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Highly pathogenic H5N1 avian influenza (HPAI H5N1) viruses occasionally infect, but typically do not transmit, in mammals. In the spring of 2024, an unprecedented outbreak of HPAI H5N1 in bovine herds occurred in the USA, with virus spread within and between herds, infections in poultry and cats, and spillover into humans, collectively indicating an increased public health risk 1 , 2 , 3 – 4 . Here we characterize an HPAI H5N1 virus isolated from infected cow milk in mice and ferrets. Like other HPAI H5N1 viruses, the bovine H5N1 virus spread systemically, including to the mammary glands of both species, however, this tropism was also observed for an older HPAI H5N1 virus isolate. Bovine HPAI H5N1 virus bound to sialic acids expressed in human upper airways and inefficiently transmitted to exposed ferrets (one of four exposed ferrets seroconverted without virus detection). Bovine HPAI H5N1 virus thus possesses features that may facilitate infection and transmission in mammals. HPAI H5N1 virus isolated from infected cow milk is characterized in mice and ferrets, was inefficiently transmitted in ferrets, and bound to sialic acids expressed in human upper airways, showing features that may facilitate infection in mammals.

Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b underwent an explosive geographic expansion in 2021 among wild birds and domestic poultry across Asia, Europe, and Africa. By the end of 2021, 2.3.4.4b viruses were detected in North America, signifying further intercontinental spread. Here we show that the western movement of clade 2.3.4.4b was quickly followed by reassortment with viruses circulating in wild birds in North America, resulting in the acquisition of different combinations of ribonucleoprotein genes. These reassortant A(H5N1) viruses are genotypically and phenotypically diverse, with many causing severe disease with dramatic neurologic involvement in mammals. The proclivity of the current A(H5N1) 2.3.4.4b virus lineage to reassort and target the central nervous system warrants concerted planning to combat the spread and evolution of the virus within the continent and to mitigate the impact of a potential influenza pandemic that could originate from similar A(H5N1) reassortants. Highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b underwent an explosive geographic expansion in 2021 among wild birds and domestic poultry. Here, Kandeil et al. show that the Western movement of this clade was followed by reassortment with viruses circulating in wild birds in North America which resulted in different genotypes exhibiting a wide range of disease severity in mammal models (mice, ferrets, chicken) ranging from asymptomatic disease to severe neurological pathology.

The outbreak of clade 2.3.4.4b highly pathogenic avian influenza viruses of the H5N1 subtype (HPAI H5N1) in dairy cattle in the USA has so far resulted in spillover infections of at least 14 farm workers 1 , 2 – 3 , who presented with mild respiratory symptoms or conjunctivitis, and one individual with no known animal exposure who was hospitalized but recovered 3 , 4 . Here we characterized A/Texas/37/2024 (huTX37-H5N1), a virus isolated from the eyes of an infected farm worker who developed conjunctivitis 5 . huTX37-H5N1 replicated efficiently in primary human alveolar epithelial cells, but less efficiently in corneal epithelial cells. Despite causing mild disease in the infected worker, huTX37-H5N1 proved lethal in mice and ferrets and spread systemically, with high titres in both respiratory and non-respiratory organs. Importantly, in four independent experiments in ferrets, huTX37-H5N1 transmitted by respiratory droplets in 17–33% of transmission pairs, and five of six exposed ferrets that became infected died. PB2-631L (encoded by bovine isolates) promoted influenza polymerase activity in human cells, suggesting a role in mammalian adaptation similar to that of PB2-627K (encoded by huTX37-H5N1). In addition, bovine HPAI H5N1 virus was found to be susceptible to polymerase inhibitors both in vitro and in mice. Thus, HPAI H5N1 virus derived from dairy cattle transmits by respiratory droplets in mammals without previous adaptation and causes lethal disease in animal models. A/Texas/37/2024 (huTX37-H5N1), a virus isolated from the eyes of an infected farm worker who developed conjunctivitis, proved lethal in mice and ferrets, spreading systemically with high titres in both respiratory and non-respiratory organs, and transmitted by respiratory droplets in ferrets.

