Exaggerated immune responses to respiratory viruses may contribute to increased morbidity in older adults. To investigate virus-specific immune activation in this population, we developed an ex vivo whole blood stimulation model using samples from 30 healthy individuals aged ≥65 years. Whole blood was stimulated with UV-inactivated influenza A virus (IAV), respiratory syncytial virus (RSV), and SARS-CoV-2, and the expression of 22 immune-related genes was assessed by quantitative RT-PCR array. All three viruses elicited responses with marked variability across individuals, as well as differences in the magnitude and distribution of cytokine expression across stimuli. RSV stimulation was associated with relatively higher expression of inflammatory mediators, while IAV and SARS-CoV-2 induced greater expression of Type I interferon. SARS-CoV-2 also led to an increased expression of regulatory cytokines. Although individual responses varied, correlation analysis indicated coordinated gene expression within functional categories, and Uniform Manifold Approximation and Projection (UMAP) showed distinct grouping of cytokine responses by virus and function. These findings describe differential immune mRNA expression profiles in response to viral stimuli in older adults and may support future studies aimed at understanding age-related differences in host–virus interactions.

Long-term care facility (LTCF) residents represent one of the populations most vulnerable to SARS-CoV-2 infection and have experienced repeated vaccination and natural viral exposure since the beginning of the COVID-19 pandemic. The long-term dynamics of humoral and cellular immunity in this population remain incompletely characterized. In this multicenter longitudinal study, SARS-CoV-2-specific antibody responses were monitored in LTCF residents over 12 months. A total of 388 residents from LTCF across five Italian regions were enrolled and stratified according to receipt of the SARS-CoV-2 XBB.1.5 mRNA booster during the 2023–2024 vaccination campaign. In a subgroup of residents, peripheral B-cell phenotypes and Spike-specific memory B cells were characterized by flow cytometry and compared with those of younger healthcare workers vaccinated with the same formulation. Anti-Spike IgG titers peaked in residents who received the XBB.1.5 booster and subsequently declined over time, consistent with contraction of vaccine-induced humoral responses. In contrast, individuals who did not receive the booster maintained lower but stable antibody levels. Anti-nucleocapsid seroconversion and clinically diagnosed intercurrent infections occurred at broadly comparable observed rates in boosted and non-boosted residents, suggesting a comparable incidence of SARS-CoV-2 infection during follow-up. Regarding B-cell-mediated immunity, LTCF residents exhibited age-associated remodeling of the B-cell compartment, with reduced total B-cell frequencies but preserved antigen-experienced memory populations. Despite declining circulating antibodies, Spike-specific memory B-cell frequencies remained stable. A late increase in anti-Spike titers coincided with rising anti-nucleocapsid seropositivity, suggesting reactivation of immune memory following natural viral exposure. These findings indicate that repeated vaccination and natural exposure generate durable immunological memory in LTCF residents. In highly exposed populations, immune maintenance may increasingly rely on reactivation of memory responses rather than persistently high antibody titers.

IntroductionCoronavirus disease 2019 (COVID-19) severity is closely associated with dysregulated inflammatory responses, with cytokines and chemokines emerging as key mediators and potential early biomarkers of adverse clinical outcomes. A retrospective study on 103 RT-PCR-confirmed COVID-19 patients during the first pandemic wave (January-May 2020) was performed to evaluate the prognostic value of a panel of cytokines and chemokines measured at hospital admission.MethodsSamples and clinical data were collected at the Department of Public Health and Infectious Diseases, Sapienza University of Rome, and sent to Istituto Superiore di Sanità for further characterization. Serum concentrations of IL-1β, IL-6, IL-8, IL-10, TNF-α, CCL3, and CXCL10 (IP-10) were quantified using multiplex ELISA. Associations with in-hospital mortality, intensive care unit (ICU) admission, and a composite outcome (death or ICU admission) were assessed using multivariable logistic regression.ResultsICU admission occurred in 6.8% of patients and mortality in 11.7%. Among inflammatory mediators, CXCL10 emerged as the strongest predictor of adverse outcomes. In adjusted models, each 1,000 pg/mL increase in CXCL10 was associated with increased odds of death (OR 1.26; 95% CI 1.17-1.35), ICU admission (OR 1.13; 95% CI 1.06-1.21), and the composite outcome (OR 1.21; 95% CI 1.12-1.31). Elevated respiratory frequency and blood urea nitrogen were also independently associated with worse outcomes, while TNF-α tended to be associated with ICU admission. Conversely, IL-6 and other cytokines were not significant predictors in the multivariable models. DiscussionThese findings identify CXCL10 as a key early immunological predictor of COVID-19 severity, suggesting that its integration with clinical parameters may improve risk stratification and guide targeted management. CXCL10 may also represent a potential therapeutic target, warranting validation in larger prospective studies.

