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Journal of Molecular Biology Aug 2023Although one member of the poxvirus family, variola virus, has caused one of the most devastating human infections worldwide, smallpox, the knowledge gained over the... (Review)
Review
Although one member of the poxvirus family, variola virus, has caused one of the most devastating human infections worldwide, smallpox, the knowledge gained over the last 30 years on the molecular, virological and immunological mechanisms of these viruses has allowed the use of members of this family as vectors for the generation of recombinant vaccines against numerous pathogens. In this review, we cover different aspects of the history and biology of poxviruses with emphasis on their application as vaccines, from first- to fourth-generation, against smallpox, monkeypox, emerging viral diseases highlighted by the World Health Organization (COVID-19, Crimean-Congo haemorrhagic fever, Ebola and Marburg virus diseases, Lassa fever, Middle East respiratory syndrome and severe acute respiratory syndrome, Nipah and other henipaviral diseases, Rift Valley fever and Zika), as well as against one of the most concerning prevalent virus, the Human Immunodeficiency Virus, the causative agent of Acquired Immunodeficiency Syndrome. We discuss the implications in human health of the 2022 monkeypox epidemic affecting many countries, and the rapid prophylactic and therapeutic measures adopted to control virus dissemination within the human population. We also describe the preclinical and clinical evaluation of the Modified Vaccinia virus Ankara and New York vaccinia virus poxviral strains expressing heterologous antigens from the viral diseases listed above. Finally, we report different approaches to improve the immunogenicity and efficacy of poxvirus-based vaccine candidates, such as deletion of immunomodulatory genes, insertion of host-range genes and enhanced transcription of foreign genes through modified viral promoters. Some future prospects are also highlighted.
Topics: Animals; Humans; Communicable Diseases, Emerging; COVID-19; Genetic Vectors; Mpox (monkeypox); Poxviridae; Smallpox; Vaccines, Attenuated; Vaccinia virus; Viral Vaccines; Virus Diseases; Zika Virus; Zika Virus Infection
PubMed: 37301278
DOI: 10.1016/j.jmb.2023.168173 -
Journal For Immunotherapy of Cancer Aug 2023Triple-negative breast cancer (TNBC) corresponds to approximately 20% of all breast tumors, with a high propensity for metastasis and a poor prognosis. Because TNBC...
BACKGROUND
Triple-negative breast cancer (TNBC) corresponds to approximately 20% of all breast tumors, with a high propensity for metastasis and a poor prognosis. Because TNBC displays a high mutational load compared with other breast cancer types, a neoantigen-based immunotherapy strategy could be effective. One major bottleneck in the development of a neoantigen-based vaccine for TNBC is the selection of the best targets, that is, tumor-specific neoantigens which are presented at the surface of tumor cells and capable of eliciting robust immune responses. In this study, we aimed to set up a platform for identification and delivery of immunogenic neoantigens in a vaccine regimen for TNBC using oncolytic vaccinia virus (VV).
METHODS
We used bioinformatic tools and cell-based assays to identify immunogenic neoantigens in TNBC patients' samples, human and murine cell lines. Immunogenicity of the neoantigens was tested in vitro (human) and ex vivo (murine) in T-cell assays. To assess the efficacy of our regimen, we used a preclinical model of TNBC where we treated tumor-bearing mice with neoantigens together with oncolytic VV and evaluated the effect on induction of neoantigen-specific CD8+T cells, tumor growth and survival.
RESULTS
We successfully identified immunogenic neoantigens and generated neoantigen-specific CD8+T cells capable of recognizing a human TNBC cell line expressing the mutated gene. Using a preclinical model of TNBC, we showed that our tumor-specific oncolytic VV was able to change the tumor microenvironment, attracting and maintaining mature cross-presenting CD8α+dendritic cells and effector T-cells. Moreover, when delivered in a prime/boost regimen together with oncolytic VV, long peptides encompassing neoantigens were able to induce neoantigen-specific CD8+T cells, slow tumor growth and increase survival.
CONCLUSIONS
Our study provides a promising approach for the development of neoantigen-based immunotherapies for TNBC. By identifying immunogenic neoantigens and developing a delivery system through tumor-specific oncolytic VV, we have demonstrated that neoantigen-based vaccines could be effective in inducing neoantigen-specific CD8+T cells response with significant impact on tumor growth. Further studies are needed to determine the safety and efficacy of this approach in clinical trials.
