Associations of faecal microbiota with influenza-like illness in participants aged 60 years or older:an observational study

Background People aged 60 years or older are at high risk for respiratory infections, one of the leading causes of mortality worldwide. Vaccination is the main way to protect against these infections; however, vaccination is less effective in older adults than in younger adults due to ageing of the immune system, so innovative strategies that improve vaccine responses could provide a major public health benefit. The gut microbiota regulates host immune homoeostasis and response against pathogens, but human studies showing the effects of the gut microbiota on respiratory infections in older adults are sparse. We aimed to investigate the composition of the microbiota in relation to respiratory infections and local and systemic immune markers in older adults during an influenza season. Methods In this observational study, participants were selected from an influenza-like illness (ILI) prospective surveillance cohort in which community-dwelling adults aged 60 years and older in the Netherlands were recruited through their general practitioner or the Civil Registry. Inclusion criteria have been described elsewhere. Participants completed questionnaires and self-reported symptoms. To measure microbiota composition, faecal samples were collected from participants registering an ILI event, with a follow-up (recovery) sample collected 7-9 weeks after the ILI event, and from asymptomatic participants not reporting any event throughout the season. We tested associations between microbiota profiles and a set of health-related variables, patient characteristics, and local and systemic immune markers. We cultured identified bacterial biomarkers for ILI with CaCo-2 cells in an in vitro intestinal epithelial model and measured the induced immune response. This study is registered with http://www.trialregister.nl, NL4666. Findings Between Oct 1, 2014, and April 30, 2015, 2425 older adults were recruited into the ILI surveillance cohort. From Oct 1, 2014, to June 15, 2015, faecal samples were collected from 397 participants, of whom 213 (54%) reported an ILI event once throughout the season and 184 (46%) did not. 192 ILI participants recovered and provided follow-up samples. Microbiota composition was altered during an ILI event. The Bacteroidetes (mean relative abundance 17.51% [SD 11.41] in the ILI group and 14.19% [10.02] in the control group; adjusted p=0.014) and the Proteobacteria (3.40% [8.10] in the ILI group and 1.57% [3.69] in the control group; adjusted p=0.015) were more abundant in the ILI group than in the control group. The abundance of Ruminococcus torques was positively associated with ILI and the abundance of Escherichia/Shigella, negatively correlated with alpha diversity, and negatively co-occurred with beneficial taxa, including butyrate producers. R torques was associated with pro-inflammatory profiles, both locally in faeces and systemically in blood. ILI-associated taxa (R torques and Escherichia coli) had symbiotic effects on the cellular immune response when cultured together in an in vitro model. Interpretation The abundances of specific bacteria could be used as potential biomarkers for susceptibility to respiratory infections and as targets for intervention in the ageing population. Copyright (C) 2020 The Author(s). Published by Elsevier Ltd

Distinct T cell responsiveness to different COVID-19 vaccines and cross-reactivity to SARS-CoV-2 variants with age and CMV status

Introduction: Accumulating evidence indicates the importance of T cell immunity in vaccination-induced protection against severe COVID-19 disease, especially against SARS-CoV-2 Variants-of-Concern (VOCs) that more readily escape from recognition by neutralizing antibodies. However, there is limited knowledge on the T cell responses across different age groups and the impact of CMV status after primary and booster vaccination with different vaccine combinations. Moreover, it remains unclear whether age has an effect on the ability of T cells to cross-react against VOCs. Methods: Therefore, we interrogated the Spike-specific T cell responses in healthy adults of the Dutch population across different ages, whom received different vaccine types for the primary series and/or booster vaccination, using IFNɣ ELISpot. Cells were stimulated with overlapping peptide pools of the ancestral Spike protein and different VOCs. Results: Robust Spike-specific T cell responses were detected in the vast majority of participants upon the primary vaccination series, regardless of the vaccine type (i.e. BNT162b2, mRNA-1273, ChAdOx1 nCoV-19, or Ad26.COV2.S). Clearly, in the 70+ age group, responses were overall lower and showed more variation compared to younger age groups. Only in CMV-seropositive older adults (>70y) there was a significant inverse relation of age with T cell responses. Although T cell responses increased in all age groups after booster vaccination, Spike-specific T cell frequencies remained lower in the 70+ age group. Regardless of age or CMV status, primary mRNA-1273 vaccination followed by BNT162b2 booster vaccination showed limited booster effect compared to the BNT162b2/BNT162b2 or BNT162b2/mRNA-1273 primary-booster regimen. A modest reduction in cross-reactivity to the Alpha, Delta and Omicron BA.1, but not the Beta or Gamma variant, was observed after primary vaccination. Discussion: Together, this study shows that age, CMV status, but also the primary-booster vaccination regimen influence the height of the vaccination-induced Spike-specific T cell response, but did not impact the VOC cross-reactivity

Distinct T cell responsiveness to different COVID-19 vaccines and cross-reactivity to SARS-CoV-2 variants with age and CMV status

