Conformational ensemble-based framework enables rapid development of Lassa virus vaccine candidates DOI Creative Commons
Nitesh Mishra, Gabriel Avillion, Sean Callaghan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

Lassa virus (LASV), an arenavirus endemic to West Africa, poses a significant public health threat due its high pathogenicity and expanding geographic risk zone. LASV glycoprotein complex (GPC) is the only known target of neutralizing antibodies, but inherent metastability conformational flexibility have hindered development GPC-based vaccines. We employed variant AlphaFold2 (AF2), called subsampled AF2, generate diverse structures GPC that capture array potential states using MSA subsampling dropout layers. Conformational ensembles identified several metamorphic domains-areas flexibility-that could be targeted stabilize in immunogenic prefusion state. ProteinMPNN was then used redesign sequences minimize mobility domains. These redesigned were further filtered leading identification promising variants for testing. A small library experimentally validated showed significantly increased protein yields compared controls. Antigenic profiles indicated these preserved essential epitopes effective immune response, suggesting their broad protective efficacy. Our results demonstrate AI-driven approaches can predict landscape pathogens. This knowledge viral proteins, such as GPC, conformation, optimizing them stability expression, offering streamlined framework vaccine design. deep learning / machine enabled contributes global efforts combat has broader implications design pandemic preparedness.

Language: Английский

Therapeutic administration of a cross-reactive mAb targeting the fusion glycoprotein of Nipah virus protects nonhuman primates DOI
Larry Zeitlin, Robert W. Cross, Courtney Woolsey

et al.

Science Translational Medicine, Journal Year: 2024, Volume and Issue: 16(741)

Published: April 3, 2024

No licensed vaccines or therapies exist for patients infected with Nipah virus (NiV), although an experimental human monoclonal antibody (mAb) cross-reactive to the NiV and Hendra (HeV) G glycoprotein, m102.4, has been tested in a phase 1 trial provided under compassionate use both HeV exposures. is highly pathogenic zoonotic paramyxovirus causing regular outbreaks humans animals South Southeast Asia. The mortality rate of infection ranges from 40% more than 90%, making it substantial public health concern. glycoprotein mediates host cell attachment, F facilitates membrane fusion infection. We hypothesized that mAb against prefusion conformation may confer better protection m102.4. To test this, two potent neutralizing mAbs protein, hu1F5 hu12B2, were compared hamster model. Hu1F5 superior hu12B2 was selected comparison m102.4 ability protect African green monkeys (AGMs) stringent challenge. AGMs exposed intranasally Bangladesh strain treated 5 days after exposure either (25 milligrams per kilogram). Whereas only one six survived until study end point, all protected. Furthermore, reduced 10 kilogram dose also complete challenge, supporting upcoming clinical advancement this postexposure prophylaxis therapy.

Language: Английский

Citations

10
Study of the immunological efficacy and safety of a candidate vaccine against Lassa hemorrhagic fever DOI Creative Commons

O. Popova,

Olga V. Zubkova, Tatiana A. Ozharovskaia

et al.

Medical Immunology (Russia), Journal Year: 2025, Volume and Issue: 27(1), P. 153 - 168

Published: Jan. 8, 2025

Lassa hemorrhagic fever is an acute human infectious disease with high mortality rate and pandemic potential. To date, there are no approved drugs for the specific treatment or prevention of in world. The aim this study was to develop evaluate immunobiological properties preclinical safety a candidate vaccine (LHF) based on recombinant adenoviral vectors. Standard genetic engineering techniques, molecular biology virological methods, animal testing procedures were used course study. A combined vector has been designed characterized. composed two components heterologous immunization prime-boost regimen. Both replication-defective adenovirus first component type 26; second 5. vectors contain codon-optimized sequence virus glycoprotein. Two experimental batches produced under GMP-conditions analyzed. results studies compliance appropriate specifications viral vaccines provided. In mice, antigen-specific IgG response detected after components, either separately, time dynamics also studied 42, 77, 119 147 days immunization. At same time, despite achieving 100% seroconversion, neutralizing antibodies any samples collected from immunized mice. biodistribution showed that 24 hours following intramuscular injection DNA only at site regional lymph nodes. Based assessments (including toxicity, chronic immunotoxicity, allergenic properties, reproductive toxicity), contraindications found initiation clinical trials. Taken together, demonstrate types 26 5 promising drug immunoprophylaxis.

Language: Английский

Citations

0
Lassa virus protein–protein interactions as mediators of Lassa fever pathogenesis DOI Creative Commons

Sharon Jan,

Kruttika S. Phadke, Victor L. Lam

et al.

