OBJECTIVE:To comprehensively evaluate the real-world effectiveness of the influenza vaccine among school-aged children across a dual-peak season, specifically examining subtype-specific protection, age variations, durability of protection over time, and the impact of repeated prior-season vaccination. METHODS:A test-negative design was used to assess vaccine effectiveness (VE) among school-aged children in Shenzhen. Based on questionnaire data and laboratory testing, patients with laboratory-confirmed influenza were classified as cases, while test-negative patients served as controls. Multivariable logistic regression was applied to compare the odds of vaccination between cases and controls. RESULTS:Among 1669 eligible participants (463 cases and 1206 test-negative controls), the overall adjusted VE against medically attended influenza was 46.36% (95% CI: 29.23-59.34%). VE differed across age groups and was mainly observed in younger children. Significant protection was observed within 14-119 days post-vaccination, became non-significant during 120-239 days, and re-emerged during the summer peak at 240-299 days. Prior-season vaccination alone provided no significant residual protection, while repeated vaccination across two consecutive seasons was associated with reduced effectiveness in the current season. Subtype-specific VE was 43.48% (95% CI: 18.00-61.04%) against influenza A(H1N1), 34.42% (95% CI: 0.55-56.76%) against influenza A(H3N2), and 56.95% (95% CI: 7.68-79.93%) against the B/Victoria lineage. During the winter-spring peak, VE was 49.84% (95% CI: 26.90-65.59%). CONCLUSIONS:Influenza vaccine provided moderate effectiveness against influenza-associated outpatient visits among school-aged children in Shenzhen during the 2024-2025 season.
Neuraminidase (NA), a key surface glycoprotein of influenza viruses, represents a more conserved antigenic target than hemagglutinin (HA) and has attracted interest as a potential target for vaccines with broader protective capacity. Nevertheless, the inefficient secretory production of tetrameric NA that maintain tetramer-like structural features remains challenging.Here, we developed an optimized signal peptide, opt-sp, by introducing valine and asparagine residues at the N-terminus of the Gaussia luciferase signal peptide (Gluc-sp) and incorporating a measles virus phosphoprotein-derived tetramerization domain. In a systematic comparison with three commonly used signal peptides, including tissue plasminogen activator (tPA), immunoglobulin G signal peptide (IgG-sp), and Gluc-sp, opt-sp was associated with increased relative secretion of NA protein under the tested expression conditions. Native PAGE analysis further suggested the presence of tetramer-like NA species. In mice，a DNA vaccine encoding opt-sp-fused NA elicited substantially stronger NA-specific humoral and cellular immune responses than constructs bearing conventional signal peptides and provided improved protection against homologous A/California/04/2009 (H1N1) challenge. These findings identify opt-sp as a promising signal peptide candidate for improving recombinant NA secretion and support further evaluation of this strategy for NA-based influenza vaccine development, including future studies of heterologous protection.
BACKGROUND:PICOBOO is a randomised, Bayesian adaptive trial evaluating immunogenicity and reactogenicity of licensed COVID-19 vaccines in immunocompetent individuals aged >12 years. We present reactogenicity data for nine vaccines administered as additional doses within adult strata based on age cohort and primary vaccination regimen. METHODS:Individuals who had not received a COVID-19 vaccine within three months were eligible. Participants were randomised within each stratum to receive a single vaccine dose. Reactogenicity events were recorded on days 1-7 following vaccination. Serious or medically attended adverse events (AEs), AEs of special interest, and AEs resulting in withdrawal were collected through day 28. Participants were followed until day 720. FINDINGS:A total of 1049 COVID-19 vaccine doses were administered to 586 adults enrolled between March 2022 and September 2024. Of these, 335 (57%), 96 (16%), 97 (17%) and 58 (10%) were randomised one, two, three and four times, respectively. At least one local reaction was reported after 786 (75%) doses and at least one systemic reaction after 798 (76%) doses. Local reactogenicity ranged from 47% (110/236) with NVX-CoV2373 (Nvx) to 90% (131/145) with Moderna, while systemic reactogenicity ranged from 69% (162/236) with Nvx to 85% (121/143) with BNT162b2. Pain was the most common local reaction; headache, fatigue, myalgia, and chills were the most common systemic reactions. Severe reactogenicity events were rare. INTERPRETATION:Reactogenicity events were common but rarely severe. Although reactogenicity appeared less frequent following Nvx than mRNA vaccines within strata, the trial was not powered for between-vaccine comparisons and findings should be interpreted descriptively. FUNDING:Medical Research Future Fund (2014690/2016473) and The Snow Foundation.
