Lauren B Reoma, Tory P Johnson, Ken Cheung, Bryan R Smith, Liliana Pérez, Amanda Wiebold, Stephen A Migueles, Mark Connors, Eli A Boritz, Manahel Zahid, Chen Lai, Jessica Gill, Swati Shah, Anna Lyndaker, Peter D Burbelo, Frank Maldarelli, H Clifford Lane, Jong Shin, Dima A Hammoud, Govind Nair, Avindra Nath
Checkpoint inhibitors are being explored for chronic central nervous system (CNS) infections such as HIV, but safety data in the absence of malignancy are limited. In this phase I, non-randomized study, six virally suppressed individuals with HIV received a single dose of pembrolizumab to assess safety and effects on immune, virologic, and CNS parameters. Over 12 months, 29 adverse events occurred, all grade 1–2, with no serious events. HIV immune responses and viral loads were unchanged, although transient CSF viral increases occurred in two participants. A single dose pembrolizumab appears safe, supporting evaluation of repeated dosing.
{"title":"Safety, immunovirological, and CNS effects of PD-1 inhibition in people with HIV without malignancy","authors":"Lauren B Reoma, Tory P Johnson, Ken Cheung, Bryan R Smith, Liliana Pérez, Amanda Wiebold, Stephen A Migueles, Mark Connors, Eli A Boritz, Manahel Zahid, Chen Lai, Jessica Gill, Swati Shah, Anna Lyndaker, Peter D Burbelo, Frank Maldarelli, H Clifford Lane, Jong Shin, Dima A Hammoud, Govind Nair, Avindra Nath","doi":"10.1093/infdis/jiag127","DOIUrl":"https://doi.org/10.1093/infdis/jiag127","url":null,"abstract":"Checkpoint inhibitors are being explored for chronic central nervous system (CNS) infections such as HIV, but safety data in the absence of malignancy are limited. In this phase I, non-randomized study, six virally suppressed individuals with HIV received a single dose of pembrolizumab to assess safety and effects on immune, virologic, and CNS parameters. Over 12 months, 29 adverse events occurred, all grade 1–2, with no serious events. HIV immune responses and viral loads were unchanged, although transient CSF viral increases occurred in two participants. A single dose pembrolizumab appears safe, supporting evaluation of repeated dosing.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147373915","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Julia M Baker,Slavica Mijatovic-Rustempasic,Mary C Casey-Moore,Brendon White,Claire P Mattison,Rachel M Burke,Shannon C Conrey,Ardythe L Morrow,Daniel C Payne,Rashi Gautam,Umesh D Parashar,Jacqueline E Tate,Mary Allen Staat,Monica M McNeal
BACKGROUNDMitigating the underlying causes of differential immunity from rotavirus infection and vaccination requires a comprehensive understanding of rotavirus natural history and immune response. A US-based birth cohort provides a unique opportunity to longitudinally examine rotavirus immune response.METHODSSerum was collected from children at birth (cord blood), 6 weeks, and 6, 12, 18 and 24 months of age. Maternally-derived rotavirus-specific IgG (birth samples) and rotavirus-specific IgA and IgG (6-week through 24-month samples) were measured via enzyme immunoassay. Stool samples were collected weekly and during episodes of acute gastroenteritis to identify rotavirus infections. Serum samples prior to and after infection or vaccination were compared to assess their impact on IgA geometric mean titers (GMT). A Generalized Estimating Equation was fit to identify predictors of IgA GMT.RESULTSThe median change in IgA GMT from vaccination comparing 6-week and 6-month samples was 38.4 U/mL [IQR 4.4-138.1]. The change in IgA following infection varied widely (median=64.5 [IQR-2.0-192.9]) with pre- and post-infection GMTs of 35.7 U/mL (95% CI:21.4-59.6) and 102.6 U/mL (95% CI:41.1-256.0), respectively. In adjusted analyses, IgA GMT was higher when mother and/or child was a secretor (ratio of means (RoM)=1.3, 95% CI: 1.1-1.4) compared to non-secretor mother-child pairs. Being fully vaccinated was more strongly associated with IgA GMT in the first (RoM=1.9, 95% CI: 1.7-2.0) compared to the second year of life (RoM=1.3, 95% CI: 1.0-1.7).CONCLUSIONSThis longitudinal assessment of rotavirus-specific immune response contributes to our understanding of multifactorial drivers of rotavirus immunity in a post-vaccine setting.
