Last data update: Jun 03, 2024. (Total: 46935 publications since 2009)
Records 1-9 (of 9 Records) |
Query Trace: Wynn NT [original query] |
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Tecovirimat resistance in Mpox patients, United States, 2022-2023
Smith TG , Gigante CM , Wynn NT , Matheny A , Davidson W , Yang Y , Condori RE , O'Connell K , Kovar L , Williams TL , Yu YC , Petersen BW , Baird N , Lowe D , Li Y , Satheshkumar PS , Hutson CL . Emerg Infect Dis 2023 29 (12) 2426-2432 During the 2022 multinational outbreak of monkeypox virus (MPXV) infection, the antiviral drug tecovirimat (TPOXX; SIGA Technologies, Inc., https://www.siga.com) was deployed in the United States on a large scale for the first time. The MPXV F13L gene homologue encodes the target of tecovirimat, and single amino acid changes in F13 are known to cause resistance to tecovirimat. Genomic sequencing identified 11 mutations previously reported to cause resistance, along with 13 novel mutations. Resistant phenotype was determined using a viral cytopathic effect assay. We tested 124 isolates from 68 patients; 96 isolates from 46 patients were found to have a resistant phenotype. Most resistant isolates were associated with severely immunocompromised mpox patients on multiple courses of tecovirimat treatment, whereas most isolates identified by routine surveillance of patients not treated with tecovirimat remained sensitive. The frequency of resistant viruses remains relatively low (<1%) compared with the total number of patients treated with tecovirimat. |
Community spread of a human monkeypox virus variant with a tecovirimat resistance-associated mutation
Garrigues JM , Hemarajata P , Espinosa A , Hacker JK , Wynn NT , Smith TG , Gigante CM , Davidson W , Vega J , Edmondson H , Karan A , Marutani AN , Kim M , Terashita D , Balter SE , Hutson CL , Green NM . Antimicrob Agents Chemother 2023 67 (11) e0097223 Tecovirimat, also known as TPOXX or ST-246, is a drug available for the treatment of mpox. Tecovirimat targets the conserved orthopoxvirus VP37 protein (also known as F13) required for extracellular virus particle generation (1, 2). Multiple VP37 mutations associated with tecovirimat resistance have been reported within the current global mpox outbreak in immunocompromised individuals with advanced HIV infection (3 – 5). In many of these cases, resistance mutation heterogeneity was observed following tecovirimat exposure, suggesting resistance emerged under selective pressure during treatment. | To monitor circulating monkeypox virus (MPXV) within California, a genomic surveillance network was established whereby clinical and commercial laboratories provided positive specimens for whole-genome sequencing using an amplicon-based protocol and subsequent analysis (6 – 9). Through this surveillance, 11 mpox cases were identified in southern California with the same tecovirimat resistance-associated mutation (Table 1): a three-nucleotide deletion in the vaccinia virus Copenhagen F13L gene homolog (OPG057) resulting in asparagine removed from position 267 in the VP37 protein (VP37:N267del) (5) (https://www.fda.gov/emergency-preparedness-and-response/mcm-issues/fda-mpox-response#therapeutics). VP37:N267del was the only tecovirimat resistance-associated mutation detected in identified specimens and had allele frequencies greater than 89% in all instances, suggesting infections may have occurred with predominantly mutant virus. Phenotypic testing in vitro (3 – 5) confirmed tecovirimat resistance in ten identified specimens with EC50 values ranging from 1.488 to 3.977 µM, corresponding to an 85- to 230-fold change compared to wild-type isolates. |
Resistance to anti-orthopoxviral drug tecovirimat (TPOXX) during the 2022 mpox outbreak in the US (preprint)
Smith TG , Gigante CM , Wynn NT , Matheny A , Davidson W , Yang Y , Condori RE , O'Connell K , Kovar L , Williams TL , Yu YC , Petersen BW , Baird N , Lowe D , Li Y , Satheshkumar PS , Hutson CL . medRxiv 2023 18 Background: During the 2022 multinational outbreak of monkeypox virus (MPXV) clade IIb, the antiviral drug tecovirimat (TPOXX) was deployed in the US on a large scale for the first time ever. The MPXV F13L gene homolog encodes the target of tecovirimat, and single amino acid changes in the F13 protein are known to cause resistance to tecovirimat in orthopoxviruses (OPXV). Method(s): Whole genome metagenomic sequencing and amplicon-based sequencing targeting the F13L gene was used to identify nine mutations previously reported to cause resistance in other OPXV along with ten novel mutations that have been identified from the 2022 mpox outbreak. A cytopathic effect assay, previously established at CDC as part of WHO