Topics: Humans; Animals; Mice; Triple Negative Breast Neoplasms; Vaccinia virus; Biological Assay; CD8-Positive T-Lymphocytes; Immunotherapy; Oncolytic Viruses; Tumor Microenvironment
PubMed: 37586771
DOI: 10.1136/jitc-2023-007336 -
Clinical Microbiology and Infection :... Dec 2023Monkeypox virus (MPXV) is an emerging zoonotic virus that has had on-going public health impacts in endemic regions of Central and West Africa for over a half-century.... (Review)
Review
BACKGROUND
Monkeypox virus (MPXV) is an emerging zoonotic virus that has had on-going public health impacts in endemic regions of Central and West Africa for over a half-century. Historically, the MPXV clade endemic in regions of Central Africa is associated with higher morbidity and mortality as compared with the clade endemic in West Africa.
OBJECTIVES
Here, we review the virological characteristics of MPXV and discuss potential relationships between virulence factors and clade- (and subclade-) specific differences in virulence and transmission patterns.
SOURCES
Targeted search was conducted in PubMed using ((monkeypox virus) OR (Orthopoxvirus)) AND (zoonosis)) OR ((monkeypox) OR (human mpox).
CONTENT
Forty-seven references were considered that included three publicly available data reports and/or press releases, one book chapter, and 44 published manuscripts.
IMPLICATIONS
Although zoonosis has been historically linked to emergence events in humans, epidemiological analyses of more recent outbreaks have identified increasing frequencies of human-to-human transmission. Furthermore, viral transmission during the 2022 global human mpox outbreak, caused by a recently identified MPXV subclade, has relied exclusively on human-to-human contact with no known zoonotic link.
Topics: Humans; Monkeypox virus; Mpox (monkeypox); Virulence; Virulence Factors; Africa, Western
PubMed: 37507009
DOI: 10.1016/j.cmi.2023.07.011 -
Microbiology Spectrum Aug 2023Monkeypox virus (MPXV) infections in humans have historically been restricted to regions of endemicity in Africa. However, in 2022, an alarming number of MPXV cases were...
Monkeypox virus (MPXV) infections in humans have historically been restricted to regions of endemicity in Africa. However, in 2022, an alarming number of MPXV cases were reported globally, with evidence of person-to-person transmission. Because of this, the World Health Organization (WHO) declared the MPXV outbreak a public health emergency of international concern. The supply of MPXV vaccines is limited, and only two antivirals, tecovirimat and brincidofovir, approved by the U.S. Food and Drug Administration (FDA) for the treatment of smallpox, are currently available for the treatment of MPXV infection. Here, we evaluated 19 compounds previously shown to inhibit different RNA viruses for their ability to inhibit orthopoxvirus infections. We first used recombinant vaccinia virus (rVACV) expressing fluorescence (mScarlet or green fluorescent protein [GFP]) and luciferase (Nluc) reporter genes to identify compounds with antiorthopoxvirus activity. Seven compounds from the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, pyrazofurin, mycophenolate mofetil, azaribine, and brequinar) and six compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) showed inhibitory activity against rVACV. Notably, the anti-VACV activity of some of the compounds in the ReFRAME library (antimycin A, mycophenolic acid, AVN-944, mycophenolate mofetil, and brequinar) and all the compounds from the NPC library (buparvaquone, valinomycin, narasin, monensin, rotenone, and mubritinib) were confirmed with MPXV, demonstrating their inhibitory activity against two orthopoxviruses. Despite the eradication of smallpox, some orthopoxviruses remain important human pathogens, as exemplified by the recent 2022 monkeypox virus (MPXV) outbreak. Although smallpox vaccines are effective against MPXV, access to those vaccines is limited. In addition, current antiviral treatment against MPXV infections is limited to the use of the FDA-approved drugs tecovirimat and brincidofovir. Thus, there is an urgent need to identify novel antivirals for the treatment of MPXV infection and other potentially zoonotic orthopoxvirus infections. Here, we show that 13 compounds, derived from two different libraries, previously found to inhibit several RNA viruses, also inhibit VACV. Notably, 11 compounds also displayed inhibitory activity against MPXV.
Topics: Humans; Mpox (monkeypox); Mycophenolic Acid; Smallpox; Antimycin A; Monensin; Rotenone; Valinomycin; Monkeypox virus; Antiviral Agents
PubMed: 37278625
DOI: 10.1128/spectrum.04745-22 -
Cell Reports Methods Oct 2023Mpox is caused by a zoonotic virus belonging to the Orthopoxvirus genus and the Poxviridae family. In this study, we develop a recombinase polymerase amplification...