Influenza A(H5N1) virus has been found in cow’s milk, and H5N1 genetic material has been identified in the commercial milk supply. In this report, investigators assess the effect of heat inactivation on viability of the virus.

Influenza A viruses (IAVs) constitute a major threat to human health. The IAV genome consists of eight single-stranded viral RNA segments contained in separate viral ribonucleoprotein (vRNP) complexes that are packaged together into a single virus particle. The structure of viral RNA is believed to play a role in assembling the different vRNPs into budding virions 1 , 2 , 3 , 4 , 5 , 6 , 7 – 8 and in directing reassortment between IAVs 9 . Reassortment between established human IAVs and IAVs harboured in the animal reservoir can lead to the emergence of pandemic influenza strains to which there is little pre-existing immunity in the human population 10 , 11 . While previous studies have revealed the overall organization of the proteins within vRNPs, characterization of viral RNA structure using conventional structural methods is hampered by limited resolution and an inability to resolve dynamic components 12 , 13 . Here, we employ multiple high-throughput sequencing approaches to generate a global high-resolution structure of the IAV genome. We show that different IAV genome segments acquire distinct RNA conformations and form both intra- and intersegment RNA interactions inside influenza virions. We use our detailed map of IAV genome structure to provide direct evidence for how intersegment RNA interactions drive vRNP cosegregation during reassortment between different IAV strains. The work presented here is a roadmap both for the development of improved vaccine strains and for the creation of a framework to ‘risk assess’ reassortment potential to better predict the emergence of new pandemic influenza strains. A combination of secondary structure probing and RNA crosslinking sequencing approaches sheds lights on the RNA conformations and the intra- and intersegment interactions of the genome inside influenza A virions.

The zoonotic origin of the COVID-19 pandemic virus highlights the need to fill the vast gaps in our knowledge of SARS-CoV-2 ecology and evolution in non-human hosts. Here, we detected that SARS-CoV-2 was introduced from humans into white-tailed deer more than 30 times in Ohio, USA during November 2021-March 2022. Subsequently, deer-to-deer transmission persisted for 2–8 months, disseminating across hundreds of kilometers. Newly developed Bayesian phylogenetic methods quantified how SARS-CoV-2 evolution is not only three-times faster in white-tailed deer compared to the rate observed in humans but also driven by different mutational biases and selection pressures. The long-term effect of this accelerated evolutionary rate remains to be seen as no critical phenotypic changes were observed in our animal models using white-tailed deer origin viruses. Still, SARS-CoV-2 has transmitted in white-tailed deer populations for a relatively short duration, and the risk of future changes may have serious consequences for humans and livestock. White-tailed deer are an important reservoir of SARS-CoV-2 in the USA and continued monitoring of the virus in deer populations is needed. In this genomic epidemiology study from Ohio, the authors show that the virus has been introduced multiple times to deer from humans, and that it has evolved faster in deer.

Vaccination, especially with multiple doses, provides substantial population-level protection against COVID-19, but emerging variants of concern (VOC) and waning immunity represent significant risks at the individual level. Here we identify correlates of protection (COP) in a multicenter prospective study following 607 healthy individuals who received three doses of the Pfizer-BNT162b2 vaccine approximately six months prior to enrollment. We compared 242 individuals who received a fourth dose to 365 who did not. Within 90 days of enrollment, 239 individuals contracted COVID-19, 45% of the 3-dose group and 30% of the four-dose group. The fourth dose elicited a significant rise in antibody binding and neutralizing titers against multiple VOCs reducing the risk of symptomatic infection by 37% [95%CI, 15%-54%]. However, a group of individuals, characterized by low baseline titers of binding antibodies, remained susceptible to infection despite significantly increased neutralizing antibody titers upon boosting. A combination of reduced IgG levels to RBD mutants and reduced VOC-recognizing IgA antibodies represented the strongest COP in both the 3-dose group (HR = 6.34, p  = 0.008) and four-dose group (HR = 8.14, p  = 0.018). We validated our findings in an independent second cohort. In summary combination IgA and IgG baseline binding antibody levels may identify individuals most at risk from future infections. Vaccination with multiple doses has been proven effective against severe COVID-19, but protection levels widely vary among individuals. This study examines the serological and immunological profiles in recipients of multiple doses of Pfizer BNT162b2 vaccine for immune markers that correlate with protection against and susceptibility for SARS-CoV-2 infection.

