Following the publication of the above article, an interested reader drew to the authors' attention that, regarding the cell invasion assay experiments shown in Fig. 5A on p. 2493, the 'WT' and 'pEF6' data panels were strikingly similar, albeit the coloration of the images differed slightly from each other, suggesting that these images were derived from the same original source. A second reader also noted that, concerning the scratch‑wound assay experiments shown in Fig. 6B, the images for the WT and pEF6 experiments at the 0 h (top panels) and 36 h (lower panels) time points contained overlapping sections (specifically, the 'WT/0 h' panel with the pEF6/0 h panel, and the 'WT/36 h' panel with the pEF6/36 h panel), suggesting that the two pairs of panels were likewise derived from the same original sources. Upon examining their original data, the authors realized that these figures had been inadvertently assembled incorrectly. Revised versions of Figs. 5 and 6, now showing the correct data for the 'WT' panel in Fig. 5A and the pEF/0 h and pEF/36 h panels in Fig. 6B, are shown on the next two pages. Note that the errors made in assembling these figures did not have a gross effect on the conclusions reported in this study. The authors thank the Editor of International Journal of Oncology for granting them the opportunity to publish this corrigendum. All the authors agree with the publication of this corrigendum; furthermore, they apologize to the readership of the journal for any inconvenience caused. [International Journal of Oncology 48: 2488‑2496, 2016; DOI: 10.3892/ijo.2016.3462].

Abstract Introduction Lipid nanoparticles (LNP) used for mRNA vaccine delivery are known to be inflammatory at high doses. Here, we hypothesized that co-immunization with low-dose mRNA-LNP and conventional influenza or protein subunit vaccine would stimulate a unique set of innate responses, correlating with enhanced adaptive immunogenicity of co-vaccination, compared to either mRNA or protein vaccine alone. Methods We generated mRNA vaccines encoding influenza virus hemagglutinin (HA), neuraminidase (NA), and M2 ectodomain (M2e), as well as non-influenza glycoproteins, and then encapsulated them into LNP. Innate immune responses, adaptive immunogenicity, and efficacy were investigated in mice after immunization with mRNA-LNP, inactivated split or protein vaccines, and combinations of mRNA-LNP and split or protein vaccines. Results Co-immunization of mice with combined (mRNA-LNP + split or protein) low-dose vaccines induced synergistically enhanced levels of humoral, cellular immune responses, and protective efficacy, compared to mRNA-LNP or split (or protein) alone vaccination. Co-immunization modulated early cytokine and chemokine profiles in blood, and induced acute recruitment of activated monocytes, macrophages, dendritic cells, and natural killer (NK) cells in spleens, draining lymph nodes (dLNs), and lungs. Activated innate immune cells expressing an mRNA-encoded antigen were preferentially recruited to the lymphoid tissues and, to a lesser degree, the lungs. DBA/2J (NK defective) mice showed severely compromised innate immune responses, resulting in lower efficacy of protection. Conclusion This study provides an insight into a unique innate immune response pattern that correlates with enhanced adaptive immunity, supporting a new effective vaccination strategy. Funding Source NIH (1R01 AI154656-01A1) Topic Categories Vaccines and Immunotherapy (VAC)

Monovalent and high-dose mRNA vaccines might be associated with limited efficacy and adverse effects, respectively. This study investigated whether a combination of low-dose multivalent mRNA and spike proteins of multiple SARS-CoV-2 variants would enhance broader cross-reactive IgG antibodies and neutralizing activity against SARS-CoV-2. A low-dose of trivalent mRNA vaccines elicited broadly cross-reactive binding IgG antibodies and receptor-binding inhibition activity against various SARS-CoV-2 variants at higher levels than a high-dose monovalent mRNA vaccine. A combination of low-dose trivalent mRNA and spike proteins of multiple SARS-CoV-2 variants further increased the levels of cross-reactive IgG antibodies and neutralizing activity against SARS-CoV-2. Furthermore, coadministration of low doses of SARS-CoV-2 spike mRNA with inactivated split influenza vaccines significantly enhanced immunogenicity and efficacy against influenza.

