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Signal Transduction and Targeted Therapy Dec 2023In 2022, a global outbreak of Mpox (formerly monkeypox) occurred in various countries across Europe and America and rapidly spread to more than 100 countries and... (Review)
Review
In 2022, a global outbreak of Mpox (formerly monkeypox) occurred in various countries across Europe and America and rapidly spread to more than 100 countries and regions. The World Health Organization declared the outbreak to be a public health emergency of international concern due to the rapid spread of the Mpox virus. Consequently, nations intensified their efforts to explore treatment strategies aimed at combating the infection and its dissemination. Nevertheless, the available therapeutic options for Mpox virus infection remain limited. So far, only a few numbers of antiviral compounds have been approved by regulatory authorities. Given the high mutability of the Mpox virus, certain mutant strains have shown resistance to existing pharmaceutical interventions. This highlights the urgent need to develop novel antiviral drugs that can combat both drug resistance and the potential threat of bioterrorism. Currently, there is a lack of comprehensive literature on the pathophysiology and treatment of Mpox. To address this issue, we conducted a review covering the physiological and pathological processes of Mpox infection, summarizing the latest progress of anti-Mpox drugs. Our analysis encompasses approved drugs currently employed in clinical settings, as well as newly identified small-molecule compounds and antibody drugs displaying potential antiviral efficacy against Mpox. Furthermore, we have gained valuable insights from the process of Mpox drug development, including strategies for repurposing drugs, the discovery of drug targets driven by artificial intelligence, and preclinical drug development. The purpose of this review is to provide readers with a comprehensive overview of the current knowledge on Mpox.
Topics: Humans; Artificial Intelligence; Mpox (monkeypox); Antibodies; Disease Outbreaks; Antiviral Agents
PubMed: 38148355
DOI: 10.1038/s41392-023-01675-2 -
Emerging Microbes & Infections Dec 2023The re-emerging mpox (formerly monkeypox) virus (MPXV), a member of genus together with variola virus (VARV) and vaccinia virus (VACV), has led to public health...
The re-emerging mpox (formerly monkeypox) virus (MPXV), a member of genus together with variola virus (VARV) and vaccinia virus (VACV), has led to public health emergency of international concern since July 2022. Inspired by the unprecedent success of coronavirus disease 2019 (COVID-19) mRNA vaccines, the development of a safe and effective mRNA vaccine against MPXV is of high priority. Based on our established lipid nanoparticle (LNP)-encapsulated mRNA vaccine platform, we rationally constructed and prepared a panel of multicomponent MPXV vaccine candidates encoding different combinations of viral antigens including M1R, E8L, A29L, A35R, and B6R. and characterization demonstrated that two immunizations of all mRNA vaccine candidates elicit a robust antibody response as well as antigen-specific Th1-biased cellular response in mice. Importantly, the penta- and tetra-component vaccine candidates AR-MPXV5 and AR-MPXV4a showed superior capability of inducing neutralizing antibodies as well as of protecting from VACV challenge in mice. Our study provides critical insights to understand the protection mechanism of MPXV infection and direct evidence supporting further clinical development of these multicomponent mRNA vaccine candidates.
Topics: Animals; Mice; Mpox (monkeypox); COVID-19; Vaccines, Synthetic; Vaccinia virus; Monkeypox virus; COVID-19 Vaccines; Antibodies, Viral; mRNA Vaccines
PubMed: 36947428
DOI: 10.1080/22221751.2023.2192815 -
Viruses Dec 2023Smallpox was a highly contagious disease caused by the variola virus. The disease affected millions of people over thousands of years and variola virus ranked as one of... (Review)
Review
Smallpox was a highly contagious disease caused by the variola virus. The disease affected millions of people over thousands of years and variola virus ranked as one of the deadliest viruses in human history. The complete eradication of smallpox in 1980, a major triumph in medicine, was achieved through a global vaccination campaign using a less virulent poxvirus, vaccinia virus. Despite this success, the herd immunity established by this campaign has significantly waned, and concerns are rising about the potential reintroduction of variola virus as a biological weapon or the emergence of zoonotic poxviruses. These fears were further fueled in 2022 by a global outbreak of monkeypox virus (mpox), which spread to over 100 countries, thereby boosting interest in developing new vaccines using molecular approaches. However, poxviruses are complex and creating modern vaccines against them is challenging. This review focuses on the structural biology of the six major neutralization determinants on poxviruses (D8, H3, A27, L1, B5, and A33), the localization of epitopes targeted by neutralizing antibodies, and their application in the development of subunit vaccines.
Topics: Humans; Poxviridae; Smallpox; Vaccinia virus; Smallpox Vaccine; Variola virus
PubMed: 38140637
DOI: 10.3390/v15122396 -
Emerging Microbes & Infections Dec 2023The worldwide outbreak of the monkeypox virus (MPXV) has become a "Public Health Emergency of International Concern" (PHEIC). Severe monkeypox virus infection can be...
