reveal an impact of NK cell differentiation phenotype on antibody-dependent NK cell activation, with highly differentiated CD56dimCD57+ NK cells being the most responsive. Conclusions These findings highlight the dual importance of vaccine-induced antibody concentration and NK cell differentiation status in promoting Fc-mediated activation of NK cells after vaccination, raising a potential role for antibody-mediated NK cell activation in vaccine-induced immune responses., We found natural killer cell degranulation and interferon γ secretion in response to recombinant Ebola virus glycoprotein and postvaccination serum samples from healthy volunteers vaccinated with the novel 2-dose heterologous adenovirus type 26.ZEBOV, modified vaccinia Ankara–BN-Filo Ebola vaccine.

Introduction: Respiratory syncytial virus (RSV) is a common cause of infant hospitalization and mortality. With multiple vaccines in development, we aimed to determine: (1) the awareness of RSV among pregnant women and healthcare professionals (HCPs), and (2) attitudes toward clinical trials and routine implementation of antenatal RSV vaccination. Methods: Separate questionnaires for pregnant women and HCPs were distributed within 4 hospitals in South England (July 2017–January 2018). Results: Responses from 314 pregnant women and 204 HCPs (18% obstetricians, 75% midwives, 7% unknown) were analyzed. Most pregnant women (88%) and midwives (66%) had no/very little awareness of RSV, unlike obstetricians (14%). Among pregnant women, 29% and 75% would likely accept RSV vaccination as part of a trial, or if routinely recommended, respectively. Younger women (16–24 years), those of 21–30 weeks’ gestation, and with experience of RSV were significantly more likely to participate in trials [odds ratio (OR): 1.42 (1.72–9.86); OR: 2.29 (1.22–4.31); OR: 9.07 (1.62–50.86), respectively]. White-British women and those of 21–30 weeks’ gestation were more likely to accept routinely recommended vaccination [OR: 2.16 (1.07–4.13); OR: 2.10 (1.07–4.13)]. Obstetricians were more likely than midwives to support clinical trials [92% vs. 68%, OR: 2.50 (1.01–6.16)] and routine RSV vaccination [89% vs. 79%, OR: 4.08 (1.53–9.81)], as were those with prior knowledge of RSV, and who deemed it serious. Conclusions: RSV awareness is low among pregnant women and midwives. Education will be required to support successful implementation of routine antenatal vaccination. Research is needed to understand reasons for vaccine hesitancy among pregnant women and HCPs, particularly midwives.

Background Respiratory syncytial virus (RSV) disease is a major cause of infant morbidity and mortality. This Phase I, randomized, observer-blind, placebo- and active-controlled study evaluated an investigational vaccine against RSV (ChAd155-RSV) using the viral vector chimpanzee-adenovirus-155, encoding RSV fusion (F), nucleocapsid, and transcription antitermination proteins. Methods Healthy 18–45-year-old adults received ChAd155-RSV, a placebo, or an active control (Bexsero) at Days (D) 0 and 30. An escalation from a low dose (5 × 109 viral particles) to a high dose (5 × 1010 viral particles) occurred after the first 16 participants. Endpoints were solicited/unsolicited and serious adverse events (SAEs), biochemical/hematological parameters, cell-mediated immunogenicity by enzyme-linked immunospot, functional neutralizing antibodies, anti RSV-F immunoglobin (Ig) G, and ChAd155 neutralizing antibodies. Results There were 7 participants who received the ChAd155-RSV low dose, 31 who received the ChAd155-RSV high dose, 19 who received the placebo, and 15 who received the active control. No dose-related toxicity or attributable SAEs at the 1-year follow-up were observed. The RSV-A neutralizing antibodies geometric mean titer ratios (post/pre-immunization) following a high dose were 2.6 (D30) and 2.3 (D60). The ratio of the fold-rise (D0 to D30) in anti-F IgG over the fold-rise in RSV-A–neutralizing antibodies was 1.01. At D7 after the high dose of the study vaccine, the median frequencies of circulating B-cells secreting anti-F antibodies were 133.3/106 (IgG) and 16.7/106 (IgA) in peripheral blood mononuclear cells (PBMCs). The median frequency of RSV-F–specific interferon γ–secreting T-cells after a ChAd155-RSV high dose was 108.3/106 PBMCs at D30, with no increase after the second dose. Conclusions In adults previously naturally exposed to RSV, ChAd155-RSV generated increases in specific humoral and cellular immune responses without raising significant safety concerns. Clinical Trials Registration NCT02491463., We investigated the safety and immunogenicity of a novel chimpanzee-adenovirus-155 vaccine against respiratory syncytial virus (RSV; ChAd155-RSV). In healthy adults with previous natural RSV exposure, ChAd155-RSV generated antigen-specific humoral and cellular immune responses without raising significant safety concerns.