The current influenza vaccine is based on immunity to hemagglutinin (HA) and provides poor cross-protection. Here, we generated mRNA vaccine encoding influenza B virus (IBV) neuraminidase (NA) conjugated to influenza A virus M2 ectodomain (M2e), encapsulated in lipid nanoparticles (LNP), capable of inducing cross-lineage IBV protection in a dose-dependent pattern. The combination of low-dose NA mRNA and inactivated split IBV vaccines was found to induce significantly higher levels of cross-reactive IgG responses, NA and HA inhibition titers, effector and memory cellular immune responses as well as cross-lineage protection than either NA mRNA or split vaccine alone. This study suggests that the NA mRNA vaccine not only provides cross-lineage protection with a high dose but also enhances the cross-protective efficacy of the combined low-dose NA mRNA and split vaccines. Our findings support a new strategy of using mRNA LNP-supplemented conventional vaccination to enhance cross-protection.IMPORTANCEThis study highlights a significant advancement in influenza vaccination strategies. To test a new vaccination strategy, we developed an influenza B virus (IBV) neuraminidase (NA) mRNA vaccine which could provide cross-lineage protection at a high dose. More importantly, the co-administration of NA mRNA and split IBV vaccine at low doses was found to significantly enhance the hemagglutinin and NA immunity as well as cross-lineage protection of seasonal IBV vaccines. This proof-of-concept study provides evidence for a novel strategy to enhance the immunogenicity and cross-protective efficacy of conventional vaccines by supplementing with new targets of mRNA vaccines.

Respiratory syncytial virus (RSV) causes high hospitalization and mortality in children and the elderly. RSV prefusion conformation-stabilized fusion (F) protein vaccines have been licensed for elderly and maternal vaccination. Nonetheless, a demand exists for an effective RSV vaccine in elderly and young children, avoiding vaccine-enhanced disease. We developed a new prefusion mRNA containing a prototype (DS-Cav1 pre-F) stabilizing and additional fusion domain mutations. The new pre-F mRNA vaccine, encapsulated in lipid nanoparticles (LNP), effectively induced neutralizing antibodies and a preferential Th1-type effector T cell response in mice. Remarkably, a combination of pre-F mRNA-LNP and pre-F protein elicited significantly higher titers of neutralizing antibodies against RSV A and B strains than either pre-F mRNA or protein vaccine alone. Pre-F mRNA and its combination with pre-F protein provided protection by clearing lung viral loads, preventing lung histopathology and inflammation, compared to the prototype pre-F protein. Combination pre-F mRNA and pre-F protein vaccination modulated balanced effector CD8 T cell responses after challenge. This study supports the idea that combining pre-F mRNA and pre-F protein vaccines would provide more effective humoral and balanced cellular immunity than either mRNA or protein vaccine alone.

Intramuscular injection of seasonal influenza vaccines provides strain-specific neutralizing antibodies, but not against variants, and no effective mucosal immunity. Here, we report that multi-subtype neuraminidase (NA) and M2 ectodomain repeat (5xM2e) virus-like particle vaccine (NA-M2e) conferred higher efficacy of broad cross-protection after two doses of intranasal delivery than intramuscular injection. The intranasally vaccinated mice displayed high levels of IgA antibodies, IFN-γ+ CD4 and CD8 T cells, germinal center B cells, plasma cells, and early innate immune cells locally in the lungs. In contrast, intramuscular vaccination systemically induced innate and adaptive immune responses in the spleen. Our findings demonstrate that the intranasal delivery of NA-M2e vaccine induces enhanced mucosal immunity and comparable serum IgG antibodies, offering improved efficacy of cross-protection against diverse influenza virus strains compared to the intramuscular injection in a mouse model.