IntroductionAccumulating evidence indicates the importance of T cell immunity in vaccination-induced protection against severe COVID-19 disease, especially against SARS-CoV-2 Variants-of-Concern (VOCs) that more readily escape from recognition by neutralizing antibodies. However, there is limited knowledge on the T cell responses across different age groups and the impact of CMV status after primary and booster vaccination with different vaccine combinations. Moreover, it remains unclear whether age has an effect on the ability of T cells to cross-react against VOCs.MethodsTherefore, we interrogated the Spike-specific T cell responses in healthy adults of the Dutch population across different ages, whom received different vaccine types for the primary series and/or booster vaccination, using IFNɣ ELISpot. Cells were stimulated with overlapping peptide pools of the ancestral Spike protein and different VOCs.ResultsRobust Spike-specific T cell responses were detected in the vast majority of participants upon the primary vaccination series, regardless of the vaccine type (i.e. BNT162b2, mRNA-1273, ChAdOx1 nCoV-19, or Ad26.COV2.S). Clearly, in the 70+ age group, responses were overall lower and showed more variation compared to younger age groups. Only in CMV-seropositive older adults (>70y) there was a significant inverse relation of age with T cell responses. Although T cell responses increased in all age groups after booster vaccination, Spike-specific T cell frequencies remained lower in the 70+ age group. Regardless of age or CMV status, primary mRNA-1273 vaccination followed by BNT162b2 booster vaccination showed limited booster effect compared to the BNT162b2/BNT162b2 or BNT162b2/mRNA-1273 primary-booster regimen. A modest reduction in cross-reactivity to the Alpha, Delta and Omicron BA.1, but not the Beta or Gamma variant, was observed after primary vaccination.DiscussionTogether, this study shows that age, CMV status, but also the primary-booster vaccination regimen influence the height of the vaccination-induced Spike-specific T cell response, but did not impact the VOC cross-reactivity

Constructing synthetic populations in the age of big data

Abstract Background To develop public health intervention models using micro-simulations, extensive personal information about inhabitants is needed, such as socio-demographic, economic and health figures. Confidentiality is an essential characteristic of such data, while the data should reflect realistic scenarios. Collection of such data is possible only in secured environments and not directly available for open-source micro-simulation models. The aim of this paper is to illustrate a method of construction of synthetic data by predicting individual features through models based on confidential data on health and socio-economic determinants of the entire Dutch population. Methods Administrative records and health registry data were linked to socio-economic characteristics and self-reported lifestyle factors. For the entire Dutch population (n = 16,778,708), all socio-demographic information except lifestyle factors was available. Lifestyle factors were available from the 2012 Dutch Health Monitor (n = 370,835). Regression model was used to sequentially predict individual features. Results The synthetic population resembles the original confidential population. Features predicted in the first stages of the sequential procedure are virtually similar to those in the original population, while those predicted in later stages of the sequential procedure carry the accumulation of limitations furthered by data quality and previously modelled features. Conclusions By combining socio-demographic, economic, health and lifestyle related data at individual level on a large scale, our method provides us with a powerful tool to construct a synthetic population of good quality and with no confidentiality issues

Antibody Levels at 3-Years Follow-Up of a Third Dose of Measles-Mumps-Rubella Vaccine in Young Adults.

Mumps outbreaks and breakthrough infections of measles and rubella have raised concerns about waning of vaccine-induced immunity after two doses of measles-mumps-rubella (MMR) vaccination. In the present follow-up study, serum IgG antibodies against mumps, measles and rubella, as well as the functional neutralizing antibodies against both the mumps vaccine strain and mumps outbreak strains were measured longitudinally in young adults that received a third MMR (MMR3) dose. The mumps-specific IgG and virus neutralizing antibody levels at 3 years after vaccination were still elevated compared to pre-vaccination antibody levels, although the differences were smaller than at earlier timepoints. Interestingly, subjects with low antibody levels to mumps before vaccination benefited the most as they showed the strongest antibody increase after an MMR3 dose. Three years after an MMR3 dose, all subjects had antibody levels to measles and rubella above the internationally agreed antibody cutoff levels for clinical protection. Our data support the recommendation that an MMR3 dose may provide additional protection for those that have become susceptible to mumps virus infection during outbreaks. MMR3 also resulted in an increase in anti-measles and rubella antibody levels that lasted longer than might have been expected

Influenza-like Illness Exacerbates Pneumococcal Carriage in Older Adults.

BACKGROUND: In older adults, pneumococcal disease is strongly associated with respiratory viral infections, but the impact of viruses on Streptococcus pneumoniae carriage prevalence and load remains poorly understood. Here, we investigated the effects of influenza-like illness (ILI) on pneumococcal carriage in community-dwelling older adults. METHODS: We investigated the presence of pneumococcal DNA in saliva samples collected in the 2014/2015 influenza season from 232 individuals aged ≥60 years at ILI onset, followed by sampling 2-3 weeks and 7-9 weeks after the first sample. We also sampled 194 age-matched controls twice 2-3 weeks apart. Pneumococcal DNA was detected with quantitative polymerase chain reaction assays targeting the piaB and lytA genes in raw and in culture-enriched saliva. Bacterial and pneumococcal abundances were determined in raw saliva with 16S and piaB quantification. RESULTS: The prevalence of pneumococcus-positive samples was highest at onset of ILI (42/232 [18%]) and lowest among controls (26/194 [13%] and 22/194 [11%] at the first and second samplings, respectively), though these differences were not significant. Pneumococcal carriage was associated with exposure to young children (odds ratio [OR], 2.71 [95% confidence interval {CI}, 1.51-5.02]; P < .001), and among asymptomatic controls with presence of rhinovirus infection (OR, 4.23 [95% CI, 1.16-14.22]; P < .05). When compared with carriers among controls, pneumococcal absolute abundances were significantly higher at onset of ILI (P < .01), and remained elevated beyond recovery from ILI (P < .05). Finally, pneumococcal abundances were highest in carriage events newly detected after ILI onset (estimated geometric mean, 1.21 × 10-5 [95% CI, 2.48 × 10-7 to 2.41 × 10-5], compared with preexisting carriage). CONCLUSIONS: ILI exacerbates pneumococcal colonization of the airways in older adults, and this effect persists beyond recovery from ILI