- Email: [email protected]
Translation of an experimental oral vaccine formulation into a commercial product
Methods 38 (2006) 65–68 www.elsevier.com/locate/ymeth
Translation of an experimental oral vaccine formulation into a commercial product K.C. Carter a, V.A. Ferro a,¤, J. Alexander a, A.B. Mullen b a
b
Department of Immunology, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK Department of Pharmaceutical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK Accepted 10 November 2005
Abstract An eVective experimental vaccine may fail to become a therapeutic reality for a number of scientiWc, regulatory or commercial reasons. In this review, we share some of our personal experiences as University-based researchers and provide an account of some of the problems that we have encountered during preliminary scale-up and assessment of an oral inXuenza vaccine formulation. Many of the problems we have faced have been non-scientiWc and related to identifying project-funding sources, Wnding suitable contract manufacturing companies that are GMP compliant, and protecting intellectual property generated from the scientiWc studies. The review is intended as a practical guide that will allow other researchers to adopt eVective strategies to permit the translation of an eVective experimental formulation to a viable commercial product. 2005 Elsevier Inc. All rights reserved. Keywords: Vaccines; Commercial; Quality control; Antibodies; Manufacturing process
1. Introduction Over the last 3 years we have been involved in the commercialisation of a ‘platform technology’ for oral vaccination, undertaken as part of a Scottish Enterprise ‘Proof-of-Concept’ project. Our delivery system uses non-ionic surfactant vesicles containing bile salts, known as ‘bilosomes,’ to deliver protein antigens administered by the oral route [1,2]. We have shown that this system is eVective at inducing speciWc IgG1, IgG2a, and IgA antibodies, with a range of antigens. Detailed below are some of the factors that have become apparent in developing an experimental vaccine formulation and how they can inXuence the progression to commercialisation. 2. What initial factors should be considered? Classically vaccines have been developed speciWcally to treat a single disease. However, a more attractive proposi*
Corresponding author. Fax: +44 141 548 4645. E-mail address: [email protected] (V.A. Ferro).
1046-2023/$ - see front matter 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ymeth.2005.11.001
tion is the development of a generic ‘platform technology’ which permits the incorporation and delivery of a range of antigens thereby, increasing the market potential of the technology. In addition, the clinical presentation of the vaccine and its dosing frequency is important since this may impact on patient compliance or provide a competitive advantage over pre-existing vaccines in the same therapeutic area. Marketing data to conWrm that there is a net gain to healthcare infrastructure, and a need for the product being developed, is therefore critical, since this will conWrm commercial potential [3]. This may be diYcult if the proposed vaccine is for the prevention of a disease prevalent in a developing country. Unless charitable agencies are willing to fund the project, the product will never be commercially viable. However, a recent study showed that vaccination can have a huge economic impact on a developing country, resulting in a 12% return in costs associated with a vaccination programme by year 1 and 18% in year 2 [4], which may make these type of vaccines more attractive to commercial sponsors. In our case we decided to develop a ‘platform technology’ incorporating antigens already employed in
66
K.C. Carter et al. / Methods 38 (2006) 65–68
existing vaccines (inXuenza haemagglutinin A, tetanus and diphtheria toxoids, and measles peptide). These antigens were selected on the basis of attracting commercial interest in the technology developed and demonstrating its worth as an oral vaccine delivery platform. 2.1. Quality control of constituents One of the factors singled out by us, which adversely aVects commercial vaccine development is the quality of the reagents used [5], as there are strict guidelines on the purity and quality of constituents used in medicinal and veterinary products [6]. It is therefore very useful in identifying at a conceptual stage, whether potential constituents to be used in the experimental vaccine comply with regulatory requirements and if not, substituting with a suitable alternative. Today, a vaccine can only be developed for commercial use if it is safe, well characterised, as well as being eYcacious. It is therefore pointless using constituents that would be unacceptable to regulatory authorities, or at concentrations that are likely to be toxic [7,8]. Therefore, early toxicity studies are also recommended. During our developmental phase, we had trouble in securing the supply of a key excipient in our formulation with consistent physicochemical properties. Subsequent investigations highlighted that variability in the performance of the chemical arose from the purchasing strategy implemented by the manufacturer. The supplier purchased the chemical from third party organisations and re-labelled it as its own product. This was done solely based