Final Report Summary - NEOSTREP (Development of Group B Streptococcal vaccine to alleviate emerging antibiotic resistance through elimination of current prophylactic antibiotic strategies in GBS prevention.)
Executive Summary:
Prevention of neonatal infections with Group B Streptococcus represents a large unmet medical need. A maternal GBS vaccine administered to pregnant women will likely address this unmet medical need. The NeoStrep project set out to advance the GBS-NN vaccine candidate from proof-of-concept in animal models to clinical development.
The project successfully resulted in the manufacture of GMP grade GBS-NN and completion of toxicology studies ahead of taking the vaccine into two clinical trials, a dose-escalation trial and a dose-confirmation trial. The vaccine was proven very safe and highly immunogenic. The immune responses obtained were found to be functional in preventing GBS infections through multiple mechanisms of action through both preventing host invasion and killing of systemic GBS infections. The vaccine was also found to effective against both laboratory and clinical isolates of GBS. Studies on naturally occurring vaccine specific antibodies also confirmed that they are likely to be actively transported across the placenta and accumulated in the baby, as wll as protect against invasive GBS disease.
The project has been widely disseminated and an exploitation plan is now being implemented.
Project Context and Objectives:
Group B Streptococcus is responsible for 50% of life-threatening infections in newborns leading to severe morbidity, mortality or life-long disabilities during the early months of life, causing pneumonia, sepsis and meningitis. Current means of intervention involve widespread administration of prophylactic antibiotics during child birth to 30% of pregnant women at risk of transmitting GBS to infants during childbirth (Intrapartum Antibiotic Prophylaxis, IAP). IAP has successfully reduced the incidence of infections occurring within the first week of life (Early Onset Infections, EOD), but has had no impact of infections occurring in utero (causing premature delivery and stillbirth) or infections occurring after the first week of life and until 3 months of age (Late Onset Infections, LOD). Furthermore, IAP has resulted in the emergence of antibiotic resistant bacteria, and negatively impacts the development of the microbiome of the newborn child. A large unmet medical need therefore exists in the prevention of GBS infections.
Development of a maternal GBS vaccine, administered during pregnancy, will result in the induction of protective antibodies in the mother, which will be transferred across the placenta to the unborn child. A vaccine will therefore protect the baby against both in utero infections, prevent premature delivery and stillbirth, and infections occurring after birth, preventing both EOD and LOD. In addition, it will ultimately make the use of IAP obsolete and hence prevent its negative impacts on antibiotic resistance and microbiome of the newborn child.
NeoStrep aimed to advance the GBS-NN vaccine candidate from late stage research into clinical development. The GBS-NN vaccine candidate is a fusion protein made up of the two N-terminal domains of the Rib and AlphaC surface proteins of the GBS.
The main objectives of the project were to:
1) manufacture a GMP batch of GBS-NN for use in clinical trials,
2) conduct appropriate toxicology studies supporting the initiation of clinical trials,
3) conduct a set of Phase I safety and dose-finding trials,
4) investigate the mechanism of action of the vaccine,
5) disseminate the results and develop a commercialization plan.
Project Results:
The manufacturing part of the project successfully resulted in the transfer of a small-scale manufacturing process to a GMP contract manufacturer. The small-scale process was up-scaled to 200 L scale, and appropriate analytical methods were developed and qualified. An engineering batch was manufactured at full scale and used for toxicology studies. The GMP batch was manufactured and released for clinical use. Finally, a stability study program initiated. The outcome of this part of the project was very successful, with high yields of very pure product being obtained. Furthermore, all the drug product components have so far proved stable for 24 months’ post manufacture, with no signs of deterioration.
The toxicology program was successfully completed in rats, rabbits and minipigs. No unusual adverse findings were observed, and the studies supported moving forward into clinical trials.
Preclinical animal studies conducted in parallel investigated various dose-regiments and the optimal adjuvant for the vaccine. These studies provided guidance on the dose-regimens and alhydrogel adjuvant to be tested in the clinical trials.
The clinical trial program involved a Phase I Part A, dose-escalation trial, involving 60 healthy adult female volunteers, and a Phase I Part B, dose-confirmation trial, involving 180 volunteers. Part A tested escalating doses of GBS-NN in the presence or absence of alhydrogel adjuvant with the primary endpoint being after 3 months. The results showed that the vaccine was very safe, and demonstrated dose-response for the tested vaccine doses with a plateau reached at the highest doses. The aim of Part B was to confirm the proposed vaccine dose and regimen derived from Part A, by testing three different regimens in larger cohorts. The primary endpoint of Part B was likewise after 3 months, which corresponds to the time of pregnancy if the vaccine were administered at the beginning of the 3rd trimester. The results of the clinical trial were very encouraging, documenting the safety of the vaccine. The vaccine was also shown to be very immunogenic with high immune responses obtained already 2 weeks after the first administration.