Purpose:Orbital fibroblast (OF) activation plays an important role in thyroid-associated orbitopathy (TAO) development. Epac1, as a cyclic adenosine monophosphate (cAMP) effector, has been recognized as a pivotal mediator of the anti-fibrosis properties of cAMP. This study investigated the role and mechanisms of Epac1 in OF activation. Methods:Clinical orbital samples were collected from patients with TAO and normal healthy volunteers, and a TAO mouse model was established using adenovirus expressing the human TSHR A subunit (Ad-TSHR), which was evaluated for histopathological features and detected for Epac1 and vimentin expression levels. Clinical TAO samples- (TAO OFs) and healthy people-derived OFs (normal OFs) were isolated and identified using immunofluorescent (IF) staining. Healthy and TAO OFs were transfected with Epac1-overexpressing plasmid (Epac1) for Epac1 overexpression or sh-Epac1 plasmid for Epac1 knockdown, treated with TGFβ1, and then examined for cell phenotypes and the expression level of Epac1 and fibrosis-related markers (α-SMA, fibronectin, and collagens). Furthermore, adeno-associated virus (AAV) overexpressing Epac1 (AAV-Epac1) was injected into TAO mouse orbital tissues to investigate the anti-fibrotic effects of Epac1 on TGFβ1-stimulated OFs in vivo. Moreover, the phosphorylation of STAT3 in the TGFβ1-stimulated TAO OFs and TAO mice model was investigated. The JAK/STAT signaling inhibitor Stattic was used to explore the involvement of the JAK/STAT signaling in the functions of Epac1. Results:Both clinical TAO samples and the TAO mouse model demonstrated significantly changed histopathology, reduced Epac1 expression, and increased vimentin level. TGFβ1 stimulation significantly facilitated cell viability and migration of normal OFs and TAO OFs, and elevated α-SMA, fibronectin, vimentin, collagen I, and collagen III expression levels. However, Epac1 overexpression in OFs could notably attenuate these pro-fibrosis effects of TGFβ1 on both normal and TAO OFs, shown as inhibiting cell viability and migration and decreasing expression of fibrotic markers. Whereas, Epac1 knockdown aggravated TGFβ1-induced fibrosis. In vivo, Epac1 overexpression also improved TAO-like symptoms in TAO model mice. Mechanically, Epac1 overexpression inhibited STAT3 phosphorylation in vitro and in vivo. Stattic effectively attenuated the effects of Epac1 knockdown on TGFβ1-treated TAO OFs. Conclusions:Epac1 was a critical regulator of fibrotic and inflammatory processes in TAO through mediating the JAK/STAT signaling pathway.

Constructing micro-/nanostructure-modulated photofields in upconversion devices to absorb low-energy photons and emit high-energy light is revolutionary for bioimaging, lasers, and photovoltaics, with proven capability to boost upconversion luminescence (UCL) by orders of magnitude. However, photoenergy dissipation and inadequate absorption result in excitation thresholds exceeding 1 mW/cm2, which exceeds retinal safety limits and hinders wearable upconversion optics. Here, we report the use of upconversion core-shell microsphere-induced infrared field convergence, NaYF4:Yb,Er shell-based resonant cavities for multiple reflection-absorption-upconversion and photonic crystal amplifiers to improve UCL intensity three orders of magnitude, and achieve ultralow threshold (0.0025 mW/cm2). The 500 nm upconversion core-shell microspheres generated 1200-fold stronger electric field through concentrated photofield and attained 8-fold infrared absorption with a forward/backward emission ratio of 150. Fabricated upconversion contact lenses significantly improved dark-light imaging clarity and vision restoration in retinal degeneration rabbits. Microsphere-mediated directional upconversion strategy maximizes photoenergy utilization, paving the way for high-performance wearable upconversion devices.

