Search Results (365)

Background: Understanding the duration and quality of immune memory following SARS-CoV-2 infection and vaccination is critical for informing public health strategies and vaccine development. While waning antibody levels have raised concerns about long-term protection, the persistence of memory B cells (MBCs) and T cells plays a vital role in sustaining immunity. Materials and Methods: We conducted a longitudinal prospective study over 12 months, enrolling 285 participants in total, either after natural infection or vaccination with BNT162b2 or mRNA-1273. Peripheral blood samples were collected at four defined time points (baseline, 1–2 months, 6–7 months, and 12–13 months after vaccination or disease onset). Immune responses were assessed through serological assays quantifying anti-RBD IgG and neutralizing antibodies, B-ELISPOT, and multiparameter flow cytometry for S1-specific memory B cells. Results: Both mRNA vaccines induced robust B cell and antibody responses, exceeding those observed after natural infection. Memory B cell frequencies peaked at 6 months and declined by 12 months, but remained above the baseline. The mRNA-1273 vaccine elicited stronger and more durable humoral and memory B-cell-mediated immunity compared to BNT162b2, likely influenced by its higher mRNA dose and longer prime-boost interval. Class-switched memory B cells and S1-specific B cells were significantly expanded in vaccine recipients. Natural infection induced more heterogeneous immune memory. Conclusions: Both mRNA vaccination and natural SARS-CoV-2 infection induce a comparable expansion of memory B cell subsets, reflecting a consistent pattern of humoral immune responses across all studied groups. These findings highlight the importance of vaccination in generating sustained immunological memory and suggest that the vaccine platform and dosage influence the magnitude and durability of immune responses against SARS-CoV-2. Full article

Background: Studies investigating the long-term cellular immune response to SARS-CoV-2 mRNA vaccines in patients with inflammatory bowel disease (IBD) remain limited, particularly among those receiving immunosuppressive therapy. Methods: We prospectively evaluated humoral and cellular immune responses at short-term (4–6 weeks) and long-term (6–12 months) time points following SARS-CoV-2 mRNA vaccination in patients with IBD receiving anti-TNF agents, thiopurines, or combination therapy. We defined the short-term response as the measurement taken 4–6 weeks after the second vaccine dose and the long-term response as the measurement taken between 6 and 12 months after the first determination. A cohort of healthy controls was included for short-term comparative analysis. Results: At long-term follow-up, quantitative humoral responses were reduced in patients receiving anti-TNF monotherapy. In contrast, a reduced quantitative cellular response was found in the thiopurine (median 0.7 UI/mL, p < 0.05) and anti-TNF combo groups (median 0.4 UI/mL, p < 0.01) compared to anti-TNF monotherapy (median 2.2 UI/mL). Conclusions: There was a robust long-term humoral and cellular response to vaccination, but a diminished quantitative cellular response in patients treated with thiopurines or combo therapy compared to anti-TNF monotherapy. Full article

Background: Mucosal immunity plays a pivotal role in preventing infections with SARS-CoV-2. While COVID-19 mRNA vaccines induce robust systemic immune responses in patients with inflammatory bowel disease (IBD), little is known about their efficacy in the mucosal immune compartment. In this sub-investigation of the ongoing STAR-SIGN study, we present the first analysis of mucosal immunity elicited by XBB.1.5 mRNA vaccines in immunocompromised patients with IBD. Methods: IgG and IgA antibodies targeting the receptor-binding domain of the SARS-CoV-2 JN.1 variant were quantified longitudinally in the saliva of IBD patients using the multiplex immunoassay MultiCoV-Ab. Antibody levels were quantified before and 2–4 weeks after vaccination with XBB.1.5 mRNA vaccines. All patients previously received three doses with original COVID-19 vaccines. Results: Mucosal IgG antibodies were readily induced by XBB.1.5 mRNA vaccines (p = 0.0013 comparing pre- and post-vaccination levels). However, mucosal IgA levels were comparable before and after vaccination (p = 0.8233). Consequently, mucosal IgG and IgA antibody levels correlated only moderately before and after immunization (pre-vaccination: r = 0.5294; p = 0.0239; post-vaccination: r = 0.4863; p = 0.0407). Contrary to a previous report in healthy individuals, vaccination did not induce serum IgA in patients with IBD (p = 0.5841 comparing pre- and post-vaccination levels). These data suggest that COVID-19 mRNA vaccines fail to elicit mucosal IgA in patients with IBD. Conclusions: Since mucosal IgA plays a pivotal role in infection control, the lack of IgA induction indicates that patients lack sufficient protection against SARS-CoV-2 infections which warrants the development of mucosal COVID-19 vaccines. Full article