Mpox is caused by a zoonotic virus belonging to the Orthopoxvirus genus and the Poxviridae family. In this study, we develop a recombinase polymerase amplification (RPA)-coupled CRISPR-Cas12a detection assay for the mpox virus. We design and test a series of CRISPR-derived RNAs(crRNAs) targeting the conserved D6R and E9L genes for orthopoxvirus and the unique N3R and N4R genes for mpox viruses. D6R crRNA-1 exhibits the most robust activity in detecting orthopoxviruses, and N4R crRNA-2 is able to distinguish the mpox virus from other orthopoxviruses. The Cas12a/crRNA assay alone presents a detection limit of 10 copies of viral DNA, whereas coupling RPA increases the detection limit to 1-10 copies. The one-tube RPA-Cas12a assay can, therefore, detect viral DNA as low as 1 copy within 30 min and holds the promise of providing point-of-care detection for mpox viral infection.
Topics: Humans; Recombinases; CRISPR-Cas Systems; Monkeypox virus; DNA, Viral; Mpox (monkeypox); Nucleotidyltransferases; Orthopoxvirus; RNA, Guide, CRISPR-Cas Systems
PubMed: 37848032
DOI: 10.1016/j.crmeth.2023.100620 -
Nature Communications Apr 2024The 2023 monkeypox (mpox) epidemic was caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage traced back to Nigeria in 1971. Person-to-person...
The 2023 monkeypox (mpox) epidemic was caused by a subclade IIb descendant of a monkeypox virus (MPXV) lineage traced back to Nigeria in 1971. Person-to-person transmission appears higher than for clade I or subclade IIa MPXV, possibly caused by genomic changes in subclade IIb MPXV. Key genomic changes could occur in the genome's low-complexity regions (LCRs), which are challenging to sequence and are often dismissed as uninformative. Here, using a combination of highly sensitive techniques, we determine a high-quality MPXV genome sequence of a representative of the current epidemic with LCRs resolved at unprecedented accuracy. This reveals significant variation in short tandem repeats within LCRs. We demonstrate that LCR entropy in the MPXV genome is significantly higher than that of single-nucleotide polymorphisms (SNPs) and that LCRs are not randomly distributed. In silico analyses indicate that expression, translation, stability, or function of MPXV orthologous poxvirus genes (OPGs), including OPG153, OPG204, and OPG208, could be affected in a manner consistent with the established "genomic accordion" evolutionary strategies of orthopoxviruses. We posit that genomic studies focusing on phenotypic MPXV differences should consider LCR variability.
Topics: Humans; Monkeypox virus; Genomics; Orthopoxvirus; Mpox (monkeypox); Poxviridae
PubMed: 38637500
DOI: 10.1038/s41467-024-46949-7 -
Clinical Microbiology and Infection :... Dec 2023The 2022 mpox outbreak drew global attention to this neglected pathogen. While most of the world was taken by surprise, some countries have seen this pathogen emerge and... (Review)
Review
BACKGROUND
The 2022 mpox outbreak drew global attention to this neglected pathogen. While most of the world was taken by surprise, some countries have seen this pathogen emerge and become endemic several decades prior to this epidemic.
OBJECTIVES
This narrative review provides an overview of mpox epidemiology since its discovery through the 2022 global outbreak.
SOURCES
We searched PubMed for relevant literature about mpox epidemiology and transmission through 28 February 2023.
CONTENT
The emergence of human mpox is intertwined with the eradication of smallpox and the cessation of the global smallpox vaccination campaign. The first human clade I and II monkeypox virus (MPXV) infections were reported as zoonoses in Central and West Africa, respectively, around 1970 with sporadic infections reported throughout the rest of the decade. Over the next five decades, Clade I MPXV was more common and caused outbreaks of increasing size and frequency, mainly in the Democratic Republic of the Congo. Clade II MPXV was rarely observed, until its re-emergence and ongoing transmission in Nigeria, since 2017. Both clades showed a shift from zoonotic to human-to-human transmission, with potential transmission through sexual contact being observed in Nigeria. In 2022, clade II MPXV caused a large human outbreak which to date has caused over 86,000 cases in 110 countries, with strong evidence of transmission during sexual contact. By February 2023, the global epidemic has waned in most countries, but endemic regions continue to suffer from mpox.
