Adenovirus serotype 26 and serotype 35 filovirus vaccines
Inventors
Sullivan, Nancy J. • Nabel, Gary J. • Asiedu, Clement • Cheng, Cheng • Pau, Maria Grazia • Goudsmit, Jaap
Assignees
Janssen Vaccines and Prevention BV • US Department of Health and Human Services • Office of Technology Transfer
Publication Number
US-9701718-B2
Publication Date
2017-07-11
Expiration Date
2031-12-14
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Abstract
Provided are recombinant adenovirus vectors (serotype 26 and serotype 35) encoding filovirus antigens. The adenovirus vectors can be used to induce protective immune responses against filovirus infection.
Core Innovation
The invention provides recombinant adenovirus vectors derived from serotypes 26 and 35 that encode filovirus antigens, specifically Ebola and Marburg virus glycoproteins. These adenovirus vectors are designed to induce protective immune responses against filovirus infections in subjects, either via single administration or heterologous prime-boost vaccination regimens. The vectors are typically replication defective and include expression cassettes with promoters such as CMV to drive antigen expression.
The problem addressed arises from the prevalence of pre-existing immunity to common adenovirus serotype 5 (rAd5) vectors, which limits their efficacy in vaccination against diseases like Ebola virus infection. To overcome this, the invention focuses on alternative adenovirus serotypes 26 and 35, which have lower seroprevalence and thus can circumvent immunity directed against rAd5. These vectors are also suitable for high-titer production under GMP conditions and have demonstrated safety and immunogenicity in humans.
The invention further discloses that heterologous prime-boost immunization, especially priming with rAd26 vectors followed by boosting with rAd35 vectors, generates durable T-cell memory and substantially improved immune responses. This vaccination strategy yields higher antibody titers and robust cellular immunity, which translates into enhanced protection against Ebola virus challenge in non-human primates. The adenoviral vectors' capsid proteins, including fiber, penton, and hexon, may be from either Ad26 or Ad35 serotypes and can be chimeric to combine desirable traits.
Claims Coverage
The patent claims cover seven main inventive features related to methods of inducing protective immune responses against Ebola virus using recombinant adenovirus vectors of serotypes 26 and 35.
A heterologous prime-boost vaccination method using rAd26 and rAd35 vectors
A method involving administering a priming vaccination with a recombinant adenovirus 26 vector encoding a first filovirus glycoprotein antigen, followed by a boosting vaccination with a recombinant adenovirus 35 vector encoding a second filovirus glycoprotein antigen, resulting in durable T-cell memory and high anti-Ebola glycoprotein EC90 antibody titers (at least 1:32,000) three weeks after boost.
Intramuscular administration of rAd26 and rAd35 vectors
Administration of the immunizations is conducted intramuscularly to induce protective immune responses against Ebola virus glycoprotein antigens.
Use of filovirus antigenic proteins from Zaire and Sudan/Gulu Ebola virus species
The recombinant adenovirus vectors encode glycoprotein antigenic proteins from specific Ebola virus species: Zaire and Sudan/Gulu, with sequences identified by SEQ ID NO:1, SEQ ID NO:2, or SEQ ID NO:3.
Use of adenovirus vectors with specific genome deletions and modifications
The recombinant adenovirus vectors used have E1/E3 deletions and incorporate an Ad5 E4orf6 sequence to facilitate vector replication in complementing cell lines, providing a replication-defective vector construction for safe vaccination.
Use of adjuvants with the prime or boost vaccinations
At least one of the priming or boosting vaccinations may comprise immune stimulants or adjuvants selected from a specified group including QS-21, MPL-SE, CpG ODN, Alum, MF59, various cytokines, growth factors, and encoding nucleic acids thereof to enhance immune response.
Simultaneous administration of multiple recombinant adenovirus 26 priming vectors encoding distinct filovirus antigens
A priming vaccination comprising immunologically effective amounts of two rAd26 vectors each encoding different Ebola virus glycoprotein antigens from two different Ebola species, followed by a boosting vaccination with two rAd35 vectors encoding the corresponding antigens.
Protective immune response inducing methods with defined antibody titers and T-cell memory
Methods of immunizing subjects by prime-boost regimens to induce durable T-cell memory and protective antibody levels against Ebola glycoproteins, which together confer protection against Ebola virus infection and death.
The claims collectively cover methods of immunization against Ebola virus using replication-defective recombinant adenovirus vectors of serotypes 26 and 35 encoding viral glycoproteins, administered in defined prime-boost schedules, optionally with adjuvants, and targeting specific antigen sequences from Ebola species, thus achieving durable and protective immune responses.
Stated Advantages
The rAd26 and rAd35 vectors effectively circumvent pre-existing immunity to Ad5, enhancing vaccine efficacy in individuals with prior Ad5 exposure.
The heterologous prime-boost regimen induces higher and more uniform antibody titers and robust T-cell responses compared to single immunizations.
The vectors can be produced at high titers under GMP conditions and have demonstrated safety and immunogenicity in primates and humans.
The approach provides durable T-cell memory and protective immunity against Ebola virus infection, potentially enabling both immediate and long-term protection with flexible dosing schedules.
Documented Applications
Vaccination of humans or other mammals to induce protective immunity against Ebola virus infection, including prophylactic and potentially post-exposure vaccination.
Use of recombinant adenovirus vectors encoding filovirus glycoproteins as vaccines administered intramuscularly in various dosing regimens, including single-shot and heterologous prime-boost protocols.
Development of immunogenic compositions comprising rAd26 and rAd35 vectors optionally combined with adjuvants for immunization against multiple Ebola virus species.
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