BACKGROUND:There are limited data on infant growth and healthcare utilization following perinatal Tdap vaccination. OBJECTIVE:To assess associations of Tdap vaccination during pregnancy or when given to lactating individuals with infant growth and healthcare utilization. STUDY DESIGN:We conducted a retrospective cohort study using electronic health records from two US healthcare systems. Prenatal care patients with a singleton live birth (2014-2022) and their linked infants were included. For pregnancy analyses, we compared outcomes in infants of those who received Tdap vaccination at ≥27 gestational weeks to those with no Tdap up to 90 days after delivery. For postpartum analyses, restricted to human milk feeders, we compared Tdap vaccination within 90 days after delivery versus none. Infant growth outcomes assessed between 3 and 12 months of age were growth faltering and slow weight gain (<5th percentile). Infant healthcare utilization outcomes were counts of outpatient visits, including well visits, and emergency department (ED) visits up to 6 months after delivery, excluding uninsured infants. We estimated adjusted prevalence ratios (aPR), or rate ratios (aRR), and 95% confidence intervals (CI). RESULTS:There were 33,261 and 25,335 pregnancies eligible for infant growth and healthcare utilization analyses, respectively. Tdap vaccination during pregnancy was not associated with growth faltering (aPR: 0.96, 95% CI: 0.85-1.09), slow weight gain (aPR: 0.93, 95% CI: 0.81-1.07) or ED visits (aRR: 1.00, 95% CI: 0.84-1.18), but was slightly associated with the rate of outpatient visits (aRR: 1.07, 95% CI: 1.01-1.12). No associations were observed among the 3034 and 3191 lactating individuals eligible for infant growth and healthcare utilization analyses, respectively. CONCLUSION:Tdap vaccination during pregnancy was not associated with adverse infant growth outcomes or ED visits. Although Tdap vaccination during pregnancy was associated with a slight increase in outpatient visits per infant, residual confounding by health seeking behavior could not be ruled out.
Intradermal vaccination can enhance immune responses, yet reproducible intradermal injection remains technically challenging, particularly for hollow microneedle delivery. Herein, using a mouse model, we aimed to establish a preclinical platform that enables more consistent intradermal vaccine delivery. We quantified age-dependent changes in mouse dorsal skin thickness and developed a pinch-type applicator, a hollow microneedle for mice, and an inserter to stabilize the skin and standardize effective skinfold thickness and insertion depth. Skinfold thickness measured using manual calipers varied with age, whereas cryosection-based measurements of the skin layer thickness from the outer surface to the dermal-subcutaneous adipose tissue interface showed only modest variations, indicating that visible age-related changes largely reflect skinfold structure. Skin-thickness-guided control of the pinching diameter markedly improved intradermal deliverability, and the feasibility of this process was confirmed in male C57BL/6J mice before vaccination. The mice were immunized twice at 2-week intervals with an mRNA-lipid nanoparticle (mRNA-LNP) vaccine encoding SARS-CoV-2 spike, delivered intramuscularly or intradermally at multiple dose levels; anti-receptor-binding domain (RBD) IgG responses measured at a fixed serum dilution and spike-specific cellular responses were evaluated 2 weeks post-boost. Intradermal administration induced measurable anti-RBD IgG responses and showed a tendency toward increased spike-specific cytokine-positive CD8a+ T cells compared with intramuscular dosing at the same dose, although this difference was not statistically significant. Collectively, this platform improved intradermal dosing consistency in mice and supported standard immunogenicity and immune-subset analyses, supporting incorporation of the intradermal route into small-animal proof-of-concept studies for the development of vaccines and therapeutics.
