Monocyte-driven inflamm-aging reduces intestinal barrier function in females.

BACKGROUND: The intestinal barrier encompasses physical and immunological components that act to compartmentalize luminal contents, such as bacteria and endotoxins, from the host. It has been proposed that an age-related decline of intestinal barrier function may allow for the passage of luminal contents into the bloodstream, triggering a low-grade systemic inflammation termed inflamm-aging. Although there is mounting evidence to support this hypothesis in model species, it is unclear if this phenomenon occurs in humans. In addition, despite being well-established that biological sex impacts aging physiology, its influence on intestinal barrier function and inflamm-aging has not been explored. RESULTS: In this study, we observed sex differences in markers of intestinal barrier integrity, where females had increased epithelial permeability throughout life as compared to males. With age, females had an age-associated increase in circulating bacterial products and metabolites such as LPS and kynurenine, suggesting reduced barrier function. Females also had age-associated increases in established markers of inflamm-aging, including peripheral blood monocytes as well as TNF and CRP. To determine if impaired barrier function was driving inflamm-aging, we performed a mediation analysis. The results show that the loss of intestinal barrier integrity was not the mediator of inflamm-aging in humans. Instead, persistent, low-grade inflammation with age preceded the increase in circulating bacterial products, which we confirmed using animal models. We found, as in humans, that sex modified age-associated increases in circulating monocytes in mice, and that inflammation mediates the loss of intestinal barrier function. CONCLUSION: Taken together, our results suggest that higher basal intestinal permeability in combination with age-associated inflammation, increases circulating LPS in females. Thus, targeting barrier permeability in females may slow the progression of inflamm-aging, but is unlikely to prevent it.

Defining an Ageing-Related Pathology, Disease or Syndrome: International Consensus Statement.

Background: Around the world, individuals are living longer, but an increased average lifespan does not always equate to an increased healthspan. With advancing age, the increased prevalence of ageing-related diseases can have a significant impact on health status, functional capacity, and quality of life. It is therefore vital to develop comprehensive classification and staging systems for ageing-related pathologies, diseases and syndromes. This will allow societies to better identify, quantify, understand, and meet the healthcare, workforce, wellbeing, and socioeconomic needs of ageing populations, while supporting the development and utilisation of interventions to prevent or to slow, halt or reverse the progression of ageing-related pathologies. Methods: The foundation for developing such classification and staging systems is to define the scope of what constitutes an ageing-related pathology, disease or syndrome. To this end, a consensus meeting was hosted by the International Consortium to Classify Ageing-Related Pathologies (ICCARP), on February 19 th , 2024, in Cardiff, UK, and was attended by 150 recognised experts. Discussions and voting were centred on provisional criteria that had been distributed prior to the meeting. The participants debated and voted on these. Each criterion required a consensus agreement of ≥70% for approval. Results: The accepted criteria for an ageing-related pathology, disease or syndrome were: Develops and/or progresses with increasing chronological age.Should be associated with, or contribute to, functional decline, or an increased susceptibility to functional decline.Evidenced by studies in humans. Conclusions: Criteria for an ageing-related pathology, disease or syndrome have been agreed by an international consortium of subject experts. These criteria will now be used by the ICCARP for the classification and ultimately staging of ageing-related pathologies, diseases and syndromes.

Canadian health care providers' and education workers' hesitance to receive original and bivalent COVID-19 vaccines.