Background COVID-19 vaccine supply shortages are causing concerns about compromised immunity in some countries as the interval between the first and second dose becomes longer. Conversely, countries with no supply constraints are considering administering a third dose. We assessed the persistence of immunogenicity after a single dose of ChAdOx1 nCoV-19 (AZD1222), immunity after an extended interval (44–45 weeks) between the first and second dose, and response to a third dose as a booster given 28–38 weeks after the second dose. Methods In this substudy, volunteers aged 18–55 years who were enrolled in the phase 1/2 (COV001) controlled trial in the UK and had received either a single dose or two doses of 5 × 1010 viral particles were invited back for vaccination. Here we report the reactogenicity and immunogenicity of a delayed second dose (44–45 weeks after first dose) or a third dose of the vaccine (28–38 weeks after second dose). Data from volunteers aged 18–55 years who were enrolled in either the phase 1/2 (COV001) or phase 2/3 (COV002), single-blinded, randomised controlled trials of ChAdOx1 nCoV-19 and who had previously received a single dose or two doses of 5 × 1010 viral particles are used for comparison purposes. COV001 is registered with ClinicalTrials.gov, NCT04324606, and ISRCTN, 15281137, and COV002 is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137, and both are continuing but not recruiting. Findings Between March 11 and 21, 2021, 90 participants were enrolled in the third-dose boost substudy, of whom 80 (89%) were assessable for reactogenicity, 75 (83%) were assessable for evaluation of antibodies, and 15 (17%) were assessable for T-cells responses. The two-dose cohort comprised 321 participants who had reactogenicity data (with prime-boost interval of 8–12 weeks: 267 [83%] of 321; 15–25 weeks: 24 [7%]; or 44–45 weeks: 30 [9%]) and 261 who had immunogenicity data (interval of 8–12 weeks: 115 [44%] of 261; 15–25 weeks: 116 [44%]; and 44–45 weeks: 30 [11%]). 480 participants from the single-dose cohort were assessable for immunogenicity up to 44–45 weeks after vaccination. Antibody titres after a single dose measured approximately 320 days after vaccination remained higher than the titres measured at baseline (geometric mean titre of 66·00 ELISA units [EUs; 95% CI 47·83–91·08] vs 1·75 EUs [1·60–1·93]). 32 participants received a late second dose of vaccine 44–45 weeks after the first dose, of whom 30 were included in immunogenicity and reactogenicity analyses. Antibody titres were higher 28 days after vaccination in those with a longer interval between first and second dose than for those with a short interval (median total IgG titre: 923 EUs [IQR 525–1764] with an 8–12 week interval; 1860 EUs [917–4934] with a 15–25 week interval; and 3738 EUs [1824–6625] with a 44–45 week interval). Among participants who received a third dose of vaccine, antibody titres (measured in 73 [81%] participants for whom samples were available) were significantly higher 28 days after a third dose (median total IgG titre: 3746 EUs [IQR 2047–6420]) than 28 days after a second dose (median 1792 EUs [IQR 899–4634]; Wilcoxon signed rank test p=0·0043). T-cell responses were also boosted after a third dose (median response increased from 200 spot forming units [SFUs] per million peripheral blood mononuclear cells [PBMCs; IQR 127–389] immediately before the third dose to 399 SFUs per milion PBMCs [314–662] by day 28 after the third dose; Wilcoxon signed rank test p=0·012). Reactogenicity after a late second dose or a third dose was lower than reactogenicity after a first dose. Interpretation An extended interval before the second dose of ChAdOx1 nCoV-19 leads to increased antibody titres. A third dose of ChAdOx1 nCoV-19 induces antibodies to a level that correlates with high efficacy after second dose and boosts T-cell responses. Funding UK Research and Innovation, Engineering and Physical Sciences Research Council, National Institute for Health Research, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research Oxford Biomedical Research Centre, Chinese Academy of Medical Sciences Innovation Fund for Medical Science, Thames Valley and South Midlands NIHR Clinical Research Network, AstraZeneca, and Wellcome.

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

Background A new variant of SARS-CoV-2, B.1.1.7, emerged as the dominant cause of COVID-19 disease in the UK from November, 2020. We report a post-hoc analysis of the efficacy of the adenoviral vector vaccine, ChAdOx1 nCoV-19 (AZD1222), against this variant. Methods Volunteers (aged ≥18 years) who were enrolled in phase 2/3 vaccine efficacy studies in the UK, and who were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 or a meningococcal conjugate control (MenACWY) vaccine, provided upper airway swabs on a weekly basis and also if they developed symptoms of COVID-19 disease (a cough, a fever of 37·8°C or higher, shortness of breath, anosmia, or ageusia). Swabs were tested by nucleic acid amplification test (NAAT) for SARS-CoV-2 and positive samples were sequenced through the COVID-19 Genomics UK consortium. Neutralising antibody responses were measured using a live-virus microneutralisation assay against the B.1.1.7 lineage and a canonical non-B.1.1.7 lineage (Victoria). The efficacy analysis included symptomatic COVID-19 in seronegative participants with a NAAT positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to vaccine received. Vaccine efficacy was calculated as 1 − relative risk (ChAdOx1 nCoV-19 vs MenACWY groups) derived from a robust Poisson regression model. This study is continuing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. Findings Participants in efficacy cohorts were recruited between May 31 and Nov 13, 2020, and received booster doses between Aug 3 and Dec 30, 2020. Of 8534 participants in the primary efficacy cohort, 6636 (78%) were aged 18–55 years and 5065 (59%) were female. Between Oct 1, 2020, and Jan 14, 2021, 520 participants developed SARS-CoV-2 infection. 1466 NAAT positive nose and throat swabs were collected from these participants during the trial. Of these, 401 swabs from 311 participants were successfully sequenced. Laboratory virus neutralisation activity by vaccine-induced antibodies was lower against the B.1.1.7 variant than against the Victoria lineage (geometric mean ratio 8·9, 95% CI 7·2–11·0). Clinical vaccine efficacy against symptomatic NAAT positive infection was 70·4% (95% CI 43·6–84·5) for B.1.1.7 and 81·5% (67·9–89·4) for non-B.1.1.7 lineages. Interpretation ChAdOx1 nCoV-19 showed reduced neutralisation activity against the B.1.1.7 variant compared with a non-B.1.1.7 variant in vitro, but the vaccine showed efficacy against the B.1.1.7 variant of SARS-CoV-2. Funding UK Research and Innovation, National Institute for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. \ud \ud \ud METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. \ud \ud \ud FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. \ud \ud \ud INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. \ud \ud \ud FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca.

