Serological Responses to Vaccine Candidate Antigens Suggests That Is the Predominant Cause of Lower Limb Cellulitis

Overview

Journal Open Forum Infect Dis

Specialty Infectious Diseases

Date 2024 Jun 14

PMID 38872850

Authors

Michael Taggart

Kristyn Langworthy

Siong Hui

Conchita Boyder

Alma Fulurija

Michael Morici

Edward Raby

Laurens Manning

Affiliations

Soon will be listed here.

Abstract

Background: A future (Strep A) vaccine will ideally prevent a significant burden of lower limb cellulitis; however, natural immune responses to proposed vaccine antigens following an episode of cellulitis remain uncharacterized.

Methods: We enrolled 63 patients with cellulitis and 26 with invasive beta hemolytic streptococci infection, using a multiplexed assay to measure immunoglobulin G against Strep A vaccine candidate antigens, including: streptolysin O (SLO), deoxyribonuclease B (DNB), group A carbohydrate (GAC), C5a peptidase (ScpA), cell envelope proteinase (SpyCEP), and adhesion and division protein (SpyAD). Responses in the invasive cohort were used to predict the infecting etiology in the cellulitis cohort.

Results: Of 41 patients with cellulitis and paired serological samples, 68.3% had evidence of beta hemolytic streptococci infection by conventional anti-SLO and/or anti-DNB criteria. A positive serological response to at least 1 of the tested antigens was seen in 78.0% of the cellulitis cohort. Individually, anti-SLO (58.5%), anti-SpyAD (46.3%), and anti-ScpA (39.0%) were the most common. Based on principal component analysis, increases in these 3 antibodies, without responses to DNB, GAC, and SpyCEP characterized (SDSE) infection.

Conclusions: SDSE appears to be the predominant cause of lower limb cellulitis. Effective Strep A vaccines incorporating antigens that provide additional cross protection against SDSE may prevent a significant burden of lower limb cellulitis.

References

. Global, regional, and national age-sex-specific mortality for 282 causes of death in 195 countries and territories, 1980-2017: a systematic analysis for the Global Burden of Disease Study 2017. Lancet. 2018; 392(10159):1736-1788. PMC: 6227606. DOI: 10.1016/S0140-6736(18)32203-7. View

STOLLERMAN G, Lewis A, Schultz I, Taranta A . Relationship of immune response to group A streptococci to the course of acute, chronic and recurrent rheumatic fever. Am J Med. 1956; 20(2):163-9. DOI: 10.1016/0002-9343(56)90185-1. View

Xie O, Morris J, Hayes A, Towers R, Jespersen M, Lees J . Inter-species gene flow drives ongoing evolution of Streptococcus pyogenes and Streptococcus dysgalactiae subsp. equisimilis. Nat Commun. 2024; 15(1):2286. PMC: 10937727. DOI: 10.1038/s41467-024-46530-2. View

Bruun T, Oppegaard O, Kittang B, Mylvaganam H, Langeland N, Skrede S . Etiology of Cellulitis and Clinical Prediction of Streptococcal Disease: A Prospective Study. Open Forum Infect Dis. 2016; 3(1):ofv181. PMC: 4699398. DOI: 10.1093/ofid/ofv181. View

Gunderson C, Martinello R . A systematic review of bacteremias in cellulitis and erysipelas. J Infect. 2011; 64(2):148-55. DOI: 10.1016/j.jinf.2011.11.004. View

Vekemans J, Gouvea-Reis F, Kim J, Excler J, Smeesters P, OBrien K . The Path to Group A Streptococcus Vaccines: World Health Organization Research and Development Technology Roadmap and Preferred Product Characteristics. Clin Infect Dis. 2019; 69(5):877-883. PMC: 6695511. DOI: 10.1093/cid/ciy1143. View

Thomas K, Crook A, Nunn A, Foster K, Mason J, Chalmers J . Penicillin to prevent recurrent leg cellulitis. N Engl J Med. 2013; 368(18):1695-703. DOI: 10.1056/NEJMoa1206300. View

Kaplan E, Wannamaker L . Suppression of the antistreptolysin O response by cholesterol and by lipid extracts of rabbit skin. J Exp Med. 1976; 144(3):754-67. PMC: 2190407. DOI: 10.1084/jem.144.3.754. View

Blyth C, Robertson P . Anti-streptococcal antibodies in the diagnosis of acute and post-streptococcal disease: streptokinase versus streptolysin O and deoxyribonuclease B. Pathology. 2006; 38(2):152-6. DOI: 10.1080/00313020600557060. View

10.