BACKGROUND: The demand for COVID-19 vaccines has diminished as the pandemic lingers. Understanding vaccine hesitancy among essential workers is important in reducing the impact of future pandemics by providing effective immunization programs delivered expeditiously. METHOD: Two surveys exploring COVID-19 vaccine acceptance in 2021 and 2022 were conducted in cohorts of health care providers (HCP) and education workers participating in prospective studies of COVID-19 illnesses and vaccine uptake. Demographic factors and opinions about vaccines (monovalent and bivalent) and public health measures were collected in these self-reported surveys. Modified multivariable Poisson regression was used to determine factors associated with hesitancy. RESULTS: In 2021, 3 % of 2061 HCP and 6 % of 3417 education workers reported hesitancy (p < 0.001). In December 2022, 21 % of 868 HCP and 24 % of 1457 education workers reported being hesitant to receive a bivalent vaccine (p = 0.09). Hesitance to be vaccinated with the monovalent vaccines was associated with earlier date of survey completion, later receipt of first COVID-19 vaccine dose, no influenza vaccination, and less worry about becoming ill with COVID-19. Factors associated with hesitance to be vaccinated with a bivalent vaccine that were common to both cohorts were receipt of two or fewer previous COVID-19 doses and lower certainty that the vaccines were safe and effective. CONCLUSION: Education workers were somewhat more likely than HCP to report being hesitant to receive COVID-19 vaccines but reasons for hesitancy were similar. Hesitancy was associated with non-receipt of previous vaccines (i.e., previous behaviour), less concern about being infected with SARS-CoV-2, and concerns about the safety and effectiveness of vaccines for both cohorts. Maintaining inter-pandemic trust in vaccines, ensuring rapid data generation during pandemics regarding vaccine safety and effectiveness, and effective and transparent communication about these data are all needed to support pandemic vaccination programs.

Methotrexate and Tumor Necrosis Factor Inhibitors Independently Decrease Neutralizing Antibodies after SARS-CoV-2 Vaccination: Updated Results from the SUCCEED Study.

Objective: SARS-CoV-2 remains the third most common cause of death in North America. We studied the effects of methotrexate and tumor necrosis factor inhibitor (TNFi) on neutralization responses after COVID-19 vaccination in immune-mediated inflammatory disease (IMID). Methods: Prospective data and sera of adults with inflammatory bowel disease (IBD), rheumatoid arthritis (RA), spondyloarthritis (SpA), psoriatic arthritis (PsA), and systemic lupus (SLE) were collected at six academic centers in Alberta, Manitoba, Ontario, and Quebec between 2022 and 2023. Sera from two time points were evaluated for each subject. Neutralization studies were divided between five laboratories, and each lab's results were analyzed separately using multivariate generalized logit models (ordinal outcomes: absent, low, medium, and high neutralization). Odds ratios (ORs) for the effects of methotrexate and TNFi were adjusted for demographics, IMID, other biologics and immunosuppressives, prednisone, COVID-19 vaccinations (number/type), and infections in the 6 months prior to sampling. The adjusted ORs for methotrexate and TNFi were then pooled in random-effects meta-analyses (separately for the ancestral strains and the Omicron BA1 and BA5 strains). Results: Of 479 individuals (958 samples), 292 (61%) were IBD, 141 (29.4%) were RA, and the remainder were PsA, SpA, and SLE. The mean age was 57 (62.2% female). For both the individual labs and the meta-analyses, the adjusted ORs suggested independent negative effects of TNFi and methotrexate on neutralization. The meta-analysis adjusted ORs for TNFi were 0.56 (95% confidence interval (CI) 0.39, 0.81) for the ancestral strain and 0.56 (95% CI 0.39, 0.81) for BA5. The meta-analysis adjusted OR for methotrexate was 0.39 (95% CI 0.19, 0.76) for BA1. Conclusions: SARS-CoV-2 neutralization in vaccinated IMID was diminished independently by TNFi and methotrexate. As SARS-CoV-2 circulation continues, ongoing vigilance regarding optimized vaccination is required.

Reassuring humoral and cellular immune responses to SARS-CoV-2 vaccination in participants with systemic sclerosis.

Individuals with systemic sclerosis (SSc) are particularly susceptible to SARS-CoV-2 infections, yet it remains to be determined if they generate humoral and cellular responses comparable to controls following SARS-CoV-2 vaccinations. Herein, we collected blood and serum after second, third, and fourth SARS-CoV-2 vaccinations in patients with SSc and controls. Following each dose, participants with SSc mounted comparable serum anti-RBD IgG, anti-RBD IgA, and spike-specific CD4+ and CD8+T cell responses to those found in controls. At 3 months post dose 2, the frequencies of Th1, Th2, Th17, and Treg spike-specific CD4+T cells in participants with SSc did not differ from controls. At 2-6 weeks post dose 3, participants with SSc displayed reduced frequencies, but not numbers, of Th17-polarized spike-specific CD4+T cells. Thus, participants with SSc did not display significantly weaker humoral or cellular responses to SARS-CoV-2 vaccination than controls, enabling reassurance of vaccine immunogenicity in participants with SSc.

COVID-19 vaccine effectiveness among South Asians in Canada.

