Search Results (1,106)

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/Objectives: mRNA vaccines introduced during the COVID-19 pandemic were a significant step forward in the rapid development and deployment of vaccines in a global pandemic context. These vaccines showed good protective efficacy, but—due to limited breadth of the immune response—they required frequent boosters with manufactured spike sequences that often lagged behind the circulating strains. In order to enhance the breadth, durability, and magnitude of immune responses, we studied the effect of combining priming with an RNA vaccine technology with boosting with protein/adjuvant using a TLR4-agonist based adjuvant. Methods: Specifically, four proprietary adjuvants (EmT4^TM, LiT4Q^TM, MiT4^TM, and AlT4^TM) were investigated in combination with multiple modes of SARS-CoV-2 vaccination (protein, peptide, RNA) for their effectiveness in boosting antibody responses to SARS-CoV-2 spike protein in murine models. Results: Results showed significant improvement in immune response strength and breadth—especially against more distant SARS-CoV-2 variants such as Omicron—when adjuvants were used in combination with boosters following an RNA vaccine prime. Conclusions: The use of novel TLR4 adjuvants in combination with protein or RNA vaccinations presents a promising strategy for improving the efficacy of vaccines in the event of future pandemics, by leveraging rapid response using an RNA vaccine prime and following up with protein/adjuvant-based vaccines to enhance the breadth of immunity. 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

The COVID-19 pandemic accelerated the rapid development and distribution of various vaccine platforms, resulting in a significant reduction in disease severity, hospitalizations, and mortality. However, persistent challenges remain concerning the durability and breadth of vaccine-induced protection, especially in the face of emerging SARS-CoV-2 variants. This review aimed to evaluate the factors influencing the immunogenicity and effectiveness of COVID-19 vaccines to inform future vaccine advancement strategies. A narrative review with systematic approach was conducted following PRISMA guidelines for narrative review. Literature was sourced from databases including PubMed, Embase, and Web of Science for studies published between December 2019 and May 2025. Encompassed studies assessed vaccine efficacy, immunogenicity, and safety across various populations and vaccine platforms. Data were collected qualitatively, with quantitative data from reviews highlighted where available. We have uncovered a decline in vaccine efficacy over time and weakened protection against novel variants such as Delta and Omicron. Booster doses, specifically heterologous regimens, improved immunogenicity and increased protection. Vaccine-induced neutralizing antibody titers have been found to correlate with clinical protection, although the long-term correlates of immunity remain poorly defined. The induction of IgG4 antibodies after repeated mRNA vaccinations raised concerns about potential modulation of the immune response. COVID-19 vaccines have contributed significantly to pandemic control; however, their efficacy is limited by the evolution of the virus and declining immunity. Forthcoming vaccine strategies should focus on broad-spectrum, variant-adapted formulations and defining robust comparisons of protection. Recognizing the immunological basis of vaccine response, including the role of specific antibody subclasses, is fundamental for optimizing long-term protection. Full article

Background. The STING protein is activated by the second messenger cGAMP to promote the innate immune response against infections. Beyond this role, a chronically overactive STING signaling has been described in several disorders. Patients with severe COVID-19 exhibit a hyper-inflammatory response (the cytokine storm) that is in part mediated by the cGAS-STING pathway. Several STING inhibitors may protect from severe COVID-19 by down-regulating several inflammatory cytokines. This pathway has been implicated in the establishment of an optimal antiviral vaccine response. STING agonists as adjuvants improved the IgG titers against the SARS-CoV-2 Spike protein vaccines. Methods. We investigated the association between two common functional STING1/TMEM173 polymorphisms (rs78233829 C>G/p.Gly230Ala and rs1131769C>T/p.His232Arg) and severe COVID-19 requiring hospitalization. A total of 801 non-vaccinated and 105 fully vaccinated (mRNA vaccine) patients, as well as 300 population controls, were genotyped. Frequencies between the groups were statistically compared. Results. There were no differences for the STING1 variant frequencies between non-vaccinated patients and controls. Vaccinated patients showed a significantly higher frequency of rs78233829 C (230Gly) compared to non-vaccinated patients (CC vs. CG + GG; p = 0.003; OR = 2.13; 1.29–3.50). The two STING1 variants were in strong linkage disequilibrium, with the rs78233829 C haplotypes being significantly more common in the vaccinated (p = 0.02; OR = 1.66; 95%CI = 1.01–2.55). We also studied the LTZFL1 rs67959919 G/A polymorphism that was significantly associated with severe COVID-19 (p < 0.001; OR = 1.83; 95%CI = 1.28–2.63). However, there were no differences between the non-vaccinated and vaccinated patients for this polymorphism. Conclusions. We report a significant association between common functional STING1 polymorphisms and the risk of developing severe COVID-19 among fully vaccinated patients. Full article

