Methods and compositions relating to adjuvants
Inventors
Levy, Ofer • Dowling, David • Bazin-Lee, Helene • Burkhart, David • Evans, Jay • SMITH, Alyson Jessica
Assignees
Boston Childrens Hospital • University of Montana Missoula
Publication Number
US-11464854-B2
Publication Date
2022-10-11
Expiration Date
2038-03-23
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Abstract
The methods and compositions described herein relate to methods of immunization or stimulating an immune response, e.g., using agonists of TLR7 and/or TLR8 as antigens. The methods and compositions described herein have particular relevance to use in infants.
Core Innovation
The invention describes compositions and methods for immunization or stimulating an immune response using adjuvants that are agonists of TLR7 and/or TLR8. The adjuvants may include compounds such as imidazoquinolines, thiazoquinolines, benzazepines, and other specified molecular structures, with particular emphasis on lipidated forms, for example 3M-052 and CRX-649. These adjuvants can be administered with one or more antigens, which are not conjugated to the adjuvant, to enhance vaccine efficacy.
The invention addresses the problem that existing adjuvants, while effective in adults, often show poor performance or are counterproductive in infants and newborns. This is a significant barrier to successful immunization of this age group, leading to suboptimal immune responses and requiring multiple vaccine doses to achieve protection. There is a need for adjuvants that can generate more robust and rapid immune responses when given to infants, including at or shortly after birth.
The core innovation involves the use of TLR7 and/or TLR8 agonist adjuvants that are not conjugated to the antigen, can be lipidated to provide local activity and reduced systemic inflammation, and are compatible with various vaccine formulations (e.g., subunit, conjugate, or attenuated vaccines). These adjuvants can be administered alone or with antigens, with or without a second adjuvant such as alum, and are particularly designed to improve vaccine responses in infants and newborns. The invention also encompasses compositions, kits, and formulations for these methods.
Claims Coverage
The patent claims cover three principal inventive features, each addressing different aspects of immunization methods, immune response stimulation, and kits comprising TLR7 and/or TLR8 agonist adjuvants.
Administration of TLR7 and/or TLR8 agonist adjuvant and antigen to immunize a subject
The method comprises administering to a subject an adjuvant comprising an agonist of TLR7 and/or TLR8 and at least one antigen. The adjuvant and antigen are not conjugated to each other. The adjuvant can be selected from compounds such as imidazoquinolines, thiazoquinolines, and benzazepines, including specific structures like CRX-649 (Formula X) and 3M-052. The method is applicable to a wide range of antigens, including those in pneumococcal, hepatitis B, acellular pertussis, diphtheria tetanus acellular pertussis, hepatitis A, and meningococcal vaccines. Further embodiments include lipidation, phosphorylation, conjugation via PEG linkers, administration to infants, and formulations with alum.
Method of stimulating an immune response using TLR7 and/or TLR8 agonist adjuvant
A method of stimulating an immune response in a subject by administering an adjuvant comprising an agonist of TLR7 and/or TLR8, where the agonist comprises a compound selected from those described as Formula IX, Formula XII, 3M-052, CRX-672, CRX-677, and CRX-748. The method covers stimulation of various immune responses, including T helper 1-cytokine production and increase in Th1 CRM-197-specific neonatal CD4+ cells.
Kit comprising TLR7 and/or TLR8 agonist adjuvant and optional antigen
The kit comprises an adjuvant comprising an agonist of TLR7 and/or TLR8, where the agonist is selected from compounds such as Formula IX, Formula XII, 3M-052, CRX-672, CRX-677, and CRX-748. The kit may further comprise at least one antigen. The formulations can be provided separately or together and are suitable for use in immunizing a subject or stimulating an immune response.
In summary, the inventive features broadly claim the use of TLR7/8 agonist adjuvant compositions and methods—especially in lipidated, non-conjugated forms—in combination with antigens for immunization or immune response stimulation, with formulations and kits adapted for infant use and improved immunogenicity.
Stated Advantages
Agonists of TLR7 and/or TLR8 used as adjuvants provide surprisingly effective adjuvant activity in newborns, improving the efficacy of vaccination and lowering the number of doses required.
Such adjuvants permit effective vaccination at or within days of birth, providing earlier protection and making vaccination more plausible for at-risk populations.
The use of these adjuvants enables greater immune response, increased rate of an immune response, and greater protection than the same dose of antigen without the adjuvant.
Administration of these adjuvants allows protection at a lower dose or with fewer doses than antigen administered without the adjuvant.
Lipidated forms, such as 3M-052, provide local activity with reduced systemic distribution, minimizing systemic inflammation and potential reactogenicity.
The adjuvants are not complexed with the vaccine antigen, allowing flexibility to mix with current vaccines and enhance immune response.
Documented Applications
Use in immunizing human infants and newborns against diseases such as pneumococcus, hepatitis B, acellular pertussis, diphtheria tetanus acellular pertussis, hepatitis A, and meningococcus.
Application in stimulating an immune response, including T helper 1-cytokine production and induction of Th1 CRM-197-specific neonatal CD4+ cells.
Formulation of kits or compositions comprising TLR7/8 agonist adjuvants for early life vaccines, including at birth or within the first days of life.
Enhancing the efficacy of vaccines requiring fewer doses or achieving protection more rapidly in infants and newborns.
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