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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 | GSE205840 | GEO
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
Project description:An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets
| PRJNA847929 | ENA
Project description:An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets [mouse]
| PRJNA847932 | ENA
Project description:An inactivated multivalent influenza A virus vaccine is broadly protective in mice and ferrets [ferret]
| PRJNA847931 | ENA
Project description:There is a crucial need for an improved H3N2 influenza virus vaccine due to low vaccine efficacy rates and increased morbidity and mortality associated with H3N2-dominated influenza seasons. Here, we utilize a computational design strategy to produce epitope-optimized, broadly cross-reactive H3 hemagglutinins in order to create a universal H3N2 influenza vaccine. The Epigraph immunogens are designed to maximize the viral population frequency of epitopes incorporated into the immunogen. We compared our Epigraph H3 vaccine to the traditional egg-based inactivated influenza vaccine from 2018-19, FluZone. Epigraph vaccination-induced stronger cross-reactive antibody responses than FluZone against 18 H3N2 viruses isolated from 1968 to 2019 in both mice and ferrets, with protective hemagglutination inhibition titers against 93-100% of the contemporary H3N2 strains compared to only 27% protection measured from FluZone. In addition, Epigraph vaccination-induced strong cross-reactive T-cell immunity which significantly contributes to protection against lethal influenza virus infection. Finally, Epigraph vaccination protected ferrets from influenza disease after challenge with two H3N2 viruses. The superior cross-reactive immunity induced by these Epigraph immunogens supports their development as a universal H3N2 influenza vaccine.
| S-EPMC9226166 | biostudies-literature
Project description:Increasing preclinical and clinical results have demonstrated that mRNA vaccines efficiently prevent infectious diseases and are safe in animal models and humans. In this study, we fabricated a multivalent influenza mRNA lipid nanoparticle (LNP) vaccine with mRNAs of hemagglutinins from influenza H1N1 and H3N2 viruses, matrix protein 1, and nucleoprotein. We found that cutaneous immunization with mRNA LNPs induced strong Th1 and Th2 cellular immunity with robust antigen-specific antibody titers and increased cytokine-secreting splenocytes and antibody-secreting cells. The supplement of cGAMP improved the immunogenicity of mRNA LNPs. Compared with αGC or cGAMP/αGC adjuvanted mRNA LNP formulations in our study, cGAMP mRNA LNPs induced more robust antibody responses. Enhanced cellular immunity with more IL-4 and IFN-γ secreting cells and effector memory T cell populations in spleens, as well as increased CD4+ resident memory (TRM) T cells in lungs were observed in cGAMP mRNA LNPs immunized group. These results demonstrated that cGAMP is an effective adjuvant for cutaneous vaccination of multivalent mRNA LNP vaccines in mice to induce stronger immune responses in the spleen and lung, and the cGAMP-adjuvanted mRNA LNPs protected against homologous and heterologous viral infection.
| S-EPMC9668623 | biostudies-literature
Project description:Current influenza virus vaccine strategies stimulate immune responses toward the globular head domain of the hemagglutinin protein in order to inhibit key steps of the virus life cycle. Because this domain is highly variable across strains, new vaccine formulations are required in most years. Here we demonstrate a novel vaccine strategy that generates immunity to the highly conserved stalk domain by using chimeric hemagglutinin constructs that express unique head and stalk combinations. By repeatedly immunizing mice with constructs that expressed the same stalk but an irrelevant head, we specifically stimulated a stalk-directed response that provided broad-based heterologous and heterosubtypic immunity in mice. Notably, our vaccination scheme provides a universal vaccine approach that protects against challenge with an H5 subtype virus. Furthermore, through in vivo studies using passively transferred antibodies or depletion of CD8(+) T cells, we demonstrated the critical role that humoral mechanisms of immunity play in the protection observed. The present data suggest that a vaccine strategy based on the stalk domain of the hemagglutinin protein could be used in humans to broadly protect against a variety of influenza virus subtypes.
| S-EPMC3676110 | biostudies-literature
Project description:COVID-19 has demonstrated the power of RNA vaccines as part of a pandemic response toolkit. Another virus with pandemic potential is influenza. Further development of RNA vaccines in advance of a future influenza pandemic will save time and lives. As RNA vaccines require formulation to enter cells and induce antigen expression, the aim of this study was to investigate the impact of a recently developed bioreducible cationic polymer, pABOL for the delivery of a self-amplifying RNA (saRNA) vaccine for seasonal influenza virus in mice and ferrets. Mice and ferrets were immunized with pABOL formulated saRNA vaccines expressing either haemagglutinin (HA) from H1N1 or H3N2 influenza virus in a prime boost regime. Antibody responses, both binding and functional were measured in serum after immunization. Animals were then challenged with a matched influenza virus either directly by intranasal inoculation or in a contact transmission model. While highly immunogenic in mice, pABOL-formulated saRNA led to variable responses in ferrets. Animals that responded to the vaccine with higher levels of influenza virus-specific neutralizing antibodies were more protected against influenza virus infection. pABOL-formulated saRNA is immunogenic in ferrets, but further optimization of RNA vaccine formulation and constructs is required to increase the quality and quantity of the antibody response to the vaccine.
| S-EPMC9384352 | biostudies-literature
Project description:Oral vaccination would provide an easy and safe measure to prevent infectious diseases by facilitating mass immunization. We investigated the feasibility of oral vaccination with inactivated whole influenza virus (A/PR8/34). Oral vaccination of mice induced high levels of serum IgG and IgA antibodies specific to the homologous virus (A/PR8) as well as cross reactive to heterologous (A/California/04/09) and heterosubtypic viruses (A/Philippines/2/82). IgG1 isotype antibodies were found to be induced at significantly higher levels than IgG2a antibodies. These antibodies induced by oral vaccination exhibited hemagglutination inhibition activities. High levels of both IgG and IgA antibodies were induced in vagina and lungs. Mucosal IgA antibodies were also elicited in other sites including saliva, urine, and fecal samples. Orally vaccinated mice were completely protected against challenge with homologous or heterologous viruses, and partially protected against heterosubtypic virus. Importantly, high recall antibody secreting cell (ASC) responses were induced in spleen, indicating the generation of memory B cells by oral vaccination. The present study therefore presents new findings of cross-reactive antibodies at systemic and diverse mucosal sites, recall antibody responses, and cross-protective efficacies by oral vaccination, thus supporting a proof-of-concept that oral delivery of vaccines can be developed as an effective vaccination route.
| S-EPMC5555299 | biostudies-other