Search Results (1,343)

Background: Individuals with autoimmune disease, inflammatory bowel disease (IBD), and transplants face a higher risk of severe COVID-19 and breakthrough hospitalizations. It is essential to understand the magnitude and durability of vaccine-induced humoral immune response in these populations. Methods: We evaluated SARS-CoV-2 spike IgG antibody levels and avidity in autoimmune, IBD, transplant, and healthy cohorts following multiple COVID-19 mRNA vaccine doses. Serum samples were collected approximately 1 month (8–52 days) and 6 months (158–202 days) post-vaccination. Antibody levels and avidity were measured using validated ELISA and chaotropic-based avidity assays. Results: Individuals with IBD and individuals with autoimmune disease, especially systemic autoimmune disease, exhibited lower antibody levels and avidity compared with healthy individuals at certain doses and time points. Transplant recipients demonstrated substantial impairments in both antibody levels and avidity, with avidity reduced across all doses and time points. Significantly lower avidity levels were observed in transplant recipients, suggesting challenges in developing or maintaining antibody quality. For example, geometric mean anti-spike IgG levels were substantially lower in transplant recipients than in healthy individuals at both 1 month (635 vs. 7685 BAU/mL; p < 0.0001) and 6 months (1146 vs. 3277 BAU/mL; p = 0.0057) post third dose. Similarly, transplant recipients had lower antibody avidity than healthy individuals after the third dose, with geometric mean AI80 values of 4.5 M vs. 5.5 M at 1 month (p < 0.0001) and 4.6 M vs. 5.4 M at 6 months (p < 0.0001). Age, sex, and vaccine manufacturer may further influence humoral immune responses in the transplant cohort. Conclusions: Vaccine-induced humoral immunity varies across autoimmune, IBD, and transplant cohorts, with the most persistent impairment observed in transplant recipients across vaccine dose groups and at both post-vaccination time points. These findings reveal immune response patterns that may guide future studies evaluating vaccination schedules, immune monitoring, and clinical outcomes in these populations. Full article

Messenger RNA (mRNA) entered clinical medicine through vaccines, where the innate immune reactivity that complicates protein therapeutics acts as a built-in adjuvant. The success of the coronavirus disease 2019 (COVID-19) mRNA vaccines inspired an expansive vision of an mRNA 2.0 era extending the modality to rare and common diseases, with delivery framed as the principal challenge. This review accepts much of that vision but argues it rests on an unstated assumption: that all protein therapeutics form a single pharmacological class. They do not. We propose a taxonomy, the Dose–Response Architecture Classification, separating two classes. Exposure-controlled therapeutics require a specific quantity of active protein on a defined regimen, as outcomes depend on reproducible exposure; examples include insulin, erythropoietin, growth hormone, coagulation factors, and narrow-therapeutic-index biologics. Threshold-response therapeutics depend on surpassing a functional threshold rather than maintaining a precise concentration; these include vaccines, many enzyme-replacement therapies, genome editing, receptor-saturating antibodies, and immune-cell reprogramming. Because an mRNA drug is dosed as an instruction, and a single message is translated into a variable number of proteins through a multiplicative, stochastic intracellular chain, the dose-to-effect relationship is inherently variable. Our central, deliberately falsifiable proposition is that mRNA is suitable for threshold-response therapeutics but unsuitable for exposure-controlled therapeutics unless a construct or delivery system demonstrates validated post-delivery output control within predefined pharmacokinetic and pharmacodynamic limits. This is a pharmacological boundary, not a delivery obstacle. We conclude that the greatest advances in mRNA 2.0 will come not from delivery alone but from disciplined indication triage by class. Full article

We report the first documented case of extreme, intact parathyroid hormone (PTH)-independent hypercalcemia mediated by a rare non-osteoclastic bone remodeling mechanism in a 65-year-old Puerto Rican woman, detected within 24 h of the second dose of the Moderna mRNA-1273 COVID-19 vaccine and leading to the diagnosis of high-risk biclonal IgA plasma cell myeloma (R-ISS Stage III). Peak serum calcium reached 17.4 mg/dL with concurrent hyperphosphatemia, normal lactate dehydrogenase (LDH), and without marrow osteoclasts or osteolytic lesions, findings inconsistent with classical cancer-associated hypercalcemia. Hypercalcemia resolved within eight days with supportive treatment alone, remaining durably normal nine months later. The temporal proximity to vaccination, together with the biochemical–histopathological profile, generates the hypothesis, without implying causation, that a vaccine-induced innate immune response triggered a rare inflammatory osteocytic perilacunar/canalicular remodeling. The biclonal gammopathy, Clone-1 (normal karyotype, CD33⁺, OCT-2⁺, MYC⁻, CD19⁺, PAX5⁻) and Clone-2 (complex high-risk karyotype, OCT-2⁻, MYC⁺low, CD19⁻), suggests epigenetic rather than genomic drivers in the predominant clone. This case proposes a novel mechanistic hypothesis for vaccine-associated hypercalcemia and generates testable questions that warrant prospective investigation. Full article

