Protective efficacy of group A streptococcal vaccines containing type-specific and conserved M protein epitopes

The amino terminal region of group A streptococcal M proteins evokes type-specific immunity while the conserved C-repeat epitopes evoke cross-protective immunity against multiple serotypes. The present studies were undertaken to compare the protective efficacy of vaccines containing either type-specific (hexavalent vaccine) or conserved C-repeat (J14 vaccine) M protein epitopes and to determine if combination vaccines resulted in enhanced levels of protection. Our results indicated that the protective efficacy of the type-specific vaccine was significantly greater than that of J14 and that the addition of J14 to vaccine formulations did not enhance the level of protection achieved with type-specific formulations.     

Potential coverage of a multivalent M protein-based group A streptococcal vaccine

Background

The greatest burden of group A streptococcal (GAS) disease worldwide is due to acute rheumatic fever (ARF) and rheumatic heart disease (RHD). Safe, effective and affordable vaccines designed to prevent GAS infections that trigger ARF could reduce the overall global morbidity and mortality from RHD. The current study evaluated the potential coverage of a new 30-valent M protein-based vaccine using GAS isolates from school children in Bamako, Mali, a population at high risk for the development of RHD.

Methods

The bactericidal activity of rabbit antisera against the 30-valent vaccine was assessed using a collection of GAS isolates recovered during a study of the epidemiology of pharyngitis in Bamako.

Results

Single isolates representing 42 of 67 emm-types, accounting for 85% of the GAS infections during the study, were evaluated. All (14/14) of the vaccine emm-types in the collection were opsonized (bactericidal killing >50%) and 26/28 non-vaccine types were opsonized. Bactericidal activity was observed against 60% of the total emm-types recovered in Bamako, which accounted for 81% of all infections.

Conclusions

Multivalent vaccines comprised of N-terminal M peptides elicit bactericidal antibodies against a broad range of GAS serotypes, indicating that their efficacy may extend beyond the emm-types included in the vaccine.     

A lipidated form of the extracellular domain of influenza M2 protein as a self-adjuvanting vaccine candidate

The highly conserved extracellular domain of Matrix protein 2 (M2e) of influenza A virus has been previously investigated as a potential target for an universal influenza vaccine. In this study we prepared four lipopeptide influenza vaccine candidates in which the TLR2 agonist S-[2,3-bis(palmitoyloxy)propyl] cysteine, (Pam2Cys) was attached to either the N- or C-terminus of the M2e consensus sequence SLLTEVETPIRNEWGCRCNDSSDP and its analogue sequence with the two cysteine residues replaced with serine residues. The results of animal study show that each of these lipopeptides induced strong M2e-specific antibody responses in the absence of extraneous T helper cell epitope(s) which are normally incorporated in the previous studies or addition of extraneous adjuvant and that these antibodies are protective against lethal challenge with influenza virus. Comparison of different routes of inoculation demonstrated that intranasal administration of M2e lipopeptide induced higher titers of IgA and IgG2b antibodies in the bronchoalveolar lavage than did subcutaneous vaccination and was better at mitigating the severity of viral challenge. Finally, we show that anti-M2e antibody specificities absent from the antibody repertoire elicited by a commercially available influenza vaccine and by virus infection can be introduced by immunization with M2e-lipopeptide and boosted by viral challenge. Immunization with this lipidated form of the M2e epitope therefore offers a means of using a widely conserved epitope to generate protective antibodies which are not otherwise induced.     

Preparation and testing of a Vi conjugate vaccine using pneumococcal surface protein A (PspA) from Streptococcus pneumoniae as the carrier protein

In the current study pneumococcal surface protein A (PspA) was conjugated to Vi capsular polysaccharide from Salmonella Typhi to make available a vaccine against typhoid fever that has the potential to also provide broad protection from Streptococcus pneumoniae. High yielding production processes were developed for the purification of PspAs from families 1 and 2. The purified PspAs were conjugated to Vi with high recovery of both Vi and PspA. The processes developed especially for PspA family 2 could readily be adapted for large scale production under cGMP conditions. Previously we have shown that conjugation of diphtheria toxoid (DT) to Vi polysaccharide improves the immune response to Vi but can also enhance the response to DT. In this study it was shown that conjugation of PspA to Vi enhanced the anti-PspA response and that PspA was a suitable carrier protein as demonstrated by the characteristics of a T-cell dependent response to the Vi. We propose that a bivalent vaccine consisting of PspA from families 1 and 2 bound to Vi polysaccharide would protect against typhoid fever and has the potential to also protect against pneumococcal disease and should be considered for use in developing countries.     

Induction of protection against divergent H5N1 influenza viruses using a recombinant fusion protein linking influenza M2e to Onchocerca volvulus activation associated protein-1 (ASP-1) adjuvant

Our previous studies have shown the adjuvanticity of an Onchocerca volvulus recombinant protein, Ov-ASP-1 (ASP-1), when administered in an aqueous formulation with bystander vaccine antigens or commercial vaccines. In this study, we reported a novel formulation that took advantage of the protein nature of the ASP-1 adjuvant by creating recombinant fusion protein vaccines linking the highly conserved extracellular domain of M2 protein (M2e) consensus sequence of H5N1 influenza viruses with the ASP-1 adjuvant. Two recombinant fusion proteins designated M2e-ASP-1 and M2e3-ASP-1 were studied, in which ASP-1 was fused with one or three tandem copies of the M2e antigen. Our results show that these novel recombinant influenza vaccines, particularly M2e3-ASP-1, induced strong anti-M2e-specific humoral and cellular immune responses in the established mouse model. Furthermore, M2e3-ASP-1 was able to provide significant cross-clade protection against divergent H5N1 viruses. Consequently, this study has demonstrated a potential novel vaccine formulation that could provide a complementary prophylactic strategy in preventing the threat of future influenza outbreak resulting from rapid evolution of the H5N1 virus and co-circulation of multiple antigenic variants in various regions.