We evaluated the effectiveness of COVID-19 vaccines among South Asians living in Ontario, Canada compared to non-South Asians and compared the odds of symptomatic COVID-19 infection and related hospitalizations and deaths among non-vaccinated South Asians and non-South Asians. This was a test negative design study conducted in Ontario, Canada between December 14, 2020 and November 15, 2021. All eligible individuals >18 years with symptoms of COVID-19 were subdivided by ethnicity (South Asian vs other) and vaccination status (vaccinated versus not). The primary outcome was vaccine effectiveness as defined by COVID-19 infections, hospitalizations, and deaths, and secondary outcome was the odds of COVID-19 infections, hospitalizations, and death comparing non-vaccinated South Asians to non-vaccinated non-South Asians. 883,155 individuals were included. Among South Asians, two doses of COVID-19 vaccine prevented 93.8% (95% CI 93.2, 94.4) of COVID-19 infections and 97.5% (95% CI 95.2, 98.6) of hospitalizations and deaths. Among non-South Asians, vaccines prevented 86.6% (CI 86.3, 86.9) of COVID-19 infections and 93.1% (CI 92.2, 93.8) of hospitalizations and deaths. Non-vaccinated South Asians had higher odds of symptomatic SARS-CoV-2 infection compared to non-vaccinated non-South Asians (OR 2.35, 95% CI 2.3, 2.4), regardless of their immigration status. COVID-19 vaccines are effective in preventing infections, hospitalizations and deaths among South Asians living in Canada. The observation that non-vaccinated South Asians have higher odds of symptomatic COVID-19 infection warrants further investigation.

Duration of Postvaccination Neutralizing Antibodies to SARS-CoV-2 and Medication Effects: Results from the Safety and Immunogenicity of COVID-19 Vaccination in Systemic Immune-Mediated Inflammatory Diseases Cohort Study.

OBJECTIVE: In the face of the ongoing circulation of SARS-CoV-2, the durability of neutralization post-COVID-19 vaccination in immune-mediated inflammatory disease (IMID) is a key issue, as are the effects of medications. METHODS: Adults (n = 112) with inflammatory bowel disease, psoriasis/psoriatic arthritis, rheumatoid arthritis, spondylarthritis, and systemic lupus were recruited from participating Canadian medical centers from 2021 to 2023. We focused on log-transformed neutralization (lentivirus methods) as a continuous outcome, with separate models for wild-type and Omicron strains BA.1 and BA.5. RESULTS: Compared with 30 to 120 days postvaccination, subsequent periods were associated with greater neutralization in unadjusted models for wild-type, BA.1, and BA.5 strains and against the BA.1 strain in adjusted models. Rituximab was associated with lower neutralization for the BA.1 strain in adjusted models, with a similar trend for BA.5. In methotrexate users, there were trends for less neutralization of BA.1 and BA.5 in all unadjusted models, whereas in adjusted models, there was significantly lower neutralization only for the wild type. Three or more doses and Omicron-specific vaccines were both independently associated with better neutralization ability for all three strains. A COVID-19 infection within six months before sampling was associated with higher neutralization of wild type and BA.1 in adjusted analyses. Anti-tumor necrosis factor agents were associated with lower neutralization ability for BA.5 in adjusted analyses. CONCLUSION: Neutralization responses in immunosuppressed individuals with IMID were durable over time and were augmented by more than three doses and Omicron-specific vaccines. Less neutralization was seen with certain medications. Our work clarifies the joint effects of vaccine history, infection, and medications on COVID-19 immunity.

Chronic TNF in the aging microenvironment exacerbates Tet2 loss-of-function myeloid expansion.

