Abstract Severe pneumonia caused by respiratory virus infection is one of the main threats to the lifespan of the aged population and physiological aging fundamentally drives poor disease outcomes in respiratory viral infections, necessitating investigation of the underlying mechanisms and the development of effective countermeasures. Pulmonary transcriptomic profiling reveals that diffuse cell death, inadequate antiviral responses, myeloid-driven excessive inflammation and immune-thrombosis dictate the pulmonary microenvironment are typical molecular pathology characteristics of the SARS-CoV-2-infected aged hamsters rather than the adult controls. The elevated pathological baseline and dysregulated immune responses are demonstrated as the key host factors of lethal viral pneumonia in the aged hamsters. Meanwhile, SARS-CoV-2 infection in the adult hamsters usually resulted in an aged-like pulmonary transcriptomic signature, suggesting a potential link among aging, dysregulated immune responses and severe illness. To reverse the progression of lethal severe pneumonia in the aged hamsters, we initiated a multidimensional combination therapy of dexamethasone, heparin and the broad-spectrum viral decoy CoVR-MV at three days after infection. Although single- and dual-drug therapies were insufficient to achieve functional cure, the three-drug combination therapy resulted in a potent reduction of high mortality, body weight loss, viral load, lung pathology and cytokine storm through the synergism of immunoregulatory, anticoagulant and antiviral effects, effectively intercepting the multifaceted pathogenic network. This study highlights physiological aging as a core driver of critical COVID-19 pathogenesis and provides valuable clues for the rational design of multi-drug and multi-target therapies against respiratory viral infections and lethal severe pneumonia in the elderly population.

Varicella-zoster virus (VZV) interacts with autophagy in a manner distinct from that of many other herpesviruses. Rather than broadly blocking autophagic flux, VZV generally induces a functional autophagic response and appears to use this pathway to support productive infection. Available data suggest that autophagy mainly plays a pro-viral role during the VZV lytic cycle in epithelial cells and fibroblasts by promoting viral glycoprotein maturation, secondary envelopment, intracellular trafficking, and egress. However, emerging evidence indicates that autophagy can exert antiviral and protective effects in neuronal cells and hematopoietic cells, highlighting the cell-type-dependent duality of autophagy in VZV infection. A notable feature of this process is the convergence of autophagic and endosomal pathways, through which VZV redirects autophagy-related vesicle trafficking away from lysosomal degradation and toward transport and exocytosis. Mechanistically, ER stress-UPR signaling acts as a major upstream regulator of VZV-induced autophagy, while the contributions of mTOR, ESCRT, and TLR-related pathways remain to be fully elucidated. This review summarizes recent advances in the mechanisms, functions, and cell-context dependence of VZV-autophagy interactions and highlights key unresolved questions relevant to viral pathogenesis and host-directed antiviral strategies.

OBJECTIVE:The objective of this study was to examine changes of age of onset and disease characteristics of gout between 2003 and 2022 in multiple centres in mainland China. METHODS:A cross-sectional cohort study was conducted among people with gout from two geographically separate centres in China. Baseline gout clinic data were collected through a electronic medical records review. The onset age trends and disease characteristics of patients who developed gout between 2003 and 2012 (first decade) and between 2013 and 2022 (second decade) were compared. RESULTS:A total of 10 658 patients were included. The age of gout onset declined over the two decades (Ptrend < 0.001), with the average onset age decreasing from 42.0 in 2003 to 38.9 years in 2022. The proportion of patients with an onset age of ≤19 and of 20-29 years increased annually by 5.8% and 9.6%, respectively (Ptrend < 0.05). Compared with age-, sex- and disease duration-matched patients in the first decade, patients who developed gout in the second decade were more likely to have a history of smoking and alcohol consumption, and less likely to engage in regular exercise (P < 0.001). Additionally, those with onset of gout in the second decade had higher rates of s.c. tophi, frequent gout flares, nephrolithiasis, hypertension and diabetes, though lower rates of dyslipidaemia (P < 0.05). CONCLUSION:Over the past two decades in mainland China, there has been a noticeable trend towards younger onset of gout, alongside an increase in disease severity and metabolic comorbidities.

