Infections caused by Streptococcus pyogenes (group A Streptococcus [GAS]) are highly prevalent in the tropics, in developing countries, and in the Indigenous populations of developed countries. These infections and their sequelae are responsible for almost 500,000 lives lost prematurely each year. A synthetic peptide vaccine (J8-DT) from the conserved region of the M protein has shown efficacy against disease that follows i.p. inoculation of bacteria. By developing a murine model for infection that closely mimics human skin infection, we show that the vaccine can protect against pyoderma and subsequent bacteremia caused by multiple GAS strains, including strains endemic in Aboriginal communities in the Northern Territory of Australia. However, the vaccine was ineffective against a hypervirulent cluster of virulence responder/sensor mutant GAS strain; this correlated with the strain’s ability to degrade CXC chemokines, thereby preventing neutrophil chemotaxis. By combining J8-DT with an inactive form of the streptococcal CXC protease, S. pyogenes cell envelope proteinase, we developed a combination vaccine that is highly effective in blocking CXC chemokine degradation and permits opsonic Abs to kill the bacteria. Mice receiving the combination vaccine were strongly protected against pyoderma and bacteremia, as evidenced by a 100–1000-fold reduction in bacterial burden following challenge. To our knowledge, a vaccine requiring Abs to target two independent virulence factors of an organism is unique.
We have developed a new procedure (Vir typing) for typing Streptococcus pyogenes, by amplifying the entire $to 7-kb variable vir regulon by long PCR. The amplified DNA is then cleaved with Haelll and visualized by ethidlum bromide fluorescence after agarose gel electrophoresis. A simple procedure for preparing DNA of sufficiently high quality from 96 samples was employed simultaneously. This DNA was also used to develop a random amplified polymorphic DNA (RAPD) procedure. The discriminatory power of the two DNA-based procedures was compared with previous methods, M typing, and multilocus enzyme electrophoresis. Both procedures were highly discriminatory, but the stoichiometric yield of restriction fragments in Vir typing allows unambiguous interpretation of results.
Abstract:A novel vaccine development platform that enables the site--specific conjugation of synthetic lipid adjuvants to recombinant proteins was produced. This technology facilitates the simple and efficient production of homogeneous, chemically--defined, semisynthetic lipoprotein vaccines. Using a polytope 'string--of--beads' approach, a synthetic gene incorporating seven Streptococcus pyogenes M protein strain--specific antigens, and a conserved M protein antigen (J14) was produced, expressed, and attached to a lipoamino acid based adjuvant (lipid core peptide; LCP). Nanoparticles (40 nm diameter) of an optimal size for stimulating antibody--mediated immunity were formed upon the addition of these lipoproteins to aqueous buffer (PBS). Systemic antigen--specific IgG antibodies were raised against all eight antigens in C57BL/6J mice, without the need to formulate with additional adjuvant. These antibodies bound cell surface M proteins of S. pyogenes strains represented within the polytope sequence, with higher antibody levels observed where a dendritic cell targeting peptide (DCpep) was incorporated within the LCP adjuvant.
BackgroundGroup A streptococcus (GAS) is a serious human pathogen that affects people of different ages and socio-economic levels. Although vaccination is potentially one of the most effective methods to control GAS infection and its sequelae, few prototype vaccines have been investigated in humans. In this study, we report the safety and immunogenicity of a novel acetylated peptide-protein conjugate vaccine candidate MJ8VAX (J8-DT), when delivered intramuscularly to healthy adults.MethodsA randomized, double-blinded, controlled Phase I clinical trial was conducted in 10 healthy adult participants. Participants were randomized 4:1 to receive the vaccine candidate (N = 8) or placebo (N = 2). A single dose of the vaccine candidate (MJ8VAX), contained 50 μg of peptide conjugate (J8-DT) adsorbed onto aluminium hydroxide and re-suspended in PBS in a total volume of 0.5 mL. Safety of the vaccine candidate was assessed by monitoring local and systemic adverse reactions following intramuscular administration. The immunogenicity of the vaccine was assessed by measuring the levels of peptide (anti-J8) and toxoid carrier (anti-DT)—specific antibodies in serum samples.ResultsNo serious adverse events were reported over 12 months of study. A total of 13 adverse events (AEs) were recorded, two of which were assessed to be associated with the vaccine. Both were mild in severity. No local reactogenicity was recorded in any of the participants. MJ8VAX was shown to be immunogenic, with increase in vaccine-specific antibodies in the participants who received the vaccine. The maximum level of vaccine-specific antibodies was detected at 28 days post immunization. The level of these antibodies decreased with time during follow-up. Participants who received the vaccine also had a corresponding increase in anti-DT serum antibodies.ConclusionsIntramuscular administration of MJ8VAX was demonstrated to be safe and immunogenic. The presence of DT in the vaccine formulation resulted in a boost in the level of anti-DT antibodies.Trial registrationACTRN12613000030774
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.
customersupport@researchsolutions.com
10624 S. Eastern Ave., Ste. A-614
Henderson, NV 89052, USA
This site is protected by reCAPTCHA and the Google Privacy Policy and Terms of Service apply.
Copyright © 2025 scite LLC. All rights reserved.
Made with 💙 for researchers
Part of the Research Solutions Family.