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  • Periodic Report Summary 1 - NEOSTREP (Development of Group B Streptococcal vaccine to alleviate emerging antibiotic resistance through elimination of current prophylactic antibiotic strategies in GBS prevention.)
FP7

NeoStrep Report Summary

Project ID: 601743
Funded under: FP7-HEALTH
Country: Sweden

Periodic Report Summary 1 - NEOSTREP (Development of Group B Streptococcal vaccine to alleviate emerging antibiotic resistance through elimination of current prophylactic antibiotic strategies in GBS prevention.)

Project Context and Objectives:
The NeoStrep project aims to develop a novel vaccine against Group B Streptococcus (GBS), the leading cause of life-threatening infections in newborns, in order to provide a safe and effective alternative to current generally implemented antibiotic prophylaxis.
GBS are responsible for 50% of life-threatening infections in newborns leading to severe morbidity, mortality or life-long disabilities. Infections occur either 1-6 days (Early Onset Disease, EOD) or 7-89 days (Late Onset Disease, LOD) after birth, causing pneumonia, sepsis and meningitis. Furthermore, GBS is responsible for over 80% of meningitis cases in neonates less than 2 months of age. Current means of intervention involve widespread administration of prophylactic antibiotics to the 20-50% of pregnant women at risk of transmitting GBS to infants during childbirth.
The implementation of prophylactic measures against GBS has reduced the incidence of EOD by 75-80% to current levels, but EOD still affects some 4,500 newborns annually in Europe and the US, and the incidences have recently been on the rise. The frequency of the serious LOD infections has remained unaffected, at 3,000 cases annually, as has the incidences of GBS induced stillbirths (900) and premature deliveries (7,000). Despite current means of intervention, improved intervention against GBS therefore remains an area of high medical need and The National Institute of Health of the US has identified prevention of GBS in newborns as a major vaccine objective. So far no approved or universally useful vaccine exists.
While antibiotic prophylaxis has been successful in partially controlling GBS infections in newborns it is being threatened by emerging antibiotic resistance. This is shown by the emergence of isolates with reduced sensitivity to penicillin (the preferred antibiotic), patterns of resistance mutations in GBS identical to those observed in Streptococcus pneumoniae prior to the breakthrough of wide spread resistance to penicillin, wide-spread resistance to other antibiotics than penicillin, and not least a recent increase in disease incidence following a long period of low incidence controlled by antibiotic prophylaxis.
Emergence of antibiotic resistance in GBS threatens to return the incidence of GBS disease to pre-prophylaxis levels resulting in significant increases in healthcare cost and morbidity/mortality as well as introducing problems in treating infections with antibiotic resistant GBS.
NeoStrep’s goal is to build on extensive positive results obtained in animal models for a novel innovative GBS vaccine candidate, with much improved immunogenicity, coverage of clinical isolates (95% compared to only 60-70% for other candidates) and ease of manufacturing over state-of-the-art GBS vaccine candidates. NeoStrep will advance the vaccine candidate through cGMP manufacturing and proof-of-concept testing in human clinical trials.

The core objectives of NeoStrep are to:

• Develop a safe and effective alternative to GBS antibiotic prophylaxis in pregnant/birthing women, and hence prevent the risk associated with antibiotic resistance.
• Define optimal dosing schedule, dose and adjuvant usage in preclinical animal models.
• Manufacture a cGMP vaccine batch, based on an already developed manufacturing process.
• Conduct pre-clinical toxicity/safety studies supporting Phase I and II proof of concept clinical trials.
• Conduct combined Phase I and Phase IIa clinical trials to establish vaccine safety, optimal dose and efficacy/immunogenecity
• Conduct a correlation study of anti-GBS-NN antibody levels in pregnant women and protection of newborns against GBS transmission, in order to establish surrogate markers of clinical efficacy in support of further clinical development and regulatory approval.
• Conduct scientific studies to address the mechanism of action of antibody protection, identification of cellular receptors and explore the potential benefits of mucosal immunity for a GBS vaccine.
Project Results:
In the initial project period, the consortium members developed plans for the implementation of the research within the project, finalising protocols and dosing assays, planning toxicology studies and the strategy relating to regulatory acceptance of the proposed programme.

NeoStrep undertook the manufacture and release of a research batch of the NN-GBS product to enable the dose finding/regime study to take place. Work commenced on the MoA studies including the Nature of Antibody protection, identification of cellular receptors and vaginal colonisation models. Immunization experiment started with cohorts of mice being immunized with NN-GBS protein ± alum as adjuvant for assessment of long-term memory. For comparative purposes, and to clarify the intrinsic immunogenic properties of NN-GBS protein, control groups of mice were immunized with other proteins, including ovalbumin and tetanus toxoid, ± alum. To elucidate the specific effect of alum in conjugation with NN-GBS protein, other cohorts of mice were immunized with NN-GBS protein together with distinct adjuvants, including the synthetic double stranded RNA analogue poly I:C. For all immunization regimes, both the primary cellular immune response and the long-term serum antibody titres are characterized with particular focus on IgG subclasses (as individual IgG subclasses differ in their ability to mediate opsonization and to cross the placenta).