BACKGROUND:Current Oka strain varicella vaccines are generally safe but may cause latent neuronal infections leading to herpes zoster in some vaccinees. A novel v7D candidate vaccine has been developed to prevent varicella and reduce these risks. METHODS:This randomized, double-blind, controlled, phase 2b clinical trial was conducted in Jiangsu, China. Healthy children 1-12 years old with no history of varicella infection or vaccination were enrolled and randomly assigned to 0-3-/6-month schedule for low/medium dose. Phase 2a participants (3-12 years of age) previously receiving low-/medium-/high-dose v7D or licensed vOka received a second dose in phase 2b (0-15-month schedule) for exploratory analysis. The primary outcome was immunogenicity via varicella-zoster virus immunoglobulin (Ig)G seroconversion and geometric mean titers at 30 and 90 days post-second vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2300068380. RESULTS:In the per-protocol analysis, IgG antibody response reached 100% seroconversion by day 30 after the second vaccination. Antibody levels were comparable among different vaccine groups under the same schedule at day 30 post-second vaccination. The occurrence of adverse reactions was similar among the different vaccine groups within the same schedule. Most adverse reactions were mild or moderate and resolved shortly. None of the serious adverse events were related to the vaccine. CONCLUSIONS:The 2-dose regimens of v7D vaccine demonstrated robust immune responses and excellent safety profiles. These findings warrant further evaluation of the safety advantages and efficacy v7D vaccine in the future.

Varicella-Zoster Virus (VZV) causes primary varicella and can reactivate later in life to induce herpes zoster with severe complications, posing a persistent threat to human health. Previous studies of VZV immunogens have focused primarily on the major envelope glycoproteins (e.g., gE, gH, and gB), whereas other potential immunogenic components remain unexplored. To broaden the repertoire of anti-VZV targets, we established a biotin-avidin membrane-protein capture strategy to screen for surface-accessible viral antigens that elicit neutralizing antibodies. Using this approach, we identified the conserved Alphaherpesvirinae-specific tegument protein pORF9 as a previously unrecognized surface-accessible antigen bearing a neutralizing epitope, which is unexpected because tegument proteins are generally considered internal virion components. Immunofluorescence, flow cytometry, and cell fractionation analysis showed that pORF9 undergoes late-stage plasma membrane association and surface accessibility, with about 30% of infected cells becoming surface positive for pORF9 by 72 hpi; this phenotype was not observed for the non-essential homolog VP22 from herpes simplex virus type 1. We mapped the neutralizing epitope to amino acid residues 111-125, which are highly conserved among 136 VZV strains spanning five phylogenetic clades, and confirmed key antibody-binding residues by alanine scanning. Moreover, chimeric hepatitis B core virus-like particles displaying this epitope induced pORF9-specific neutralizing antibodies in mice. Collectively, these findings refine current views of VZV tegument protein localization and immunological function, establish pORF9 as a dual B- and T-cell target, and support further exploration of pORF9 as a potential target for anti-VZV interventions.

Coxsackievirus B1 (CVB1), a clinically significant human enterovirus, causes a wide spectrum of diseases ranging from mild illness to severe, life-threatening conditions in susceptible individuals. However, investigations into CVB1 infection pathogenesis, as well as the development and evaluation of antiviral strategies, have long been constrained by the lack of immunocompetent animal models that recapitulate human CVB1 infections. In this study, we established a lethal CVB1 infection model in immunocompetent adult BALB/c mice. Using a reverse genetics approach, we generated the CVB1-XM0108 virus from a clinical isolate and infected adult BALB/c mice. Our results demonstrated that this virus exhibited a strong tropism for the pancreas, liver, and skeletal muscles, leading to extensive inflammation in these organs. Passive immunization with anti-CVB1 serum dose-dependently reduced viral replication, tissue damage, weight loss, and mortality. This pathologically relevant mouse model provides a valuable platform for advancing CVB1 therapeutic and vaccine development.

