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.
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.
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.
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).
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.
Project description:Subunit vaccine conferred lung protection against heterologous strain through the augmentaion of lung tissue resident memmory CD4+ T-cells.
Project description:To compare the effects of different types of SARS-CoV-2 vaccines in booster immunization, this study established a population cohort vaccinated with inactivated vaccine and protein subunit vaccine as the third booster vaccine, respectively. We collected serum and PBMC samples from participants in chronological order, and performed a systematic review of distinct antibody signatures and microtranscriptomics to provide data support for booster immunization.
Project description:Vaccine development involves time-consuming and expensive evaluation of candidate vaccines in animal models. As mediators of both innate and adaptive immune responses dendritic cells (DCs) are considered to be highly important for vaccine performance. Here we evaluated in how far the response of DCs to a vaccine in vitro is in line with the immune response the vaccine evokes in vivo. To this end, we investigated the response of murine bone marrow-derived DCs to whole inactivated virus (WIV) and subunit (SU) influenza vaccine preparations. These vaccine preparations were chosen because they differ in the immune response they evoke in mice with WIV being superior to SU vaccine through induction of higher virus-neutralizing antibody titers and a more favorable Th1-skewed response phenotype. To evaluate if in vivo immunogenicity is reflected by DC reactions in vitro we studied the gene expression signature of murine bone-marrow-derived conventional DCs (cDCs) upon stimulation with WIV or SU influenza vaccine or, for reasons of comparison, with live influenza virus. Dendritic cells stimulated with PBS served as a control. Gene expression analysis was performed on samples 4, 12 and 24 hours after the start of stimulation.
Project description:To compare the effects of different types of SARS-CoV-2 vaccines in booster immunization in Elderly Adults, this study established a population cohort vaccinated with inactivated vaccine and protein subunit vaccine as the third booster vaccine in Elderly Adults over 70 Years of Age, respectively. We collected serum and PBMC samples from participants, and performed a systematic review of distinct antibody signatures and microtranscriptomics to provide data support for booster immunization.
