Reformulation of a thermostable broadly protective recombinant vaccine against human papilloma virus

The causal relationship between Human Papilloma Virus (HPV) infection and cervical cancer has motivated the development, and further improvement, of prophylactic vaccines against this virus. 70% of cervical cancers, 80% of which in low-resources countries, are associated to HPV16 and HPV18 infection, with 13 additional HPV types, classified as high-risk, responsible for the remaining 30% of tumors. Current vaccines, Cervarix® (GlaxoSmithKline) and Gardasil®(Merk), are based on virus-like particles (VLP) obtained by self-assembly of the major capsid protein L1. Despite their undisputable immunogenicity and safety, the fact that protection afforded by these vaccines is largely limited to the cognate serotypes included in the vaccine (HPV 16 and 18, plus five additional viral types incorporated into a newly licensed nonavalent vaccine) along with high production costs and reduced thermal stability, are pushing the development of 2nd generation HPV vaccines based on minor capsid protein L2. The increase in protection broadness afforded by the use of L2 cross-neutralizing epitopes, plus a marked reduction of production costs due to bacterial expression of the antigens and a considerable increase in thermal stability could strongly enhance vaccine distribution and usage in low-resource countries. Previous studies from our group identified three tandem repeats of the L2 aa. 20-38 peptide as a strongly immunogenic epitope if exposed on the scaffold protein thioredoxin (Trx). The aim of this thesis work is the improvement of the Trx-L2 vaccine formulation with regard to cross-protection and thermostability, in order to identify an antigen suitable for a phase I clinical trial. By testing Trx from different microorganisms, we selected P. furiosus thioredoxin (PfTrx) as the optimal scaffold because of its sustained peptide epitope constraining capacity and striking thermal stability (24 hours at 100°C). Alternative production systems, such as secretory Trx-L2 expression in the yeast P. pastoris, have also been set-up and evaluated as possible means to further increase production yields, with a concomitant reduction of production costs. Limitations in immune-responsiveness caused by MHC class II polymorphisms –as observed, for example, in different mouse strains- have been overcome by introducing promiscuous T-helper (Th) epitopes, e.g., PADRE (Pan DR Epitope), at both ends of PfTrx. This allowed us to obtain fairly strong immune responses even in mice (C57BL/6) normally unresponsive to the basic Trx-L2 vaccine. Cross-protection was not increased, however. I thus designed, produced and tested a novel multi-epitope formulation consisting of 8 and 11 L2(20-38) epitopes derived from different HPV types, tandemly joined into a single thioredoxin molecule (“concatemers”). To try to further increase immunogenicity, I also fused our 8X and 11X PfTrx-L2 concatemers to the N-terminus of an engineered complement-binding protein (C4bp), capable to spontaneously assemble into ordered hepatmeric structures, previously validated as a molecular adjuvant. Fusion to C4bp indeed improved antigen presentation, with a fairly significant increase in both immunogenicity and cross-protection. Another important issue I addressed, is the reduction of vaccine doses/treatment, which can be achieved by increasing immunogenicity, while also allowing for a delayed release of the antigen. I obtained preliminary, yet quite encouraging results in this direction with the use of a novel, solid-phase vaccine formulation, consisting of the basic PfTrx-L2 vaccine and its C4bp fusion derivative adsorbed to mesoporus silica-rods (MSR).