Small ruminant lentiviruses (SRLV) cause lifelong persistent infections in sheep and goats, impairing productivity and restricting livestock trade. Serological ELISA testing is the primary method for SRLV epidemiological monitoring, and most commercial ELISAs use capsid (CA), envelope, or a combination of both proteins as antigens. We previously developed a CA-based indirect ELISA (iELISA) to detect SRLV antibodies. Here, we expressed full-length recombinant SRLV Gag protein and further developed an iELISA using Gag as the coating antigen. The cut-off value of the established Gag-based iELISA was set at 0.093 based on S/P ratio analysis of 100 SRLV-negative sera. Parallel testing of 228 sera using the Gag-iELISA, CA-iELISA, and a commercial ELISA showed that the Gag-iELISA had a 2.71-fold higher positive rate than the CA-iELISA and 4.39 percentage points higher than the commercial ELISA. All samples that tested positive by either the CA-iELISA or the commercial ELISA were also positive by the Gag-iELISA. Samples testing positive by the Gag-iELISA but negative by the CA-iELISA or the commercial ELISA were confirmed as SRLV antibody-positive by Western blot. Concordance analysis of the Gag-iELISA and commercial ELISA showed 95.61% overall agreement. Endpoint dilution assays showed that the Gag-iELISA had two-fold higher analytical sensitivity than the CA-iELISA and comparable sensitivity to the commercial ELISA. Furthermore, testing of 761 ovine sera from Hulunbuir during 2024–2025 revealed an overall SRLV seroprevalence of 54.80%, with regional positive rates ranging from 0.00% to 84.44%. Collectively, this Gag-based iELISA is a sensitive and practical tool for large-scale SRLV serological surveillance.

Objective The purpose of this study is to understand the knowledge, attitude, and practice (KAP) of influenza vaccine inoculation and their influencing factors, among Chinese college students and further support the formulation of implementation plans to promote influenza vaccination. Methods From April 7th to May 31st, 2024, a convenience sampling method was used to select college students in Beijing Jiaotong Unversity to complete a questionnaire survey. The content included basic information, cognition, attitude, behavior towards influenza virus and vaccine, and expected channels for science popularization, etc. Logistic regression analysis were used to explore factors influencing college students' KAP towards influenza virus vaccination.Results A total of 295 valid questionnaires from college students were collected. Female students and vaccination history were associated with a higher correct rate of knowledge, while infection history was associated with a lower correct rate of knowledge. Female students were more likely to recognize the severity of influenza virus infection, higher grade students and those with infection history believed they were more likely to be infected with influenza. Female students, students with vaccination history and third-year students were more willing to actively search and share health information about vaccination in daily life, students majoring in science were more likely to share health information about vaccination. Conclusion Numerous factors influenced college students’ KAP level. The vaccine efficacy rate can be increased through effective measures such as improving the education and publicity of healthcare providers, establishing centralized and convenient vaccination sites, providing convenient vaccination times, and implementing vaccine cost reimbursement policies.

Human papillomavirus (HPV) is a prevalent sexually transmitted infection associated with various diseases, including genital warts, recurrent respiratory papillomatosis (RRP), and multiple pre-cancerous diseases and cancers. HPV causes over 90