Background/Objectives: The COVID-19 pandemic has caused sickness and death among many health care workers. However, the apparent resistance of health care workers to SARS-CoV-2 infection despite their high-risk work environment remains unclear. To investigate if inflammation and circadian disruption contribute to resistance or diminished susceptibility to the SARS-CoV-2 virus, we retrospectively evaluated a cohort of volunteer hospital nurses (VHNs). Methods: A total of 246 apparently healthy VHNs (mean age 37.4 ± 5.9 years) who had received the BNT162b2 mRNA vaccine were asked to report their sleep quality, according to the Pittsburgh Sleep Quality Index, and number of SARS-CoV-2 infections during the observational study period (from the end of December 2020 to April 2025). The expression of inflammation-associated mediators and circadian transcription factors in peripheral blood mononuclear cells, as well as sleep quality, were examined. Results: Our findings revealed no anthropometric, biochemical, or inflammation-associated parameters but demonstrated significantly greater levels of NFE2L2, also known as nuclear factor erythroid-derived 2-like 2 (NFR2), gene expression in peripheral blood mononuclear cells among VHNs who had never been infected with SARS-CoV-2 (n = 97) than in VHNs with only one (n = 119) or with two or more (n = 35) prior SARS-CoV-2 infections (p < 0.01). This result was confirmed through one-to-one propensity score matching (p < 0.01). Moreover, NRF2 gene expression was not associated with the number of COVID-19 vaccinations (p = 0.598). Finally, NRF2 gene expression was higher among participants who reported better sleep quality (p < 0.01). Conclusions: Our findings suggest possible interactions among NRF2 gene expression, protection against SARS-CoV-2 infection, and the modulation of COVID-19 vaccination efficacy. Full article

Background/Objectives: Vaccine immunogenicity is often suboptimal in vulnerable populations such as the elderly, infants, and individuals in low- and middle-income countries. One contributing factor may be pre-existing immunomodulatory conditions, including helminth infections. This study investigates the impact of Fasciola hepatica (F. hepatica) derived molecules on the early humoral response to the COVID-19 mRNA vaccine Comirnaty^® in a mouse model. Methods: BALB/c mice were pretreated with a F. hepatica protein extract (FH) or complete Freund’s adjuvant (CFA) prior to vaccination. Cytokine production and antibody responses were assessed at 0, 14, and 21 days post-vaccination (dpv) through serum analysis and ex vivo splenocyte stimulation with the SARS-CoV-2 receptor-binding domain (RBD) or LPS. Results: At 0 dpv, FH-treated mice showed increased serum IL-10, while CFA treatment induced IL-12. FH- but not CFA-treated splenocytes secreted IL-10 upon RBD or LPS stimulation. At 21 dpv, FH-treated mice lacked IFN-γ production but maintained IL-10 and showed elevated IL-4, consistent with a Th2-skewed profile. Although total anti-RBD IgG levels were similar between groups, FH-treated mice exhibited reduced IgG avidity and a higher IgG1/IgG2 ratio. CFA-treated mice showed delayed avidity maturation. Conclusions: Prior exposure to F. hepatica antigens can modulate the early immune response to Comirnaty^®, affecting both cellular activation and antibody quality. This altered response may reflect a reduced early protective capacity of the vaccine, which might need to be considered when designing or evaluating vaccination strategies using mRNA vaccines in helminth-endemic regions. Full article