IntroductionThe Global Platform for the Prevention of Autoimmune Diabetes-SINT1A Study is designed as a randomised, placebo-controlled, double-blind, multicentre, multinational, primary prevention study aiming to assess whether daily administration of Bifidobacterium infantis from age 7 days to 6 weeks until age 12 months to children with elevated genetic risk for type 1 diabetes reduces the cumulative incidence of beta-cell autoantibodies in childhood.Methods and analysisInfants aged 7 days to 6 weeks from Germany, Poland, Belgium, UK and Sweden are eligible for study participation if they have a >10.0% expected risk for developing multiple beta-cell autoantibodies by age 6 years as determined by genetic risk score or family history and HLA genotype. Infants are randomised 1:1 to daily administration of B. infantis EVC001 or placebo until age 12 months and followed for a maximum of 5.5 years thereafter. The primary outcome is the development of persistent confirmed multiple beta-cell autoantibodies. Secondary outcomes are (1) Any persistent confirmed beta-cell autoantibody, defined as at least one confirmed autoantibody in two consecutive samples, including insulin autoantibodies, glutamic acid decarboxylase, islet tyrosine phosphatase 2 or zinc transporter 8, (2) Diabetes, (3) Transglutaminase autoantibodies associated with coeliac disease, (4) Respiratory infection rate in first year of life during supplementation and (5) Safety. Exploratory outcomes include allergy, antibody response to vaccines, alterations of the gut microbiome or blood metabolome, stool pH and calprotectin.Ethics and disseminationThe study was approved by the local ethical committees of the Technical University Munich, Medical Faculty, the Technische Universität Dresden, the Medizinische Hochschule Hannover, the Medical University of Warsaw, EC Research UZ Leuven and the Swedish ethical review authority. The results will be disseminated through peer-reviewed journals and conference presentations and will be openly shared after completion of the study.Trial registration numberNCT04769037.

BACKGROUND: Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19, in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. METHODS: In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18-55 years, 56-69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18-55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56-69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5-6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18-55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. FINDINGS: Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18-55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56-69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18-55 years group, 22 (73%) of 30 in the 56-69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18-55 years group, 23 (77%) in the 56-69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18-55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898-33 550], n=39; 56-69 years, 16 170 AU/mL [10 233-40 353], n=26; and ≥70 years 17 561 AU/mL [9705-37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18-55 years, 193 [IQR 113-238], n=39; 56-69 years, 144 [119-347], n=20; and ≥70 years, 161 [73-323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18-55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841-2428], n=24; 56-69 years: 797 SFCs [383-1817], n=29; and ≥70 years: 977 SFCs [458-1914], n=48). INTERPRETATION: ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.

Summary Background To address the unmet medical need for an effective prophylactic vaccine against Ebola virus we assessed the safety and immunogenicity of three different two-dose heterologous vaccination regimens with a replication-deficient adenovirus type 26 vector-based vaccine (Ad26.ZEBOV), expressing Zaire Ebola virus glycoprotein, and a non-replicating, recombinant, modified vaccinia Ankara (MVA) vector-based vaccine, encoding glycoproteins from Zaire Ebola virus, Sudan virus, and Marburg virus, and nucleoprotein from the Tai Forest virus. Methods This randomised, observer-blind, placebo-controlled, phase 2 trial was done at seven hospitals in France and two research centres in the UK. Healthy adults (aged 18–65 years) with no history of Ebola vaccination were enrolled into four cohorts. Participants in cohorts I–III were randomly assigned (1:1:1) using computer-generated randomisation codes into three parallel groups (randomisation for cohorts II and III was stratified by country and age), in which participants were to receive an intramuscular injection of Ad26.ZEBOV on day 1, followed by intramuscular injection of MVA-BN-Filo at either 28 days (28-day interval group), 56 days (56-day interval group), or 84 days (84-day interval group) after the first vaccine. Within these three groups, participants in cohort II (14:1) and cohort III (10:3) were further randomly assigned to receive either Ad26.ZEBOV or placebo on day 1, followed by either MVA-BN-Filo or placebo on days 28, 56, or 84. Participants in cohort IV were randomly assigned (5:1) to receive one dose of either Ad26.ZEBOV or placebo on day 1 for vector shedding assessments. For cohorts II and III, study site personnel, sponsor personnel, and participants were masked to vaccine allocation until all participants in these cohorts had completed the post-MVA-BN-Filo vaccination visit at 6 months or had discontinued the trial, whereas cohort I was open-label. For cohort IV, study site personnel and participants were masked to vaccine allocation until all participants in this cohort had completed the post-vaccination visit at 28 days or had discontinued the trial. The primary outcome, analysed in all participants who had received at least one dose of vaccine or placebo (full analysis set), was the safety and tolerability of the three vaccination regimens, as assessed by participant-reported solicited local and systemic adverse events within 7 days of receiving both vaccines, unsolicited adverse events within 42 days of receiving the MVA-BN-Filo vaccine, and serious adverse events over 365 days of follow-up. The secondary outcome was humoral immunogenicity, as measured by the concentration of Ebola virus glycoprotein-binding antibodies at 21 days after receiving the MVA-BN-Filo vaccine. The secondary outcome was assessed in the per-protocol analysis set. This study is registered at ClinicalTrials.gov , NCT02416453 , and EudraCT, 2015-000596-27. Findings Between June 23, 2015, and April 27, 2016, 423 participants were enrolled: 408 in cohorts I–III were randomly assigned to the 28-day interval group (123 to receive Ad26.ZEBOV and MVA-BN-Filo, and 13 to receive placebo), the 56-day interval group (124 to receive Ad26.ZEBOV and MVA-BN-Filo, and 13 to receive placebo), and the 84-day interval group (117 to receive Ad26.ZEBOV and MVA-BN-Filo, and 18 to receive placebo), and 15 participants in cohort IV were assigned to receive Ad26.ZEBOV and MVA-BN-Filo (n=13) or to receive placebo (n=2). 421 (99·5%) participants received at least one dose of vaccine or placebo. The trial was temporarily suspended after two serious neurological adverse events were reported, one of which was considered as possibly related to vaccination, and per-protocol vaccination was disrupted for some participants. Vaccinations were generally well tolerated. Mild or moderate local adverse events (mostly pain) were reported after 206 (62%) of 332 Ad26.ZEBOV vaccinations, 136 (58%) of 236 MVA-BN-Filo vaccinations, and 11 (15%) of 72 placebo injections. Systemic adverse events were reported after 255 (77%) Ad26.ZEBOV vaccinations, 116 (49%) MVA-BN-Filo vaccinations, and 33 (46%) placebo injections, and included mostly mild or moderate fatigue, headache, or myalgia. Unsolicited adverse events occurred after 115 (35%) of 332 Ad26.ZEBOV vaccinations, 81 (34%) of 236 MVA-BN-Filo vaccinations, and 24 (33%) of 72 placebo injections. At 21 days after receiving the MVA-BN-Filo vaccine, geometric mean concentrations of Ebola virus glycoprotein-binding antibodies were 4627 ELISA units (EU)/mL (95% CI 3649–5867) in the 28-day interval group, 10 131 EU/mL (8554–11 999) in the 56-day interval group, and 11 312 mL (9072–14106) in the 84-day interval group, with antibody concentrations persisting at 1149–1205 EU/mL up to day 365. Interpretation The two-dose heterologous regimen with Ad26.ZEBOV and MVA-BN-Filo was safe, well tolerated, and immunogenic, with humoral and cellular immune responses persisting for 1 year after vaccination. Taken together, these data support the intended prophylactic indication for the vaccine regimen. Funding Innovative Medicines Initiative and Janssen Vaccines & Prevention BV. Translation For the French translation of the abstract see Supplementary Materials section.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of Coronavirus Disease 2019 (COVID-19), has caused a global pandemic, and safe, effective vaccines are urgently needed

