Aug 2026· EBioMedicine· Vol 131· 0 citations· 31 references
Medicine
TL;DR
It is demonstrated that the AS03-adjuvanted A(H5N8)-based stockpiled vaccine provides strong cross-protective efficacy against bovine A(H5N1) viruses during the early phase of a pandemic.
Abstract
Summary Background Since early 2024, highly pathogenic avian influenza A(H5N1) viruses of clade 2.3.4.4b have caused extensive outbreaks in dairy cattle in the United States, with spillover into mammalian species, including humans. A bovine-derived A(H5N1) virus isolated from a human case retains high pathogenicity and transmissibility in mammalian models, highlighting its pandemic potential. Stockpiled pre-pandemic influenza vaccines are intended to provide early protection before strain-matched vaccines are available; however, their protective efficacy against bovine A(H5N1) viruses has not been directly evaluated in vivo. Methods In this study, we assessed the protective efficacy of an AS03-adjuvanted A/Astrakhan/3212/2020 (H5N8) clade 2.3.4.4b-based influenza vaccine stockpiled in Japan using mouse and ferret models. Vaccinated and unvaccinated animals were challenged with a virus genetically identical to a human isolate of bovine A(H5N1) virus. Neutralising antibody responses, viral replication in organs, and survival were evaluated. Findings Vaccination with the AS03-adjuvanted A(H5N8)-based stockpiled vaccine induced robust neutralising antibody responses in both animal models, significantly suppressed viral replication, and conferred complete protection against lethal challenge. In contrast, all unvaccinated mice and ferrets succumbed to infection. These findings demonstrate that the AS03-adjuvanted A(H5N8)-based stockpiled vaccine provides strong cross-protective efficacy against bovine A(H5N1) viruses. Interpretation An AS03-adjuvanted A(H5N8)-based vaccine stockpiled in Japan could serve as an immediate countermeasure against bovine A(H5N1) viruses during the early phase of a pandemic. Funding This work was supported by grants from the Japan Program for Infectious Diseases Research and Infrastructure (JP20wm0125002) and the Japan Initiative for World-leading Vaccine Research and Development Centers (JP223fa627001) from the 10.13039/100009619Japan Agency for Medical Research and Development.
Avian influenza viruses (AIVs) continue to cause substantial economic losses to the poultry industry and pose a significant burden on global public health systems. The increasing diversity and geographical spread of different subtypes of influenza viruses in poultry populations increases the risk for reassortment events and the emergence of novel strains. Vaccination remains a key strategy for preventing influenza infection and its complications, especially high pathogenic avian influenza (HPAI), as it can reduce morbidity, mortality, and viral transmission. However, vaccine effectiveness is closely tied to the antigenic match between vaccine strains and circulating viruses. In this study, we tested six commonly used commercial poultry H5 vaccines in Egypt to evaluate mortality, and virus shedding following experimental infection of specific pathogen free chickens with clade 2.3.4·4b H5N1 and H5N8 HPAI viruses. Our results showed that most of the tested vaccines provided detectable antibody titers and protected against mortality but were not able to control virus shedding. ValleyVac vaccines induced high HI titers (up to 9 log2) against recent clade 2.3.4·4b A(H5N1) and A(H5N8) strains, while Zoetis and Egy-flu R 2-in-1 induced lower HI titers (<6 log2). Although some of the commercial vaccines did not elicit considerable HI titers, vaccines provided 71%–100% protection against clade 2.3.4·4b viruses. Importantly, virus titers were detected till seven days post-infection (dpi). This incomplete protection is likely due to genetic and antigenic mismatches between the vaccine seed strains and the H5N1 and H5N8 viruses detected in Egypt. These results highlight the urgent need to revise H5Nx prevention and control strategies in Egypt and update vaccine seed strains to reflect currently circulating HPAI viruses.