The tech transfer required for the project was completed, including transfer of RCB and interim reference material. The project manufactured 30 RCB vials to be used for upstream and manufacture of the MCB. MCP manufacture and testing, upstream optimization, downstream development, formulation development and analytical development were all completed.
Efforts were made towards finding the optimal adjuvant selection, defining the route of administration and the dosing regimen of the NeoStrep vaccine, setting up the analytical methods, developing the manufacturing and toxicology plans to be submitted to a national health authority (the Swedish MPA) and drafting the clinical trials protocol.

Work was done to determine the optimal GBS-NN dose range for immunization of CD-1 outbreed mice. The results showed that the adjuvant alum is at least as efficient as a TLR agonist in augmenting the vaccination effect of GBS-NN. To study the longevity of the serum IgG titres induced after GBS-NN plus alum immunization.

The establishment of the process for manufacturing of the vaccine for clinical trials progressed as planned. The preliminary manufacturing process was transferred to the GMP manufacturer, and cell banking, process optimization and qualification of analytical methods took place. The analytical methods SDS-PAGE, SE-HPLC, OD-280 were tested applicable and the Master Cell Bank was successfully prepared and tested. Three (3) fermentations run in 20L scale were successfully completed and showed good expression yield according to SDS-PAGE. Furthermore, the process was upscaled to 200L scale and a non-GMP tax batch was manufactured and released. GMP manufacturing at the same scale is now being completed.

A 580 pages pre-clinical package on the toxicology and safety plan for the development of the NeoStrep vaccine was prepared and submitted for discussion with the Swedish Medical Products Association (MPA). Following a meeting in Stockholm, the Swedish MPA endorsed the toxicology and manufacturing plans and advised on the proposed questions.

BKE prepared the final version of the clinical study synopsis, which combined both phases 1 and 2 of the trial. A pharmacy procedure for assembly of GBS-NN and placebo doses was drafted with input from Minervax.

The website established for the project – www.neostrep.eu – was made available for communication and public dissemination activities. Further dissemination activities were undertaken by Minervax CEO Per Fischer through the participation in global vaccine events.


Potential Impact:
Health Impacts
A GBS vaccine will eliminate this threat from antibiotic resistance in GBS, greatly reducing the use of prophylactic antibiotics in birthing women and independently prevent infections with both antibiotic sensitive and resistant GBS strains. The elimination of antibiotic prophylaxis will greatly reduce the selective pressure on GBS strains for development of further antibiotic resistance, hence aiding the treatment of breakthrough infections. This is supported by results obtained by introduction of a pneumococcal vaccine for infants in the USA in 2000. The introduction of this vaccine resulted in a 57% decline in invasive disease caused by penicillin-resistant strains and a 59% decline in strains resistant to multiple antibiotics by 2004 across a broad spectrum: 81% among children under 2 years of age and 49% among persons aged 65 years and older.

Economic Impacts
In a scenario where full antibiotic resistance does occur, totally eliminating current preventive strategies, it is estimated that a doubling of the annual cost associated with GBS disease in the EU alone would occur. Under this scenario, a fully effective GBS vaccine would have the potential to prevent as many as 10-15,000 cases of EOD and 1,800 cases of LOD annually in the EU at a cost of some 60,000 EUR each, 550 long term disabilities at a cost of some 600,000 EUR each, and 4,000 very preterm deliveries at a cost of some 70,000 EUR each. Altogether, a vaccine has the potential of saving up to some 1.6 bEUR in healthcare cost at the cost of vaccinating some 2,500,000 first time pregnant women annually at an estimated cost of 165 EUR each, equivalent to 415 mEUR, resulting in a total cost saving of some 1.2 bEUR.

Employment and EU competitiveness
Reducing the prevalence of infections that have developed or are at the risk of developing significant anti-microbial resistance will facilitate a better allocation of resources within the health system. Reducing global child mortality by encouraging universal access to safe vaccines is a moral obligation for the international community and a cornerstone of good public health, helping to reduce inequalities and poverty.

Social Impacts
NeoStrep will, through developing a vaccination against GBS, help reduce the negative social impacts experienced by GBS sufferers and their families. More effective treatment of GBS, as this project proposes, can therefore have often far reaching societal benefits.

3.1.3. Policy Impacts
The importance of addressing nosocomial infections and antimicrobial resistance in the EU has been promoted in Annex 1 of Commission Decision 2000/96/EC of 22 December 1999 amended in 2009/312/EC on the communicable diseases. Other policy impacts include: EU Policy: Towards Health Work Programme 2013 which aims to improve the health of European citizens. COM (2011) 748 “Communication from the Commission to the European Parliament and the Council regarding an action plan against the rising threats from Antimicrobial Resistance.” Innovative Medicines Initiative (IMI) – in May 2012, IMI announced an initiative dubbed “NewDrugs4BadBugs (ND4BB)” to combat antibiotic resistance. TATFAR – Transatlantic task force on urgent antimicrobial resistance (2009) which aims to increase the mutual understanding of EU and US activities relevant to antimicrobial resistance issues.

List of Websites:
www.neostrep.eu

Contact

Stina Ahlenius, (Administrative Director)
Tel.: +46 46173465
Fax: +46 46130064
E-mail

Subjects

Life Sciences
Record Number: 163974 / Last updated on: 2015-06-01
Information source: SESAM
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