{"title":"Rotavirus-specific IgA and IgG Patterns During the First Two Years of Life in the PREVAIL Birth Cohort.","authors":"Julia M Baker,Slavica Mijatovic-Rustempasic,Mary C Casey-Moore,Brendon White,Claire P Mattison,Rachel M Burke,Shannon C Conrey,Ardythe L Morrow,Daniel C Payne,Rashi Gautam,Umesh D Parashar,Jacqueline E Tate,Mary Allen Staat,Monica M McNeal","doi":"10.1093/infdis/jiag141","DOIUrl":"https://doi.org/10.1093/infdis/jiag141","url":null,"abstract":"BACKGROUNDMitigating the underlying causes of differential immunity from rotavirus infection and vaccination requires a comprehensive understanding of rotavirus natural history and immune response. A US-based birth cohort provides a unique opportunity to longitudinally examine rotavirus immune response.METHODSSerum was collected from children at birth (cord blood), 6 weeks, and 6, 12, 18 and 24 months of age. Maternally-derived rotavirus-specific IgG (birth samples) and rotavirus-specific IgA and IgG (6-week through 24-month samples) were measured via enzyme immunoassay. Stool samples were collected weekly and during episodes of acute gastroenteritis to identify rotavirus infections. Serum samples prior to and after infection or vaccination were compared to assess their impact on IgA geometric mean titers (GMT). A Generalized Estimating Equation was fit to identify predictors of IgA GMT.RESULTSThe median change in IgA GMT from vaccination comparing 6-week and 6-month samples was 38.4 U/mL [IQR 4.4-138.1]. The change in IgA following infection varied widely (median=64.5 [IQR-2.0-192.9]) with pre- and post-infection GMTs of 35.7 U/mL (95% CI:21.4-59.6) and 102.6 U/mL (95% CI:41.1-256.0), respectively. In adjusted analyses, IgA GMT was higher when mother and/or child was a secretor (ratio of means (RoM)=1.3, 95% CI: 1.1-1.4) compared to non-secretor mother-child pairs. Being fully vaccinated was more strongly associated with IgA GMT in the first (RoM=1.9, 95% CI: 1.7-2.0) compared to the second year of life (RoM=1.3, 95% CI: 1.0-1.7).CONCLUSIONSThis longitudinal assessment of rotavirus-specific immune response contributes to our understanding of multifactorial drivers of rotavirus immunity in a post-vaccine setting.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"43 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346444","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Advances in basic and translational HIV research have refined our understanding of viral persistence while informing new strategies aimed at prevention and durable virologic control. Here, we present an overview of selected advances in HIV vaccine development, cure-directed strategies, and new insights into the mechanisms of HIV persistence, highlighting key basic and translational studies published over the past year and featured in What's Hot in HIV Basic Science 2025. Notable progress includes promising results in germline-targeting and sequential immunization for the induction of broadly neutralizing antibody precursors, a better understanding of the mechanisms of reservoir persistence and encouraging signals that immune-based strategies can lead to post-intervention control. Collectively, these insights emphasize the value of experimental medicine trials and underscore a shift toward more precise, mechanism-informed strategies for HIV prevention and cure, pointing to a future in which durable virologic control may be achievable through rationally designed combination approaches.
{"title":"What's Hot in HIV in 2025-A Basic and Translational Science Review from IDWeek 2025.","authors":"Ana Rafaela Teixeira,Marina Caskey","doi":"10.1093/infdis/jiag135","DOIUrl":"https://doi.org/10.1093/infdis/jiag135","url":null,"abstract":"Advances in basic and translational HIV research have refined our understanding of viral persistence while informing new strategies aimed at prevention and durable virologic control. Here, we present an overview of selected advances in HIV vaccine development, cure-directed strategies, and new insights into the mechanisms of HIV persistence, highlighting key basic and translational studies published over the past year and featured in What's Hot in HIV Basic Science 2025. Notable progress includes promising results in germline-targeting and sequential immunization for the induction of broadly neutralizing antibody precursors, a better understanding of the mechanisms of reservoir persistence and encouraging signals that immune-based strategies can lead to post-intervention control. Collectively, these insights emphasize the value of experimental medicine trials and underscore a shift toward more precise, mechanism-informed strategies for HIV prevention and cure, pointing to a future in which durable virologic control may be achievable through rationally designed combination approaches.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"27 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147346445","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Christian Rosas-Salazar,Tebeb Gebretsadik,James D Chappell,R Stokes Peebles,William D Dupont,Meghan H Shilts,Samadhan J Jadhao,Larry J Anderson,Suman R Das,Tina V Hartert
Our objective was to test the hypothesis that respiratory syncytial virus (RSV) infection during infancy with genotypes containing previously reported G gene sequence duplications (Gdups) is associated with an increased risk of childhood asthma. In a population-based, prospective, birth cohort of healthy, term children, we found that children with RSV-A Gdup+ (adjusted odds ratio [aOR] = 2.00, 95%CI = 1.15-3.47) and RSV-B Gdup + (aOR = 1.78, 95%CI = 1.01-3.11) infections during infancy had higher odds of 5-year current asthma than those without RSV infection during infancy. These findings are proof-of-concept evidence that RSV genetic variation is associated with variable childhood asthma risk.