ABSTRACT: Somatic mutations in the TET2 gene occur more frequently with age, imparting an intrinsic hematopoietic stem cells (HSCs) advantage and contributing to a phenomenon termed clonal hematopoiesis of indeterminate potential (CHIP). Individuals with TET2-mutant CHIP have a higher risk of developing myeloid neoplasms and other aging-related conditions. Despite its role in unhealthy aging, the extrinsic mechanisms driving TET2-mutant CHIP clonal expansion remain unclear. We previously showed an environment containing tumor necrosis factor (TNF) favors TET2-mutant HSC expansion in vitro. We therefore postulated that age-related increases in TNF also provide an advantage to HSCs with TET2 mutations in vivo. To test this hypothesis, we generated mixed bone marrow chimeric mice of old wild-type (WT) and TNF-/- genotypes reconstituted with WT CD45.1+ and Tet2-/- CD45.2+ HSCs. We show that age-associated increases in TNF dramatically increased the expansion of Tet2-/- cells in old WT recipient mice, with strong skewing toward the myeloid lineage. This aberrant myelomonocytic advantage was mitigated in old TNF-/- recipient mice, suggesting that TNF signaling is essential for the expansion Tet2-mutant myeloid clones. Examination of human patients with rheumatoid arthritis with clonal hematopoiesis revealed that hematopoietic cells carrying certain mutations, including in TET2, may be sensitive to reduced TNF bioactivity following blockade with adalimumab. This suggests that targeting TNF may reduce the burden of some forms of CHIP. To our knowledge, this is the first evidence to demonstrate that TNF has a causal role in driving TET2-mutant CHIP in vivo. These findings highlight TNF as a candidate therapeutic target to control TET2-mutant CHIP.

Nasal cathelicidin is expressed in early life and is increased during mild, but not severe respiratory syncytial virus infection.

Respiratory syncytial virus is the major cause of acute lower respiratory tract infections in young children, causing extensive mortality and morbidity globally, with limited therapeutic or preventative options. Cathelicidins are innate immune antimicrobial host defence peptides and have antiviral activity against RSV. However, upper respiratory tract cathelicidin expression and the relationship with host and environment factors in early life, are unknown. Infant cohorts were analysed to characterise early life nasal cathelicidin levels, revealing low expression levels in the first week of life, with increased levels at 9 months which are comparable to 2-year-olds and healthy adults. No impact of prematurity on nasal cathelicidin expression was observed, nor were there effects of sex or birth mode, however, nasal cathelicidin expression was lower in the first week-of-life in winter births. Nasal cathelicidin levels were positively associated with specific inflammatory markers and demonstrated to be associated with microbial community composition. Importantly, levels of nasal cathelicidin expression were elevated in infants with mild RSV infection, but, in contrast, were not upregulated in infants hospitalised with severe RSV infection. These data suggest important relationships between nasal cathelicidin, upper airway microbiota, inflammation, and immunity against RSV infection, with interventional potential.

A Scoping Review of the Relationship Between Maternal BMI and Offspring Incidence of Respiratory Infection: Where Do We Go From Here?

Introduction: Pregnancy complications, including high maternal BMI, are associated with altered early development and child health outcomes. A growing body of work links the prenatal environment, specifically maternal BMI, with respiratory infections in offspring. In this rapid review, the authors review the literature supporting the hypothesis that high maternal BMI during pregnancy is associated with childhood respiratory infection incidence. Methods: The authors employed systematic search criteria in known databases-EMBASE, EMCARE, MEDLINE, CINAHL, and PsychINFO-searching from inception to January 2023. Included were primary research studies that involved (1) human pregnancy, (2) pregravid or gestational overweight or obesity, and (3) childhood respiratory infection with or without hospitalization. Results: Only 7 population-based cohort studies met the criteria, investigating maternal BMI as an exposure and childhood respiratory infection as an outcome (age 6 months to 18 years). Therefore, the authors conducted a qualitative analysis, and outcomes were reported. The authors found that >85% of the albeit few published studies support the hypothesis that maternal BMI may have independent and profound consequences on respiratory infection risk across childhood. Discussion: This area of research needs large-scale, well-controlled studies to better understand the relationship between maternal BMI and childhood respiratory infection. Possible resources such as cohort catalogs and combined databases are discussed. These findings add to the growing evidence that early environmental factors influence lifelong respiratory health. By incorporating a life course approach to infectious disease risk, policy makers can put this research to work and target health vulnerabilities before they arise.

Neutrophil-mediated innate immune resistance to bacterial pneumonia is dependent on Tet2 function.

