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Vaccine Apr 2024Chinese Hamster Ovary (CHO) cells, employed primarily for manufacturing monoclonal antibodies and other recombinant protein (r-protein) therapeutics, are emerging as a... (Review)
Review
Chinese Hamster Ovary (CHO) cells, employed primarily for manufacturing monoclonal antibodies and other recombinant protein (r-protein) therapeutics, are emerging as a promising host for vaccine antigen production. This is exemplified by the recently approved CHO cell-derived subunit vaccines (SUV) against respiratory syncytial virus (RSV) and varicella-zoster virus (VZV), as well as the enveloped virus-like particle (eVLP) vaccine against hepatitis B virus (HBV). Here, we summarize the design, production, and immunogenicity features of these vaccine and review the most recent progress of other CHO-derived vaccines in pre-clinical and clinical development. We also discuss the challenges associated with vaccine production in CHO cells, with a focus on ensuring viral clearance for eVLP products.
Topics: Cricetinae; Animals; Humans; CHO Cells; Cricetulus; Respiratory Syncytial Virus Infections; Antibodies, Neutralizing; Antibodies, Viral; Respiratory Syncytial Virus, Human; Vaccines, Virus-Like Particle; Herpesvirus 3, Human; Vaccines, Subunit; Respiratory Syncytial Virus Vaccines
PubMed: 38503664
DOI: 10.1016/j.vaccine.2024.03.034 -
Journal of Experimental & Clinical... Oct 2023Oncolytic viruses are now well recognized as potential immunotherapeutic agents against cancer. However, the first FDA-approved oncolytic herpes simplex virus 1 (HSV-1),...
BACKGROUND
Oncolytic viruses are now well recognized as potential immunotherapeutic agents against cancer. However, the first FDA-approved oncolytic herpes simplex virus 1 (HSV-1), T-VEC, showed limited benefits in some patients in clinical trials. Thus, the identification of novel oncolytic viruses that can strengthen oncolytic virus therapy is warranted. Here, we identified a live-attenuated swine pseudorabies virus (PRV-LAV) as a promising oncolytic agent with broad-spectrum antitumor activity in vitro and in vivo.
METHODS
PRV cytotoxicity against tumor cells and normal cells was tested in vitro using a CCK8 cell viability assay. A cell kinase inhibitor library was used to screen for key targets that affect the proliferation of PRV-LAV. The potential therapeutic efficacy of PRV-LAV was tested against syngeneic tumors in immunocompetent mice, and against subcutaneous xenografts of human cancer cell lines in nude mice. Cytometry by time of flight (CyTOF) and flow cytometry were used to uncover the immunological mechanism of PRV-LAV treatment in regulating the tumor immune microenvironment.
RESULTS
Through various tumor-specific analyses, we show that PRV-LAV infects cancer cells via the NRP1/EGFR signaling pathway, which is commonly overexpressed in cancer. Further, we show that PRV-LAV kills cancer cells by inducing endoplasmic reticulum (ER) stress. Moreover, PRV-LAV is responsible for reprogramming the tumor microenvironment from immunologically naïve ("cold") to inflamed ("hot"), thereby increasing immune cell infiltration and restoring CD8 T cell function against cancer. When delivered in combination with immune checkpoint inhibitors (ICIs), the anti-tumor response is augmented, suggestive of synergistic activity.
CONCLUSIONS
PRV-LAV can infect cancer cells via NRP1/EGFR signaling and induce cancer cells apoptosis via ER stress. PRV-LAV treatment also restores CD8 T cell function against cancer. The combination of PRV-LAV and immune checkpoint inhibitors has a significant synergistic effect. Overall, these findings point to PRV-LAV as a serious potential candidate for the treatment of NRP1/EGFR pathway-associated tumors.
Topics: Humans; Animals; Swine; Mice; Herpesvirus 1, Suid; Vaccines, Attenuated; Mice, Nude; Immune Checkpoint Inhibitors; Oncolytic Virotherapy; Oncolytic Viruses; Neoplasms; ErbB Receptors; Tumor Microenvironment
PubMed: 37891570
DOI: 10.1186/s13046-023-02848-1 -
American Journal of Obstetrics and... Aug 2023
Topics: Female; Humans; Herpes Zoster; Herpesvirus 3, Human; Vulva
PubMed: 36828295
DOI: 10.1016/j.ajog.2023.02.013 -
Skin Therapy Letter Jul 2023The lifetime risk for herpes zoster (HZ) of approximately 1 in 3 is increased with advancing age, a family history of HZ, diseases with altered immune function,...