我们的目的是验证这样一种假设，即在婴儿时期感染含有先前报道的G基因序列重复（Gdups）的呼吸道合胞病毒（RSV）与儿童哮喘风险增加有关。在以人群为基础的健康足月儿童出生队列中，我们发现婴儿期感染RSV- a Gdup+（校正优势比[aOR] = 2.00, 95%CI = 1.15-3.47）和RSV- b Gdup+ (aOR = 1.78, 95%CI = 1.01-3.11)的儿童5年当前哮喘的发生率高于婴儿期未感染RSV的儿童。这些发现是RSV基因变异与可变儿童哮喘风险相关的概念验证证据。
{"title":"Infant Infection With Respiratory Syncytial Virus Genotypes and Subsequent Childhood Asthma Risk.","authors":"Christian Rosas-Salazar,Tebeb Gebretsadik,James D Chappell,R Stokes Peebles,William D Dupont,Meghan H Shilts,Samadhan J Jadhao,Larry J Anderson,Suman R Das,Tina V Hartert","doi":"10.1093/infdis/jiag104","DOIUrl":"https://doi.org/10.1093/infdis/jiag104","url":null,"abstract":"Our objective was to test the hypothesis that respiratory syncytial virus (RSV) infection during infancy with genotypes containing previously reported G gene sequence duplications (Gdups) is associated with an increased risk of childhood asthma. In a population-based, prospective, birth cohort of healthy, term children, we found that children with RSV-A Gdup+ (adjusted odds ratio [aOR] = 2.00, 95%CI = 1.15-3.47) and RSV-B Gdup + (aOR = 1.78, 95%CI = 1.01-3.11) infections during infancy had higher odds of 5-year current asthma than those without RSV infection during infancy. These findings are proof-of-concept evidence that RSV genetic variation is associated with variable childhood asthma risk.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147329534","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Chris K P Mok,Airu Zhu,Jamiu O Oladipo,Haoshi Bai,Samuel M S Cheng,Sulyman A Kuranga,Huibin Lv,Jincun Zhao,Malik Peiris
Middle East respiratory syndrome coronavirus (MERS-CoV) is assessed to have high pandemic risk, and dromedary camels are the source of zoonotic spillover. More than 75% of MERS-CoV-infected dromedary camels are found in Africa, but no zoonotic disease has been reported from Africa where there is little awareness of MERS-CoV as a potential cause of respiratory disease. Antibody responses are a poor indicator of mild infection. We found that 47 of 60 (78%) dromedary camel abattoir workers in Kano, Nigeria, had MERS-CoV-specific T-cell responses while none of 18 controls did, suggesting that zoonotic infection is common in camel-exposed individuals in Africa.