Background:. The conjoint fascial sheath (CFS) has been widely utilized for blepharoptosis correction recently. However, the different effects of various surgical techniques and the intraoperative palpebral fissure height (PFH) under general anesthesia are unclear. Therefore, we compared and observed the effects of CFS suspension and levator muscle (LM)-CFS complex suspension under general anesthesia. Methods:. A retrospective analysis was performed on children with congenital moderate-to-severe blepharoptosis who underwent CFS suspension (group A) from January to December 2019 and LM-CFS complex suspension (group B) from January to December 2021. The main indices included the PFH, margin reflex distance 1 (MRD-1) value preoperatively and immediately, 1 day, 1 week, 1 month, and 6 months after surgery. Results:. Thirty-six patients in group A and 51 patients in group B were included in the final statistical analysis. There was no significant difference in the preoperative mean PFH and MRD-1 values between the 2 groups (P > 0.05). The mean PFH and MRD-1 values in group B were significantly higher than those in group A at 6 months after surgery (8.05 ± 0.90 mm versus 6.75 ± 1.50 mm, P < 0.001; 3.71 ± 0.72 mm versus 2.64 ± 1.63 mm, P = 0.001). The postoperative satisfaction rate of patients in group B was significantly higher than that in group A (92.16% versus 72.22%, P = 0.013). Conclusions:. Compared with CFS suspension, LM-CFS complex suspension for the treatment of moderate-to-severe blepharoptosis in children under general anesthesia had better results, with relatively more stable PFH.

Current influenza vaccines are not effective in conferring protection against antigenic variants and pandemics. To improve cross-protection of influenza vaccination, we developed a 5xM2e messenger RNA (mRNA) vaccine encoding the tandem repeat conserved ectodomain (M2e) of ion channel protein M2 derived from human, swine, and avian influenza A viruses. The lipid nanoparticle (LNP)-encapsulated 5xM2e mRNA vaccine was immunogenic, eliciting high levels of M2e-specific IgG antibodies, IFN-γ+ T cells, T follicular helper cells, germinal center phenotypic B cells, and plasma cells. The mice with 5xM2e mRNA vaccination were broadly protected against lethal infection regardless of hemagglutinin (H1, H3, H5) subtypes by preventing severe weight loss. Injection of 5xM2e mRNA LNP vaccine induced acute innate responses recruiting monocytes, macrophages, and diverse subsets of dendritic cells. A single dose of combined 5xM2e mRNA LNP and split vaccines resulted in significantly enhanced and sustainable IgG antibody responses to viral antigens and protection against homologous and heterologous viruses. This study provides a new strategy of combined mRNA and seasonal vaccination, significantly enhancing vaccine protective efficacy.

Subsequently to the publication of the above article, an interested reader drew to the authors' attention that, concerning the cell invasion assays shown in Fig. 5A on p. 1436, the 'WT' and 'pEF6' data panels contained apparently overlapping sections of data, such that these experiments were apparently derived from the same original source where the results of differently performed experiments were intended to have been portrayed. After re‑examining their original data, the authors have realized that the data panel in Fig. 5A for the 'pEF6' experiment was inadvertently selected incorrectly. The revised version of Fig. 5, showing all the correct data for Fig. 5A, is shown on the next page. The authors are grateful to the Editor of International Journal of Oncology for allowing them this opportunity to publish a Corrigendum, and all the authors agree with its publication. Furthermore, the authors apologize to the readership for any inconvenience caused. [International Journal of Oncology 47: 1429‑1439, 2015; DOI: 10.3892/ijo.2015.3121].

The middle turbinate axilla (MTA) is a crucial anatomical landmark for localizing the lacrimal sac (LS) during endonasal dacryocystorhinostomy (En-DCR). Despite being a standard surgical procedure, En-DCR may lead to severe complications, such as cerebrospinal fluid (CSF) leakage, which is closely associated with anatomical variations between the LS and the anterior skull base (ASB). This study aimed to investigate the anatomical location of the LS relative to the MTA and ASB in Chinese patients with nasolacrimal duct obstruction (NLDO) and analyze the influencing factors. This cross-sectional study enrolled 227 Chinese patients who were diagnosed with NLDO and underwent computed tomographic dacryocystography (CT-DCG). Anatomical distances between LS and MTA, as well as LS and ASB, were measured using CT-DCG images. The mean distances from the superior and inferior edges of the LS to the MTA were 9.94 ± 4.70 mm and − 0.23 ± 4.15 mm, respectively. Male patients showed significantly more superior–anterior displacement of the LS compared to female patients (P < 0.001), while patients with chronic dacryocystitis (CD) had an inferior and posterior LS position relative to those with simple NLDO (P = 0.005, P = 0.001). The mean distance from the intersection (Point P) of the superior and posterior boundaries of the LS to the ASB (MP) was 18.35 ± 4.48 mm, which was shorter in females and those with frontal sinus aplasia (P = 0.001; P < 0.001). A subgroup (28/227, 12.3

