MinervaX is developing a novel vaccine candidate against Group B Streptococci (GBS).
Most clinically important strains of GBS express either Rib or alpha (α), two related surface proteins (1). It has been demonstrated in a mouse model, that Rib and α elicit protective immunity to lethal infection with GBS strains expressing the corresponding protein (2-4). This was demonstrated in both passive and active vaccination studies. Importantly, Rib is expressed by most serotype III strains, and by all strains of the hyper-virulent clone ST-17. The α protein is expressed by many strains of types Ia, Ib and II (1). In active immunization studies, Rib and α elicit protective immunity when administered in alum, an adjuvant accepted for use in humans, indicating that Rib and α are of interest for the development of a vaccine against GBS (3).
IgG antibodies to Rib and α have been found in serum from both neonates and their mothers (5). A correlation was demonstrated between the antibody levels in neonatal and maternal sera, implying that maternal antibodies to Rib and α are transferred to the fetus during pregnancy. Moreover, low levels of antibodies to Rib and α in neonatal sera appears to be a risk factor for invasive GBS infection, implying that a vaccine based on Rib and α may confer protection against neonatal GBS disease (5).
Using a mouse model, it has been shown that antibodies elicited by the intact Rib and α proteins are directed almost exclusively against repeat regions at the C-terminal region, while almost no antibodies are directed against the non-repeated N-terminal regions (6). Thus, the repeat regions of Rib and α are immunodominant. However, it was hypothesized that the immunodominance of the repeats might reflect an immune evasion mechanism allowing the bacteria to avoid an antibody response directed against the N-terminal region of Rib and α, as these regions may have a particularly important function. This hypothesis prompted a study of the N-terminal regions as vaccine candidates. A recombinant fusion protein, designated RibN-αN or “NN”, derived from the non-immunodominant N-terminal regions of Rib and α was therefore constructed. In active immunization experiments using GBS-NN administered with alum, mice were significantly protected against lethal infection with multiple GBS serotypes (6). Moreover, antibodies to NN were more efficient in conferring protection than antibodies to the repeats, supporting our hypothesis that the N-terminal regions of Rib and α are of particular interest for vaccine development.
In active immunizations with NN, this protein was equally immunogenic for mice when administered with CFA, alum or PBS, indicating that NN may have intrinsic self-adjuvanting properties (6). Thus, it is possible that NN would elicit protective immunity even if administered without adjuvant.
1. Lindahl, G., M. Stålhammar-Carlemalm, and T. Areschoug. 2005. Surface proteins of Streptococcus agalactiae and related proteins in other bacterial pathogens. Clin Microbiol Rev 18:102-127.
2. Larsson, C., M. Stålhammar-Carlemalm, and G. Lindahl. 1996. Experimental vaccination against group B streptococcus, an encapsulated bacterium, with highly purified preparations of cell surface proteins Rib and alpha. Infect Immun 64:3518-3523.
3. Larsson, C., M. Stålhammar-Carlemalm, and G. Lindahl. 1999. Protection against experimental infection with group B streptococcus by immunization with a bivalent protein vaccine. Vaccine 17:454-458.
4. Stålhammar-Carlemalm, M., L. Stenberg, and G. Lindahl. 1993. Protein Rib: a novel group B streptococcal cell surface protein that confers protective immunity and is expressed by most strains causing invasive infections. J Exp Med 177:1593-1603.
5. Larsson, C., M. Lindroth, P. Nordin, M. Stålhammar-Carlemalm, G. Lindahl, and I. Krantz. 2006. Association between low concentrations of antibodies to protein alpha and Rib and invasive neonatal group B streptococcal infection. Arch Dis Child Fetal Neonatal Ed 91:F403-408.
6. Stålhammar-Carlemalm, M., J. Waldemarsson, E. Johnsson, T. Areschoug, and G. Lindahl. 2007. Nonimmunodominant regions are effective as building blocks in a streptococcal fusion protein vaccine. Cell Host Microbe 2:427-434.