{"title":"Middle East Respiratory Syndrome Coronavirus-Specific T-Cell Responses in Dromedary Camel Abattoir Workers in Nigeria Suggests Frequent Zoonotic Spillover.","authors":"Chris K P Mok,Airu Zhu,Jamiu O Oladipo,Haoshi Bai,Samuel M S Cheng,Sulyman A Kuranga,Huibin Lv,Jincun Zhao,Malik Peiris","doi":"10.1093/infdis/jiag095","DOIUrl":"https://doi.org/10.1093/infdis/jiag095","url":null,"abstract":"Middle East respiratory syndrome coronavirus (MERS-CoV) is assessed to have high pandemic risk, and dromedary camels are the source of zoonotic spillover. More than 75% of MERS-CoV-infected dromedary camels are found in Africa, but no zoonotic disease has been reported from Africa where there is little awareness of MERS-CoV as a potential cause of respiratory disease. Antibody responses are a poor indicator of mild infection. We found that 47 of 60 (78%) dromedary camel abattoir workers in Kano, Nigeria, had MERS-CoV-specific T-cell responses while none of 18 controls did, suggesting that zoonotic infection is common in camel-exposed individuals in Africa.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"70 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-03-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147329539","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Li Wang, Jieru Wang, Jaber Hossain, Hans C Cooper, Cindy Adolphus, Michael Currier, Ginger Atteberry, Chenchen Feng, Marie K Kirby, Han Di, John R Barnes, Taronna R Maines, Tracie L Williams, John R Barr, Li-Mei Chen, Terrence M Tumpey, Ruben O Donis, C Todd Davis, Vivien G Dugan, David E Wentworth, Bin Zhou
High pathogenicity avian influenza A(H5) viruses pose a pandemic threat. These viruses have rapidly evolved in birds and frequently crossed species barriers, resulting in over 1,000 confirmed human infections, with a case fatality proportion of approximately 50%. In response, the U.S. CDC has developed dozens of A(H5) candidate vaccine viruses (CVVs) over the past two decades, primarily targeting clades known to infect humans. This report summarizes the development and characterization of the CVVs, with a particular focus on their antigenic relationships with clades 2.3.2.1e and 2.3.4.4b A(H5N1) viruses, which have been responsible for the majority of recent human infections.
高致病性甲型禽流感（H5）病毒构成大流行威胁。这些病毒在鸟类中迅速进化，并经常跨越物种屏障，导致1000多例确诊人间感染，病死率约为50%。作为回应，美国疾病控制与预防中心在过去二十年中开发了数十种A（H5）候选疫苗病毒（cvv），主要针对已知感染人类的分支。本报告总结了cvv的发展和特征，特别侧重于它们与2.3.2.1e和2.3.4.4b a （H5N1）进化支的抗原关系，这两个进化支是最近大多数人类感染的原因。
{"title":"Development and Characterization of Candidate Vaccine Viruses against High Pathogenicity Avian Influenza A(H5) Viruses for Rapid Pandemic Response","authors":"Li Wang, Jieru Wang, Jaber Hossain, Hans C Cooper, Cindy Adolphus, Michael Currier, Ginger Atteberry, Chenchen Feng, Marie K Kirby, Han Di, John R Barnes, Taronna R Maines, Tracie L Williams, John R Barr, Li-Mei Chen, Terrence M Tumpey, Ruben O Donis, C Todd Davis, Vivien G Dugan, David E Wentworth, Bin Zhou","doi":"10.1093/infdis/jiag132","DOIUrl":"https://doi.org/10.1093/infdis/jiag132","url":null,"abstract":"High pathogenicity avian influenza A(H5) viruses pose a pandemic threat. These viruses have rapidly evolved in birds and frequently crossed species barriers, resulting in over 1,000 confirmed human infections, with a case fatality proportion of approximately 50%. In response, the U.S. CDC has developed dozens of A(H5) candidate vaccine viruses (CVVs) over the past two decades, primarily targeting clades known to infect humans. This report summarizes the development and characterization of the CVVs, with a particular focus on their antigenic relationships with clades 2.3.2.1e and 2.3.4.4b A(H5N1) viruses, which have been responsible for the majority of recent human infections.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"113 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147314862","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jennifer J Fowler, Amanda Metz, Meghan Barnes, Shannon L Gearhart, Thomas D Filardo, Brian Wakeman, Jessica Prince-Guerra, Heather Colley, Thuy Kim, Francis Chu, Kristen Pringle, Adria D Mathis, Kelley Raines, Abbi Berg, Danni Pinnick, Sara Bowman, Sara Lovett, Jayne Griffith, Emma Stanislawski, Erin Phipps, Olivia Arizmendi, Kimberly Singler, David Sugerman, Clive Brown, Sundari Mase, Alida M Gertz
Objective Travelers who fly on commercial aircraft while infectious with measles are reported to CDC by health departments. CDC contacts airlines to collect information on potentially exposed travelers. Traveler locating information is shared with health departments to facilitate aircraft contact investigations. In May 2025, CDC was notified of a traveler who flew from Europe to Colorado while infectious with measles, transited through Denver International Airport, then flew from Colorado to North Dakota. This report describes details of the subsequent contact investigations, environmental assessment, and laboratory testing results. Methods CDC laboratories conducted testing on a majority of case samples. Data from the CDC laboratory, CDC’s Port Health Activity Reporting System, and health department investigations were analyzed to describe the index case, contacts, test results, and travel details. Flight records and visual inspection were used to describe relative locations of index and secondary case-patients at Denver International Airport. Results The index case was in an unvaccinated adult. Aircraft contact investigations identified 135 exposed domestic travelers. Fifteen secondary cases were identified among people exposed during the international (5) and domestic (3) flights, and at the airport (7). Two tertiary case-patients were also identified. Five of the secondary case-patients had at least one documented prior measles vaccination. Conclusion Measles transmission may occur during travel. Measles vaccination is recommended prior to international travel for all travelers aged 6 months or older. Travelers with fever and other overt signs of transmissible illness, such as coughing or malaise, should be strongly encouraged to delay travel while symptomatic.
