Search

Crimean-Congo haemorrhagic fever (CCHF) is a widely distributed and potentially fatal tick-borne viral disease with no licensed specific treatments or vaccines. In 2019, WHO published an advanced draft of a research and development roadmap for CCHF that prioritised the development and deployment of the medical countermeasures most needed by CCHF-affected countries. This Personal View presents updated CCHF research and development priorities and is the product of broad consultation with a working group of 20 leading experts in 2023-24. The strategic goals, milestones, and timelines have been revised and expanded to reflect scientific advances since 2019, including the identification of antibodies with therapeutic potential and the progression of four vaccine candidates through phase 1 clinical trials. This update emphasises the need for a One Health approach to manage CCHF, from integrated cross-sectoral surveillance to novel interventions that target ticks and their vertebrate hosts to reduce CCHF virus transmission to humans. The overarching vision for rapid diagnostics and specific therapeutics by 2028, followed by options to limit CCHF virus transmission and control disease by 2030, is deliberately ambitious and will only be achieved through coordinated international action from affected countries, funders, scientists, product developers, manufacturers, regulators, national authorities, and policy makers., Competing Interests: Declaration of interests JF declares a grant from the Ministerio de Ciencia e Innovación/Agencia Estatal de Investigación, Spain (grant number MCIN/AEI/10.13039/501100011033) and the EU–European Regional Development Fund (grant number BIOGAL PID2020–116761GB-I00). JF has also received support from the Federal University of Uberlândia and the Brazilian Federal Foundation for Support and Evaluation of Graduate Education (grant number 88887.936876/2024–00) to attend the 2024 Annual Scientific Meeting of the European Veterinary Parasitology College at the University of Agronomic Sciences and Veterinary Medicine, Bucharest, Romania. TF declares funding (paid to his institution) from GuardRX (not-for-profit) and the Pandemic Institute (Liverpool) for the UMIT-1 phase 1b Crimean–Congo haemorrhagic fever (CCHF) therapeutics trial in Türkiye; from the Medical Research Council (MRC) for the UMIT-2 phase 2b CCHF therapeutics trial in Türkiye and Iraq; from the MRC for the GeneDrive PCR platform and for development of a CCHF lateral flow test. SG has received grants (paid to his institution) from the German Research Foundation, European Commission, German Government, Coalition for Epidemic Preparedness Innovations (CEPI), and Kirmser Foundation; and has received speaker honoraria and support for attending meetings from WHO and CEPI. RH is in receipt of grant funding from the Biotechnology and Biological Sciences Research Council, the Defense Threat Reduction Agency, and the MRC to investigate CCHF virus genome reassortment, sequence CCHF virus variants, and develop diagnostics for low-resource settings; and is an investigator in the EU H2020-funded CCHFVaccine project. RH is a named inventor on a patent (PCT/GB2013/0503174; WO 2014/132013) for a vectored CCHF vaccine. GKob received federal funding from the Canadian Institute for Health Research to develop immunogens based on CCHF glycoproteins (2016–21), is an inventor on a patent for CCHF virus immunogenic compositions, and received funding from Université Laval and GUARDRx (not-for-profit) to attend meetings related to the original CCHF Research and Development (R&D) Roadmap (2018–20). AC, PCF, PJH, and JPG worked at the Wellcome Trust during the time that the CCHF Roadmap was being revised and this Personal View was written. TJGB, AES, and JW received support from WHO to attend meetings related to the original CCHF R&D Roadmap (2018–20). TJGB, AES, JW, and JO received funding from the Wellcome Trust (grant number 226729/Z/22/Z) to coordinate the 2023–24 update to the CCHF R&D Roadmap and to complete this Personal View. In addition, the Wellcome Trust covered convening costs for TJGB, AES, JW, VB, M-PP, LHB, TF, PBHF, SG, RH, BJ, JF, GP, AP, and HS to attend a meeting of the CCHF working group in London, UK (Feb 13–14, 2023). All other authors declare no competing interests. The authors alone are responsible for the views expressed in this Personal View; they do not necessarily represent the views, decisions, or policies of the institutions with which the authors are affiliated. Editorial note: The Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations., (Crown Copyright © 2024 Published by Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Nipah virus causes highly lethal disease, with case-fatality rates ranging from 40% to 100% in recognised outbreaks. No treatments or licensed vaccines are currently available for the prevention and control of Nipah virus infection. In 2019, WHO published an advanced draft of a research and development roadmap for accelerating development of medical countermeasures, including diagnostics, therapeutics, and vaccines, to enable effective and timely emergency response to Nipah virus outbreaks. This Personal View provides