Individuals with clonal hematopoiesis of indeterminate potential (CHIP) are at increased risk of aging related health conditions and all-cause mortality, but whether CHIP affects risk of infection is much less clear. Using UK Biobank data, we revealed a positive association between CHIP and incident pneumonia in 438,421 individuals. We show that inflammation enhanced pneumonia risk, as CHIP carriers with a hypomorphic IL6 receptor polymorphism were protected. To better characterize the pathways of susceptibility, we challenged hematopoietic Tet Methylcytosine Dioxygenase 2-knockout (Tet2-/-) and floxed control mice (Tet2fl/fl) with Streptococcus pneumoniae. As with human CHIP carriers, Tet2-/- mice had hematopoietic abnormalities resulting in the expansion of inflammatory monocytes and neutrophils in peripheral blood. Yet, these cells were insufficient in defending against S. pneumoniae and resulted in increased pathology, impaired bacterial clearance, and higher mortality in Tet2-/- mice. We delineated the transcriptional landscape of Tet2-/- neutrophils and found that, while inflammation-related pathways were upregulated in Tet2-/- neutrophils, migration and motility pathways were compromised. Using live-imaging techniques, we demonstrated impairments in motility, pathogen uptake, and neutrophil extracellular trap (NET) formation by Tet2-/- neutrophils. Collectively, we show that CHIP is a risk factor for bacterial pneumonia related to innate immune impairments.

When Should I Get My Next COVID-19 Vaccine? Data From the Surveillance of Responses to COVID-19 Vaccines in Systemic Immune-Mediated Inflammatory Diseases (SUCCEED) Study.

OBJECTIVE: To determine how serologic responses to coronavirus disease 2019 (COVID-19) vaccination and infection in immune-mediated inflammatory disease (IMID) are affected by time since last vaccination and other factors. METHODS: Post-COVID-19 vaccination, data, and dried blood spots or sera were collected from adults with rheumatoid arthritis, inflammatory bowel disease, systemic lupus erythematosus, ankylosing spondylitis and spondylarthritis, and psoriasis and psoriatic arthritis. The first sample was collected at enrollment, then at 2 to 4 weeks and 3, 6, and 12 months after the latest vaccine dose. Multivariate generalized estimating equation regressions (including medications, demographics, and vaccination history) evaluated serologic response, based on log-transformed anti-receptor-binding domain (RBD) IgG titers; we also measured antinucleocapsid (anti-N) IgG. RESULTS: Positive associations for log-transformed anti-RBD titers were seen with female sex, number of doses, and self-reported COVID-19 infections in 2021 to 2023. Negative associations were seen with prednisone, anti-tumor necrosis factor agents, and rituximab. Over the 2021-2023 period, most (94%) of anti-N positivity was associated with a self-reported infection in the 3 months prior to testing. From March 2021 to February 2022, anti-N positivity was present in 5% to 15% of samples and was highest in the post-Omicron era, with antinucleocapsid positivity trending to 30% to 35% or higher as of March 2023. Anti-N positivity in IMID remained lower than Canada's general population seroprevalence (> 50% in 2022 and > 75% in 2023). Time since last vaccination was negatively associated with log-transformed anti-RBD titers, particularly after 210 days. CONCLUSION: Ours is the first pan-Canadian IMID assessment of how vaccine history and other factors affect serologic COVID-19 vaccine responses. These findings may help individuals personalize vaccination decisions, including consideration of additional vaccination when > 6 months has elapsed since last COVID-19 vaccination/infection.

Navigating the Landscape of Translational Geroscience in Canada: A Comprehensive Evaluation of Current Progress and Future Directions.

The inaugural Canadian Conferences on Translational Geroscience were held as 2 complementary sessions in October and November 2023. The conferences explored the profound interplay between the biology of aging, social determinants of health, the potential societal impact of geroscience, and the maintenance of health in aging individuals. Although topics such as cellular senescence, molecular and genetic determinants of aging, and prevention of chronic disease were addressed, the conferences went on to emphasize practical applications for enhancing older people's quality of life. This article summarizes the proceeding and underscores the synergy between clinical and fundamental studies. Future directions highlight national and global collaborations and the crucial integration of early-career investigators. This work charts a course for a national framework for continued innovation and advancement in translational geroscience in Canada.

Chronic TNF exposure induces glucocorticoid-like immunosuppression in the alveolar macrophages of aged mice that enhances their susceptibility to pneumonia.