{"title":"Multiple Measles Transmission Events Associated with a Single Traveler Arriving in the United States, May 2025","authors":"Jennifer J Fowler, Amanda Metz, Meghan Barnes, Shannon L Gearhart, Thomas D Filardo, Brian Wakeman, Jessica Prince-Guerra, Heather Colley, Thuy Kim, Francis Chu, Kristen Pringle, Adria D Mathis, Kelley Raines, Abbi Berg, Danni Pinnick, Sara Bowman, Sara Lovett, Jayne Griffith, Emma Stanislawski, Erin Phipps, Olivia Arizmendi, Kimberly Singler, David Sugerman, Clive Brown, Sundari Mase, Alida M Gertz","doi":"10.1093/infdis/jiag129","DOIUrl":"https://doi.org/10.1093/infdis/jiag129","url":null,"abstract":"Objective Travelers who fly on commercial aircraft while infectious with measles are reported to CDC by health departments. CDC contacts airlines to collect information on potentially exposed travelers. Traveler locating information is shared with health departments to facilitate aircraft contact investigations. In May 2025, CDC was notified of a traveler who flew from Europe to Colorado while infectious with measles, transited through Denver International Airport, then flew from Colorado to North Dakota. This report describes details of the subsequent contact investigations, environmental assessment, and laboratory testing results. Methods CDC laboratories conducted testing on a majority of case samples. Data from the CDC laboratory, CDC’s Port Health Activity Reporting System, and health department investigations were analyzed to describe the index case, contacts, test results, and travel details. Flight records and visual inspection were used to describe relative locations of index and secondary case-patients at Denver International Airport. Results The index case was in an unvaccinated adult. Aircraft contact investigations identified 135 exposed domestic travelers. Fifteen secondary cases were identified among people exposed during the international (5) and domestic (3) flights, and at the airport (7). Two tertiary case-patients were also identified. Five of the secondary case-patients had at least one documented prior measles vaccination. Conclusion Measles transmission may occur during travel. Measles vaccination is recommended prior to international travel for all travelers aged 6 months or older. Travelers with fever and other overt signs of transmissible illness, such as coughing or malaise, should be strongly encouraged to delay travel while symptomatic.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"19 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-25","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147314864","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Jiayi Wang, Madalina E Carter-Timofte, Birgit Ritter, Michelle M Thomsen, Abel Viejo-Borbolla, Trine H Mogensen
Introduction Varicella zoster virus (VZV) is a ubiquitous human alphaherpesvirus, latently present in the majority of the population. Knowledge on the molecular mechanisms underlying VZV reactivation from peripheral ganglia is incomplete, as is our understanding of why only a small number of individuals develop life-threatening complications following reactivation. Previously, we have reported a pathogenic mutation in the POLR3F subunit of the cytosolic DNA sensor RNA polymerase III in two monozygotic twins diagnosed with recurring encephalitis and vasculitis, caused by VZV reactivation. Objective The main objective of this study was to determine the role of POLR3F mutations in VZV pathogenesis in a model of viral reactivation Methods We generated human SH-SY5Y (POLR3F+/-) knockout cells. We determined the impact of POLR3F heterozygosity on VZV control during acute infection of differentiated SH-SY5Y neuronal cells by quantifying gene expression by RT-qPCR. We also established a quiescent infection model and quantified spontaneous reactivation by detection of viral proteins fused to fluorophores. Results VZV infection of undifferentiated as well as terminally differentiated early passage SH-SY5Y cells resulted in higher viral gene expression and more VZV reactivation in the POLR3F neuronal heterozygous (POLR3F+/-) knockout cells, reflecting the patient phenotype, compared to wild type cells. Conclusion This work identifies a novel role for POLR3F as a sentinel for VZV reactivation in neuronal cells and lends further support to the hypothesis that POL III plays a role in immunity to VZV mainly upon reactivation in humans and that POL III defects predispose to VZV central nervous system infection.