More than 190 vaccines are currently in development to prevent infection by the novel severe acute respiratory syndrome coronavirus 2. Animal studies suggest that while neutralizing antibodies against the viral spike protein may correlate with protection, additional antibody functions may also be important in preventing infection. Previously, we reported early immunogenicity and safety outcomes of a viral vector coronavirus vaccine, ChAdOx1 nCoV-19 (AZD1222), in a single-blinded phase 1/2 randomized controlled trial of healthy adults aged 18-55 years ( NCT04324606 ). Now we describe safety and exploratory humoral and cellular immunogenicity of the vaccine, from subgroups of volunteers in that trial, who were subsequently allocated to receive a homologous full-dose (SD/SD D56; n = 20) or half-dose (SD/LD D56; n = 32) ChAdOx1 booster vaccine 56 d following prime vaccination. Previously reported immunogenicity data from the open-label 28-d interval prime-boost group (SD/SD D28; n = 10) are also presented to facilitate comparison. Additionally, we describe volunteers boosted with the comparator vaccine (MenACWY; n = 10). In this interim report, we demonstrate that a booster dose of ChAdOx1 nCoV-19 is safe and better tolerated than priming doses. Using a systems serology approach we also demonstrate that anti-spike neutralizing antibody titers, as well as Fc-mediated functional antibody responses, including antibody-dependent neutrophil/monocyte phagocytosis, complement activation and natural killer cell activation, are substantially enhanced by a booster dose of vaccine. A booster dose of vaccine induced stronger antibody responses than a dose-sparing half-dose boost, although the magnitude of T cell responses did not increase with either boost dose. These data support the two-dose vaccine regime that is now being evaluated in phase 3 clinical trials.

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.

IntroductionCapsular group B Neisseria meningitidis (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 Neisseria 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 analysisThe ‘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 Neisseria 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 disseminationThis 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 numbersISRCTN75858406; Pre-results, EudraCT 2017-004609-42.

Children have a low risk of COVID-19 and are disproportionately harmed by precautions.

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 CRM197 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.

Summary of study A multi-country randomized, placebo-controlled trial of the safety, immunogenicity and efficacy of respiratory syncytial virus (RSV) F-protein nanoparticle vaccine was undertaken in 4,636 pregnant women and their infants. RSV F-protein vaccine was safe and immunogenic in the pregnant women inducing anti-F IgG, palivizumab-competing antibodies and RSV neutralizing antibodies that were transferred to the fetus. Although the primary endpoint of prevention of RSV-specific medically-significant lower respiratory tract infection (MS-LRTI) was not met per protocol criteria for efficacy (i.e. 97.52% lower bound >30%), vaccine efficacy was 39.4% (97.52% CI: -1.0, 63.7%; p=0.0278) in infants 0-90 days age. Furthermore, there was a 58.8% (95% CI 31.9, 75.0%) lower rate of RSV LRTI with severe hypoxemia (secondary endpoint) through to 90 days of age in the expanded intent-to-treat analysis. The number of women needed to be vaccinated to prevent RSV-specific MS-LRTI or LRTI with severe hypoxemia in their infants through to 180 days of life were 88 and 82, respectively. Background RSV is the dominant cause of severe lower respiratory tract infection (LRTI) in infants, with most severe disease concentrated in younger-age infants. Methods Healthy, pregnant women between 28 and 36 weeks gestation, with expected delivery near the start of the RSV season, were randomized to a single intramuscular dose of nanoparticle RSV F-protein vaccine, or placebo in a 2:1 ratio. Their infants were followed for 180 days for medically-significant LRTI (MS-LRTI), LRTI with severe hypoxemia and/or LRTI- hospitalization. RSV detection was performed centrally by PCR. Safety evaluation continued until 364 days age. Results 4,636 women were randomized, with 4,579 live births. Over the first 90 days of life, efficacy against RSV-MS-LRTI was 39.4% (97.52%CI: -1.0, 63.7%; p=0.0278) and 41.4% (95%CI: 5.3, 61.2%) in the per protocol and expanded intent-to-treat (eITT) analyses, respectively. There was a lower rate (efficacy 58.8%; 95%CI 31.9, 75.0% in eITT analysis; not adjusted for multiplicity) of RSV-LRTI with severe hypoxemia in infants of vaccinees through 90 days age. Pneumonia reported as a serious adverse events was 49.4% less common in infants of vaccinees (2.6%) than placebo-recipients through 364 days age. Conclusions Maternal vaccination with RSV F-nanoparticle vaccine was safe and immunogenic. The prespecified primary endpoint success criterion (efficacy 97.5% lower bound ≥30%) was not achieved. However, maternal immunization was associated with reduced risk of RSV-confirmed MS-LRTI and LRTI with severe hypoxemia in early infancy. Trial Registration Number ClinicalTrials.Gov: NCT02624947. Funding statement Funded by Novavax, with supporting grant from the Bill and Melinda Gates Foundation.

