Immunization with C5a peptidase from either group A or B streptococci enhances clearance of group A streptococci from intranasally infected mice (original) (raw)
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A Vaccine against Streptococcus pyogenes
American Journal of Cardiovascular Drugs, 2013
Streptococcus pyogenes causes severe, invasive infections such as the sequelae associated with acute rheumatic fever, rheumatic heart disease, acute glomerulonephritis, uncomplicated pharyngitis, and pyoderma. Efforts to produce a vaccine against S. pyogenes began several decades ago, and different models have been proposed. We have developed a vaccine candidate peptide, StreptInCor, comprising 55 amino acid residues of the C-terminal portion of the M protein and encompassing both the T-and B-cell protective epitopes. The present article summarizes data from the previous 5 years during which we tested the immunogenicity and safety of StreptInCor in different animal models. We showed that StreptInCor overlapping peptides induced cellular and humoral immune responses of individuals bearing different HLA class II molecules. These results are consistent with peptides that have a universal vaccine epitope. The tridimensional molecular structure of StreptInCor was elucidated by nuclear magnetic resonance spectroscopy, which showed that its structure is composed of two microdomains linked by an 18-residue a-helix. Additionally, we comprehensively evaluated the structural stability of the StreptInCor peptide in different physicochemical conditions using circular dichroism. Additional experiments were performed with inbred, outbred, and HLA class II transgenic mice. Analysis of several organs of these mice showed neither deleterious nor autoimmune reactions even after a long period of vaccination, indicating that the StreptInCor candidate peptide could be considered as an immunogenic and safe vaccine.
The Journal of Infectious Diseases, 2005
Infection with group A streptococcus (GAS) may result in a number of clinical conditions, including the potentially life-threatening postinfectious sequelae of rheumatic fever and rheumatic heart disease. As part of the search for a vaccine to prevent GAS infection, a conformationally constrained and minimally conserved peptide, J14, from the M protein of GAS has been defined. In the present study, J14 was formulated with bacterial outer membrane proteins (proteosomes) and then intranasally administered to outbred mice without additional adjuvant. Such immunization led to high titers of J14-specific serum immunoglobulin (Ig) G and mucosal IgA. After upper respiratory tract GAS challenge, immunized mice demonstrated increased survival and reduced GAS colonization of the throat.
Preclinical immunogenicity and safety of a Group A streptococcal M protein-based vaccine candidate
Human vaccines & immunotherapeutics, 2016
Streptococcus pyogenes (group A streptococcus, GAS) causes a wide range of clinical manifestations ranging from mild self-limiting pyoderma to invasive diseases such as sepsis. Also of concern are the post-infectious immune-mediated diseases including rheumatic heart disease. The development of a vaccine against GAS would have a large health impact on populations at risk of these diseases. However, there is a lack of suitable models for the safety evaluation of vaccines with respect to post-infectious complications. We have utilized the Lewis Rat model for cardiac valvulitis to evaluate the safety of the J8-DT vaccine formulation in parallel with a rabbit toxicology study. These studies demonstrated that the vaccine did not induce abnormal pathology. We also show that in mice the vaccine is highly immunogenic but that 3 doses are required to induce protection from a GAS skin challenge even though 2 doses are sufficient to induce a high antibody titer.