on which third party company provided the lowest tender for the chemical that met their minimum speciWcation on quality (chemical purity). This speciWcation was set too low for our requirements and resulted in appreciable variability in the appearance and performance of the chemical (and the vaccine) over a 2-year period. This took considerable time and resources to resolve and to identify an alternate supplier who could consistently provide us with the chemical in bulk quantity to a satisfactory physicochemical speciWcation to enable reproducible vaccine performance. Therefore, at the outset, we strongly advise that manufacturers should be identiWed for each constituent, with the facilities to supply large-scale GMP compliant batches of excipients and actives for production of the Wnal product. It is also important to develop analytical methods that allow quantitative and qualitative identiWcation of individual constituents, and their potential breakdown products in the vaccine formulation. This provides stability data on a formulation, and permits determination of likely shelf life and storage conditions for the endproduct [9]. 2.2. Quality control of manufacture The manufacturing process of the vaccine is also important since it is advantageous if it can be simply produced to keep the cost of each dosage unit competitive [10]. Developing a manufacturing method reliant on a process that is
unlikely to be GMP compliant, or permit scale up, will hinder the commercial development of the experimental vaccine. We encountered this problem during the manufacture of a GMP grade vaccine formulation for preliminary evaluation in an animal model under GLP conditions. A key stage in the laboratory scale method involved the use of an ultracentrifuge. However, this step became problematic when scale-up of the vaccine by the contracted manufacturer was performed. To compensate, the processing method had to be changed and this necessitated additional experiments on bench scale to conWrm that the eYcacy of the formulation had not been compromised. Such challenges can be critically important when trying to meet deWned milestones with Wnite funding. 2.3. Animal models In most cases, preliminary research on vaccines are performed using rodent species since they are easy to maintain and a wide range of well-characterised immunochemicals are available for assessing immunological responses (e.g., antibody titres and cytokine analysis), following vaccination. However, using these species present a number of practical problems, for example, equivalence units for use in humans. Furthermore, the administration route and formulation used in rodents may not necessarily reXect the intended route in humans. For example, many oral experimental formulations are administered to mice by intra-gastric gavage, which is not practical for clinical applications and so need further development. 2.4. Measurement of appropriate immunological outputs Decisions on how to assess vaccine eYcacy, and what type of controls will be used in studies, are essential. The positive control used in many experimental studies involves immunising animals via a totally diVerent route (e.g., intraperitoneally) compared with the prototype vaccine and may also use an adjuvant (e.g., Freund’s adjuvant) neither of which can be used in veterinary or clinical products. This makes comparative assessment diYcult. In the case of mucosal immunisation, the ability to generate speciWc IgG sub-class antibodies responses are used as an indicator of in vivo Th1 or Th2 responses. However, speciWc IgA production following immunisation should also be determined [11] since IgA is the major antibody class that mediates protection of mucosal surfaces due to its speciWc properties (resistance to host proteases, inhibition of bacterial adhesion to the mucosa, neutralisation capability against viruses, and enhancement of non-speciWc defence mechanisms leading to antigen clearance [12]). In our studies, we knew that protection against inXuenza is associated with the development of speciWc IgG antibodies, which can be produced independently of T cells [13]. Cytokine production by in vitro stimulated lymphocytes from vaccinated and control animals were carried out to indicate the type of immune response generated. For example, protection
K.C. Carter et al. / Methods 38 (2006) 65–68
against inXuenza is associated with the induction of Th1 cytokines [14]. 2.5. Appropriate disease models In addition to demonstrating that an experimental vaccine induces the correct immune responses, investigators must also demonstrate that the vaccine is protective in a relevant disease model. For example, we have carried out studies in the ‘industry gold standard’ ferret model of inXuenza [15] to prove that the observed murine immunological responses to our vaccine correlates with a protective eVect. This also has the added beneWt of demonstrating the vaccine is eVective and safe in more than one species. This is important as it enhances the commercial potential of the experimental vaccine and is an important piece of information when attempting to secure additional funds to collect data necessary for regulatory submission. 