Immunization and Drug Metabolizing Enzymes: Focus on Hepatic Cytochrome P450 3A

Jonsson-Schmunk, Kristina; Ghose, Romi; Croyle, Maria A.

doi:10.1080/14760584.2021.1899818

Cited by 6 publications

(5 citation statements)

References 97 publications

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“…Two other genes, namely CPM and CYP3A5 were down-regulated after ZOSAL vaccination but, in contrast, were increased upon Shingrix vaccination. The exact physiological outcomes of changes in CYP3A5 expression by two different vaccines remain unknown, but it was likely to be associated with drug metabolization and the resulting toxicity since CYP3A5 -encoded liver enzyme is critical to metabolize and detoxify xenobiotics [ 34 , 35 ]. Genes that were altered in their expression by the two vaccines were further identified, amongst which a large number of genes ( ccl8, ifnb1, serping 1 , etc) related to interferon (IFN) response, complement pathway, and chemotaxis were up-regulated and commonly shared by the two groups ( Figure 3 e).…”

Section: Resultsmentioning

confidence: 99%

Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques

Huang,

Zhao,

Zhao

et al. 2024

Emerging Microbes & Infections

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Herpes zoster remains an important global health issue and mainly occurs in aged and immunocompromised individuals with an early exposure history to Varicella Zoster Virus (VZV). Although the licensed vaccine Shingrix has remarkably high efficacy, undesired reactogenicity and increasing global demand causing vaccine shortage urged the development of improved or novel VZV vaccines. In this study, we developed a novel VZV mRNA vaccine candidate (named as ZOSAL) containing sequence-optimized mRNAs encoding full-length glycoprotein E encapsulated in an ionizable lipid nanoparticle. In mice and rhesus macaques, ZOSAL demonstrated superior immunogenicity and safety in multiple aspects over Shingrix, especially in the induction of strong T-cell immunity. Transcriptomic analysis revealed that both ZOSAL and Shingrix could robustly activate innate immune compartments, especially Type-I IFN signalling and antigen processing/presentation. Multivariate correlation analysis further identified several early factors of innate compartments that can predict the magnitude of T-cell responses, which further increased our understanding of the mode of action of two different VZV vaccine modalities. Collectively, our data demonstrated the superiority of VZV mRNA vaccine over licensed subunit vaccine. The mRNA platform therefore holds prospects for further investigations in next-generation VZV vaccine development.

show abstract

Section: Resultsmentioning

confidence: 99%

Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques

Huang,

Zhao,

Zhao

et al. 2024

Emerging Microbes & Infections

View full text Add to dashboard Cite

show abstract

“…Two other genes, namely CPM and CYP3A5 were down-regulated after ZOSAL vaccination but in contrast were increased upon Shingrix vaccination. The exact physiological outcomes of changes in CYP3A5 expression by two different vaccines remains unknow, but it was likely to be associated with drug metabolization and the resulting toxicity since CYP3A5 -encoded liver enzyme is critical to metabolize and detoxify xenobiotics [34,35]. Genes that were altered in their expression by the two vaccines were further identified, amongst which a large number of genes ( ccl8, ifnb1, serping 1 , etc) related to interferon (IFN) response, complement pathway and chemotaxis were up-regulated and commonly shared by the two groups ( Figure 3e ).…”