The COVID-19 pandemic highlighted the critical need for adaptable, rapid-response vaccine platforms. While mRNA vaccines enabled fast and scalable development, their stringent cold-chain requirements limited global accessibility. DNA vaccines offer a similarly fast and flexible vaccine design, but require far less complex manufacturing and distribution conditions, which is an advantage during a pandemic response. However, DNA vaccines have generally shown low immunogenicity in humans, which has hindered their clinical translation. Therefore, strategies that can enhance the potency of DNA vaccines are critical for realizing the full potential of this platform.Here, we apply a modular Tag/Catcher capsid virus-like particle (cVLP) technology to improve the immunogenicity of a DNA vaccine expressing the SARS-CoV-2 receptor-binding domain (RBD). Specifically, by administering a mixture of two plasmids, one encoding the RBD antigen and the other encoding a cVLP scaffold, each fused to a complementary Tag/Catcher binding partner, we induce in vivo assembly of cVLPs displaying multiple copies of the RBD antigen. In comparison to a control DNA vaccine encoding soluble RBD, the modular cVLP-display approach enhances both neutralizing antibody titers and RBD-specific CD8+ T-cell responses in mice.These findings demonstrate that the modular Tag/Catcher approach for cVLP display offers a widely applicable strategy for enhancing the immunogenicity of DNA vaccines, which could be combined with ongoing advances in DNA delivery for additive or synergistic benefit. Incorporating the Tag/Catcher cVLP technology may thus help establish the DNA platform as a viable tool for pandemic preparedness and cost-effective immunization in humans and animals.
BACKGROUND:Despite consistent evidence of safety and efficacy of immunization against COVID-19, vaccine hesitancy remains prevalent among pregnant individuals. Reactogenicity (post-vaccination inflammatory symptoms) has been cited as a significant factor in decreasing vaccine acceptance. The seasonal overlap in the vaccination schedule for COVID-19 and influenza provides an opportunity to increase vaccine accessibility and uptake while decreasing healthcare burden through coadministration. METHODS:The Canadian COVID-19 Vaccine Registry for Pregnant Women and Pregnant People (COVERED) is a national prospective cohort study that enrolled pregnant participants in Canada, irrespective of vaccination status, from September 2023 to March 2024. Vaccine reactogenicity and significant health events (defined as a new or worsening health problem), within seven days of COVID-19 vaccination, were assessed using serial online surveys, and compared between those who received COVID-19 vaccine only and those who received concurrent COVID-19 and influenza vaccines (coadministration). RESULTS:Among 754 participants, 344 (45.6%) received COVID-19 vaccination during pregnancy, with 85 of 344 (24.7%) also receiving a same-day influenza vaccination. Within seven days of COVID-19 vaccination, the adverse events most reported were local injection site reaction (166/344 [48.3%]), fatigue (139/344 [40.4%]), and myalgia (135/344 [39.2%]). Increased rates of COVID-19 injection site reaction (57/85 [67.1%] vs. 109/259 [42.1%], p < .01) and chills (16/85 [18.8%] vs. 22/259 [8.5%], p = .03) were reported in those who received COVID-19 and influenza vaccines together when compared to those who received the COVID-19 vaccine alone. No new or worsening health problems were reported after coadministration of COVID-19 and influenza vaccines during pregnancy. CONCLUSIONS:COVID-19 vaccination in pregnancy, with or without influenza vaccine coadministration, was safe and well-tolerated by survey respondents. Local injection site reaction and chills were more common after COVID-19 vaccination in those who also received a same-day influenza vaccination. There were no reports of significant health events after COVID-19 and influenza vaccine coadministration.
Low- and middle-income countries with seasonal influenza immunization programs, prior to the COVID-19 pandemic were able to deliver vaccines faster and achieve, higher coverage compared to countries without such capabilities. Middle Income, (lower- and upper-) countries participating in the Partnership for International Vaccine, Initiatives (PIVI) described influenza processes and systems that contributed to more, efficient and effective COVID-19 mass vaccination campaigns because of existing, capacities. Some routine systems were easy to pivot while others required, modifications to address the need for speed and volume when responding to the, COVID-19 pandemic. While annual influenza programs are a natural "warm base" (i.e., keeping operations such as staffing and supply chains operating at a minimum sustainable level during non-crisis periods) for honing emergency response readiness in vaccination, investments in areas more specific to pandemic preparedness remain a need. Regional variations in readiness and opportunities for cooperation should also be explored.
