High-resolution African HLA resource uncovers HLA-DRB1 expression effects underlying vaccine response.

How human genetic variation contributes to vaccine effectiveness in infants is unclear, and data are limited on these relationships in populations with African ancestries. We undertook genetic analyses of vaccine antibody responses in infants from Uganda (n = 1391), Burkina Faso (n = 353) and South Africa (n = 755), identifying associations between human leukocyte antigen (HLA) and antibody response for five of eight tested antigens spanning pertussis, diphtheria and hepatitis B vaccines. In addition, through HLA typing 1,702 individuals from 11 populations of African ancestry derived predominantly from the 1000 Genomes Project, we constructed an imputation resource, fine-mapping class II HLA-DR and DQ associations explaining up to 10% of antibody response variance in our infant cohorts. We observed differences in the genetic architecture of pertussis antibody response between the cohorts with African ancestries and an independent cohort with European ancestry, but found no in silico evidence of differences in HLA peptide binding affinity or breadth. Using immune cell expression quantitative trait loci datasets derived from African-ancestry samples from the 1000 Genomes Project, we found evidence of differential HLA-DRB1 expression correlating with inferred protection from pertussis following vaccination. This work suggests that HLA-DRB1 expression may play a role in vaccine response and should be considered alongside peptide selection to improve vaccine design.

The Impact of Infant Bacille Calmette-Guérin Vaccination on the Immunogenicity of Other Vaccines: A Randomized Exploratory Study.

The effect of the Bacille Calmette-Guérin (BCG) vaccine on the immunogenicity of separately administered serogroup C meningococcal vaccine and other vaccinations was examined in 28 infants randomized to receive BCG at age ≤7 days, at 3 months or after study completion. Immunogenicity of the serogroup C meningococcal vaccine and other routine vaccines might be improved when BCG is administered in early infancy.

Protective mucosal SARS-CoV-2 antibodies in the majority of the general population in the Netherlands.

Antibodies to SARS-CoV-2 on the mucosal surfaces of the respiratory tract are understood to contribute to protection against SARS-CoV-2 infection. We aimed to describe the prevalence, levels, and functionality of mucosal antibodies in the general Dutch population. Nasal samples were collected from 778 randomly selected participants, 1-90 years of age, nested within the nationwide prospective SARS-CoV-2 PIENTER corona serosurvey in the Netherlands. Spike-specific immunoglobulin (Ig)G was detected in the nasal samples of 94.6% (in case of the wild-type S1 variant) and 94.9% (Omicron BA.1) of the individuals, whereas 44.2% and 62.7% of the individuals were positive for wild-type and Omicron BA.1 S1 IgA, respectively. The lowest prevalence of mucosal antibodies was observed in children under 12 years of age. The prevalence and levels of IgA and IgG were higher in individuals with a history of SARS-CoV-2 infection. Mucosal antibodies inhibited the binding of Wuhan, Delta, and Omicron BA.1 receptor binding domain to human angiotensin-converting enzyme 2 in 94.4%, 95.4%, and 92.6% of the participants, respectively. Higher levels of mucosal antibodies were associated with a lower risk of future infection.

Immune response following a two-dose schedule of bivalent HPV vaccination among girls and boys.

Background: This longitudinal cohort study describes the kinetics in antibody levels after two doses of the bivalent human papillomavirus (HPV) vaccine in girls (birth cohort 2001) vaccinated in the routine Dutch vaccination program at 12 years of age, up to 7.5 years post-vaccination. Also, the antibody response one month post-vaccination of the first cohort of boys (birth cohort 2012, vaccinated at 10 years of age) eligible for HPV vaccination in the Netherlands is presented. Method: Blood samples and questionnaire data were collected of girls and boys. HPV type-specific antibody concentrations (LU/mL) against HPV16/18/31/33/45/52/58 were assessed using a validated virus-like particle (VLP) multiplex immunoassay. For girls, antibody decays over time were modelled using the modified power-law decay model and the exponential decay model. Results: The Geometric Mean Concentrations (GMCs) remained higher for HPV16/18 than for HPV types 31, 33, 45, 52, and 58 among girls up to 7.5 years post-vaccination. The antibody levels of HPV16 and HPV18 reached plateau values of 482 and 159 LU/mL, respectively. Mathematical modelling showed that the half-life values of HPV16/18 were 2.4- to 4.5-fold higher compared with the half-life values of the other HPV types. Among boys (aged 10 years), the GMC for HPV16 was significantly higher than among girls one month post-vaccination (aged 12 years). Conclusion: The GMCs of all HPV types declined over time, although the GMCs of HPV16/18 remained relatively high up to 7.5 years post-vaccination. The GMCs for HPV16/18 among boys were at least equally high as the GMCs among girls at one month post-vaccination. Further follow-up of the cohort of boys is needed to gain knowledge on long-term immune responses of young boys following bivalent HPV vaccination.

