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An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets [ferret]

ABSTRACT: Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics and pandemics as well as from viruses adapted to a variety of animals including poultry, pigs, and horses. Vaccines that broadly protect against all such IAVs, so-called “universal” influenza vaccines, do not currently exist, but are urgently needed. Here, we demonstrated that an inactivated, multivalent whole virus vaccine, delivered intramuscularly or intranasally, was broadly protective against challenges with multiple IAV hemagglutinin and neuraminidase subtypes in both mice and ferrets. The vaccine is comprised of four beta-propiolactone-inactivated low pathogenicity avian influenza A virus subtypes of H1N9, H3N8, H5N1, or H7N3. Vaccinated mice and ferrets demonstrated substantial protection against a variety of IAVs, including the 1918 H1N1 strain, the highly pathogenic avian H5N8 strain, and H7N9. We also observed protection against challenge with antigenically variable and heterosubtypic avian, swine, and human viruses. Compared to mock vaccinated animals, vaccinated mice and ferrets demonstrated marked reductions in viral titers, lung pathology, and host inflammatory responses. This vaccine approach indicates the feasibility of eliciting broad, heterosubtypic IAV protection and identifies a promising candidate for influenza vaccine clinical development.

ORGANISM(S): Mustela putorius furo

PROVIDER: GSE205840 | GEO | 2022/07/21

REPOSITORIES: GEO

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An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets [mouse]

Project description:Influenza A viruses (IAVs) present major public health threats from annual seasonal epidemics and pandemics as well as from viruses adapted to a variety of animals including poultry, pigs, and horses. Vaccines that broadly protect against all such IAVs, so-called “universal” influenza vaccines, do not currently exist, but are urgently needed. Here, we demonstrated that an inactivated, multivalent whole virus vaccine, delivered intramuscularly or intranasally, was broadly protective against challenges with multiple IAV hemagglutinin and neuraminidase subtypes in both mice and ferrets. The vaccine is comprised of four beta-propiolactone-inactivated low pathogenicity avian influenza A virus subtypes of H1N9, H3N8, H5N1, or H7N3. Vaccinated mice and ferrets demonstrated substantial protection against a variety of IAVs, including the 1918 H1N1 strain, the highly pathogenic avian H5N8 strain, and H7N9. We also observed protection against challenge with antigenically variable and heterosubtypic avian, swine, and human viruses. Compared to mock vaccinated animals, vaccinated mice and ferrets demonstrated marked reductions in viral titers, lung pathology, and host inflammatory responses. This vaccine approach indicates the feasibility of eliciting broad, heterosubtypic IAV protection and identifies a promising candidate for influenza vaccine clinical development.

2022-07-21 | GSE205839 | GEO

Administration of multivalent influenza virus recombinant hemagglutinin vaccine in combination-adjuvant elicits broad reactivity beyond the vaccine components

Project description:Combining variant antigens into a multivalent vaccine is a traditional approach used to provide broad coverage against antigenically variable pathogens, such as polio, human papilloma and influenza viruses. However, strategies for increasing the breadth of antibody coverage beyond the vaccine are not well understood, but may provide more anticipatory protection. Influenza virus hemagglutinin (HA) is a prototypic variant antigen. Vaccines that induce HA-specific neutralizing antibodies lose efficacy as amino acid substitutions accumulate in neutralizing epitopes during influenza virus evolution. Here we studied the effect of a potent combination adjuvant (CpG/MPLA/squalene-in-water emulsion) on the breadth and maturation of the antibody response to a representative variant of HA subtypes H1, H5 and H7. Using HA protein microarrays and antigen-specific B cell labelling, we show when administered individually, each HA elicits a cross-reactive antibody profile for multiple variants within the same subtype and other closely-related subtypes (homosubtypic and heterosubtypic cross-reactivity, respectively). Despite a capacity for each subtype to induce heterosubtypic cross-reactivity, broader coverage was elicited by simply combining the subtypes into a multivalent vaccine. Importantly, multiplexing did not compromise antibody avidity or affinity maturation to the individual HA constituents. The use of adjuvants to increase the breadth of antibody coverage beyond the vaccine antigens may help future-proof vaccines against newly-emerging variants.

