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Background：Mounting evidence has demonstrated that hypoxia-inducible factor-1α （HIF-1α） could attenuate brain injuries after cerebral ischemia and reperfusion （CIR）.However,few reports have addressed the therapeutic efficacies of a recombinant adenovirus vector containing HIF-1o （AdHIF-1o） gene after ischemia and reperfusion.The aim of this study was to examine the antiapoptotic and neuroprotective effects ofAdHIF-1o gene for cerebral injuries after ischemia and reperfusion in rats.Methods：From February to December 2016,male Sprague-Dawley rats were randomly divided into normal,sham,CIR,AdHIF-1α,and recombinant adenovirus （Ad） groups.Middle cerebral artery occlusion model was established by Longa＇s method and reperfusion resumed at 2 h postocclusion.AdHIF-1α solution,Ad solution,and phosphate-buffered saline were injected into the right lateral ventricle of rats in AdHIF-lα,Ad,and CIR groups.Brain tissue sections were observed under fluorescent microscope to confirm the definite expression of recombinant adenovirus in Ad and AdHIF-1o groups.The expressions of HIF-lα protein were analyzed by immunohistochemical staining at 6 h,24 h,and 72 h postreperfusion.Brain water content and neurological deficit scores were evaluated at 6 h,24 h,and 72 h postreperfusion.Pathological brain injuries were examined after hematoxylin and eosin stain and nerve cell apoptosis was measured after terminal-deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling （TUNEL） stain at 72 h postreperfusion.Comparisons were conducted with one-way analysis of variance by post hoc Scheffe＇s test among different experimental groups.Results：Green fluorescent protein was successfully expressed in brain tissue ofAd andAdHIF-1α groups from 24 h to 21 days postinjection.As detected by immunohistochemical staining,the expressions of HIF-lα protein were obviously enhanced in AdHIF-1o group than those in CIR and Ad groups at 24 h and 72 h postreperfusion,respectively.There were significant reductions of brain water content （78.83% ± 0.34% vs.83.21% ± 0.50% and 83.35% ± 0.32%;84.13% ± 0.24% vs.89.76% ± 0.34% and 89.70% ± 0.18%;respectively;all P 〈 0.05） and neurological deficit scores （2.90 ± 0.74 vs.3.50 ± 0.52 and 3.60 ± 0.53 at 24 h;2.40 ± 0.84 vs.3.60 ± 0.52 and 3.50 ± 0.53 at 72 h;respectively;all P 〈 0.05） in AdHIF-1 α group versus CIR and Ad groups at 24 h and 72 h postreperfusion,respectively.The pathologic changes ofAdHIF-1 α group were milder than those in CIR and Ad groups at 72 h postreperfusion.The percentage of TUNEL-positive cells in cerebral subcortex decreased significantly in AdHIF-1α group versus CIR and Ad groups at 72 h postreperfusion （P 〈 0.05）.Conclusion：AdHIF-1α has an obvious neuroprotective effect on ischemia and reperfusion in rat brains possibly through inhibiting the apoptosis of nerve cells.

COVID-19 vaccines are being developed urgently worldwide. Here, we constructed two adenovirus vectored COVID-19 vaccine candidates of Sad23L-nCoV-S and Ad49L-nCoV-S carrying the full-length gene of SARS-CoV-2 spike protein. The immunogenicity of two vaccines was individually evaluated in mice. Specific immune responses were observed by priming in a dose-dependent manner, and stronger responses were obtained by boosting. Furthermore, five rhesus macaques were primed with 5 × 10 9 PFU Sad23L-nCoV-S, followed by boosting with 5 × 10 9 PFU Ad49L-nCoV-S at 4-week interval. Both mice and macaques well tolerated the vaccine inoculations without detectable clinical or pathologic changes. In macaques, prime-boost regimen induced high titers of 10 3.16 anti-S, 10 2.75 anti-RBD binding antibody and 10 2.38 pseudovirus neutralizing antibody (pNAb) at 2 months, while pNAb decreased gradually to 10 1.45 at 7 months post-priming. Robust T-cell response of IFN-γ (712.6 SFCs/10 6 cells), IL-2 (334 SFCs/10 6 cells) and intracellular IFN-γ in CD4 + /CD8 + T cell (0.39%/0.55%) to S peptides were detected in vaccinated macaques. It was concluded that prime-boost immunization with Sad23L-nCoV-S and Ad49L-nCoV-S can safely elicit strong immunity in animals in preparation of clinical phase 1/2 trials.