Investigating sources of non-response bias in a population-based seroprevalence study of vaccine-preventable diseases in the Netherlands.

BACKGROUND: PIENTER 3 (P3), conducted in 2016/17, is the most recent of three nationwide serological surveys in the Netherlands. The surveys aim to monitor the effects of the National Immunisation Programme (NIP) by assessing population seroprevalence of included vaccine preventable diseases (VPDs). The response rate to the main sample was 15.7% (n = 4,983), following a decreasing trend in response compared to the previous two PIENTER studies (P1, 55.0%; 1995/1996 [n = 8,356] and P2, 33.0%; 2006/2007 [n = 5,834]). Non-responders to the main P3 survey were followed-up to complete a "non-response" questionnaire, an abridged 9-question version of the main survey covering demographics, health, and vaccination status. We assess P3 representativeness and potential sources of non-response bias, and trends in decreasing participation rates across all PIENTER studies. METHODS: P3 invitees were classified into survey response types: Full Participants (FP), Questionnaire Only (QO), Non-Response Questionnaire (NRQ) and Absolute Non-Responders (ANR). FP demographic and health indicator data were compared with Dutch national statistics, and then the response types were compared to each other. Random forest algorithms were used to predict response type. Finally, FPs from all three PIENTERs were compared to investigate the profile of survey participants through time. RESULTS: P3 FPs were in general healthier, younger and higher educated than the Dutch population. Random forest was not able to differentiate between FPs and ANRs, but when predicting FPs from NRQs we found evidence of healthy-responder bias. Participants of the three PIENTERs were found to be similar and are therefore comparable through time, but in line with national trends we found P3 participants were less inclined to vaccinate than previous cohorts. DISCUSSION: The PIENTER biobank is a powerful tool to monitor population-level protection against VPDs across 30 years in The Netherlands. However, future PIENTER studies should continue to focus on improving recruitment from under-represented groups, potentially by considering alternative and mixed survey modes to improve both overall and subgroup-specific response. Whilst non-responder bias is unlikely to affect seroprevalence estimates of high-coverage vaccines, the primary aim of the PIENTER biobank, other studies with varied vaccination/disease exposures should consider the influence of bias carefully.

Young infants display heterogeneous serological responses and extensive but reversible transcriptional changes following initial immunizations.

Infants necessitate vaccinations to prevent life-threatening infections. Our understanding of the infant immune responses to routine vaccines remains limited. We analyzed two cohorts of 2-month-old infants before vaccination, one week, and one-month post-vaccination. We report remarkable heterogeneity but limited antibody responses to the different antigens. Whole-blood transcriptome analysis in an initial cohort showed marked overexpression of interferon-stimulated genes (ISGs) and to a lesser extent of inflammation-genes at day 7, which normalized one month post-vaccination. Single-cell RNA sequencing in peripheral blood mononuclear cells from a second cohort identified at baseline a predominantly naive immune landscape including ISGhi cells. On day 7, increased expression of interferon-, inflammation-, and cytotoxicity-related genes were observed in most immune cells, that reverted one month post-vaccination, when a CD8+ ISGhi and cytotoxic cluster and B cells expanded. Antibody responses were associated with baseline frequencies of plasma cells, B-cells, and monocytes, and induction of ISGs at day 7.

Effect of age and season on respiratory mucosal immune marker profiles.