The lifetime risk for herpes zoster (HZ) of approximately 1 in 3 is increased with advancing age, a family history of HZ, diseases with altered immune function, immunosuppression, physical trauma and psychological stress. In dermatology, monotherapy with current biologics does not increase risk, however systemic steroids, Janus kinase inhibitors and combination biologic/conventional disease-modifying antirheumatics do. The recombinant zoster vaccine (RZV, Shingrix®), an adjuvanted non-live subunit vaccine against the glycoprotein E subunit of varicella zoster virus, is approved for prevention of HZ in adults ≥50 years of age, and adults ≥18 years of age who are or will be at increased risk of HZ due to immunodeficiency or immunosuppression due to disease or treatment. It is administered as two 0.5 ml intramuscular injections 2-6 months apart. In immunocompromised individuals, the spacing between injections may be reduced to 1-2 months. Where possible, the first dose should be administered at least 14 days before onset of immunosuppressive treatment. Studies in immunocompetent individuals have shown high efficacy including prevention of HZ, postherpetic neuralgia and other complications, with persistence of effect 10 years after vaccination. The acceptable safety profile and efficacy in five different immunocompromised populations support its use in at-risk adult dermatologic patients.
Topics: Adult; Humans; Dermatology; Herpes Zoster; Herpes Zoster Vaccine; Neuralgia, Postherpetic; Herpesvirus 3, Human
PubMed: 37440693
DOI: No ID Found -
Human Vaccines & Immunotherapeutics Dec 2023Herpes zoster (HZ) results from waning immunity following childhood infection with varicella zoster virus (VZV) but is preventable by vaccination with recombinant HZ...
Herpes zoster (HZ) results from waning immunity following childhood infection with varicella zoster virus (VZV) but is preventable by vaccination with recombinant HZ vaccine or live HZ vaccine (two doses or one dose, respectively). Vaccine efficacy declines with age, live HZ vaccine is contraindicated in immunosuppressed individuals, and severe local reactogenicity of recombinant HZ vaccine is seen in up to 20% of older adults, indicating a potential need for new vaccines. Nonreplicating chimpanzee adenovirus (ChAd) vectors combine potent immunogenicity with well-established reactogenicity and safety profiles. We evaluated the cellular and humoral immunogenicity of ChAdOx1 encoding VZV envelope glycoprotein E (ChAdOx1-VZVgE) in mice using IFN-γ ELISpot, flow cytometry with intracellular cytokine staining, and ELISA. In outbred CD-1 mice, one dose of ChAdOx1-VZVgE (1 × 10 infectious units) elicited higher gE-specific T cell responses than two doses of recombinant HZ vaccine (1 µg) or one dose of live HZ vaccine (1.3 × 10 plaque-forming units). Antibody responses were higher with two doses of recombinant HZ vaccine than with two doses of ChAdOx1-VZVgE or one dose of live HZ vaccine. ChAdOx1-VZVgE boosted T cell and antibody responses following live HZ vaccine priming. The frequencies of polyfunctional CD4+ and CD8+ T cells expressing more than one cytokine (IFN-γ, TNF-α and IL-2) were higher with ChAdOx1-VZVgE than with the conventional vaccines. Results were similar in young and aged BALB/c mice. These findings support the clinical development of ChAdOx1-VZVgE for prevention of HZ in adults aged 50 years or over, including those who have already received conventional vaccines.
Topics: Animals; Mice; Herpesvirus 3, Human; Adenovirus Vaccines; Adenoviridae; Antibodies, Viral; Herpes Zoster; Herpes Zoster Vaccine; Vaccination; Cytokines; Immunogenicity, Vaccine
PubMed: 36785938
DOI: 10.1080/21645515.2023.2175558 -
Human Vaccines & Immunotherapeutics Dec 2023The growing burden of herpes zoster (HZ) in Hong Kong, due to an aging population with increasing life expectancy, may be reduced by vaccination. This study aimed to...