smallpox research, was adapted to MPXV for tecovirimat phenotype testing of virus isolated from mpox patients. Result(s): As of March 2023, in total, 70 isolates from 40 patients were tested, and 50 of these isolates from 26 patients were found to have a resistant phenotype. Most resistant isolates were associated with severely immunocompromised mpox patients on multiple courses of TPOXX treatment; while isolates with F13 mutations identified by routine surveillance of patients not treated with TPOXX have remained sensitive. Conclusion(s): These data indicate that tecovirimat resistance is developing in immunocompromised patients treated with TPOXX and that for isolates that we have analyzed, the frequency of resistant viruses remain relatively low (< 1%) compared to the total number of patients treated with TPOXX. These findings inform our understanding of when tecovirimat resistance is likely to occur and highlight the need for additional OPXV therapeutics. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. |
Transmission potential of vaccinated and unvaccinated persons infected with the SARS-CoV-2 Delta variant in a federal prison, July-August 2021 (preprint)
Salvatore PP , Lee CC , Sleweon S , McCormick DW , Nicolae L , Knipe K , Dixon T , Banta R , Ogle I , Young C , Dusseau C , Salmonson S , Ogden C , Godwin E , Ballom T , Ross T , Wynn NT , David E , Bessey TK , Kim G , Suppiah S , Tamin A , Harcourt JL , Sheth M , Lowe L , Browne H , Tate JE , Kirking HL , Hagan LM . medRxiv 2021 19 Background The extent to which vaccinated persons who become infected with SARS-CoV-2 contribute to transmission is unclear. During a SARS-CoV-2 Delta variant outbreak among incarcerated persons with high vaccination rates in a federal prison, we assessed markers of viral shedding in vaccinated and unvaccinated persons. Methods Consenting incarcerated persons with confirmed SARS-CoV-2 infection provided mid-turbinate nasal specimens daily for 10 consecutive days and reported symptom data via questionnaire. Real-time reverse transcription-polymerase chain reaction (RT-PCR), viral whole genome sequencing, and viral culture was performed on these nasal specimens. Duration of RT-PCR positivity and viral culture positivity was assessed using survival analysis. Results A total of 978 specimens were provided by 95 participants, of whom 78 (82%) were fully vaccinated and 17 (18%) were not fully vaccinated. No significant differences were detected in duration of RT-PCR positivity among fully vaccinated participants (median: 13 days) versus those not fully vaccinated (median: 13 days; p=0.50), or in duration of culture positivity (medians: 5 days and 5 days; p=0.29). Among fully vaccinated participants, overall duration of culture positivity was shorter among Moderna vaccine recipients versus Pfizer (p=0.048) or Janssen (p=0.003) vaccine recipients. Conclusions As this field continues to develop, clinicians and public health practitioners should consider vaccinated persons who become infected with SARS-CoV-2 to be no less infectious than unvaccinated persons. These findings are critically important, especially in congregate settings where viral transmission can lead to large outbreaks. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. This article is a US Government work. It is not subject to copyright under 17 USC 105 and is also made available for use under a CC0 license. |
Identification of tecovirimat resistance-associated mutations in human monkeypox virus - Los Angeles County
Garrigues JM , Hemarajata P , Karan A , Shah NK , Alarcón J , Marutani AN , Finn L , Smith TG , Gigante CM , Davidson W , Wynn NT , Hutson CL , Kim M , Terashita D , Balter SE , Green NM . Antimicrob Agents Chemother 2023 67 (7) e0056823 Tecovirimat (also known as TPOXX or ST-246) is a drug available for the treatment of mpox through the Centers for Disease Control and Prevention’s Expanded Access Investigational New Drug “compassionate use” protocol (https://www.cdc.gov/poxvirus/monkeypox/clinicians/Tecovirimat.html). In Los Angeles County, a fatal case of mpox with tecovirimat resistance was previously reported (1). Epidemiologic surveillance in Los Angeles County has since identified additional cases of severe mpox that did not improve after multiple rounds of tecovirimat treatment, including one involving a person who succumbed to infection (Table 1). Consistent with reports describing severe manifestations of mpox within the current global outbreak (1, 2), the identified cases involved host immunodeficiency due to advanced HIV infection. |
Transmission potential of vaccinated and unvaccinated persons infected with the SARS-CoV-2 Delta variant in a federal prison, July-August 2021.