Healthcare workers (HCW) are at increased risk for SARS-CoV-2 exposure and infection and have been preferentially prioritised in vaccination campaigns. The present study aims to monitor vaccine-induced humoral immune response over a 6-month period in a cohort of 494 HCW who received a booster immunization with bivalent mRNA SARS-CoV-2 vaccines. Overall, the study sample displayed high anti-trimeric Spike IgG levels at baseline (prior vaccine administration), which increased one month after the bivalent booster but declined over the subsequent six months. Sex, type of vaccine, concomitant seasonal flu vaccination, and anti-N IgG seropositivity had no significant impact on antibody levels one-month post-vaccination, while higher antibody increase was seen in individuals with lower baseline immunity and older age groups. Sera from 45 HCWs were tested in neutralization assays against the BA.5 and XBB.1.5 subvariants. Almost all sera neutralized BA.5 before vaccination; 23 (51.1 %) neutralized XBB.1.5 before vaccination, rising to 35 (77.8 %) after six months. MNT against BA.5 was higher than against XBB.1.5 at both time points, and anti-trimeric S IgG levels correlated with MNT for both strains. In conclusion, the present study suggests significant pre-existing immunity, possibly from prior infections, asymptomatic exposure to SARS-CoV-2, and multiple vaccine doses. We found that individuals with lower baseline immunity exhibited a stronger and faster antibody response to vaccination, which was also beneficial in providing a broader antibody repertoire against newly circulating variants. Overall, these findings offer crucial insights for shaping future immunization policies in a population that remains at elevated risk.

BACKGROUND:The continuous emergence of SARS-CoV-2 variants and subvariants poses significant public health challenges. The latest designated subvariant JN.1, with all its descendants, shows more than 30 mutations in the spike gene. JN.1 has raised concerns due to its genomic diversity and its potential to enhance transmissibility and immune evasion. This study aims to analyse the molecular characteristics of JN.1-related lineages (JN.1*) identified in Italy from October 2023 to April 2024 and to evaluate the neutralization activity against JN.1 of a subsample of sera from individuals vaccinated with XBB.1.5 mRNA. METHODS:The genomic diversity of the spike gene of 794 JN.1* strain was evaluated and phylogenetic analysis was conducted to compare the distance to XBB.1.5. Moreover, serum neutralization assays were performed on a subsample of 19 healthcare workers (HCWs) vaccinated with the monovalent XBB.1.5 mRNA booster to assess neutralizing capacity against JN.1. RESULTS:Sequence analysis displayed high spike variability between JN.1* and phylogenetic investigation confirmed a substantial differentiation between JN.1* and XBB.1.5 spike regions with 29 shared mutations, of which 17 were located within the RBD region. Pre-booster neutralization activity against JN.1 was observed in 42% of HCWs sera, increasing significantly post-booster, with all HCWs showing neutralization capacity three months after vaccination. A significant correlation was found between anti-trimeric Spike IgG levels and neutralizing titers against JN.1. CONCLUSIONS:The study highlights the variability of JN.1* in Italy. Results on a subsample of sera from HCWs vaccinated with XBB.1.5 mRNA booster vaccine suggested enhanced neutralization activity against JN.1.

The early innate immune response to vaccination plays a crucial role in shaping adaptive immunity and long-term protection. In this study, we investigated the early cytokine response to COVID-19 and flu vaccination and its association with mid-term humoral immunity. Twenty-nine healthcare workers (HCWs) who received the monovalent SARS-CoV-2 XBB.1.5 mRNA vaccine along with the seasonal quadrivalent inactivated influenza vaccine were enrolled. Serum samples were collected at baseline (T0), five days (T1), three months (T2), and six months (T3) post-vaccination. The levels of seven innate cytokines and chemokines were quantified at T0 and T1, while anti-trimeric spike (S) IgG titers were measured at T0, T2 and T3. Our analysis revealed a significant increase in CXCL10, TNF-α, and IL-6 at T1, whereas CCL3 and IL-8 mean levels remained unchanged. Spearman's correlation analysis showed a coordinated activation of inflammatory mediators, with IL-6 and IL-8 exhibiting the strongest correlation. Notably, early cytokine responses were associated with humoral immunity, as IL-6 and IL-8 levels at T1 were negatively correlated with anti-trimeric S IgG titers at T2 and T3. These findings suggest that early inflammatory cytokine increases may limit the persistence of vaccine-induced antibody response.