Background/Objectives: The SARS-CoV-2 pandemic challenged patients with inflammatory bowel disease (IBD) under immunosuppressive therapies. We used data from the RisCoin cohort to investigate factors associated with a poor immune response to mRNA vaccination in these patients. Methods: From 4115 RisCoin participants, we matched 110 IBD patients by age and time interval since the second mRNA vaccination with 306 healthcare workers (HCW) without comorbidities (HCW-healthy) and 292 with medical conditions (HCW-plus); all were SARS-CoV-2 infection naïve. Basic questionnaires collected data on medication, COVID-19 vaccinations and side-effects, dietary patterns, lifestyle factors, and self-perceived stress. Main outcomes included anti-spike immunoglobulin levels and antibody-mediated live-virus neutralization immunity (NT) to the Omicron BA.1 variant (threshold NT ≥ 10 defined as IC50 values ≥1:10 serum dilution) after the second (baseline) and third vaccinations. Results: At baseline, IBD patients treated with anti-TNF but not those under vedolizumab or ustekinumab therapy had lower anti-spike levels compared to HCW-healthy and HCW-plus (166 versus 1384 and 1258 BAU/mL, respectively; p < 0.0001). Anti-TNF compared to vedolizumab/ustekinumab-treated patients reached NT titers above threshold in 17% versus 64%, respectively, and HCW-subgroups in 73% and 79% (all p < 0.0001). Current smokers showed a four to five times increased risk for non-neutralizing immunity compared to non-smokers. After the third vaccination, NT titers did not reach threshold in 15% anti-TNF compared to 5% vedolizumab/ustekinumab-treated patients and none of HCW (p < 0.01). Patients with IBD reported fewer clinical symptoms after vaccination. Perceived stress was not increased. Conclusions: Our findings support individualized schedules for mRNA-based vaccines in IBD patients with different immunosuppressive therapies and enforcement of non-smoking. Full article

Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare thrombotic disorder first identified in 2021 as a catastrophic syndrome associated with anti-SARS-CoV-2 adenoviral vector (AdV)-vaccine administration. It is characterized by the presence of oligo- or monoclonal anti-PF4 antibodies able to induce in vitro platelet activation in the presence of PF4. In addition to this immune-based pathomechanism, random splicing events of the Adv-vector DNA encoding for SARS-CoV-2 spike protein resulting in the secretion of soluble spike variants have been postulated as a possible pathophysiological mechanism. More recently, some novel clinical-pathological anti-PF4-associated entities also characterized by thrombosis, thrombocytopenia, and VITT-like antibodies but independent from heparin or AdV-vaccine administration have been identified. To date, these VITT-like disorders have been reported following the administration of vaccines different from anti-SARS-CoV-2 AdV-vaccines, like human papillomavirus (HPV) and mRNA-based COVID-19 vaccines, following a bacterial or viral respiratory infection, and in patients with a monoclonal gammopathy of undetermined significance. The purpose of this review is to provide an update on the knowledge on VITT pathogenesis, focusing on recent findings on anti-PF4 antibodies, on a possible genetic predisposition to VITT, on VITT-antibody intracellular activated pathways, on lipid metabolism alterations, and on new VITT-like disorders. Full article

Background/Objectives: This study examines the longitudinal dynamics of anti-nucleocapsid (anti-N) and anti-spike (anti-S) antibody responses to SARS-CoV-2 infection and mRNA vaccination based on 81,878 serum samples from 23,616 healthcare workers (HCWs) across five European countries. It includes data across four scheduled vaccine doses—predominantly BNT162b2—with 25% of samples originating from individuals with confirmed prior infection, as evidenced by elevated anti-S levels, positive Anti-N antibodies, or PCR results. Methods: The study employed a shifted transformation method for data normalization and utilized the Bass diffusion model to predict antibody titer dynamics influenced by both internal factors—such as immune activation contextualized through sociodemographic issues—and external factors, including infection and vaccination. Despite the absence of direct measurements for some internal variables, the model effectively inferred their impact, enabling a rigorous and nuanced delineation of immune response profiles. Results: The Bass diffusion model rigorously captured variations in antibody titers, analyzed through demographic factors such as gender, age, and job role, while thoroughly accounting for pre-infection status. The results indicate that Anti-N antibodies, exclusively produced post-infection, exhibited a rapid decline, while anti-S antibodies, generated from both infection and vaccination, demonstrated prolonged persistence. A significant decline in anti-S levels was observed 3–5 months post-vaccination, with adaptive immunity—characterized by the dominance of internal factors effects relative to external ones—achieved in most groups after the fourth dose. However, adaptive immunity post second dose was limited to specific demographics. Conclusions: These findings emphasize the significance of the Bass Method in predicting vaccine-induced, hybrid immune responses and detecting adaptive immunity by overcoming limitations in internal factor data, thereby advancing effective vaccination and infection control strategies during public health crises. These findings highlight the Bass Method’s value in predicting vaccine-induced and hybrid immunity, effectively addressing internal factor data gaps to enhance vaccination and infection control strategies. Full article