Analysis of the characteristics and functionality of the immune response in vaccinated subjects allowed for investigations of the putative mechanism of action of the vaccine as well as its breadth of coverage of clinical isolates. The analysis documented that the vaccine induced almost exclusively IgG1 and IgA antibodies. IgG1 is a very desirable isotype as it is actively transferred across the placenta, has a long serum half-life and is functionally active. IgA is important as it will be transferred to mucosal surfaces and secreted into the milk of the mother. The antisera were also found to bind to the surface of GBS bacteria and kill them via opsono-phagocytosis. Finally, the antisera were found to be capable of completely inhibiting the invasion of epithelial cells by GBS. In summary, vaccine antibodies likely work in two ways: the block the invasion of epithelial cells by GBS and hence prevent systemic infections, and in case systemic infections do occur, the antibodies are capable of killing the bacteria. When testing the breadth of coverage of the vaccine, vaccine antisera were found to bind also to clinical isolates of GBS derived from cases of invasive neonatal disease.
In addition to clinical testing of the GBS-NN vaccine candidate, naturally antibodies against the GBS-NN occurring in both healthy pregnant women and their off-spring as well as cases of neonatal invasive GBS disease were also studied. Naturally occurring antibodies originating from commensal colonization of subjects with GBS. Studies of the naturally occurring antibodies reveal that these consist of IgG1 and IgA antibodies just like the vaccine induced antibodies. Importantly, the IgG1 vaccine specific antibodies were actively transferred across the placenta resulting in 25% higher levels in the newborn babies than in the mothers. Analysis of sera from cases of invasive neonatal GBS infections and matched controls also demonstrated correlation between high levels of vaccine specific antibodies and protection against invasive disease, hence providing good evidence of the protective ability of vaccine induced antibodies.
Potential Impact:
The NeoStrep project has demonstrated the safety and likely competitive advantage of the GBS-NN vaccine over competing GBS vaccine candidates based on capsular polysaccharides.
Two options for exploitation of the results exists:
1) advance the project further into clinical trials,
2) partner the project with a larger pharmaceutical company.
The results have been widely disseminated as conferences and to potential pharmaceutical partners. A large commercial assessment of the project was undertaken in preparation of exploitation activities. An exploitation plan involving fundraising and partnering activities in parallel have been prepared and is actively pursued.
List of Websites:
www.neostrep.eu
Project Coordinator:
Prof. Bengt Johansen Lindbom
Lund University
bengt.johansson_lindbom@med.lu.se
Project Owner:
MinervaX
Ole Maaløes Vej 3
2200 Copenhagen N
Denmark
Att. Per Fischer, CEO
pbf@minervax.com
Prevention of neonatal infections with Group B Streptococcus represents a large unmet medical need. A maternal GBS vaccine administered to pregnant women will likely address this unmet medical need. The NeoStrep project set out to advance the GBS-NN vaccine candidate from proof-of-concept in animal models to clinical development.
The project successfully resulted in the manufacture of GMP grade GBS-NN and completion of toxicology studies ahead of taking the vaccine into two clinical trials, a dose-escalation trial and a dose-confirmation trial. The vaccine was proven very safe and highly immunogenic. The immune responses obtained were found to be functional in preventing GBS infections through multiple mechanisms of action through both preventing host invasion and killing of systemic GBS infections. The vaccine was also found to effective against both laboratory and clinical isolates of GBS. Studies on naturally occurring vaccine specific antibodies also confirmed that they are likely to be actively transported across the placenta and accumulated in the baby, as wll as protect against invasive GBS disease.
The project has been widely disseminated and an exploitation plan is now being implemented.
Project Context and Objectives:
Group B Streptococcus is responsible for 50% of life-threatening infections in newborns leading to severe morbidity, mortality or life-long disabilities during the early months of life, causing pneumonia, sepsis and meningitis. Current means of intervention involve widespread administration of prophylactic antibiotics during child birth to 30% of pregnant women at risk of transmitting GBS to infants during childbirth (Intrapartum Antibiotic Prophylaxis, IAP). IAP has successfully reduced the incidence of infections occurring within the first week of life (Early Onset Infections, EOD), but has had no impact of infections occurring in utero (causing premature delivery and stillbirth) or infections occurring after the first week of life and until 3 months of age (Late Onset Infections, LOD). Furthermore, IAP has resulted in the emergence of antibiotic resistant bacteria, and negatively impacts the development of the microbiome of the newborn child. A large unmet medical need therefore exists in the prevention of GBS infections.
Development of a maternal GBS vaccine, administered during pregnancy, will result in the induction of protective antibodies in the mother, which will be transferred across the placenta to the unborn child. A vaccine will therefore protect the baby against both in utero infections, prevent premature delivery and stillbirth, and infections occurring after birth, preventing both EOD and LOD. In addition, it will ultimately make the use of IAP obsolete and hence prevent its negative impacts on antibiotic resistance and microbiome of the newborn child.
