Group A Streptococcus Vaccines

Introduction

Although a reinvigorated global vaccine development effort gives legitimate reason for cautious optimism, it is a sad reality that in 2019 the best introduction to a discussion on vaccines for group A Streptococcus (GAS) comes from 1967, by Professor Gene Stollerman:

… one might have expected that the vast amount of biochemical and immunologic information about this organism would have led to the successful induction of artificial immunity in man against one of his major pathogens. The rewards for such an achievement remain great: the eradication of rheumatic fever and perhaps one major form of glomerulonephritis. The prospect of attaining the same goals by chemotherapy alone is limited … Why, then, have all but a few laboratories abandoned the direct pursuit of so worthy an objective? And what are the prospects for success for those who persist in this tantalizing search?

By any of its multiple names: the anachronistic Streptococcus haemolyticus ; the historical Lancefield Group A β-hemolytic Streptococcus ; the microbiological Streptococcus pyogenes ; or simply “Strep A,” the scourge of GAS diseases has proven to be a remarkably potent and persistent problem. The global burden of GAS diseases spans mild to severe, local and systemic, acute and chronic, infectious and noninfectious syndromes. Although the distribution of GAS diseases has changed with development and control efforts including antibiotics, and the greatest burden continues to fall upon low- and middle-income countries, morbidity and mortality from GAS diseases occur at all ages and in every social and geographic setting. ^,

Conservative global estimates of GAS diseases are of 615 million incident cases of GAS pharyngitis, 162 million prevalent cases of impetigo, 660,000 incident cases of invasive GAS infection, 470,000 incident cases of acute poststreptococcal glomerulonephritis (APSGN), and 470,000 incident cases of acute rheumatic fever (ARF), and over 33 million prevalent cases of rheumatic heart disease (RHD). GAS is a major contributor to an estimated 61 million annual cases of cellulitis. ^, Despite retaining universal susceptibility to penicillin, GAS is associated with at least 500,000 annual deaths, including 320,000 from RHD alone. Case-fatality rates are over 25% for the most severe invasive GAS infections. RHD and APSGN are important contributors to chronic noncommunicable disease states including heart failure, stroke, and chronic kidney disease. Pharyngitis and impetigo cause a less conspicuous but still major impact on healthcare utilization, absenteeism, and antibiotic use. ^, Inappropriate treatment of suspected GAS pharyngitis in an estimated 70% of cases has a direct cost of $200 million (USD) and a difficult-to-estimate indirect cost associated with antimicrobial resistance. ^{, ,} Despite this evidence of substantial morbidity, mortality, and cost due to GAS diseases, investment in GAS vaccine development has been miniscule and no current candidate vaccine has entered efficacy trials. ^,

The promise of vaccination to prevent ARF and RHD was recognized as the causal link with GAS infection was established. Before that, preceding even recognition and classification of the streptococci, there were active and passive vaccination efforts targeting scarlet fever, another GAS syndrome. ^, Despite the prodigious proliferation of GAS research continuing since Stollerman's prophetic words above, vaccine development has been impeded by scientific, regulatory, and commercial obstacles and this promise remains unrealized. ^{, ,} GAS vaccine development is now a stated priority of the World Health Organization (WHO), as the only healthcare intervention with a realistic prospect of achieving a sizable and sustainable reduction in the global burden of all GAS diseases. ^, The importance of vaccine development for RHD specifically was recognized in the 2018 WHO Global Resolution on Rheumatic Fever and Rheumatic Heart Disease. Only partial effects have been seen with major public investment in strategies for primary and secondary prevention of ARF and RHD, ^, and the management of patients with invasive GAS infections regularly stretches the capacities of even the most well-resourced high-technology hospitals. ^, There is now a coordinated global effort gathering momentum to overcome roadblocks to GAS vaccine development and carry candidate vaccines forward toward Phase 2b/3 trials to demonstrate vaccine safety and efficacy, initially against pharyngitis and possibly impetigo. ^,

Issues in GAS Vaccine Development

Strain Diversity. The pioneering streptococcal microbiologist professor Rebecca Lancefield initially segregated the streptococci pathogenic in humans on the basis of the serologic specificity of capsular polysaccharides. Lancefield group A carbohydrate strains, the group A streptococci, were further characterized according to serologic specificity of surface-expressed M-proteins. From approximately 50 M serotypes, molecular typing of the M-protein hypervariable region has now described more than 220 emm genotypes, which have subsequently been grouped by genetic and functional similarities into smaller emm “clusters.” Although the M serotypes, emm genotypes, and emm clusters are related, they are not fully compatible classification systems. Sequencing of the hypervariable emm region and whole genome sequencing has more recently given insight into even greater levels of complexity and strain diversity. ^,

The earliest vaccine studies employed relatively crude preparations of mixtures of killed GAS strains. Mid-20th century research focused on the M-protein as the apparent immunodominant GAS antigen, finding that M-serotype-specific bactericidal immune responses correlated with protection against homologous infection but not against infection with heterologous strains. It is largely unknown whether the conclusions reached by these studies finding type-specific bactericidal responses for some serotypes can be extrapolated across all ∼50 M serotypes, or to the >220 emm genotypes, and the extent to which emm clusters correspond to cross-reactive functional antibody responses.