{"title":"RNA Polymerase III suppresses varicella zoster virus in human neurons","authors":"Jiayi Wang, Madalina E Carter-Timofte, Birgit Ritter, Michelle M Thomsen, Abel Viejo-Borbolla, Trine H Mogensen","doi":"10.1093/infdis/jiag117","DOIUrl":"https://doi.org/10.1093/infdis/jiag117","url":null,"abstract":"Introduction Varicella zoster virus (VZV) is a ubiquitous human alphaherpesvirus, latently present in the majority of the population. Knowledge on the molecular mechanisms underlying VZV reactivation from peripheral ganglia is incomplete, as is our understanding of why only a small number of individuals develop life-threatening complications following reactivation. Previously, we have reported a pathogenic mutation in the POLR3F subunit of the cytosolic DNA sensor RNA polymerase III in two monozygotic twins diagnosed with recurring encephalitis and vasculitis, caused by VZV reactivation. Objective The main objective of this study was to determine the role of POLR3F mutations in VZV pathogenesis in a model of viral reactivation Methods We generated human SH-SY5Y (POLR3F+/-) knockout cells. We determined the impact of POLR3F heterozygosity on VZV control during acute infection of differentiated SH-SY5Y neuronal cells by quantifying gene expression by RT-qPCR. We also established a quiescent infection model and quantified spontaneous reactivation by detection of viral proteins fused to fluorophores. Results VZV infection of undifferentiated as well as terminally differentiated early passage SH-SY5Y cells resulted in higher viral gene expression and more VZV reactivation in the POLR3F neuronal heterozygous (POLR3F+/-) knockout cells, reflecting the patient phenotype, compared to wild type cells. Conclusion This work identifies a novel role for POLR3F as a sentinel for VZV reactivation in neuronal cells and lends further support to the hypothesis that POL III plays a role in immunity to VZV mainly upon reactivation in humans and that POL III defects predispose to VZV central nervous system infection.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147287441","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Brittany A Riggle, Athanasios Chamzas, Mathangi Gopalakrishnan, Osward M Nyirenda, Nginache Nampota-Nkomba, Jane E Mallewa, Rhoda Masonga, Cynthia Manyozo, Kingsley Zuze, Alice M Liomba, Jesse Alt, Rana Rais, Barbara Slusher, Neshen Moodley, Louis H Miller, Susan K Pierce, Nicole O’Brien, Matthew B Laurens, Douglas G Postels
Background Cerebral malaria (CM) is a common cause of febrile coma among African children. Despite treatment with highly efficacious intravenous artesunate, CM remains associated with high mortality and neurologic sequelae. In a mouse CM model, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) demonstrated robust efficacy as a potential adjuvant therapy. Before testing DON in children with CM, we investigated tolerability in African adults, including individuals with malaria. Methods We conducted an open-label, prospective, dose-escalation, Phase I clinical trial of single dose intravenous DON in Blantyre, Malawi. Participants included healthy adults and adults with uncomplicated malaria, enrolled in dose-cohorts of ten and administered DON at 0.1, 1.0, 5.0, or 10 mg/kg. We assessed adverse events (AEs) and plasma pharmacokinetics. Results Forty healthy adults and 38 adults with uncomplicated malaria received DON. Transient, asymptomatic creatinine elevation occurred 12 hours post-infusion in 18% of all participants. Nausea and vomiting were uncommon at 0.1 and 1.0 mg/kg but occurred more frequently at 5.0 and 10 mg/kg DON. All DON-related AEs resolved rapidly, without sequelae, and did not significantly differ between healthy and uncomplicated malaria participants. In healthy adults, maximum plasma concentrations increased proportional to dose, but adults with malaria had greater than dose-proportional increases. Terminal half-life ranged from 1.7–4.1 hours. Conclusions DON was well tolerated in healthy adults and adults with uncomplicated malaria. Higher doses were associated with transient gastrointestinal AEs. Pharmacokinetics were minimally influenced by malaria disease. These results provide critical data to guide dosing strategies for adjunctive DON in children with CM. ClinicalTrials.gov: NCT05478720
