Dataset Information

Sequential Immunization With Live-Attenuated Chimeric Hemagglutinin-Based Vaccines Confers Heterosubtypic Immunity Against Influenza A Viruses in a Preclinical Ferret Model.

ABSTRACT: Due to continuous antigenic drift and occasional antigenic shift, influenza viruses escape from human adaptive immunity resulting in significant morbidity and mortality in humans. Therefore, to avoid the need for annual reformulation and readministration of seasonal influenza virus vaccines, we are developing a novel chimeric hemagglutinin (cHA)-based universal influenza virus vaccine, which is comprised of sequential immunization with antigens containing a conserved stalk domain derived from a circulating pandemic H1N1 strain in combination with "exotic" head domains. Here, we show that this prime-boost sequential immunization strategy redirects antibody responses toward the conserved stalk region. We compared the vaccine efficacy elicited by distinct vaccination approaches in the preclinical ferret model of influenza. All ferrets immunized with cHA-based vaccines developed stalk-specific and broadly cross-reactive antibody responses. Two consecutive vaccinations with live-attenuated influenza viruses (LAIV-LAIV) conferred superior protection against pH1N1 and H6N1 challenge infection. Sequential immunization with LAIV followed by inactivated influenza vaccine (LAIV-IIV regimen) also induced robust antibody responses. Importantly, the LAIV-LAIV immunization regimen also induced HA stalk-specific CD4+IFN-?+ and CD8+IFN-?+ effector T cell responses in peripheral blood that were recalled by pH1N1 viral challenge. The findings from this preclinical study suggest that an LAIV-LAIV vaccination regimen would be more efficient in providing broadly protective immunity against influenza virus infection as compared to other approaches tested here.

SUBMITTER: Liu WC

PROVIDER: S-EPMC6499175 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Sequential Immunization With Live-Attenuated Chimeric Hemagglutinin-Based Vaccines Confers Heterosubtypic Immunity Against Influenza A Viruses in a Preclinical Ferret Model.

Liu Wen-Chun WC Nachbagauer Raffael R Stadlbauer Daniel D Solórzano Alicia A Berlanda-Scorza Francesco F García-Sastre Adolfo A Palese Peter P Krammer Florian F Albrecht Randy A RA

Frontiers in immunology 20190410

Due to continuous antigenic drift and occasional antigenic shift, influenza viruses escape from human adaptive immunity resulting in significant morbidity and mortality in humans. Therefore, to avoid the need for annual reformulation and readministration of seasonal influenza virus vaccines, we are developing a novel chimeric hemagglutinin (cHA)-based universal influenza virus vaccine, which is comprised of sequential immunization with antigens containing a conserved stalk domain derived from a ...[more]

PMID: 31105689

Similar Datasets

Project description:The development of universal influenza vaccines has been a priority for more than 20 years. We conducted a preclinical study in ferrets of two sets of live attenuated influenza vaccines (LAIVs) expressing chimeric hemagglutinin (cHA). These vaccines contained the HA stalk domain from H1N1pdm09 virus but had antigenically unrelated globular head domains from avian influenza viruses H5N1, H8N4 and H9N2. The viral nucleoproteins (NPs) in the two sets of universal LAIV candidates were from different sources: one LAIV set contained NP from A/Leningrad/17 master donor virus (MDV), while in the other set this gene was from wild-type (WT) H1N1pdm09 virus, in order to better match the CD8 T-cell epitopes of currently circulating influenza A viruses. To avoid any difference in protective effect of the various anti-neuraminidase (NA) antibodies, all LAIVs were engineered to contain the NA gene of Len/17 MDV. Naïve ferrets were sequentially immunized with three doses of (i) classical LAIVs containing non-chimeric HA and NP from MDV (LAIVs (NP-MDV)); (ii) cHA-based LAIVs containing NP from MDV (cHA LAIVs (NP-MDV)); and (iii) cHA-based LAIVs containing NP from H1N1pdm09 virus (cHA LAIVs (NP-WT)). All vaccination regimens were safe, producing no significant increase in body temperature or weight loss, in comparison with the placebo group. The two groups of cHA-based vaccines induced a broadly reactive HA stalk-directed antibody, while classical LAIVs did not. A high-dose challenge with H1N1pdm09 virus induced significant pathology in the control, non-immunized ferrets, including high virus titers in respiratory tissues, clinical signs of disease and histopathological changes in nasal turbinates and lung tissues. All three vaccination regimens protected animals from clinical manifestations of disease: immunized ferrets did not lose weight or show clinical symptoms, and their fever was significantly lower than in the control group. Further analysis of virological and pathological data revealed the following hierarchy in the cross-protective efficacy of the vaccines: cHA LAIVs (NP-WT) > cHA LAIVs (NP-MDV) > LAIVs (NP-MDV). This ferret study showed that prototype universal cHA-based LAIVs are highly promising candidates for further clinical development.

Project description:Recurring epizootic influenza A virus (IAV) infections in domestic livestock such as swine and poultry are associated with a substantial economic burden and pose a constant threat to human health. Therefore, universally applicable and safe animal vaccines are urgently needed. We recently demonstrated that a reassortment-incompatible chimeric bat H17N10 virus harboring the A/swan/Germany/R65/2006 (H5N1) surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) can be efficiently used as a modified live influenza vaccine (MLIV). To ensure vaccine safety and, thus, improve the applicability of this novel MLIV for mammalian usage, we performed consecutive passaging in eggs and chickens. Following passaging, we identified mutations in the viral polymerase subunits PB2 (I382S), PB1 (Q694H and I695K), and PA (E141K). Strikingly, recombinant chimeric viruses encoding these mutations showed no growth deficiencies in avian cells but displayed impaired growth in human cells and mice. Homologous prime-boost immunization of mice with one of these avian-adapted chimeric viruses, designated rR65mono/H17N10EP18, elicited a strong neutralizing antibody response and conferred full protection against lethal highly pathogenic avian influenza virus (HPAIV) H5N1 challenge infection. Importantly, the insertion of the avian-adaptive mutations into the conventional avian-like A/SC35M/1980 (H7N7) and prototypic human A/PR/8/34 (H1N1) viruses led to attenuated viral growth in human cells and mice. Collectively, our data show that the polymerase mutations identified here can be utilized to further improve the safety of our novel H17N10-based MLIV candidates for future mammalian applications. IMPORTANCE Recurring influenza A virus outbreaks in livestock, particularly in swine and chickens, pose a constant threat to humans. Live attenuated influenza vaccines (LAIVs) might be a potent tool to prevent epizootic outbreaks and the resulting human IAV infections; however, LAIVs have several disadvantages, especially in terms of reassortment with circulating IAVs. Notably, the newly identified bat influenza A viruses H17N10 and H18N11 cannot reassort with conventional IAVs. Chimeric bat influenza A viruses encoding surface glycoproteins of conventional IAV subtypes might thus function as safe and applicable modified live influenza vaccines (MLIVs).

Dataset Information

Sequential Immunization With Live-Attenuated Chimeric Hemagglutinin-Based Vaccines Confers Heterosubtypic Immunity Against Influenza A Viruses in a Preclinical Ferret Model.

Publications

Sequential Immunization With Live-Attenuated Chimeric Hemagglutinin-Based Vaccines Confers Heterosubtypic Immunity Against Influenza A Viruses in a Preclinical Ferret Model.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets