Update on Group A Streptococcal Vaccine development

James B. Dale; Mark J. Walker

Disclosures

Curr Opin Infect Dis. 2020;33(3):244-250. 

In This Article

Abstract and Introduction

Abstract

Purpose of review: There is a global need for well tolerated, effective, and affordable vaccines to prevent group A streptococcal infections and their most serious complications. The aim of this review is to highlight the recent progress in the identification of promising vaccine antigens and new approaches to vaccine design that address the complexities of group A streptococcal pathogenesis and epidemiology.

Recent findings: Combination vaccines containing multiple shared, cross-protective antigens have proven efficacious in mouse and nonhuman primate models of infection. The development of complex multivalent M protein-based vaccines is continuing and several have progressed through early-stage human clinical trials. Formulations of vaccines containing universal T-cell epitopes, toll-like receptor agonists, and other adjuvants more potent than alum have been shown to enhance protective immunogenicity. Although the group A streptococcal vaccine antigen landscape is populated with a number of potential candidates, the clinical development of vaccines has been impeded by a number of factors. There are now concerted global efforts to raise awareness about the need for group A streptococcal vaccines and to support progress toward eventual commercialization and licensure.

Summary: Preclinical antigen discovery, vaccine formulation, and efficacy studies in animal models have progressed significantly in recent years. There is now a need to move promising candidates through the clinical development pathway to establish their efficacy in preventing group A streptococcal infections and their complications.

Introduction

Group A streptococcus (Strep A) is a ubiquitous human-specific pathogen responsible for a wide array of infections. Uncomplicated infections, such as pharyngitis and impetigo, account for the greatest global burden of disease, affecting millions of children annually.[1] Serious invasive infections, which include necrotizing fasciitis, streptococcal toxic shock syndrome, puerperal sepsis, and pneumonia, are not as common but are associated with significant morbidity and mortality.[2,3] Poststreptococcal glomerulonephritis (PSGN) and acute rheumatic fever (ARF) are immune-mediated diseases that may follow seemingly uncomplicated infections. On a global level, rheumatic heart disease (RHD) is associated with the greatest disease burden because it primarily affects children and young adults, is associated with excess mortality, and often results in debilitating heart disease when individuals reach their prime productive years.[4] Theoretically, all Strep A infections and thus their immune-mediated complications are vaccine-preventable, yet after decades of research there is not a licensed vaccine.

Strep A vaccine development has been ongoing for decades. In the 1940s, over 4000 young adults were injected with whole killed bacteria and monitored for Strep A infections.[5] The vaccines were highly reactogenic and did not prevent disease. Based on these early observations, investigators in the 1960s vaccinated adult volunteers with fractions of cell walls or partially purified M proteins which were also reactogenic and did not produce consistent immune responses.[6,7] To achieve immunizing doses of partially purified M antigens, Massell repeatedly injected children with lower amounts of the toxic preparations.[8] The authors later concluded that the immunized children experienced a higher attack rate of ARF compared to historical control subjects.[9] Whether this was causally related to the vaccine is still debated. Nonetheless, in 1978, the controversy resulted in a US FDA ban on subsequent vaccine trials which was eventually overturned 30 years later. Prior to the FDA ban, more precise methods were used to purify M proteins used in landmark studies in the 1970s undertaken by Fox et al. They demonstrated that immunization, either subcutaneously or via the mucosal route, could prevent infection with the homologous M type of Strep A after challenge infections delivered to the pharynx and tonsils.[10,11] Beachey et al. also conducted limited human studies of a highly purified M protein preparation which was free of toxicity and elicited type-specific bactericidal antibodies.[12]

More recent vaccine development efforts have taken advantage of genomics, proteomics, reverse vaccinology, and precisely defined antigen/epitope content of vaccines. Vaccine candidates include N-terminal M peptides configured in recombinant multivalent proteins, conserved M epitopes from the central region of the M protein, cell wall carbohydrate, and multiple secreted and cell surface proteins, many of which have defined roles as determinants of virulence and pathogenesis (Table 1). In this review, we provide an update of the current status of Strep A vaccine development, describe the impediments to the clinical development of promising vaccine candidates, and highlight ongoing international efforts to overcome the barriers preventing the eventual licensing of safe, affordable, and effective vaccines.

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