BACKGROUND: The upper respiratory tract is continuously exposed to microorganisms and noxious elements, leading to local immune responses and the secretion of immune markers. While several studies describe immune marker profiles in respiratory mucosal samples in defined patient cohorts, mucosal immune profiles from the general population during the different seasons are lacking. Such baseline profiles are essential to understand the effect of various exposures to the mucosal immune system throughout life. OBJECTIVE: We sought to establish baseline local upper respiratory mucosal immune profiles in the general population and assess these profiles with regard to age, sex, seasonality, and basic health and lifestyle factors. METHODS: We measured the concentrations of 35 immune markers involved in a broad range of immunological processes at the mucosa in nasopharyngeal swab samples from 951 individuals, aged 0 to 86 years, from a nationwide study. RESULTS: Clustering analysis showed that immune marker profiles clearly reflected immunological functions, such as tissue regeneration and antiviral responses. Immune marker concentrations changed strongly with seasonality and age, with the most profound changes occurring in the first 25 years of life; they were also associated with sex, body mass index, smoking, mild symptoms of airway infection, and chronic asthma and hay fever. CONCLUSION: Immunological analyses of noninvasive mucosal samples provide insight into mucosal immune responses to microbial and noxious element exposure in the general population. These data provide a baseline for future studies on respiratory mucosal immune responses and for the development of mucosal immune-based diagnostics.

Age-specific severity of severe acute respiratory syndrome coronavirus 2 in February 2020 to June 2021 in the Netherlands.

Background: The severity of Severe Acute Respiratory Syndrome Coronavirus 2 infection varies with age and time. Here, we quantify how age-specific risks of hospitalization, intensive care unit (ICU) admission, and death upon infection changed from February 2020 to June 2021 in the Netherlands. Methods: A series of large representative serology surveys allowed us to estimate age-specific numbers of infections in three epidemic periods (late-February 2020 to mid-June 2020, mid-June 2020 to mid-February 2021, and mid-February 2021 to late-June 2021). We accounted for reinfections and breakthrough infections. Severity measures were obtained by combining infection numbers with age-specific numbers of hospitalization, ICU admission, and excess all-cause deaths. Results: There was an accelerating, almost exponential, increase in severity with age in each period. The rate of increase with age was the highest for death and the lowest for hospitalization. In late-February 2020 to mid-June 2020, the overall risk of hospitalization upon infection was 1.5% (95% confidence interval [CI] 1.3-1.8%), the risk of ICU admission was 0.36% (95% CI: 0.31-0.42%), and the risk of death was 1.2% (95% CI: 1.0-1.4%). The risk of hospitalization was significantly increased in mid-June 2020 to mid-February 2021, while the risk of ICU admission remained stable over time. The risk of death decreased over time, with a significant drop among ≥70-years-olds in mid-February 2021 to late-June 2021; COVID-19 vaccination started early January 2021. Conclusion: Whereas the increase in severity of Severe Acute Respiratory Syndrome Coronavirus 2 with age remained stable, the risk of death upon infection decreased over time. A significant drop in risk of death among elderly coincided with the introduction of COVID-19 vaccination.

Cytomegalovirus and Epstein-Barr virus co-infected young and middle-aged adults can have an aging-related T-cell phenotype.

Cytomegalovirus (CMV) is known to alter circulating effector memory or re-expressing CD45RA+ (TemRA) T-cell numbers, but whether Epstein-Barr virus (EBV) does the same or this is amplified during a CMV and EBV co-infection is unclear. Immune cell numbers in blood of children and young, middle-aged, and senior adults (n = 336) were determined with flow cytometry, and additional multivariate linear regression, intra-group correlation, and cluster analyses were performed. Compared to non-infected controls, CMV-seropositive individuals from all age groups had more immune cell variance, and CMV+ EBV- senior adults had more late-differentiated CD4+ and CD8+ TemRA and CD4+ effector memory T-cells. EBV-seropositive children and young adults had a more equal immune cell composition than non-infected controls, and CMV- EBV+ senior adults had more intermediate/late-differentiated CD4+ TemRA and effector memory T-cells than non-infected controls. CMV and EBV co-infected young and middle-aged adults with an elevated BMI and anti-CMV antibody levels had a similar immune cell composition as senior adults, and CMV+ EBV+ middle-aged adults had more late-differentiated CD8+ TemRA, effector memory, and HLA-DR+ CD38- T-cells than CMV+ EBV- controls. This study identified changes in T-cell numbers in CMV- or EBV-seropositive individuals and that some CMV and EBV co-infected young and middle-aged adults had an aging-related T-cell phenotype.

Seroprevalence of Toxoplasma gondii and associated risk factors for infection in the Netherlands: third cross-sectional national study.

