The global spread of the highly pathogenic avian influenza (HPAI) A(H5N1) virus poses a serious pandemic threat, necessitating the swift development of effective vaccines. The success of messenger RNA (mRNA) vaccine technology in the COVID-19 pandemic, marked by its rapid development and scalability, demonstrates its potential for addressing other infectious threats, such as HPAI A(H5N1). We therefore evaluated mRNA vaccine candidates targeting panzootic influenza A(H5) clade 2.3.4.4b viruses, which have been shown to infect a range of mammalian species, including most recently being detected in dairy cattle. Ferrets were immunized with mRNA vaccines encoding either hemagglutinin alone or hemagglutinin and neuraminidase, derived from a 2.3.4.4b prototype vaccine virus recommended by the World Health Organization. Kinetics of the immune responses, as well as protection against a lethal challenge dose of A(H5N1) virus, were assessed. Two doses of mRNA vaccination elicited robust neutralizing antibody titers against a 2022 avian isolate and a 2024 human isolate. Further, mRNA vaccination conferred protection from lethal challenge, whereas all unvaccinated ferrets succumbed to infection. It also reduced viral titers in the upper and lower respiratory tracts of infected ferrets. These results underscore the effectiveness of mRNA vaccines against HPAI A(H5N1), showcasing their potential as a vaccine platform for future influenza pandemics.

Background: The origin of divergent SARS-CoV-2 spike sequences found in wastewater, but not in clinical surveillance, remains unclear. These "cryptic" wastewater sequences have harbored many of the same mutations that later emerged in Omicron lineages. We first detected a cryptic lineage in municipal wastewater in Wisconsin in January 2022. Named the "Wisconsin Lineage", we sought to determine this virus's geographic origin and characterize its persistence and evolution over time. Method(s): We systematically sampled maintenance holes to trace the Wisconsin Lineage's origin. We sequenced spike RBD domains, and where possible, whole viral genomes, to characterize the evolution of this lineage over the 13 consecutive months that it was detectable. Finding(s): The persistence of the Wisconsin Lineage signal allowed us to trace it from a central wastewater plant to a single facility, with a high concentration of viral RNA. The viral sequences contained a combination of fixed nucleotide substitutions characteristic of Pango lineage B.1.234, which circulated in Wisconsin at low levels from October 2020 to February 2021, while mutations in the spike gene resembled those subsequently found in Omicron variants. Interpretation(s): We propose that prolonged detection of the Wisconsin Lineage in wastewater represents persistent shedding of SARS-CoV-2 from an infected individual, with ongoing within-host viral evolution leading to an ancestral B.1.234 virus accumulating "Omicron-like" mutations. Copyright The copyright holder for this preprint is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC 4.0 International license.

The United States designated the B.1.1.529 (Omicron) variant of SARS-CoV-2 (the virus that causes COVID-19) a variant of concern on November 30, 2021, and the first U.S. Omicron COVID-19 case was reported on December 1 (1). By December 18, Omicron was estimated to account for 37.9% of U.S. COVID-19 cases.* Early warning systems, such as sewage (wastewater) surveillance,† can help track the spread of SARS-CoV-2 variants across communities (2). | | The National Wastewater Surveillance System (NWSS) comprises 43 health departments funded by CDC to provide data on presence of and trends in SARS-CoV-2 infections that are independent of clinical testing. In addition to total SARS-CoV-2 testing, some health departments track SARS-CoV-2 variants by detecting variant-associated mutations in wastewater. Health departments in four states (California, Colorado, New York, and Texas) were the first wastewater surveillance programs to detect evidence of Omicron in community wastewater. This report describes the initial detections in wastewater during November 21–December 16, 2021, and the interpretative framework for these types of data. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.§

BACKGROUND: The Longitudinal Epidemiologic Assessment of Diabetes Risk (LEADR) study uses a novel Electronic Health Record (EHR) data approach as a tool to assess the epidemiology of known and new risk factors for type 2 diabetes mellitus (T2DM) and study how prevention interventions affect progression to and onset of T2DM. We created an electronic cohort of 1.4 million patients having had at least 4 encounters with a healthcare organization for at least 24-months; were aged ≥18 years in 2010; and had no diabetes (i.e., T1DM or T2DM) at cohort entry or in the 12 months following entry. EHR data came from patients at nine healthcare organizations across the U.S. between January 1, 2010-December 31, 2016. RESULTS: Approximately 5.9% of the LEADR cohort (82,922 patients) developed T2DM, providing opportunities to explore longitudinal clinical care, medication use, risk factor trajectories, and diagnoses for these patients, compared with patients similarly matched prior to disease onset. CONCLUSIONS: LEADR represents one of the largest EHR databases to have repurposed EHR data to examine patients' T2DM risk. This paper is first in a series demonstrating this novel approach to studying T2DM. IMPLICATIONS: Chronic conditions that often take years to develop can be studied efficiently using EHR data in a retrospective design. LEVEL OF EVIDENCE: While much is already known about T2DM risk, this EHR's cohort's 160 M data points for 1.4 M people over six years, provides opportunities to investigate new unique risk factors and evaluate research hypotheses where results could modify public health practice for preventing T2DM.