IMPLICATIONS
The changing epidemiology of mpox demonstrates how neglected zoonosis turned into a global health threat within a few decades. Thus, mpox pathophysiology and transmission dynamics need to be further investigated, and preventive and therapeutic interventions need to be evaluated. Outbreak response systems need to be strengthened and sustained in endemic regions to reduce the global threat of mpox.
Topics: Animals; Humans; Smallpox; Mpox (monkeypox); Variola virus; Zoonoses; Disease Outbreaks
PubMed: 37574113
DOI: 10.1016/j.cmi.2023.08.008 -
Cancer Biology & Medicine Aug 2023Oncolytic virotherapy has emerged as a promising treatment for human cancers owing to an ability to elicit curative effects systemic administration. Tumor cells often... (Review)
Review
Oncolytic virotherapy has emerged as a promising treatment for human cancers owing to an ability to elicit curative effects systemic administration. Tumor cells often create an unfavorable immunosuppressive microenvironment that degrade viral structures and impede viral replication; however, recent studies have established that viruses altered genetic modifications can serve as effective oncolytic agents to combat hostile tumor environments. Specifically, oncolytic vaccinia virus (OVV) has gained popularity owing to its safety, potential for systemic delivery, and large gene insertion capacity. This review highlights current research on the use of engineered mutated viruses and gene-armed OVVs to reverse the tumor microenvironment and enhance antitumor activity and , and provides an overview of ongoing clinical trials and combination therapies. In addition, we discuss the potential benefits and drawbacks of OVV as a cancer therapy, and explore different perspectives in this field.
Topics: Humans; Immunotherapy; Neoplasms; Oncolytic Virotherapy; Oncolytic Viruses; Tumor Microenvironment; Vaccinia virus; Clinical Trials as Topic
PubMed: 37615308
DOI: 10.20892/j.issn.2095-3941.2023.0202 -
International Journal of Biological... Aug 2023Since May 2022, the mpox virus (MPXV) has spread worldwide and become a potential threat to global public health. Vaccines are important tools for preventing MPXV... (Review)
Review
Since May 2022, the mpox virus (MPXV) has spread worldwide and become a potential threat to global public health. Vaccines are important tools for preventing MPXV transmission and infection in the population. However, there are still no available potent and applicable vaccines specifically for MPXV. Herein, we highlight several potential vaccine targets for MPVX and emphasize potent immunogens, such as M1R, E8L, H3L, A29L, A35R, and B6R proteins. These proteins can be integrated into diverse vaccine platforms to elicit powerful B-cell and T-cell responses, thereby providing protective immunity against MPXV infection. Overall, research on the MPXV vaccine targets would provide valuable information for developing timely effective MPXV-specific vaccines.
Topics: Viral Vaccines; Monkeypox virus; B-Lymphocytes
PubMed: 37353117
DOI: 10.1016/j.ijbiomac.2023.125515 -
Nature Communications Sep 2023The recent outbreaks of mpox have raised concerns over the need for effective vaccines. However, the current approved vaccines have either been associated with safety...
The recent outbreaks of mpox have raised concerns over the need for effective vaccines. However, the current approved vaccines have either been associated with safety concerns or are in limited supply. mRNA vaccines, which have shown high efficacy and safety against SARS-CoV-2 infection, are a promising alternative. In this study, three mRNA vaccines are developed that encode monkeypox virus (MPXV) proteins A35R and M1R, including A35R extracellular domain -M1R fusions (VGPox 1 and VGPox 2) and a mixture of encapsulated full-length mRNAs for A35R and M1R (VGPox 3). All three vaccines induce early anti-A35R antibodies in female Balb/c mice, but only VGPox 1 and 2 generate detectable levels of anti-M1R antibodies at day 7 after vaccination. However, all three mRNA vaccine groups completely protect mice from a lethal dose of vaccinia virus (VACV) challenge. A single dose of VGPox 1, 2, and 3 provide protection against the lethal viral challenge within 7 days post-vaccination. Long-term immunity and protection were also observed in all three candidates. Additionally, VGPox 2 provided better passive protection. These results suggest that the VGPox series vaccines enhance immunogenicity and can be a viable alternative to current whole-virus vaccines to defend against mpox.
Topics: Female; Animals; Mice; Vaccinia virus; Monkeypox virus; Mpox (monkeypox); COVID-19; SARS-CoV-2; Mice, Inbred BALB C; mRNA Vaccines
PubMed: 37739969
DOI: 10.1038/s41467-023-41628-5