A third nationally representative serosurvey was performed to study the changes in Toxoplasma gondii (T. gondii) seroprevalence in the Netherlands over a 20-year time span and to identify and confirm risk factors for acquired toxoplasmosis. This cross-sectional study (conducted in 2016/2017) was designed similarly to the previous two studies (1995/1996 and 2006/2007) and included a questionnaire and serum sampling among Dutch residents. Factors associated with seropositivity for T. gondii were determined using multivariable analysis of the questionnaire-derived data. The earlier observed decrease in T. gondii seroprevalence between 1995/1996 and 2006/2007 (from 40.5% to 26.0%) did not continue into 2016/2017 (29.9%). Similarly to the previous studies, the seroprevalence increased with age and varied among regions. In all studies, higher T. gondii seropositivity was associated with increasing age, lower educational level, not living in the Southeast, and eating raw or semi-cooked pork. The incidence of congenital toxoplasmosis was estimated at 1.3/1000 (95% CI 0.9-1.8) live-born children in 2017. As the seroprevalence of T. gondii in the Netherlands did not decrease over the last decade, an increase in public health awareness is needed and prevention measures may need to be taken to achieve a further reduction in T. gondii infections in the Netherlands.

Targeting hepatitis B vaccine escape using immunogenetics in Bangladeshi infants.

Hepatitis B virus (HBV) vaccine escape mutants (VEM) are increasingly described, threatening progress in control of this virus worldwide. Here we studied the relationship between host genetic variation, vaccine immunogenicity and viral sequences implicating VEM emergence. In a cohort of 1,096 Bangladeshi children, we identified human leukocyte antigen (HLA) variants associated with response vaccine antigens. Using an HLA imputation panel with 9,448 south Asian individuals DPB1*04:01 was associated with higher HBV antibody responses (p=4.5×10-30). The underlying mechanism is a result of higher affinity binding of HBV surface antigen epitopes to DPB1*04:01 dimers. This is likely a result of evolutionary pressure at the HBV surface antigen 'a-determinant' segment incurring VEM specific to HBV. Prioritizing pre-S isoform HBV vaccines may tackle the rise of HBV vaccine evasion.

Assessing West Nile virus (WNV) and Usutu virus (USUV) exposure in bird ringers in the Netherlands: a high-risk group for WNV and USUV infection?

Introduction: In 2020, the first Dutch West Nile virus (WNV) infected birds were detected through risk-targeted surveillance of songbirds. Retrospective testing of patients with unexplained neurological disease revealed human WNV infections in July and August 2020. Bird ringers are highly exposed to mosquito bites and possibly avian excrements during ringing activities. This study therefore investigates whether bird ringers are at higher risk of exposure to WNV and Usutu virus (USUV). Methods: Dutch bird ringers were asked to provide a single serum sample (May - September 2021) and to fill out a survey. Sera were screened by protein microarray for presence of specific IgG against WNV and USUV non-structural protein 1 (NS1), followed by focus reduction virus neutralization tests (FRNT). Healthcare workers (2009-2010), the national immunity cohort (2016-2017) and blood donors (2021) were used as control groups without this occupational exposure. Results: The majority of the 157 participating bird ringers was male (132/157, 84%) and the median age was 62 years. Thirty-seven participants (37/157, 23.6%) showed WNV and USUV IgG microarray signals above background, compared to 6.4% (6/94) in the community cohort and 2.1% (2/96) in blood donors (p < 0.01). Two seroreactive bird ringers were confirmed WNV or USUV positive by FRNT. The majority of seroreactive bird ringers travelled to EU countries with reported WNV human cases (30/37, 81%) (p = 0.07). No difference was observed between bird ringers with and without previous yellow fever vaccination. Discussion: The higher frequency of WNV and/or USUV IgG reactive bird ringers indicates increased flavivirus exposure compared to the general population, suggesting that individuals with high-exposure professions may be considered to complement existing surveillance systems. However, the complexity of serological interpretation in relation to location-specific exposure (including travel), and antibody cross-reactivity, remain a challenge when performing surveillance of emerging flaviviruses in low-prevalence settings.

Seroprevalence and Risk Factors of Lyme Borreliosis in The Netherlands: A Population-Based Cross-Sectional Study.