Pseudomonas aeruginosa is a critical-priority pathogen responsible for life-threatening infections in immunocompromised individuals, yet its extensive antigenic heterogeneity has impeded the development of immunotherapeutics. Alginate, a structurally conserved surface polysaccharide that forms the backbone of the biofilm matrix of mucoid P. aeruginosa strains in chronic infections, represents a compelling target. Here, we report the generation and functional evaluation of mAb 546B, a murine IgG1 monoclonal antibody directed against the synthetic mannuronic acid tetrasaccharide epitope 1. This antibody bound to the surface alginate of both mucoid and nonmucoid P. aeruginosa strains and induced pronounced bacterial aggregation. Notably, 546B inhibited biofilm formation, disrupted established biofilms, and reduced the minimum inhibitory concentration of meropenem across multiple strains. In a bacterial clearance model, 546B monotherapy reduced lung bacterial burden compared to PBS controls, and its combination with meropenem achieved a marked reduction accompanied by significantly attenuated pulmonary inflammation and histopathological injury. In a lethal PAO1 pneumonia model, 546B alone improved the 7-day survival rate of mice, and combination with meropenem could further enhance the survival rate. These findings establish 546B as a promising monoclonal antibody that targets alginate-mediated biofilms, supporting its further development as a passive immunotherapeutic against P. aeruginosa infection.
Avian influenza virus (AIV) and infectious bronchitis virus (IBV) are major respiratory pathogens of poultry, and their co-circulation complicates disease control. Here, we developed a chimeric subunit vaccine, RBD-HA, in which the receptor-binding domain (RBD) of the QX-type IBV spike protein replaced the immunodominant head domain of H9N2 AIV haemagglutinin. Structural analyses showed that RBD-HA formed a stable trimeric assembly, supporting the use of the HA stalk as an antigen-presenting scaffold. In chickens, RBD-HA induced humoral responses against both viruses and protected against homologous and heterologous H9N2 AIV challenge. In parallel, RBD-HA induced IBV-reactive and neutralizing antibody responses and provided protection against QX-type IBV challenge. The vaccine also elicited cross-reactive neutralizing activity and reduced viral shedding and tissue damage after H6N6 AIV challenge. These findings provide proof of concept for a bivalent subunit vaccine targeting two major avian respiratory viruses.
Highly pathogenic avian influenza (HPAI) A(H5) viruses can be transmitted from infected birds to various mammalian species, including humans. Avian influenza viruses (AIVs), members of the Orthomyxoviridae family, possess segmented RNA genomes prone to reassortment, favoring the emergence of novel genetic traits that may alter transmissibility, pathogenicity, and antigenicity. Although no sustained human-to-human transmission has been reported, the potential adaptation of these viruses poses a significant pandemic threat. This study aimed to evaluate the non-clinical safety, toxicity, and humoral immune responses induced by an adjuvanted H5 influenza vaccine in rats and rabbits, to support future clinical safety trials in humans. Male and female Wistar rats and New Zealand rabbits were observed for 14, 28, and 90 days after receiving two intramuscular doses of the H5N8 vaccine (15 μg HA/dose) formulated with the IB160 oil-in-water emulsion adjuvant. No systemic comorbidities, central nervous system alterations, or relevant clinical signs were observed. Hematological parameters remained within normal ranges, with total and differential leukocyte counts showing only minor fluctuations (<1% of total leukocytes). Mild biochemical variations in urea and hepatic transaminase levels were not correlated with histopathological alterations. The vaccine elicited a robust humoral response soon after immunization, with all groups reaching protective HAI-antibody titers. Although antibody levels declined over time, particularly in males, they remained significantly above baseline, indicating durable immunological memory. Furthermore, the vaccine induced a specific cellular immune response, confirmed by IL-2 and TNF production by antigen-specific T lymphocytes in splenic cell cultures after the booster dose. In conclusion, the H5N8 vaccine with the IB160 adjuvant was well tolerated locally and systemically, without compromising vital organ function. The safety and immunogenicity findings are consistent with expectations for adjuvanted influenza vaccines, demonstrating strong and durable humoral and cellular immune responses.