BACKGROUND NK cells are activated by innate cytokines and viral ligands to kill virus-infected cells. These functions are enhanced during secondary immune responses and after vaccination by synergy with effector T cells and virus-specific antibodies. In human Ebola virus infection, clinical outcome is strongly associated with the initial innate cytokine response, but the role of NK cells has not been thoroughly examined. METHODS The novel 2-dose heterologous Adenovirus type 26.ZEBOV (Ad26.ZEBOV) and modified vaccinia Ankara-BN-Filo (MVA-BN-Filo) vaccine regimen is safe and provides specific immunity against Ebola glycoprotein, and is currently in phase 2 and 3 studies. Here, we analyzed NK cell phenotype and function in response to Ad26.ZEBOV, MVA-BN-Filo vaccination regimen and in response to in vitro Ebola glycoprotein stimulation of PBMCs isolated before and after vaccination. RESULTS We show enhanced NK cell proliferation and activation after vaccination compared with baseline. Ebola glycoprotein–induced activation of NK cells was dependent on accessory cells and TLR-4–dependent innate cytokine secretion (predominantly from CD14+ monocytes) and enriched within less differentiated NK cell subsets. Optimal NK cell responses were dependent on IL-18 and IL-12, whereas IFN-γ secretion was restricted by high concentrations of IL-10. CONCLUSION This study demonstrates the induction of NK cell effector functions early after Ad26.ZEBOV, MVA-BN-Filo vaccination and provides a mechanism for the activation and regulation of NK cells by Ebola glycoprotein. TRIAL REGISTRATION ClinicalTrials.gov NCT02313077. FUNDING United Kingdom Medical Research Council Studentship in Vaccine Research, Innovative Medicines Initiative 2 Joint Undertaking, EBOVAC (grant 115861) and Crucell Holland (now Janssen Vaccines and Prevention B.V.), European Union’s Horizon 2020 research and innovation programme and European Federation of Pharmaceutical Industries and Associations (EFPIA).

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

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.

BackgroundUptake rates of influenza and pertussis vaccination in pregnancy remain suboptimal.AimTo determine the acceptability of routine vaccination among pregnant women; the confidence of maternity healthcare professionals (HCPs) discussing vaccination; and HCP opinion with regards to the optimum healthcare site for vaccine administration.MethodSeparate questionnaires for pregnant women and maternity HCPs were distributed within four NHS trusts in South England from July 2017–January 2018.ResultsResponses from 314 pregnant women and 204 HCPs (18% obstetricians, 75% midwives [both hospital and community], 7% unidentified) were analysed. Actual/intended uptake of influenza and pertussis vaccination was 78% and 92%, respectively. The commonest reason for declining vaccination was feared side effects for their child. White British women (79%) were significantly more accepting of influenza (odds ratio [OR] 3.25, 95% confidence interval [CI] = 1.67 to 6.32) and pertussis vaccination (OR 4.83, 95% CI = 1.77 to 13.19) compared with non-white British women. Among HCPs, 25% were not-at-all or slightly confident discussing vaccination. Obstetricians felt significantly more confident discussing pertussis vaccination than midwives (OR 2.05, 95% CI = 1.02 to 4.12). Among HCPs, 53%, 25%, and 16% thought vaccines should be administered in primary care (general practice), community midwifery, and the hospital setting, respectively.ConclusionMisconceptions exist regarding safety and efficacy of maternal vaccination, and framing information towards safety for the child may increase uptake. Education of HCPs is essential, and vaccine promotion should be incorporated into routine antenatal care, with an emphasis on women from ethnic minorities. Administration of vaccines in primary care may present a logistical barrier to women, however support for alternative sites appears low among HCPs.

BACKGROUND: Following programmatic introduction of the 13-valent pneumococcal conjugate vaccine (PCV13), there is residual carriage and disease due to PCV13 covered serotypes. METHODS: 988 PCV13-immunised children aged 13-48 months were enrolled between February 2014 and August 2015 (late-PCV13), and had nasopharyngeal pneumococcal carriage compared with 567 PCV7-immunised children enrolled into a study between November 2010 and September 2011 (early-PCV13). Nasopharyngeal pneumococci were molecular-serotyped by microarray. Invasive pneumococcal disease (IPD) cases were identified through enhanced national surveillance. Blood collected from the late-PCV13 cohort was assessed for levels of serotype-specific serum IgG by multiplex immunoassay. RESULTS: Compared with PCV7-immunised children, carriage among PCV13-immunised children was significantly lower for serotypes 19A (OR=0.08, 95% CI 0.02-0.25), 6C (OR=0.11, 95% CI 0.03-0.32) and 7F (8 vs 0 cases).IPD incidence in children

Background - Use of a polysaccharide vaccine challenge to demonstrate immunologic memory after priming with capsular group C meningococcal conjugate vaccines (MenCC) risks induction of immunologic hyporesponsiveness. For this reason, MenCC vaccines are now used as probes of immunologic memory, however, no studies have demonstrated their ability to distinguish primed from unprimed children.Methods - This study was part of a randomised controlled trial investigating the immunogenicity of a booster dose of the combined Haemophilus influenzae type b and MenC-tetanus toxoid vaccine (Hib-MenC-TT) in infants receiving reduced dose MenCC vaccine priming schedules (one MenC-CRM/MenC-TT or two MenC-CRM vaccine doses) compared with an unprimed group. Antibody kinetics were studied in a subset of 269 children by measuring changes in the MenC serum bactericidal antibody, using rabbit complement, (MenC rSBA) titres and MenC specific IgG memory B-cells before and at 6 and 28 days following the 12 month booster vaccination.Results - At 6 days after the 12 month MenCC vaccine, the rise in MenC rSBA titres and MenC specific IgG memory B-cells of the primed groups were significantly higher than the infant MenCC naïve group. Participants primed with one MenC-TT dose had the highest increase in MenC rSBA titres compared with all other groups. The MenC rSBA titres at the 28th compared with the 6th day after boosting was significantly higher in those primed with a single MenC-TT/MenC-CRM vaccine in infancy compared with those who were not primed or who were primed with two doses of the MenC-CRM vaccine.Conclusion - Immunologic memory can be demonstrated by a MenCC booster vaccination but is affected by the type and number of MenCC doses used for infant priming. The MenC rSBA responses can be used to demonstrate successful immunologic priming.