3. What factors can inXuence commercial development of an eVective vaccine? Once a vaccine formulation has been identiWed, shown to be physicochemically stable, with appropriate shelf-life at a range of storage conditions, and is eVective in an infection model, then there are at least three related hurdles to launching a product on to the market. 3.1. Safety issues First, a vaccine must be safe for use in humans or animals, a factor that involves carrying out clinical trials and extensive toxicology studies. Indeed one of the stumbling blocks that may hinder commercial development of a potential vaccine is securing funding for the extensive toxicology studies required [16]. There are often sources of funding for ‘Proof-of-Principle’ studies for a vaccine, and there are companies willing to take on products with toxicological data, but it is often diYcult to secure funding to bridge the gap between laboratory research and commercialisation. Awareness of these problems is becoming recognised by government and non-government funding agencies at both the national (e.g., Scottish Enterprise Proof-of-Concept Fund and The Wellcome Trust Translational Award in the UK) and international level (World Health Organisation Tropical Disease Research [WHO/ TDR], The International Finance Facility for Immunization [IFFIm] and The Global Alliance on Vaccines and Immunization [GAVI]). 3.2. Cost issues The second factor limiting vaccine development is cost, since a vaccine must be cost-eVective if it is to be attractive to a commercial partner and have a competitive advantage over existing products [10]. Related to this is the patent life of the technology developed as this can impact on securing
67
industrial funding. A long interval between Wling a patent on a technology and developing a viable product reduces the time available for a company to recapture their investment. Therefore, the continual pursuit of extending the intellectual property related to the technology is essential to ensure commercial interest. 3.3. Public perception The third hurdle to vaccine development is public opinion, which can have a major impact on whether a product is commercially viable. Recently in the UK, public concerns regarding the safety proWle of the measles, mumps, and rubella (MMR) vaccine and its controversial association with autism, resulted in a dramatic reduction in vaccination uptake rates in children, despite government reassurances and independent evidence from non-government agencies [17]. Therefore, outside factors can reduce the market share for a vaccine, despite the fact that it protects against potentially life-threatening diseases and is safe and cost eVective. By contrast, an opposite driving force can be perpetuated by media hype, e.g., the current bird Xu and bioterrorist scares. 4. How to commercialise your product? The most obvious avenues are forming a spin out company, where Universities or research organisations retain the intellectual property rights for the product, or licensing the technology to a commercial partner. One option is to have a licence or a collaborative agreement with a large pharmaceutical company and for a University derived product this may be perceived as the ideal route for a number of reasons; for example, researchers can oversee the regulatory development of the product in a consultancy capacity, while continuing with academic pursuits. In this case, the industrial partner would help to steer the product through regulatory compliance, fund expensive clinical trials and use their manufacturing and marketing know-how to maximise the potential of the technology. Development of a platform technology enables licensing of the core technology to multiple biopharmaceutical companies for speciWc applications in diVerent diseases. It is interesting to note that there are now only Wve major vaccine manufacturers worldwide [4], namely, SanoW Pasteur, Novartis-Chiron partnership, Merck and Co., GlaxoSmithKline, and Wyeth Pharmaceuticals, therefore the choice for setting up a collaborative agreement with a big manufacturer is limited. Various methods are used to highlight technology to relevant potential partners, e.g., a company contact, production of non-conWdential Xyers to target companies and conWdential reports providing relevant information, presentations at trade conferences or meetings, or via media promotion. A realization that a global increase in vaccine investment and vaccine provision is required, resulted in the creation of The Global Alliance for Vaccines and Immunization (GAVI),
68
K.C. Carter et al. / Methods 38 (2006) 65–68
which brings together public and private partners, e.g., governments from developing and industrialised countries, vaccine manufacturers, research institutes, UNICEF, the World Health Organization, the Bill & Melinda Gates Foundation and the World Bank. However, continuity in funding throughout the development of a vaccine remains the biggest issue for realising the potential of all vaccine candidates. If this issue can be addressed then, there could be an increase in the frequency of successful products coming on to the market. Acknowledgments The authors are grateful to Scottish Enterprise for Proof-of-Concept and Proof-of-Concept Plus funding and to the Synergy (University Challenge) Fund. References [1] J.F. Mann, V.A. Ferro, A.B. Mullen, L. Tetley, M. Mullen, K.C. Carter, et al., Vaccine 22 (19) (2004) 2425–2429.