The future of manufacturing

Anyone who looks at the title of this special issue will agree that the intent behind the preparation of this volume was ambitious: to predict and discuss “The Future of Manufacturing”. Will manufacturing be important in the future? Even though some sceptics might say not, and put on the table some old familiar arguments, we would strongly disagree. To bring subsidies for the argument we issued the call-for-papers for this special issue of Journal of Manufacturing Technology Management, fully aware of the size of the challenge in our hands. But we strongly believed that the enterprise would be worthwhile. The point of departure is the ongoing debate concerning the meaning and content of manufacturing. The easily visualised internal activity of using tangible resources to make physical products in factories is no longer a viable way to characterise manufacturing. It is now a more loosely defined concept concerning the organisation and management of open, interdependent, systems for delivering goods and services, tangible and intangible, to diverse types of markets. Interestingly, Wickham Skinner is the most cited author in this special issue of JMTM. He provides the departure point of several articles because his vision and insights have guided and inspired researchers in production and operations management from the late 1960s until today. However, the picture that we draw after looking at the contributions in this special issue is intrinsically distinct, much more dynamic, and complex. Seven articles address the following research themes: 1.new patterns of organisation, where the boundaries of firms become blurred and the role of the firm in the production system as well as that of manufacturing within the firm become contingent; 2.new approaches to strategic decision-making in markets characterised by turbulence and weak signals at the customer interface; 3.new challenges in strategic and operational decisions due to changes in the profile of the workforce; 4.new global players, especially China, modifying the manufacturing landscape; and 5.new techniques, methods and tools that are being made feasible through progress in new technological domains. Of course, many other important dimensions could be studied, but these themes are representative of current changes and future challenges. Three articles look at the first theme: organisational evolution of production and operations in firms and networks. Karlsson's and Skold's article represent one further step in their efforts to characterise “the extraprise”. In the article, they advance the construction of a new framework, based on “the network perspective” by defining the formal elements which compose it and exploring the meaning of different types of relationships. The way in which “actors, resources and activities” are conceptualised extends the existing boundaries of analytical thinking in operations management and open new avenues for research, teaching and practice. The higher level of abstraction, an intrinsic feature of the framework, is associated to the increasing degree of complexity that characterises decisions related to strategy and implementation in the manufacturing and operations area, a feature that is expected to become more and more pervasive as time proceeds. Riis, Johansen, Englyst and Sorensen have also based their article on their previous work, which in this case is on “the interactive firm”. They advance new propositions on strategic roles of manufacturing and discuss why the configuration of strategic manufacturing roles, at the level of the network, will become a key issue and how the indirect strategic roles of manufacturing will become increasingly important. Additionally, by considering that value chains will become value webs, they predict that shifts in strategic manufacturing roles will look like a sequence of moves similar to a game of chess. Then, lastly under the first theme, Fleury and Fleury develop a conceptual framework for the study of production systems in general derived from field research in the telecommunications industry, here considered a prototype of the coming information society and knowledge economy. They propose a new typology of firms which, on certain dimensions, complements the propositions found in the other two articles. Their telecoms-based framework (TbF) comprises six types of companies characterised by distinct profiles of organisational competences, which interact according to specific patterns of relationships, thus creating distinct configurations of production networks. The second theme is addressed by Kyläheiko and SandstroÍm in their article “Strategic options based framework for management of dynamic capabilities in manufacturing firms”. They propose a new approach to strategic decision-making in markets characterised by turbulence and weak signals at the customer interface. Their framework for a manufacturing firm in the digital age leads to active asset selection (strategic investments in both tangible and intangible assets) and efficient orchestrating of the global value net in “thin” intangible asset markets. The framework consists of five steps based on Porter's five-forces model, the resources-based view, complemented by means of the concepts of strategic options and related flexibility issues. Thun, GroÍssler and Miczka's contribution to the third theme brings the human dimension to the debate regarding the future of manufacturing. Their article focuses on the challenges brought to management by the ageing of workers in Germany but, in the arguments that are raised, the future challenges associated to workers and work organisation in every production system become visible and relevant. An interesting point in the approach adopted by the authors is that not only the factual problems and solutions are taken into account but the perception of the managers is brought into the picture. China cannot be absent in the discussion of the future of manufacturing. Therefore, within the fourth theme, Vaidya, Bennett and Liu provide the evidence of the gradual improvement of Chinese companies in the medium and high-tech sectors, by using the revealed comparative advantage (RCA) analysis. The Chinese evolution is shown to be based on capabilities developed through combining international technology transfer and indigenous learning. The main implication for the Western companies is the need to take account of the accelerated rhythm of capability development in China. For other developing countries China's case provides lessons of great importance. Finally, under the fifth theme, Kuehnle's article: “Post mass production paradigm (PMPP) trajectories” provides a futuristic scenario of what is already around us and might become prevalent in the future. It takes a very intensive look at a whole set of dimensions that are affecting manufacturing now, and will influence manufacturing in the future, ranging from the application of ICT to the need for social transparency. In summary, this special issue of JMTM presents a brief, but undisputable, demonstration of the possible richness of manufacturing in the future. Indeed, we could even say that manufacturing has no future if we only stick to the past perspectives. Embracing the new is not easy. The new configurations of production systems, the distributed and complementary roles to be performed by distinct types of companies in diversified networked structures, leveraged by the new emergent technologies and associated the new challenges for managing people, are all themes that are carriers of the future. The Guest Editors of this special issue on the future of manufacturing are strongly convinced that their undertaking has been worthwhile.

