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Principal Investigator: ROBIN J SHATTOCK
Organization: IMPERIAL COLLEGE OF SCIENCE, TECHNOLOGY AND MEDICINE
Fiscal Year: 2023
Award: $341,645
Funding agency: National Institute of Allergy and Infectious Diseases
Abstract/summary
There is currently no vaccine in clinical use to combat group A streptococcal infection, despite
the considerable global burden of acute and chronic disease attributable to this pathogen.
The long-term goal of this work is the development of a combination vaccine that can combat
group A streptococcal pharyngitis worldwide, without risk of vaccine escape, in order to eradicate
future cases of rheumatic heart disease and reduce the risk of invasive infections.
The objective of this proposal is to use self-amplifying RNA (saRNA) technology to identify the
optimum combination of antigens to include in a new, broad-acting group A streptococcal saRNA
vaccine that protects against experimental nasopharyngeal and soft tissue infection.
Adults are broadly immune to group A streptococcal pharyngitis, whereas younger children are
highly susceptible. The rationale for our approach, is that understanding adult immunity to group
A streptococcus will directly inform the requirements for immunity in children. Pooled
immunoglobulin donated by adults contains antibodies that promote clearance of group A
streptococcus, both in human blood and in experimental models. Having identified and ranked
the antigenic targets of these antibodies, this project will use saRNA to evaluate each antigen
alone, and in combination. The specific aims are: (1) Develop saRNA constructs that express the
new panel of streptococcal antigens. (2) Rank individual saRNA antigens based on protective
efficacy in experimental murine soft tissue infection challenge and in nasopharyngeal infection
challenge. (3) Evaluate second order interactions between top-ranking saRNA antigens via paired
combinations in soft tissue and nasopharyngeal models of infection. (4) Predict the optimum
combination of up to 5 saRNA antigens to combat nasopharyngeal infection, using computer-
assisted modelling and test the optimized combination in vivo, using standard and humanized
murine models of infection, as well as following nasal immunization.
Deliverables from the work will be an optimized combination saRNA vaccine that provides
protection from experimental group A streptococcal infection, and a methodology to advance
combination vaccine discovery in the future. The longer-term impact on human health would
be considerable: Elimination of group A streptococcal pharyngitis would reduce antimicrobial
consumption, reduce the health and socio-economic burden of streptococcal disease, reduce
future cases of invasive streptococcal infection and rheumatic heart disease and therefore
reduce global mortality from this infection.
Terms: <0-11 years old><21+ years old><Acute Articular Rheumatisms><Acute Disease><Address><Adult><Adult Human><Antibiotic Agents><Antibiotic Drugs><Antibiotics><Antibodies><Antigens><Autoimmune><Autoimmune Responses><Bacterial Infections><Blood><Blood Reticuloendothelial System><Cessation of life><Child><Child Youth><Children (0-21)><Chronic Disease><Chronic Illness><Clinical><Combination Vaccines><Combined Vaccines><Computer Assisted><Consumption><Coupled><DNA Recombination><Death><Development><Disease><Disorder><Economic Burden><Experimental Models><Fear><Foundations><Fright><Future><Genetic Alteration><Genetic Change><Genetic Recombination><Genetic defect><Genome><Genotype><Goals><Health><Horizontal Gene Transfer><Human><IGIV><IV Immunoglobulins><IVIG><Immune><Immune Globulins><Immune globulin IV><Immunes><Immunity><Immunization><Immunoglobulins><Individual><Infection><Intravenous Antibodies><Intravenous IG><Intravenous Immune Globulin><Intravenous Immunoglobulins><Investigation><Lateral Gene Transfer><Life><M protein><Methodology><Mice><Mice Mammals><Miscellaneous Antibiotic><Modeling><Modern Man><Murine><Mus><Mutation><Nasal><Nasal Passages Nose><Nasopharynx><Necrotizing fasciitis><Nose><Pharyngitis><Predisposition><Preparation><Proteins><Public Health><RNA amplification><RNA vaccine><RNA-based vaccine><Recombination><Respiratory System, Nose, Nasal Passages><Rheumatic Fever><Rheumatic Heart Disease><Rhinopharynx><Risk><Risk Reduction><S pyogenes><S. pyogenes><Series><Serotyping><Soft Tissue Infections><Streptococcal Infections><Streptococcus><Streptococcus Group A><Streptococcus infection><Streptococcus pyogenes><Susceptibility><System><Technology><Testing><Toxic Shock><Toxic Shock Syndrome><Vaccinated><Vaccine Antigen><Vaccines><Work><acute disease/disorder><acute disorder><adulthood><anti-microbial><antimicrobial><bacteria infection><bacterial disease><chronic disorder><combat><computer aided><develop a vaccine><develop vaccines><development of a vaccine><developmental><discover vaccines><experimental group><genome mutation><health economics><human pathogen><immunogen><in vivo><innovate><innovation><innovative><interest><kids><lead candidate><mRNA vaccine><mRNA-based vaccine><mortality><mouse model><multiple myeloma M Protein><murine model><nasopharnygeal><pathogen><preparations><prevent><preventing><protective efficacy><reduce risk><reduce risks><reduce that risk><reduce the risk><reduce these risks><reduces risk><reduces the risk><reducing risk><reducing the risk><risk-reducing><socio-economic><socio-economically><socioeconomically><socioeconomics><soft tissue><vaccine development><vaccine discovery><youngster>