[2] M. Conacher, J. Alexander, J.M. Brewer, Vaccine 19 (20–22) (2001) 2965–2974. [3] H. Grabowski, Health AV. (Millwood) 24 (3) (2005) 697–700. [4] D. Bloom, D. Canning, W. Weston, World Economics 6 (15–39) (2005). [5] G. Peter, M.G. Myers, Pediatrics 110 (6) (2002) e67. [6] D.F. Nellis, D.L. Ekstrom, D.B. Kirpotin, J. Zhu, R. Andersson, T.L. Broadt, et al., Biotechnol Prog. 21 (1) (2005) 205–220. [7] D. Favre, J.F. Viret, Vaccine (2005). [8] J. Okonkowski, L. Kizer-Bentley, K. Listner, D. Robinson, M. Chartrain, Biotechnol. Prog. 21 (4) (2005) 1038–1047. [9] T.Y. Lin, C.W. Chen, J. Biopharm. Stat. 13 (3) (2003) 337–354. [10] S.A. Plotkin, Nat. Med. 11 (4 Suppl.) (2005) S5–S11. [11] B. Corthesy, F. Spertini, Biol. Chem. 380 (11) (1999) 1251–1262. [12] J.M. Woof, J. Mestecky, Immunol. Rev. 206 (64–82) (2005). [13] B.O. Lee, J. Rangel-Moreno, J.E. Moyron-Quiroz, L. Hartson, M. Makris, F. Sprague, et al., J. Immunol. 175 (9) (2005) 5827–5838. [14] D.M. Brown, E. Roman, S.L. Swain, Semin. Immunol. 16 (3) (2004) 171–177. [15] V.P. Mishin, M.S. Nedyalkova, F.G. Hayden, L.V. Gubareva, Vaccine 23 (22) (2005) 2922–2927. [16] F. Verdier, Toxicology 174 (1) (2002) 37–43. [17] R. Casiday, T. Cresswell, D. Wilson, C. Panter-Brick, Vaccine (2005).
Translation of an experimental oral vaccine formulation into a commercial product K.C. Carter a, V.A. Ferro a,¤, J. Alexander a, A.B. Mullen b a
b
Department of Immunology, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK Department of Pharmaceutical Sciences, University of Strathclyde, 27 Taylor Street, Glasgow G4 0NR, UK Accepted 10 November 2005
Abstract An eVective experimental vaccine may fail to become a therapeutic reality for a number of scientiWc, regulatory or commercial reasons. In this review, we share some of our personal experiences as University-based researchers and provide an account of some of the problems that we have encountered during preliminary scale-up and assessment of an oral inXuenza vaccine formulation. Many of the problems we have faced have been non-scientiWc and related to identifying project-funding sources, Wnding suitable contract manufacturing companies that are GMP compliant, and protecting intellectual property generated from the scientiWc studies. The review is intended as a practical guide that will allow other researchers to adopt eVective strategies to permit the translation of an eVective experimental formulation to a viable commercial product. 2005 Elsevier Inc. All rights reserved. Keywords: Vaccines; Commercial; Quality control; Antibodies; Manufacturing process
1. Introduction Over the last 3 years we have been involved in the commercialisation of a ‘platform technology’ for oral vaccination, undertaken as part of a Scottish Enterprise ‘Proof-of-Concept’ project. Our delivery system uses non-ionic surfactant vesicles containing bile salts, known as ‘bilosomes,’ to deliver protein antigens administered by the oral route [1,2]. We have shown that this system is eVective at inducing speciWc IgG1, IgG2a, and IgA antibodies, with a range of antigens. Detailed below are some of the factors that have become apparent in developing an experimental vaccine formulation and how they can inXuence the progression to commercialisation. 2. What initial factors should be considered? Classically vaccines have been developed speciWcally to treat a single disease. However, a more attractive proposi*
Corresponding author. Fax: +44 141 548 4645. E-mail address: [email protected] (V.A. Ferro).