an update to the WHO roadmap by defining current research priorities for development of Nipah virus medical countermeasures, based primarily on literature published in the last 5 years and consensus opinion of 15 subject matter experts with broad experience in development of medical countermeasures for Nipah virus or experience in the epidemiology, ecology, or public health control of outbreaks of Nipah virus. The research priorities are organised into four main sections: cross-cutting issues (for those that apply to more than one category of medical countermeasures), diagnostics, therapeutics, and vaccines. The strategic goals and milestones identified in each section focus on key achievements that are needed over the next 6 years to ensure that the necessary tools are available for rapid response to future outbreaks of Nipah virus or related henipaviruses., Competing Interests: Declaration of interests CCB declares grant U19AI142764 from the National Institute of Allergy and Infectious Diseases (NIAID), the National Institutes of Health (NIH). CCB received royalties from the licensing of Hendra sG to Zoetis (Equivac HeV), Auro Vaccines (subsidiary of Aurobindo Pharma USA), and monoclonal antibodies to Henipaviruses, Absolute Antibody, UK, created and operating under the laws of the UK. CCB declares patents planned, issued, or pending for “Soluble forms of Hendra and Nipah virus G glycoprotein” (Australian patent number 2005327194; US patent numbers 8865171, 9045532, 9056902, 9533038, and 10053495); “Soluble forms of Hendra and Nipah virus F glycoprotein and uses thereof” (Australian patent numbers 2013276968; US patent numbers 10040825 and 10590172); “Human monoclonal antibodies against Hendra and Nipah viruses” (US patent numbers 7988971, 8313746, and 8858938); “Antibodies against F glycoprotein of Hendra and Nipah viruses” (US patent numbers 9982038 and 10738104); and “Cedar virus and methods of use” (US patent number 10227664). EdW received financial support from the Intramural Research Program, NIAID, NIH; and royalties related to the vesicular stomatitis virus Nipah vaccine mentioned in this manuscript. ESG received funding (through a grant to ESG's institution) from Stanford University (Coalition for Epidemic Preparedness Innovations [CEPI] was the primary donor) to work on two studies related to development of Nipah vaccines, including development of consent documents for future trials in Bangladesh. ESG is also the principal investigator of a U01 (cooperative agreement) from NIAID, NIH for the study of Nipah virus spillovers in Bangladesh. ESG also received funding (grant to institution) from the Defense Advanced Research Projects Agency to study the dynamics of Nipah virus transmission in bats in Bangladesh. ESG received a consultancy contract from Montana State University to provide technical guidance to a study collecting biological samples from bats in Bangladesh; and served as an unpaid elected board member for the American Society for Tropical Medicine and Hygiene. LTM received financial support as a science consultant at FIND; and received consulting fees as a science consultant at FIND. SPL received research funding from CEPI to support the development of two vaccine candidates against Nipah virus. SP received research funding from Public Health Vaccines through a subaward from Stanford University. CFS declares patents planned, issued, or pending for “Nipah Henipavirus virus replicon particles and their use” (US patent number WO2023/133077 A1). KAM, AJM, NMM, JTO, MTO, and AKU received financial support for the completion of this Personal View from the Wellcome Trust (grant number 226538/Z/22/Z; payments were made to the University of Minnesota). Wellcome supported travel to attend the workshop identified in this Personal View for CCB, EdW, ANF, ESG, KH, SPL, LTM, KAM, JTO, M-PP, MTO, SP, and MR. PCF, PJH, and JPG worked at the Wellcome Trust during the time that this Personal View was completed. No authors were paid by a pharmaceutical company or any other agency to write this Personal View. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

In 2016, WHO designated Lassa fever a priority disease for epidemic preparedness as part of the WHO Blueprint for Action to Prevent Epidemics. One aspect of preparedness is to promote development of effective medical countermeasures (ie, diagnostics, therapeutics, and vaccines) against Lassa fever. Diagnostic testing for Lassa fever has important limitations and key advancements are needed to ensure rapid and accurate diagnosis. Additionally, the only treatment available for Lassa fever is ribavirin, but controversy exists regarding its effectiveness. Finally, no licensed vaccines are available for the prevention and control of Lassa fever. Ongoing epidemiological and behavioural studies are also crucial in providing actionable information for medical countermeasure development, use, and effectiveness in preventing and treating Lassa fever. This Personal View provides current research priorities for development of Lassa fever medical countermeasures based on literature published primarily in the last 5 years and consensus opinion of 20 subject matter experts with broad