BACKGROUND Both the 13- and 10-valent pneumococcal conjugate vaccines (PCV-13; PCV-10) are immunogenic and effective against vaccine-type pneumococcal disease when given to young children. However, limited data are available regarding the interchangeability of these 2 vaccines. METHODS UK children (n = 178) who had previously been vaccinated with PCV-13 at 2 and 4 months were randomized to receive either a PCV-13 or a PCV-10 booster at 12 months of age. PCV-13 vaccine-type antipolysaccharide serum immunoglobulin G (IgG) concentrations and opsonophagocytic assay titers were measured before and at 1 and 12 months following vaccination. The primary objective was to assess noninferiority of PCV-10 compared with PCV-13. RESULTS For 8 of the PCV-10 serotypes at least 97% of participants in both groups had IgG concentrations ≥0.35 µg/mL at 1 month after vaccination; inferior responses were seen for serotypes 5 and 9V following the PCV-10 compared with the PCV-13 booster. Post booster geometric mean IgG concentrations and opsonophagocytic assay titers were significantly superior for most serotypes in PCV-13 compared with PCV-10 recipients, whereas similar or inferior responses were seen for serotypes 4, 18C, and 19F. Although some increase in antibody was seen in PCV-10 recipients against the serotypes 6A and 19A (serotypes that cross-react with 6B and 19F in PCV-10, respectively) at 1-month post booster, these responses were significantly lower than in the PCV-13 group. CONCLUSIONS In PCV-13 primed infants, a PCV-10 booster is generally less immunogenic than a PCV-13 booster. For the 3 serotypes in PCV-10 with higher antigen content and/or conjugation to diphtheria or tetanus toxoid carrier proteins, higher or similar booster responses were seen in PCV-10 recipients. Although these findings suggest that responses are generally better with a PCV-13 booster among PCV-13 primed children, the clinical significance of these differences in immunogenicity is unclear.

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.

BACKGROUND: A new formulation of the live-attenuated varicella vaccine Varilrix (GSK) produced without human serum albumin (HSA) was developed to minimize a theoretical risk of transmission of infectious diseases. A previous study showed that the vaccine was immunologically non-inferior to the HSA-containing vaccine and well-tolerated in toddlers; low-grade fever was numerically higher in children receiving the vaccine without HSA, but the study lacked power to conclude on this difference. METHODS: In this phase III, double-blind, multi-center study, healthy 12-23-month-olds were randomized (1:1) to receive two doses of the varicella vaccine without (Var-HSA group) or with HSA (Var + HSA group) at days 0 and 42. The primary objective compared safety of the vaccines in terms of incidence of fever > 39.0 °C in the 15-day period post-first vaccination. The objective was considered met if the upper limit of the 95% confidence interval for the between-group difference in the incidence of fever > 39.0 °C was ≤5% (Var-HSA group minus Var + HSA group). Safety, reactogenicity and immune responses were evaluated. RESULTS: Six hundred fifteen children in the Var-HSA group and 616 in the Var + HSA group received ≥1 vaccination. Fever > 39.0 °C was reported in 3.9 and 5.2% of participants in the Var-HSA and Var + HSA groups, with a between-group difference of - 1.29 (95% confidence interval: - 3.72-1.08); therefore, the primary objective was achieved. Fever rates post-each dose and the incidence of solicited local and general adverse events (AEs) were comparable between groups. Unsolicited AEs were reported for 43.9 and 36.5% of children in the Var-HSA group and 45.8 and 36.0% of children in the Var + HSA group, during 43 days post-dose 1 and 2, respectively. Serious AEs occurred in 2.1% (group Var-HSA) and 2.4% (group Var + HSA) of children, throughout the study. In a sub-cohort of 364 children, all had anti-varicella-zoster virus antibody concentrations ≥50 mIU/mL post-dose 2; comparable geometric mean concentrations were observed between the groups. CONCLUSIONS: The varicella vaccine formulated without HSA did not induce higher rates of fever during the 15 day-post-vaccination period, as compared with the original HSA-containing vaccine. The two vaccines displayed similar safety and immunogenicity profiles in toddlers. TRIAL REGISTRATION:NCT02570126 , registered on 5 October 2015 (www.clinicaltrials.gov).

Supplemental Digital Content is available in the text., Background: It has not yet been demonstrated whether 2 doses of inactivated quadrivalent influenza vaccine (IIV4) prime a booster response in infants. We evaluated the anamnestic immune response to an IIV4 in children 17−48 months of age. Methods: Children were randomized to 2 doses of IIV4 or control in the primary phase III study (NCT01439360). One year later, in an open-label revaccination extension study (NCT01702454), a subset of children who received IIV4 in the primary study (primed group) received 1 IIV4 dose and children who received control in the primary study (unprimed) received 2 IIV4 doses 28 days apart. The primary objective was to evaluate hemagglutination inhibition (HI) antibody titers 7 days after first IIV4 vaccination in the per-protocol cohort (N = 224 primed; N = 209 unprimed). Neutralizing and antineuraminidase antibodies were also measured. Safety was analyzed in the total vaccinated cohort (N = 241 primed; N = 229 unprimed). Results: An anamnestic response was observed in primed children relative to unprimed controls, measured by age-adjusted geometric mean HI titer ratios against strains homologous (A/H1N1: 9.0; B/Victoria: 3.9) and heterologous (A/H3N2: 2.7; B/Yamagata: 6.7) to those in the primary vaccination series. The anamnestic response in primed children included increases in neutralizing antibodies (mean geometric increase: 5.0–10.6) and antineuraminidase antibodies (4.9–8.8). No serious adverse events related to vaccination were reported. Conclusions: In this study, 2-dose priming with IIV4 induced immune memory that was recalled with 1-dose IIV4 the following year to boost HI, antineuraminidase and neutralizing antibodies, even though the IIV4 strain composition partially changed.