1046-2023/$ - see front matter 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ymeth.2005.11.001
tion is the development of a generic ‘platform technology’ which permits the incorporation and delivery of a range of antigens thereby, increasing the market potential of the technology. In addition, the clinical presentation of the vaccine and its dosing frequency is important since this may impact on patient compliance or provide a competitive advantage over pre-existing vaccines in the same therapeutic area. Marketing data to conWrm that there is a net gain to healthcare infrastructure, and a need for the product being developed, is therefore critical, since this will conWrm commercial potential [3]. This may be diYcult if the proposed vaccine is for the prevention of a disease prevalent in a developing country. Unless charitable agencies are willing to fund the project, the product will never be commercially viable. However, a recent study showed that vaccination can have a huge economic impact on a developing country, resulting in a 12% return in costs associated with a vaccination programme by year 1 and 18% in year 2 [4], which may make these type of vaccines more attractive to commercial sponsors. In our case we decided to develop a ‘platform technology’ incorporating antigens already employed in
66
K.C. Carter et al. / Methods 38 (2006) 65–68
existing vaccines (inXuenza haemagglutinin A, tetanus and diphtheria toxoids, and measles peptide). These antigens were selected on the basis of attracting commercial interest in the technology developed and demonstrating its worth as an oral vaccine delivery platform. 2.1. Quality control of constituents One of the factors singled out by us, which adversely aVects commercial vaccine development is the quality of the reagents used [5], as there are strict guidelines on the purity and quality of constituents used in medicinal and veterinary products [6]. It is therefore very useful in identifying at a conceptual stage, whether potential constituents to be used in the experimental vaccine comply with regulatory requirements and if not, substituting with a suitable alternative. Today, a vaccine can only be developed for commercial use if it is safe, well characterised, as well as being eYcacious. It is therefore pointless using constituents that would be unacceptable to regulatory authorities, or at concentrations that are likely to be toxic [7,8]. Therefore, early toxicity studies are also recommended. During our developmental phase, we had trouble in securing the supply of a key excipient in our formulation with consistent physicochemical properties. Subsequent investigations highlighted that variability in the performance of the chemical arose from the purchasing strategy implemented by the manufacturer. The supplier purchased the chemical from third party organisations and re-labelled it as its own product. This was done solely based on which third party company provided the lowest tender for the chemical that met their minimum speciWcation on quality (chemical purity). This speciWcation was set too low for our requirements and resulted in appreciable variability in the appearance and performance of the chemical (and the vaccine) over a 2-year period. This took considerable time and resources to resolve and to identify an alternate supplier who could consistently provide us with the chemical in bulk quantity to a satisfactory physicochemical speciWcation to enable reproducible vaccine performance. Therefore, at the outset, we strongly advise that manufacturers should be identiWed for each constituent, with the facilities to supply large-scale GMP compliant batches of excipients and actives for production of the Wnal product. It is also important to develop analytical methods that allow quantitative and qualitative identiWcation of individual constituents, and their potential breakdown products in the vaccine formulation. This provides stability data on a formulation, and permits determination of likely shelf life and storage conditions for the endproduct [9]. 2.2. Quality control of manufacture The manufacturing process of the vaccine is also important since it is advantageous if it can be simply produced to keep the cost of each dosage unit competitive [10]. Developing a manufacturing method reliant on a process that is