The initial promise of multivalent vaccines targeting strains belonging to emm types most prevalent in high-income countries has been undermined by evidence of extensive global GAS strain diversity, and the potential for rapid emergence of new strains, especially in the highest-burden settings. ^, The hope that cluster-based cross-reactivity might address this coverage challenge has been only partially substantiated. An alternative but untested approach that has emerged is the notion that a novel synthetic protein vaccine could exploit conserved structural patterns lying beneath more superficial hypervariability of the most immunogenic M-protein regions. A similar approach has also been discussed for vaccines based on the GAS T-antigen. Other groups have shifted focus away from the M-protein hypervariable region to more conserved elements, or away from the M-protein entirely to other conserved antigens. Conserved “cryptic” epitopes from the C-repeat region of the M-protein that are not highly immunogenic after natural exposure have been developed as vaccine antigens, with promising preclinical and phase I results. A growing list of conserved non-M-protein antigens have also shown promise in preclinical studies, some known for many decades (e.g., the group A carbohydrate, streptolysin O, T-antigen) and others more recently identified by reverse vaccinology methods. ^,

Protective immune responses. There is no established correlate of natural or vaccine-induced protection against GAS infection in humans and very few longitudinal data from which putative correlates may be inferred. It is a longstanding and widely propagated tenet that decreasing incidence of GAS pharyngitis with age is related to cumulative immunity following natural infections, although this does not offer lifelong protection and there is a spike in incidence of cellulitis and severe invasive GAS infections later in life. A study by Lancefield reporting that, “In 12 individuals type-specific antibodies against 11 different homologous types following 14 separate infections persisted for 4–32 years,” has been widely referenced as indicative of long-lived type-specific protective immunity. However, the sentence immediately following describes another 13 individuals without a type-specific bactericidal response 1–31 years after known GAS infections, including 3 who previously had a homologous type-specific response soon after infection. In 1970s controlled human infection studies with M1, M3, and M12 GAS strains, baseline serum type-specific bactericidal responses did not clearly correlate with protection against experimental pharyngitis caused by homologous strains applied by swab to the pharynx of healthy adult volunteers. Others have demonstrated that antibody responses targeting the group A carbohydrate correlate with protection against GAS pharyngeal colonization, and in vitro responses against a number of other antigens do increase with age.

Development of methods to measure relevant immune responses is central to vaccine development. For GAS, there are presently no widely available standardized high-throughput methods. Widely used enzyme-linked immunosorbent assays to measure binding antibody suffer from a lack of standardization and reference GAS sera. Work continues on newer opsonophagocytic functional antibody assays to replace the laborious Lancefield serum bactericidal assay, which does not produce results that can be compared between assays or laboratories. ^, Qualification and validation of these newer assays, with availability of GAS reference serum, will be an important step forward.

Autoimmunity. The specter of autoimmune complications induced by vaccines against GAS has arguably been the greatest obstacle standing in the way of vaccine development. ARF (with subsequent RHD) and APSGN are nonsuppurative immunological complications following GAS infections. The pediatric autoimmune neuropsychiatric disorders associated with streptococcal infections (PANDAS) hypothesis are also discussed in these terms. There have been extensive studies of humoral and cellular cross-reactivity and homology between human proteins and streptococcal antigens, focusing mostly on M-protein but also on non-M antigens including the group A carbohydrate (discussed in detail in Chapter 2 ). Autoreactive T lymphocytes recognizing the N-terminal and midprotein domains of the M-protein have been described in ARF and cloned from the valves of RHD patients. Although many studies have found cross-reactivity and homology, particularly for some M-protein regions and the G1cNAc moiety of the group A carbohydrate, none has conclusively implicated an antigen or antigenic region in the causal pathway of ARF or APSGN in humans. Nonetheless, vaccine developers have been understandably cautious in avoiding the potentially cross-reactive antigens in their candidates.

Animal models. GAS is exquisitely adapted and restricted to its human host. Professor Rebecca Lancefield illustrated this by recounting the difficulty she had experienced in attempts to infect mice, requiring multiple repeated passages, whereas accidental exposure of laboratory assistants to such a strain easily caused infection in humans, even when the strains had not seen a human host in many years. It is possible to passage strains for adaption to some other species (typically mammalian) such as mice, or if nonhuman primates are inoculated with very high doses of bacteria. Still, human host restriction for certain virulence factors may not be overcome, although humanized transgenic models can go some way to addressing this problem. Importantly, even if every animal model was considered together, the diversity of human GAS disease syndromes has not been reproduced by animal models.