With maternal and infant vaccines against respiratory syncytial virus (RSV) in development, it is timely to consider how the deployment of these vaccines might vary according to local RSV disease seasonality. In temperate regions RSV infection is predictably limited to a period of 3 to 5 months, while in tropical regions disease seasonality is often both more variable and more prolonged. Accordingly, in tropical regions a year-round immunisation schedule for both maternal and infant immunisation might be appropriate. In contrast, in temperate regions the benefit of year-round maternal immunisation would be heavily dependent on the duration of protection this provided, potentially necessitating a strategy directed at children due to be born in the months immediately prior to the RSV season. This review will consider the impact of seasonality on maternal and infant immunisation strategies against RSV, and the potential of an alternative approach of passive immunisation for all infants immediately prior to the RSV season.

BACKGROUND: The capsular group B meningococcal vaccine (4CMenB) is recommended for children with complement deficiencies, asplenia, and splenic dysfunction; however, data on the immunogenicity of 4CMenB in these “at-risk” children are missing. METHODS: Participants aged 2 to 17 years in Italy, Spain, Poland, the United Kingdom, and Russia with complement deficiencies, asplenia, or splenic dysfunction received 2 doses of 4CMenB 2 months apart, as did healthy children in the control group. Exogenous and endogenous human complement serum bactericidal activity (SBA) was determined at baseline and 1 month after the second immunization against 4 test strains: H44/76 (assessing vaccine antigen factor H binding protein), 5/99 (Neisserial adhesion A), NZ98/254 (Porin A), and M10713 (Neisserial heparin binding antigen). RESULTS: Of 239 participants (mean age 10.3 years, 45% female), 40 children were complement deficient (9 eculizumab therapy, 4 terminal-chain deficiencies, 27 “other”), 112 children had asplenia or splenic dysfunction (8 congenital asplenia, 8 functional asplenia, 96 splenectomy), and 87 children were in the control group. After immunization, the proportions of complement-deficient participants with exogenous complement SBA titers ≥1:5 were 87% (H44/76), 95% (5/99), 68% (NZ98/254), and 73% (M10713), compared with 97%, 100%, 86%, and 94%, respectively, for asplenic children and 98%, 99%, 83%, and 99% for children in the control group. When testing with endogenous complement, strain-specific bactericidal activity was evident in only 1 eculizumab-treated participant and 1 terminal chain complement-deficient participant. CONCLUSIONS: 4CMenB administration is similarly immunogenic in healthy children and those with asplenia or splenic dysfunction. The significance of the trend to lower responses of SBA titers in complement-deficient children (especially those with terminal chain complement deficiency or those on eculizumab therapy) must be determined by ongoing surveillance for vaccine failures.

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. Background: Immunization site pain is a common and unpleasant experience for both children and adults. It is a source of anxiety and distress and may ultimately result in nonadherence to vaccination schedules. There is limited information on how different brands of vaccines affect the intensity of immediate pain at the time of vaccine injection. Methods: Children in the United Kingdom (n = 178) were randomized to receive a booster dose of either the 10- or the 13-valent pneumococcal conjugate vaccine (PCV-10 or PCV-13). Immediate immunization site pain was assessed using validated pain assessment tools and crying time to investigate factors that may interfere with parental compliance to vaccination. Results: Pain measurements were available for n ≥ 74 and n ≥ 78 PCV-10 and PCV-13 recipients, respectively. PCV-13 recipients had significantly higher scores on the observer-rated modified behavioral pain scale than did those receiving PCV-10. No significant differences in the induction of pain between the 2 vaccines were found when a parent-rated pain assessment tool or crying time was used. Conclusions: PCV-10 administration was associated with slightly less acute pain compared with the injection of PCV-13, but the size of the difference was small and is of unknown clinical significance.

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

BACKGROUND: The multicomponent serogroup B meningococcal (4CMenB) vaccine induces antibodies against indicator strains of serogroup B meningococcus under various schedules. We investigated the persistence of antibodies in 5-year-old children 18-20 months after their last dose (at about 3.5 years of age). METHODS: We assessed 5-year-old children who received the 4CMenB vaccine or a recombinant protein vaccine in a previous randomized trial. We also recruited 50 vaccine-naive 5-year-olds and administered 2 doses of 4CMenB to each child. We measured serum bactericidal antibody titres against 4 indicator strains of serogroup B meningococcus matched to each individual vaccine component and against 4 mismatched strains. RESULTS: Of those who received the 4CMenB vaccine at 2, 4, 6, 12 and 40 months (n = 16), the percentage with protective antibody titres (≥ 1:4) at 60 months ranged from 44% to 88% against matched strains and from 13% to 81% against mismatched strains. Loss of protective titres was also observed for those who received the 4CMenB vaccine at 12, 40 and 42 months (n = 5) (80%-100% against matched strains, 60%-100% against mismatched strains) or at 40 and 42 months (n = 29) (31%-100% against matched strains, 41%-81% against mismatched strains). Administering the 4CMenB vaccine to 5-year-old children yielded protective titres against matched strains in 92%-100% and against mismatched strains in 59%-100%. The majority of these children reported injection-site pain (40/50 [80%] after dose 1, 39/46 [85%] after dose 2) and erythema (47/50 [94%] and 40/46 [87%], respectively); rates of fever were low (5/50 [10%] and 2/46 [4%], respectively). INTERPRETATION: Waning of immunity by 5 years of age occurred after receipt of the 4CMenB vaccine in infancy, even with an additional booster at 40 months. The 4CMenB vaccine is immunogenic and was fairly well tolerated by 5-year-old children, although injection-site pain was noteworthy. TRIAL REGISTRATION: ClinicalTrials.gov, no. NCT01027351.