Zika virus (ZIKV) is primarily transmitted through mosquito bites and, occasionally, via breast milk, making postnatal ZIKV infections common among newborns and infants, particularly in tropical regions. Previous studies, including ours, have demonstrated that neonatal ZIKV infection can be fatal, highlighting a severe health issue of ZIKV in newborns. However, the pathogenesis and functional outcomes of postnatal ZIKV infection remain largely unexplored. The mechanisms underlying organ failure in infected neonates are still unknown. Here, we investigated postnatal ZIKV (PRVABC59) infection in neonatal mice and found significant cardiac abnormalities. Electrocardiogram (EKG) analysis revealed extended P-R intervals (indicative of the atrioventricular block), widened QRS complexes (suggesting intraventricular block), and elevated ST wave (a biomarker of myocardium impairment), implying defects in myocardial conduction. In addition, ZIKV infection caused increased levels of cTnT, cTnI, CK, CK-MB, CCL2, CXCL9, and CXCL10-biomarkers associated with cardiovascular diseases and infarction-like myocardial pathology. To further elucidate the underlying mechanisms, we analyzed cytokine and chemokine responses and observed a significant increase in multiple inflammatory mediators, including M-CSF, LIF, IL-6, IL-15, CCL2, CCL4, CCL5, CCL11, CXCL1, CXCL9, CXCL10, TNF-α, and VEGF. Notably, ZIKV infection also led to the degradation of connexin 43 (Cx43), a critical protein involved in heart development and intercellular communication among myocardial cells. In summary, our neonatal mouse model of ZIKV infection suggests that ZIKV-induced myocarditis and cardiac dysfunction may contribute to fatal outcomes in newborns. These findings provide new insights into ZIKV pathogenesis and underscore the need for further research into its impact on the cardiovascular system in early life.IMPORTANCEZika virus (ZIKV) is a known teratogen responsible for microcephaly in neonates born to mothers infected during pregnancy. Mouse models have been instrumental in elucidating ZIKV pathogenesis; however, most published studies utilize interferon (IFN)-compromised animals, either genetically modified or antibody-treated. In this study, we employed immunocompetent neonatal mice to investigate postnatal ZIKV infection and uncovered its impact on heart function. We detected high viral loads in heart tissue at early, middle, and late stages of infection using RT-qPCR. Electrocardiogram (EKG) analysis demonstrated cardiac dysfunction, including conduction abnormalities. At the same time, elevated levels of cTnT, cTnI, CK, CK-MB, LDH, α-HBDH, CCL2, and CXCL10-hallmarks of cardiovascular pathology-suggested inflammatory responses associated with heart failure. These findings indicate that neonatal mortality following postnatal ZIKV infection may be driven by virus-induced cardiac dysfunction. Our results provide new insights into ZIKV pathogenesis, suggesting that postnatal ZIKV infection poses a significant risk for severe cardiac disease in neonates.

In order to solve the problem of limited number of training data and insufficient feature representation for malware classification, in this paper, the data augmentation and pretrained image classification models based algorithm is proposed. First, two malware image construction and augmentation approaches are proposed. The malware data is preprocessed and converted into RGB image by mapping. Then, the deep convolutional generative adversarial network is utilized for image augmentation of each channel. And the structural similarity index is proposed for generated malware image filtering. For another, the denoising diffusion implicit model is utilized for malware data augmentation of each class. After the cosine similarity and Jensen-Shannon divergence based data filtering, the Gramian angular summation field method is used for malware image construction. Second, the pretrained VGG16 and ResNet50 models are proposed for feature extraction by transfer learning. Moreover, three feature fusion strategies are designed. At last, by the off-line training, the malware classification model is obtained. Experiment results demonstrate that the proposed algorithm has better malware classification performance than some existing methods.

With the rapid development of Cryo Electron Microscopy (Cryo EM) technology, significant progress has been made in protein structure analysis, opening up new avenues for research in the fields of biology and medicine. This study aims to review the latest progress of cryo electron microscopy technology in protein structure analysis, and explore its research significance and application prospects. Through in-depth analysis of technological optimization, method innovation, and its application in the study of complex biological macromolecular structures, it was found that cryoelectron microscopy technology not only improves resolution and signal-to-noise ratio, but also successfully analyzes various complex protein structures, providing powerful tools for research in the fields of biology and medicine. The development of cryoelectron microscopy technology not only deepens the understanding of protein structure and function relationships, but also provides new ideas and methods for drug development and disease treatment. Therefore, further promoting the development and application of cryoelectron microscopy technology is of great significance for promoting progress in the field of life sciences.