Kaplan E, Anthony B, CHAPMAN S, Ayoub E, Wannamaker L . The influence of the site of infection on the immune response to group A streptococci. J Clin Invest. 1970; 49(7):1405-14. PMC: 322614. DOI: 10.1172/JCI106358. View

11.

Giannini F, Cannon J, Cadarette D, Bloom D, Moore H, Carapetis J . Modeling the potential health impact of prospective Strep A vaccines. NPJ Vaccines. 2023; 8(1):90. PMC: 10256967. DOI: 10.1038/s41541-023-00668-0. View

12.

Gao N, Rodas Lima E, Nizet V . Immunobiology of the Classical Lancefield Group A Streptococcal Carbohydrate Antigen. Infect Immun. 2021; 89(12):e0029221. PMC: 8594609. DOI: 10.1128/IAI.00292-21. View

13.

Webb E, Neeman T, Bowden F, Gaida J, Mumford V, Bissett B . Compression Therapy to Prevent Recurrent Cellulitis of the Leg. N Engl J Med. 2020; 383(7):630-639. DOI: 10.1056/NEJMoa1917197. View

14.

Jeng A, Beheshti M, Li J, Nathan R . The role of beta-hemolytic streptococci in causing diffuse, nonculturable cellulitis: a prospective investigation. Medicine (Baltimore). 2010; 89(4):217-226. DOI: 10.1097/MD.0b013e3181e8d635. View

15.

Cannon J, Rajakaruna G, Dyer J, Carapetis J, Manning L . Severe lower limb cellulitis: defining the epidemiology and risk factors for primary episodes in a population-based case-control study. Clin Microbiol Infect. 2018; 24(10):1089-1094. DOI: 10.1016/j.cmi.2018.01.024. View

16.

Wright C, Moorin R, Pearson G, Dyer J, Carapetis J, Manning L . Invasive Infections Caused by Lancefield Groups C/G and A Streptococcus, Western Australia, Australia, 2000-2018. Emerg Infect Dis. 2022; 28(11):2190-2197. PMC: 9622247. DOI: 10.3201/eid2811.220029. View

17.

Whitcombe A, Hanson-Manful P, Jack S, Upton A, Atatoa Carr P, Williamson D . Development and Evaluation of a New Triplex Immunoassay That Detects Group A Antibodies for the Diagnosis of Rheumatic Fever. J Clin Microbiol. 2020; 58(9). PMC: 7448642. DOI: 10.1128/JCM.00300-20. View

18.

Kaplan E, Ferrieri P, Wannamaker L . Comparison of the antibody response to streptococcal cellular and extracellular antigens in acute pharyngitis. J Pediatr. 1974; 84(1):21-8. DOI: 10.1016/s0022-3476(74)80548-2. View

19.

Clarke M, Cheng A, Pollard J, Birch M, Cowan R, Linke J . Lessons Learned From a Randomized Controlled Trial of Short-Course Intravenous Antibiotic Therapy for Erysipelas and Cellulitis of the Lower Limb (Switch Trial). Open Forum Infect Dis. 2019; 6(9):ofz335. PMC: 6798252. DOI: 10.1093/ofid/ofz335. View

20.

Karppelin M, Siljander T, Haapala A, Aittoniemi J, Huttunen R, Kere J . Evidence of streptococcal origin of acute non-necrotising cellulitis: a serological study. Eur J Clin Microbiol Infect Dis. 2014; 34(4):669-72. DOI: 10.1007/s10096-014-2274-9. View