Background/Objectives: SARS-CoV-2 vaccine candidates comprising the receptor binding domain (RBD) of the spike protein have been shown to confer protection against infection. Previous research evaluating vaccine candidates with SARS-CoV-2 RBD fused to ferritin (RBD-ferritin) and other scaffolds suggested that multimeric assemblies of RBD can enhance antigen presentation to improve the potency and breadth of immune responses. Though RBDs directly fused to a self-assembling scaffold can be delivered as messenger RNA (mRNA) formulated with lipid nanoparticles (LNPs), reports of SARS-CoV-2 vaccine candidates that combine these approaches remain scarce. Methods: Here, we designed RBD fused to AP205 or TIP60 self-assembling nanoparticles following a search of available structures focused on several scaffold properties. RBD-AP205 and RBD-TIP60 were tested for antigenicity following transfection and for immunogenicity and neutralization potency when delivered as mRNA in mice, with RBD-ferritin as a direct comparator. Results: All scaffolded RBD constructs were readily secreted to transfection supernatant and showed antigenicity in ELISA, though clear heterogeneity in assembly was observed. RBD-AP205 and RBD-TIP60 also exhibited robust antibody binding and neutralization titers in mice that were comparable to those elicited by RBD-ferritin or a full-length membrane-bound spike. Conclusions: These data suggest that AP205 and TIP60 can present RBD as effectively as ferritin and induce similar immune responses. By describing additional scaffolds for multimeric display that accommodate mRNA delivery platforms, this work can provide new tools for future vaccine design efforts. Full article

Background: Kidney transplant recipients (KTRs) exhibit a significantly diminished immune response to Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) vaccines compared with the general population, primarily due to ongoing immunosuppressive therapy. This study evaluated the immunogenicity of a third SARS-CoV-2 mRNA vaccine dose in KTRs and assessed the association between antibody response and protection against SARS-CoV-2 breakthrough infection. Additionally, the clinical and immunological correlates of post-vaccination SARS-CoV-2 infection were examined. Methods: A prospective cohort of 135 KTRs received a third vaccine dose approximately six months following the second dose. Plasma samples were collected at baseline (pre-vaccination), six months after the second dose, and six weeks following the third dose. Humoral responses were assessed using SARS-CoV-2-specific Immunoglobulin G (IgG) titers and virus neutralization assays against wild-type (WT) and viral strains, including multiple Omicron sub-lineages. Results: After the third vaccine dose, 74% of the KTRs had detectable SARS-CoV-2-specific IgG antibodies, compared with 48% following the second dose. The mean IgG titers increased approximately ten-fold post-booster. Despite this increase, neutralizing activity against the Omicron variants remained significantly lower than that against the WT strain. KTRs who subsequently experienced a SARS-CoV-2 breakthrough infection demonstrated reduced neutralizing antibody activity across all variants tested. Additionally, individuals receiving triple immunosuppressive therapy had a significantly higher risk of SARS-CoV-2 breakthrough infection compared with those on dual or monotherapy. A multivariate machine learning analysis identified age and neutralizing activity against WT, Delta, and Omicron BA.2 as the most robust correlates of SARS-CoV-2 breakthrough infection. Conclusions: A third SARS-CoV-2 mRNA vaccine dose significantly improves SARS-CoV-2-specific IgG levels in KTRs; however, the neutralizing response against Omicron variants remains suboptimal. Diminished neutralizing capacity and intensified immunosuppression are key determinants of SARS-CoV-2 breakthrough infection in this immunocompromised population. Full article

