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Viruses Aug 2022Monkeypox disease (MPX) is currently considered a global threat after COVID-19. European Medicines Agency (EMA) approved Tecovirimat in capsule dosage form (200 mg) as... (Review)
Review
Monkeypox disease (MPX) is currently considered a global threat after COVID-19. European Medicines Agency (EMA) approved Tecovirimat in capsule dosage form (200 mg) as the first treatment for MPX in January 2022. This article highlights Tecovirimat's development and patent literature review and is believed to benefit the scientists working on developing MPX treatments. The literature for Tecovirimat was gathered from the website of SIGA Technologies (developer of Tecovirimat), regulatory agencies (EMA, United States Food and Drug Administration (USFDA), and Health Canada), PubMed, and freely accessible clinical/patent databases. Tecovirimat was first recognized as an anti-orthopoxvirus molecule in 2002 and developed by SIGA Technologies. The USFDA and Health Canada have also recently approved Tecovirimat to treat smallpox in 2018 and 2021, respectively. The efficacy of Tecovirimat was verified in infected non-human primates (monkeys) and rabbits under the USFDA's Animal Rule. Most clinical studies have been done on Tecovirimat's safety and pharmacokinetic parameters. The patent literature has revealed inventions related to the capsule, injection, suspension, crystalline forms, amorphous form, and drug combinations (Tecovirimat + cidofovir) and process for preparing Tecovirimat. The authors foresee the off-label use of Tecovirimat in the USA and Canada for MPX and other orthopoxvirus infections. The authors also trust that there is immense scope for developing new Tecovirimat-based treatments (new drug combinations with other antivirals) for orthopoxvirus and other viral diseases. Drug interaction studies and drug resistance studies on Tecovirimat are also recommended. Tecovirimat is believed to handle the current MPX outbreak and is a new hope of biosecurity against smallpox or orthopoxvirus-related bioterrorism attack.
Topics: Animals; Antiviral Agents; COVID-19; Cidofovir; Disease Outbreaks; Immunoglobulin A, Secretory; Mpox (monkeypox); Monkeypox virus; Orthopoxvirus; Rabbits; Smallpox; United States; Variola virus
PubMed: 36146675
DOI: 10.3390/v14091870 -
MSphere Apr 2023The ongoing worldwide monkeypox outbreak is caused by viral lineages (globally referred to as hMPXV1) that are related to but distinct from clade IIb MPXV viruses...
The ongoing worldwide monkeypox outbreak is caused by viral lineages (globally referred to as hMPXV1) that are related to but distinct from clade IIb MPXV viruses transmitted within Nigeria. Analysis of the genetic differences has indicated that APOBEC-mediated editing might be responsible for the unexpectedly high number of mutations observed in hMPXV1 genomes. Here, using 1,624 publicly available hMPXV1 sequences, we analyzed the mutations that accrued between 2017 and the emergence of the current predominant variant (B.1), as well as those that that have been accumulating during the 2022 outbreak. We confirmed an overwhelming prevalence of C-to-T and G-to-A mutations, with a sequence context (5'-TC-3') consistent with the preferences of several human APOBEC3 enzymes. We also found that mutations preferentially occur in highly expressed viral genes, although no transcriptional asymmetry was observed. A comparison of the mutation spectrum and context was also performed against the human-specific variola virus (VARV) and the zoonotic cowpox virus (CPXV), as well as fowlpox virus (FWPV). The results indicated that in VARV genomes, C-to-T and G-to-A changes were more common than the opposite substitutions, although the effect was less marked than for hMPXV1. Conversely, no preference toward C-to-T and G-to-A changes was observed in CPXV and FWPV. Consistently, the sequence context of C-to-T changes confirmed a preference for a T in the -1 position for VARV, but not for CPXV or FWPV. Overall, our results strongly support the view that, irrespective of the transmission route, orthopoxviruses infecting humans are edited by the host APOBEC3 enzymes. Analysis of the viral lineages responsible for the 2022 monkeypox outbreak suggested that APOBEC enzymes are driving hMPXV1 evolution. Using 1,624 public sequences, we analyzed the mutations that accumulated between 2017 and the emergence of the predominant variant and those that characterize the last outbreak. We found that the mutation spectrum of hMPXV1 has been dominated by TC-to-TT and GA-to-AA changes, consistent with the editing activity of human APOBEC3 proteins. We also found that mutations preferentially affect highly expressed viral genes, possibly because transcription exposes single-stranded DNA (ssDNA), a target of APOBEC3 editing. Notably, analysis of the human-specific variola virus (VARV) and the zoonotic cowpox virus (CPXV) indicated that in VARV genomes, TC-to-TT and GA-to-AA changes are likewise extremely frequent. Conversely, no preference toward TC-to-TT and GA-to-AA changes is observed in CPXV. These results suggest that APOBEC3 proteins have an impact on the evolution of different human-infecting orthopoxviruses.