Section: Resultsmentioning

confidence: 99%

Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques

Huang,

Zhao,

Zhao

et al. 2023

Preprint

View full text Add to dashboard Cite

Herpes zoster remains an important global health issue and mainly occurs in aged and immunocompromised individuals with an early exposure history to Varicella Zoster Virus (VZV). Although the licensed vaccine Shingrix has a remarkably high efficacy, undesired reactogenicity and increasing global demand causing vaccine shortage urged the development of improved or novel VZV vaccines. In this study, we developed a novel VZV mRNA vaccine candidate (named as ZOSAL) containing sequence-optimized mRNAs encoding full-length glycoprotein E encapsulated in an ionizable lipid nanoparticle. In mice and rhesus macaques, ZOSAL demonstrated superior immunogenicity and safety in multiple aspects over Shingrix, especially in the induction of strong T cell immunity. Transcriptomic analysis revealed that both ZOSAL and Shingrix could robustly activate innate immune compartments, especially Type-I IFN signaling and antigen processing/presentation. Multivariate correlation analysis further identified several early factors of innate compartments that can predict the magnitude of T cell responses, which further increased our understanding of the mode of action of two different VZV vaccine modalities. Collectively, our data demonstrated the superiority of VZV mRNA vaccine over licensed subunit vaccine. The mRNA platform therefore holds prospects for further investigations in next-generation VZV vaccine development.

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“…The CRS was demonstrated by raised inflammatory markers, thrombocytopaenia, elevated cytokine levels (IFN-γ/IL-2R/IL-18/IL-16/IL-10) and steroid responsiveness [ 127 ]. Adenovirus-based vaccines expressing mouse-adapted H1N1 influenza viruses were found to suppress CYP3A activity by 55% in mice after 24 hours [ 128 ]. These findings suggest that vaccinations leading to immune response activation and cytokine release could suppress CYP expression.…”

Section: Covid-19 Vaccines: Cyp2c9 Downregulationmentioning

confidence: 99%

Role of Cytochrome P450 2C9 in COVID-19 Treatment: Current Status and Future Directions

Lim

Bishtawi

Lim

2023

Eur J Drug Metab Pharmacokinet

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The major human liver drug metabolising cytochrome P450 (CYP) enzymes are downregulated during inflammation and infectious disease state, especially during coronavirus disease 2019 (COVID-19) infection. The influx of proinflammatory cytokines, known as a ‘cytokine storm’, during severe COVID-19 leads to the downregulation of CYPs and triggers new cytokine release, which further dampens CYP expression. Impaired drug metabolism, along with the inevitable co-administration of drugs or ‘combination therapy’ in patients with COVID-19 with various comorbidities, could cause drug–drug interactions, thus worsening the disease condition. Genetic variability or polymorphism in CYP2C9 across different ethnicities could contribute to COVID-19 susceptibility. A number of drugs used in patients with COVID-19 are inducers or inhibitors of, or are metabolised by, CYP2C9, and co-administration might cause pharmacokinetic and pharmacodynamic interactions. It is also worth mentioning that some of the COVID-19 drug interactions are due to altered activity of other CYPs including CYP3A4. Isoniazid/rifampin for COVID-19 and tuberculosis co-infection; lopinavir/ritonavir and cobicistat/remdesivir combination therapy; or multi-drug therapy including ivermectin, azithromycin, montelukast and acetylsalicylic acid, known as TNR4 therapy, all improved recovery in patients with COVID-19. However, a combination of CYP2C9 inducers, inhibitors or both, and plausibly different CYP isoforms could lead to treatment failure, hepatotoxicity or serious side effects including thromboembolism or bleeding, as observed in the combined use of azithromycin/warfarin. Further, herbs that are CYP2C9 inducers and inhibitors, showed anti-COVID-19 properties, and in silico predictions postulated that phytochemical compounds could inhibit SARS-CoV-2 virus particles. COVID-19 vaccines elicit immune responses that activate cytokine release, which in turn suppresses CYP expression that could be the source of compromised CYP2C9 drug metabolism and the subsequent drug–drug interaction. Future studies are recommended to determine CYP regulation in COVID-19, while recognising the involvement of CYP2C9 and possibly utilising CYP2C9 as a target gene to tackle the ever-mutating SARS-CoV-2.

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Immunization and Drug Metabolizing Enzymes: Focus on Hepatic Cytochrome P450 3A

Cited by 6 publications

References 97 publications

Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques

Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques

Herpes zoster mRNA vaccine induces superior vaccine immunity over licensed vaccine in mice and rhesus macaques

Role of Cytochrome P450 2C9 in COVID-19 Treatment: Current Status and Future Directions

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