Background: Kidney transplant (KTx) recipients exhibit impaired responses to SARS-CoV-2 vaccination. Correlates of vaccine-induced immunity and risk factors for breakthrough infection are not fully defined. This study evaluated the humoral response trajectories and determinants of breakthrough infection in KTx recipients. Methods: KTx recipients received two doses of the BNT162b2 mRNA vaccine three weeks apart and a booster after six months. Patients were categorized based on pre-vaccination status: previous COVID-19 disease (DIS), asymptomatic SARS-CoV-2 infection (INF), or infection-naïve (NEG). Serum anti-spike antibody titers were assessed at baseline, before the second dose, and at 1, 3, 6, 9, and 12 months. Linear mixed models and survival analyses were performed. Results: Of 326 enrolled patients, 189 with complete time-point data were included in the longitudinal analysis. Antibodies were detectable in 89% of DIS/INF at baseline and 91% before the second dose, but were negligible in NEG. In NEG, the seropositivity increased after vaccination and booster, reaching 78% at 12 months. Age (−5% per year, p < 0.001) and BMI (+10% per unit, p = 0.004) influenced titers; antimetabolites and steroids had strong negative effects (−70%, p = 0.005; −84%, p = 0.001). Breakthrough infections occurred in 104 (31.9%); 40% were asymptomatic, and 2 patients died. An mTOR inhibitor was associated with a reduced infection risk (OR 0.27 [CI: 0.09–0.70], p = 0.009). Higher antibody titers correlated with delayed infection (p = 0.063). Conclusions: In KTx patients, humoral response to SARS-CoV-2 vaccination is limited in infection-naïve patients but improved by booster dosing; the hybrid immunity is more effective. Immunosuppressive regimens influence the immune response, and mTOR inhibitors may protect against breakthrough infection. Full article

Background: The 2019 coronavirus disease (COVID-19) pandemic had a severe impact on frail, end-stage kidney disease (ESKD) patients, either on dialysis or transplanted, with a high mortality rate in the early waves. Vaccination against SARS-CoV-2 with mRNA vaccines has led to reduced hospitalization and mortality rates in the general population and ESKD patients. Neutralizing antibodies (NAbs) are a valuable correlate of protection after vaccination, and IgG anti-spike antibodies are considered a surrogate marker of protection. Methods: This study investigated the correlates of protection brought by NAb and anti-spike IgG antibodies against SARS-CoV-2 wild-type Wuhan strain and variants of concern in a cohort of 128 French patients on dialysis after vaccination with the BNT162b2 mRNA vaccine. The correlate was assessed using Receiver Operating Characteristic curves. Results: The level of protection for IgG anti-spike antibodies was set at 917 BAU/mL for the original Wuhan strain and 980 BAU/mL and 1450 BAU/mL, respectively, for the Delta and Omicron BA.1 variants. Conclusions: The level of protection can be regularly monitored by measuring IgG anti-spike antibody concentrations to allow tailored boosters of SARS-CoV-2 vaccination in this frail and immunocompromised ESKD population. Full article

