Group B Streptococcal Vaccine for prevention of life-threatening infections in newborns.
MinervaX is engaged in clinical development of a Group B Streptococcal vaccine targeting pregnant women for the prevention of life-threatening infections in newborns. So far the vaccine has been dosed to 240 healthy adult women. The vaccine has proven safe, highly immunogenic and giving rise to functionally active antibodies.
Prevention of Group B Streptococcal infections in newborns represents a large unmet medical need.
GBS is responsible for 50% of life-threatening infections in newborns and affects 0.5-3 in 1,000 such babies, depending on the geographical region. At any given time, some 15-25% of women are spontaneously colonized with GBS, and they run the risk of transmitting the bacteria both to their child in the womb, during birth and during the first months of life. GBS infection in the unborn child may lead to premature delivery or stillbirth, and GBS infection in the newborn child may result in sepsis, pneumonia or meningitis, all of which carry a significant risk of severe morbidity, long-term disability or death. Annually, GBS is responsible for some 6,500 infections in newborns, 500 deaths and 800 life-long disabilities in Europe and US.
Current GBS intervention, involving antibiotic prophylaxis during childbirth (known as intra-partum antibiotic prophylaxis or IAP) in women colonized with GBS or otherwise at risk of transmitting the bacteria to the newborn, has reduced the incidence of Early Onset Disease (EOD) occurring within the first 6 days of life by some 80% since its introduction in year 2000. However,
- IAP has failed to fully eradicate EOD for a number of practical reasons, and is not universally implemented in all countries;
- IAP has no impact on GBS-induced premature delivery and stillbirth caused by infection of the unborn child;
- IAP has no impact on Late Onset Disease occurring from 7 days to 3 months of age, where the burden of meningitis is highest. 50% of babies who recover from GBS meningitis have long-term sequelae, including brain damage, cerebral palsy, severe learning difficulties, hearing loss, and/or blindness;
- IAP is currently only available in high-income countries and is unlikely to be implemented in low-income countries;
- the efficacy of IAP is currently under threat from emerging antibiotic resistance in GBS, including the most commonly used antibiotics such as penicillin;
- the wide spread use of broad-spectrum prophylactic antibiotic in birthing women has lead to an increase in antibiotic resistance amongst other bacteria also infecting newborns, particularly in preterm babies;
- and finally, wide-spread antibiotic prophylaxis in birthing women may negatively impact the developing intestinal microbiota of the newborn increasing the risk of eczema, asthma, ADHD, and learning disabilities.
The development of an efficacious GBS vaccine for maternal immunization capable of reducing this wide-spread use of antibiotic prophylaxis in birthing women and preventing more GBS infections both of early and late onset therefore addresses two significant medical needs.
MinervaX is developing a novel innovative vaccine candidate against Group B Streptococcus.
MinervaX is developing a novel innovative single component, protein-only vaccine based on a fusion of highly immunogenic and protective protein domains from two surface proteins of GBS (N-terminals of AlphaC and Rib, GBS-NN) (1). MinervaX believes its vaccine is likely to have superior characteristics compared with other GBS vaccine candidates in development, which are based on traditional capsular polysaccharide (CPS) conjugate technology. Given the broad distribution of proteins from which the vaccine originates (serotypes Ia, Ib, II, III, IV, V and VIII) as well as cross-reactive proteins (serotypes VI and VII), it is expected that MinervaX’s single component vaccine will protect against up to 95% of GBS isolates. More importantly, the Rib protein is expressed on all isolates of the hyper-virulent clone ST-17.
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. 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 were 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 “GBS-NN”, derived from the non-immunodominant N-terminal regions of Rib and α was therefore constructed. In active immunization experiments using GBS-NN, 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.
The GBS-NN vaccine candidate has since been demonstrated to elicit a very high and long-lasting immune response in animal models, confer protection against lethal challenges with GBS both in adult and neonatal challenge models. Antibodies directed against GBS-NN also has opsonic activity and prevents invasion of epithelial cell. Finally, naturally occurring antibodies against GBS-NN do exist in pregnant women, and correlation studies are currently under way to assess their ability to prevent GBS infections in vivo.
The GBS-NN vaccine candidate is easily manufactured in E.coli. in large quantities and non-clinical safety studies have given rise to no adverse findings. The vaccine has now been tested in 240 healthy adult women in Phase I trials, and demonstrated a very favourable safety profile. The vaccine has proven to be very immunogenic, inducing high levels of antibodies already 14 days after first dose. Moreover the antibodies are functionally active and cause opsono-phagocytic killing of GBS as well as inhibit invasion of epithelial cells by GBS, which is likely a key step in GBS host invasion and pathogenesis.
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.
 Ten different serotypes have been identified to date, Serotypes Ia, Ib and II-IX. Serotypes Ia, Ib, II, III and V are responsible for the vast majority of GBS infections in newborns.