Chronic low-grade inflammation, particularly elevated tumor necrosis factor (TNF) levels, occurs due to advanced age and is associated with greater susceptibility to infection. One reason for this is age-dependent macrophage dysfunction (ADMD). Herein, we use the adoptive transfer of alveolar macrophages (AM) from aged mice into the airway of young mice to show that inherent age-related defects in AM were sufficient to increase the susceptibility to Streptococcus pneumoniae, a Gram-positive bacterium and the leading cause of community-acquired pneumonia. MAPK phosphorylation arrays using AM lysates from young and aged wild-type (WT) and TNF knockout (KO) mice revealed multilevel TNF-mediated suppression of kinase activity in aged mice. RNAseq analyses of AM validated the suppression of MAPK signaling as a consequence of TNF during aging. Two regulatory phosphatases that suppress MAPK signaling, Dusp1 and Ptprs, were confirmed to be upregulated with age and as a result of TNF exposure both ex vivo and in vitro. Dusp1 is known to be responsible for glucocorticoid-mediated immune suppression, and dexamethasone treatment increased Dusp1 and Ptprs expression in cells and recapitulated the ADMD phenotype. In young mice, treatment with dexamethasone increased the levels of Dusp1 and Ptprs and their susceptibility to infection. TNF-neutralizing antibody reduced Dusp1 and Ptprs levels in AM from aged mice and reduced pneumonia severity following bacterial challenge. We conclude that chronic exposure to TNF increases the expression of the glucocorticoid-associated MAPK signaling suppressors, Dusp1 and Ptprs, which inhibits AM activation and increases susceptibility to bacterial pneumonia in older adults.

Dissecting mechanisms of fecal microbiota transplantation efficacy in disease.

Fecal microbiota transplantation (FMT) has emerged as an alternative or adjunct experimental therapy for microbiome-associated diseases following its success in the treatment of recurrent Clostridioides difficile infections (rCDIs). However, the mechanisms of action involved remain relatively unknown. The term 'dysbiosis' has been used to describe microbial imbalances in relation to disease, but this traditional definition fails to consider the complex cross-feeding networks that define the stability of the microbiome. Emerging research transitions toward the targeted restoration of microbial functional networks in treating different diseases. In this review, we explore potential mechanisms responsible for the efficacy of FMT and future therapeutic applications, while revisiting definitions of 'dysbiosis' in favor of functional network restoration in rCDI, inflammatory bowel diseases (IBDs), metabolic diseases, and cancer.

Immunomodulatory drugs have divergent effects on humoral and cellular immune responses to SARS-CoV-2 vaccination in people living with rheumatoid arthritis.

Understanding the efficacy of SARS-CoV-2 vaccination in people on immunosuppressive drugs, including those with rheumatoid arthritis (RA), is critical for their protection. Vaccine induced protection requires antibodies, CD4+ T cells, and CD8+ T cells, but it is unclear if these are equally affected by immunomodulatory drugs. Here, we determined how humoral and cellular SARS-CoV-2 vaccination responses differed between people with RA and controls, and which drug classes impacted these responses. Blood was collected from participants with RA on immunomodulatory drugs and controls after their second, third, and fourth SARS-CoV-2 vaccinations. Receptor binding domain (RBD)-specific antibodies were quantified by ELISA. Spike-specific memory T cells were quantitated using flow cytometry. Linear mixed models assessed the impact of age, sex, and immunomodulatory drug classes on SARS-CoV-2 vaccination responses. Compared to non-RA controls (n = 35), participants with RA on immunomodulatory drugs (n = 62) had lower anti-RBD IgG and spike-specific CD4+ T cell levels, but no deficits in spike-specific CD8+ T cells, following SARS-CoV-2 vaccination. Use of costimulation inhibitors was associated with lower humoral responses. JAK inhibitors were associated with fewer spike-specific CD4+ T cells. Participants with RA on immunomodulatory drugs mounted weaker responses to SARS-CoV-2 vaccination, with different drug classes impacting the cellular and humoral compartments.

Early humoral and cellular responses after bivalent SARS-CoV-2 mRNA-1273.214 vaccination in long-term care and retirement home residents in Ontario, Canada: An observational cohort study.

