Aug 2026· Emerging Microbes and Infections· Vol 15· 0 citations· 48 references
Medicine
TL;DR
A bivalent chimeric inactivated vaccine, designated cHANA, is developed by combining two individually rescued chimeric inactivated viruses, cHANA1 and cHANA2, by combining two individually rescued chimeric inactivated viruses to eliciting more potent cross-reactive antibody responses and T cell immunity in mice.
Abstract
ABSTRACT The H9N2 avian influenza virus (AIV) has caused substantial economic losses to the global poultry industry and poses a zoonotic threat to humans. Vaccination constitutes a pivotal strategy for the prevention and control of H9N2 AIVs. However, the ongoing antigenic evolution of the viruses pose a persistent challenge to the protective efficacy of existing vaccines. Therefore, the development of a broadly protective H9N2 influenza vaccine capable of eliciting cross-reactive immune responses is crucial for mitigating both the disease burden and the risk of pandemics. Here, we developed a bivalent chimeric inactivated vaccine, designated cHANA, by combining two individually rescued chimeric inactivated viruses, cHANA1 and cHANA2. Each recombinant virus carries one set of Epigraph-designed HA and NA immunogens, and the two sets were computationally optimized from global H9N2 HA and NA sequence datasets to complement each other in epitope coverage across the H9N2 viral population. Compared to the WHO-recommended candidate vaccine virus (CVV), AL/39, cHANA elicited more potent cross-reactive antibody responses and T cell immunity in mice. Furthermore, it elicited effective cross-protection against lethal challenge with heterologous H9N2 virus and significantly reduced pulmonary viral loads of mice. By conferring broad protective immunity, this vaccine represents a promising universal vaccine candidate for controlling H9N2 outbreaks.
Avian influenza A viruses pose a persistent zoonotic threat to humans owing to their expanding host range and high case fatality rates. In particular, viruses from the 2.3.4.4b clade of the H5 subtype have now been detected in over 60 mammalian species, raising serious pandemic concerns. Understanding immune recognition of the H5 hemagglutinin (HA) is therefore critical for effective vaccine design and pandemic preparedness. To understand the breadth of cross-recognition induced by different H5 strains, we selected genetically diverse H5 human isolates from 2003-2023 and assessed neutralising antibody responses elicited by adjuvanted recombinant HA protein-based vaccines in C57BL/6 mice. Neutralisation activity of sera was determined against seven H5 HA variants using pseudotyped viruses and a PR8-reassortant virus in micro-neutralisation assays. Our results showed a wide variety of cross-strain neutralisation across H5 HA antigen variants. The conventional vaccine strain A/Indonesia/05/2005 displayed narrow activity against emerging clade 2.3.4.4b viruses, whereas ancestral variants exhibited cross-neutralisation profiles showing a diversity of breath but with limited potency. Polyvalent H5 HA formulations and nanoparticle-displayed H5 HA platforms substantially broadened cross-neutralisation against diverse H5 strains. To examine the impact of pre-existing immunity on H5 vaccine immunogenicity in mouse models, mice were primed with either seasonal influenza infection or quadrivalent influenza vaccine (QIV) prior to H5 HA immunisation. QIV pre-vaccination, but not prior influenza infection, enhanced subsequent neutralizing responses towards A/Fujian-Sanyuan/21099/2017 (clade 2.3.4.4b) H5. Collectively, our results demonstrate that immunogen selection and prior immunity shape antibody breadth following immunisation with avian A(H5) hemagglutinin. Importance Highly pathogenic avian influenza H5 viruses continue to spread across an unprecedented range of mammalian hosts, heightening the risk of a human pandemic. Current vaccine approaches for H5 rely on frequent recommendations of candidate vaccine viruses to match emerging H5 strains. Developing broadly protective H5 vaccines is thus a priority as part of pandemic preparedness. This study demonstrates a considerable variability in the potential of H5 vaccine antigens to induce neutralisation breadth, as well as the potential for multivalent vaccines and ferritin nanoparticle-based strategies to robustly augment immunity across antigenic variants. Furthermore, prior immunity established by seasonal QIV impacts the immunogenicity of subsequent 2.3.4.4b HA vaccination against H5 diversity. These findings provide critical insights to guide the rational design of broadly reactive H5 vaccines and inform pre-pandemic preparedness strategies.