The worldwide outbreak of the monkeypox virus (MPXV) has become a "Public Health Emergency of International Concern" (PHEIC). Severe monkeypox virus infection can be fatal, however, effective therapeutic methods are yet to be developed. Mice were immunized with A35R protein and A29L protein of MPXV, and the binding and neutralizing activities of the immune sera against poxvirus-associated antigens and viruses were identified. A29L protein and A35R protein-specific monoclonal antibodies (mAbs) were generated and their antiviral activities of these mAbs were characterized in vitro and in vivo. Immunization with the MPXV A29L protein and A35R protein induced neutralizing antibodies against the orthopoxvirus in mice. None of the mAbs screened in this study against A35R could effectively neutralize the vaccinia virus (VACV), while three mAbs against A29L protein, 9F8, 3A1 and 2D1 were confirmed to have strong broad binding and neutralizing activities against orthopoxvirus, among which 9F8 showed the best neutralizing activity. 9F8, 3A1, and 2D1 recognized different epitopes on MPXV A29L protein, showing synergistic antiviral activity in vitro against the VACV Tian Tan and WR strains; the best activity was observed when the three antibodies were combined. In the vivo antiviral prophylactic and therapeutic experiments, 9F8 showed complete protective activity, whereas 3A1 and 2D1 showed partial protective activity. Similarly, the three antibodies showed synergistic antiviral protective activity against the two VACVs. In conclusion, three mAbs recognized different epitopes on MPXV A29L protein were developed and showed synergistic effects against orthopoxvirus.
Topics: Animals; Mice; Antibodies, Neutralizing; Orthopoxvirus; Mpox (monkeypox); Epitopes; Antibodies, Viral; Viral Proteins; Vaccinia virus; Monkeypox virus; Communicable Diseases; Antibodies, Monoclonal
PubMed: 37288876
DOI: 10.1080/22221751.2023.2223669 -
Cell Oct 2023The mpox outbreak of 2022-2023 involved rapid global spread in men who have sex with men. We infected 18 rhesus macaques with mpox by the intravenous, intradermal, and...
The mpox outbreak of 2022-2023 involved rapid global spread in men who have sex with men. We infected 18 rhesus macaques with mpox by the intravenous, intradermal, and intrarectal routes and observed robust antibody and T cell responses following all three routes of infection. Numerous skin lesions and high plasma viral loads were observed following intravenous and intradermal infection. Skin lesions peaked on day 10 and resolved by day 28 following infection. On day 28, we re-challenged all convalescent and 3 naive animals with mpox. All convalescent animals were protected against re-challenge. Transcriptomic studies showed upregulation of innate and inflammatory responses and downregulation of collagen formation and extracellular matrix organization following challenge, as well as rapid activation of T cell and plasma cell responses following re-challenge. These data suggest key mechanistic insights into mpox pathogenesis and immunity. This macaque model should prove useful for evaluating mpox vaccines and therapeutics.
Topics: Animals; Humans; Male; Homosexuality, Male; Macaca mulatta; Mpox (monkeypox); Sexual and Gender Minorities; Monkeypox virus
PubMed: 37734373
DOI: 10.1016/j.cell.2023.08.023 -
Acta Medica Portuguesa Jul 2023
Topics: Humans; Mpox (monkeypox); Communicable Diseases, Emerging; Disease Outbreaks
PubMed: 35687526
DOI: 10.20344/amp.18639 -
Cell Mar 2024In response to the 2022 outbreak of mpox driven by unprecedented human-to-human monkeypox virus (MPXV) transmission, we designed BNT166, aiming to create a highly...
In response to the 2022 outbreak of mpox driven by unprecedented human-to-human monkeypox virus (MPXV) transmission, we designed BNT166, aiming to create a highly immunogenic, safe, accessible, and scalable next-generation vaccine against MPXV and related orthopoxviruses. To address the multiple viral forms and increase the breadth of immune response, two candidate multivalent mRNA vaccines were evaluated pre-clinically: a quadrivalent vaccine (BNT166a; encoding the MPXV antigens A35, B6, M1, H3) and a trivalent vaccine (BNT166c; without H3). Both candidates induced robust T cell responses and IgG antibodies in mice, including neutralizing antibodies to both MPXV and vaccinia virus. In challenge studies, BNT166a and BNT166c provided complete protection from vaccinia, clade I, and clade IIb MPXV. Furthermore, immunization with BNT166a was 100% effective at preventing death and at suppressing lesions in a lethal clade I MPXV challenge in cynomolgus macaques. These findings support the clinical evaluation of BNT166, now underway (NCT05988203).
Topics: Animals; Humans; Mice; Macaca fascicularis; Monkeypox virus; Mpox (monkeypox); Smallpox Vaccine; Vaccines, Combined; Vaccinia virus
PubMed: 38366591
DOI: 10.1016/j.cell.2024.01.017 -
Proceedings of the National Academy of... Aug 2023Zoonotic poxviruses such as mpox virus (MPXV) continue to threaten public health safety since the eradication of smallpox. Vaccinia virus (VACV), the prototypic poxvirus...