Lyme borreliosis (LB) is not notifiable in many European countries, and accurate data on the incidence are often lacking. This study aimed to determine the seroprevalence of Borrelia burgdorferi sensu lato (s.l.)-specific antibodies in the general population of The Netherlands, and to determine risk factors associated with seropositivity. Sera and questionnaires were obtained from participants (n = 5592, aged 0-88 years) enrolled in a nationwide serosurveillance study. The sera were tested for B. burgdorferi s.l.-specific IgM and IgG antibodies using ELISA and immunoblot. Seroprevalence was estimated controlling for the survey design. Risk factors for seropositivity were analyzed using a generalized linear mixed-effect model. In 2016/2017, the seroprevalence in The Netherlands was 4.4% (95% CI 3.5-5.2). Estimates were higher in men (5.7% [95% CI 4.4-7.2]) than in women (3.1% [95% CI 2.0-4.0]), and increased with age from 2.6% (95% CI 1.4-4.4) in children to 7.7% (95% CI 5.9-7.9) in 60- to 88-year-olds. The seroprevalence for B. burgdorferi s.l. in the general population in The Netherlands was comparable to rates reported in European countries. The main risk factors for seropositivity were increasing age, being male and the tick bite frequency. The dynamics of LB infection are complex and involve variables from various disciplines. This could be further elucidated using infectious disease modelling.

BCG Vaccination of Health Care Workers Does Not Reduce SARS-CoV-2 Infections nor Infection Severity or Duration: a Randomized Placebo-Controlled Trial.

Bacillus Calmette-Guerin (BCG) vaccination has been hypothesized to reduce severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severity, and/or duration via trained immunity induction. Health care workers (HCWs) in nine Dutch hospitals were randomized to BCG or placebo vaccination (1:1) in March and April 2020 and followed for 1 year. They reported daily symptoms, SARS-CoV-2 test results, and health care-seeking behavior via a smartphone application, and they donated blood for SARS-CoV-2 serology at two time points. A total of 1,511 HCWs were randomized and 1,309 analyzed (665 BCG and 644 placebo). Of the 298 infections detected during the trial, 74 were detected by serology only. The SARS-CoV-2 incidence rates were 0.25 and 0.26 per person-year in the BCG and placebo groups, respectively (incidence rate ratio, 0.95; 95% confidence interval, 0.76 to 1.21; P = 0.732). Only three participants required hospitalization for SARS-CoV-2. The proportions of participants with asymptomatic, mild, or moderate infections and the mean infection durations did not differ between randomization groups. In addition, unadjusted and adjusted logistic regression and Cox proportional hazards models showed no differences between BCG and placebo vaccination for any of these outcomes. The percentage of participants with seroconversion (7.8% versus 2.8%; P = 0.006) and mean SARS-CoV-2 anti-S1 antibody concentration (13.1 versus 4.3 IU/mL; P = 0.023) were higher in the BCG than placebo group at 3 months but not at 6 or 12 months postvaccination. BCG vaccination of HCWs did not reduce SARS-CoV-2 infections nor infection duration or severity (ranging from asymptomatic to moderate). In the first 3 months after vaccination, BCG vaccination may enhance SARS-CoV-2 antibody production during SARS-CoV-2 infection. IMPORTANCE While several BCG trials in adults were conducted during the 2019 coronavirus disease epidemic, our data set is the most comprehensive to date, because we included serologically confirmed infections in addition to self-reported positive SARS-CoV-2 test results. We also collected data on symptoms for every day during the 1-year follow-up period, which enabled us to characterize infections in detail. We found that BCG vaccination did not reduce SARS-CoV-2 infections nor infection duration or severity but may have enhanced SARS-CoV-2 antibody production during SARS-CoV-2 infection in the first 3 months after vaccination. These results are in agreement with other BCG trials that reported negative results (but did not use serological endpoints), except for two trials in Greece and India that reported positive results but had few endpoints and included endpoints that were not laboratory confirmed. The enhanced antibody production is in agreement with prior mechanistic studies but did not translate into protection from SARS-CoV-2 infection.

Reduced Antibody Acquisition with Increasing Age following Vaccination with BNT162b2: Results from Two Longitudinal Cohort Studies in The Netherlands.