Yee-Chen Liu, Andrew Kelly, R. Esterbauer et al.· bioRxiv· 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
The hemagglutinin (HA) glycoprotein of seasonal influenza viruses undergoes continual antigenic drift, contributing to vaccine mismatch and reduced effectiveness of strain-specific seasonal vaccines. Although vaccination remains the most effective strategy for preventing influenza disease, conventional egg-based vaccine production requires several months and may not keep pace with viral evolution. Messenger RNA (mRNA) vaccines offer a promising alternative because they can be rapidly updated to encode emerging antigens and are manufactured through a scalable, cell-free process that avoids propagation associated adaptations. To address the challenges of antigenic drift and vaccine mismatch, we combined mRNA vaccine technology with Computationally Optimized Broadly Reactive Antigens (COBRA) to develop broadly protective influenza HA vaccines. These COBRA H1 and H3 mRNA HA vaccines elicited robust antigen-specific IgG, hemagglutination inhibition (HAI), and neutralizing antibody responses against diverse historical and contemporary influenza strains in cohorts of influenza naïve and pre-immune mice. Vaccination also induced strong cellular immunity, characterized by the expansion of antigen-specific antibody and cytokine secreting cells. These responses were further enhanced in animals with pre-existing influenza immunity, as demonstrated by an increased frequency of IFN-γ producing cells recognizing conserved HA stalk-based peptides. Together, these findings demonstrate that COBRA HA encoding mRNA vaccines can effectively leverage immunological memory while expanding responses to conserved HA epitopes, supporting improved protection against antigenically drifted strains. Thus, the combination of broadly reactive COBRA HA antigens with a rapidly adaptable and manufacturable mRNA platform represents a promising strategy for next-generation influenza vaccination. Importance Recent influenza seasons have demonstrated that vaccine mismatch can have significant public health consequences, leading to increased disease burden, hospitalizations, and transmission. Modern mRNA vaccines offer a promising alternative to traditional egg-based vaccines because they can be rapidly manufactured and updated to better match emerging viral variants while eliciting strong antiviral immune responses. Importantly, the flexibility of the mRNA platform enables the expression of custom-designed antigens optimized for broad protection. Advances in computational antigen design now make it possible to incorporate immunologically relevant epitopes from multiple circulating viruses into a single vaccine antigen. By expanding immune responses beyond strain-matched protection, these broadly reactive antigens can elicit antibodies that recognize both dominant and emerging viral variants. As a result, they have the potential to establish immune memory against antigenically diverse strains before they become prevalent in the population, improving vaccine effectiveness during periods of antigenic drift.
James D. Allen, Jessica M. Medina, Camila Caetano et al.· bioRxiv· 0 citations
The findings suggest that internal gene backbone compatibility may influence vaccine immunogenicity and warrant further validation to support a refined vaccine design strategy for H7N9 and potentially other avian influenza subtypes.
Yi Liu, Meng-Yuan Bai, Tao Zhang et al.· Microorganisms· 0 citations
Avian influenza virus (AIV) and infectious bronchitis virus (IBV) are major respiratory pathogens of poultry, and their co-circulation complicates disease control. Here, we developed a chimeric subunit vaccine, RBD-HA, in which the receptor-binding domain (RBD) of the QX-type IBV spike protein replaced the immunodominant head domain of H9N2 AIV haemagglutinin. Structural analyses showed that RBD-HA formed a stable trimeric assembly, supporting the use of the HA stalk as an antigen-presenting scaffold. In chickens, RBD-HA induced humoral responses against both viruses and protected against homologous and heterologous H9N2 AIV challenge. In parallel, RBD-HA induced IBV-reactive and neutralizing antibody responses and provided protection against QX-type IBV challenge. The vaccine also elicited cross-reactive neutralizing activity and reduced viral shedding and tissue damage after H6N6 AIV challenge. These findings provide proof of concept for a bivalent subunit vaccine targeting two major avian respiratory viruses.
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
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