Application of Transthoracic Echocardiography for Cardiac Safety Evaluation in the Clinical Development Process of Vaccines Against Streptococcus pyogenes

Abstract

Superficial infections with Streptococcus pyogenes (Strep A), pharyngitis and impetigo can induce acute rheumatic fever, an autoimmune sequela manifesting mostly with arthritis and rheumatic carditis. Valvular heart damage can persist or advance following repeated episodes of acute rheumatic fever, causing rheumatic heart disease. Acute rheumatic fever and rheumatic heart disease disproportionately affect children and young adults in developing countries and disadvantaged communities in developed countries. People living with rheumatic heart disease are at risk of experiencing potentially fatal complications such as heart failure, bacterial endocarditis or stroke. Transthoracic echocardiography plays a central role in diagnosing both rheumatic carditis and rheumatic heart disease. Despite the obvious medical need, no licensed Strep A vaccines are currently available, as their clinical development process faces several challenges, including concerns for cardiac safety. However, the development of Strep A vaccines has been recently relaunched by many vaccine developers. In this context, a reliable and consistent safety evaluation of Strep A vaccine candidates, including the use of transthoracic echocardiography for detecting cardiac adverse events, could greatly contribute to developing a safe and efficacious product in the near future. Here, we propose a framework for the consistent use of transthoracic echocardiography to proactively detect cardiac safety events in clinical trials of Strep A vaccine candidates.

Fig. 1

Graphical summary. Echo echocardiography, Strep A Group A Streptococcus

Fig. 2

Natural history of disease caused by Streptococcus pyogenes. The syringe icon indicates potential points where vaccines can be used for preventing S. pyogenes infections/acute rheumatic fever (ARF) recurrences/rheumatic heart disease (RHD). The echo icon indicates points where echocardiography (Echo) can be useful for the diagnosis and follow-up of ARF, ARF recurrences and RHD. PSGN post-streptococcal glomerulonephritis

Fig. 3

Burden of rheumatic heart disease in low-income and middle-income countries. Data included in the figure were selectively extracted from the World Life Expectancy website (available from: https://www.worldlifeexpectancy.com/cause-of-death/rheumatic-heart-disease/by-country/; https://www.worldlifeexpectancy.com/world-rankings-total-deaths, accessed 19 May, 2022) and refer to the year 2020. Numbers indicate the total number of deaths caused by rheumatic heart disease in each depicted country

Fig. 4

Proposed process flow for pre-vaccination assessment in Strep A vaccine clinical development programmes. AESI adverse event of special interest, ARF acute rheumatic fever, ECG electrocardiography, POC point-of-care, *see ESM, **see Fig. 5

Fig. 5

Proposed decision tree for monitoring rheumatic carditis as an adverse event of special interest (AESI) in Group A Streptococcus vaccine clinical development programmes. ARF acute rheumatic fever, DMC Data Monitoring Committee, ECG electrocardiography, pIMDs potential immune-mediated diseases, POC point of care, TTE transthoracic echocardiography, *see Fig. 4, **see ESM, ***determining anti-streptolysin O titres to obtain evidence of Streptococcus pyogenes infection would not be useful in clinical trials of Group A Streptococcus vaccines that contain streptolysin O; nevertheless, infection can be confirmed according to the modified Jones criteria based on anti-DNase B titres or combined serology testing, throat culture and POC tests