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PubMed2004

Safety and immunogenicity of a recombinant multivalent group a streptococcal vaccine in healthy adults: phase 1 trial.

CONTEXT: Group A streptococcal infections and their sequelae represent a global health problem. Recent advances have allowed previous obstacles associated with group A streptococcal vaccine development to be overcome. OBJECTIVE: To preliminarily evaluate the safety and immunogenicity of ascending doses of a recombinant fusion peptide group A streptococcal vaccine containing N-terminal M protein fragments from serotypes 1, 3, 5, 6, 19, and 24 in healthy volunteers. DESIGN, SETTING, AND PARTICIPANTS: An open-label, uncontrolled, dose-ascending phase 1 vaccine trial of 28 healthy adult volunteers aged 18 to 50 years recruited from the metropolitan area of Baltimore, Md, between October 5, 1999, and February 26, 2003, using newspaper advertisements and posted fliers, and evaluated in the outpatient facility of the Center for Vaccine Development. INTERVENTIONS: Each volunteer received 3 spaced intramuscular injections of 50 microg (n = 8), 100 micro g (n = 10), or 200 microg (n = 10) of hexavalent group A streptococcal vaccine formulated with aluminum hydroxide into the deltoid muscle of alternating arms. MAIN OUTCOME MEASURES: Assessments of clinical safety, including elicitation of antibodies that cross-react with host tissues, and immunogenicity as measured by enzyme-linked immunosorbent assay (ELISA) and assays of opsonophagocytic- and bactericidal-antibody responses. RESULTS: One year of intensive follow-up revealed the vaccine to be well tolerated. There was no evidence of tissue cross-reactive antibodies or immunological complications. At the highest (200 microg) dose, vaccination elicited significant increases in geometric mean antibody levels to all 6 component M antigens by ELISA (all P<.01) and to 5 of 6 M types in the opsonophagocytosis assay (all P<.05). In addition, postvaccination increases in serum bactericidal activity of at least 30% were observed in 31 (55%) of 56 assays. CONCLUSION: These results provide the first evidence in humans that a hybrid fusion protein is a feasible strategy for evoking type-specific opsonic antibodies against multiple serotypes of group A streptococcus without eliciting antibodies that cross-react with host tissues, which represents a critical step in the development of a vaccine.

Adult↗

PubMed1976

Erythrocyte antinuclear antibodies in sera of chickens hyperimmunized with group A streptococcal vaccine.

Chickens hyperimmunized with group A streptococcal vaccine often synthesize high levels of antibody to group A streptococcal carbohydrate (SACHO). Indirect immunofluorescent analysis revealed that sera of these chickens also contain antinuclear antibodies capable of reacting with chicken erythrocyte nuclei (EANA) at titers up to 2,560. Removal of the anti-SACHO antibodies from hyperimmune serum did not significantly reduce EANA titers, indicating that anti-SACHO antibodies are not responsible for the EANA reactions. The time course for antibody development as well as the immunoglobulin class distribution of EANA and anti-SACHO antibodies were very similar. Localization of EANA activity to Fab fragments indicated that the immunfluorescent reaction represents an antigen-antibody reaction. Findings point out an important consequence of using chicken immunoglobulin Y in immunofluorescent assays. The purified Fc fragment of immunoglobulin Y is cytophilic for the substrate when tested at high concentrations, which suggests that some cytophilic immunoglobulins are involved in the reaction.

Animals↗

PubMed2005

Prospects for a group A streptococcal vaccine.

Group A streptococcal (GAS) infections are associated with a number of human diseases, including pharyngitis, impetigo, necrotizing fasciitis, streptococcal toxic shock syndrome and rheumatic heart disease. An increase in the incidence of severe GAS infections in Western countries, and the awareness of the burden of GAS-associated diseases in developing nations, which remains high in spite of the availability of antibiotics, has provided the impetus for development of a safe and efficacious GAS vaccine. This has focused on the M protein, a major GAS virulence factor, however, with the publication of several GAS genomes, a number of non-M vaccine candidates are now under investigation.

Animals↗

PubMed1989

[Treatment of chronic recurrent erysipelas with streptococcal vaccine].

One hundred patients suffering from relapsing erysipelas were treated with streptococcal vaccine consisting of a phenol- und heat-inactivated mixture of 12 different types of streptococci. Simultaneously the entry point was cured and general disposition and local terrain factors were treated. In the majority of cases further relapses were avoided or their frequency reduced. The results of the treatment with streptococcal vaccine were compared with those of long-term benzathine-penicillin therapy in 47 patients. The vaccine has proved to be equivalent to the penicillin therapy and can be recommended as a real alternative to it for prevention of further infections and late sequelae, especially those of chronic lymphedema. The beneficial therapeutic effect of the vaccine is probably attributable to a non-specific immune stimulation. A partial cellular immune defect involving the protective M-antigen together with simultaneous partial abnormalities of immune reactivity is discussed as a cause of relapsing erysipelas.