Safety and Immunogenicity of 26-Valent Group A Streptococcus Vaccine in Healthy Adult Volunteers
Clinical Infectious Diseases, 2005
Background. Group A streptococcus (GAS) causes illness ranging from uncomplicated pharyngitis to lifethreatening necrotizing fasciitis, toxic shock, and rheumatic fever. Attempts to develop an M protein-based vaccine have been hindered by the fact that some M proteins elicit both protective antibodies and antibodies that crossreact with human tissues. New molecular techniques have allowed the previous obstacles to be largely overcome. Methods. The vaccine is comprised of 4 recombinant proteins adsorbed to aluminum hydroxide that contain N-terminal peptides from streptococcal protective antigen and M proteins of 26 common pharyngitis, invasive, and/or rheumatogenic serotypes. Thirty healthy adult subjects received intramuscular 26-valent GAS vaccine (400 mg) at 0, 1, and 4 months, with clinical and laboratory follow-up for safety and immunogenicity using assays for tissue cross-reactive antibodies, type-specific M antibodies to 27 vaccine antigens, and functional (opsonization) activity of M protein antibodies. Results. The incidence of local reactogenicity was similar to that for other aluminum hydroxide-adsorbed vaccines in adults. No subject developed evidence of rheumatogenicity or nephritogenicity, and no induction of human tissue-reactive antibodies was detected. Overall, 26 of 27 antigenic peptides evoked a 14-fold increase in the geometric mean antibody titer over baseline. The mean log 2 fold-increase in serum antibody titer ע( standard error of the mean) for all 27 antigens was 3.67 ע 0.21. A significant mean log 2 reduction in streptococcal bacterial counts in serum samples obtained after immunization was seen in opsonization assays for all M serotypes. Conclusions. On the basis of epidemiological data demonstrating that the majority of cases of pharyngitis, necrotizing fasciitis, and other invasive streptococcal infections are caused by a limited number of serotypes, this 26-valent vaccine could have significant impact on the overall burden of streptococcal disease. Streptococcus pyogenes (group A streptococcus [GAS]) is an important human pathogen that causes an estimated 25-35 million infections per year in the United States [1, 2]. Although uncomplicated pharyngitis and skin and soft-tissue infections account for the majority of infections, the incidence of life-threatening illnesses, such as necrotizing fasciitis and toxic shock syndrome, is increasing [3, 4]. Uncomplicated infection can lead to serious sequelae, such as acute rheumatic fever and
Infection and Immunity, 2004
We have previously shown that a hexavalent group A streptococcal M protein-based vaccine evoked bactericidal antibodies after intramuscular injection. In the present study, we show that the hexavalent vaccine formulated with several different mucosal adjuvants and delivered intranasally induced serum and salivary antibodies that protected mice from intranasal challenge infections with virulent group A streptococci. The hexavalent vaccine was formulated with liposomes with or without monophosphorylated lipid A (MPL), cholera toxin B subunit with or without holotoxin, or proteosomes from Neisseria meningitidis outer membrane proteins complexed with lipopolysaccharide from Shigella flexneri. Intranasal immunization with the hexavalent vaccine mixed with these adjuvants resulted in significant levels of antibodies in serum 2 weeks after the final dose. Mean serum antibody titers were equivalent in all groups of mice except those that were immunized with hexavalent protein plus liposomes without MPL, which were significantly lower. Salivary antibodies were also detected in mice that received the vaccine formulated with the four strongest adjuvants. T-cell proliferative assays and cytokine assays using lymphocytes from cervical lymph nodes and spleens from mice immunized with the hexavalent vaccine formulated with proteosomes indicated the presence of hexavalent protein-specific T cells and a Th1-weighted mixed Th1-Th2 cytokine profile. Intranasal immunization with adjuvanted formulations of the hexavalent vaccine resulted in significant levels of protection (80 to 100%) following intranasal challenge infections with type 24 group A streptococci. Our results indicate that intranasal delivery of adjuvanted multivalent M protein vaccines induces protective antibody responses and may provide an alternative to parenteral vaccine formulations.
Identification and assessment of new vaccine candidates for group A streptococcal infections
Vaccine, 2004
Group A Streptococcus (GAS) is a human-specific pathogen responsible for a wide variety of human diseases. Numerous GAS surface antigens interact with the human immune system and only some of these proteins have been studied in depth. A few of these may elicit protective response against GAS infection. In this study, we have used an in silico approach to identify antigenic peptides from GAS surface proteins. Putative GAS surface proteins from the M1 GAS genome were identified by the presence on LPxTG cell-wall anchoring motif and an export signal sequence. This technique identified 17 proteins of known or putative function, and another 11 which do not have known homologues. Peptides derived from predicted antigenic sequences near the amino terminus of six of these proteins, and another seven peptides derived from the two known surface proteins, GRAB and MtsA, were conjugated to keyhole lymphocyanin (KLH), and investigated for their capacity to induce opsonic antibody responses in outbred Quackenbush mice. All peptide-KLH antisera demonstrated opsonic capacity against both 88/30 and M1 GAS. However, KLH sera alone was also able to induce opsonic antibodies, suggesting that anti-KLH antibodies contributed to the opsonisation seen in the peptide-KLH antisera. KLH is therefore a promising carrier molecule for potential GAS peptide vaccines.