To evaluate the effect of the levator muscle-conjoint Fascial Sheath Complex Suspension on ocular biometric parameters and refractive status in children with congenital blepharoptosis. We reviewed the clinical records of 68 patients with congenital blepharoptosis who attended our hospital from 2021 to 2023 and underwent ptosis surgery with detailed examination. The changes of corneal topography and refractive characteristics before and 1 month, 3 months, 6 months after surgery were compared and analyzed. Before surgery, ptosis eyes had statistically significant flatter flat keratometry (P = 0.015), thicker subfoveal choroidal thickness (P = 0.021), higher astigmatic magnitude(P = 0.006) than non-blepharoptosis eyes. The 1-month postoperative steep keratometry and the astigmatic magnitude were significantly higher than the preoperative values in unilateral ptosis (P = 0.032, P = 0.014), without affecting astigmatic power vectors and central corneal thickness (P > 0.05); The astigmatic magnitude at 3 months after surgery were higher than the preoperative values in unilateral ptosis (P = 0.042). In all patients, the postoperative change of astigmatic magnitude was greatest in severe ptosis. Ptosis repair surgery for congenital ptosis seems to cause increase of steep K value and astigmatism over early postoperative period but no refraction alteration over the long-term postoperative period. A significant myopic shift was observed at the 6-month postoperative follow-up in severe unilateral ptosis.

It is a high priority to enhance the efficacy of seasonal influenza vaccines based on hemagglutinin (HA) strain-specific neutralizing immunity. Here, we investigated a vaccination strategy of supplementing inactivated split seasonal vaccines with a virus-like particle vaccine containing multi-subtype neuraminidase (NA) and M2 ectodomain (M2e) repeat (NA-M2e) in mice. NA-M2e and split combined vaccine (S + NA-M2e) stimulated a unique pattern of innate immune responses within a day after intramuscular injection of mice. The combined S + NA-M2e vaccination induced enhanced levels of IgG antibodies to viral antigens, hemagglutination inhibiting activities, and humoral and cellular immune responses to NA and M2e. The addition of NA-M2e to split vaccination provided higher efficacy of protection against homologous and heterologous viruses compared to split alone, where NA-M2e significantly contributed to enhancing protection under naïve and primed mouse models. This study supports a vaccination strategy to improve the efficacy of seasonal vaccines by providing additional immunity to NA and M2e.

Current influenza vaccine is not effective in providing cross-protection against variants. We evaluated the immunogenicity and efficacy of multi-subtype neuraminidase (NA) and M2 ectodomain virus-like particle (m-cNA-M2e VLP) and chimeric M2e-H3 stalk protein vaccines (M2e-H3 stalk) in ferrets. Our results showed that ferrets with recombinant m-cNA-M2e VLP or M2e-H3 stalk vaccination induced multi-vaccine antigen specific IgG antibodies (M2e, H3 stalk, NA), NA inhibition, antibody-secreting cells, and IFN-γ secreting cell responses. Ferrets immunized with either m-cNA-M2e VLP or M2e-H3 stalk vaccine were protected from H1N1 and H3N2 influenza viruses by lowering viral titers in nasal washes, trachea, and lungs after challenge. Vaccinated ferret antisera conferred broad humoral immunity in naïve mice. Our findings provide evidence that immunity to M2e and HA-stalk or M2e plus multi-subtype NA proteins induces cross-protection in ferrets.

