Formulations for small intestinal delivery of RSV and norovirus antigens
Inventors
Trager, George • Tucker, Sean • Kim, Leesun • Scallan, Ciaran
Assignees
Publication Number
US-11433146-B2
Publication Date
2022-09-06
Expiration Date
2036-06-08
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Abstract
Provided herein are compositions and methods for generating an immunogenic response in humans. Further provided are methods for designing such compositions, e.g., for vaccines.
Core Innovation
The invention provides immunogenic compositions and methods for more effective vaccination in humans and non-human animals by delivering immunogenic biological agents specifically to the ileum of the subject. These compositions are designed to elicit robust immune responses, including both humoral (serum IgG) and mucosal (intestinal secretory IgA) immunity, through targeted delivery of antigens such as norovirus VP1 or RSV fusion proteins, using enteric coatings or delivery devices that ensure release in the ileum.
The approach addresses significant limitations of current injectable vaccines, such as the need for sterile administration, professional oversight, and challenges in mass immunization during pandemics. Oral vaccination allows for distribution without human contact and overcomes aversion to injections, while tableting enables rapid, sanitary production without expensive sterile processes. The method leverages pH-sensitive or otherwise controlled-release enteric coatings to bypass degradation in the stomach and upper small intestine, releasing the immunogenic agent in the ileum for optimal immune stimulation.
The invention further includes the use of recombinant adenoviral vectors encoding pathogen-specific antigens and double-stranded RNA adjuvants, provided in oral dosage forms (e.g., tablets or capsules) with specified enteric coatings. Compositions may comprise different enteric polymer mixtures, and the invention establishes that targeted ileal delivery results in more potent immune responses, as demonstrated through human, animal, and preclinical studies described in the patent.
Claims Coverage
The patent contains two independent claims, each reflecting a distinct main inventive feature.
Immunogenic composition for ileal delivery of norovirus VP1 using E1/E3-deleted adenoviral vector and enteric coating
The composition comprises an E1/E3-deleted replication-incompetent serotype 5 adenoviral vector encoding a norovirus viral protein 1 (VP1) polypeptide and a dsRNA adjuvant, encompassed by an enteric coating that has a threshold pH of 5.8-7.0 to direct delivery and release of the vector to the human ileum. The VP1-encoding nucleic acid must have at least 90% identity to SEQ ID NO:3 or SEQ ID NO:1. The composition is specified to be capable of eliciting both serum IgG and intestinal secretory IgA immune responses in a human.
Expression vector encoding norovirus VP1 with defined sequence identity
An expression vector comprising a heterologous nucleic acid encoding norovirus VP1, where the nucleic acid sequence has at least 90% identity to SEQ ID NO:3 or SEQ ID NO:1. This feature relates to the nucleic acid component intended for use in immunogenic compositions.
The claims cover targeted ileal delivery of an adenoviral-vectored norovirus antigen with specific enteric coatings and nucleotide sequence identity, as well as expression vectors for norovirus VP1. The inventive features focus on the composition's ability to elicit specific immune responses upon delivery to the ileum and the distinct nucleic acid constructs used.
Stated Advantages
More effective vaccines and greater immune response are achieved by ileal delivery compared to non-ileal or non-targeted delivery, including higher antibody and cellular immune responses.
Oral immunization avoids the need for sterile injection, professional administration, and reduces biohazard waste from syringes and needles.
Tableting is a rapid, sanitary process that does not require expensive sterile fill and finishing processes required with injected vaccines, enabling mass production and distribution.
Oral vaccines can be distributed without human-to-human contact (e.g., by mail), which is beneficial in pandemic situations with social distancing.
Targeted ileal release enables more reliable and durable induction of neutralizing and mucosal immune responses, providing protection against infection.
Compositions are stable at room temperature for extended periods, making storage and distribution more practical.
Documented Applications
Vaccination for prevention and/or treatment of norovirus infection using ileal targeted oral immunization.
Vaccination for prevention and/or treatment of respiratory syncytial virus (RSV) infection via oral delivery targeted to the ileum.
Vaccination for prevention and/or treatment of influenza using oral tablet formulations targeting the ileum.
Prevention and treatment of diseases caused by other viral, bacterial, parasitic, and fungal pathogens, and cancer, through ileal-targeted oral immunization as described in the examples and summary.
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