Understanding the long-term dynamics of SARS-CoV-2 neutralizing antibodies is critical for evaluating vaccine-induced protection and informing booster strategies. In this longitudinal study, we analyzed 114 serum samples from 19 individuals across six time points over a three-year period following mRNA vaccination (Comirnaty) and natural SARS-CoV-2 infection. Using pseudotype-based neutralization assays against nine SARS-CoV-2 variants, including major Omicron subvariants (BA.1–BA.5, BQ.1.1, XBB), and anti-S1 IgG ELISA, we observed that antibody levels peaked after the third vaccine dose and remained relatively stable two years later. Neutralization titers rose markedly after the second and third doses, with the highest neutralization observed at two years post-booster. Strong correlations were found between anti-S1 IgG levels and mean neutralization titers for pre-Omicron variants (r = 0.79–0.93; p < 0.05), but only moderate for Omicron subvariants (r ≈ 0.50–0.64). Notably, hybrid immunity (vaccination plus infection) resulted in higher neutralization titers at the final time point compared to vaccine-only participants. The lowest neutralization was observed against XBB, underscoring the immune evasiveness of emerging variants. These findings support the importance of booster vaccination and highlight the added durability of hybrid immunity in long-term protection. Full article

mRNA vaccines have demonstrated considerable efficacy and safety against SARS-CoV-2, limiting the pandemic burden worldwide. The emergence of new variants of concern and the decline in neutralizing activity observed several weeks post-vaccination reinforced the call for repeated mRNA vaccination. We and others have shown that vaccine efficacy does not exclusively rely on antibody neutralizing activites; Fc-effector functions play an important role as well. However, it is well known that long-term exposure and repeated antigen stimulation elicit the IgG4 subclass of antibodies, which are inefficient at mediating Fc-effector functions. In this regard, recent studies highlighted concerns about IgG4 induction by mRNA vaccines. Here, we explored the impact of repeated mRNA vaccination on IgG4 induction and its impact on Fc-effector functions. We observed anti-Spike IgG4 elicitation after three doses of mRNA vaccine; the antibody levels further increased with additional doses. Vaccine-elicited IgG4 preferentially bound the ancestral D614G Spike. We also observed that Breakthrough Infection (BTI) after several doses of vaccine strongly increased IgG1 levels but had no impact on IgG4 levels, thereby improving Fc-effector functions. Finally, we observed that elderly donors vaccinated with Moderna mRNA vaccines elicited higher IgG4 levels and presented lower Fc-effector functions than donors vaccinated with the Pfizer mRNA vaccine. Altogether, our results highlight the importance of monitoring the IgG subclasses elicited by vaccination. Full article

Background/Objectives: People with HIV (PWH) often have a suboptimal response to vaccines, raising concerns regarding the efficacy of coronavirus disease 2019 (COVID-19) vaccines in this population. We aimed to evaluate the humoral immune response to the B.1 lineage and Omicron variant in PWH on antiretroviral therapy (ART) following COVID-19 vaccination. Methods: We conducted a prospective study of 19 PWH on ART who received a two-dose series of the COVID-19 mRNA vaccine and a booster six months later. Participants without HIV infection (n = 25) were included as a healthy control (HC) group. The humoral response to the COVID-19 vaccine (anti-SARS-CoV-2 S IgG levels and ability to block ACE2-S interaction) against both the original B.1 lineage and the Omicron variant was assessed using immunoassays. Results: The humoral response in PWH was very strong (geometric mean fold rise, GMFR > 8) after the second dose and strong (GMFR > 4) after the booster dose for both the B.1 lineage and the Omicron variant. We found comparable humoral responses to the B.1 lineage and Omicron variant between PWH and HC groups after the second and booster doses (q-value > 0.05). The COVID-19 vaccine generated a significantly weaker humoral response against the Omicron variant compared to the B.1 lineage in both groups (q-value < 0.05). However, this response improved after the booster dose, although it remained weaker in PWH. Conclusions: PWH showed a strong humoral response to the COVID-19 vaccine against B.1 and Omicron, though the Omicron response was weaker than B.1. Booster doses in PWH improved the Omicron response, but it stayed lower than B.1. Findings confirm vaccine effectiveness in PWH, stressing the critical role of boosters and potential need for updated vaccines for variants like Omicron. Full article