A. El Taweel, M. Gomaa, Yassmin Moatasim et al.· Poultry Science and Manageme...· 0 citations
ABSTRACT The incursion of Eurasian-origin genotype A6 A(H5N5) virus into North America expanded the genetic diversity among North American highly pathogenic avian influenza viruses and heightened concern about zoonotic risk. Following a fatal human infection with the A(H5N5) virus A/Washington/2148/2025, viral replication was assessed in polarized human bronchial epithelial cells, and pathogenicity, transmissibility in direct contact and respiratory droplet models, and airborne virus shedding were evaluated in ferrets to inform pandemic risk assessment. A(H5N5) displayed robust replication in Calu-3 cells at 33°C and 37°C, showing kinetics and peak titers comparable to those of contemporary genotype B3.13 and D1.1 A(H5N1) viruses. In ferrets, A(H5N5) replicated efficiently in the respiratory tract, disseminated to extrapulmonary tissues, and caused fatal disease in all inoculated animals. Airborne transmission was not observed, and infrequent, low-level detection of virus in air samples paralleled that of A(H5) viruses that are not transmissible via air in ferrets. In a direct contact model, limited transmission was detected within 4 days of exposure, with evidence of lower respiratory tract replication in contact animals. These findings indicate that the A(H5N5) virus has the capacity for robust replication in an airway epithelial cell line and can cause severe systemic infection and mortality in ferrets but has not acquired adaptations for airborne spread in mammals. Collectively, these results underscore heterogeneity among clade 2.3.4.4b A(H5Nx) viruses in North America and the need for genotype-by-genotype evaluation of newly emerged viruses to understand public health risk. IMPORTANCE The emergence of Eurasian-origin genotype A6 highly pathogenic avian influenza A(H5N5) virus in North America has increased viral diversity and raised concerns about zoonotic and pandemic risk. In this study, we evaluated the replication kinetics, pathogenesis, and transmission of A/Washington/2148/2025 A(H5N5) virus, which was isolated from the first reported human infection with this influenza virus subtype, using polarized human bronchial epithelial cells and the ferret model. The A(H5N5) virus replicated efficiently in vitro at temperatures representative of the upper and lower respiratory tracts and caused fatal systemic disease in inoculated ferrets. Limited transmission was observed during 4 days of direct contact. Airborne virus detection was infrequent and did not result in airborne transmission. These findings show that A(H5N5) virus can replicate robustly in mammalian cells and cause severe disease but lacks adaptations supporting efficient airborne spread, informing assessment of the pandemic risk posed by genotype A6 influenza viruses. The emergence of Eurasian-origin genotype A6 highly pathogenic avian influenza A(H5N5) virus in North America has increased viral diversity and raised concerns about zoonotic and pandemic risk. In this study, we evaluated the replication kinetics, pathogenesis, and transmission of A/Washington/2148/2025 A(H5N5) virus, which was isolated from the first reported human infection with this influenza virus subtype, using polarized human bronchial epithelial cells and the ferret model. The A(H5N5) virus replicated efficiently in vitro at temperatures representative of the upper and lower respiratory tracts and caused fatal systemic disease in inoculated ferrets. Limited transmission was observed during 4 days of direct contact. Airborne virus detection was infrequent and did not result in airborne transmission. These findings show that A(H5N5) virus can replicate robustly in mammalian cells and cause severe disease but lacks adaptations supporting efficient airborne spread, informing assessment of the pandemic risk posed by genotype A6 influenza viruses.
J. Pulit-Penaloza, J. Belser, N. Brock et al.· Journal of Virology· 0 citations
Current evidence on cross-reactive and cross-protective immunity to H5N1 in humans, focusing primarily on humoral immune responses is summarized, and particular attention is given to antibodies targeting conserved regions of hemagglutinin (HA) as well as neuraminidase (NA), which may provide heterosubtypic protection.
Iván Sanz-Muñoz, Carlos J. Ciria-Gil, Marta Hernández et al.· Journal of Infection· 0 citations
Highly pathogenic avian influenza (HPAI) virus H5N1of clade 2.3.4.4b has emerged as the predominant lineage circulating in poultry flocks worldwide, raising concerns regarding the protective efficacy of currently available commercial vaccines, particularly in domestic ducks, which play an important role in virus maintenance and transmission. Thus, this study evaluated the immunogenicity along with the protective efficacy of four inactivated H5 vaccines against a recently isolated local HPAI-H5N1 (Newvalley-3-H5N1-2024, clade 2.3.4.4b) strain in Pekin ducks in Egypt. A total of 150 seronegative ducks were divided into vaccinated and control groups (10 groups) and vaccinated at 10 days of age. At 31 days of age, the vaccinated and positive control groups were challenged using 106.5 EID50/0.5 mL/duck with the local isolate (Newvalley-3-H5N1-2024) via the oculo-nasal route. The vaccine efficacy was assessed through clinical signs, survival rate, hemagglutination inhibition (HI) antibody titer, tracheal and cloacal viral shedding quantified by real-time RT-PCR, and histopathological examination of trachea, lung, pancreas, and brain tissues. Generally, all ducks vaccinated with the ValleyVac Avian Flu H5 plus and MEFLUVACTM H5 PLUS 8 showed a significantly higher survival rate (100%) at 10 days post-vaccination (DPV) than those in the positive control (66.7% mortality rate). In contrast, ducks exhibited mortality rates ranging from 6.7% in the SERVAC Flu H5N1 group to 13.4% in the Sinder Fluvac group. The ValleyVac Avian Flu H5 plus and MEFLUVAC™ H5 PLUS 8 vaccines induced the highest HI antibody titers at 7, 14, 21, and 28 DPV in both homologous and heterologous AIV antigens, resulting in a significant reduction in viral load among all vaccinated duck groups (p-value < 0.05) comparable to the positive control group. Conversely, the SERVAC Flu H5N1 and Sinder Fluvac vaccines provided partial protection, suboptimal immunogenicity at different time points, and elevated viral shedding. Histopathological findings in ValleyVac Avian Flu H5 plus and MEFLUVAC™ H5 PLUS 8 vaccines exhibited mild tissue alterations following AIV challenge. Marked pathological lesions were observed in the SERVAC Flu H5N1 and Sinder Fluvac vaccinated groups. Among tested vaccines, both ValleyVac Avian Flu H5 plus and MEFLUVACTM H5 PLUS 8 showed the highest level of protective efficacy against the circulating AIV strain compared with other commercial vaccines. This study highlights the need for continuous molecular surveillance, antigenic matching, and regular updating of vaccine seed strains to ensure efficient HPAI control in Egypt.