Background: People living with human immunodeficiency virus (HIV) (PLWH) remain at increased risk of severe COVID-19 outcomes; however, conflicting evidence exists regarding the seroconversion rates of COVID-19 vaccines in this population. Methods: A systematic review and meta-analysis were conducted on studies reporting seroconversion outcomes following COVID-19 vaccination in PLWH. Results: Forty-four studies (5391 PLWH) were included in the meta-analysis. The overall pooled seroconversion proportion was 93.5%. Bootstrap analysis confirmed robustness (92.8%). Subgroup analyses revealed significantly higher seroconversion rates for mRNA vaccines (98.2%) compared to non-mRNA vaccines (80.5%). CD4 count demonstrated a graded association: <200 cells/mm³ (53.8%), 200–500 cells/mm³ (86.2%), and >500 cells/mm³ (93.5%). Prior COVID-19 infection (99.1% vs. 89.5%) and antiretroviral therapy (ART) status (93.5% vs. 49.6%) were significant determinants. Safety data demonstrated a favorable profile, with predominantly mild-to-moderate local (injection-site pain: 23.8%) and systemic (headache: 12.95%, fatigue: 6.4%) adverse events; serious adverse events were rare and no consistent association with HIV disease progression was observed. Conclusions: COVID-19 vaccination induces high seroconversion rates in PLWH, particularly among those receiving mRNA vaccines, with preserved CD4 counts, on ART, or with prior infection. Full article

Background: Despite the circulation of evolutionarily related cold-causing coronaviruses (CCCs) in the pre-COVID era, most individuals lacked pre-existing serum IgG and/or class-switched memory B cell (B_mem) reactivity for the SARS-CoV-2 Spike (S) glycoprotein expressed by the ancestral Wuhan-Hu-1 (WH1) strain. Subsequent priming of the immune system through natural infection or prophylactic COVID-19 mRNA vaccination successfully generated robust B_mem responses against the WH1-S antigen, along with eliciting cross-reactivity for the future Omicron (BA.1) variant responsible for breakthrough infections (BTIs). However, to what extent immunological imprinting of B_mem towards the WH1-S antigen detrimentally constrains the elicitation of variant-specific antibody responses following subsequent booster vaccinations or BTIs—a phenomena referred to as “original antigenic sin”—remains an unresolved and open question. Methods: Using ImmunoSpot^®, we evaluated peripheral blood mononuclear cells (PBMCs) from defined human cohorts for IgG⁺ ASC reactivity against Spike proteins representing CCCs and SARS-CoV-2. Additionally, we developed a novel dual-label inverted FluoroSpot assay to distinguish between strain-specific and cross-reactive IgG⁺ ASCs recognizing epitopes in the receptor binding domain (RBD) of SARS-CoV-2 Omicron variants. Results: Our data demonstrate a lack of appreciable back-boosting of IgG⁺ B_mem recognizing structurally conserved epitopes shared between CCCs and SARS-CoV-2. Moreover, we found evidence for immunological imprinting and the preferential expansion of B_mem recognizing cross-reactive epitopes in the RBD following BTI. Nevertheless, Omicron strain-specific B_mem were detected in PBMC donors collected in 2025. Conclusions: Our novel inverted dual-label FluoroSpot methodology evidenced preferential expansion of cross-reactive B_mem following breakthrough SARS-CoV-2 infection and supports the influence of original antigenic sin shaping the recall response. Moreover, the inverted dual-label assay provides a highly flexible and easily implementable technique for distinguishing between strain-specific and cross-reactive B cell responses and has broad applications in translational vaccine research against pathogens that undergo antigenic drift. Full article

