Immunogenicity of a 26-Valent Group A Streptococcal Vaccine

Abstract

A multivalent vaccine containing amino-terminal M protein fragments from 26 different serotypes of group A streptococci was constructed by recombinant techniques. The vaccine consisted of four different recombinant proteins that were formulated with alum to contain 400 g of protein per dose. Rabbits were immunized via the intramuscular route at 0, 4, and 16 weeks. Immune sera were assayed for the presence of type-specific antibodies against the individual recombinant M peptides by enzyme-linked immunosorbent assay and for opsonic antibodies by in vitro opsonization tests and indirect bactericidal tests. The 26-valent vaccine was highly immunogenic and elicited fourfold or greater increases in antibody levels against 25 of the 26 serotypes represented in the vaccine. The immune sera were broadly opsonic and were bactericidal against the majority of the 26 different serotypes. Importantly, none of the immune sera cross-reacted with human tissues. Our results indicate that type-specific, protective M protein epitopes can be incorporated into complex, multivalent vaccines designed to elicit broadly protective opsonic antibodies in the absence of tissue-cross-reactive antibodies.Group A streptococcal pharyngitis is one of the most common bacterial infections in school age children. In addition, invasive streptococcal infections afflict thousands of children and adults each year, often resulting in death or significant morbidity (37). Although the incidence of acute rheumatic fever (ARF), a nonsuppurative sequela of streptococcal pharyngitis, has declined in developed countries, the disease is rampant in developing countries (40). Efforts to develop a vaccine that would prevent group A streptococcal infections have been ongoing for more than 8 decades (22,28). New molecular techniques (8) and a better understanding of the biology of group A streptococci (11) have allowed the previous obstacles associated with vaccine development to be overcome.Previous studies have shown that the surface M protein is the major virulence determinant and the major protective antigen of group A streptococci (29). The type specificity of each M protein, of which more than 100 are now known, is largely determined by the epitopes located in the amino-terminal 40 to 50 amino acid residues (3,8,14,27). These regions of M proteins have been shown to evoke antibodies with the greatest bactericidal (protective) activity and are least likely to crossreact with human tissues (2,14,20). Thus, our approach has been to combine small amino-terminal M protein peptides to make multivalent vaccines that would elicit opsonic antibodies against epidemiologically important serotypes of group A streptococci (12,21).In the present study, we constructed a 26-valent M proteinbased vaccine by recombinant technology. The vaccine is composed of four different fusion proteins that contain six or seven M protein fragments linked in tandem. Each component protein of the vaccine was designed to serve as its own carrier, thus obviating the need for unrelated proteins. ...

Construction and analysis of variants of a polyvalent Lyme disease vaccine: Approaches for improving the immune response to chimeric vaccinogens

“…In one, the C-terminal type D epitope was reiterated to yield ABKDD. Epitope repetition has been previously demonstrated to increase antibody titer by an unknown mechanism [41,[49][50][51]. To determine if decreased titer could be simply due to C-terminal epitope location, the type D epitope was relocated in the construct (ADBK).…”

Enfermedades invasoras por Streptococcus pyogenes 2005-2013: Hospital Pediátrico del Centro Hospitalario Pereira Rossell, Uruguay

“…Cabe destacar que 3 de los 4 tipos emm (emm1, 3 y 12) se encuentran en la formulación de una vacuna multivalente que aún no está disponible comercialmente 27 . Mantener la vigilancia epidemiológica de estas infecciones para conocer y divulgar la distribución nacional de tipos emm permitirá la toma de decisiones entre las diferentes fórmulas vacunales y servirá de base para la evaluación de la eficacia de la vacuna.…”

Host–pathogen interactions in Streptococcus pyogenes infections, with special reference to puerperal fever and a comment on vaccine development

“…Moreover, possible cross-reactions between M protein and human tissues have caused major concerns [3]. However, work is in progress to develop a multivalent vaccine based on a combination of many different HVRs, which may not elicit unwanted cross-reactivities [33]. Possibly, a vaccine could also be based on the conserved parts of M protein [34,35] although antibodies directed against this part might be expected to have poor activity because they do not block the antiphagocytic function of the HVR.…”