背景：脑疟疾（CM）是非洲儿童发热性昏迷的常见病因。尽管采用高效的静脉注射青蒿琥酯治疗，CM仍然与高死亡率和神经系统后遗症相关。在小鼠CM模型中，谷氨酰胺拮抗剂6-重氮-5-氧- l -去甲亮氨酸（DON）作为一种潜在的辅助治疗显示出强大的疗效。在对患有CM的儿童进行DON检测之前，我们调查了非洲成年人（包括疟疾患者）的耐受性。方法我们在马拉维布兰太尔进行了一项开放标签、前瞻性、剂量递增、单剂量静脉注射DON的I期临床试验。参与者包括健康成年人和患有无并发症疟疾的成年人，他们被纳入10人的剂量队列，并按0.1、1.0、5.0或10 mg/kg给予DON。我们评估了不良事件（ae）和血浆药代动力学。结果40名健康成人和38名无并发症疟疾成人接受了DON治疗。在所有参与者中，18%的人在输注后12小时出现短暂的无症状肌酐升高。当浓度为0.1和1.0 mg/kg时，恶心和呕吐不常见，但当浓度为5.0和10 mg/kg时，恶心和呕吐更常见。所有与don相关的不良反应都迅速消退，无后遗症，并且在健康和非复杂疟疾参与者之间没有显著差异。在健康成人中，最大血浆浓度与剂量成正比增加，但患有疟疾的成人的增幅大于剂量比例。终端半衰期为1.7-4.1小时。结论DON在健康成人和无并发症疟疾患者中耐受性良好。较高剂量与短暂性胃肠道不良反应相关。药代动力学受疟疾影响最小。这些结果为指导CM患儿辅助性DON的给药策略提供了关键数据。ClinicalTrials.gov: NCT05478720
{"title":"Safety, tolerability, and pharmacokinetics of 6-diazo-5-oxo-L-norleucine (DON) in Malawian adults with and without malaria: a Phase I dose-escalation clinical trial","authors":"Brittany A Riggle, Athanasios Chamzas, Mathangi Gopalakrishnan, Osward M Nyirenda, Nginache Nampota-Nkomba, Jane E Mallewa, Rhoda Masonga, Cynthia Manyozo, Kingsley Zuze, Alice M Liomba, Jesse Alt, Rana Rais, Barbara Slusher, Neshen Moodley, Louis H Miller, Susan K Pierce, Nicole O’Brien, Matthew B Laurens, Douglas G Postels","doi":"10.1093/infdis/jiag121","DOIUrl":"https://doi.org/10.1093/infdis/jiag121","url":null,"abstract":"Background Cerebral malaria (CM) is a common cause of febrile coma among African children. Despite treatment with highly efficacious intravenous artesunate, CM remains associated with high mortality and neurologic sequelae. In a mouse CM model, the glutamine antagonist 6-diazo-5-oxo-L-norleucine (DON) demonstrated robust efficacy as a potential adjuvant therapy. Before testing DON in children with CM, we investigated tolerability in African adults, including individuals with malaria. Methods We conducted an open-label, prospective, dose-escalation, Phase I clinical trial of single dose intravenous DON in Blantyre, Malawi. Participants included healthy adults and adults with uncomplicated malaria, enrolled in dose-cohorts of ten and administered DON at 0.1, 1.0, 5.0, or 10 mg/kg. We assessed adverse events (AEs) and plasma pharmacokinetics. Results Forty healthy adults and 38 adults with uncomplicated malaria received DON. Transient, asymptomatic creatinine elevation occurred 12 hours post-infusion in 18% of all participants. Nausea and vomiting were uncommon at 0.1 and 1.0 mg/kg but occurred more frequently at 5.0 and 10 mg/kg DON. All DON-related AEs resolved rapidly, without sequelae, and did not significantly differ between healthy and uncomplicated malaria participants. In healthy adults, maximum plasma concentrations increased proportional to dose, but adults with malaria had greater than dose-proportional increases. Terminal half-life ranged from 1.7–4.1 hours. Conclusions DON was well tolerated in healthy adults and adults with uncomplicated malaria. Higher doses were associated with transient gastrointestinal AEs. Pharmacokinetics were minimally influenced by malaria disease. These results provide critical data to guide dosing strategies for adjunctive DON in children with CM. ClinicalTrials.gov: NCT05478720","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"54 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147292745","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background A two-dose hepatitis B vaccination schedule is highly immunogenic in children aged ≥1 year, but data for infants are scarce. Our goal was to compare the immunogenicity of two- and three-dose hepatitis B vaccination schedules in this population. Methods Children in the experimental