Topics: Animals; Humans; Orthopoxvirus; Mpox (monkeypox); Cowpox virus; Variola virus; Smallpox; Mutation; APOBEC Deaminases
PubMed: 36920219
DOI: 10.1128/msphere.00062-23 -
Scientific Reports Nov 2023Mpox is a neglected zoonotic disease endemic in West and Central Africa. The Mpox outbreak with more than 90,000 cases worldwide since 2022 generated great concern about...
Mpox is a neglected zoonotic disease endemic in West and Central Africa. The Mpox outbreak with more than 90,000 cases worldwide since 2022 generated great concern about future outbreaksĀ and highlighted the need for a simple and rapid diagnostic test. The Mpox virus, MPV, is a member of the Orthopoxvirus (OPV) genus that also contains other pathogenic viruses including variola virus, vaccinia virus, camelpox virus, and cowpox virus. Phylogenomic analysis of 200 OPV genomes identified 10 distinct phylogroups with the New World OPVs placed on a very long branch distant from the Old World OPVs. Isolates derived from infected humans were found to be distributed across multiple phylogroups interspersed with isolates from animal sources, indicating the zoonotic potential of these viruses. In this study, we developed a simple and sensitive colorimetric LAMP assay for generic detection of Old World OPVs. We also developed an MPV-specific probe that differentiates MPV from other OPVs in the N1R LAMP assay. In addition, we described an extraction-free protocol for use directly with swab eluates in LAMP assays, thereby eliminating the time and resources needed to extract DNA from the sample. Our direct LAMP assays are well-suited for low-resource settings and provide a valuable tool for rapid and scalable diagnosis and surveillance of OPVs and MPV.
Topics: Humans; Animals; Orthopoxvirus; Monkeypox virus; Mpox (monkeypox); Variola virus
PubMed: 38036581
DOI: 10.1038/s41598-023-48391-z -
Vaccine Aug 2020Smallpox, a contagious and deadly disease caused by variola virus, was eradicated by a strategy that included vaccination with vaccinia virus, a live-virus vaccine....
Short-term and longer-term protective immune responses generated by subunit vaccination with smallpox A33, B5, L1 or A27 proteins adjuvanted with aluminum hydroxide and CpG in mice challenged with vaccinia virus.
Smallpox, a contagious and deadly disease caused by variola virus, was eradicated by a strategy that included vaccination with vaccinia virus, a live-virus vaccine. Because the threat of bioterrorism with smallpox persists and infections with zoonotic poxvirus infections like monkeypox continue, and there may be a time when an alternative vaccine platform is needed, recombinant-subunit vaccine strategies for poxviruses have been pursued. Our prior work focused on understanding the immune responses generated to vaccine-formulations containing the virus protein L1. In this work, we examine vaccine-formulations with additional key protein targets: A33 and B5 (components of the extracellular virus) and another protein on the mature virus (A27) adjuvanted with aluminum hydroxide (AH) with and without CpG- oligonucleotide. Each vaccine was formulated to allow either adsorption or non-adsorption of the protein (and CpG) to AH. Mice given a prime and single boost produced long-lasting antibody responses. A second boost (given ~5-months after the first) further increased antibody titers. Similar to our prior findings with L1 vaccine-formulations, the most protective A33 vaccine-formulations included CpG, resulted in the generation of IgG2a-antibody responses. Unlike the prior findings with L1 (where formulations that adsorbed both the protein and the CpG to AH resulted in 100% survival after challenge and minimal weight loss), the AH-adsorption status of A33 and CpG did not play as important a role, since both AH-adsorbed and non-adsorbed groups lost weight after challenge and had similar survival. Vaccination with B5-formulations gave different results. While CpG-containing formulations were the only ones that generated IgG2a-antibody responses, the vaccine-formulation that adsorbed B5 to AH (without CpG) was as equally effective in protecting mice after challenge. These results indicate that the mechanism of how antibodies against A33 and B5 protect differ. The data also show the complexity of designing optimized vaccine-formulations containing multiple adjuvants and recombinant protein-based antigens.