Eman Abd El Menum Shosha, I. Eldaghayes, Ahmed A. H. Ali et al.· Viruses· 0 citations
Highly pathogenic avian influenza (HPAI) A(H5) viruses can be transmitted from infected birds to various mammalian species, including humans. Avian influenza viruses (AIVs), members of the Orthomyxoviridae family, possess segmented RNA genomes prone to reassortment, favoring the emergence of novel genetic traits that may alter transmissibility, pathogenicity, and antigenicity. Although no sustained human-to-human transmission has been reported, the potential adaptation of these viruses poses a significant pandemic threat. This study aimed to evaluate the non-clinical safety, toxicity, and humoral immune responses induced by an adjuvanted H5 influenza vaccine in rats and rabbits, to support future clinical safety trials in humans. Male and female Wistar rats and New Zealand rabbits were observed for 14, 28, and 90 days after receiving two intramuscular doses of the H5N8 vaccine (15 μg HA/dose) formulated with the IB160 oil-in-water emulsion adjuvant. No systemic comorbidities, central nervous system alterations, or relevant clinical signs were observed. Hematological parameters remained within normal ranges, with total and differential leukocyte counts showing only minor fluctuations (<1% of total leukocytes). Mild biochemical variations in urea and hepatic transaminase levels were not correlated with histopathological alterations. The vaccine elicited a robust humoral response soon after immunization, with all groups reaching protective HAI-antibody titers. Although antibody levels declined over time, particularly in males, they remained significantly above baseline, indicating durable immunological memory. Furthermore, the vaccine induced a specific cellular immune response, confirmed by IL-2 and TNF production by antigen-specific T lymphocytes in splenic cell cultures after the booster dose. In conclusion, the H5N8 vaccine with the IB160 adjuvant was well tolerated locally and systemically, without compromising vital organ function. The safety and immunogenicity findings are consistent with expectations for adjuvanted influenza vaccines, demonstrating strong and durable humoral and cellular immune responses.
D. Maria, Isabela Mancini Martins, Giselle Pidde Marques Porto et al.· Vaccine· 0 citations
H5N1 highly pathogenic avian influenza (HPAI) represents a persistent global threat to both poultry and public health, necessitating the development of safe and effective vaccines. We utilized an established bat influenza vector to develop live attenuated vaccines, and demonstrated their safety and immunogenicity. In this study, we developed a bat influenza-vectored H5N1 vaccine (WT H17-H5N1) and its avian-adapted candidate (AA H17-H5N1) by introducing specific amino acid mutations (PB2 I382S, PB1 Q694H/I695K, and PA E141K) into the Bat09 polymerase complex to enhance avian adaptation and reduce safety concerns in potential mammalian use. To evaluate vaccine safety and immunogenicity, groups of specific pathogen free (SPF) chickens were intranasally primed and boosted with either 105 TCID50 of wild-type (WT) or avian-adapted prototype vaccine at 2 weeks interval, respectively. One group of chickens was mock-immunized as blank control. The birds were then monitored for clinical signs daily. Laryngotracheal and cloacal swabs were collected from each vaccinated bird at day 1, 3, 5 and 7 days post-immunization (dpi) to detect virus shedding. Three chickens in each group were euthanized at 3 and 5 dpi and tissue samples including brain, lung, heart, trachea, and intestine were collected for viral titration. Blood samples were collected from each bird at 2, 3 and 4 weeks post immunization to determine humoral immune responses through hemagglutination inhibition (HI) and neutralization assays. All chickens from mock-immunized and vaccine-immunized groups did not show clinical signs and grew normally. No virus was detected from swab and tissue samples collected from two groups of vaccinated chickens. HI and neutralization antibodies were detected from each bird of both vaccination groups. However, a higher HI and neutralization titer was found in avian-adapted prototype vaccine group than wild-type vaccine group. These results demonstrate safety and immunogenicity of bat influenza vectored H5 vaccine candidates and indicate that polymerase compatibility with the avian host can enhance the vaccine immunogenicity.
Chao Dai· 0 citations
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