Background: The BNT162b2 vaccine is safe and effective for COVID-19 prevention. BNT162b2 safety and immunogenicity have been evaluated in immunocompromised individuals in real-world observational studies, particularly in pediatric populations, but not in clinical trials. Methods: This phase 2b single-arm trial descriptively evaluated a Dose 3 (age-appropriate) BNT162b2 primary series with a Dose 4 in immunocompromised individuals 2–<5, 5−<12, 12–<18, and ≥18 years of age without a previous clinical or microbiological COVID-19 diagnosis. Primary objectives were to describe immune responses, reactogenicity, and adverse events following vaccination. Results: Out of 124 participants enrolled, 119 received Dose 3 and 90 received Dose 4. Among participants without evidence of past SARS-CoV-2 infection, neutralizing geometric mean titers (GMTs) and geometric mean fold rises (GMFRs) against the SARS-CoV-2 ancestral strain ranged from 344.6 to 1584.4 and 7.9 to 36.4 at 1 month after Dose 3 and from 1474.0 to 4157.9 and 31.0 to 95.6 at 1 month after Dose 4, respectively, across age groups. Among participants with or without evidence of past infection, GMTs and GMFRs ranged from 787.1 to 2940.6 and 9.6 to 54.3 at 1 month after Dose 3 and from 1031.3 to 13,457.1 and 9.1 to 220.0 at 1 month after Dose 4. Percentages of participants with or without evidence of past SARS-CoV-2 infection achieving seroresponse ranged from 50.0 to 92.9% at 1 month after Dose 3, and from 75.0 to 100% and 33.3 to 100.0% at 1 and 6 months after Dose 4 across age groups, respectively. No new safety signals were identified. Conclusions: BNT162b2 was immunogenic, increasing GMTs in immunocompromised individuals ≥2 years old, particularly after Doses 3 and 4. GMT increases were generally similar across age groups and disease subsets. Three or four BNT162b2 doses had a favorable risk-benefit profile in this population. Full article

Background: This study evaluated the potential effects of different COVID-19 vaccine platforms (mRNA and inactivated) on acute coronary syndrome (ACS) through Galectin-3, a biomarker of chronic inflammation and fibrosis. It aimed to compare serum Galectin-3 levels among NSTEMI patients according to COVID-19 vaccination status and vaccine type. Methods: A total of 75 patients with NSTEMI were prospectively enrolled and categorized into three groups: inactivated vaccine recipients (n = 25), mRNA vaccine recipients (n = 25), and unvaccinated controls (n = 25). Serum Galectin-3 levels were measured to assess chronic inflammatory status. Additionally, markers of acute myocardial injury and inflammatory response were analyzed. Results: Galectin-3 levels were similar across the inactivated vaccine, mRNA vaccine, and unvaccinated NSTEMI group, with no statistically significant difference observed (p = 0.481). Although troponin I levels and acute inflammatory cell burden were higher in vaccinated patients compared with the unvaccinated NSTEMI group, Galectin-3 levels remained comparable among all groups. No significant differences in Galectin-3 levels were observed according to vaccination status or vaccine type. Conclusions: In this exploratory cohort of NSTEMI patients, serum Galectin-3 levels did not differ significantly according to COVID-19 vaccination status or vaccine type. These findings suggest no detectable association between vaccination history and Galectin-3 levels in the study population. Larger prospective studies with longitudinal follow-up are needed to confirm these observations. Full article

Background: While vaccines are designed to elicit targeted immune responses, in some cases, the immunogenic molecules employed can inherently interact with broader host cellular pathways as a secondary consequence. This phenomenon can be exemplified by COVID-19 vaccines. COVID-19 vaccines, including mRNA platforms, use the SARS-CoV-2 spike protein as an immunogen to induce the production of neutralizing antibodies. The spike protein binds the ACE2 (angiotensin-converting enzyme 2) receptor on human cells, mediating viral entry and infection. ACE2 is widely expressed across multiple tissues and is a key component of the renin–angiotensin–aldosterone system (RAAS) that acts as a homeostatic regulator of systemic and local blood flow, blood pressure, cardiac function, fluid balance and immunity. Some studies have proposed the interaction between the spike protein and ACE2 as a possible contributing factor to rare adverse effects observed following COVID-19 vaccination, including myocarditis, pericarditis, thrombosis, and reported alterations in blood pressure, though these mechanisms remain to be fully elucidated. Objectives: As a proof-of-concept approach in vaccine antigen development, we engineered SARS-CoV-2 spike mutants with impaired binding to the host receptor ACE2. Methods: By rational design, we produced and validated in vitro and in vivo spike point mutants that do not effectively bind ACE2. Results: The engineered spike mutants do not effectively bind the human entry receptor ACE2 while retaining the immunogenic properties equal to or better than the wild type spike and thus generate a protective response in animals when used as a vaccination agent. Conclusions: By establishing a straightforward molecular strategy for rational vaccine design, this work demonstrates the feasibility of limiting specific antigen–host receptor interactions while maintaining immunogenicity. This approach may be applicable to future vaccination strategies where antigen interaction with host cells could potentially interfere with physiological pathways. Full article