The emergence of a novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) virus closely related to SARS-CoV and officially known as Betacoronavirus pandemicum precipitated a substantial surge in vaccine development that culminated during the global COVID-19 pandemic. At present, there are dozens of vaccines for the prevention of SARS-CoV-2 being utilized across the globe. However, only 10 of these vaccines have been authorized by the World Health Organization (WHO). These include mRNA-based, viral vector, subunit and whole-virion inactivated vaccines. At the current end of the pandemic, there has been a decline in the global vaccination rate, both for the general population and for those most at risk of severe illness from the virus. This suggests that the effectiveness of the vaccines may be waning. The decline occurs alongside a decrease in testing and sequencing for SARS-CoV-2. Furthermore, the process of tracking viruses becomes increasingly complex, thereby providing a selective advantage for SARS-CoV-2 and allowing it to evolve stealthily. In this review, we provide a comprehensive overview of viral evolution and vaccine development. We also discuss ways to overcome viral variability and test universal vaccines for all SARS-CoV-2 variants. 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

Narrative review synthesizes the most current literature on the SARS-CoV-2 XEC variant, focusing on its genomic evolution, immune evasion characteristics, epidemiological dynamics, and public health implications. To achieve this, we conducted a structured search of the literature of peer-reviewed articles, preprints, and official surveillance data from 2023 to early 2025, prioritizing virological, clinical, and immunological reports related to XEC and its parent lineages. Defined by the distinctive spike protein mutations, T22N and Q493E, XEC exhibits modest reductions in neutralization in vitro, although current evidence suggests that mRNA booster vaccines, including those targeting JN.1 and KP.2, retain cross-protective efficacy against symptomatic and severe disease. The XEC strain of SARS-CoV-2 has drawn particular attention due to its increasing prevalence in multiple regions and its potential to displace other Omicron subvariants, although direct evidence of enhanced replicative fitness is currently lacking. Preliminary analyses also indicated that glycosylation changes at the N-terminal domain enhance infectivity and immunological evasion, which is expected to underpin the increasing prevalence of XEC. The XEC variant, while still emerging, is marked by a unique recombination pattern and a set of spike protein mutations (T22N and Q493E) that collectively demonstrate increased immune evasion potential and epidemiological expansion across Europe and North America. Current evidence does not conclusively associate XEC with greater disease severity, although additional research is required to determine its clinical relevance. Key knowledge gaps include the precise role of recombination events in XEC evolution and the duration of cross-protective T-cell responses. New research priorities include genomic surveillance in undersampled regions, updated vaccine formulations against novel spike epitopes, and long-term longitudinal studies to monitor post-acute sequelae. These efforts can be augmented by computational modeling and the One Health approach, which combines human and veterinary sciences. Recent computational findings (GISAID, 2024) point to the potential of XEC for further mutations in under-surveilled reservoirs, enhancing containment challenges and risks. Addressing the potential risks associated with the XEC variant is expected to benefit from interdisciplinary coordination, particularly in regions where genomic surveillance indicates a measurable increase in prevalence. Full article

Objectives: The durability and breadth of neutralizing antibodies following SARS-CoV-2 mRNA vaccination remain incompletely understood. This study aimed to investigate how longitudinal changes in antibody isotype composition impact neutralization against structurally diverse SARS-CoV-2 variants. Methods: After screening a broader cohort of mRNA-vaccinated sera, time-matched samples collected one month (1 mpv) and three months post-vaccination (3 mpv) were selected for detailed analysis. Neutralization assays against live virus variants, enzyme-linked immunosorbent assays (ELISA), and immunogold electron microscopy were performed to assess antibody titers, isotype levels, and virion morphology. Results: Neutralization titers declined markedly at 3 mpv, particularly against immune-evasive variants. Notably, the Lambda variant showed disproportionately high sensitivity to early-phase sera despite its divergence from the vaccine strain. Antibody isotyping showed that IgA and IgM decreased over time, while IgG levels were relatively more sustained. Electron microscopy revealed broader virion size heterogeneity in Lambda (50–200 nm) compared to Wuhan (80–120 nm), potentially enhancing multivalent antibody engagement. Consistently, ELISA under reduced spike density conditions showed that IgA and IgM retained stronger binding than IgG. Conclusions: These findings indicate that the decline of IgA and IgM compromises neutralization breadth, especially against structurally divergent variants such as Lambda. Sustaining dynamic multivalent isotype responses that adapt to diverse spike morphologies may be critical for broad cross-variant immunity. Full article