Topics: Aluminum Hydroxide; Animals; Antibodies, Viral; Mice; Mice, Inbred BALB C; Smallpox; Smallpox Vaccine; Vaccination; Vaccines, Subunit; Vaccinia virus; Variola virus
PubMed: 32741672
DOI: 10.1016/j.vaccine.2020.07.018 -
Pharmaceutical Research Feb 2023Modern research is increasingly focusing on the study of new viruses and the re-emergence of past microbes, such as Coronaviruses, particularly Sars-Cov2 that was...
PURPOSE
Modern research is increasingly focusing on the study of new viruses and the re-emergence of past microbes, such as Coronaviruses, particularly Sars-Cov2 that was responsible for the very recent pandemic.
METHODS AND RESULTS
This infection manifested itself and still continues to manifest as a severe respiratory syndrome. The main discriminator of whether or not one succeeds in overcoming this infection may depend on a great many factors, but the main one is definitely determined by vaccination, which has minimized hospitalizations and more severe syndromes.
CONCLUSION
Recently, a new virus, the monkeypox virus, which was previously confined to Central and West Africa but is now gradually spreading to more than 30 countries including the United States of America, where such an infection is not endemic, is coming forward again.
Topics: United States; Humans; Variola virus; Mpox (monkeypox); RNA, Viral; COVID-19; SARS-CoV-2
PubMed: 36451069
DOI: 10.1007/s11095-022-03447-z -
Antimicrobial Agents and Chemotherapy Dec 2022Tecovirimat is an antiviral drug initially developed against variola virus (VARV) to treat smallpox infection. Due to its mechanism of action, it has activity against... (Review)
Review
Tecovirimat is an antiviral drug initially developed against variola virus (VARV) to treat smallpox infection. Due to its mechanism of action, it has activity against the family of orthopoxviruses, including vaccinia and the human monkeypox virus (HMPXV). Efficacy studies have thus far been limited to animal models, with human safety trials showing no serious adverse events. Currently approved by the FDA only for the treatment of smallpox, tecovirimat shows promise for the treatment of HMPXV. Tecovirimat has been prescribed via an expanded access for an investigational new drug protocol during the 2022 outbreak. This review will examine the literature surrounding tecovirimat's mechanism of action, pharmacokinetics, safety, efficacy, and potential for resistance.
Topics: Animals; Humans; Smallpox; Monkeypox virus; Variola virus; Antiviral Agents; Benzamides; Isoindoles; Mpox (monkeypox)
PubMed: 36374026
DOI: 10.1128/aac.01226-22 -
British Medical Journal May 1950
Topics: Humans; Smallpox; Variola virus
PubMed: 15420442
DOI: No ID Found -
British Medical Journal Mar 1951
Topics: Humans; Smallpox; Variola virus
PubMed: 14821454
DOI: No ID Found -
The New England Journal of Medicine Apr 2002
Review
Topics: Chickenpox; Diagnosis, Differential; Disease Notification; Humans; Smallpox; Smallpox Vaccine; Variola virus
PubMed: 11923491
DOI: 10.1056/NEJMra020025 -
British Medical Journal May 1950
Topics: Humans; Smallpox; Variola virus
PubMed: 15420422
DOI: No ID Found