Background: In response to the SARS-CoV-2 pandemic, a massive vaccination campaign was launched. Nonetheless, concerns arose regarding some peculiar groups of patients, including those affected by Systemic Lupus Erythematosus (SLE), because of the immune-suppressive drugs routinely administered to patients and the risk of possible disease flares. Since the effects of the third booster vaccination in SLE have been poorly assessed, this study aims to evaluate the immunogenicity and safety of the third BNT162b2 vaccine dose, together with the effects of immunosuppressive drugs. Methods: A monocentric SLE cohort and a cohort of age- and sex-matched healthy controls (HCs) (all vaccinated with three homologous doses) were consecutively enrolled 6 months (T1) after their third vaccine shot. Vaccine immunogenicity was evaluated by analyzing humoral and cellular immune responses at T1 and 12 months (T2). Vaccine safety was evaluated by assessing adverse events related to vaccination (T0) and comparing disease activity among T0, T1, and T2. Effects of immunosuppressive drugs were assessed by stratifying patients according to therapy at vaccination: (1) receiving (IS) or (2) not receiving immunosuppressive drugs (Non-IS). Results: At T1, the humoral responses were comparable between SLE and HC subjects, while the cellular response was significantly higher in HC (p = 0.01). No differences were found at T2 between cohorts. Similarly, both at T1 and T2, the immune responses of IS and Non-IS groups were comparable. Moreover, lupus disease flares were limited and mostly mild, and no life-threatening adverse events were reported. Conclusions: The booster BNT162b2 vaccine is safe and induces an immune response, which is persistent and not affected by ongoing immunosuppressive drugs. Full article

Background: Lipid nanoparticles (LNPs) have proven effective in delivering RNA-based modalities. Rapid approval of the COVID-19 vaccines highlights the promise of LNPs as a delivery platform for nucleic acid-based therapies and vaccines. Nevertheless, improved LNP designs are needed to advance next-generation vaccines and other gene therapies toward greater clinical success. Lipid components and LNP formulation excipients play a central role in biodistribution, immunogenicity, and stability. Therefore, it is important to understand, identify, and assess the appropriate lipid components for developing a safe and effective formulation. Herein, this study focused on developing a novel Polysorbate-80 (PS-80)-based LNP. We hypothesized that substituting conventional linear PEG-lipids with PS-80, a widely used, biocompatible injectable surfactant featuring a branched PEG-like structure, may change the LNPs biodistribution pattern and enhance long-term stability. By leveraging PS-80’s unique structural properties, this study aimed to develop an mRNA-LNP platform with improved extrahepatic delivery and robust freeze/thaw tolerance. Methods: We employed a stepwise optimization to establish both the lipid composition and formulation buffer to yield a stable, high-performing PS-80-based SARS-CoV-2 mRNA-LNP (SC2-PS80 LNP). We compared phosphate- versus tris-based buffers for long-term stability, examined multiple lipid ratios, and evaluated the impact of incorporating PS-80 (a branched PEG-lipid) on in vivo biodistribution. Various analytical assays were performed to assess particle size, encapsulation efficiency, mRNA purity, and in vitro potency of the developed formulation and a humanized mouse model was used to measure its immunogenicity over six months of storage at −80 °C. Results: Replacing the standard 1,2-dimyristoyl-rac-glycero-3-methoxy polyethylene glycol-2000 (PEG-DMG) lipid with PS-80 increased spleen-specific expression of the mRNA-LNPs after intramuscular injection. Formulating in a tris-sucrose-salt (TSS) buffer preserved the LNP’s physicochemical properties and in vitro potency over six months at −80 °C, whereas a conventional PBS-sucrose (PSS) buffer was less protective under frozen conditions. Notably, TSS-based SC2-PS80 LNPs elicited potent humoral immunity in mice, including high anti-spike IgG titers and robust pseudovirus neutralization, comparable to freshly prepared formulations. Conclusions: A PS-80-based mRNA-LNP platform formulated in TSS buffer confers improved extrahepatic delivery, long-term frozen stability, and strong immunogenicity against SARS-CoV-2 following six months. These findings offer a promising pathway for the design of next-generation mRNA vaccines and therapeutics with enhanced stability and clinical potential. Full article