Background: The dynamics of humoral immune responses following primary and booster COVID-19 vaccinations are crucial to understand in order to optimize vaccination strategies. This study evaluates the magnitude and durability of SARS-CoV-2-specific IgG antibody responses across different vaccines in a large cohort of Bangladeshi adults. Methods: A total of 6300 adults from nine hospitals across eight divisions of Bangladesh were enrolled. Participants received two primary doses of either ChAdOx1 nCoV-19 (Covishield, Serum Institute of India, n = 2855), mRNA-1273 (Moderna, n = 578), BNT162b2 (Pfizer-BioNTech, n = 121), or Vero-cell-inactivated (Sinopharm, n = 2746) vaccines. Booster doses were administered at one-year intervals post-primary vaccination. SARS-CoV-2 spike receptor-binding domain (RBD)-specific IgG antibody responses were measured by ELISA using serum from vaccinees at multiple time points after two primary and two booster doses. Results: A total of 3745 individuals received booster 1 (third dose), with 59% receiving heterologous boosters (a different vaccine regimen than the primary doses). Only 5.5% (n = 347) of participants received a second booster one year after the first booster (among them, 99% received BNT162b2). Our results suggest that heterologous boosters with the mRNA vaccine induced higher IgG levels than homologous boosters for individuals who received primary vaccination with adenovirus vector-based ChAdOx1 nCoV-19 or a Vero-cell-inactivated vaccine. However, in those who initially received the mRNA-based vaccine, both homologous and heterologous boosters produced comparable IgG responses. Among all vaccine types, booster immunization with the Vero-cell-inactivated vaccine induced the lowest antibody responses. Longitudinal analysis demonstrated significantly high IgG levels over the 12 months following the first booster (p < 0.0001); however, IgG levels declined significantly after the second booster dose (fourth dose). Conclusions: Heterologous boosting strategies, particularly those involving mRNA vaccines, elicit stronger and more sustained IgG responses compared to a homologous booster. However, antibody waning after the second booster highlights the need for continued monitoring and potential additional vaccine strategies. Full article

Background/Objectives: In the first months of their life, infants rely on maternal antibodies for immune protection. Breastmilk is a major source of these defenses, supplying secretory IgA, IgG, and IgM that help guard mucosal surfaces against pathogens such as SARS-CoV-2. Most studies on breastmilk immunity in the context of COVID-19 have emphasized circulating monomeric IgA, rather than the multimeric secretory IgA (sIgA) that is active at mucosal barriers. This study assessed in-depth the contribution of breastmilk antibody subtypes to SARS-CoV-2 neutralization capacity and how these profiles differ following maternal COVID-19 infection versus vaccination during pregnancy or postpartum. Methods: In this prospective cohort study, breastmilk samples were collected longitudinally from individuals who had COVID-19 during pregnancy or received COVID-19 mRNA vaccination during pregnancy or postpartum. Serological assays measured IgG, IgM, systemic IgA, and secretory IgA against SARS-CoV-2 spike and nucleocapsid antigens. Results: COVID-19 infection during pregnancy resulted in significantly higher systemic and secretory IgA levels compared to vaccination. Secretory IgA demonstrated a strong correlation with neutralization capacity. Principal component analysis revealed distinct antibody profiles in COVID-19-exposed individuals versus vaccinated cohorts, with significant overlap between pregnancy and postpartum vaccination groups. Conclusions: Although both COVID-19 vaccination and disease elicit sustained COVID-19-related antibodies in breastmilk, COVID-19 infection elicits a broader and more diverse antibody response in breastmilk, specifically with a greater secretory IgA generation. These findings support the value of maternal vaccination to safely confer mucosal immunity to neonates and the need for optimized vaccine formulations for mucosal immunity. Full article