Objective: SARS-CoV-2 vaccination can bring an important benefit for older people in terms of reduction of mortality and hospitalization; however, reports of rare adverse effects like altered consciousness and delirium among this demographic have raised concerns. This study aimed to assess delirium incidence post-SARS-CoV-2 vaccination and its predictors in older residents across 60 Italian long-term care facilities (LTCFs). Design: This is a prospective cohort study considering data from GeroCovid Vax, a multicenter cohort study jointly performed by the Italian Society of Gerontology and Geriatrics (SIGG) (Florence, Italy) and the Italian National Institute of Health (Istituto Superiore di Sanit & agrave;dISS, Rome, Italy), and sponsored by the Italian Medicines Agency (Agenzia Italiana del FarmacodAIFA). Setting and Participants: GeroCovid Vax enrolled LTCFs residents aged >= 60 who received at least 1 anti eSARS-CoV-2 vaccine dose. Methods: Baseline data covered sociodemographic details, chronic diseases, medications, nutritional status, cognitive and functional assessments, mobility, and frailty. Delirium was assessed post-first, second, and booster vaccine doses using DSM-5 criteria. Data analysis involved descriptive statistics, multivariate logistic regression, and network analysis. Results: A total of 2521 participants (mean age 83.10 f 9.21 years, 70.7% female) were analyzed. Delirium cognitive disorders, and frailty were significant predictors of delirium, with odds ratios (ORs) of 1.70 (95% CI, 1.08-2.77), 2.05 (95% CI, 1.40-2.97), and 1.77 (95% CI, 1.25-2.52), respectively. Prior use of antipsychotics (OR, 1.75; 95% CI, 1.22-2.51) and antidepressants (OR, 1.77; 95% CI, 1.25-2.52) correlated significantly with Conclusion and Implications: Post-vaccination delirium is infrequent and decreases with subsequent doses. Timely assessments for frailty and cognitive impairment could aid in stratifying delirium risk among LTCF (c) 2024 The Author(s). Published by Elsevier Inc. on behalf of Post-Acute and Long-Term Care Medical Association. This is an open access article under the CC BY license (http://creativecommons.org/licenses/

In this pilot study, a multi-parametric analysis comparing immune responses in sera of adult healthy subjects (HS) or people with type 2 diabetes mellitus (T2D) undergoing the single or simultaneous administration of mRNA-based COVID-19 and cellular quadrivalent inactivated influenza vaccines was conducted. While SARS-CoV-2 antibodies remains comparable, influenza antibody titers and seroconversion were significantly higher upon simultaneous vaccination. Magnitude of anti-influenza humoral response closely correlated with an early innate immune signature, previously described for the COVID-19 vaccine, composed of IL-15, IL-6, TNF-α, IFN-γ, CXCL-10 and here extended also to acute-phase protein Pentraxin 3. People with T2D receiving simultaneous vaccination showed a protective response comparable to HS correlating with the early induction of IFN-γ/CXCL10 and a significant reduction of the circulating glucose level due to increased oxidation of glucose digestion and consumption. These data, although preliminary and in-need of validation in larger cohorts, might be exploited to optimize future vaccination in people with chronic disorders, including diabetes.

Objectives To evaluate humoral and cell-mediated response after three doses of BNT162b2 SARS-CoV-2 vaccine in patients with systemic lupus erythematosus (SLE) treated with Belimumab (BLM). Methods SLE patients were vaccinated with three doses of BNT162b2-mRNA vaccine (two-dose primary vaccination, third booster dose after 6 months). The humoral immune response was assessed one and 6 months after the second dose (T1, T2), and 6 months after the booster dose (T3). Serological assay was performed (The Liaison® SARS-CoV-2 TrimericS IgG chemiluminescent). Spike-specific T-cell response was monitored 6 months after the second vaccine dose and the percentage of cytokines producing T cells was assessed by flow cytometry. Results Twelve patients [12F; median age 46 years (IQR 8.25); median disease duration 156 months (IQR 188)] were enrolled. At T1, all patients showed seroconversion (median anti-Spike IgG levels 1610 BAU/mL, IQR 1390). At T2––day of the third dose––a significant reduction of median anti-Spike IgG antibodies levels was observed [214 BAU/mL (IQR 94); p = 0.0009]. Anti-Spike IgG were significantly increased at T3, reaching a median value of 1440 BAU/mL (IQR 1316; p = 0.005). Despite declining humoral immunity, almost 60% of patients mounted a virus-specific CD4 + T-cell response 6 months after primary vaccination. Conclusions BLM does not impair humoral response to primary BNT162b2 SARS-CoV-2 vaccination. During the follow-up, a decline in antibody levels is evident and the third dose is crucial to increase the specific immune response. Finally, we observed a recall T-cell response to the Spike antigen 6 months after the first vaccination cycle.