unlikely to be GMP compliant, or permit scale up, will hinder the commercial development of the experimental vaccine. We encountered this problem during the manufacture of a GMP grade vaccine formulation for preliminary evaluation in an animal model under GLP conditions. A key stage in the laboratory scale method involved the use of an ultracentrifuge. However, this step became problematic when scale-up of the vaccine by the contracted manufacturer was performed. To compensate, the processing method had to be changed and this necessitated additional experiments on bench scale to conWrm that the eYcacy of the formulation had not been compromised. Such challenges can be critically important when trying to meet deWned milestones with Wnite funding. 2.3. Animal models In most cases, preliminary research on vaccines are performed using rodent species since they are easy to maintain and a wide range of well-characterised immunochemicals are available for assessing immunological responses (e.g., antibody titres and cytokine analysis), following vaccination. However, using these species present a number of practical problems, for example, equivalence units for use in humans. Furthermore, the administration route and formulation used in rodents may not necessarily reXect the intended route in humans. For example, many oral experimental formulations are administered to mice by intra-gastric gavage, which is not practical for clinical applications and so need further development. 2.4. Measurement of appropriate immunological outputs Decisions on how to assess vaccine eYcacy, and what type of controls will be used in studies, are essential. The positive control used in many experimental studies involves immunising animals via a totally diVerent route (e.g., intraperitoneally) compared with the prototype vaccine and may also use an adjuvant (e.g., Freund’s adjuvant) neither of which can be used in veterinary or clinical products. This makes comparative assessment diYcult. In the case of mucosal immunisation, the ability to generate speciWc IgG sub-class antibodies responses are used as an indicator of in vivo Th1 or Th2 responses. However, speciWc IgA production following immunisation should also be determined [11] since IgA is the major antibody class that mediates protection of mucosal surfaces due to its speciWc properties (resistance to host proteases, inhibition of bacterial adhesion to the mucosa, neutralisation capability against viruses, and enhancement of non-speciWc defence mechanisms leading to antigen clearance [12]). In our studies, we knew that protection against inXuenza is associated with the development of speciWc IgG antibodies, which can be produced independently of T cells [13]. Cytokine production by in vitro stimulated lymphocytes from vaccinated and control animals were carried out to indicate the type of immune response generated. For example, protection
K.C. Carter et al. / Methods 38 (2006) 65–68
against inXuenza is associated with the induction of Th1 cytokines [14]. 2.5. Appropriate disease models In addition to demonstrating that an experimental vaccine induces the correct immune responses, investigators must also demonstrate that the vaccine is protective in a relevant disease model. For example, we have carried out studies in the ‘industry gold standard’ ferret model of inXuenza [15] to prove that the observed murine immunological responses to our vaccine correlates with a protective eVect. This also has the added beneWt of demonstrating the vaccine is eVective and safe in more than one species. This is important as it enhances the commercial potential of the experimental vaccine and is an important piece of information when attempting to secure additional funds to collect data necessary for regulatory submission. 3. What factors can inXuence commercial development of an eVective vaccine? Once a vaccine formulation has been identiWed, shown to be physicochemically stable, with appropriate shelf-life at a range of storage conditions, and is eVective in an infection model, then there are at least three related hurdles to launching a product on to the market. 3.1. Safety issues First, a vaccine must be safe for use in humans or animals, a factor that involves carrying out clinical trials and extensive toxicology studies. Indeed one of the stumbling blocks that may hinder commercial development of a potential vaccine is securing funding for the extensive toxicology studies required [16]. There are often sources of funding for ‘Proof-of-Principle’ studies for a vaccine, and there are companies willing to take on products with toxicological data, but it is often diYcult to secure funding to bridge the gap between laboratory research and commercialisation. Awareness of these problems is becoming recognised by government and non-government funding agencies at both the national (e.g., Scottish Enterprise Proof-of-Concept Fund and The Wellcome Trust Translational Award in the UK) and international level (World Health Organisation Tropical Disease Research [WHO/ TDR], The International Finance Facility for Immunization [IFFIm] and The Global Alliance on Vaccines and Immunization [GAVI]). 3.2. Cost issues The second factor limiting vaccine development is cost, since a vaccine must be cost-eVective if it is to be attractive to a commercial partner and have a competitive advantage over existing products [10]. Related to this is the patent life of the technology developed as this can impact on securing
67
