Methods and compositions for enhancing immune responses
Inventors
VOLKMANN, Ariane • Steigerwald, Robin • Dirmeier, Ulrike • CALLENDRET, Benoit Christophe Stephan • DOUOGUIH, Macaya Julie • WARD, Lucy A.
Assignees
Bavarian Nordic AS • Janssen Vaccines and Prevention BV • US Department of Health and Human Services
Publication Number
US-10561722-B2
Publication Date
2020-02-18
Expiration Date
2035-09-03
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Abstract
Compositions and methods are described for generating an improved effective immune response against an immunogen in humans. The enhanced immune response, is obtained by using an MVA vector as a prime and an adenovirus vector as a boost and is characterized by a high level of antibody response specific to the immunogen, and an enhanced cellular immune response. The compositions and methods can be used to provide a protective immunity against a disease, such as an infection of one or more subtypes of Ebola and Marburg filoviruses, in humans.
Core Innovation
This invention relates to methods and compositions for enhancing an immune response in a human subject by using a specific prime-boost regimen of replication incompetent viral vectors. Specifically, the invention discovers that using an MVA vector as a prime followed by an adenovirus vector as a boost unexpectedly generates a superior immune response characterized by a strong induction of T cell activity and a high level of antibody response specific to the immunogen. This is contrary to previous animal studies which generally found MVA-prime followed by adenovirus-boost regimens to be less effective than the reverse order.
The problem addressed by the invention arises from the need for safe and strong vaccines against emerging and re-emerging pathogens, including highly lethal filoviruses such as Ebola and Marburg viruses, as well as cancers. Existing vaccines sometimes confer suboptimal protection, and developing an effective pan-filovirus vaccine that elicits broad and strong immune responses remains a challenge. Previous vaccine approaches using adenovirus and MVA vectors in different prime-boost sequences failed to demonstrate enhanced immune responses in humans. There remains an unmet need for improved vaccination regimens that provide protective immunity against such diseases.
The invention provides a method comprising administering to a human subject a first composition comprising an immunologically effective amount of an MVA vector encoding an antigenic protein or immunogenic polypeptide thereof for priming, followed by administration of a second composition comprising an immunologically effective amount of an adenovirus vector encoding the same or related immunogen for boosting. This regimen enhances both humoral and cellular immune responses relative to the reverse prime-boost order, including enhanced CD4+ and CD8+ T cell responses and antibody responses, characterized by increased proportions of responders, polyfunctional T cells expressing multiple cytokines, and higher antibody titers.
Claims Coverage
The patent includes a set of independent claims focused on a method of enhancing immune responses against filovirus subtypes in human subjects using a specific prime-boost regimen. The key inventive features involve the use of an MVA vector for priming and an adenovirus vector for boosting, the nature of the immune response enhanced, timing of administration, and specific antigenic proteins encoded.
Use of MVA vector for priming and adenovirus vector for boosting an immune response against filoviruses
A method comprising administering to a human subject a first composition of an MVA vector encoding an antigenic protein of at least one filovirus subtype for priming, followed by administering a second composition of an adenovirus vector encoding the antigenic protein for boosting the immune response.
Enhanced antibody and cellular immune responses
The method generates an enhanced immune response comprising elevated antibody responses, enhanced CD4+ and/or CD8+ T cell responses, increased dominant and polyfunctional T cell populations specific to the antigenic protein, relative to the reverse (adenovirus prime, MVA boost) regimen.
Protective immunity provision
The enhanced immune response provides protective immunity to the human subject against diseases related to the antigenic protein, including infections by filovirus subtypes.
Timing of boost administration
The boosting step is conducted 1 to 12 weeks (preferred 1, 2, 4, or 8 weeks) after the priming step, and can be repeated one or more times thereafter to maintain or enhance the immune response.
Use of specific adenovirus vectors and antigenic proteins
The adenovirus vector is preferably a replication-defective rAd26 vector. The antigenic proteins encoded correspond to amino acid sequences selected from SEQ ID NOs: 1, 2, 3, 4, and 5, with MVA vectors encoding SEQ ID NOs: 1, 2, 4, and 5, and adenovirus vectors encoding at least one of SEQ ID NOs: 1, 2, or 3.
The claims cover a method of enhancing immune responses against filoviruses in humans by priming with an MVA vector and boosting with an adenovirus vector, preferably rAd26, encoding specified antigenic proteins. The invention focuses on improved antibody and cellular immune responses with specific timing and antigen selection to provide protective immunity.
Stated Advantages
The prime-boost regimen using MVA as a prime and adenovirus as a boost elicits a superior immune response characterized by strong induction of T cell activity and high antibody titers compared to the reverse order.
The method induces enhanced CD4+ and CD8+ T cell responses, including polyfunctional T cells expressing multiple cytokines (IFN-gamma, IL-2, TNF-alpha), which are important for long-lived and effective immunity.
The regimen provides protective immunity against infections by multiple filovirus subtypes, including Ebola and Marburg viruses, and has potential for use against tumors.
MVA vectors used have enhanced safety profiles, being replication incompetent in human cells, allowing for safe human administration and large scale production.
The adenovirus vectors, particularly rAd26, circumvent pre-existing immunity issues associated with more common adenovirus serotypes, improving clinical utility.
Documented Applications
Providing a protective immunity against infectious diseases caused by filoviruses, including multiple Ebola virus subtypes (Zaire, Sudan, Bundibugyo, Taï Forest) and Marburg virus in humans.
Enhancing immune responses against tumors by priming and boosting with MVA and adenovirus vectors encoding tumor antigenic proteins.
Use as a vaccine regimen in human subjects for prevention and treatment of infections by viruses, bacteria, fungi, protozoa, and cancers through enhanced humoral and cellular immune responses.
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