A multivalent T-antigen-based vaccine for Group A Streptococcus
Scientific Reports, 2021
Pili of Group A Streptococcus (GAS) are surface-exposed structures involved in adhesion and colonisation of the host during infection. The major protein component of the GAS pilus is the T-antigen, which multimerises to form the pilus shaft. There are currently no licenced vaccines against GAS infections and the T-antigen represents an attractive target for vaccination. We have generated a multivalent vaccine called TeeVax1, a recombinant protein that consists of a fusion of six T-antigen domains. Vaccination with TeeVax1 produces opsonophagocytic antibodies in rabbits and confers protective efficacy in mice against invasive disease. Two further recombinant proteins, TeeVax2 and TeeVax3 were constructed to cover 12 additional T-antigens. Combining TeeVax1–3 produced a robust antibody response in rabbits that was cross-reactive to a full panel of 21 T-antigens, expected to provide over 95% vaccine coverage. These results demonstrate the potential for a T-antigen-based vaccine to prev...
Frontiers in Microbiology, 2021
Both Streptococcus agalactiae [group B streptococcus (GBS)] and Streptococcus pneumoniae (pneumococcus) remain significant pathogens as they cause life threatening infections mostly in children and the elderly. The control of diseases caused by these pathogens is dependent on antibiotics use and appropriate vaccination. The introduction of the pneumococcal conjugate vaccines (PCVs) against some serotypes has led to reduction in pneumococcal infections, however, the subsequent serotype switching, and replacement has been a serious challenge. On the other hand, no vaccine is yet licensed for use in the control of GBS diseases. In this review, we provide an overview of the history and global disease burden, disease pathophysiology and management, vaccines update, and the biology of both pathogens. Furthermore, we address recent findings regarding structural similarities that could be explored for vaccine targets across both mucosal pathogens. Finally, we conclude by proposing future ge...
Group A Streptococcus Infections: Their Mechanisms, Epidemiology, and Current Scope of Vaccines
Cureus
Group A streptococci (GAS) are gram-positive, cocci-shaped bacteria that cause a wide variety of infections and are a cause of significant health burden, particularly in lower-and middle-income nations. The GAS genome contains a number of virulence factors such as the M-protein, hyaluronic acid, C5a peptidase, etc. Despite its significant health burden across the globe, a proper vaccine against GAS infections is not yet available. Various candidates for an effective GAS vaccine are currently being researched. These are based on various parts of the streptococcal genome. These include candidates based on the N-terminal region of the M protein, the conserved C-terminal region of the M protein, and other parts of the streptococcal genome. The development of a vaccine against GAS infections is hampered by certain challenges, such as extensive genetic heterogeneity and high protein sequence variation. This review paper sheds light on the various virulence factors of GAS, their epidemiology, the different vaccine candidates currently being researched, and the challenges associated with M-protein and non-M-protein-based vaccines. This review also sheds light on the current scenario regarding the status of vaccine development against GAS-related infections.
Protection against Streptococcus pneumoniae Elicited by Immunization with Pneumolysin and CbpA
Infection and Immunity, 2001
The need for the development of cheap and effective vaccines against pneumococcal disease has necessitated the evaluation of common virulence-associated proteins of Streptococcus pneumoniae as potential vaccine antigens. In this study, we examined the capacity of active immunization with a genetic toxoid derivative of pneumolysin (PdB) and/or a fragment of choline binding protein A (CbpA; also known as PspC, Hic, and SpsA) to protect mice from intraperitoneal challenge with medium to very high doses of a highly virulent capsular type 2 pneumococcal strain, D39. The median survival times for mice immunized with the individual protein antigens in different adjuvant combinations were significantly longer than those for mice that received the respective adjuvants alone. Mice immunized with CbpA alone were significantly better protected than mice immunized with PdB alone. Correspondingly, the median survival times for mice that were immunized with a combination of PdB and CbpA were significantly longer than those for mice that received PdB alone but not significantly different from those that received CbpA alone. Mice immunized with the protein antigens in a mixture of monophospholipid A (MPL) and aluminium phosphate (AlPO 4 ) adjuvants had higher antibody titers than mice that received the antigens in AlPO 4 alone. Mice immunized with PdB in MPL plus AlPO 4 were also significantly better protected than mice that received PdB in AlPO 4 alone.