Background: Adenovirus-vectored vaccines played an important role in the global response to SARS-CoV-2. Adenovirus platforms have many advantages including a simple and readily transferred manufacturing process, low cost, and thermostability. Speed of production of an initial Good Manufacturing Practice (GMP)-compliant batch has, however, been viewed as a limitation of adenovirus vectors relative to mRNA platforms. Production of the initial viral starting material and release testing are key rate-limiting steps. Methods: Production of viral starting material from DNA, and release testing in accordance with regulatory expectations, for first-in-human trials of adenovirus-vectored vaccines. Results: We describe experience of these stages in the production of the first GMP batches for multiple adenovirus-vectored candidates and the adaptations made for ChAdOx1 nCoV-19 (the Oxford COVID-19 vaccine) in early 2020. We also report development of a streamlined approach to starting material generation, enabling initial GMP batch availability within c. 60 days of publication of a new pathogen sequence. Using a New World arenavirus vaccine construct as a proof of concept, we demonstrate reproducible execution of this pipeline, maintaining acceptable infectivity and other quality attributes. Conclusions: We discuss opportunities for additional time savings in the future. This work demonstrates suitability of an adenovirus platform to contribute to the “100 Days Mission” for vaccines against “Disease X”. Full article

Background/Objectives: HXP-GPOVac is a locally produced, inactivated Newcastle disease virus-based (NDV-HXP-S) COVID-19 vaccine manufactured in Thailand. This phase II trial compared its safety and immunogenicity with the mRNA vaccine BNT162b2 in adults aged 18–75 years. Methods: In this randomized, double-blind, active-controlled trial registered with the Thai Clinical Trials Registry (TCTR20220819003), 300 participants were assigned 3:1 to receive HXP-GPOVac or BNT162b2 on Days 1 and 29. Solicited adverse events (AEs) were recorded for 7 days after each dose, AEs were summarized through 28 days after each dose, and serious adverse events (SAEs), medically attended AEs (MAAEs), and adverse events of special interest (AESIs) were collected through Day 197. Humoral immunogenicity was assessed by pseudovirus 50% neutralization titers (NT₅₀) and anti-spike IgG concentrations at baseline, Day 29, Day 43, and Day 197. Seroconversion was defined as a ≥4-fold increase from baseline. A predefined subset underwent interferon-γ (IFN-γ) and interleukin-5 (IL-5) ELISpot assays to assess cell-mediated immune responses. The primary immunogenicity analysis assessed non-inferiority of HXP-GPOVac compared with BNT162b2 based on the NT₅₀ geometric mean titer ratio, with a prespecified non-inferiority margin of 0.5. Results: Solicited AEs were predominantly mild and occurred more frequently after the first dose in both groups; one or more solicited local or systemic AEs were reported by 23.7% (95% CI: 18.3–29.8) of HXP-GPOVac recipients and 44.7% (95% CI: 33.3–56.6) of BNT162b2 recipients after the first dose. AEs through 28 days after vaccination and SAEs were uncommon; MAAEs occurred in 17.0% of HXP-GPOVac recipients and 22.4% of BNT162b2 recipients, and none were considered related to vaccination. In the HXP-GPOVac group, NT₅₀ geometric mean titers increased from 5.6 at baseline to 65.5 at Day 29 and 505 at Day 43, declining to 63.6 at Day 197. Anti-spike IgG geometric mean concentrations rose from 7.5 BAU/mL at baseline to 102.7 BAU/mL at Day 29 and 514.6 BAU/mL at Day 43, decreasing to 61.0 BAU/mL at Day 197. BNT162b2 induced higher antibody levels at all time points. The NT₅₀ GMT ratio (HXP-GPOVac/BNT162b2) at Day 43 was 0.51 (95% CI: 0.39–0.67); the lower bound did not exceed the prespecified non-inferiority margin of 0.5, and non-inferiority was not established. Seroconversion rates at Day 43 were 97.6% for HXP-GPOVac and 97.1% for BNT162b2 (neutralizing antibody) and 98.6% and 97.1%, respectively (anti-spike IgG). ELISpot analyses demonstrated increased IFN-γ responses after the second dose without evidence of Th2-dominant skewing. Conclusions: HXP-GPOVac was well tolerated and induced substantial humoral and cellular immune responses, with high seroconversion rates and balanced T-cell polarization. Although absolute antibody levels were lower than those induced by BNT162b2 and the prespecified non-inferiority criterion was not met, these findings support continued evaluation of the inactivated NDV-HXP-S vaccine platform. Full article