Adenovirus (Ad) vectors are a promising next-generation vaccine modality currently under development. An Ad particle is composed of three major capsid proteins—fiber, penton base, and hexon—that play critical roles in cellular entry. However, the extents to which the receptor-mediated cellular entry pathways influence the efficacy of Ad vector-based vaccines are not well understood. In this study, we examined the effects of the cellular uptake pathway on the vaccine efficacy of Ad vectors by using the β-galactosidase (β-gal)-expressing, capsid-modified Ad vectors that utilize the different cellular entry routes. Following intramuscular vaccination, all capsid-modified Ad vectors induced serum anti-β-gal antibody levels comparable to those induced by the conventional Ad vector. In contrast, after intranasal vaccination, the Ad vectors with mutations in the penton base or hexon elicited anti-β-gal antibody titers in the serum, bronchoalveolar lavage fluid (BALF), and nasal wash at levels comparable with the conventional Ad vector. On the other hand, the coxsackievirus-adenovirus receptor (CAR)-binding-ablated Ad vector exhibited a significant reduction in the anti-β-gal IgG titers in the serum and BALF, and anti-β-gal IgA titers in the BALF and nasal wash. These findings highlight that CAR-mediated transduction is crucial for efficient vaccination with an Ad vector after intranasal administration.

ABSTRACT Human adenoviruses (Ad) are increasingly used as vaccine vectors, especially after Ad5, Ad26, and ChAdY25 (ChAdOx1) were employed as vectors for SARS-CoV-2 vaccines. So far, more than 116 adenovirus genotypes have been identified, divided into 7 species (A-G). Most adenoviruses do not cause diseases or are mildly pathogenic, with only species B and E leading to acute respiratory infections or conjunctival inflammation and species F causing gastrointestinal infections. Previous studies have shown that the seroprevalence of neutralizing antibodies against adenoviruses can be limiting when applying adenoviral vectors. On the other hand, for highly pathogenic adenoviruses, neutralizing antibodies is beneficial for preventing the diseases caused by these adenoviruses. Here, we summarized the studies on the seroprevalence of adenoviruses, especially adenoviruses that may be utilized as vectors for vaccine and gene therapy. We also analysed possible factors associated with the seroprevalence and neutralizing titres. Given the trend of increasing adenoviral vector application, it is necessary to continue the investigation of the seroprevalence of neutralizing antibodies against adenoviruses in different geographic locations and populations.

Background Successful mass vaccination programmes are public health achievements of the contemporary world. While pharmaceutical companies are actively developing new vaccines, and demonstrating results of effectiveness and safety profiles, concerns on COVID-19 vaccine management are under-reported. We aimed to synthesise the evidence for efficient cold chain management of COVID vaccines. Methods The scoping review’s conduct and reporting were based on the PRISMA–ScR 2018 checklist. We searched from April 2020 to January 2022 for publications in PubMed (LitCovid), Scopus and ScienceDirect. All review stages were pilot-tested to calibrate 2 reviewers. Articles on cold chain logistics and management were included, while publications solely describing COVID vaccines, their development and clinical aspects of the vaccine, were excluded. To capture relevant data, charting was conducted by one reviewer and verified by another. Results were analysed thematically and summarised descriptively in a table and in-text. Results and discussion We assessed 6984 potentially relevant citations. We included 14 publications originating from USA ( n  = 6), India ( n  = 2), Finland, Spain, Bangladesh, Netherlands, Switzerland and Ethiopia. They were reported as reviews (4), policy or guidance documents (3), experimental studies (2), case reports (2), expert commentary (1), phenomenological study (1), and decision-making trial and evaluation laboratory trial (1). The findings were presented in three themes: (i) regulatory requirements for cold-chain logistics, (ii) packaging and storage, and (iii) transportation and distribution. A conceptual framework emerged linking regulatory requirements, optimal logistics operation and formulation stability as the key to efficient cold chain management. Recommendations were made for improving formulation stability, end-product storage conditions, and incorporating monitoring technologies. Conclusion COVID-19 vaccines require special end-to-end supply cold chain requirements, from manufacture, and transportation to warehouses and healthcare facilities. To sustain production, minimise wastage, and for vaccines to reach target populations, an efficient and resilient vaccine supply chain which is assisted by temperature monitoring technologies is imperative.