Vaccine-induced protection against severe COVID-19, hospitalization, and death is of the utmost importance, especially in the elderly. However, limited data are available on humoral immune responses following COVID-19 vaccination in the general population across a broad age range. We performed an integrated analysis of the effect of age, sex, and prior SARS-CoV-2 infection on Spike S1-specific (S1) IgG concentrations up to three months post-BNT162b2 (Pfizer/BioNTech; Comirnaty) vaccination. In total, 1735 persons, eligible for COVID-19 vaccination through the national program, were recruited from the general population (12 to 92 years old). Sixty percent were female, and the median vaccination interval was 35 days (interquartile range, IQR: 35−35). All participants had seroconverted to S1 one month after two vaccine doses. S1 IgG was higher in participants with a history of SARS-CoV-2 infection (median: 4535 BAU/mL, IQR: 2341−7205) compared to infection-naive persons (1842 BAU/mL, 1019−3116), p < 0.001. In infection-naive persons, linear mixed effects regression showed a strong negative association between age and S1 IgG (p < 0.001) across the entire age range. Females had higher S1 IgG than males (p < 0.001). In persons with an infection history, age nor sex was associated with S1 IgG concentrations. The lower magnitude of S1 antibodies in older persons following COVID-19 vaccination will affect long-term protection.

Characterization of the early cellular immune response induced by HPV vaccines.

Introduction: Current human papillomavirus (HPV) vaccines consist of virus-like particles (VLPs) which are based on the L1 protein, but they are produced by different expression systems and use different adjuvants. We performed in-depth immunophenotyping of multiple innate and adaptive immune cells after vaccination with bivalent versus nonavalent HPV vaccines. Method: Twenty pre-menopausal HPV-seronegative women were enrolled and randomized to receive three-doses of either the bivalent or the nonavalent HPV vaccine. Blood samples were collected at multiple time points from baseline up to 7 months after first vaccination. Four extensive EuroFlow flow cytometry antibody panels were used to monitor various immune cell subsets. Additionally, HPV-specific memory B- and T cells were determined by ELISPOT and HPV-specific antibody levels were measured by a VLP-based multiplex immunoassay. Results: In both cohorts, the numbers of plasma cells expanded in the first week after both primary and tertiary vaccination. HPV16 and HPV18-specific antibody levels and memory B and T-cell responses were higher in the bivalent than in the nonavalent vaccinees one month post third vaccination. For HPV31 and HPV45-specific antibody levels this pattern was reversed. Monocytes showed an expansion one day after vaccination in both cohorts but were significantly higher in the bivalent vaccine cohort. Large heterogeneity in responses of the other cell subsets was observed between donors. Conclusion: This pilot study showed a consistent response of monocytes and plasma cells after vaccination and a considerable variation in other circulating immune cells in both types of HPV vaccines between donors.

Effect of early two-dose measles vaccination on childhood mortality and modification by maternal measles antibody in Guinea-Bissau, West Africa: A single-centre open-label randomised controlled trial.

Background: Early 2-dose measles vaccine (MV) at 4 and 9 months of age vs. the WHO strategy of MV at 9 months of age reduced all-cause child mortality in a previous trial. We aimed to test two hypotheses: 1) a 2-dose strategy reduces child mortality between 4 and 60 months of age by 30%; 2) receiving early MV at 4 months in the presence versus absence of maternal measles antibodies (MatAb) reduces child mortality by 35%. Methods: Single-centre open-label community-based randomised controlled trial in Guinea-Bissau, with 2:1 block-randomisation by sex to a 2-dose (4 + 9 months) vs. 1-dose (9 months) MV strategy. Healthy children were eligible 4 weeks after the 3rd diphtheria-tetanus-pertussis-containing vaccine. Before randomisation a blood sample was collected to determine MatAb level. The primary outcome was all-cause mortality. Hazard ratios (HR) were derived from Cox regression in the per protocol population. We tested for interactions with national campaigns with oral polio vaccine (C-OPV). Trial registration: NCT01486355. Findings: Between August 2011-April 17th 2015, 6,636 children were enroled, 6,598[n2-dose=4,397; n1-dose=2,201] were included in the analysis of the primary outcome, The HR(2-dose/1-dose) between 4 and 60 months was 1.38 (95%CI: 0.92-2.06) [deaths: n2-dose=90; n1-dose=33]. Before the 9-month MV and the HR(1-dose/no dose) was 0.94 (0.45-1.96) [deaths: n2-dose=21; n1-dose=11]. The HR(2-dose/1-dose) was 0.81 (0.29-2.22) for children, who received no C-OPV [deaths/children: n2-dose=10/2,801; n1-dose=6/1,365], and 4.73 (1.44-15.6) for children, who received C-OPV before and after enrolment (p for interaction=0.027) [deaths/children: n2-dose=27/1,602; n1-dose=3/837]. In the 2-dose group receiving early MV at 4 months, mortality was 50% (20-68%) lower for those vaccinated in the presence of MatAb vs. the absence of MatAb [deaths/children: nMatAb=51/3,132; nnoMatAb=31/1,028]. Interpretation: The main result contrasts with previous findings but may, though based on a small number of events, be explained by frequent OPV campaigns that reduced the mortality rate, but apparently interacted negatively with early MV. The beneficial non-specific effects of MV in the presence of MatAb should be investigated further. Funding: ERC, Danish National Research Foundation, the Danish Council for Development Research, Ministry of Foreign Affairs, Novo Nordisk Foundation, European Union and the Lundbeck Foundation.