Bringing a new drug to market is a complex, costly, and lengthy process, averaging $2.6 billion and about ten years of research and development. It involves multiple stages, from target discovery to post-approval monitoring, and relies heavily on innovation driven by collaboration among pharmaceutical sciences, biology, biochemistry, engineering, and artificial intelligence. Drug discovery can be divided into four main stages: target selection and validation; compound screening and optimization; preclinical studies; and clinical trials. First, researchers identify and validate a biological target associated with a disease using genomic, proteomic, and bioinformatic approaches. Next, potential compounds (“hits”) are identified through methods such as high-throughput and virtual screening, followed by iterative chemical optimization and functional testing. Promising candidates undergo preclinical in vivo studies to assess pharmacokinetics, pharmacodynamics, and toxicity. Clinical development proceeds in three phases: Phase I evaluates safety in healthy volunteers; Phase II assesses efficacy in patients; and Phase III confirms efficacy and safety in larger populations. After successful trials, regulatory agencies review the data for approval. While small molecules have long dominated due to their stability and oral bioavailability, biologics—such as monoclonal antibodies and mRNA-based therapies—have grown rapidly, highlighted by COVID-19 vaccine development and increasing FDA approvals. Full article

The surface spike (S) protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a key target for the development of Coronavirus Disease 2019 (COVID-19) vaccines. Nevertheless, the mutations in the S protein, particularly in its receptor-binding domain region, have resulted in a reduced or complete loss of immunogenicity and/or protective efficacy in early vaccines against the Omicron variant and subvariants. Accordingly, continuous efforts are required to develop effective vaccines against multiple Omicron subvariants to reduce current and future threats. In this study, we designed an mRNA vaccine targeting the S protein of a recent Omicron-XEC subvariant (XEC-S-mRNA) and assessed its immunogenicity, including its broad neutralizing activity, and its protective efficacy against multiple Omicron subvariants. Our results demonstrated that the lipid nanoparticle-formulated mRNA vaccine formed an appropriate particle size with strong stability and successful antigen expression. It elicited durable cellular immune responses and broad neutralizing antibodies against multiple early and recent Omicron subvariants, thereby cross-protecting transgenic mice from challenge with a heterologous Omicron strain (KP.3). Moreover, the vaccine-induced neutralizing antibodies alone were sufficient to prevent Omicron-KP.3 infection. Overall, this study shows promise for further development of the candidate vaccine against current and future Omicron infections. Full article

Background/Objectives: We still do not clearly know whether COVID-19 continues to impose a greater clinical burden than influenza in the “post-pandemic” era. Our study quantified and compared monthly COVID-19 and influenza hospitalization incidence among adult subgroups from October 2022 through December 2024. We assessed vaccine coverage trends and examined vaccination status among those hospitalized. Methods: Using the Veradigm linked claims and electronic health record dataset, we conducted a non-interventional, retrospective cohort study; three monthly cohorts included individuals aged 65+, high-risk (HR) adults (defined as adults 18+ with HR conditions and/or aged 65+), and adults aged 50–64 years who were enrolled with both medical and pharmacy coverage. We estimated monthly cumulative incidence of COVID-19 and influenza-related hospitalizations, vaccination coverage rates, and the proportion of hospitalized individuals who had received yearly updated vaccines. Results: COVID-19 hospitalizations consistently exceeded those of influenza across months and populations. Among adults aged 65+, COVID-19 hospitalization rates were 2–3 times higher than influenza in winter and 20–30 times higher during off-season months, with similar trends observed in high risk adults. COVID-19 incidence surged in summer, while influenza remained seasonally confined. Vaccination coverage for influenza peaked near 50% annually; COVID-19 coverage was lower, peaking at ~26% by December each year. Most hospitalizations occurred among unvaccinated individuals, particularly for COVID-19. Conclusions: COVID-19 continues to impose a substantial, year-round burden, particularly in older and high-risk adults, exceeding that of influenza. The high proportion of unvaccinated hospitalizations highlight a critical gap in prevention efforts and underscore the need for improved public health messaging and vaccine adoption. Full article