Salvatore PP , Lee CC , Sleweon S , McCormick DW , Nicolae L , Knipe K , Dixon T , Banta R , Ogle I , Young C , Dusseau C , Salmonson S , Ogden C , Godwin E , Ballom T , Rhodes T , Wynn NT , David E , Bessey TK , Kim G , Suppiah S , Tamin A , Harcourt JL , Sheth M , Lowe L , Browne H , Tate JE , Kirking HL , Hagan LM . Vaccine 2022 41 (11) 1808-1818 BACKGROUND: The extent to which vaccinated persons who become infected with SARS-CoV-2 contribute to transmission is unclear. During a SARS-CoV-2 Delta variant outbreak among incarcerated persons with high vaccination rates in a federal prison, we assessed markers of viral shedding in vaccinated and unvaccinated persons. METHODS: Consenting incarcerated persons with confirmed SARS-CoV-2 infection provided mid-turbinate nasal specimens daily for 10 consecutive days and reported symptom data via questionnaire. Real-time reverse transcription-polymerase chain reaction (RT-PCR), viral whole genome sequencing, and viral culture was performed on these nasal specimens. Duration of RT-PCR positivity and viral culture positivity was assessed using survival analysis. RESULTS: A total of 957 specimens were provided by 93 participants, of whom 78 (84 %) were vaccinated and 17 (16 %) were unvaccinated. No significant differences were detected in duration of RT-PCR positivity among vaccinated participants (median: 13 days) versus those unvaccinated (median: 13 days; p = 0.50), or in duration of culture positivity (medians: 5 days and 5 days; p = 0.29). Among vaccinated participants, overall duration of culture positivity was shorter among Moderna vaccine recipients versus Pfizer (p = 0.048) or Janssen (p = 0.003) vaccine recipients. In post-hoc analyses, Moderna vaccine recipients demonstrated significantly shorter duration of culture positivity compared to unvaccinated participants (p = 0.02). When restricted to participants without reported prior infection, the difference between Moderna vaccine recipients and unvaccinated participants was more pronounced (medians: 3 days and 6 days, p = 0.002). CONCLUSIONS: Infectious periods for vaccinated and unvaccinated persons who become infected with SARS-CoV-2 are similar and can be highly variable, though some vaccinated persons are likely infectious for shorter durations. These findings are critically important, especially in congregate settings where viral transmission can lead to large outbreaks. In such settings, clinicians and public health practitioners should consider vaccinated, infected persons to be no less infectious than unvaccinated, infected persons. |
Monkeypox case investigation - Cook County Jail, Chicago, Illinois, July-August 2022
Hagan LM , Beeson A , Hughes S , Hassan R , Tietje L , Meehan AA , Spencer H , Turner J , Richardson M , Howard J , Schultz A , Ali S , Butler MM , Arce Garza D , Morgan CN , Kling C , Baird N , Townsend MB , Carson WC , Lowe D , Wynn NT , Black SR , Kerins JL , Rafinski J , Defuniak A , Auguston P , Mosites E , Ghinai I , Zawitz C . MMWR Morb Mortal Wkly Rep 2022 71 (40) 1271-1277 Knowledge about monkeypox transmission risk in congregate settings is limited. In July 2022, the Chicago Department of Public Health (CDPH) confirmed a case of monkeypox in a person detained in Cook County Jail (CCJ) in Chicago, Illinois. This case was the first identified in a correctional setting in the United States and reported to CDC during the 2022 multinational monkeypox outbreak. CDPH collaborated with CCJ, the Illinois Department of Public Health (IDPH), and CDC to evaluate transmission risk within the facility. Fifty-seven residents were classified as having intermediate-risk exposures to the patient with monkeypox during the 7-day interval between the patient's symptom onset and his isolation. (Intermediate-risk exposure was defined as potentially being within 6 ft of the patient with monkeypox for a total of ≥3 hours cumulatively, without wearing a surgical mask or respirator, or potentially having contact between their own intact skin or clothing and the skin lesions or body fluids from the patient or with materials that were in contact with the patient's skin lesions or body fluids.) No secondary cases were identified among a subset of 62% of these potentially exposed residents who received symptom monitoring, serologic testing, or both. Thirteen residents accepted postexposure prophylaxis (PEP), with higher acceptance among those who were offered counseling individually or in small groups than among those who were offered PEP together in a large group. Monkeypox virus (MPXV) DNA, but no viable virus, was detected on one surface in a dormitory where the patient had been housed with other residents before he was isolated. Although monkeypox transmission might be limited in similar congregate settings in the absence of higher-risk exposures, congregate facilities should maintain recommended infection control practices in response to monkeypox cases, including placing the person with monkeypox in medical isolation and promptly and thoroughly cleaning and disinfecting spaces where the person has spent time. In addition, officials should provide information to residents and staff members about monkeypox symptoms and transmission modes, facilitate confidential monkeypox risk and symptom disclosure and prompt medical evaluation for symptoms that are reported, and provide PEP counseling in a private setting. |
Orthopoxvirus Testing Challenges for Persons in Populations at Low Risk or Without Known Epidemiologic Link to Monkeypox - United States, 2022.
