Streptococcus Pyogenes Vaccine Candidates Do Not Induce Autoimmune Responses in a Rheumatic Heart Disease Model

Overview

Journal NPJ Vaccines

Date 2023 Feb 4

PMID 36739443

Authors

Simone Reynolds

Rukshan Ahamed Mohamed Rafeek

Adam Hamlin

Ailin Lepletier

Manisha Pandey

Natkunam Ketheesan

Michael F Good

Affiliations

Soon will be listed here.

Abstract

We have developed a candidate vaccine to protect against multiple strains of Streptococcus pyogenes infections. The candidate vaccine contains two synthetic peptides derived from S. pyogenes proteins: the M-protein epitope, p*17 and the IL-8 degrading S. pyogenes Cell-Envelope Proteinase (SpyCEP) epitope, K4S2. In this study we utilise a rat autoimmune valvulitis model that displays both the cardiac and neurobehavioural pathology associated with post-streptococcal sequelae, to assess if the vaccine candidate antigens induce autoimmune complications and inflammatory pathology. Each antigen was conjugated to carrier protein diphtheria toxoid (DT) and independently assessed for potential to induce autoimmune pathology in female Lewis rats. Rats were administered three subcutaneous doses, and one intranasal dose over a four-week study with a two-week recovery period. A positive control group received recombinant S. pyogenes M5 (rM5) protein, and the negative control group received PBS. Rats that received rM5 developed significant cardiac and neurological pathologies. There was no evidence of these pathologies in the PBS control group, or the rats administered either P*17-DT or K4S2-DT. This study provides further preclinical evidence of the safety of the vaccine candidates p*17 and K4S2 and their appropriateness as candidates in human clinical trials.

Citing Articles

Methods for Establishing a Rat Model of Rheumatic Heart Disease.

Xian S, Zeng Z Rev Cardiovasc Med. 2024; 25(9):346.

PMID: 39355577 PMC: 11440394. DOI: 10.31083/j.rcm2509346.

Strep A: challenges, opportunities, vaccine-based solutions, and economics.

Bloom D, Carapetis J NPJ Vaccines. 2024; 9(1):80.

PMID: 38641634 PMC: 11031564. DOI: 10.1038/s41541-024-00863-7.

Conserved molecular chaperone PrsA stimulates protective immunity against group A Streptococcus.

Lai C, Xie J, Lai M, Wu Z, Lin J, Huang Y NPJ Vaccines. 2024; 9(1):46.

PMID: 38409165 PMC: 10897429. DOI: 10.1038/s41541-024-00839-7.

The full health, economic, and social benefits of prospective Strep A vaccination.

Cadarette D, Ferranna M, Cannon J, Abbas K, Giannini F, Zucker L NPJ Vaccines. 2023; 8(1):166.

PMID: 37903813 PMC: 10616198. DOI: 10.1038/s41541-023-00758-z.

: Pathogenesis and the Current Status of Vaccines.

Wang J, Ma C, Li M, Gao X, Wu H, Dong W Vaccines (Basel). 2023; 11(9).

PMID: 37766186 PMC: 10534548. DOI: 10.3390/vaccines11091510.

References

Greer J, Capecchi M . Hoxb8 is required for normal grooming behavior in mice. Neuron. 2002; 33(1):23-34. DOI: 10.1016/s0896-6273(01)00564-5. View

Batzloff M, Hayman W, Davies M, Zeng M, Pruksakorn S, Brandt E . Protection against group A streptococcus by immunization with J8-diphtheria toxoid: contribution of J8- and diphtheria toxoid-specific antibodies to protection. J Infect Dis. 2003; 187(10):1598-608. DOI: 10.1086/374800. View

Dop D, Marcu I, Padureanu R, Niculescu C, Padureanu V . Pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (Review). Exp Ther Med. 2020; 21(1):94. PMC: 7725005. DOI: 10.3892/etm.2020.9526. View

Brandt E, Hayman W, Currie B, Carapetis J, Wood Y, Jackson D . Opsonic human antibodies from an endemic population specific for a conserved epitope on the M protein of group A streptococci. Immunology. 1996; 89(3):331-7. PMC: 1456558. DOI: 10.1046/j.1365-2567.1996.d01-754.x. View

Cunningham M, Cox C . Autoimmunity against dopamine receptors in neuropsychiatric and movement disorders: a review of Sydenham chorea and beyond. Acta Physiol (Oxf). 2015; 216(1):90-100. PMC: 5812018. DOI: 10.1111/apha.12614. View

Nordstrom T, Pandey M, Calcutt A, Powell J, Phillips Z, Yeung G . Enhancing Vaccine Efficacy by Engineering a Complex Synthetic Peptide To Become a Super Immunogen. J Immunol. 2017; 199(8):2794-2802. DOI: 10.4049/jimmunol.1700836. View

