Periodic Reporting for period 1 - NOSEVAC (INNOVATIVE NASAL VACCINES TO PREVENT PATHOGEN COLONIZATION AND INFECTION IN THE UPPER RESPIRATORY TRACT)
Période du rapport: 2023-05-01 au 2024-10-31
Bacterial and viral respiratory infections are significant contributors to global morbidity and mortality. Streptococcus pneumoniae and Bordetella pertussis, along with influenza virus and SARS-CoV-2, are causative agents of respiratory diseases that have substantial public health implications; acquired pneumonia, whooping cough, influenza, and COVID-19, respectively. The available vaccines against these diseases are often administered via intramuscular or subcutaneous injection, and do not effectively prevent colonisation or infection of the upper respiratory tract (URT). Consequently, their impact on pathogen transmission is limited.
The NOSEVAC consortium, operating under the coordination of the European Vaccine Initiative (EVI), endeavours to cultivate and evaluate inventive nasal vaccine platforms as a ground-breaking approach to prevent the earliest stage of infection, thereby inhibiting URT colonisation, transmission, and disease. The project relies upon a distinctive consortium comprising 12 distinguished and complementary research teams hailing from the European Union (EU), UK and Switzerland.
The NOSEVAC consortium geared up to develop novel nasal vaccines targeting S. pneumoniae and B. pertussis infections. Further, the consortiumwill develop a bivalent nasal vaccine to simultaneously prevent influenza and COVID-19.
in addition to develop new nasal vaccine candidates, will:
• Develop vaccine formulations for nasal delivery of RNA- and protein-based antigens
• Discover bacterial antigens that promote colonisation of the URT
• Identify human host immune factors involved long-term protection of the URT
• Address acceptability of nasal vaccination, beg an important part of social sciences and humanities
It is expected that NOSEVAC will establish strategic research pathways to combat respiratory pathogens, encompassing those with the potential for large outbreaks. Furthermore, the organisation can serve as a catalyst for evidence-driven decision-making for policymakers and investors.
The NOSEVAC consortium, operating under the coordination of the European Vaccine Initiative (EVI), endeavours to cultivate and evaluate inventive nasal vaccine platforms as a ground-breaking approach to prevent the earliest stage of infection, thereby inhibiting URT colonisation, transmission, and disease. The project relies upon a distinctive consortium comprising 12 distinguished and complementary research teams hailing from the European Union (EU), UK and Switzerland.
The NOSEVAC consortium geared up to develop novel nasal vaccines targeting S. pneumoniae and B. pertussis infections. Further, the consortiumwill develop a bivalent nasal vaccine to simultaneously prevent influenza and COVID-19.
in addition to develop new nasal vaccine candidates, will:
• Develop vaccine formulations for nasal delivery of RNA- and protein-based antigens
• Discover bacterial antigens that promote colonisation of the URT
• Identify human host immune factors involved long-term protection of the URT
• Address acceptability of nasal vaccination, beg an important part of social sciences and humanities
It is expected that NOSEVAC will establish strategic research pathways to combat respiratory pathogens, encompassing those with the potential for large outbreaks. Furthermore, the organisation can serve as a catalyst for evidence-driven decision-making for policymakers and investors.
Work performed in the first 18 months of the project demonstrates progress across antigen discovery, formulation development, preclinical testing, and experimental medicinetrials preparation, with promising data to guide next steps:
WP1: Discovery of Antigens of S. pneumoniae and B. pertussis required for nasal colonization: A nasal colonization model with S. pneumoniae serotype 6B (VL4140) has been developed for proteomic screening. CRISPRi screening identified six essential genes for lung colonization, with two proteins under further evaluation as lead candidates. For B. pertussis, growth conditions mimicking the human nasal cavity were optimized and patented in 2024 (EP24305982). Transcriptomic and proteomic analyses identified two overexpressed antigens as vaccine candidates. Comparative data will confirm antigen selection.
WP2: Development of innovative formulations for nasal bivalent vaccines using mRNA, saRNA, or protein antigens to target CAP and whooping cough, or Influenza and COVID-19: Two reporter proteins and five model antigens were selected, and 11 mRNA sequences were designed, produced, and characterized for formulation studies. Nanocarrier formulation for protein antigens is in early development, with ongoing characterization and optimization.
WP3: Characterization of bivalent vaccines’ Interactions with human nasal epithelium and immune cells: Results with human nasal epithelial cells and PBMCs suggest that the GFP-LNP preparation is likely pyrogen-free, with no toxic effects or cellular activation. Although protein-loaded nanocarrier prototypes are yet to be produced, data from mRNA-containing LNPs will guide future experiments with lipidic and polymeric nanocarriers, including protein-loaded versions. The PBMC-based in vitro model shows promise for nasal formulations.