Despite the reported sex-related variations in the immune response to vaccination, whether the effects of SARS-CoV-2 vaccination differ by sex is still under debate, especially considering old vulnerable individuals, such as long-term care facilities (LTCFs) residents. This study aimed to evaluate COVID-19 infections, adverse events, and humoral response after vaccination in a sample of LTCF residents. A total of 3259 LTCF residents (71% females; mean age: 83.4 ± 9.2 years) were enrolled in the Italian-based multicenter GeroCovid Vax study. We recorded the adverse effects occurring during the 7 days after vaccine doses and COVID-19 cases over 12 months post-vaccination. In a subsample of 524 residents (69% females), pre- and post-vaccination SARS-CoV-2 trimeric S immunoglobulin G (Anti-S-IgG) were measured through chemiluminescent assays at different time points. Only 12.1% of vaccinated residents got COVID-19 during the follow-up, without any sex differences. Female residents were more likely to have local adverse effects after the first dose (13.3% vs. 10.2%, p = 0.018). No other sex differences in systemic adverse effects and for the following doses were recorded, as well as in anti-S-IgG titer over time. Among the factors modifying the 12-month anti-S-IgG titers, mobility limitations and depressive disorder were more likely to be associated with higher and lower levels in the antibody response, respectively; a significantly lower antibody titer was observed in males with cardiovascular diseases and in females with diabetes or cognitive disorders. The study suggests that, among LTCF residents, SARS-CoV-2 vaccination was effective regardless of sex, yet sex-specific comorbidities influenced the antibody response. Local adverse reactions were more common in females.