experience in public health or the development of diagnostics, therapeutics, and vaccines for Lassa fever. These priorities provide an important framework to ensure that Lassa fever medical countermeasures are developed and readily available for use in endemic and at-risk areas by the end of the decade., Competing Interests: Declaration of interests KAM, AJM, NMM, JTO, MTO, and AKU declare receiving financial support for the completion of this Personal View from Wellcome (grant number 226538/Z/22/Z), payments were made to the University of Minnesota. ADTB is a member of the Vaccine Research, Development and Manufacturing Committee of the Coalition for Epidemic Preparedness Innovations (CEPI). DME is employed by FIND. RFG declares grants U01AI151812, U19AI135995, R01AI132223, R01AI132244, and U19AI142790, all awarded from the National Institute of Allergy and Infectious Diseases, LEAP4WA awarded by the European & Developing Countries Clinical Trials Partnership, and ESEP1904 and INTU1901, both awarded by CEPI; stocks in and royalties or licenses from Zalgen Labs; ownership of a monoclonal antibody patent (WO2018106712A1); and travel support from Wellcome to attend the workshop identified in this Personal View. SG declares financial support for this Personal View from WHO and Wellcome; the receipt of drugs for clinical trials from Toyama–Fujifilm; grants (all payments were made to SG's institutions) from the German Research Foundation (grants GU 883/4-2, GU 883/5-1, and GU 883/7-1), the European Commission (project 101103204—INTEGRATE), the German Government, Ministry of Health (projects ZMI1-2521WHO002 and ZMII2-2523GHP006), CEPI (framework agreement for implementing partner services); the Kirmser Foundation (donation of equipment); speaker honoraria for continuing medical education on viral haemorrhagic fevers; and support for attending meetings from WHO, Wellcome, and CEPI, including travel support from Wellcome to attend the workshop identified in this Personal View. LTM declares being a science consultant at FIND, for which she receives grants, contracts, and consulting fees; and travel support from Wellcome to attend the workshop identified in this Personal View. SAO declares a consulting contract with CEPI (payments made to SAO); is a member of the INTEGRATE consortium with grants from the European & Developing Countries Clinical Trials Partnership (payments made to SAO's institution); and support from CEPI and EDCTP funds (payments made to travel agencies and through SAO's institution). CR declares participation on a Data Safety Monitoring Board or Advisory Board (this advisory board was designated after CR's participation in the work leading to this Personal View). WKA is Executive Director of the African Vaccine Manufacturing Initiative, and Cheif Executive of National Vaccine Institute, Ghana. DAA, IMA, WKA, ADTB, DGB, EF-C, IdC, DSG, SBG, MJ, KAM, JTO, MTO, AKU, and CSS declare Wellcome supported for travel to attend the workshop identified in this Personal View. PCF, PJH, and JPG worked at Wellcome during the time that this Personal View was completed. All other authors declare no competing interests. No authors were paid by a pharmaceutical company or any other agency to write this Personal View. The authors alone are responsible for the views expressed in this Personal View and they do not necessarily represent the views, decisions, or policies of the institutions with which they are affiliated. Editorial note: The Lancet Group takes a neutral position with respect to territorial claims in published maps and institutional affiliations., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Improved influenza vaccines are urgently needed to reduce the burden of seasonal influenza and to ensure a rapid and effective public-health response to future influenza pandemics. The Influenza Vaccines Research and Development (R&D) Roadmap (IVR) was created, through an extensive international stakeholder engagement process, to promote influenza vaccine R&D. The roadmap covers a 10-year timeframe and is organized into six sections: virology; immunology; vaccinology for seasonal influenza vaccines; vaccinology for universal influenza vaccines; animal and human influenza virus infection models; and policy, finance, and regulation. Each section identifies barriers, gaps, strategic goals, milestones, and additional R&D priorities germane to that area. The roadmap includes 113 specific R&D milestones, 37 of which have been designated high priority by the IVR expert taskforce. This report summarizes the major issues and priority areas of research outlined in the IVR. By identifying the key issues and steps to address them, the roadmap not only encourages research aimed at new solutions, but also provides guidance on the use of innovative tools to drive breakthroughs in influenza vaccine R&D., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Kristine Moore, Julia Ostrowsky, Angela Mehr, Michael Osterholm report financial support was provided by Wellcome Trust. Kristine Moore, Michael Osterholm report a relationship with Wellcome Trust that includes: funding grants. Coauthor received grants to the organization from Sanofi Pasteur, received