The growing burden of herpes zoster (HZ) in Hong Kong, due to an aging population with increasing life expectancy, may be reduced by vaccination. This study aimed to estimate public health impact of HZ vaccination in Hong Kong. The ZOster ecoNomic Analysis (ZONA) model was adapted with Hong Kong-specific key model inputs/assumptions, where available. Base case analysis involved adults ≥50 years of age (YOA), exploring three vaccination strategies (no vaccination/recombinant zoster vaccine [RZV]/zoster vaccine live [ZVL]) under private market (5% coverage) and mass vaccination (40% coverage) settings. Scenario and sensitivity analyses were performed. In the base case population (3.13 million), without vaccination, 891,024 HZ (28.4%), 156,097 post-herpetic neuralgia (PHN) (5.0%), and 38,755 (1.2%) HZ ophthalmicus (HZO) were projected over their remaining lifetime. Mass RZV vaccination reduced HZ, PHN, and HZO cases by 204,875 (-23.0%), 31,949 (-20.5%), and 8,471 (-21.9%), respectively, which was 4-5 times that reduced with ZVL. RZV was more efficient than ZVL, with lower number needed to vaccinate to prevent one HZ/PHN/HZO case (RZV: 7/40/148; ZVL: 27/163/709). Among all age cohorts, the greatest reduction in cases was projected for RZV (versus no vaccination/ZVL) in the youngest cohort, 50-59 YOA. Results were robust under scenario and sensitivity analyses. HZ burden in Hong Kong is substantial. Mass RZV vaccination is expected to considerably reduce public health burden of HZ among individuals ≥50 YOA, compared with no vaccination/ZVL. Results may support value assessment and decision-making regarding vaccination strategies for HZ prevention in Hong Kong.
Topics: Humans; Aged; Herpes Zoster Vaccine; Public Health; Hong Kong; Cost-Benefit Analysis; Herpes Zoster; Neuralgia, Postherpetic; Vaccination; Herpesvirus 3, Human; Vaccines, Synthetic
PubMed: 36854447
DOI: 10.1080/21645515.2023.2176065 -
European Journal of Medical Research Oct 2023Infection rate of varicella zoster virus (VZV) is 95% in humans, and VZV infection is strongly associated with ischemic stroke (IS). However, the underlying molecular...
BACKGROUND
Infection rate of varicella zoster virus (VZV) is 95% in humans, and VZV infection is strongly associated with ischemic stroke (IS). However, the underlying molecular mechanisms of VZV-induced IS are still unclear, and there are no effective agents to treat and prevent VZV-induced IS.
OBJECTIVE
By integrating bioinformatics, this study explored the interactions between VZV and IS and potential medication to treat and prevent VZV-induced IS.
METHODS
In this study, the VZV and IS datasets from the GEO database were used to specify the common genes. Then, bioinformatics analysis including Gene Ontology, Kyoto Encyclopedia Genes Genomes and Protein-Protein Interaction network analysis was performed. Further, the hub genes, transcription factor (TF) gene interactions, TF-miRNA co-regulatory network and potential drug were obtained. Finally, validation was performed using molecular docking and molecular dynamics simulations.
RESULTS
The potential molecular mechanisms of VZV-induced IS were studied using multiple bioinformatics tools. Ten hub genes were COL1A2, DCN, PDGFRB, ACTA2, etc. TF genes and miRNAs included JUN, FOS, CREB, BRCA1, PPARG, STAT3, miR-29, etc. A series of mechanism may be involved, such as inflammation, oxidative stress, blood-brain barrier disruption, foam cell generation and among others. Finally, we proposed resveratrol as a potential therapeutic medicine for the prevention and treatment of VZV-induced IS. Molecular docking and molecular dynamics results showed that resveratrol and hub genes exhibited strong binding score.
CONCLUSIONS
Resveratrol could be an alternative for the prevention and treatment of VZV-IS. More in vivo and in vitro studies are needed in the future to fully explore the molecular mechanisms between VZV and IS and for medication development.
Topics: Humans; Herpesvirus 3, Human; Herpes Zoster; Resveratrol; Ischemic Stroke; Molecular Docking Simulation; MicroRNAs
PubMed: 37794518
DOI: 10.1186/s40001-023-01291-4 -
Cleveland Clinic Journal of Medicine Oct 2023
Topics: Humans; Chickenpox; Herpesvirus 3, Human; Herpes Zoster; Vaccines
PubMed: 37783498
DOI: 10.3949/ccjm.90a.23008 -
Journal of Virology Jul 2023Pseudorabies virus (PRV), the causative pathogen of Aujeszky's disease, is one of the most important pathogens threatening the global pig industry. Although vaccination...