The rapid development of vaccines against SARS-CoV-2 infection and their use through mass vaccination campaigns has proved to be a highly successful strategy to reduce the effects of the COVID-19 pandemic. The deployment of SARS-CoV-2 vaccines to older adults at risk of severe disease has been a priority in most countries.1Cadeddu C Rosano A Villani L et al.Planning and organization of the COVID-19 vaccination campaign: an overview of eight European countries.Vaccines (Basel). 2022; 101631 Google Scholar Monitoring of the immune response represents a fundamental complement to vaccination campaigns. Studies so far have shown that although SARS-CoV-2 vaccines are less effective in older individuals,2Wang J Tong Y Li D Li J Li Y The impact of age difference on the efficacy and safety of COVID-19 vaccines: a systematic review and meta-analysis.Front Immunol. 2021; 12758294 Crossref Scopus (26) Google Scholar, 3Fedele G Trentini F Schiavoni I et al.Evaluation of humoral and cellular response to four vaccines against COVID-19 in different age groups: a longitudinal study.Front Immunol. 2022; 131021396 Crossref Scopus (3) Google Scholar a good response is achieved after two-dose primary vaccination.3Fedele G Trentini F Schiavoni I et al.Evaluation of humoral and cellular response to four vaccines against COVID-19 in different age groups: a longitudinal study.Front Immunol. 2022; 131021396 Crossref Scopus (3) Google Scholar, 4Blain H Tuaillon E Gamon L et al.Antibody response after one and two jabs of the BNT162b2 vaccine in nursing home residents: the CONsort-19 study.Allergy. 2022; 77: 271-281Crossref PubMed Scopus (22) Google Scholar A decline over time of vaccine-induced immune response has also been shown, together with the beneficial effect of a third booster dose.5Fedele G Palmieri A Malara A et al.A third dose of mRNA COVID-19 vaccine significantly enhances anti-SARS-CoV-2 spike IgG response in nursing home residents in Italy.J Am Med Dir Assoc. 2022; 23: 1114-1115Summary Full Text Full Text PDF PubMed Scopus (4) Google Scholar, 6Romero-Olmedo AJ Schulz AR Hochstätter S et al.Induction of robust cellular and humoral immunity against SARS-CoV-2 after a third dose of BNT162b2 vaccine in previously unresponsive older adults.Nat Microbiol. 2022; 7: 195-199Crossref PubMed Scopus (21) Google Scholar Most of the studies focused on the immune response induced by SARS-CoV-2 vaccines in frail older adults living in long-term health-care facilities or specific clinical risk groups, such as patients with cancer or on dialysis. Moreover, only a few studies analysed vaccine-induced T-cell responses. T-cell immunity plays a central role in the control of SARS-CoV-2, and increasing evidence supports a potential role in both preventing initial infection and reducing the severity of disease.7Moss P The T cell immune response against SARS-CoV-2.Nat Immunol. 2022; 23: 186-193Crossref PubMed Scopus (355) Google Scholar Data collected so far have highlighted an impaired T-cell response in people older than 80 years compared with younger adults aged 20–53 years after two vaccine doses,6Romero-Olmedo AJ Schulz AR Hochstätter S et al.Induction of robust cellular and humoral immunity against SARS-CoV-2 after a third dose of BNT162b2 vaccine in previously unresponsive older adults.Nat Microbiol. 2022; 7: 195-199Crossref PubMed Scopus (21) Google Scholar and the immune-potentiating effect of a third booster dose in previously less responsive older adults.6Romero-Olmedo AJ Schulz AR Hochstätter S et al.Induction of robust cellular and humoral immunity against SARS-CoV-2 after a third dose of BNT162b2 vaccine in previously unresponsive older adults.Nat Microbiol. 2022; 7: 195-199Crossref PubMed Scopus (21) Google Scholar, 8Schiavoni I Palmieri A Olivetta E et al.T-cell mediated response after primary and booster SARS-CoV-2 messenger RNA vaccination in nursing home residents.J Am Med Dir Assoc. 2023; 24: 140-147.e2Summary Full Text Full Text PDF PubMed Scopus (2) Google Scholar Anthony Ravussin and colleagues9Ravussin A Robertson AH Wolf A-S et al.Determinants of humoral and cellular immune responses to three doses of mRNA SARS-CoV-2 vaccines in older adults: a longitudinal cohort study.Lancet Healthy Longev. 2023; 4: e188-e199Google Scholar describe the immune responses to mRNA SARS-CoV-2 vaccines and epidemiological factors affecting these responses in a national Norwegian cohort of adults aged 65–80 years. The accessibility to a longitudinal cohort of more than 4500 senior adults favourably positioned the authors to understand whether functional and clinical factors can affect the response to SARS-CoV-2 vaccination. In fact, poorer evidence is available on the trajectories of immunity induced by vaccines in the general older age population, and further epidemiological data are needed on this vulnerable population, together with the possibility to identify factors influencing vaccine response. Of importance, the confounding effects of SARS-CoV-2 infection on vaccine responses were excluded through close monitoring of participants during the pandemic. Results of the immunological analyses, done on a subgroup of individuals representative of the whole cohort, confirmed good serological and cellular responses after two vaccine doses, responses which were further improved after the third dose, particularly after heterologous boosting. The authors found that both vaccine type and time since vaccination influenced antibody levels after primary vaccination; after three doses, hypertension was associated with decreased antibody levels. Except for hypertension, the authors did not find any associations between immune response to vaccination and chronic condition or frailty index. However, individuals older than 80 years were not included in the study cohort and the percentage of frail individuals was lower than in the Norwegian population of the same age. Vaccine efficacy against emerging variants of concern (VOCs) is an ongoing concern. In their study, Ravussin and colleagues9Ravussin A Robertson AH Wolf A-S et al.Determinants of humoral and cellular immune responses to three doses of mRNA SARS-CoV-2 vaccines in older adults: a longitudinal cohort study.Lancet Healthy Longev. 2023; 4: e188-e199Google Scholar found that vaccine-induced T lymphocytes recognise mutated epitopes from alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529 or BA.1) VOCs. This suggests that vaccine-mediated cellular cross-protection against SARS-CoV-2 VOCs in older adults might compensate for evasion of neutralising antibodies by mutated spike proteins. Albeit roughly 30% of the enrolled participants had a breakthrough infection, most of them had very mild illness, supporting a cross-protective role for T-cell immunity. Overall, Ravussin and colleagues provide important information on vaccination in older adults, a population which requires close monitoring and the implementation of effective preventive measures (ie, booster doses). However, further studies are needed for a better understanding of the heterogeneity of the immune response in older adults considering the changing epidemiological picture. The rapid spread of omicron VOCs had prompted the development of new generation bivalent mRNA SARS-CoV-2 vaccines, containing spike antigen from the ancestral Wuhan strain and the BA.1 or the BA.4-5 omicron VOCs. The administration of additional fourth and fifth vaccine boosters to older adults is being implemented in several countries.10European Centre for Disease Prevention and ControlECDC-EMA statement on booster vaccination with Omicron adapted bivalent COVID-19 vaccines. Sept 6, 2022. European Centre for Disease Prevention and Control, Solna2022Google Scholar Monitoring studies are needed to identify how immune responses change with new formulations and additional vaccine doses, and continuously tracing the effects of SARS-CoV-2 vaccination is mandatory. Answering questions on duration of vaccine-induced immunity, on the definition of immunological surrogates of protection from breakthrough infections and severe disease, and on the identification of at-risk patients and vaccine low-responders will bring key support to public health decisions on the definition of future vaccination strategies in the older age. We declare no competing interests. Determinants of humoral and cellular immune responses to three doses of mRNA SARS-CoV-2 vaccines in older adults: a longitudinal cohort studyMost older adults, including those with comorbidities, generated good serological and cellular responses after two vaccine doses. Responses further improved after three doses, particularly after heterologous boosting. Vaccination also generated cross-reactive T cells against variants of concern and seasonal coronaviruses. Frailty was not associated with impaired immune responses, but hypertension might indicate reduced responsiveness to vaccines even after three doses. Individual differences identified through longitudinal sampling enables better prediction of the variability of vaccine responses, which can help guide future policy on the need for subsequent doses and their timing. Full-Text PDF Open Access

