Method of vaccination with an attenuated RSV vaccine formulation
Inventors
Collins, Peter L. • Buchholz, Ursula J.
Assignees
US Department of Health and Human Services
Publication Number
US-12102671-B2
Publication Date
2024-10-01
Expiration Date
2036-11-04
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
Abstract
Respiratory syncytial virus (RSV) infection may lead to severe respiratory illness in young children. Thus, there is a need for a live attenuated vaccine, which would mimic the natural course of infection without causing illness; however, restricting viral replication also reduces the immune response. Reported herein is a method of vaccination using a single dose of a recombinant RSV lacking the M2-2 protein that surprisingly induced a stronger immune response to RSV than previous vaccine candidates despite being more restricted in replication.
Core Innovation
The invention relates to a method of vaccinating a human subject against respiratory syncytial virus (RSV) by administering a composition comprising a single dose of a recombinant RSV particle with a functional deletion in the M2-2 open reading frame (ORF). This recombinant RSV lacks expression of the M2-2 protein, which down-regulates viral RNA replication and up-regulates gene transcription and antigen synthesis. The method targets subjects less than about 24 months of age, and the vaccine is live attenuated with restricted replication but enhanced immunogenicity.
The background identifies RSV as a major viral cause of severe lower respiratory illness in infants and children, leading to significant hospitalization rates and global mortality. While live attenuated vaccines are preferred to mimic natural infection without causing illness, previous vaccine candidates have struggled to balance sufficient attenuation with robust immune responses. Conventional attenuation methods either insufficiently attenuate or excessively restrict viral replication, diminishing immune response and requiring multiple doses. There has been a need for improved vaccination methods that elicit strong immune responses with acceptable safety in young children.
This invention addresses those problems by developing an RSV vaccine candidate, designated RSV MEDI ΔM2-2, which is genetically stable due to a deletion of nucleotides 8201-8434 in the M2-2 ORF. This vaccine surprisingly induces a stronger RSV-neutralizing serum antibody response in RSV-seronegative infants and children after a single intranasal dose, despite exhibiting restricted replication compared to prior candidates. Clinical evaluation showed significant restriction in virus shedding, absence of lower respiratory illness post-vaccination, and protection against wild-type RSV infection with a primed anamnestic immune response. This represents an unexpected advancement by achieving both attenuation and high immunogenicity with a single-dose live vaccine.
Claims Coverage
The patent contains one independent claim outlining a single method of vaccinating a human subject against RSV with several inventive features.
Single-dose vaccination with RSV particle lacking M2-2 protein
Administering a single dose composition comprising an RSV particle with an RSV genome or antigenome that has a functional deletion in the M2-2 open reading frame (ORF), specifically a deletion of nucleotides 8201-8434, to a human subject less than about 24 months old.
Specific nucleotide modifications in RSV genome
The RSV genome or antigenome includes specific nucleotide changes: presence of G at positions corresponding to 1209 (encoding Alanine at position 24 in the N protein) and 779 (encoding Arginine at position 51 in the NS2 protein); presence of nucleotides G5639 and T7481; and presence of nucleotides C404 in NS1, G1181 in N gene, C6215 and C7214 in F gene, G7701 in M2 gene, A8197 and G8198 in M2-2 gene, and A13633 in L gene.
Presence of nucleotide dimorphisms in the RSV genome
Inclusion of one or more dimorphisms in the RSV genome: A/G dimorphism at nucleotide 285 in NS1 gene resulting in S/G at amino acid 63; C/T dimorphism at nucleotide 900 in NS2 gene without amino acid effect; and T/G dimorphism at nucleotide 4311 in SH gene resulting in N/K at amino acid 3.
The independent claim sets forth a method of vaccinating young children with a single dose of live attenuated RSV vaccine characterized by a deletion in M2-2, specific nucleotide modifications, and nucleotide dimorphisms that collectively provide restricted viral replication, genetic stability, and enhanced immunogenicity.
Stated Advantages
The vaccine induces a stronger RSV-neutralizing serum antibody response than previous live attenuated RSV vaccines despite more restricted replication.
The genetic stability of the vaccine is improved due to the large deletion in the M2-2 gene, reducing risk of reversion to a virulent form.
A single dose is sufficient to provide protective immunity and prime the subject for anamnestic response upon subsequent wild-type RSV exposure.
The vaccine exhibits low reactogenicity and does not cause lower respiratory illness in seronegative infants and children.
The intranasal administration provides direct stimulation of local respiratory tract immunity and circumvents immunosuppressive effects of maternally derived serum antibodies.
Documented Applications
Method of vaccinating infants and young children less than about 24 months of age against RSV infection using a single intranasal dose of a live attenuated recombinant RSV vaccine with a deletion in the M2-2 ORF.
Use in immunizing RSV-seronegative or RSV-naïve subjects to induce protective neutralizing antibody responses.
Priming the immune system for anamnestic response to subsequent wild-type RSV exposure, thereby providing protection without illness.
Interested in licensing this patent?