Immunogenicity of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) bivalent mRNA-1273.214 vaccine (Original/Omicron B.1.1.529 [BA.1]) is underreported in vulnerable older adults in congregate care settings. In residents of 26 long-term care and retirement homes in Ontario, Canada, humoral (i.e., serum anti-spike and anti-receptor binding domain [anti-RBD]) IgG and IgA antibodies and live SARS-CoV-2 neutralization) and cellular (i.e., CD4+ and CD8+ activation-induced marker spike-specific T cell memory) responses were assessed 7-120 days postvaccination with four monovalent mRNA vaccines (n = 494) or subsequent bivalent mRNA-1273.214 vaccination (fifth vaccine) (n = 557). Within 4 months, anti-spike and anti-RBD antibody levels were similar after monovalent and bivalent vaccination in infection-naïve individuals. Hybrid immunity (i.e., vaccination and natural infection) generally increased humoral responses. After bivalent vaccination, compared to monovalent vaccination, residents with hybrid immunity had elevated anti-spike and anti-RBD IgG and IgA antibodies. Omicron BA.1 antibody-mediated neutralization, and CD8+ T cell memory responses to the Omicron BA.1 spike protein, were also higher after bivalent vaccination. Humoral and cellular responses were, therefore, noninferior within 4 months of bivalent mRNA-1273.214 vaccination compared to monovalent mRNA vaccination. Waning of humoral but not cellular immunity was particularly evident in individuals without hybrid immunity. Continued monitoring of vaccine-associated and hybrid immunity against emerging Omicron variants of concern is necessary to assess longevity of protection.

The impact of respiratory infections and probiotic use on the nasal microbiota of frail residents in long-term care homes.

Background: Residents in long-term care homes, who tend to be of advanced age and frail, are at increased risk of respiratory infections. The respiratory microbiota is known to change with age, but whether these changes contribute to the risk of infection is not known. Our goal was to determine how the nasal microbiota of frail older adults changes during symptoms of influenza-like illness (ILI) and how this may be impacted by enrolment in a placebo-controlled trial testing the feasibility of administering a Lactobacillus rhamnosus GG probiotic to prevent respiratory infection (2014-2017). Methods: The microbiome of the nasal (mid-turbinate) of 150 residents of long-term care homes was interrogated using 16S rRNA gene sequencing. Results: We identified a diverse and individualised microbiota which could be separated into nine distinct clusters based on Bray-Curtis distances. Samples collected during symptoms of ILI differed statistically from those collected pre- and post-cold and influenza season, and we observed decreased temporal stability (as measured by movement between clusters) in individuals who experienced ILI compared to those who did not. Conclusions: The use of probiotics decreased ILI-induced changes to the microbiota; however, it is not clear whether this decrease is sufficient to prevent respiratory illness.

Early Omicron infection is associated with increased reinfection risk in older adults in long-term care and retirement facilities.

Background: Older adults are at increased risk of SARS-CoV-2 Omicron infection and severe disease, especially those in congregate living settings, despite high SARS-CoV-2 vaccine coverage. It is unclear whether hybrid immunity (combined vaccination and infection) after one Omicron infection provides increased protection against subsequent Omicron reinfection in older adults. Methods: Incidence of SARS-CoV-2 Omicron infection was examined in 750 vaccinated residents of long-term care and retirement homes in the observational cohort COVID in Long-Term Care Study in Ontario, Canada, within a 75-day period (July to September 2022). Risk of infection was assessed by Cox proportional hazards regression. Serum anti-spike and anti-RBD SARS-CoV-2 IgG and IgA antibodies, microneutralization titres, and spike-specific T cell memory responses, were examined in a subset of 318 residents within the preceding three months. Findings: 133 of 750 participants (17.7%) had a PCR-confirmed Omicron infection during the observation period. Increased infection risk was associated with prior Omicron infection (at 9-29 days: 47.67 [23.73-95.76]), and this was not attributed to days since fourth vaccination (1.00 [1.00-1.01]) or residence outbreaks (>6 compared to ≤6: 0.95 [0.37-2.41]). Instead, reinfected participants had lower serum neutralizing antibodies to ancestral and Omicron BA.1 SARS-CoV-2, and lower anti-RBD IgG and IgA antibodies, after their initial Omicron infection. Interpretation: Counterintuitively, SARS-CoV-2 Omicron infection was associated with increased risk of Omicron reinfection in residents of long-term care and retirement homes. Less robust humoral hybrid immune responses in older adults may contribute to risk of Omicron reinfection. Funding: COVID-19 Immunity Task Force of the Public Health Agency of Canada.