ABSTRACT OBJECTIVE: Type 2 Diabetes mellitus may affect the humoral immune response following vaccinations, but data concerning COVID-19 vaccines are scarce. We evaluated the impact of diabetes mellitus on antibody response to the SARS-CoV-2 vaccination in older long-term care facilities (LTCF) residents and tested for differences according to anti-diabetic treatment. RESEARCH DESIGN AND METHODS: 555 older LTCF residents participating in the GeroCovid Vax study were included for this analysis. SARS-CoV-2 trimeric S Immunoglobulin G (anti-S-IgG) concentrations using chemiluminescent assays were tested before the first dose and after 2- and 6-months. The impact of diabetes on anti-S-IgG levels was evaluated using linear mixed models, which included the interaction between time and the presence of diabetes. A second model considered also diabetes treatment: no insulin therapy (including dietary only or use of oral anti-diabetic agents) and insulin therapy (alone or in combination with oral anti-diabetic agents). RESULTS: The sample's mean age was 82.1 years, 68.1% were women and 25.2% were diabetic. In linear mixed models, the presence of diabetes mellitus was associated with lower anti-S-IgG levels 2 (β=-0.20, 95%CI:-0.34,-0.06) and 6 months (β=-0.22, 95%CI:-0.37,-0.07) after the first vaccine dose. Compared to those without diabetes, diabetic residents not using insulin had lower IgG levels at 2- and 6-month assessments (β=-0.24, 95%CI:-0.43,-0.05, and β=-0.30, 95%CI:-0.50,-0.10, respectively), while no differences were observed for those under insulin. CONCLUSION: Older LTCF residents with diabetes tended to have weaker antibody response to COVID-19 vaccination. Insulin treatment might buffer this effect and establish a humoral immunity similar to non-diabetic individuals.

Effectiveness against severe COVID-19 of a second booster dose of the bivalent (original/BA.4–5) mRNA vaccine 7–90 days post-administration, relative to a first booster dose of an mRNA vaccine received ≥ 120 days earlier, was ca 60% both in persons ≥ 60 years never infected and in those infected > 6 months before. Relative effectiveness in those infected 4–6 months earlier indicated no significant additional protection (10%; 95% CI: −44 to 44). A second booster vaccination 6 months after the latest infection may be warranted.