Pseudorabies virus (PRV), the causative pathogen of Aujeszky's disease, is one of the most important pathogens threatening the global pig industry. Although vaccination has been used to prevent PRV infection, the virus cannot be eliminated in pigs. Thus, novel antiviral agents as complementary to vaccination are urgently needed. Cathelicidins (CATHs) are host defense peptides that play an important role in the host immune response against microbial infections. In the study, we found that the chemical synthesized chicken cathelicidin B1 (CATH-B1) could inhibit PRV regardless of whether CATH-B1 was added pre-, co-, or post-PRV infection and . Furthermore, coincubation of CATH-B1 with PRV directly inactivated virus infection by disrupting the virion structure of PRV and mainly inhibited virus binding and entry. Importantly, pretreatment of CATH-B1 markedly strengthened the host antiviral immunity, as indicated by the increased expression of basal interferon-β (IFN-β) and several IFN-stimulated genes (ISGs). Subsequently, we investigated the signaling pathway responsible for CATH-B1-induced IFN-β production. Our results showed that CATH-B1 induced phosphorylation of interferon regulatory transcription factor 3 (IRF3) and further led to production of IFN-β and reduction of PRV infection. Mechanistic studies revealed that the activation of Toll-like receptor 4 (TLR4), endosome acidification, and the following c-Jun N-terminal kinase (JNK) was responsible for CATH-B1-induced IRF3/IFN-β pathway activation. Collectively, CATH-B1 could markedly inhibit PRV infection via inhibiting virus binding and entry, direct inactivation, and regulating host antiviral response, which provided an important theoretical basis for the development of antimicrobial peptide drugs against PRV infection. Although the antiviral activity of cathelicidins could be explained by direct interfering with the viral infection and regulating host antiviral response, the specific mechanism of cathelicidins regulating host antiviral response and interfering with pseudorabies virus (PRV) infection remains elusive. In this study, we investigated the multiple roles of cathelicidin CATH-B1 against PRV infection. Our study showed that CATH-B1 could suppress the binding and entry stages of PRV infection and direct disrupt PRV virions. Remarkably, CATH-B1 significantly increased basal interferon-β (IFN-β) and IFN-stimulated gene (ISG) expression levels. Furthermore, TLR4/c-Jun N-terminal kinase (JNK) signaling was activated and involved in IRF3/IFN-β activation in response to CATH-B1. In conclusion, we elucidate the mechanisms by which the cathelicidin peptide direct inactivates PRV infection and regulates host antiviral IFN-β signaling.
Topics: Swine; Animals; Herpesvirus 1, Suid; Cathelicidins; Toll-Like Receptor 4; Interferon-beta; Antiviral Agents; Pseudorabies
PubMed: 37314341
DOI: 10.1128/jvi.00706-23 -
Human Vaccines & Immunotherapeutics Dec 2024Few papers focus their attention on VZV vaccination effectiveness among people living with HIV (PLWH). Flanking the live attenuated vaccine (VZL) available, a newly... (Review)
Review
Few papers focus their attention on VZV vaccination effectiveness among people living with HIV (PLWH). Flanking the live attenuated vaccine (VZL) available, a newly recombinant vaccine (RZV) was recently introduced and approved for HZ prevention among adults. PLWH represents a population on which a particular attention should be applied, in order to guarantee the vaccine efficacy and safety. We performed a literature search in USNLM, PubMed, PubMed Central, PMC and Cochrane Library. From all the publications found eligible, data were extracted and processed per population, vaccine type, immunogenicity and ADRs. The review of the 13 included studies shows that both RZV and VZL are immunogenic and have an acceptable safety profile in adults and children living with HIV. However, given the lack of research available about vaccine efficacy in preventing VZV and HZ in PLWH, additional studies need to be performed, in order to achieve a full completeness of data.
Topics: Humans; Vaccines, Attenuated; HIV Infections; Herpes Zoster Vaccine; Vaccines, Synthetic; Herpes Zoster; Vaccines, Inactivated; Immunogenicity, Vaccine; Vaccine Efficacy; Herpesvirus 3, Human; Adult; Child; Vaccination; Chickenpox Vaccine
PubMed: 38650460
DOI: 10.1080/21645515.2024.2341456