grants from US CDC, PATH, Wellcome Trust, South African MRC. (CC) Coauthor is a former Director of one of the WHO International Reference Centres for influenza and was part of the biannual strain selection group. His family superannuation fund holds some shares in companies which produce vaccines, including Influenza vaccine (Pfizer, Merck and CSL) and specific antiviral agents (Vaxart). (IG) Coauthor is an independent Director of two organisations that support vaccine development, the Coalition for Epidemic Preparedness Innovations and MSD Wellcome Trust Hilleman Laboratories Pvt; Ltd. Neither is working on influenza vaccines. (GK) Coauthor has the following declarations: The Icahn School of Medicine at Mount Sinai has filed patent applications relating to universal influenza virus vaccines, SARS-CoV-2 serological assays and NDV-based SARS-CoV-2 vaccines which name me as inventor. I would also like to note the following, which could be perceived as a conflict of interest: I have previously published work on influenza virus vaccines with S. Gilbert (University of Oxford); have consulted for Curevac, Merck and Pfizer (before 2020); I am currently consulting for Pfizer, Seqirus and Avimex; my laboratory is collaborating with Pfizer on animal models of SARS-CoV-2 and with Dynavax on influenza virus vaccines; my laboratory is collaborating with N. Pardi at the University of Pennsylvania on mRNA vaccines against SARS-CoV-2 and my laboratory was working in the past with GlaxoSmithKline on the development of influenza virus vaccines and two of my mentees have recently joined Moderna. (FK)]., (Copyright © 2021 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Molecular surveillance provides a powerful approach to monitoring the resistance status of parasite populations in the field and for understanding resistance evolution. Oxamniquine was used to treat Brazilian schistosomiasis patients (mid-1970s to mid-2000s) and several cases of parasite infections resistant to treatment were recorded. The gene underlying resistance (SmSULT-OR) encodes a sulfotransferase required for intracellular drug activation. Resistance has a recessive basis and occurs when both SmSULT-OR alleles encode for defective proteins. Here we examine SmSULT-OR sequence variation in a natural schistosome population in Brazil ∼40years after the first use of this drug. We sequenced SmSULT-OR from 189 individual miracidia (1-11 per patient) recovered from 49 patients, and tested proteins expressed from putative resistance alleles for their ability to activate oxamniquine. We found nine mutations (four non-synonymous single nucleotide polymorphisms, three non-coding single nucleotide polymorphisms and two indels). Both mutations (p.E142del and p.C35R) identified previously were recovered in this field population. We also found two additional mutations (a splice site variant and 1bp coding insertion) predicted to encode non-functional truncated proteins. Two additional substitutions (p.G206V, p.N215Y) tested had no impact on oxamniquine activation. Three results are of particular interest: (i) we recovered the p.E142del mutation from the field: this same deletion is responsible for resistance in an oxamniquine selected laboratory parasite population; (ii) frequencies of resistance alleles are extremely low (0.27-0.8%), perhaps due to fitness costs associated with carriage of these alleles; (iii) that four independent resistant alleles were found is consistent with the idea that multiple mutations can generate loss-of-function alleles., (Copyright © 2016 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Esterases have been implicated in metabolic resistance to synthetic pyrethroids in several insect species but little is yet known of the molecular basis for these effects. In this work modern directed evolution technology was used to test to what extent it is possible to genetically enhance the pyrethroid hydrolytic activity of the E3 carboxylesterase from the blowfly Lucilia cuprina. High throughput screening of a random mutant library with individual stereoisomers of fluorogenic analogues of two type II pyrethroids identified 17 promising variants that were then also tested with the commercial pyrethroid deltamethrin. Between them, these variants displayed significantly improved activities for all the substrates tested. Amino acid substitutions at ten different residues were clearly implicated in the improvements, although most only enhanced activity for a subset of the stereoisomers. Several new combinations of the most promising amino acid substitutions were then made, and negative epistatic effects were found in most of the combinations, but significant improvements were also found in a minority of them. The best mutant recovered contained three amino acid changes and hydrolysed deltamethrin at more than 100 times the rate of wild-type E3. Structural analysis shows that nine of the ten mutated residues improving pyrethroid or analogue activities cluster in putative substrate binding pockets in the active site, with the three mutations of largest effect all increasing the volume of the acyl pocket., (Crown Copyright © 2012. Published by Elsevier Ltd. All rights reserved.)