Emergent BioSolutions (United States)

Chikungunya virus (CHIKV) causes periodic outbreaks and is endemic in more than 110 countries. VIMKUNYA, a CHIKV virus-like particle (CHIKV VLP) vaccine, was recently approved by regulators in the United States, European Union, and United Kingdom. Efficacy of VIMKUNYA in endemic settings is difficult to evaluate due to outbreak unpredictability. We used cynomolgus macaques, which model human CHIKV viremia and disease, to assess CHIKV VLP vaccine efficacy. Doses as low as 1.25 mg of CHIKV VLP with aluminum hydroxide adjuvant and passively transferred IgG from vaccinated humans significantly reduced viremia, disease, and joint pathology. Despite having IgG doses yielding neutralizing titers below the established predicted protective threshold of ≥100, animals fared better than the CHIKV-infected control animals, suggesting clinical benefits may occur at lower antibody levels. These findings demonstrate immunogenicity and protective efficacy of CHIKV VLP and relevance of neutralizing antibodies in protection, reinforcing its use in humans to protect against chikungunya disease.

Pharmacoepidemiologic studies, which promote rational drug use and improve health outcomes, often require Anatomical Therapeutic Chemical Classification System (ATC) drug classification within real-world data (RWD) sources. Existing classification tools are expensive, brittle, or have restrictive terms of service, and lack context that may inform classification itself. This study sought to establish large language models (LLMs) as an assisting technology in the drug classification task. This included developing artificial intelligence prompts that reason about drugs using RWD and showing that the resulting accuracy, efficiency, and effectiveness are favorable to alternative methods. A prompt was constructed to classify aspirin as either an analgesic or antithrombotic and evaluated within 12,294 anonymized daily dose strings from a polychronic population residing in the United States and Canada. The patients used a smart medication dispenser called "spencer" and consented to the use of their data for research. The LLM prompt requested that the best and next-best second-level ATC code be returned, and grading was performed on a 3-point scale. After success in a pilot sample of 20, an inference sample of 200 was taken without replacement. Finite population inference was carried out on the proportion of outputs receiving 1 of the top 2 grades. As a benchmark, Google's Programmable Search Engine was used to query the drug name plus "ATC code" followed by regex-based extraction of ATC codes. All imperfect results were reviewed. The population consisted of 12,294 daily dose strings from 86.26% (2908/3371) patients residing in Canada and 13.73% (463/3371) residing in the United States. A prompt using the chain-of-thought reasoning was able to distinguish between aspirin's analgesic versus antithrombotic therapeutic uses and performed well in the pilot sample. In the inferential sample, 87.5% (175/200) were graded as perfect, 5% (10/200) had a minor issue, and 7.5% (15/200) had a major issue. The estimate of the proportion of at least mostly correct classification was 92.5% (185/200, 80% CI 90.1%-94.9%). For the search-based algorithm, 82.5% (165/200) were deemed acceptable. The chain-of-thought reasoning was most helpful with supplements (eg, folic acid) when high doses indicated antianemic preparations. The problem formulation of daily dose inputs and multiple ATC outputs was sometimes incompatible with the drug (eg, pregabalin, calcitriol, and methotrexate). GPT-4o offers cost-effective drug classification from RWD without violating any terms of service. Using a chain-of-thought prompting technique, GPT-4o can reason about drug dosages that affect the class. The wide accessibility of LLMs gives every research team the ability to classify drugs at scale, a key prerequisite of pharmacoepidemiologic research.

Dupuytren's disease is a common fibroproliferative disease that can result in debilitating hand deformities. Partial correction and return of deformity are common with surgical or clinical treatments at present. While current treatments are limited to local procedures for relatively late effects of the disease, the pathophysiology of this connective tissue disorder is associated with both local and systemic processes (e.g., fibrosis, inflammation). Hence, a better understanding of the systemic circulation of Dupuytren related cytokines and growth factors may provide important insights into disease progression. In addition, systemic biomarker analysis could yield new concepts for treatments of Dupuytren that attenuate circulatory factors (e.g., anti-inflammatory agents, neutralizing antibodies). Progress in the development of any disease modifying biologic treatment for Dupuytren has been hampered by the lack of clinically useful biomarkers. The characterization of nonsurgical Dupuytren biomarkers will permit disease staging from diagnostic and prognostic perspectives, as well as allows evaluation of biologic responses to treatment. Identification of such markers may transcend their use in Dupuytren treatment, because fibrotic biological processes fundamental to Dupuytren are relevant to fibrosis in many other connective tissues and organs with collagen-based tissue compartments. There is a wide range of potential Dupuytren biomarker categories that could be informative, including disease determinants linked to genetics, collagen metabolism, as well as immunity and inflammation (e.g., cytokines, chemokines). This narrative review provides a broad overview of previous studies and emphasizes the importance of inflammatory mediators as candidate circulating biomarkers for monitoring Dupuytren's disease.

