Arthrogenic alphavirus vaccine
Inventors
Mahalingam, Surendran • Taylor, Adam
Assignees
Publication Number
US-11090384-B2
Publication Date
2021-08-17
Expiration Date
2037-05-25
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Abstract
The invention relates to a vaccine comprising live attenuated recombinant alphavirus comprising mutated capsid protein. The invention also relates to a method of preventing a subject from contracting an alphaviral infection that would otherwise produce clinical signs of disease. In an embodiment the mutated capsid protein is Chikungunya virus (CHIKV) capsid protein having a mutated nucleolar localisation signal/sequence (NoLS), preferably the mutant NLS 101/95.
Core Innovation
The invention relates to a vaccine comprising a live attenuated recombinant alphavirus having a mutated capsid protein. More specifically, the mutated capsid protein features a mutation in the nucleolar localisation signal/sequence (NoLS), which substantially impairs or abolishes its ability to localise to the nucleolus of host cells. The preferred embodiment involves mutation of the Chikungunya virus (CHIKV) capsid protein NoLS, especially the mutant forms designated NLS 101 and NLS 101/95.
The problem addressed by the invention arises from the absence of effective antivirals or commercially available vaccines for alphaviral infections such as CHIKV, which cause severe and often chronic human joint diseases characterized by debilitating arthralgia. Alphaviruses, including CHIKV and related viruses like Ross River virus and Semliki Forest virus, can cause large epidemics with substantial social and economic burdens. Existing vaccine strategies such as chimeric live vaccines, virus-like particles, and DNA vaccines often require multiple immunizations and are costly to manufacture. There is a need for a live attenuated vaccine that is immunogenic, provides durable protection, and is cost-effective.
The invention solves this problem by developing a recombinant alphavirus vaccine with a mutated capsid protein that disrupts nucleolar localisation but still allows nucleocapsid assembly. This mutation substantially attenuates viral replication yet elicits a strong protective immune response. Experimental results show that the disclosed mutant CHIKV capsid proteins cause no clinical signs of disease in mice, induce neutralizing antibodies, and protect against wild-type CHIKV challenge. Additionally, cross-protection against related alphaviruses is demonstrated. The invention also contemplates chimeric alphaviruses comprising mutated capsid proteins that may offer enhanced immunogenicity and cross-protection against arthritogenic and encephalitic alphaviruses.
Claims Coverage
The patent includes multiple independent claims covering vaccines and methods related to mutated alphaviral capsid proteins. The main inventive features extract the nature of the mutated capsid protein, vaccine compositions, and methods of use to prevent or treat alphaviral infections.
Vaccine compositions comprising mutated capsid protein
Vaccines comprising isolated, purified, synthetic or recombinant CHIKV mutated capsid protein having at least a mutated nucleolar localisation region (NoLS) incapable or substantially incapable of nucleolar localisation. Such vaccines include live attenuated recombinant viruses, chimeric alphaviruses, inactivated attenuated recombinant viruses, recombinant genomes, nascent structural polyproteins, and sub-unit vaccines. The mutated capsid protein comprises mutations at specific amino acid positions (62, 63, 65, 66, 68, 69, 101 and 102) or sequences selected from SEQ. ID NO. 4 to 7.
Chimeric alphaviruses with mutated capsid protein for broad protection
Use of chimeric alphaviruses comprising a mutated CHIKV capsid protein for cross-protection. Chimeric alphaviruses include alphaviruses such as Ross River virus, Barmah Forest virus, O'nyong-nyong virus, Mayaro virus, Sindbis virus group, and Semliki Forest virus.
Methods of preventing and treating alphaviral infections
Methods of preventing alphaviral infection or disease, eliciting alphaviral-protective immune responses, and treating alphaviral disease by administering vaccines or compositions that include the mutated capsid protein or vaccines comprising it as described above.
The claims comprehensively cover vaccines comprising mutated alphaviral capsid proteins incapable of nucleolar localisation, including live attenuated, recombinant, and chimeric forms, compositions thereof, and their use in preventing, treating, and diagnosing alphaviral infections. The invention particularly emphasizes the mutation of the nucleolar localisation sequence of CHIKV capsid protein.
Stated Advantages
The mutated capsid protein attenuates viral replication resulting in significantly reduced disease signs and viral titers in subjects.
The live attenuated vaccine induces a robust and durable protective immune response after a single dose, including production of neutralizing antibodies.
The vaccine shows cross-protection potential against other arthritogenic alphaviruses, extending its utility.
The vaccine candidate is phenotypically stable, maintaining attenuation after multiple cell culture passages.
The vaccine can be produced in large quantities with little loss of yield after filtration and remains viable for long-term storage at conventional freezer temperatures (−20° C. and −80° C.).
Documented Applications
Prevention of alphaviral infections such as Chikungunya virus infection.
Vaccination to elicit alphaviral-protective immune responses in subjects.
Treatment of subjects having alphaviral disease or reducing disease severity via administration of neutralising antibodies or serum from vaccinated subjects.
Cross-protection against related arthritogenic alphaviruses including Ross River virus, Barmah Forest virus, Semliki Forest virus, Mayaro virus, O'nyong-nyong virus, and Sindbis virus group.
Use in sub-unit vaccines, recombinant virus constructs, and chimeric alphavirus vaccine development for broader alphavirus disease control.
Screening or diagnosis of alphaviral infections by detection of reactivity with vaccine-induced alphavirus-neutralising antibodies.
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