BACKGROUND:The Brighton Collaboration published its standard harmonized case definition for thrombocytopenia in 2007 to facilitate collection of valid and reproducible vaccine safety evidence and enable valid comparisons across studies. A companion guide to this case definition (including background incidence, risk factors, evidence for or against an association with vaccination, medical codes, data collection forms, and algorithms to support level of diagnostic certainty assessment) was initially published in 2021 and updated in 2025 based on a formal scoping review. This article reports the results of this scoping review, summarizing current evidence regarding the background incidence of and risk factors for thrombocytopenia, including immune thrombocytopenia (ITP) and its potential association with vaccination. METHODS:Two PubMed searches were conducted in July 2024: one for background incidence and non-vaccine risk factors, and one for vaccine associations. Search results were screened and relevant data were extracted and added to the corresponding companion guide tables. FINDINGS:Twenty-two articles contributed to the updated summary of background incidence, 36 articles contributed to the updated summary of non-vaccine risk factors, and 93 articles contributed to the updated summary of vaccine associations. Estimates of the background incidence of thrombocytopenia range between 1.6 and 92.1 per 100,000 person-years, depending on the study, region, and age range. Non-vaccine risk factors for thrombocytopenia include age, sex, genetics, season, geography, comorbidities, iatrogenesis, infection, medication, and food. While studies have consistently found an increased risk of ITP with measles-containing vaccines, and multiple studies found an increased risk following adenoviral COVID-19 vaccination, studies of other vaccines (including mRNA and inactivated COVID-19 vaccines) have largely found no association. CONCLUSION:Though rare, thrombocytopenia has many risk factors, including vaccination against measles. This review should be useful to stakeholders attempting to assess the occurrence of thrombocytopenia across a variety of settings, including as an adverse event following immunization.
Immunometabolism shapes vaccine immunogenicity, yet how HIV vaccine platforms affect metabolic programs and whether those programs predict immunogenicity remain poorly understood. We applied untargeted serum metabolomics to nine rhesus macaques receiving an HIV-1 DNA-prime/protein-boost regimen, sampling at weeks 0, 1, 2, and 8 after first protein boost. Vaccination induced acute and sustained metabolic changes. Lipid metabolism showed the broadest perturbation: free fatty acids were transiently depleted during the effector phase, while acylcholines, lysophospholipids, and endocannabinoid-like ethanolamides remained elevated through week 8. Glutamate, γ-glutamyl amino acids, and glycylvaline were elevated through week 8, with continued nitrogen recycling, glutathione turnover, and proteolytic activity. High antibody responders showed greater mitochondrial fatty acid oxidation and lower bile acid levels at baseline, and greater membrane lipid remodeling at the effector phase. These data define metabolic signatures of HIV vaccination and identify serum correlates of immunogenicity for prospective validation.
Influenza A virus (IAV) remains a global health challenge, and current intramuscular vaccines often fail to induce strong mucosal immunity in the airways. We have developed a novel intranasal vaccination strategy in mice using a Protease-Activated Receptor 2 (PAR-2)-activating peptide (AP) as an adjuvant co-delivered with influenza virosomes. We have previously shown that this peptide enhances virosome-induced CD8+ T cell responses and protection against lethal IAV challenge. Here we studied the immune changes induced by this peptide in draining lymph nodes and the lung. We show that AP promotes accumulation of lymphoid and myeloid cells to the mediastinal lymph nodes, including CD3+ T cells and CD11b-/CD11b+ dendritic cells (DCs), and enhances DC maturation and CCR7 expression, which facilitates migration to lymph nodes. Along with accumulation of antigen-presenting cells, we detected increases in naïve, central memory (TCM), and effector memory (TEM) T cells. In addition, AP promoted the presence of tissue-resident memory T cells (TRM) and monocytes in the lungs, supporting rapid tissue-targeted immunity. These results demonstrate that AP functions as a potent mucosal adjuvant by enhancing early immune cell recruitment, DC activation, and adaptive T cell responses in lymph nodes, ultimately promoting tissue-resident immunity. Our findings highlight the potential of PAR-2 activation to improve efficacy of mucosal influenza vaccines.
Immunization is a procedure that trains and strengthens host immunity against harmful foreign agents from damaging and even taking the life of the host. Immunization or vaccination has opened the era of modern medicine, contributed to independence, health, and prosperity of the nation. Resonating with current USA scientific progress, vaccinology needs to take an appropriate leap forward. The review traces the history of vaccine development in USA, recaps multidiscipline-nary research more than four-decade on acquired immunodeficiency syndrome (AIDS), appeals to generating a next-generation vaccine - chromatin vaccine and elicits the newly defined host immunity - epigenetic immunity for a cure.