Virology Journal, Journal Year: 2025, Volume and Issue: 22(1)

Published: Feb. 28, 2025

Abstract Viral hemorrhagic Lassa fever (LF), caused by virus (LASV), is a significant public health concern endemic in West Africa with high morbidity and mortality rates, limited treatment options, potential for international spread. Despite advances interrogating its epidemiology clinical manifestations, the molecular mechanisms driving pathogenesis of LASV other arenaviruses remain incompletely understood. This review synthesizes current knowledge regarding role host-virus interactions mediating LF, emphasis on between viral host proteins. Through investigation these critical protein–protein interactions, we identify therapeutic targets discuss their implications development medical countermeasures including antiviral drugs. provides an update recent literature important informing targeted therapies improving outcomes LF patients. Knowledge gaps are highlighted as opportunities future research efforts that would advance field arenavirus pathogenesis.

Language: Английский

Citations

0
Preclinical development of a replication-competent vesicular stomatitis virus-based Lassa virus vaccine candidate advanced into human clinical trials DOI Creative Commons
Christopher L. Cooper, Gavin Morrow, Maoli Yuan

et al.

EBioMedicine, Journal Year: 2025, Volume and Issue: 114, P. 105647 - 105647

Published: April 1, 2025

SummaryBackgroundLassa fever (LF) is a zoonotic haemorrhagic disease caused by Lassa virus (LASV), which endemic in West African countries. The multimammate rat the main animal reservoir and its geographic range expected to expand due influences like climate change land usage, this will place larger parts of Africa at risk. We conducted preclinical development on promising experimental vaccine that allowed advancement into human trials.MethodsThe LF based vesicular stomatitis (VSV) vector VSV glycoprotein (G) was replaced with LASV complex (GPC). Earlier studies showed (VSVΔG-LASV-GPC) efficacious macaques, thus we regenerated VSVΔG-LASV-GPC using laboratory documentation practices required support manufacturing trials. efficacy clinical candidate assessed cynomolgus macaques more extensive immunologic analysis performed than previously investigate immune responses associated protection.FindingsA single vaccination elicited innate, humoural cellular responses, prevented substantial viraemia, protected animals from disease. Vaccinated developed polyfunctional antibodies serum shown neutralize expressing GPCs representative geographically diverse lineages.InterpretationThe immunity 10 vaccinated supporting use program, recently progressed phase 2 Moreover, virus-neutralizing likely played role preventing macaques.FundingThis work supported Coalition for Epidemic Preparedness Innovations (CEPI), National Institute Allergy Infectious Diseases (NIAID)/National Institutes Health (NIH), Bill Melinda Gates Global Vaccine Accelerator Program, Burroughs Wellcome Fund, financial gifts Nancy Zimmerman, Mark Lisa Schwartz, Terry Susan Ragon.

Language: Английский

Citations

0
Expansion of myeloid suppressor cells and suppression of Lassa virus-specific T cells during fatal Lassa fever DOI Creative Commons
Blaise Lafoux, Gustave Fourcaud, Jimmy Hortion

et al.

PLoS Pathogens, Journal Year: 2025, Volume and Issue: 21(4), P. e1013111 - e1013111

Published: April 17, 2025

Lassa fever is a highly lethal hemorrhagic endemic to West Africa. In the absence of efficient prophylactic or therapeutic countermeasures, it poses substantial threat public health in this region. The pathophysiological mechanisms underlying severity disease are poorly known because virus (LASV), its causative agent, has be handled BSL-4 laboratories and access clinical samples difficult. control associated with rapid well-balanced immune response viral clearance. However, severe characterized by uncontrolled innate activation symptoms reminiscent sepsis cytokine storm. model cynomolgus monkeys infected two different strains virus, one causing moderate other outcome, we show that LASV infection induction LASV-specific T-cell response, whereas expansion suppressive myeloid cells, alterations stromal network secondary lymphoid organs, anergy specific T cells. These results suggest cells crucial for immunomodulatory therapeutics, such as checkpoint inhibitors, could contribute new strategies treat fever. They also highlight how immunosuppressive described cancer patients may play role pathogenicity fever, well similar fevers.