2021-06-26 | GSE178932 | GEO

Multivalent Influenza DNA vaccine induces cross-reactive polyfunctional T lymphocytes and promotes rapid clearance of heterologous challenge strain in non-human primates

Project description:Recent avian and swine-origin influenza virus outbreaks illustrate the ongoing threat of influenza pandemic. New vaccines that offer accelerated production and broader, more universal protection against drifted and shifted strains are needed. Here, we investigated a multivalent PMED DNA vaccine for the ability to induce antibody and T cell responses against four HA antigens, nucleoprotein and the ectodomain of M2 (M2e). Macaques in the Vaccinated and Control groups were intramuscularly anaesthetized with ketamine (10 mg/kg) and inoculated with a suspension containing 10^6.5 p.f.u. ml-1 of CA09 virus through a combination of intratracheal (4.5 ml), intranasal (0.5 ml per nostril), ocular (0.1 ml per eye) and oral (1 ml) routes (resulting in a total infectious dose of 10^7.4 PFU). Bronchoalveolar lavages were collected two weeks prior to challenge and at days 3, 7, and 10 post-infection. We performed microarray analysis on these samples.

2016-07-31 | E-GEOD-77824 | biostudies-arrayexpress

Allelic Polymorphism Gates Autoreactivity and Vaccine-Elicitation of Human Broadly Neutralizing Antibodies Against Influenza Virus

Project description:Human broadly neutralizing antibodies (bnAbs) targeting the hemagglutinin stalk of group 1 influenza A viruses (IAVs) are biased for IGHV1-69 alleles that use phenylalanine (F54) but not leucine (L54) within their CDRH2 loops. Despite this, we demonstrate that both alleles encode for human IAV bnAbs that employ structurally convergent modes of contact to the same epitope. To resolve differences in lineage-expandability, we compared F54 vs L54 as substrate within humanized mice where antibodies develop with human-like CDRH3 diversity but are restricted to single VH-genes. While both alleles encoded for bnAb precursors, only F54 IGHV1-69 supported elicitation of heterosubtypic serum bnAbs following immunization with a stalk-only nanoparticle vaccine. L54 IGHV1-69 was unproductive, co-encoding for anergic B cells and autoreactive stalk antibodies that were cleared from B cell memory. Moreover, human stalk antibodies also demonstrated L54-dependent autoreactivity. IGHV1-69 polymorphism, which is skewed ethnically, therefore gates tolerance and vaccine-expandability of influenza bnAbs.

2022-07-02 | GSE207054 | GEO

Multivalent Influenza DNA vaccine induces cross-reactive polyfunctional T lymphocytes and promotes rapid clearance of heterologous challenge strain in non-human primates

2016-07-31 | GSE77824 | GEO

miRNA profile in mice lung after influenza A infection

Project description:The regulation of host defense against influenza A viruses (IAVs) infection has attracted much attention, especially for type I interferon (IFN)-mediated innate response. Here we revealed that miR-93 expression was significantly downregulated in Alveolar epithelial type II cells (AT2) upon IAVs infection through RIG-I/JNK pathway. Inhibition of miR-93 was found to suppress host antiviral innate response by facilitating type I IFN effector signaling, and JAK1 was identified to be directly targeted by miR-93. Importantly, in vivo administration of miR-93 antagomiR significantly inhibited miR-93 expression and markedly suppressed IAVs infection, which in turn prevented the death of IAVs infected mice. Hence, the inducible downregulation of miR-93 suppress IAVs infection by upregulation IFN-JAK-STAT effector pathway, and in vivo inhibition of miR-93 bears considerable therapeutic potential for suppressing IAVs infection. The miRNA profiling in mice lung was measured at 24 and 36 hours after gave each mouse 50µl of influenza A (50 µl of 10-6 TCID50/µl) via retropharyngeal instillation. Three mice were performed at each time (24 or 36 hours) and RNA from different donors was mixed before determination.