Zoonotic poxviruses such as mpox virus (MPXV) continue to threaten public health safety since the eradication of smallpox. Vaccinia virus (VACV), the prototypic poxvirus used as the vaccine strain for smallpox eradication, is the best-characterized member of the poxvirus family. VACV encodes a serine protease inhibitor 1 (SPI-1) conserved in all orthopoxviruses, which has been recognized as a host range factor for modified VACV Ankara (MVA), an approved smallpox vaccine and a promising vaccine vector. FAM111A (family with sequence similarity 111 member A), a nuclear protein that regulates host DNA replication, was shown to restrict the replication of a VACV SPI-1 deletion mutant (VACV-ΔSPI-1) in human cells. Nevertheless, the detailed antiviral mechanisms of FAM111A were unresolved. Here, we show that FAM111A is a potent restriction factor for VACV-ΔSPI-1 and MVA. Deletion of FAM111A rescued the replication of MVA and VACV-ΔSPI-1 and overexpression of FAM111A significantly reduced viral DNA replication and virus titers but did not affect viral early gene expression. The antiviral effect of FAM111A necessitated its trypsin-like protease domain and DNA-binding domain but not the PCNA-interacting motif. We further identified that FAM111A translocated into the cytoplasm upon VACV infection by degrading the nuclear pore complex via its protease activity, interacted with VACV DNA-binding protein I3, and promoted I3 degradation through autophagy. Moreover, SPI-1 from VACV, MPXV, or lumpy skin disease virus was able to antagonize FAM111A by prohibiting its nuclear export. Our findings reveal the detailed mechanism by which FAM111A inhibits VACV and provide explanations for the immune evasive function of VACV SPI-1.
Topics: Animals; Cattle; Humans; Vaccinia virus; Serine Proteinase Inhibitors; Vaccinia; Viral Proteins; Smallpox; DNA Replication; Host Specificity; DNA, Viral; Virus Replication; Poxviridae; Receptors, Virus
PubMed: 37607234
DOI: 10.1073/pnas.2304242120 -
Acta Medica Indonesiana Jan 2024Mpox is caused by the Monkeypox virus, which belongs to the Orthopoxvirus genus and Poxviridae family. The Monkeypox virus was first identified as a cause of disease in...
Mpox is caused by the Monkeypox virus, which belongs to the Orthopoxvirus genus and Poxviridae family. The Monkeypox virus was first identified as a cause of disease in humans in the 1970s in the Democratic Republic of the Congo. Mpox was considered endemic in several African countries. A global outbreak of Mpox was first recognized in Europe in May 2022 and was declared a public health emergency of international concern on July 23, 2022. The first reported Mpox case in Indonesia was in October 2022 which was identified as an imported case, there were no new confirmed Mpox cases until 13 October 2023. Since then there were 72 cases of confirmed Mpox cases in Indonesia by the end of 2023, distributed across 6 provinces, mostly in the Java island.We present two different spectrums of Mpox skin lesions in patients living with HIV, with a positive polymerase chain reaction test for Mpox. The first patient is a 48-year-old male, who developed a maculopapular lesion, that was initially noticed on the face, the lesions were then spread to the back and hand. He identifies as men who have sex with men and living with HIV for the past 18 years. There were no lesions on the genitalia or mucosa. The second patient is a 28-year-old male, the initial symptom was fever, followed by skin lesions after around 1 week of fever. The lesion initially appears as pustules on the face and then spreads throughout the whole body, the lesions also grow larger and become pseudo-pustules and ulcers. There were also mucosal involvements in the mouth, making oral intake difficult. This patient also identified as men who have sex with men with multiple partners, HIV status was not known at the initial presentation. HIV screening was done with positive results.
Topics: Male; Humans; Middle Aged; Adult; Homosexuality, Male; Mpox (monkeypox); Sexual and Gender Minorities; Disease Outbreaks; HIV Infections
PubMed: 38561878
DOI: No ID Found -
Revista de La Facultad de Ciencias... Dec 2023the recent mpox outbreak was considered an international public health emergency.
INTRODUCTION
the recent mpox outbreak was considered an international public health emergency.
OBJECTIVE
describe the epidemiological and clinical characteristics of mpox in a hospital in the province of Buenos Aires.
METHODS
case series study in patients ≥15 years of age in the Dermatology service of the Hospital Interzonal General de Agudos "San Martín" in La Plata between August and November 2022.
RESULTS
10 patients were included. The mean age of presentation was 35 years. Seven of the patients were men and the remaining three were women. Most of them presented risky sexual intercourse as an epidemiological history. Pseudopustules were observed in 70% of the patients and all had genital, gluteal or perianal lesions. The complications observed were: local edema, proctitis, conjunctivitis and pharyngitis.
CONCLUSION
we present 3 female patients out of a total of 24 women reported in the country, which represent only 2% of mpox infections in Argentina. In most cases we observe pseudopustules, an elementary lesion recently described for this entity. One patient presented ocular involvement, a complication reported in 1% of cases in the current outbreak.
Topics: Humans; Mpox (monkeypox); Argentina; Eye; Hospitals
PubMed: 38150198
DOI: 10.31053/1853.0605.v80.n4.42303