Adult↗

PubMed1983

Association of bacterial carbohydrate-specific cold agglutinin antibody production with immunization by group C, group B type III, and Streptococcus pneumoniae type XIV streptococcal vaccines.

Rabbits immunized with group B type III, group C, and Streptococcus pneumoniae type XIV streptococcal vaccines developed autoantibodies reactive with autologous and isologous erythrocytes and human O-positive erythrocytes at reduced temperatures. The cold agglutinin antibodies were present in both the immunoglobulin M (IgM) and IgG fractions of group C streptococcal antiserum and in the IgM fraction of group B type III and S. pneumoniae type XIV antisera. BALB/c, CF1, and local strains of mice immunized with group B type III and S. pneumoniae type XIV streptococcal vaccines also produced a cold agglutinin antibody reactive with rabbit and human erythrocytes. The cold agglutinin antibodies were reactive with saccharide compounds representative of the determinants present on the individual bacterial carbohydrate structures, individual vaccine preparations, and isolated polysaccharides. The group C antibodies in rabbits were reactive with sugar ligands in the following order: N-acetylgalactosamine greater than melibiose greater than lactose greater than galactose greater than glucose. Group B type III and S. pneumoniae type XIV cold agglutinin antibodies in rabbit antisera, however, displayed reactivities different from group C antibodies and from each other. Group B type III antibodies reacted with galactose greater than lactose greater than N-acetylgalactosamine greater than glucose greater than rhamnose; S. pneumoniae type XIV antibodies reacted with lactose greater than melibiose greater than galactose greater than glucose greater than N-acetylgalactosamine. The same relative ligand specificity was observed for the cold agglutinin antibodies in S. pneumoniae type XIV mouse antisera. The cold agglutinin antibodies in group B type III and S. pneumoniae type XIV antiserum reacted with erythrocytes at higher temperatures (up to 31 degrees C) than did group C antibodies (up to 14 degrees C). In addition, S. pneumoniae type XIV antibodies did not discriminate between I- or i-bearing human erythrocytes to a significant extent. The results obtained provide substantial evidence that autoreactive cold agglutinin antibodies produced by immunization with these vaccines represent subpopulations of bacterial carbohydrate-specific antibodies that cross-react with mammalian carbohydrate structures.

Agglutinins↗

PubMed1988

Protective immunity evoked by locally administered group A streptococcal vaccines in mice.

The present studies were undertaken to determine the pathogenicity of group A streptococci introduced intranasally (i.n.) into mice in an attempt to mimic mucosal infections in humans and to determine the efficacy of streptococcal vaccines administered via the mucosal route. The LD50 of type 24 streptococci (M24 strep) administered i.n. was 3 x 10(4) CFU. Throat cultures were performed in M24 strep-inoculated mice. Of 11 mice that died, 9 had positive throat cultures 3 or 4 days after i.n. challenge, and of 9 mice that survived, only 1 had a positive throat culture, indicating an association between mucosal infection and death. Postmortem examination performed on 35 mice that died after i.n. challenge showed that all had evidence of disseminated infections, and group A streptococci were recovered from the cervical lymph nodes, blood, spleen, liver, and brain. To determine vaccine efficacy, heat-killed M24 strep or pep M24 were administered i.n. to groups of mice. Whole, heat-killed streptococci and pep M24 administered locally protected mice against death from i.n. challenge infections with homologous M24 strep. The whole cell vaccine also protected against i.n. challenge infections with heterologous type 6 streptococci. Our data suggest that streptococcal vaccines administered locally evoke protective immunity against streptococcal infections.

Administration, Intranasal↗

PubMed1977

Autoantibodies detected in rabbits hyperimmunized with group A, C, and G streptococcal vaccines.

Rabbits hyperimmunized with group A, C, and G streptococcal vaccines developed autoantibodies with affinities for different tissues (smooth muscle, cytoplasmic, and myocardial antibodies) and for autologous proteins (anti-albumin and anti-immunoglobulin antibodies). The presence of anti-albumin and smooth muscle antibodies, associated with a high level of immunoglobulin, suggests the development of hepatic disorders in the hyperimmunized rabbits.

Animals↗

PubMed1987

The proliferative response of human peripheral blood lymphocytes to group A streptococcal vaccine.