group were recruited at 2 months of age and randomized to receive a homologous (Infanrix-hexa/Infanrix-hexa) or heterologous (Infanrix-hexa/Twinrix) two-dose schedule at 2 and 12 months. Children in the control group were recruited at 18 months and had received a homologous three-dose schedule (Infanrix-hexa/Infanrix-hexa/Infanrix-hexa) at 2, 4 and 18 months. All groups received a challenge dose (Twinrix) three years later. Results One month after the primary series, seroprotection rates (anti-HBs ≥10 mIU/mL) were high and similar among the three groups (heterologous two-dose, 91.7%; homologous two-dose, 90.9%; three-dose, 94.2%). Geometric mean titers (GMTs) were lower in the two-dose groups than in the three-dose group. Post-challenge dose, the majority exhibited an anamnestic response, similar across all three groups (heterologous two-dose, 97.2%; homologous two-dose, 95.5%; three-dose, 92.7%). GMTs were numerically higher in the heterologous two-dose group (9380.5 mIU/mL) than in the three-dose group (6900.6 mIU/mL) (p=0.4). The proportion exhibiting local reactions was significantly lower after the heterologous two-dose schedule than after the homologous two-dose schedule. Conclusion The anamnestic response three years after two- (2, 12 months) and three-dose (2, 4, 18 months) hepatitis B vaccination schedules was similar. The heterologous two-dose schedule was more immunogenic and less reactogenic than the homologous two-dose schedule.
{"title":"Immunogenicity of two versus three doses of hepatitis B vaccine when administered to children aged 2-18 months: a randomized clinical trial.","authors":"Koffi Barnabé Kegbevi, Yossi Febriani, Chantal Sauvageau, Marie-Michelle Ursu, Caroline Quach, Michaël Desjardins, Julie Bestman-Smith, Vladmir Gilca, Nicholas Brousseau","doi":"10.1093/infdis/jiag122","DOIUrl":"https://doi.org/10.1093/infdis/jiag122","url":null,"abstract":"Background A two-dose hepatitis B vaccination schedule is highly immunogenic in children aged ≥1 year, but data for infants are scarce. Our goal was to compare the immunogenicity of two- and three-dose hepatitis B vaccination schedules in this population. Methods Children in the experimental group were recruited at 2 months of age and randomized to receive a homologous (Infanrix-hexa/Infanrix-hexa) or heterologous (Infanrix-hexa/Twinrix) two-dose schedule at 2 and 12 months. Children in the control group were recruited at 18 months and had received a homologous three-dose schedule (Infanrix-hexa/Infanrix-hexa/Infanrix-hexa) at 2, 4 and 18 months. All groups received a challenge dose (Twinrix) three years later. Results One month after the primary series, seroprotection rates (anti-HBs ≥10 mIU/mL) were high and similar among the three groups (heterologous two-dose, 91.7%; homologous two-dose, 90.9%; three-dose, 94.2%). Geometric mean titers (GMTs) were lower in the two-dose groups than in the three-dose group. Post-challenge dose, the majority exhibited an anamnestic response, similar across all three groups (heterologous two-dose, 97.2%; homologous two-dose, 95.5%; three-dose, 92.7%). GMTs were numerically higher in the heterologous two-dose group (9380.5 mIU/mL) than in the three-dose group (6900.6 mIU/mL) (p=0.4). The proportion exhibiting local reactions was significantly lower after the heterologous two-dose schedule than after the homologous two-dose schedule. Conclusion The anamnestic response three years after two- (2, 12 months) and three-dose (2, 4, 18 months) hepatitis B vaccination schedules was similar. The heterologous two-dose schedule was more immunogenic and less reactogenic than the homologous two-dose schedule.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"12 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-02-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"147287442","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
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