BACKGROUND:The Oka varicella vaccine strain remains neurovirulent and can establish lifelong latent infection, raising safety concerns about vaccine-related herpes zoster. In this study, we aimed to evaluate the immunogenicity and safety of a skin-attenuated and neuro-attenuated varicella vaccine candidate (v7D vaccine). METHODS:We did this randomised, double-blind, controlled, phase 2a clinical trial in Jiangsu, China. Healthy children aged 3-12 years with no history of varicella infection or vaccination were enrolled and randomly assigned (1:1:1:1) to receive a single subcutaneous injection of the v7D vaccine at 3·3 log10 plaque forming units (PFU; low-dose v7D group), 3·9 log10 PFU (medium-dose v7D group), and 4·2 log10 PFU (high-dose v7D group), or the positive control varicella vaccine (vOka vaccine group). All the participants, laboratory personnel, and investigators other than the vaccine preparation and management staff were masked to the vaccine allocation. The primary outcome was assessment of the geometric mean titres (GMTs) and seroconversion rates of anti-varicella zoster virus immunoglobulin G (IgG) induced by different dose groups of v7D vaccine at 0, 42, 60, and 90 days after vaccination in the per-protocol set for humoral immune response analysis. Safety was a secondary outcome, focusing on adverse events within 42 days post-vaccination, and serious adverse events within 6 months after vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2000034434. FINDINGS:On Aug 18-21, 2020, 842 eligible volunteers were enrolled and randomly assigned treatment. After three participants withdrew, 839 received a low dose (n=211), middle dose (n=210), or high dose (n=210) of v7D vaccine, or the vOka vaccine (n=208). In the per-protocol set for humoral immune response analysis, the anti-varicella zoster virus IgG antibody response was highest at day 90. At day 90, the seroconversion rates of the low-dose, medium-dose, and high-dose groups of v7D vaccine and the positive control vOka vaccine group were 100·0% (95% CI 95·8-100·0; 87 of 87 participants), 98·9% (93·8-100·0; 87 of 88 participants), 97·8% (92·4-99·7; 91 of 93 participants), and 96·4% (89·8-99·2; 80 of 83 participants), respectively; the GMTs corresponded to values of 30·8 (95% CI 26·2-36·0), 31·3 (26·7-36·6), 28·2 (23·9-33·2), and 38·5 (31·7-46·7). The v7D vaccine, at low dose and medium dose, elicited a humoral immune response similar to that of the vOka vaccine. However, the high-dose v7D vaccine induced a marginally lower GMT compared with the vOka vaccine at day 90 (p=0·027). In the per-protocol set, the three dose groups of the v7D vaccine induced a similar humoral immune response at each timepoint, with no statistically significant differences. The incidence of adverse reactions in the low-dose, medium-dose, and high-dose groups of v7D vaccine was significantly lower than that in the vOka vaccine group (17% [35 of 211 participants], 20% [41 of 210 participants], and 13% [27 of 210 participants] vs 24% [50 of 208 participants], respectively; p=0·025), especially local adverse reactions (10% [22 of 211 participants], 14% [30 of 210 participants] and 9% [18 of 210 participants] vs 18% [38 of 208 participants], respectively; p=0·016). None of the serious adverse events were vaccine related. INTERPRETATION:The three dose groups of the candidate v7D vaccine exhibit similar humoral immunogenicity to the vOka vaccine and are well tolerated. These findings encourage further investigations on two-dose vaccination schedules, efficacy, and the potential safety benefit of v7D vaccine in the future. FUNDING:The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, the Fundamental Research Funds for the Central Universities, and Beijing Wantai. TRANSLATION:For the Chinese translation of the abstract see Supplementary Materials section.

Depending on the source of the blastophore, there are various subtypes of laryngeal cancer, each with a unique metastatic risk and prognosis. The forecasting of their prognosis is a pressing issue that needs to be resolved. This study comprised 5953 patients with glottic carcinoma and 4465 individuals with non-glottic type (supraglottic and subglottic). Five clinicopathological characteristics of glottic and non-glottic carcinoma were screened using univariate and multivariate regression for CoxPH (Cox proportional hazards); for other models, 10 (glottic) and 11 (non-glottic) clinicopathological characteristics were selected using least absolute shrinkage and selection operator (LASSO) regression analysis, respectively; the corresponding survival models were established; and the best model was evaluated. We discovered that RSF (Random survival forest) was a superior model for both glottic and non-glottic carcinoma, with a projected concordance index (C-index) of 0.687 for glottic and 0.657 for non-glottic, respectively. The integrated Brier score (IBS) of their 1-year, 3-year, and 5-year time points is, respectively, 0.116, 0.182, 0.195 (glottic), and 0.130, 0.215, 0.220 (non-glottic), demonstrating the model's effective correction. We represented significant variables in a Shapley Additive Explanations (SHAP) plot. The two models are then combined to predict the prognosis for two distinct individuals, which has some effectiveness in predicting prognosis. For our investigation, we established separate models for glottic carcinoma and non-glottic carcinoma that were most effective at predicting survival. RSF is used to evaluate both glottic and non-glottic cancer, and it has a considerable impact on patient prognosis and risk factor prediction.