BackgroundAV7909 (Anthrax Vaccine Adsorbed, Adjuvanted) vaccine was developed for post-exposure prophylaxis (PEP) of disease following suspected or confirmed exposure to Bacillus anthracis administered in conjunction with recommended antibacterial regimen. A drug-vaccine interaction study (NCT04067011) was conducted to examine whether co-administration of AV7909 with ciprofloxacin (CIP) or doxycycline (DOX) affects antibiotic pharmacokinetics (PK) or AV7909 immunogenicity in healthy adults.MethodsA Phase 2, randomized, open-label study was conducted to assess the effects of AV7909 (intramuscularly (IM) at 0, 2 weeks) on PK profiles of orally administered CIP and DOX in healthy adults between 18 and 45 years of age. Participants (n=210) were randomized to receive AV7909+CIP, AV7909+DOX or AV7909 alone. Serum concentrations of CIP and DOX were determined using liquid chromatography with tandem mass spectrometry, while AV7909 immunogenicity was evaluated using 50% neutralizing factor (NF50) values generated by a toxin neutralizing antibody (TNA) assay. Steady-state maximum concentration, Cmax and area under the curve from 0 to 12 hours, AUC0-12hrs for CIP and DOX were calculated. Safety was evaluated by collection of solicited reactogenicity and reports of adverse events (AEs).ResultsPrimary PK endpoint for CIP was met, wherein 90% confidence intervals (CIs) of mean ratios for steady-state AUC0-12h [90% CI: 0.89, 1.07] and Cmax [90% CI: 0.87, 1.08] were contained within the equivalence criteria [0.80, 1.25]. The endpoint was marginally missed for DOX, wherein lower bound (LB) of 90% CI for AUC0-12h [90% CI: 0.82, 1.03] was within the equivalence criteria, but LB of 90% CI for Cmax (0.79) was below the equivalence criteria [0.80, 1.25]. This result for steady-state DOX Cmax is likely limited given that its efficacy is mainly AUC-driven. The immunogenicity endpoint was met, wherein LB of two-sided 95% CI of the geometric mean ratio of TNA NF50 was >0.5 (0.78 for CIP, 0.81 for DOX). The majority of solicited reactogenicities and AEs were Grade 1 or 2 in severity.ConclusionCo-administration of CIP or DOX with AV7909 did not alter the relevant PK parameters of antibacterials or immunogenicity of AV7909 and was well tolerated in healthy adults.DisclosuresGideon Akintunde, Director Clinical Development, Emergent Biosolutions: Employee Bojan Drobic, Director Clinical Development, Emergent Biosolutions: Employee Lisa Bedell, Director Biostatistic, Emergent Biosolutions: Employee Lu Gan, Director Biostatistic, Emergent Biosolutions: Employee Julia Kim, Scientist Clinical Development, Emergent Biosolutions: Employee Marinda Beah, Manager Clinical Trials Development, Emergent Biosolutions: Employee Isaac Ghinai, Medical Director, Emergent Biosolutions: Employee Santiago Barona Collado, Medical Director, Emergent Biosolutions: Employee

Abstract Background Traditional influenza vaccine production often leads to mismatch due to antigenic drift, thereby reducing protection. Alternate vaccine strategies that are peptide-based, nanoparticle-based or nucleic acid-based are being developed. Composite multi-epitope peptides provide a cost-effective and easily scalable strategy towards a universal influenza vaccine. In this study, we demonstrate that unconjugated, multi-epitope peptides formulated with the highly potent adjuvant Army Liposome Formulation with QS-21 (ALFQ) generate broadly reactive durable antibodies to human and avian influenza viruses when administered intramuscularly or intradermally. Methods ICR mice were immunized with an unconjugated composite influenza peptide vaccine comprising HA+NA (Flu Pep11) and Matrix (M1/M2/M2e)+T-cell epitope (Flu Pep5906) formulated with ALFQ. A low-dose (1 µg) and high-dose (20 µg) of vaccine was administered intramuscularly or intradermally. Isotype-specific IgG titers to composite peptides, individual epitopes, and multiple strains of influenza A (H1N1, H3N2, H5N1), and B (Yamagata, Victoria) were analyzed by ELISA. Neutralizing titers against Group 1 and Group 2 viruses were determined using microneutralization assay. Results A robust IgG1 and IgG2b antibody response was seen at day 21 post primary immunization and remained steady for all groups up to day 200 (duration of study). IgG2a and IgG3 titers were also generated. Antibodies recognized multiple strains each of human and avian influenza A and influenza B virus subtypes, 200 days post primary immunization, and were comparable between doses and routes. Strong neutralizing titers were shown against Group 1 and 2 influenza viruses. Conclusion An unconjugated peptide vaccine comprising multiple highly conserved epitopes of HA, NA and Matrix formulated with ALFQ adjuvant and administered intramuscularly or intradermally, generated broad and durable antibodies to human and avian influenza viruses. Induced antibodies neutralized seasonal and pandemic influenza strains. These composite peptides adjuvanted with ALFQ generate durable and broad immunity and provide a cost-effective and easily scalable strategy that moves us closer to a universal influenza vaccine. Disclosures All Authors: No reported disclosures

PXVX0047 is an investigational vaccine developed for active immunization to prevent febrile acute respiratory disease (ARD) caused by adenovirus serotypes 4 (Ad4) and 7 (Ad7). PXVX0047 consists of a modernized, plasmid-derived vaccine that was generated using a virus isolated from Wyeth Ad4 and Ad7 vaccine tablets. A phase 1 two-arm, randomized, double-blind, active-controlled study was conducted to evaluate the safety profile and immunogenicity of the investigational adenovirus vaccines. The two components of PXVX0047 were administered orally together in a single dose to 11 subjects. For comparison, three additional subjects received the Ad4/Ad7 vaccine that is currently in use by the US military. The results of this study show that the tolerability and immunogenicity of the PXVX0047 Ad7 component are comparable with that of the control Ad4/Ad7 vaccine; however, the immunogenicity of the PXVX0047 Ad4 component was lower than expected. Clinical trial number NCT03160339.