industrial funding. A long interval between Wling a patent on a technology and developing a viable product reduces the time available for a company to recapture their investment. Therefore, the continual pursuit of extending the intellectual property related to the technology is essential to ensure commercial interest. 3.3. Public perception The third hurdle to vaccine development is public opinion, which can have a major impact on whether a product is commercially viable. Recently in the UK, public concerns regarding the safety proWle of the measles, mumps, and rubella (MMR) vaccine and its controversial association with autism, resulted in a dramatic reduction in vaccination uptake rates in children, despite government reassurances and independent evidence from non-government agencies [17]. Therefore, outside factors can reduce the market share for a vaccine, despite the fact that it protects against potentially life-threatening diseases and is safe and cost eVective. By contrast, an opposite driving force can be perpetuated by media hype, e.g., the current bird Xu and bioterrorist scares. 4. How to commercialise your product? The most obvious avenues are forming a spin out company, where Universities or research organisations retain the intellectual property rights for the product, or licensing the technology to a commercial partner. One option is to have a licence or a collaborative agreement with a large pharmaceutical company and for a University derived product this may be perceived as the ideal route for a number of reasons; for example, researchers can oversee the regulatory development of the product in a consultancy capacity, while continuing with academic pursuits. In this case, the industrial partner would help to steer the product through regulatory compliance, fund expensive clinical trials and use their manufacturing and marketing know-how to maximise the potential of the technology. Development of a platform technology enables licensing of the core technology to multiple biopharmaceutical companies for speciWc applications in diVerent diseases. It is interesting to note that there are now only Wve major vaccine manufacturers worldwide [4], namely, SanoW Pasteur, Novartis-Chiron partnership, Merck and Co., GlaxoSmithKline, and Wyeth Pharmaceuticals, therefore the choice for setting up a collaborative agreement with a big manufacturer is limited. Various methods are used to highlight technology to relevant potential partners, e.g., a company contact, production of non-conWdential Xyers to target companies and conWdential reports providing relevant information, presentations at trade conferences or meetings, or via media promotion. A realization that a global increase in vaccine investment and vaccine provision is required, resulted in the creation of The Global Alliance for Vaccines and Immunization (GAVI),
68
K.C. Carter et al. / Methods 38 (2006) 65–68
which brings together public and private partners, e.g., governments from developing and industrialised countries, vaccine manufacturers, research institutes, UNICEF, the World Health Organization, the Bill & Melinda Gates Foundation and the World Bank. However, continuity in funding throughout the development of a vaccine remains the biggest issue for realising the potential of all vaccine candidates. If this issue can be addressed then, there could be an increase in the frequency of successful products coming on to the market. Acknowledgments The authors are grateful to Scottish Enterprise for Proof-of-Concept and Proof-of-Concept Plus funding and to the Synergy (University Challenge) Fund. References [1] J.F. Mann, V.A. Ferro, A.B. Mullen, L. Tetley, M. Mullen, K.C. Carter, et al., Vaccine 22 (19) (2004) 2425–2429.
[2] M. Conacher, J. Alexander, J.M. Brewer, Vaccine 19 (20–22) (2001) 2965–2974. [3] H. Grabowski, Health AV. (Millwood) 24 (3) (2005) 697–700. [4] D. Bloom, D. Canning, W. Weston, World Economics 6 (15–39) (2005). [5] G. Peter, M.G. Myers, Pediatrics 110 (6) (2002) e67. [6] D.F. Nellis, D.L. Ekstrom, D.B. Kirpotin, J. Zhu, R. Andersson, T.L. Broadt, et al., Biotechnol Prog. 21 (1) (2005) 205–220. [7] D. Favre, J.F. Viret, Vaccine (2005). [8] J. Okonkowski, L. Kizer-Bentley, K. Listner, D. Robinson, M. Chartrain, Biotechnol. Prog. 21 (4) (2005) 1038–1047. [9] T.Y. Lin, C.W. Chen, J. Biopharm. Stat. 13 (3) (2003) 337–354. [10] S.A. Plotkin, Nat. Med. 11 (4 Suppl.) (2005) S5–S11. [11] B. Corthesy, F. Spertini, Biol. Chem. 380 (11) (1999) 1251–1262. [12] J.M. Woof, J. Mestecky, Immunol. Rev. 206 (64–82) (2005). [13] B.O. Lee, J. Rangel-Moreno, J.E. Moyron-Quiroz, L. Hartson, M. Makris, F. Sprague, et al., J. Immunol. 175 (9) (2005) 5827–5838. [14] D.M. Brown, E. Roman, S.L. Swain, Semin. Immunol. 16 (3) (2004) 171–177. [15] V.P. Mishin, M.S. Nedyalkova, F.G. Hayden, L.V. Gubareva, Vaccine 23 (22) (2005) 2922–2927. [16] F. Verdier, Toxicology 174 (1) (2002) 37–43. [17] R. Casiday, T. Cresswell, D. Wilson, C. Panter-Brick, Vaccine (2005).