2015-06-22 | E-GEOD-70125 | biostudies-arrayexpress

Systems biology of vaccination for seasonal influenza in humans

Project description:This SuperSeries is composed of the following subset Series: GSE29614: Time Course of Young Adults Vaccinated with Influenza TIV Vaccine during 2007/08 Flu Season GSE29615: Time Course of Young Adults Vaccinated with Influenza LAIV Vaccine during 2008/09 Flu Season GSE29617: Time Course of Young Adults Vaccinated with Influenza TIV Vaccine during 2008/09 Flu Season GSE29618: FACS-sorted cells from Young Adults Vaccinated with Influenza TIV or LAIV Vaccines during 2008/09 Flu Season Refer to individual Series

2011-07-10 | E-GEOD-29619 | biostudies-arrayexpress

miRNA profile in mice lung after influenza A infection

2015-06-22 | GSE70125 | GEO

Host responses that correlate with respiratory droplet transmission of swine-origin influenza viruses in ferrets.

Project description:The determinants of influenza transmission remain poorly understood. Swine influenza viruses preferentially attach to receptors found in the upper airways; however, most swine influenza viruses fail to transmit efficiently from swine to humans, and from human-to-human. The pandemic 2009 H1N1 (H1N1pdm) virus was a rare exception of a swine virus that acquired efficient transmissibility from human-to-human, and is reflected in efficient respiratory droplet transmission in ferrets. We hypothesize that virus-induced host responses in the upper airways correlate with airborne transmission in ferrets. To address this question, we used the H1N1pdm virus and swine influenza A/swine/Hong Kong/201/2010 (HK201) virus that has comparable titre in the ferret nasopharynx, but it exhibits differential transmissibility in ferrets via respiratory droplet route. We performed a transcriptomic analysis of tissues from the upper and lower respiratory tract from ferrets infected with either H1N1pdm or HK201 viruses using ferret-specific Agilent oligonucleotide arrays. We found differences in the kinetics of the innate immune response elicited by these two viruses that varied across tissues.

2017-03-31 | GSE79282 | GEO

FLUAV RAM-IGIP: A modified live influenza virus vaccine that enhances humoral and mucosal responses against influenza. Vaccine Encoding the IgA-Inducing Protein

Project description:Influenza A virus (FLUAV) poses a significant threat to both humans and animals. While vaccination serves as the primary defense against influenza, the effectiveness of currently approved vaccines is suboptimal. To address this issue, we have developed modified live virus (MLV) vaccines against influenza using genome rearrangement techniques targeting the internal gene segments of FLUAV. The rearranged M2 (RAM) strategy involves cloning the M2 ORF downstream of the PB1 ORF in segment 2 and incorporating multiple early stop codons within the M2 ORF in segment 7. Additionally, the IgA-inducing protein (IGIP) coding region was inserted into the HA segment to further attenuate the virus and enhance protective mucosal responses. RAM-IGIP viruses exhibit similar growth rates to wild type (WT) viruses in vitro and remain stable during multiple passages in cells and embryonated eggs. The safety, immunogenicity, and protective efficacy of the RAM-IGIP MLV vaccine against the prototypical 2009 pandemic H1N1 strain A/California/04/2009 (H1N1) (Ca/04) were evaluated in Balb/c mice and compared to a prototypic cold-adapted live attenuated virus vaccine. The results demonstrate that the RAM-IGIP virus exhibits attenuated virulence in vivo. Mice vaccinated with RAM-IGIP and subsequently challenged with an aggressive lethal dose of the Ca/04 strain exhibited complete protection. Analysis of the humoral immune response revealed that the inclusion of IGIP enhanced the production of neutralizing antibodies and augmented the antibody-dependent cellular cytotoxicity response. Similarly, the RAM-IGIP potentiated the mucosal immune response against various FLUAV subtypes. Moreover, increased antibodies against NP and NA responses were observed. These findings support the development of MLVs utilizing genome rearrangement strategies in conjunction with the incorporation of immunomodulators.

2024-01-10 | GSE252919 | GEO

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