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Background: The increase in syphilis rates worldwide necessitates development of a vaccine with global efficacy. We aimed to explore Treponema pallidum subspecies pallidum (TPA) molecular epidemiology essential for vaccine research by analysing clinical data and specimens from early syphilis patients using whole-genome sequencing (WGS) and publicly available WGS data., Methods: In this multicentre, cross-sectional, molecular epidemiology study, we enrolled patients with primary, secondary, or early latent syphilis from clinics in China, Colombia, Malawi, and the USA between Nov 28, 2019, and May 27, 2022. Participants aged 18 years or older with laboratory confirmation of syphilis by direct detection methods or serological testing, or both, were included. Patients were excluded from enrolment if they were unwilling or unable to give informed consent, did not understand the study purpose or nature of their participation, or received antibiotics active against syphilis in the past 30 days. TPA detection and WGS were conducted on lesion swabs, skin biopsies, skin scrapings, whole blood, or rabbit-passaged isolates. We compared our WGS data to publicly available genomes and analysed TPA populations to identify mutations associated with lineage and geography., Findings: We screened 2802 patients and enrolled 233 participants, of whom 77 (33%) had primary syphilis, 154 (66%) had secondary syphilis, and two (1%) had early latent syphilis. The median age of participants was 28 years (IQR 22-35); 154 (66%) participants were cisgender men, 77 (33%) were cisgender women, and two (1%) were transgender women. Of the cisgender men, 66 (43%) identified as gay, bisexual, or other sexuality. Among all participants, 56 (24%) had HIV co-infection. WGS data from 113 participants showed a predominance of SS14-lineage strains with geographical clustering. Phylogenomic analyses confirmed that Nichols-lineage strains were more genetically diverse than SS14-lineage strains and clustered into more distinct subclades. Differences in single nucleotide variants (SNVs) were evident by TPA lineage and geography. Mapping of highly differentiated SNVs to three-dimensional protein models showed population-specific substitutions, some in outer membrane proteins (OMPs) of interest., Interpretation: Our study substantiates the global diversity of TPA strains. Additional analyses to explore TPA OMP variability within strains is vital for vaccine development and understanding syphilis pathogenesis on a population level., Funding: US National Institutes of Health National Institute for Allergy and Infectious Disease, the Bill & Melinda Gates Foundation, Connecticut Children's, and the Czech Republic National Institute of Virology and Bacteriology., Competing Interests: Declaration of interests ACS reports royalties from UptoDate; honoraria from the University of Alabama at Birmingham; and support for meetings or travel from the American STD Association as a member of the Executive Board outside the scope of the current work. JAG-L reports honoraria from the Universidad de Antioquia; support for meetings or travel from Carnott Laboratories, Cantabria Labs, Epidermique, Pharmaderm, and Janssen; receipt of writing materials from Epidermique, Cantabria labs, Isdin, Pharmaderm, Skindrugs, Loreal, Galderma, Cetaphil, Cerave, Isispharma, Carnott, Janssen, Pharmalab, Novartis, Pfizer, and Lilly outside of the scope of work. JJJ reports membership in the Worldwide Antimalarial Resistance Network. KLH reports honoraria from the Eastern Virginia Medical School and the Lawrence Livermore National Laboratory. JDR receives royalties from Biokit, Chembio, and Span Diagnostics for syphilis serodiagnostic reagents; and support for meetings or travel from Indiana University outside the scope of the current work. JBP reports research support from Gilead Sciences; non-financial support from Abbott Diagnostics; and consulting for Zymeron Corporation, all outside the scope of the current work., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