Introduction Maternal vaccination is increasingly part of antenatal care in the UK and worldwide. Trials of Group B streptococcus vaccines are ongoing. This study investigated the attitudes of pregnant women and healthcare professionals towards antenatal vaccination, both in routine care and a clinical trial setting. Material and methods Survey of 269 pregnant women, 273 midwives/obstetricians and 97 neonatal doctors across seven sites in the UK assessing attitudes towards antenatal vaccinations, knowledge of Group B streptococcus, a hypothetical Group B streptococcus vaccine, and participation in clinical vaccine trials. Results 68% of pregnant women intended to receive a vaccine during their current pregnancy (183/269) and 43% (of all respondents, 115/269) reported they would be very/fairly likely to accept a vaccine against Group B streptococcus despite only 29% (55/269) knowing what Group B streptococcus was. This increased to 69% after additional information about Group B streptococcus was provided. Twenty-four percent of pregnant women reported they would be likely to take part in a clinical trial of an unlicensed Group B streptococcus vaccine. Fifty-nine percent of maternity professionals and 74% of neonatologists would be likely to recommend participation in a Group B streptococcus vaccine trial to women, with the vast majority (>99%) willing to be involved in such a study. Incentives to take part cited by pregnant women included extra antenatal scans and the opportunity to be tested for Group B streptococcus. Conclusion Pregnant women and healthcare professionals were open to the idea of an antenatal Group B streptococcus vaccine and involvement in clinical trials of such a vaccine. Education and support from midwives would be key to successful implementation.

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.

The prevention of paediatric bacterial meningitis and septicaemia has recently entered a new era with the availability of two vaccines against capsular group B meningococcus (MenB). Both of these vaccines are based on sub-capsular proteins of the meningococcus, an approach that overcomes the challenges set by the poorly immunogenic MenB polysaccharide capsule but adds complexity to predicting and measuring the impact of their use. This review describes the development and use of MenB vaccines to date, from the use of outer membrane vesicle (OMV) vaccines in MenB outbreaks around the world, to emerging evidence on the effectiveness of the newly available vaccines. While recent data from the United Kingdom supports the potential for protein-based vaccines to provide direct protection against MenB disease in immunised children, further research is required to understand the breadth and duration of this protection. A more detailed understanding of the impact of immunisation with these vaccines on nasopharyngeal carriage of the meningococcus is also required, to inform both their potential to induce herd immunity and to preferentially select for carriage of strains not susceptible to vaccine-induced antibodies. Although a full understanding of the potential impact of these vaccines will only be possible with this additional information, the availability of new tools to prevent the devastating effect of invasive MenB disease is a significant breakthrough in the fight against childhood sepsis and meningitis.

Pneumococcal protein-polysaccharide conjugate vaccines provide direct protection against Streptococcus pneumoniae through the induction of persistent anti-polysaccharide antibodies, and by priming for a rapid secondary antibody response. Memory B cells (BMEM) generated during an initial immune response are responsible for both the more rapid and quantitatively greater secondary antibody response and are also thought to contribute to the ongoing production of plasma cells providing long-term antibody persistence. We recruited 3.5-year-old children who had participated in a previous clinical trial comparing infant immunization with either a 7-valent (PCV-7) or a 13-valent pneumococcal conjugate vaccine (PCV-13) to investigate whether prior priming with pneumococcal antigens influences BMEM responses. Blood was taken before and 1month after a PCV-13 booster. BMEM were quantified using a cultured ELISpot assay for pneumococcal serotypes 1, 3, 4, 14, 19A, 23F, and with diphtheria and tetanus toxoid as controls, and then correlated with serotype-specific IgG concentrations and opsonophagocytic activity (OPA) titers. In total, blood samples from 62 participants were available for analysis. Serotype-specific BMEM frequencies were generally low at baseline (before boost) although for serotypes 14 and 3, they were significantly higher in children primed with PCV-13 than PCV-7 primed children. Following the PCV-13 booster, BMEM frequencies increased and were not different between the groups for all serotypes. A strong inverse correlation was found between antibody concentrations and OPA titers at baseline and BMEM following booster vaccination for serotype 3 but not for other serotypes suggesting that, for this serotype, pre-existing serotype-specific antibodies may inhibit BMEM formation in response to vaccination. Clinicaltrials.gov registration number: NCT01095471.

Meningococcal conjugate vaccines are today successfully deployed in universal programs for children and adolescents in different geographic regions to control meningitis and septicemia. However, in adults, the advantages of these conjugates over the older polysaccharide vaccines are less clear. In this randomized clinical trial, we demonstrated that both conjugate and polysaccharide quadrivalent meningococcal vaccines elicit protective antibody responses in adults aged 18 to 70. (This study has been registered atwww.clinicaltrials.govunder registration no. NCT00901940.)

Summary: Vaccines have revolutionized public health, preventing millions of deaths each year, particularly in childhood. Yet, there is considerable variability in the magnitude and persistence of vaccine-induced immunity. Maintenance of specific antibody is essential for continuity of vaccine-induced serological protection. We conducted a genome-wide association study into the persistence of immunity to three childhood vaccines: capsular group C meningococcal (MenC), Haemophilus influenzae type b, and tetanus toxoid (TT) vaccines. We detail associations between variants in a locus containing a family of signal-regulatory proteins and the persistence MenC immunity. We postulate a regulatory role for the lead SNP, with supporting epigenetic and expression quantitative trait loci data. Furthermore, we define associations between SNPs in the human leukocyte antigen (HLA) locus and the persistence of TT-specific immunity. Moreover, we describe four classical HLA alleles, HLA DRB1∗0301, HLA DQB1∗0201, HLA DQB1∗0602, and HLA DRB1∗1501, associated with TT-specific immunity, independent of the lead SNP association. : Genetic variants impact immune responses to antigenic stimuli. O’Connor et al. show that variants within the human leukocyte antigen (HLA) and signal-regulatory proteins loci are associated with persistence of immunity following immunization, suggesting these genes are involved in regulating immune responses to routine childhood immunization. Keywords: vaccine-induced immunity, GWAS, persistence of immunity, meningococcal disease, HLA, SIRPG