The Bacillus Calmette-Guérin (BCG) vaccine confers broad, non-specific immunity that may bolster defenses against respiratory viruses. While NOD2 (nucleotide-binding oligomerization domain-containing protein 2)-driven pathways are central to innate immune responses, the contribution of surface receptor modulation on monocytes to shaping these responses remains underexplored. We analyzed whole-blood cultures from BCG-vaccinated Polish children, stratified by serostatus to SARS-CoV-2 and RSV, and stimulated for 48 h with live BCG, purified viral antigens, or both. RT-qPCR quantified mRNA levels of NOD2 and key cytokines (IL-1β, IL-2, IL-4, IL-6, IL-8, IL-10, TNF), while flow cytometry assessed CD14, HLA-DR, CD11b, and CD206 expression. Co-stimulation with BCG + RSV elicited the strongest transcriptional response, notably a 2–4-fold upregulation of NOD2, IL-1β, and IL-6 versus RSV alone. In SARS-CoV-2(+) donors, RSV alone induced higher NOD2 expression than BCG or BCG + RSV, while IL-2 peaked following BCG + SARS-CoV-2. Across conditions, NOD2 positively correlated with IL-4 and IL-6 but negatively correlated with IL-1β in SARS-CoV-2 cultures. Viral antigens increased CD14 and HLA-DR on monocytes, suggesting activation; CD206 rose only in dual-seropositive children. Our findings indicate that BCG stimulation affects pediatric antiviral immunity through NOD2-related cytokine production and induction of a CD14⁺HLA-DR⁺ phenotype, supporting its potential role in boosting innate defenses against respiratory pathogens. 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

Patients undergoing peritoneal dialysis (PD) represent a uniquely vulnerable population due to intrinsic immunological dysfunction and a high prevalence of comorbid conditions. This review examines the complex interplay between natural and vaccine-induced immune responses to SARS-CoV-2 in this group, focusing on viral entry, immune activation, and immune evasion mechanisms. Particular attention is given to the impaired cellular and humoral responses seen in PD patients, including reduced T-cell function, diminished antibody production, and abnormal cytokine signaling, all of which contribute to an elevated risk of severe COVID-19 outcomes. The immunogenicity and clinical efficacy of various vaccine platforms, including inactivated, vector-based, and mRNA formulations, are critically assessed, with an emphasis on the role of booster doses in enhancing protection amid waning immunity and evolving viral variants. Furthermore, the review highlights the advantages of PD as a home-based modality that is compatible with telemedicine and may reduce the risk of viral exposure. These insights underscore the importance of developing individualized vaccination strategies, maintaining close immunological surveillance, and implementing innovative dialysis care approaches to improve clinical outcomes during the ongoing pandemic and future public health crises. Tailored booster strategies and telemedicine-integrated care models are essential for improving outcomes in this high-risk population. Full article

Background/Objectives: Chronic illness after COVID-19 vaccination (longvax) lacks a therapeutic protocol anchored in pathophysiology. Persistent vaccine derived spike protein appears to trigger microvascular fibrin amyloid microclots, immune dysfunction, pathogen reactivation and multisystem injury. This article proposes an integrative approach, Vaxtherapy, to tackle these mechanisms. Methods: A narrative synthesis of peer reviewed literature from 2021 to 2025 on spike related injury and vaccine adverse events was conducted, supplemented by clinical case series and mechanistic observations from long COVID. The findings were arranged into a four stage therapeutic sequence ordered by pathophysiological precedence. Results: Stage one aims to reopen hypoperfused tissue through oral fibrinolytics that degrade fibrin amyloid resistant microclots; stage two intends to neutralise circulating or tissue bound spike via a receptor binding domain monoclonal antibody cocktail; stage three seeks to eliminate reactivated viral or microbial reservoirs with targeted antivirals or antimicrobials once perfusion is improved; and stage four aspires to support tissue repair with mitochondrial supplements and, when indicated, cell based therapies. Omitting or reordering stages may reduce efficacy or foster resistance. Conclusions: This hypothesis driven framework outlines a biologically plausible roadmap for longvax research. By matching interventions to specific mechanisms (fibrinolysis, spike neutralisation, pathogen clearance and regeneration), it aims to guide controlled trials and compassionate pilot programs directed at durable recovery rather than chronic symptom management. Full article