While the coronavirus disease 2019 (COVID-19) pandemic continues to present global challenges, sufficient time has passed to reflect on lessons learned and use those insights to inform policy and approaches to prepare for the next pandemic. In May 2022, the Duke Clinical Research Institute convened a think tank with thought leaders from academia, clinical practice, the pharmaceutical industry, patient advocacy, the National Institutes of Health, the US Food and Drug Administration, and the Centers for Disease Control and Prevention to share, firsthand, expert knowledge of the insights gained from the COVID-19 pandemic and how this acquired knowledge can help inform the next pandemic response. The think tank focused on pandemic preparedness, therapeutics, vaccines, and challenges related to clinical trial design and scale-up during the early phase of a pandemic. Based on the multi-faceted discussions, we outline 10 key steps to an improved and equitable pandemic response., Competing Interests: Potential conflicts of interest. A. F. H. reports contracts with Pfizer and Merck and consulting fees from Merck. B. L. is an employee of and owns stock in Moderna and reports support for travel to a meeting from Moderna. C. W. W. reports consulting fees from Arena Pharmaceuticals, BioFire, FHI Clinical, Giner, Karius, and SeLux Diagnostics; grants or contracts (paid to institution) from Defense Advanced Research Projects Agency, National Institutes of Health (NIH)-Antibacterial Resistance Leadership Group/National Institute of Allergy and Infectious Diseases/NIH Vaccine and Treatment Evaluation Units/National Institute of Mental Health/National Institute of General Medical Sciences, Sanofi, Najit, the Centers for Disease Control and Prevention (CDC), Patient-Centered Outcomes Research, United States Army Medical Research Acquisition Activity, Department of Defence, Abbott, and Pfizer; support for attending meetings and/or travel from the American Society for Microbiology (ASM); participation on a data and safety monitoring board (DSMB) or advisory board for IDbyDNA, Janssen, Regeneron, Roche Molecular Sciences; a leadership or fiduciary role for ASM and the American Society of Tropical Medicine and Hygiene; being employed by Duke University, Durham Veterans Affairs Hospital, Biomeme, and Equity/Founder of Predigen, Inc; and planned, issued, or pending patents for biomarkers for the molecular classification of bacterial infection, methods to diagnose and treat acute respiratory infections, gene expression signatures useful to predict or diagnose sepsis and methods of using the same, host-based molecular signatures of human infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2 (coronavirus disease 2019 [COVID-19]), methods of identifying infectious disease and assays for identifying infectious disease, and nasopharyngeal protein biomarkers of acute respiratory virus infection and methods of using same. H. C. and S. C. B. are employees of and hold or may hold stock in AstraZeneca. J. W. reports being an employee of and owns stock/stock options in and received equipment, materials, drugs, medical writing, gifts, and other services from Johnson & Johnson and, as CMO, has been deposed in litigation; patents issued that do not relate to the current article (available on request); and a role on the Brooklyn College Cancer Center Advisory Board, a Brooklyn College Foundation Trustee, and on the Fellowships at Auschwitz for the Study of Professional Ethics, Academic Committee. J. R. D. is an employee and shareholder in Eli Lilly and Company. L. H. C. reports consulting fees from Regeneron for the NFL Players Association and grants or contracts from NIH for PCORI. L. S. reports stock/stock options in Novartis. L. R. is an employee of and owns stock/stock options in and received support for attending meetings and/or travel from Bayer AG. M. S. reports consulting fees from AbbVie, Assembly Bio, Antios, Arbutus, Gilead Sciences, Precision Bio, and GSK for scientific advisory boards and participation on a DSMB for Gilead Sciences and AbbVie and a role as editor of the Journal Viral Hepatitis. O. V. is an employee of Boehringer Ingelheim. P. P. has a patent pending for sotrovimab and is an employee and shareholder of Vir Biotechnology. S. N. reports consulting fees from Pardes Biosciences, Theratechnologies, and Silverback Therapeutics; stock/stock options in Vir Biotechnology; grants or contracts (paid to institution) from Gilead Sciences and AbbVie; participation on an advisory board for Vir Biotechnology, a DSMB for Personal Health Insights, Inc; and serving on an event adjudication committee for Bristol–Myers Squibb/PRA. M. A. M. reports consulting fees from Abcam; stock/stock options in Grid Therapeutics; a role as an advisory board member for GSK Belimumab Pregnancy Registry; and funding to Duke from NIAD (U01 AI151378): Centers for Research in Emerging Infectious Disease (CREID) Network Coordinating Center, HHS 75N93019C00050: Duke Collaborative Influenza Vaccine Innovation Centers (CIVICs) A: Vaccine Center, HHS 75N93019C00054: Duke CIVICs C: Clinical Core, U19 AI144177: A Global Syphilis Vaccine Targeting Outer Membrane Proteins Of Treponema pallidum, 2P01 AI089618: Structure-Function Analysis Of Infection- And Vaccine-Induced B Cell Repertoires. S. E. T. reports royalties from UptoDate; grants or contracts (paid to institution) from the CDC; payment or honoraria (to