Decreased Antibody Response After Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination in Patients With Down Syndrome.

The risk of a severe course of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in adults with Down syndrome is increased, resulting in an up to 10-fold increase in mortality, in particular in those >40 years of age. After primary SARS-CoV-2 vaccination, the higher risks remain. In this prospective observational cohort study, SARS-CoV-2 spike S1-specific antibody responses after routine SARS-CoV-2 vaccination (BNT162b2, messenger RNA [mRNA]-1273, or ChAdOx1) in adults with Down syndrome and healthy controls were compared. Adults with Down syndrome showed lower antibody concentrations after 2 mRNA vaccinations or after 2 ChAdOx1 vaccinations. After 2 mRNA vaccinations, lower antibody concentrations were seen with increasing age. CLINICAL TRIALS REGISTRATION: NCT05145348.

Gut colonisation by extended-spectrum ß-lactamase-producing Escherichia coli and its association with the gut microbiome and metabolome in Dutch adults: a matched case-control study.

BACKGROUND: Gut colonisation by extended-spectrum ß-lactamase (ESBL)-producing Escherichia coli is a risk factor for developing overt infection. The gut microbiome can provide colonisation resistance against enteropathogens, but it remains unclear whether it confers resistance against ESBL-producing E coli. We aimed to identify a potential role of the microbiome in controlling colonisation by this antibiotic-resistant bacterium. METHODS: For this matched case-control study, we used faeces from 2751 individuals in a Dutch cross-sectional population study (PIENTER-3) to culture ESBL-producing bacteria. Of these, we selected 49 samples that were positive for an ESBL-producing E coli (ESBL-positive) and negative for several variables known to affect microbiome composition. These samples were matched 1:1 to ESBL-negative samples on the basis of individuals' age, sex, having been abroad or not in the past 6 months, and ethnicity. Shotgun metagenomic sequencing was done and taxonomic species composition and functional annotations (ie, microbial metabolism and carbohydrate-active enzymes) were determined. Targeted quantitative metabolic profiling (proton nuclear magnetic resonance spectroscopy) was done to investigate metabolomic profiles and combinations of univariate (t test and Wilcoxon test), multivariate (principal coordinates analysis, permutational multivariate analysis of variance, and partial least-squares discriminant analysis) and machine-learning approaches (least absolute shrinkage and selection operator and random forests) were used to analyse all the molecular data. FINDINGS: No differences in diversity parameters or in relative abundance were observed between ESBL-positive and ESBL-negative groups based on bacterial species-level composition. Machine-learning approaches using microbiota composition did not accurately predict ESBL status (area under the receiver operating characteristic curve [AUROC]=0·41) when using either microbiota composition or any of the functional profiles. The metabolome also did not differ between ESBL groups, as assessed by various methods including random forest (AUROC=0·61). INTERPRETATION: By combining multiomics and machine-learning approaches, we conclude that asymptomatic gut carriage of ESBL-producing E coli is not associated with an altered microbiome composition or function. This finding might suggest that microbiome-mediated colonisation resistance against ESBL-producing E coli is not as relevant as it is against other enteropathogens and antibiotic-resistant bacteria. FUNDING: None.