WP4: Evaluation of the immunogenicity, mode of action (MoA), and protective efficacy of selected bivalent bacterial and viral nasal vaccines in animal models of respiratory infection, colonization, and transmission: Vaccine formulations with the LafB model antigen (protein and mRNA) were tested in mice for nasal and intramuscular immunization. Intramuscular data showed both tested mRNAs in LNPs were immunogenic, with one selected for nasal mRNA and saRNA formulation development. Procedures for isolating cells from nasal tissues, lungs, and lymph nodes for flow cytometry, RNA sequencing, and functional assays have been established. In ferrets, bivalent mRNA vaccines induced primary and recall immune responses. ELISpot assays were optimized to measure virus-specific T-cells and mucosal antibody responses.
WP5: Clinical Activities: Recruitment for the NoseLAIV-Kids study began in October 2024, and recruitment for NoseSpnLAIV-Elderly is scheduled for November 2024. Recruitment for NoseSpn-Elderly and NoseFlu-Kids at UNIGE will begin in December 2024. FloQswabs were validated as the best method for nasal mucosa sampling, consistently yielding higher cell counts and sampling multiple nasal compartments.
WP6: Acceptability of nasal vaccines: Theoretical and clinical insights aim to improve vaccine uptake by addressing social and psychological factors such as motivation, risk perception, and gender biases. A survey has been developed and pre-tested to inform trial designs and facilitate vaccine acceptance.
WP1: Discovery of Antigens of S. pneumoniae and B. pertussis required for nasal colonization: A nasal colonization model with S. pneumoniae serotype 6B (VL4140) has been developed for proteomic screening. CRISPRi screening identified six essential genes for lung colonization, with two proteins under further evaluation as lead candidates. For B. pertussis, growth conditions mimicking the human nasal cavity were optimized and patented in 2024 (EP24305982). Transcriptomic and proteomic analyses identified two overexpressed antigens as vaccine candidates. Comparative data will confirm antigen selection.
WP2: Development of innovative formulations for nasal bivalent vaccines using mRNA, saRNA, or protein antigens to target CAP and whooping cough, or Influenza and COVID-19: Two reporter proteins and five model antigens were selected, and 11 mRNA sequences were designed, produced, and characterized for formulation studies. Nanocarrier formulation for protein antigens is in early development, with ongoing characterization and optimization.
WP3: Characterization of bivalent vaccines’ Interactions with human nasal epithelium and immune cells: Results with human nasal epithelial cells and PBMCs suggest that the GFP-LNP preparation is likely pyrogen-free, with no toxic effects or cellular activation. Although protein-loaded nanocarrier prototypes are yet to be produced, data from mRNA-containing LNPs will guide future experiments with lipidic and polymeric nanocarriers, including protein-loaded versions. The PBMC-based in vitro model shows promise for nasal formulations.
WP4: Evaluation of the immunogenicity, mode of action (MoA), and protective efficacy of selected bivalent bacterial and viral nasal vaccines in animal models of respiratory infection, colonization, and transmission: Vaccine formulations with the LafB model antigen (protein and mRNA) were tested in mice for nasal and intramuscular immunization. Intramuscular data showed both tested mRNAs in LNPs were immunogenic, with one selected for nasal mRNA and saRNA formulation development. Procedures for isolating cells from nasal tissues, lungs, and lymph nodes for flow cytometry, RNA sequencing, and functional assays have been established. In ferrets, bivalent mRNA vaccines induced primary and recall immune responses. ELISpot assays were optimized to measure virus-specific T-cells and mucosal antibody responses.
WP5: Clinical Activities: Recruitment for the NoseLAIV-Kids study began in October 2024, and recruitment for NoseSpnLAIV-Elderly is scheduled for November 2024. Recruitment for NoseSpn-Elderly and NoseFlu-Kids at UNIGE will begin in December 2024. FloQswabs were validated as the best method for nasal mucosa sampling, consistently yielding higher cell counts and sampling multiple nasal compartments.
WP6: Acceptability of nasal vaccines: Theoretical and clinical insights aim to improve vaccine uptake by addressing social and psychological factors such as motivation, risk perception, and gender biases. A survey has been developed and pre-tested to inform trial designs and facilitate vaccine acceptance.
The NOSEVAC project has worked towards addressing social and psychological factors to improve nasal vaccine uptake. Further, during the first 18 months of the project, consortium partner Institute Pateru Lille submitted a patent application (2024-EP24305982) covering culture media and methods for cultivating Bordatella bacteria. Additionally, the Technology Transfer Office at Unviersity of Lausanne (PACTT) has successfully finalized an exclusive licensing agreement for the pre-existing vaccine antigen LafB patent (No. PCT/EP2022/071098), which is shared with IPL, and the US-based company I-Seq Biotechnology.