The contribution of modularity to green operations practices

This paper discusses the possible contributions from modularity and industrial condominiums towards enhancing environmental performance in the automotive industry. The research described in this study is underpinned by a review of journal articles and books on the topics of: modularity of production systems; green operations practices, and the automotive industry and sustainability. The methodology is based on theoretical analysis of the contribution of the modular production system characteristics used in the automotive industry for Green Operations Practices (GOP). The following GOPs were considered: green buildings, eco-design, green supply chains, greener manufacturing, and reverse logistics. The results are theoretical in nature; however, due to the small number of studies that investigate the relationship between modularity and sustainability, this work is relevant to increase knowledge in academic circles and among practitioners in order to understand the possible environmental benefits from modular production systems. For instance, based upon our analysis, we could deduce that the existing modular production systems in the automotive industry may contribute in different ways to the implementation of GOPs. In all types of modularity, product simplification through the use of modules can enhance environmental performance and facilitate further activities such as maintenance and repair contributing to a longer life of cars on the road. Moreover, modules will make automobiles easier to disassembly, so increasing the chances of reuse of valuable components and a better final disposal of scrap. Regarding the potential benefits of each type of modularity, it is expected that modular consortia will have a better integration of environmental practices with suppliers and seize on high efficiency during manufacturing and logistics compared with conventional production systems.

Symbiotic approaches to work and technology

Symbiotic design methods aim to take into account technical, social and organizational criteria simultaneously. Over the years, many symbiotic methods have been developed and applied in various countries. Nevertheless, the diagnosis that only technical criteria receive attention in the design of production systems, is still made repeatedly. Examples of symbiotic approaches are presented at three different levels: technical systems, organizations, and the process. From these, discussion points are generated concerning the character of the approaches, the importance of economic motives, the impact of national environments, the necessity of a guided design process, the use of symbiotic methods, and the roles of participants in the design process.

An application of decision process modelling to manufacturing system design

As levels of investment in advanced manufacturing systems increase, effective project management becomes ever more critical. This paper demonstrates how the model proposed by Mintzberg, Raisinghani and Theoret in 1976, which structures complicated strategic decision processes, can be applied to the design of new production systems for both descriptive and analytical research purposes. This paper sets a detailed case study concerning the design and development of an advanced manufacturing system within the Mintzberg decision model and so breaks down the decision sequence into constituent parts. It thus shows how a structured model can provide a framework for the researcher who wishes to study decision episodes in the design of manufacturing facilities in greater depth.

LacO-LacI interaction in affinity adsorption of plasmid DNA

Current approaches for purifying plasmids from bacterial production systems exploit the physiochemical properties of nucleic acids in non-specific capture systems. In this study, an affinity system for plasmid DNA (pDNA) purification has been developed utilizing the interaction between the lac operon (lacO) sequence contained in the pDNA and a 64mer synthetic peptide representing the DNA-binding domain of the lac repressor protein, LacI. Two plasmids were evaluated, the native pUC19 and pUC19 with dual lacO3/lacOs operators (pUC19lacO3/lacOs), where the lacOs operator is perfectly symmetrical. The DNA-protein affinity interaction was evaluated by surface plasmon resonance using a Biacore system. The affinity capture of DNA in a chromatography system was evaluated using LacI peptide that had been immobilized to Streamline™ adsorbent. The KD-values for double stranded DNA (dsDNA) fragments containing lacO1 and lacO3 and lacOs and lacO3 were 5.7 ± 0.3 × 10 -11 M and 4.1 ± 0.2 × 10-11 M respectively, which compare favorably with literature reports of 5 × 10-10 - 1 × 10-9 M for native laCO1 and 1-1.2 × 10-10 M for lacO1 in a saline buffer. Densitometric analysis of the gel bands from the affinity chromatography run clearly showed a significant preference for capture of the supercoiled fraction from the feed pDNA sample. The results indicate the feasibility of the affinity approach for pDNA capture and purification using native protein-DNA interaction. © 2006 Wiley Periodicals, Inc.