Cervical squamous cell carcinoma (CSCC) is a prevalent gynecological malignancy worldwide. Current treatments for CSCC can impact fertility and cause long-term complications, underscoring the need for new therapeutic strategies. Oncolytic virotherapy has emerged as a promising option for cancer treatment. Previous research has demonstrated the oncolytic activity of the coxsackievirus B3 strain 2035 A (CVB3/2035A) against various tumor types. This study aims to evaluate the clinical viability of CVB3/2035A for CSCC treatment, focusing on its oncolytic effect in patient-derived CSCC organoids. The oncolytic effects of CVB3/2035A were investigated using human CSCC cell lines in vitro and mouse xenograft models in vivo. Preliminary tests for tumor-selectivity were conducted on patient-derived CSCC tissue samples and compared to normal cervical tissues ex vivo. Three patient-derived CSCC organoid lines were developed and treated with CVB3/2035A alone and in combination with paclitaxel. Both cytotoxicity and virus replication were evaluated in vitro. CVB3/2035A exhibited significant cytotoxic effects in human CSCC cell lines and xenograft mouse models. The virus selectively induced oncolysis in patient-derived CSCC tissue samples while sparing normal cervical tissues ex vivo. In patient-derived CSCC organoids, which retained the immunohistological characteristics of the original tumors, CVB3/2035A also demonstrated significant cytotoxic effects and efficient replication, as evidenced by increased viral titers and presence of viral nucleic acids and proteins. Notably, the combination of CVB3/2035A and paclitaxel resulted in enhanced cytotoxicity and viral replication. CVB3/2035A showed oncolytic activity in CSCC cell lines, xenografts, and patient-derived tissue cultures and organoids. Furthermore, the virus exhibited synergistic anti-tumor effects with paclitaxel against CSCC. These results suggest CVB3/2035A could serve as an alternative or adjunct to current CSCC chemotherapy regimens.

BACKGROUND:Varicella zoster virus (VZV), which is a human restricted alpha-herpesvirus, causes varicella (chickenpox) and zoster (shingles). The subsequent post-herpetic neuralgia (PHN) due to VZV infection is excruciating for most patients. Thus, developing specific therapeutics against VZV infection is imperative. RNA interference (RNAi) represents an effective approach for alternative antiviral therapy. This study aimed to develop a novel anti-VZV therapeutics based on RNAi.RESULTS:In this study, we screened and found the open reading frame 7 (ORF7) of the VZV genome was an ideal antiviral target based on RNAi. Therefore, a novel siRNA targeting ORF7 (si-ORF7) was designed to explore the potential of RNAi antiviral treatment strategy toward VZV. We used a bio-engineering approach to manufacture recombinant siRNA agents with high yield in E. coli. Then, the efficacy of recombinant ORF7-siRNA (r/si-ORF7) in inhibiting VZV infection both in cellular level and 3D human epidermal skin model was evaluated. The r/si-ORF7 was proved to inhibit the VZV replication and reduce the virus copy numbers significantly in vitro. Furthermore, flexible nano-liposomes were established to deliver r/si-ORF7 to 3D human epidermal skin model and found r/si-ORF7 also could inhibit the VZV infection, thus maintaining normal skin morphology.CONCLUSIONS:Taken together, our results highlighted that transdermal administration of antiviral r/si-ORF7 was a promising therapeutic strategy for functional cure of VZV infection.