The proliferative response of human peripheral blood mononuclear cells to group A streptococcal vaccine (strain J17A4) was assessed by measurement of [3H]thymidine incorporation. This was maximal after 7 days in cultures containing 1 X 10(5) lymphocytes. Cells from 33 out of 38 adult donors (87%) yielded stimulation indices between 2.0 and 81. Responding cells were predominantly of the OKT4+, Ia+, Tac+ phenotype expressed by activated helper T lymphocytes. In contrast, no response was observed in 10 out of 12 samples of cord blood lymphocytes. Addition of conventional rabbit or monoclonal murine anti-Ia (HLA-DR) antibodies to the culture medium abrogated the vaccine-induced proliferative response. Frequencies of responding cells estimated by limiting dilution analysis were between 1 in 2370 and 1 in 4580 lymphocytes. The results suggest that lymphocyte stimulations induced with streptococcal group A vaccine represented an in vitro anamnestic cellular immune response.

Antibody-Producing Cells↗

PubMed2006

Synthesis of a highly pure lipid core peptide based self-adjuvanting triepitopic group A streptococcal vaccine, and subsequent immunological evaluation.

We have developed a highly pure, self-adjuvanting, triepitopic Group A Streptococcal vaccine based on the lipid core peptide system, a vaccine delivery system incorporating lipidic adjuvant, carrier, and peptide epitopes into a single molecular entity. Vaccine synthesis was performed using native chemical ligation. Due to the attachment of a highly lipophilic adjuvant, addition of 1% (w/v) sodium dodecyl sulfate was necessary to enhance peptide solubility in order to enable ligation. The vaccine was synthesized in three steps to yield a highly pure product (97.7% purity) with an excellent overall yield. Subcutaneous immunization of B10.BR (H-2(k)) mice with the synthesized vaccine, with or without the addition of complete Freund's adjuvant, elicited high serum IgG antibody titers against each of the incorporated peptide epitopes.

Animals↗

PubMed1973

Immune response of rats to group A streptococcal vaccine.

Adult female Sprague-Dawley rats were hyperimmunized with group A streptococcal vaccine in an attempt to evaluate this species for its immunological responsiveness to the group A streptococcal carbohydrate. Pronounced hyperproteinemia, generally attributable to hypergammaglobulinemia was produced in 30 to 40% of the animals. The immune response of the rats was extremely variable, yielding precipitating antibody concentrations ranging from <0.1 mg per ml to >26 mg per ml. Antibody levels also varied considerably in the same rat at different times during the immunization routine. The highest concentration of precipitating antibody was 26.3 mg per ml. Evidence is presented to suggest the production of antibodies of restricted heterogeneity and the production of non-streptococcal antibodies during the immune response.

Absorption↗

PubMed1979

Experimental immune glomerulonephritis induced in the rabbit with streptococcal vaccine.

Heavy C3 glomerular deposits were observed in rabbits injected intravenously with C5 streptococcal vaccine. Immunoglobulin deposits appeared later in a few rabbits. Although some data favour the presence of circulating immune complexes during the course of this glomerulonephritis, no evidence for their initiating role could be demonstrated. Streptococcal components are known to activate the alternative pathway of complement. It is suggested that complexes made of streptococcal components and activated C3 might deposit in glomerular tufts.

Agglutinins↗

PubMed2004

Prospecting for new group A streptococcal vaccine candidates.

BACKGROUND & OBJECTIVES: Most group A streptococcal (GAS) vaccine strategies focused on the surface M protein of the GAS. However, vaccine based on M protein have some drawbacks. In the present study, we used two approaches to identify new proteins and peptides that may have utility as vaccine candidates. METHODS: A whole gel elution procedure was used to separate GAS surface antigens into 9 size fractionated pools. Mice were vaccinated with each pool and antibody titre, opsonic ability and protective capacity measured. In an alternative approach BioInformatics was used to identify putative GAS surface proteins. Peptides from within these proteins were then selected on the basis of predicted antigenicity or location. These peptides were conjugated to keyhole lymphocyanin (KLH) and immunogenicity measured in a mouse model. RESULTS: One pool of GAS surface proteins (approximately 29kDa) induced antibodies that were both opsonic and potentially protective. Immunoflourescent microscopy demonstrated that these antibodies bound to the surface of M1 GAS. Amino acid sequencing subsequently identified superoxide dismutase as the major antigen in this pool. A BioInformatic search of the M1 GAS genome and subsequent analysis identified several peptides that fulfilled criteria as potential vaccine candidates. Each peptide when conjugated to KLH was able to induce a strong antibody response. INTERPRETATION & CONCLUSION: Several new antigens were identified that may have potential as vaccine targets. A future GAS vaccine may have multiple peptide epitopes, providing protection against multiple GAS strains.

