An Experimental Group A Streptococcus Vaccine That Reduces Pharyngitis and Tonsillitis in a Nonhuman Primate Model

Abstract

Group A Streptococcus (GAS) infections account for an estimated 500,000 deaths every year. This bacterial pathogen is responsible for a variety of mild and life-threatening infections and the triggering of chronic autoimmune sequelae. Pharyngitis caused by group A Streptococcus (GAS), but not asymptomatic GAS carriage, is a prerequisite for acute rheumatic fever (ARF). Repeated bouts of ARF may trigger rheumatic heart disease (RHD), a major cause of heart failure and stroke accounting for 275,000 deaths annually. A vaccine that prevents pharyngitis would markedly reduce morbidity and mortality from ARF and RHD. Nonhuman primates (NHPs) have been utilized to model GAS diseases, and experimentally infected rhesus macaques develop pharyngitis. Here we use an NHP model of GAS pharyngitis to evaluate the efficacy of an experimental vaccine, Combo5 (arginine deiminase [ADI], C5a peptidase [SCPA], streptolysin O [SLO], interleukin-8 [IL-8] protease [SpyCEP], and trigger factor [TF]), specifically designed to exclude GAS components potentially linked to autoimmune complications. Antibody responses against all Combo5 antigens were detected in NHP serum, and immunized NHPs showed a reduction in pharyngitis and tonsillitis compared to controls. Our work establishes the NHP model as a gold standard for the assessment of GAS vaccines. IMPORTANCE GAS-related diseases disproportionally affect disadvantaged populations (e.g., indigenous populations), and development of a vaccine has been neglected. A recent strong advocacy campaign driven by the World Health Organization and the International Vaccine Institute has highlighted the urgent need for a GAS vaccine. One significant obstacle in GAS vaccine development is the lack of a widely used animal model to assess vaccine efficacy. Researchers in the field use a wide range of murine models of infection and in vitro assays, sometimes yielding conflicting results. Here we present the nonhuman primate pharyngeal infection model as a tool to assess vaccine-induced protection against colonization and clinical symptoms of pharyngitis and tonsillitis. We have tested the efficacy of an experimental vaccine candidate with promising results. We believe that the utilization of this valuable tool by the GAS vaccine research community could significantly accelerate the realization of a safe and effective GAS vaccine for humans.

Vaccine-Induced Th1-Type Response Protects against Invasive Group A Streptococcus Infection in the Absence of Opsonizing Antibodies

“…Using alum as an adjuvant, we have tested Combo5 in different animal models with various results. Immunization with Combo5/alum provided protection in a superficial skin infection model in mice (13) and decreased the severity of pharyngitis and tonsillitis clinical signs in a pharyngitis model in nonhuman primates (12). On the other hand, the same formulation failed to provide protection using the humanized plasminogen mouse model of invasive lethal infection (13).…”

“…Mouse models are ideal for initial preclinical testing of vaccine candidates, and in this particular case, the humanized plasminogen mouse model allowed us to investigate the effect of different adjuvants to promote the protective efficacy of Combo5. To further advance Combo5/SMQ as a vaccine candidate, it is crucial to investigate its efficacy using more-representative models of infection, such as the pharyngitis model in nonhuman primates (12) or, potentially, the experimental human challenge models that are being developed (33). formamide at 37°C with 5% CO 2 for 5 to 6 days and diluted in opsonization buffer to 1 ϫ 10 7 cells/ml.…”

“…We previously tested Combo5 formulated with alum in murine and nonhuman primate (NHP) models of infection with various results. While immunization with Combo5/alum decreased the severity of clinical signs but did not reduce colonization in a NHP pharyngitis model of infection (12) and provided protection in a murine superficial skin infection model, the same formulation failed to protect in a murine invasive model of disease (13). In this study, taking advantage of the opportunity presented by these findings, we examined the protective capacity of Combo5 formulated with a panel of different adjuvants (Table 1) using the invasive GAS disease model.…”

Immunotherapy targeting the Streptococcus pyogenes M protein or streptolysin O to treat or prevent influenza A superinfection

“…Similarly, antibodies to the exoprotein streptolysin S enhanced GAS killing by neutralizing the cytolytic activity of the toxin [43]. Finally, active vaccination of non-human primates with an SLO toxoid (also containing other GAS antigens) induced non-opsonizing SLO-specific antibodies and decreased pharyngitis [44]. Thus, the antisera to the M protein and SLO likely enhanced opsonophagocytosis (Fig 2) and neutralized cytolytic activity (Table 1), respectively.…”

Opsonic Activity of Conservative Versus Variable Regions of the Group A Streptococcus M Protein

“…Currently, antibiotics (e.g., penicillin) are the primary treatment for GAS infection, but antibiotic resistance is becoming a concern [ 4 ]. A vaccine to address the global burden of GAS would reduce the rates of GAS-associated infections and deaths, but to date, a safe and effective commercial vaccine is currently not available [ 5 ].…”