Efficient production of adenovirus vectors is crucial for their clinical use. Adenovirus death protein (ADP), which is encoded in the E3 region of the adenovirus genome, is involved in host-cell lysis and the subsequent release of progeny virus; however, the ADP gene is often removed from the adenovirus vector genome. We have developed adenovirus vectors that possess the ADP gene and maintain a relatively large insertion capacity for foreign genes by deleting the partial E3 region. Adenovirus vector-mediated transgene expression levels and virus titers were examined. The adenovirus vectors maintaining the ADP gene showed cytopathic effect earlier than conventional adenovirus vector without the ADP gene following treatment of HEK293 cells, although there were no significant differences in total virus titers. The adenovirus vectors possessing the ADP gene showed efficient spread of progeny virus infection following transduction in HEK293 cells.

Cancer is a major health problem. Most of the treatments exhibit systemic toxicity, as they are not targeted or specific to cancerous cells and tumors. Adenoviruses are very promising gene delivery vectors and have immense potential to deliver targeted therapy. Here, we review a wide range of strategies that have been tried, tested, and demonstrated to enhance the specificity of oncolytic viruses towards specific cancer cells. A combination of these strategies and other conventional therapies may be more effective than any of those strategies alone.

Gene therapy with viral vectors has significantly advanced in the past few decades, with adenovirus being one of the most commonly employed vectors for cancer gene therapy. Adenovirus vectors can be divided into 2 groups: (1) replication-deficient viruses; and (2) replication-competent, oncolytic (OVs) viruses. Replication-deficient adenoviruses have been explored as vaccine carriers and gene therapy vectors. Oncolytic adenoviruses are designed to selectively target, replicate, and directly destroy cancer cells. Additionally, virus-mediated cell lysis releases tumor antigens and induces local inflammation (e.g., immunogenic cell death), which contributes significantly to the reversal of local immune suppression and development of antitumor immune responses (“cold” tumor into “hot” tumor). There is a growing body of evidence suggesting that the host immune response may provide a critical boost for the efficacy of oncolytic virotherapy. Additionally, genetic engineering of oncolytic viruses allows local expression of immune therapeutics, thereby reducing related toxicities. Therefore, the combination of oncolytic virus and immunotherapy is an attractive therapeutic strategy for cancer treatment. In this review, we focus on adenovirus-based vectors and discuss recent progress in combination therapy of adenoviruses with immunotherapy in preclinical and clinical studies.

The activation of a neuronal ensemble in the central nucleus of the amygdala (CeA) during alcohol withdrawal has been hypothesized to induce high levels of alcohol drinking in dependent rats. In the present study we describe that the CeA neuronal ensemble that is activated by withdrawal from chronic alcohol exposure contains ~80% corticotropin-releasing factor (CRF) neurons and that the optogenetic inactivation of these CeA CRF+ neurons prevents recruitment of the neuronal ensemble, decreases the escalation of alcohol drinking, and decreases the intensity of somatic signs of withdrawal. Optogenetic dissection of the downstream neuronal pathways demonstrates that the reversal of addiction-like behaviors is observed after the inhibition of CeA CRF projections to the bed nucleus of the stria terminalis (BNST) and that inhibition of the CRF CeA-BNST pathway is mediated by inhibition of the CRF-CRF 1 system and inhibition of BNST cell firing. These results suggest that the CRF CeA-BNST pathway could be targeted for the treatment of excessive drinking in alcohol use disorder. Withdrawal from alcohol activates neurons in the central amygdala (CeA) and increases craving for alcohol. The authors show that these neurons predominantly express CRF and project to the BNST. Inactivation of this pathway reduces the dependence-related escalation of alcohol drinking.

Automated in ovo vaccination is an efficient method for mass immunization of poultry. Although in ovo vaccination has been used to mass immunize chickens against several infectious diseases, there are common poultry diseases for which in ovo-compatible vaccines are not commercially available. It was recently demonstrated that in ovo administration of a nonreplicating human adenovirus vector encoding an avian influenza virus hemagglutinin induced protective immunity against highly pathogenic avian influenza. The advantages of this new class of poultry vaccine include in ovo delivery of a wide variety of pathogen-derived antigens, high potency in a single-dose regimen, rapid production in response to increased demand, no replication of the vector, no pre-existing immunity to human adenovirus in chickens, compatibility with automated in ovo administration and no interference with epidemiological surveys of natural infections.