Background Limited evidence is available on the additional protection conferred by second mRNA vaccine boosters against severe COVID-19 caused by omicron BA.5 infection, and whether the adapted bivalent boosters provide additional protection compared with the monovalent ones. In this study, we aimed to estimate the relative effectiveness of a second booster with monovalent or bivalent mRNA vaccines against severe COVID-19 in Italy.Methods Linking data from the Italian vaccination registry and the SARS-CoV-2 surveillance system, between Sept 12, 2022, and Jan 7, 2023, we matched 1:1 each person aged 60 years or older receiving a second booster with a person who had received the first booster only at least 120 days earlier. We used hazard ratios, estimated through Cox proportional hazard models, to compare the hazard of severe COVID-19 between the first booster group and each type of second booster (monovalent mRNA vaccine targeting the original strain of SARS-CoV-2, bivalent mRNA vaccine targeting the original strain plus omicron BA.1 [bivalent original/BA.1], and bivalent mRNA vaccine targeting the original strain plus omicron BA.4 and BA.5 [bivalent original/BA.4-5]). Relative vaccine effectiveness (rVE) was calculated as (1-hazard ratio) x 100.Findings We analysed a total of 2 129 559 matched pairs. The estimated rVE against severe COVID-19 with the bivalent original/BA.4-5 booster was 50 center dot 6% (95% CI 46 center dot 0-54 center dot 8) in the overall time interval 14-118 days post administration. Overall, rVE was 49 center dot 3% (43 center dot 6-54 center dot 4) for the bivalent original/BA.1 booster and 26 center dot 9% (11 center dot 8-39 center dot 3) for the monovalent booster. For the bivalent original/BA.4-5 booster, we did not observe relevant differences in rVE between the 60-79-year age group (overall, 53 center dot 6%; 46 center dot 8-59 center dot 5) and those aged 80 years or older (overall, 48 center dot 3%; 41 center dot 9-54 center dot 0).Interpretation These findings suggest that a second booster with mRNA vaccines provides additional protection against severe COVID-19 due to omicron BA.5 (the predominant circulating subvariant in Italy during the study period) in people aged 60 years or older. Although rVE decreased over time, a second booster with the original/BA.4-5 mRNA vaccine, currently the most used in Italy, was found to be still providing protection 4 months post administration.

A real-world population-based longitudinal study, aimed at determining the magnitude and duration of immunity induced by different types of vaccines against COVID-19, started in 2021 by enrolling a cohort of 2,497 individuals at time of their first vaccination. The study cohort included both healthy adults aged ≤65 years and elderly subjects aged >65 years with two or more co-morbidities. Here, patterns of anti-SARS-CoV-2 humoral and cell-mediated specific immune response, assessed on 1,182 remaining subjects, at 6 (T6) and 12 months (T12) after the first vaccine dose, are described. At T12 median anti-Spike IgG antibody levels were increased compared to T6. The determinants of increased anti-Spike IgG were the receipt of a third vaccine dose between T6 and T12 and being positive for anti-Nucleocapside IgG at T12, a marker of recent infection, while age had no significant effect. The capacity of T12 sera to neutralize in vitro the ancestral B strain and the Omicron BA.5 variant was assessed in a subgroup of vaccinated subjects. A correlation between anti-S IgG levels and sera neutralizing capacity was identified and higher neutralizing capacity was evident in healthy adults compared to frail elderly subjects and in those who were positive for anti-Nucleocapside IgG at T12. Remarkably, one third of T12 sera from anti-Nucleocapside IgG negative older individuals were unable to neutralize the BA.5 variant strain. Finally, the evaluation of T-cell mediated immunity showed that most analysed subjects, independently from age and comorbidity, displayed Spike-specific responses with a high degree of polyfunctionality, especially in the CD8 compartment. In conclusion, vaccinated subjects had high levels of circulating antibodies against SARS-CoV-2 Spike protein 12 months after the primary vaccination, which increased as compared to T6. The enhancing effect could be attributable to the administration of a third vaccine dose but also to the occurrence of breakthrough infection. Older individuals, especially those who were anti-Nucleocapside IgG negative, displayed an impaired capacity to neutralize the BA.5 variant strain. Spike specific T-cell responses, able to sustain immunity and maintain the ability to fight the infection, were present in most of older and younger subjects assayed at T12.

Innate immune responses to coronavirus infections are highly cell specific. Tissue-resident macrophages, which are infected by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in patients but are inconsistently infected in vitro, exert critical but conflicting effects by secreting both antiviral type I interferons (IFNs) and tissue-damaging inflammatory cytokines. Steroids, the only class of host-targeting drugs approved for the treatment of coronavirus disease 2019 (COVID-19), indiscriminately suppress both responses, possibly impairing viral clearance. Here, we established in vitro cell culture systems that enabled us to separately investigate the cell-intrinsic and cell-extrinsic proinflammatory and antiviral activities of mouse macrophages infected with the prototypical murine coronavirus MHV-A59. We showed that the nuclear factor κB–dependent inflammatory response to viral infection was selectively inhibited by loss of the lysine demethylase LSD1, which was previously implicated in innate immune responses to cancer, with negligible effects on the antiviral IFN response. LSD1 ablation also enhanced an IFN-independent antiviral response, blocking viral egress through the lysosomal pathway. The macrophage-intrinsic antiviral and anti-inflammatory activity of Lsd1 inhibition was confirmed in vitro and in a humanized mouse model of SARS-CoV-2 infection. These results suggest that LSD1 controls innate immune responses against coronaviruses at multiple levels and provide a mechanistic rationale for potentially repurposing LSD1 inhibitors for COVID-19 treatment.