NeoStrep aimed to advance the GBS-NN vaccine candidate from late stage research into clinical development. The GBS-NN vaccine candidate is a fusion protein made up of the two N-terminal domains of the Rib and AlphaC surface proteins of the GBS.
The main objectives of the project were to:
1) manufacture a GMP batch of GBS-NN for use in clinical trials,
2) conduct appropriate toxicology studies supporting the initiation of clinical trials,
3) conduct a set of Phase I safety and dose-finding trials,
4) investigate the mechanism of action of the vaccine,
5) disseminate the results and develop a commercialization plan.
Project Results:
The manufacturing part of the project successfully resulted in the transfer of a small-scale manufacturing process to a GMP contract manufacturer. The small-scale process was up-scaled to 200 L scale, and appropriate analytical methods were developed and qualified. An engineering batch was manufactured at full scale and used for toxicology studies. The GMP batch was manufactured and released for clinical use. Finally, a stability study program initiated. The outcome of this part of the project was very successful, with high yields of very pure product being obtained. Furthermore, all the drug product components have so far proved stable for 24 months’ post manufacture, with no signs of deterioration.
The toxicology program was successfully completed in rats, rabbits and minipigs. No unusual adverse findings were observed, and the studies supported moving forward into clinical trials.
Preclinical animal studies conducted in parallel investigated various dose-regiments and the optimal adjuvant for the vaccine. These studies provided guidance on the dose-regimens and alhydrogel adjuvant to be tested in the clinical trials.
The clinical trial program involved a Phase I Part A, dose-escalation trial, involving 60 healthy adult female volunteers, and a Phase I Part B, dose-confirmation trial, involving 180 volunteers. Part A tested escalating doses of GBS-NN in the presence or absence of alhydrogel adjuvant with the primary endpoint being after 3 months. The results showed that the vaccine was very safe, and demonstrated dose-response for the tested vaccine doses with a plateau reached at the highest doses. The aim of Part B was to confirm the proposed vaccine dose and regimen derived from Part A, by testing three different regimens in larger cohorts. The primary endpoint of Part B was likewise after 3 months, which corresponds to the time of pregnancy if the vaccine were administered at the beginning of the 3rd trimester. The results of the clinical trial were very encouraging, documenting the safety of the vaccine. The vaccine was also shown to be very immunogenic with high immune responses obtained already 2 weeks after the first administration.
Analysis of the characteristics and functionality of the immune response in vaccinated subjects allowed for investigations of the putative mechanism of action of the vaccine as well as its breadth of coverage of clinical isolates. The analysis documented that the vaccine induced almost exclusively IgG1 and IgA antibodies. IgG1 is a very desirable isotype as it is actively transferred across the placenta, has a long serum half-life and is functionally active. IgA is important as it will be transferred to mucosal surfaces and secreted into the milk of the mother. The antisera were also found to bind to the surface of GBS bacteria and kill them via opsono-phagocytosis. Finally, the antisera were found to be capable of completely inhibiting the invasion of epithelial cells by GBS. In summary, vaccine antibodies likely work in two ways: the block the invasion of epithelial cells by GBS and hence prevent systemic infections, and in case systemic infections do occur, the antibodies are capable of killing the bacteria. When testing the breadth of coverage of the vaccine, vaccine antisera were found to bind also to clinical isolates of GBS derived from cases of invasive neonatal disease.
In addition to clinical testing of the GBS-NN vaccine candidate, naturally antibodies against the GBS-NN occurring in both healthy pregnant women and their off-spring as well as cases of neonatal invasive GBS disease were also studied. Naturally occurring antibodies originating from commensal colonization of subjects with GBS. Studies of the naturally occurring antibodies reveal that these consist of IgG1 and IgA antibodies just like the vaccine induced antibodies. Importantly, the IgG1 vaccine specific antibodies were actively transferred across the placenta resulting in 25% higher levels in the newborn babies than in the mothers. Analysis of sera from cases of invasive neonatal GBS infections and matched controls also demonstrated correlation between high levels of vaccine specific antibodies and protection against invasive disease, hence providing good evidence of the protective ability of vaccine induced antibodies.
Potential Impact:
The NeoStrep project has demonstrated the safety and likely competitive advantage of the GBS-NN vaccine over competing GBS vaccine candidates based on capsular polysaccharides.
Two options for exploitation of the results exists:
1) advance the project further into clinical trials,
2) partner the project with a larger pharmaceutical company.
The results have been widely disseminated as conferences and to potential pharmaceutical partners. A large commercial assessment of the project was undertaken in preparation of exploitation activities. An exploitation plan involving fundraising and partnering activities in parallel have been prepared and is actively pursued.
List of Websites:
www.neostrep.eu
Project Coordinator:
Prof. Bengt Johansen Lindbom
Lund University
bengt.johansson_lindbom@med.lu.se
Project Owner:
MinervaX
Ole Maaløes Vej 3
2200 Copenhagen N
Denmark
Att. Per Fischer, CEO
pbf@minervax.com