Hydrogels for dermal applications

This thesis is concerned with the development of hydrogels that adhere to skin and can be used for topical or trans dermal release of active compounds for therapeutic or cosmetic use. The suitability of a range of monomers and initiator systems for the production of skin adhesive hydro gels by photopolymerisation was explored and an approximate order of monomer reactivity in aqueous solution was determined. Most notably, the increased reactivity of N-vinyl pyrrolidone within an aqueous system, as compared to its low rate of polymerisation in organic solvents, was observed. The efficacy of a series of photoinitiator systems for the preparation of sheet hydrogels was investigated. Supplementary redox and thermal initiators were also examined. The most successful initiator system was found to be Irgacure 184, which is commonly used in commercial moving web production systems that employ photopolymerisation. The influence of ionic and non-ionic monomers, crosslinking systems, water and glycerol on the adhesive and dynamic mechanical behaviour of partially hydrated hydrogel systems was examined. The aim was to manipulate hydrogel behaviour to modify topical and transdermal delivery capability and investigated the possibility of using monomer combinations that would influence the release characteristics of gels by modifying their hydrophobic and ionic nature. The copolymerisation of neutral monomers (N-vinyl pyrrolidone, N,N-dimethyl acrylamide and N-acryloyl morpholine) with ionic monomers (2-acrylamido-2-methylpropane sulphonic acid; sodium salt, and the potassium salt of 3-sulphopropyl acrylate) formed the basis of the study. Release from fully and partially hydrated hydrogels was studied, using model compounds and a non-steroidal anti-inflammatory drug, Ibuprofen. Release followed a common 3-stage kinetic profile that includes an initial burst phase, a secondary phase of approximate first order release and a final stage of infinitesimally slow release such that the compound is effectively retained within the hydrogel. Use of partition coefficients, the pKa of the active and a knowledge of charge-based and polar interactions of polymer and drug were complementary in interpreting experimental results. In summary, drug ionisation, hydrogel composition and external release medium characteristics interact to influence release behaviour. The information generated provides the basis for the optimal design of hydrogels for specific dermal release applications and some understanding of the limitations of these systems for controlled release applications.

Investigative framework for research into the design of manufacturing processes

This paper is based a major research project run by a team from the Innovation, Design and Operations Management Research Unit at the Aston Business School under SERC funding. International Computers Limited (!CL), the UK's largest indigenous manufacturer of mainframe computer products, was the main industrial collaborator in the research. During the period 1985-89 an integrated production system termed the "Modular Assembly Cascade'' was introduced to the Company's mainframe assembly plant at Ashton-under-Lyne near Manchester. Using a methodology primarily based upon 'participative observation', the researchers developed a model for analysing this manufacturing system design called "DRAMA". Following a critique of the existing literature on Manufacturing Strategy, this paper will describe the basic DRAMA model and its development from an industry specific design methodology to DRAMA II, a generic model for studying organizational decision processes in the design and implementation of production systems. From this, the potential contribution of the DRAMA model to the existing knowledge on the process of manufacturing system design will be apparent.

Impact of just-in-time on job content, employee attitudes and well-being:a longitudinal study

Just-in-time (JIT) production systems are increasingly being seen as a vital way for manufacturing organizations to enhance their competitiveness. A number of commentators have suggested that this will simplify jobs and reduce employee well-being. This paper presents a conceptual framework for interpreting the effects of JIT and reports findings from a study of the impact of JIT on the content of workers'jobs and on job satisfaction and psychological strain. The introduction of JIT led to a reduction in control over work timing, an increase in production pressure, and a drop in job satisfaction. Contrary to claims in the literature, no changes were found in control over work methods, other aspects of cognitive demands and skill use, and in psychological strain. The study shows that JIT can be implemented without radical changes in job content or adverse impact in terms of employee strain, and the implications of these findings are discussed.