Amino Acid Sequence↗

PubMed1999

Group A streptococcal vaccines.

The pathogenesis of group A streptococcal infections, and antigens that contribute to protective immune responses are reviewed. Several approaches to vaccine development are discussed. Data are provided from preclinical studies of multivalent M protein-based vaccines that evoke protective antibodies in laboratory animals. Also discussed are future strategies for the development of broadly protective vaccines, and their potential impact on the incidence of streptococcal infections, and acute rheumatic fever.

Animals↗

PubMed1997

Group A and group B streptococcal vaccine development. A round table presentation.

The data presented above provide a broad overview of ongoing work to develop vaccines against group A and group B streptococcal infections. The encouraging results of human trials with conjugate group B polysaccharide vaccines suggest that this approach will lead to a safe and effective method for preventing these devastating infections in newborn infants. The results of preclinical studies of the various strategies to develop group A streptococcal vaccines are also encouraging. Whether one approach will be more advantageous or efficacious than another will need to await clinical trials. Nevertheless, we predict that in the next decade we will make significant strides in preventing streptococcal infections and their complications.

Adhesins, Bacterial↗

PubMed1978

Lymphoid thyroiditis following immunization with group A streptococcal vaccine.

Severe lymphoid thyroiditis and associated hypothyroidism occurred in all of 7 male and 4 female F(7) derivatives (seventh generation) of rats immunized in each generation against Group A streptococci. This evidence of thyroiditis produced by immunization against a nonthyroidal antigen suggests that some cases of Hashimoto's thyroiditis in humans may result from nonspecific immune responses.

Animals↗

PubMed2004

Toward the development of a synthetic group a streptococcal vaccine of high purity and broad protective coverage.

Using native chemical ligation, we synthesized a group A streptococcal (GAS) vaccine that contained three different GAS M protein peptide epitopes in a chemically well-characterized construct in high purity. Two of the peptide epitopes represented variable amino terminal serotype determinants, and the third represented a carboxyl terminal conserved region determinant of the GAS M protein. We also synthesized a lipid core peptide (LCP) construct containing the same three peptides. Upon immunization of mice, the non-LCP construct only elicited antibody responses to all three epitopes with the use of adjuvant. The LCP construct, however, elicited excellent antibody responses to all three epitopes without the need for any additional adjuvant or carrier. We have synthesized the LCP synthetic vaccine system with good reproducibility.

Amino Acid Sequence↗

PubMed1978

Specific and cross-reactive activation of rabbit peripheral blood lymphocytes by streptococcal vaccines.

The ability of primed rabbit blood lymphocytes to respond in vitro to the homologous streptococcal group antigen depends on its presence in culture in the form of vaccine or cell walls thereof. These lymphocytes can also be stimulated in vitro by streptococcal vaccines with chemically related group antigens. The basis for this cross-stimulation apparently resides in shared rhamnose moieties. Activation of these lymphocytes was not achieved by vaccines from unrelated bacteria. There is also the suggestion that rabbits of different genetic origin differentiate between cross-stimulating antigens, probably at the level of antigenic determinants. The data support the view that recognition and response pattern of the immune system rely heavily on a network of antigens.

Animals↗

PubMed1999

Multivalent group A streptococcal vaccine designed to optimize the immunogenicity of six tandem M protein fragments.

One of the major challenges in the development of group A streptococcal M protein-based vaccines is the multiplicity of M types expressed by these organisms. Previous studies have shown that multivalent vaccines containing as many as eight M protein fragments in tandem were immunogenic and evoked opsonic antibodies. It was also noted that the C-terminal fragments of these hybrid proteins were often not immunogenic or evoked only low levels of opsonic antibodies, suggesting that the C-terminus of the molecule may have been preferentially degraded or altered in vivo. In the present studies, we designed a hexavalent vaccine containing protective M protein peptides from types 24, 5, 6, 19, 1, and 3 group A streptococci. In order to "protect" the carboxy-terminal components, the amino-terminal M24 fragment was reiterated on the carboxy-terminal end of the construct. The hexavalent vaccine was immunogenic in laboratory animals and evoked high titers of antibodies against each of the native M proteins represented in the vaccine and bactericidal antibodies against all six sterotypes of group A streptococci. The vaccine was equally immunogenic when delivered in alum or in complete Freund's adjuvant. None of the immune sera contained antibodies that crossreacted with human heart tissue. Our results show that complex multivalent group A streptococcal vaccines can be designed in such a way that each M protein fragment is immunogenic and evokes protective antibodies.

Alum Compounds↗