Since early 2024, highly pathogenic avian influenza H5N1 viruses have been causing outbreaks in dairy cattle in the United States. Here, we compared the replicative capacity of A/dairy cattle/Texas/24-008749-001/2024 (H5N1; Cow-H5N1) isolated from a dairy cow, A/chicken/Ghana/AVL-76321VIR7050-39/2021 (H5N1; Chicken-H5N1) isolated from a chicken, and a human H1N1 2009 pandemic virus in ex vivo explant cultures of mammary gland and teat from lactating cows. We also examined the expression of influenza virus receptors in these organs. We observed that human influenza virus receptors are widely distributed throughout the epithelium of alveoli, ducts, and gland cisterns within the mammary gland, and in the teat cistern epithelium of dairy cattle, whereas avian influenza virus receptors are distributed on the alveolar, ductal, and teat cistern epithelium. We also found that Cow-H5N1 virus replicates more efficiently than Chicken-H5N1 or human H1N1pdm viruses in the gland cistern epithelium of dairy cattle. Notably, bovine H5N1 viruses replicated efficiently in the epithelium of the bovine teat cistern. These findings suggest that H5N1 viruses invade the mammary gland through the teat canal, which is easily accessed by viruses.

Influenza B viruses are important contributors to seasonal influenza epidemics. Two antigenically distinct lineages, B/Victoria and B/Yamagata, have been circulating since the late 1980s. However, the B/Yamagata lineage has not been detected in most countries since 2020, potentially resulting in waning immunity that may leave people vulnerable to B/Yamagata virus infections, should this lineage reemerge. We investigated the impact of the recent lack of B/Yamagata virus circulation on immunity in adults by analyzing the hemagglutination-inhibition (HI) titers of serum samples (n = 504) collected from 2013 through 2024 against influenza B viruses circulating from 1958 to 2019. Human serum HI titers to B/Yamagata viruses have not markedly declined since B/Yamagata viruses were last detected in the US in 2020. Human serum HI titers were highest against the first encountered B/Victoria- and B/Yamagata-lineage viruses, respectively, revealing imprinting effects. The recent disappearance of the B/Yamagata lineage has not led to a substantial decline in antibody levels against this lineage.

Evidence suggests that innate and adaptive cellular responses mediate resistance to the influenza virus and confer protection after vaccination. However, few studies have resolved the contribution of cellular responses within the context of preexisting antibody titers. Here, we measured the peripheral immune profiles of 206 vaccinated or unvaccinated adults to determine how baseline variations in the cellular and humoral immune compartments contribute independently or synergistically to the risk of developing symptomatic influenza. Protection correlated with diverse and polyfunctional CD4 + and CD8 + T, circulating T follicular helper, T helper type 17, myeloid dendritic and CD16 + natural killer (NK) cell subsets. Conversely, increased susceptibility was predominantly attributed to nonspecific inflammatory populations, including γδ T cells and activated CD16 − NK cells, as well as TNFα + single-cytokine-producing CD8 + T cells. Multivariate and predictive modeling indicated that cellular subsets (1) work synergistically with humoral immunity to confer protection, (2) improve model performance over demographic and serologic factors alone and (3) comprise the most important predictive covariates. Together, these results demonstrate that preinfection peripheral cell composition improves the prediction of symptomatic influenza susceptibility over vaccination, demographics or serology alone. Thomas and colleagues examine preinfection baseline parameters of cellular and serologic immunity. Their findings collectively show that peripheral cell composition provides better correlates of immune protection from symptomatic influenza infection than vaccination, demographics or serology alone.