Agile or adaptable? Finding a paradigm for an uncertain world

This paper looks at the way in which, over recent years, paradigms for manufacturing management have evolved as a result of changing economic and environmental circumstances. The lean production concept, devised during the 1980s, proved robust only until the end of the bubble economy in Japan caused firms to re-examine the underlying principles of the lean production paradigm and redesign their production systems to suit the changing circumstances they were facing. Since that time a plethora of new concepts have emerged, most of which have been based on improving the way that firms are able to respond to the uncertainties of the new environment in which they have found themselves operating. The main question today is whether firms should be agile or adaptable. Both concepts imply a measure of responsiveness, but recent changes in the nature of the uncertainties have heightened the debate about what strategies should be adopted in the future.

Competitive edge through operations management

A view has emerged within manufacturing and service organizations that the operations management function can hold the key to achieving competitive edge. This has recently been emphasized by the demands for greater variety and higher quality which must be set against a background of increasing cost of resources. As nations' trade barriers are progressively lowered and removed, so producers of goods and service products are becoming more exposed to competition that may come from virtually anywhere around the world. To simply survive in this climate many organizations have found it necessary to improve their manufacturing or service delivery systems. To become real ''winners'' some have adopted a strategic approach to operations and completely reviewed and restructured their approach to production system design and operations planning and control. The articles in this issue of the International journal of Operations & Production Management have been selected to illustrate current thinking and practice in relation to this situation. They are all based on papers presented to the Sixth International Conference of the Operations Management Association-UK which was held at Aston University in June 1991. The theme of the conference was "Achieving Competitive Edge" and authors from 15 countries around the world contributed to more than 80 presented papers. Within this special issue five topic areas are addressed with two articles relating to each. The topics are: strategic management of operations; managing change; production system design; production control; and service operations. Under strategic management of operations De Toni, Filippini and Forza propose a conceptual model which considers the performance of an operating system as a source of competitive advantage through the ''operation value chain'' of design, purchasing, production and distribution. Their model is set within the context of the tendency towards globalization. New's article is somewhat in contrast to the more fashionable literature on operations strategy. It challenges the validity of the current idea of ''world-class manufacturing'' and, instead, urges a reconsideration of the view that strategic ''trade-offs'' are necessary to achieve a competitive edge. The importance of managing change has for some time been recognized within the field of organization studies but its relevance in operations management is now being realized. Berger considers the use of "organization design", ''sociotechnical systems'' and change strategies and contrasts these with the more recent idea of the ''dialogue perspective''. A tentative model is suggested to improve the analysis of different strategies in a situation specific context. Neely and Wilson look at an essential prerequisite if change is to be effected in an efficient way, namely product goal congruence. Using a case study as its basis, their article suggests a method of measuring goal congruence as a means of identifying the extent to which key performance criteria relating to quality, time, cost and flexibility are understood within an organization. The two articles on production systems design represent important contributions to the debate on flexible production organization and autonomous group working. Rosander uses the results from cases to test the applicability of ''flow groups'' as the optimal way of organizing batch production. Schuring also examines cases to determine the reasons behind the adoption of ''autonomous work groups'' in The Netherlands and Sweden. Both these contributions help to provide a greater understanding of the production philosophies which have emerged as alternatives to more conventional systems -------for intermittent and continuous production. The production control articles are both concerned with the concepts of ''push'' and ''pull'' which are the two broad approaches to material planning and control. Hirakawa, Hoshino and Katayama have developed a hybrid model, suitable for multistage manufacturing processes, which combines the benefits of both systems. They discuss the theoretical arguments in support of the system and illustrate its performance with numerical studies. Slack and Correa's concern is with the flexibility characteristics of push and pull material planning and control systems. They use the case of two plants using the different systems to compare their performance within a number of predefined flexibility types. The two final contributions on service operations are complementary. The article by Voss really relates to manufacturing but examines the application of service industry concepts within the UK manufacturing sector. His studies in a number of companies support the idea of the ''service factory'' and offer a new perspective for manufacturing. Harvey's contribution by contrast, is concerned with the application of operations management principles in the delivery of professional services. Using the case of social-service provision in Canada, it demonstrates how concepts such as ''just-in-time'' can be used to improve service performance. The ten articles in this special issue of the journal address a wide range of issues and situations. Their common aspect is that, together, they demonstrate the extent to which competitiveness can be improved via the application of operations management concepts and techniques.