author) from the Infectious Disease Society of America (IDSA) and Emerson Hospital; support from DCRI to attend the meeting upon which this article was based. L. R. B. is involved in human immunodeficiency virus (HIV) and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network, COVID Vaccine Prevention Network, International AIDS Vaccine Initiative, Crucell/Janssen, Moderna, Military HIV Research Program, the Gates Foundation, and Harvard Medical School. reports participation on a DSMB for NIH and AMDAC Committee for the FDA (research funded by the NIH, Welcome Trust, and the Gates Foundation). R. T. G. reports a leadership or fiduciary role on the NIH COVID Treatment Guidelines Panel and IDSA COVID Treatment Guidelines Panel. R. G. reports grants (to institution) from NIH/NIAID, book chapter royalties from Elsevier, and section editor royalties from UpToDate. All remaining authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Introduction: Hemagglutination inhibition (HAI) antibody titers to seasonal influenza strains are important surrogates for vaccine-elicited protection. However, HAI assays can be variable across labs, with low sensitivity across diverse viruses due to lack of standardization. Performing qualification of these assays on a strain specific level enables the precise and accurate quantification of HAI titers. Influenza A (H3N2) continues to be a predominant circulating subtype in most countries in Europe and North America since 1968 and is thus a focus of influenza vaccine research., Methods: As a part of the National Institutes of Health (NIH)-funded Collaborative Influenza Vaccine Innovation Centers (CIVICs) program, we report on the identification of a robust assay design, rigorous statistical analysis, and complete qualification of an HAI assay using A/Texas/71/2017 as a representative H3N2 strain and guinea pig red blood cells and neuraminidase (NA) inhibitor oseltamivir to prevent NA-mediated agglutination., Results: This qualified HAI assay is precise (calculated by the geometric coefficient of variation (GCV)) for intermediate precision and intra-operator variability, accurate calculated by relative error, perfectly linear (slope of -1, R-Square 1), robust (<25% GCV) and depicts high specificity and sensitivity. This HAI method was successfully qualified for another H3N2 influenza strain A/Singapore/INFIMH-16-0019/2016, meeting all pre-specified acceptance criteria., Discussion: These results demonstrate that HAI qualification and data generation for new influenza strains can be achieved efficiently with minimal extra testing and development. We report on a qualified and adaptable influenza serology method and analysis strategy to measure quantifiable HAI titers to define correlates of vaccine mediated protection in human clinical trials., Competing Interests: EBW has received funding support from Pfizer, Moderna, Sequiris, Najit Technologies Inc, and Clinetic for the conduct of clinical trials and clinical research. EBW has served as an advisor to Vaxcyte and consultant to ILiAD biotechnologies. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Sawant, Gurley, Overman, Sharak, Mudrak, Oguin, Sempowski, Sarzotti-Kelsoe, Walter, Xie, Pasetti, Moody and Tomaras.)

The death of CD4(+) CCR5(+) T cells is a hallmark of human immunodeficiency virus (HIV) infection. We studied the plasma levels of cell death mediators and products--tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), Fas ligand, TNF receptor type 2 (TNFR-2), and plasma microparticles--during the earliest stages of infection following HIV type 1 (HIV-1) transmission in plasma samples from U.S. plasma donors. Significant plasma TRAIL level elevations occurred a mean of 7.2 days before the peak of plasma viral load (VL), while TNFR-2, Fas ligand, and microparticle level elevations occurred concurrently with maximum VL. Microparticles had been previously shown to mediate immunosuppressive effects on T cells and macrophages. We found that T-cell apoptotic microparticles also potently suppressed in vitro immunoglobulin G (IgG) and IgA antibody production by memory B cells. Thus, release of TRAIL during the onset of plasma viremia (i.e., the eclipse phase) in HIV-1 transmission may initiate or amplify early HIV-1-induced cell death. The window of opportunity for a HIV-1 vaccine is from the time of HIV-1 transmission until establishment of the latently infected CD4(+) T cells. Release of products of cell death and subsequent immunosuppression following HIV-1 transmission could potentially narrow the window of opportunity during which a vaccine is able to extinguish HIV-1 infection and could place severe constraints on the amount of time available for the immune system to respond to the transmitted virus.