Language: Английский

Citations

0
Structure-guided design of a prefusion GPC trimer induces neutralizing responses against LASV DOI Creative Commons

Shaoyan Wang,

Ruihua Li, Xiaoyan Pan

et al.

npj Vaccines, Journal Year: 2025, Volume and Issue: 10(1)

Published: Feb. 22, 2025

Lassa virus (LASV) belongs to the Arenaviridae family and causes severe hemorrhagic fever in humans. Although many vaccine candidates for exist, no vaccines have been approved clinical use currently. The precursor glycoprotein complex (GPC), which is expressed as a trimer on viral surface, main target development. However, it has significant challenge elicit effective neutralizing antibodies against LASV. In this study, we designed produced prefusion GPC antigen of LASV, named GPCv2. Based structural information GPC, made modifications by replacing amino acid at position 328 with proline appending trimerization domain. This resulted highly trimeric form GPCv2 that retained important conformational epitopes stimulated higher levels antibodies. Moreover, vaccination protected mice from LASV pseudovirus challenge. Additionally, immune repertoire sequencing showed induced clones group were more convergent its own unique V-J pairing bias compared monomeric group. These findings demonstrate potential promising candidate an

Language: Английский

Citations

0
Lassa Fever: Critical Review and Prospects for Control DOI Open Access

Marianne E. Besson,

Michel Pépin,

Pierre-Alexandre Metral

et al.

Published: July 22, 2024

Lassa Fever is a deadly viral haemorrhagic disease, causing annually several hundreds of deaths in the Gulf Guinea. This zoonotic disease primarily transmitted to humans by rodents genus Mastomys, while secondary interhuman transmission accounts for approximately 20% cases. Although this has been endemic rural zones years, it also characterised epidemic outbreaks dry season, responsible heavy death tolls. No licensed vaccine or satisfying treatment currently available. Disease management hindered incomplete knowledge epidemiology and distribution resulting from an inadequate health surveillance system. Additional scientific constraints such as genetic diversity virus lack understanding mechanisms immune protection complexify development vaccine. The intricate socio-economic context affected regions, monetary incentive drug development, allow persist some West Africa’s poorest communities. increase number reported cases fatality rate, expansion area, well threat represents internationally should urge global community work on control prevention. requires collaborative research medical countermeasures tailored public policies. Fever, created interconnection between animals, humans, ecosystems, embedded social context, be addressed with ‘One Health’ approach. article provides overview focusing Nigeria, discusses perspectives disease.

Language: Английский

Citations

1
Current perspectives on vaccines and therapeutics for Lassa Fever DOI Creative Commons
Bryce M. Warner, David Safronetz, Derek R. Stein

et al.

Virology Journal, Journal Year: 2024, Volume and Issue: 21(1)

Published: Dec. 19, 2024

Language: Английский

Citations

1
Lassa Fever: Critical Review and Prospects for Control DOI Creative Commons

Marianne E. Besson,

Michel Pépin,

Pierre-Alexandre Metral

et al.

Tropical Medicine and Infectious Disease, Journal Year: 2024, Volume and Issue: 9(8), P. 178 - 178

Published: Aug. 14, 2024

Lassa Fever is a deadly viral haemorrhagic disease, causing annually several hundreds of deaths in West Africa. This zoonotic disease primarily transmitted to humans by rodents the genus

Language: Английский

Citations

0
Conformational ensemble-based framework enables rapid development of Lassa virus vaccine candidates DOI Creative Commons
Nitesh Mishra, Gabriel Avillion, Sean Callaghan

et al.

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2024, Volume and Issue: unknown

Published: Nov. 22, 2024

Lassa virus (LASV), an arenavirus endemic to West Africa, poses a significant public health threat due its high pathogenicity and expanding geographic risk zone. LASV glycoprotein complex (GPC) is the only known target of neutralizing antibodies, but inherent metastability conformational flexibility have hindered development GPC-based vaccines. We employed variant AlphaFold2 (AF2), called subsampled AF2, generate diverse structures GPC that capture array potential states using MSA subsampling dropout layers. Conformational ensembles identified several metamorphic domains-areas flexibility-that could be targeted stabilize in immunogenic prefusion state. ProteinMPNN was then used redesign sequences minimize mobility domains. These redesigned were further filtered leading identification promising variants for testing. A small library experimentally validated showed significantly increased protein yields compared controls. Antigenic profiles indicated these preserved essential epitopes effective immune response, suggesting their broad protective efficacy. Our results demonstrate AI-driven approaches can predict landscape pathogens. This knowledge viral proteins, such as GPC, conformation, optimizing them stability expression, offering streamlined framework vaccine design. deep learning / machine enabled contributes global efforts combat has broader implications design pandemic preparedness.

Language: Английский

Citations

0