Antibody discovery against complex antigens is limited by the availability of a reproducible pure source of concentrated properly folded antigen. We have developed a technology to enable direct incorporation of membrane proteins such as GPCRs and into the membrane of poxvirus. The protein of interest is correctly folded and expressed in the cell-derived viral membrane and does not require any detergents or refolding before downstream use. The poxvirus is selective in which proteins are incorporated into the viral membrane, making the antigen poxvirus an antigenically cleaner target for in vitro panning. Antigen-expressing virus can be readily purified at scale and used for antibody selection using any in vitro display platform.

Background The real-world data of long-term protection under moderate vaccination coverage is limited. This study aimed to evaluate varicella epidemiology and the long-term effectiveness under moderate coverage levels in Ganyu District, Lianyungang City, Jiangsu Province. Methods This was a population-based, retrospective birth cohort study based on the immunization information system (IIS) and the National Notifiable Disease Surveillance System (NNDSS) in Ganyu District. Varicella cases reported from 2009 to 2020 were included to describe the epidemiology of varicella, and eleven-year consecutive birth cohorts (2008–2018) were included to estimate the vaccine effectiveness (VE) of varicella by Cox regression analysis. Results A total of 155,232 native children and 3,251 varicella cases were included. The vaccination coverage was moderate with 37.1%, correspondingly, the annual incidence of varicella infection increased 4.4-fold from 2009 to 2020. A shift of the varicella cases to older age groups was observed, with the peak proportion of cases shifting from 5–6 year-old to 7–8 year-old. The adjusted effectiveness of one dose of vaccine waned over time, and the adjusted VE decreased from 72.9% to 41.8% in the one-dose group. Conclusions The insufficient vaccination coverage (37.1%) may have contributed in part to the rising annual incidence of varicella infection, and a shift of varicella cases to older age groups occurred. The effectiveness of one dose of varicella vaccine was moderate and waned over time. It is urgent to increase varicella vaccine coverage to 80% to reduce the incidence of varicella and prevent any potential shift in the age at infection in China.

Background Despite the success in decreasing varicella-related disease burden, live-attenuated Oka vaccine strain of varicella-zoster virus (vOka) remains neuro-virulence and may establish latency and reactivate, raising safety concerns. Here we aimed to evaluate the safety and immunogenicity of a skin-and neuro-attenuated varicella vaccine candidate (v7D).Methods This is a randomized, double-blind, placebo-controlled, dose-escalation and age de-escalation phase 1 clinical trial conducted in Liuzhou, China (ChiCTR1900022284). Eligible healthy participants aged 1-49 years, with no history of varicella vaccination and had no history of varicella or herpes zoster were sequentially enrolled and allocated to subcutaneously receive one of the three doses (3.3, 3.9, and 4.2 lg PFU) of v7D, vOka or placebo in a dose-escalation and age de-escalation manner. The primary outcome was safety, assessed by adverse events/ reactions within 42 days after vaccination and serious adverse events (SAEs) throughout six months after vaccination. The secondary outcome was immunogenicity, assessed by the VZV IgG antibodies measured with fluorescent antibody to membrane antigen (FAMA) assay.Findings Between April 2019 and March 2020, totally 224 participants were enrolled. Within 42 days post-vaccination, the incidences of adverse reactions were 37.5%-38.7% in the three doses of v7D groups which were similar to that of the vOka (37.5%) and placebo (34.4%) groups. No SAE has been judged as causally related to vaccination. At 42 days post-vaccination, 100% of children aged 1-12 years in the per-protocol set of immunogenicity cohort of the v7D groups became seropositive. Meanwhile, in the intent-to-treat set of immunogenicity cohort of subjects aged 1-49 years, the geometric mean increases of the three groups of v7D vaccine were 3.8, 5.8 and 3.2, respectively, which were similar to that of the vOka vaccine group (4.4) and significantly higher than that of the placebo group (1.3). Interpretation The candidate v7D vaccine has been preliminarily shown to be well-tolerated and immunogenic in humans. The data warrant further evaluation of the safety advantage and efficacy of v7D as a varicella vaccine.