The emergence of new SARS-CoV-2 variants continues to cause challenging problems for the effective control of COVID-19. In this study, we tested the hypothesis of whether a strategy of multivalent and sequential heterologous spike protein vaccinations would induce a broader range and higher levels of neutralizing antibodies against SARS-CoV-2 variants and more effective protection than homologous spike protein vaccination in a mouse model. We determined spike-specific IgG, receptor-binding inhibition titers, and protective efficacy in the groups of mice that were vaccinated with multivalent recombinant spike proteins (Wuhan, Delta, Omicron), sequentially with heterologous spike protein variants, or with homologous spike proteins. Trivalent (Wuhan + Delta + Omicron) and sequential heterologous spike protein vaccinations were more effective in inducing serum inhibition activities of receptor binding to spike variants and virus neutralizing antibody titers than homologous spike protein vaccination. The higher efficacy of protection was observed in mice with trivalent and sequential heterologous spike protein vaccination after a challenge with a mouse-adapted SARS-CoV-2 MA10 strain compared to homologous spike protein vaccination. This study provides evidence that a strategy of multivalent and sequential heterologous variant spike vaccination might provide more effective protection against emerging SARS-CoV-2 variants than homologous spike vaccination and significantly alleviate severe inflammation due to COVID-19.

Download This Paper Open PDF in Browser Add Paper to My Library Share: Permalink Using these links will ensure access to this page indefinitely Copy URL Preprints with The Lancet is part of SSRN´s First Look, a place where journals identify content of interest prior to publication. Authors have opted in at submission to The Lancet family of journals to post their preprints on Preprints with The Lancet. The usual SSRN checks and a Lancet-specific check for appropriateness and transparency have been applied. Preprints available here are not Lancet publications or necessarily under review with a Lancet journal. These preprints are early stage research papers that have not been peer-reviewed. The findings should not be used for clinical or public health decision making and should not be presented to a lay audience without highlighting that they are preliminary and have not been peer-reviewed. For more information on this collaboration, see the comments published in The Lancet about the trial period, and our decision to make this a permanent offering, or visit The Lancet´s FAQ page, and for any feedback please contact preprints@lancet.com. Targeting Glycine Receptor 3 for the Treatment of Chronic Pain in the Endometriosis 25 Pages Posted: 27 Feb 2024 See all articles by Peiya FanPeiya FanHuazhong University of Science and TechnologyRong LiuHuazhong University of Science and TechnologyYan LiHuazhong University of Science and TechnologyShixuan WangHuazhong University of Science and TechnologyTian LiHuazhong University of Science and Technology More... Abstract Background: Endometriosis often results in pain sensitization and neuropsychiatric symptoms. However, the molecular underpinnings are not fully understood, underscoring the need for novel therapeutic targets. Methods: In this study, we evaluated the impact of Glra3 gene knockout in mouse models of endometriosis. Our approach included Glra3 knockout mice with endometriosis (KO), wild-type endometriosis mice (EM), and wild-type sham-operated controls (Sham). We used behavioral assessments, MRI, western blotting, and immunofluorescence to investigate microglial, astrocytic, and neuronal activation. Findings: KO mice demonstrated reduced mechanical pain responses and neuropsychiatric symptoms compared to EM mice. MRI scans revealed less gray matter loss in KO mice, suggesting neuroprotection. Furthermore, KO mice exhibited decreased microglial (Iba1) and astrocytic (GFAP) activation. c-Fos activation, indicating pain sensitization, was mitigated in KO mice's prefrontal cortex but unchanged in the somatosensory cortex. Interpretation: Glra3 gene knockout appears to confer analgesic and neuroprotective effects in endometriosis, with potential implications for understanding and treating pain sensitization. Funding: National Natural Science Foundation of China (No.82071627).Declaration of Interest: The authors have no conflicts of interest to declare.Ethical Approval: This study was approved by the Animal Ethics Committee of Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology. Keywords: Endometriosis, Glra3, Pain, MRI, Microglia, Astrocytes Suggested Citation: Suggested Citation Fan, Peiya and Liu, Rong and Li, Yan and Wang, Shixuan and Li, Tian, Targeting Glycine Receptor 3 for the Treatment of Chronic Pain in the Endometriosis. Available at SSRN: https://ssrn.com/abstract=4738708 Peiya Fan Huazhong University of Science and Technology ( email ) Rong Liu Huazhong University of Science and Technology ( email ) Yan Li Huazhong University of Science and Technology ( email ) Shixuan Wang Huazhong University of Science and Technology ( email ) Tian Li (Contact Author) Huazhong University of Science and Technology ( email ) Download This Paper Open PDF in Browser Please enable JavaScript to view the comments powered by Disqus. 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Abstract Current influenza vaccine based on hemagglutinin (HA) immunity is not effective in providing cross protection against circulating variants and new pandemic viruses. In prior studies, we developed universal influenza vaccine candidates of multi-subtype neuraminidase and M2 ectodomain virus-like particles (m-cNA-M2e VLP) and chimeric M2e-H3 stalk protein vaccine (M2e-H3stalk), which were effective in inducing cross-protective immunity in mice. Here, we evaluated the immunogenicity and efficacy of these recombinant universal influenza vaccines in ferrets. Our results showed that immunization of ferrets with recombinant universal vaccines induced high levels of IgG antibody responses (M2e, H3stalk, multi-subtype NA), NA inhibition (NAI), antibody-secreting plasma cells in spleens, and IFN-γ secreting blood mononucleate cells. Ferrets with either m-cNA-M2e VLP or M2e-H3stalk vaccine were moderately protected from H1N1 and H3N2 influenza viruses as evidenced by lower viral titers in nasal washes, trachea and lung after challenge. Tests of passive immunity of vaccinated ferret antisera indicate that multi-NA plus M2e vaccine conferred more effective and broader humoral immunity in naïve mice than M2e-H3stalk vaccine. Our findings support that immunity to M2e, HA-stalk, and multi subtypes NA will induce broader cross protection in ferrets, which is likely translational to humans.