Rafeek R, Lobbe C, Wilkinson E, Hamlin A, Andronicos N, McMillan D . Group A streptococcal antigen exposed rat model to investigate neurobehavioral and cardiac complications associated with post-streptococcal autoimmune sequelae. Animal Model Exp Med. 2021; 4(2):151-161. PMC: 8212825. DOI: 10.1002/ame2.12164. View

Rafeek R, Sikder S, Hamlin A, Andronicos N, McMillan D, Sriprakash K . Requirements for a Robust Animal Model to Investigate the Disease Mechanism of Autoimmune Complications Associated With ARF/RHD. Front Cardiovasc Med. 2021; 8:675339. PMC: 8131511. DOI: 10.3389/fcvm.2021.675339. View

Pruksakorn S, Currie B, Brandt E, Phornphutkul C, Hunsakunachai S, Manmontri A . Identification of T cell autoepitopes that cross-react with the C-terminal segment of the M protein of group A streptococci. Int Immunol. 1994; 6(8):1235-44. DOI: 10.1093/intimm/6.8.1235. View

10.

Urakawa S, Hida H, Masuda T, Misumi S, Kim T, Nishino H . Environmental enrichment brings a beneficial effect on beam walking and enhances the migration of doublecortin-positive cells following striatal lesions in rats. Neuroscience. 2006; 144(3):920-33. DOI: 10.1016/j.neuroscience.2006.10.038. View

11.

Dooley L, Ahmad T, Pandey M, Good M, Kotiw M . Rheumatic heart disease: A review of the current status of global research activity. Autoimmun Rev. 2020; 20(2):102740. DOI: 10.1016/j.autrev.2020.102740. View

12.

Rafeek R, Hamlin A, Andronicos N, Lawlor C, McMillan D, Sriprakash K . Characterization of an experimental model to determine streptococcal M protein-induced autoimmune cardiac and neurobehavioral abnormalities. Immunol Cell Biol. 2022; 100(8):653-666. PMC: 9545610. DOI: 10.1111/imcb.12571. View

13.

Wu L, Ong S, Talor M, Barin J, Baldeviano G, Kass D . Cardiac fibroblasts mediate IL-17A-driven inflammatory dilated cardiomyopathy. J Exp Med. 2014; 211(7):1449-64. PMC: 4076595. DOI: 10.1084/jem.20132126. View

14.

Lymbury R, Olive C, Powell K, Good M, Hirst R, LaBrooy J . Induction of autoimmune valvulitis in Lewis rats following immunization with peptides from the conserved region of group A streptococcal M protein. J Autoimmun. 2003; 20(3):211-7. DOI: 10.1016/s0896-8411(03)00026-x. View

15.

Gorton D, Sikder S, Williams N, Chilton L, Rush C, Govan B . Repeat exposure to group A streptococcal M protein exacerbates cardiac damage in a rat model of rheumatic heart disease. Autoimmunity. 2016; 49(8):563-570. PMC: 5177596. DOI: 10.1080/08916934.2016.1217999. View

16.

Lotan D, Benhar I, Alvarez K, Mascaro-Blanco A, Brimberg L, Frenkel D . Behavioral and neural effects of intra-striatal infusion of anti-streptococcal antibodies in rats. Brain Behav Immun. 2014; 38:249-62. PMC: 4000697. DOI: 10.1016/j.bbi.2014.02.009. View

17.

Gorton D, Blyth S, Gorton J, Govan B, Ketheesan N . An alternative technique for the induction of autoimmune valvulitis in a rat model of rheumatic heart disease. J Immunol Methods. 2010; 355(1-2):80-5. DOI: 10.1016/j.jim.2010.02.013. View

18.

Cunningham M . Molecular Mimicry, Autoimmunity, and Infection: The Cross-Reactive Antigens of Group A Streptococci and their Sequelae. Microbiol Spectr. 2019; 7(4). PMC: 6684244. DOI: 10.1128/microbiolspec.GPP3-0045-2018. View

19.

Pandey M, Mortensen R, Calcutt A, Powell J, Batzloff M, Dietrich J . Combinatorial Synthetic Peptide Vaccine Strategy Protects against Hypervirulent CovR/S Mutant Streptococci. J Immunol. 2016; 196(8):3364-74. DOI: 10.4049/jimmunol.1501994. View

20.

Reynolds S, Pandey M, Dooley J, Calcutt A, Batzloff M, Ozberk V . Preclinical safety and immunogenicity of Streptococcus pyogenes (Strep A) peptide vaccines. Sci Rep. 2021; 11(1):127. PMC: 7794325. DOI: 10.1038/s41598-020-80508-6. View