BackgroundNumerous individual and organizational factors can influence the spread of SARS-CoV-2 infection in Long Term Care Facilities (LTCFs). A range of outbreak control measures are still implemented in most facilities involving administrations, staff, residents and their families. This study aims to evaluate which measure could influence the transmission of SARS-CoV-2 infection among residents during the period March 2021-June 2022.MethodsWe enrolled 3,272 residents aged ≥60 years. The outbreak control measures adopted to prevent or manage the infection included entry regulations, contact-regulating procedures, and virological surveillance of residents and staff. The association between LTCFs' and participants' characteristics with new cases of COVID-19 infections was analyzed using multilevel logistic regression models.ResultsIn 33.8% of the facilities 261 cases of SARS-CoV-2 infection were reported. Among participant characteristics, gender and age were not associated with SARS-CoV-2 infection, while having received the vaccine booster dose was protective against infection [Odds Ratio (OR) = 0.34, 95% Confidence Interval (CI) 0.12–0.99, p = 0.048]. In addition, the implementation of protected areas for family visits was associated with a significant reduction of the probability of infections (OR = 0.18, 95% CI 0.03–0.98, p = 0.047). Overall, about 66% of the variability in the probability of SARS-CoV-2 infection during the observational period may be due to facility structure characteristics and 34% to the participant characteristics.ConclusionsThese data showed that vaccination booster doses and family visit restriction-control are still needed to make the LTCFs safer against SARS-CoV-2 infection.

Objectives: Nursing home (NH) residents have been significantly affected by the coronavirus disease 2019 (COVID-19) pandemic. Studies addressing the immune responses induced by COVID-19 vaccines in NH residents have documented a good postvaccination antibody response and the beneficial effect of a third booster vaccine dose. Less is known about vaccine-induced activation of cell-mediated immune response in frail older individuals in the long term. The aim of the present study is to monitor messenger RNA SARS-CoV-2 vaccine-induced T-cell responses in a sample of Italian NH residents who received primary vaccine series and a third booster dose and to assess the interaction between T-cell responses and hu -moral immunity. Design: Longitudinal cohort study. Setting and Participants: Thirty-four residents vaccinated with BNT162b2 messenger RNA SARS-CoV-2 vaccine between February and April 2021 and who received a third BNT162b2 booster dose between October and November 2021 were assessed for vaccine-induced immunity 6 (prebooster) and 12 (postbooster) months after the first BNT162b2 vaccine dose. Methods: Pre-and postbooster cell-mediated immunity was assessed by intracellular cytokine staining of peripheral blood mononuclear cells stimulated in vitro with peptides covering the immunodominant sequence of SARS-CoV-2 spike protein. The simultaneous production of interferon -g, tumor necrosis factor-a, and interleukin-2 was measured. Humoral immunity was assessed in parallel by measuring serum concentration of antitrimeric spike IgG antibodies. Results: Before the booster vaccination, 31 out of 34 NH residents had a positive cell-mediated immunity response to spike. Postbooster, 28 out of 34 had a positive response. Residents without a previous history of SARS-CoV-2 infection, who had a lower response prior the booster administration, showed a greater increase of T-cell responses after the vaccine booster dose. Humoral and cell-mediated immunity were, in part, correlated but only before booster vaccine administration.Conclusions and Implications: The administration of the booster vaccine dose restored spike-specific T-cell responses in SARS-CoV-2 naive residents who responded poorly to the first immunization, while a previous SARS-CoV-2 infection had an impact on the magnitude of vaccine-induced cell-mediated im-munity at earlier time points. Our findings imply the need for a continuous monitoring of the immune status of frail NH residents to adapt future SARS-CoV-2 vaccination strategies. (c) 2022 Published by Elsevier Inc. on behalf of AMDA -The Society for Post-Acute and Long-Term Care Medicine.