OBJECTIVE:High-risk human papillomavirus (HR-HPV) infection is the chief cause of cervical intraepithelial neoplasia (CIN) and cervical carcinoma. The Erhuang suppository (EHS) is a traditional Chinese medicine (TCM) prepared from realgar (As2S2), Coptidis rhizoma, alumen, and borneolum syntheticum and has been used for antiviral and antitumor purposes. However, whether EHS can efficiently alleviate HR-HPV infection remains unclear. This study was conducted to evaluate the efficacy of EHS for the treatment of persistent HR-HPV infection in the uterine cervix. METHODS:In this study, we evaluated the therapeutic efficacy of EHS in a randomized controlled clinical trial with a 3-month follow-up. Totally, 70 patients with persistent HR-HPV infection were randomly assigned to receive intravaginal administration of EHS or placebo. HPV DNA, ThinPrep cytologic test (TCT), colposcopy, and safety evaluation were carried out after treatment. Microarray analysis was performed to compare transcriptome profiles before and after EHS treatment. A K14-HPV16 mouse model was generated to confirm the efficiency of EHS. RESULTS:After 3 months, 74.3% (26/35) of the patients in the treatment group were HPV negative, compared to 6.9% (2/29) in the placebo group. High-throughput microarrays revealed distinct transcriptome profiles after treatment. The differentially expressed genes were significantly enriched in complement activation, immune response, and apoptotic processes. The K14-HPV16 mouse model also validated the remarkable efficacy of EHS. CONCLUSION:This study demonstrated that EHS is effective against HR-HPV infection and cervical lesions. Additionally, no obvious systemic toxicity was observed in patients during the trial. The superior efficacy and safety of EHS demonstrated its considerable value as a potential cost-effective drug for the treatment of HPV infection and HPV-related cervical diseases.