Minhaj FS , Petras JK , Brown JA , Mangla AT , Russo K , Willut C , Lee M , Beverley J , Harold R , Milroy L , Pope B , Gould E , Beeler C , Schneider J , Mostafa HH , Godfred-Cato S , Click ES , Borah BF , Galang RR , Cash-Goldwasser S , Wong JM , McCormick DW , Yu PA , Shelus V , Carpenter A , Schatzman S , Lowe D , Townsend MB , Davidson W , Wynn NT , Satheshkumar PS , O'Connor SM , O'Laughlin K , Rao AK , McCollum AM , Negrón ME , Hutson CL , Salzer JS . MMWR Morb Mortal Wkly Rep 2022 71 (36) 1155-1158 Since May 2022, approximately 20,000 cases of monkeypox have been identified in the United States, part of a global outbreak occurring in approximately 90 countries and currently affecting primarily gay, bisexual, and other men who have sex with men (MSM) (1). Monkeypox virus (MPXV) spreads from person to person through close, prolonged contact; a small number of cases have occurred in populations who are not MSM (e.g., women and children), and testing is recommended for persons who meet the suspected case definition* (1). CDC previously developed five real-time polymerase chain reaction (PCR) assays for detection of orthopoxviruses from lesion specimens (2,3). CDC was granted 510(k) clearance for the nonvariola-orthopoxvirus (NVO)-specific PCR assay by the Food and Drug Administration. This assay was implemented within the Laboratory Response Network (LRN) in the early 2000s and became critical for early detection of MPXV and implementation of public health action in previous travel-associated cases as well as during the current outbreak (4-7). PCR assays (NVO and other Orthopoxvirus laboratory developed tests [LDT]) represent the primary tool for monkeypox diagnosis. These tests are highly sensitive, and cross-contamination from other MPXV specimens being processed, tested, or both alongside negative specimens can occasionally lead to false-positive results. This report describes three patients who had atypical rashes and no epidemiologic link to a monkeypox case or known risk factors; these persons received diagnoses of monkeypox based on late cycle threshold (Ct) values ≥34, which were false-positive test results. The initial diagnoses were followed by administration of antiviral treatment (i.e., tecovirimat) and JYNNEOS vaccine postexposure prophylaxis (PEP) to patients' close contacts. After receiving subsequent testing, none of the three patients was confirmed to have monkeypox. Knowledge gained from these and other cases resulted in changes to CDC guidance. When testing for monkeypox in specimens from patients without an epidemiologic link or risk factors or who do not meet clinical criteria (or where these are unknown), laboratory scientists should reextract and retest specimens with late Ct values (based on this report, Ct ≥34 is recommended) (8). CDC can be consulted for complex cases including those that appear atypical or questionable cases and can perform additional viral species- and clade-specific PCR testing and antiorthopoxvirus serologic testing. |
Development of a new oral poliovirus vaccine for the eradication end game using codon deoptimization.
Konopka-Anstadt JL , Campagnoli R , Vincent A , Shaw J , Wei L , Wynn NT , Smithee SE , Bujaki E , Te Yeh M , Laassri M , Zagorodnyaya T , Weiner AJ , Chumakov K , Andino R , Macadam A , Kew O , Burns CC . NPJ Vaccines 2020 5 (1) 26 Enormous progress has been made in global efforts to eradicate poliovirus, using live-attenuated Sabin oral poliovirus vaccine (OPV). However, as the incidence of disease due to wild poliovirus has declined, vaccine-derived poliovirus (VDPV) has emerged in areas of low-vaccine coverage. Coordinated global cessation of routine, type 2 Sabin OPV (OPV2) use has not resulted in fewer VDPV outbreaks, and continued OPV use in outbreak-response campaigns has seeded new emergences in low-coverage areas. The limitations of existing vaccines and current eradication challenges warranted development of more genetically stable OPV strains, most urgently for OPV2. Here, we report using codon deoptimization to further attenuate Sabin OPV2 by changing preferred codons across the capsid to non-preferred, synonymous codons. Additional modifications to the 5' untranslated region stabilized known virulence determinants. Testing of this codon-deoptimized new OPV2 candidate (nOPV2-CD) in cell and animal models demonstrated that nOPV2-CD is highly attenuated, grows sufficiently for vaccine manufacture, is antigenically indistinguishable from Sabin OPV2, induces neutralizing antibodies as effectively as Sabin OPV2, and unlike Sabin OPV2 is genetically stable and maintains an attenuation phenotype. In-human clinical trials of nOPV2-CD are ongoing, with potential for nOPV strains to serve as critical vaccine tools for achieving and maintaining polio eradication. |
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