Porcine reproductive and respiratory syndrome virus (PRRSV) and porcine circovirus type 2 (PCV2) are major swine pathogens that cause severe disease and frequently occur as coinfections in pig herds. Current vaccination strategies against PRRSV and PCV2 commonly rely on separate vaccines, which may increase the complexity of immunization programs and require repeated animal handling. Therefore, a bivalent vaccine platform capable of inducing immune responses against both pathogens would be valuable for simplifying vaccination strategies. In this study, the attenuated PRRSV strain HuN4-F112 was used as a live viral vector to express the PCV2d capsid (Cap) protein. The recombinant virus rHuN4-F112-Cap was successfully rescued using a reverse-genetics system. rHuN4-F112-Cap showed growth characteristics comparable to those of the parental HuN4-F112 strain in MARC-145 cells, and expression of the inserted PCV2 Cap gene was confirmed. A single intramuscular immunization with rHuN4-F112-Cap induced PRRSV and PCV2 specific antibody responses in piglets, as well as PCV2-neutralizing antibodies before challenge. In separate challenge models, vaccinated piglets showed reduced PCV2 DNA loads and milder lymphoid lesions after PCV2 challenge, and reduced clinical signs, lower PRRSV RNA loads, milder pulmonary lesions, and improved survival after highly pathogenic PRRSV challenge compared with DMEM-inoculated controls. These findings indicate that rHuN4-F112-Cap has potential as a bivalent live-vector vaccine candidate against PRRSV and PCV2.
Porcine contagious pleuropneumonia (PCP) is caused by Actinobacillus pleuropneumoniae (APP) and inflicts heavy economic losses on the swine industry. However, existing inactivated vaccines provide limited cross-protection, highlighting the need for improved vaccine strategies. In this study, we combined pangenome analysis with subtractive proteomics to screen the APP core genome and identified 11 potential antigens. Seven of them showed immunoreactivity by ELISA and Western blotting. These antigens, together with the ApxI-III toxins, were used for T and B cell epitope prediction. On this basis, a multi-epitope fusion protein MVAPP was constructed. In silico molecular docking with swine immune receptors and immune simulations suggested that MVAPP has the potential to induce immune responses. In the mouse model, that MVAPP elicited specific antibody responses, shifted the splenic T-cell subset distribution toward CD4+ T cells, and provided partial protection against challenge with strains from two serovars. In conclusion, MVAPP represents a potential multi-epitope vaccine candidate for further development against APP.
BACKGROUND:Conducting tuberculosis vaccine trials in high-transmission settings offers potential gains in efficiency, yet the impact of repeated exposure in the presence of incomplete protection on measured vaccine efficacy is uncertain. We evaluated the effect of vaccine characteristics and epidemiological context on estimates of vaccine efficacy and requisite sample size for tuberculosis vaccine trials. METHODS:We simulated clinical trials of hypothetical tuberculosis vaccines using a stochastic compartmental model of tuberculosis natural history. We considered vaccines that confer "leaky" (50% per-exposure reduction) versus "all-or-none" protection against infection and/or disease that were evaluated in QuantiFERON Gold Plus (QFT) positive, negative or mixed populations with 2% (medium burden; incidence 400 per 100,000), 5% (high burden; 800 per 100,000) or 50% (very high burden; 4500 per 100,000) annual risk of infection (ARI), including protection against infection alone. We compared estimates of vaccine efficacy and statistical power to detect differences according to sample size for each vaccine archetype and epidemiologic setting. FINDINGS:Simulated trials of vaccines protecting against disease, alone or with protection against infection, gave comparable estimates of efficacy across epidemiological settings, whether all-or-none or leaky. The largest reduction was for a leaky vaccine protecting against both infection and disease in QFT negative participants, whose efficacy fell from 75% at medium ARI to 67% at very high ARI (relative reduction 11%). A vaccine acting only by preventing infection fell further, from 50% to 36% (28%). Trials at very high ARI could nonetheless achieve 90% power with 80-96% fewer participants than at medium ARI. INTERPRETATION:While vaccines conferring leaky protection against infection and disease tested in settings with very high ARI could modestly underestimate efficacy, trials could be adequately powered with a fraction of the sample size in such settings. Further, trials could enroll a mixture of QFT negative and positive individuals, increasing generalizability.
