Why might regional vaccinology networks fail? The case of the Dutch-Nordic Consortium
© The Author(s). 2016
Received: 14 April 2016
Accepted: 22 June 2016
Published: 7 July 2016
We analyzed an attempt to develop and clinically test a pneumococcal conjugate vaccine for the developing world, undertaken by public health institutions from the Netherlands, Sweden, Denmark, Norway and Finland: the Dutch Nordic Consortium (DNC), between 1990 and 2000. Our review shows that the premature termination of the project was due less to technological and scientific challenges and more to managerial challenges and institutional policies. Various impeding events, financial and managerial challenges gradually soured the initially enthusiastic collaborative spirit until near the end the consortium struggled to complete the minimum objectives of the project. By the end of 1998, a tetravalent prototype vaccine had been made that proved safe and immunogenic in Phase 1 trials in adults and toddlers in Finland. The planned next step, to test the vaccine in Asia in infants, did not meet approval by the local authorities in Vietnam nor later in the Philippines and the project eventually stopped.
The Dutch DNC member, the National Institute of Public Health and the Environment (RIVM) learned important lessons, which subsequently were applied in a following vaccine technology transfer project, resulting in the availability at affordable prices for the developing world of a conjugate vaccine against Haemophilus influenzae type b. We conclude that vaccine development in the public domain with technology transfer as its ultimate aim requires major front-end funding, committed leadership at the highest institutional level sustained for many years and a competent recipient-manufacturer, which needs to be involved at a very early stage of the development.
At the national level, RIVM’s policy to consolidate its national manufacturing task through securing a key global health position in support of a network of public vaccine manufacturers proved insufficiently supported by the relevant ministries of the Dutch government. Difficulties to keep up with high costs, high-risk innovative vaccine development and production in a public sector setting led to the gradual loss of production tasks and to the 2009 Government decision to privatize the vaccine production tasks of the Institute.
KeywordsGlobalization Pneumococcal conjugate vaccine development Regional networks Public sector consortium Privatization WHO Developing countries
In May 1974, the World Health Assembly adopted a resolution formally establishing what became known as the Expanded Programme on Immunization (or EPI). The principal objective was to help countries “develop or maintain immunization and surveillance programmes against some or all of the following diseases: diphtheria, pertussis, tetanus, measles, poliomyelitis, tuberculosis, smallpox and others, where applicable, according to the epidemiological situation in their respective countries”. Recognizing that this would only be possible if public health authorities had access to good quality vaccines at reasonable cost, the resolution also committed the WHO to studying the possibilities for expanding vaccine supply including “developing local competence to produce vaccines at the national level”. In the years that followed, as an increasingly globalized pharmaceutical industry increased its commitment to vaccine production, and as a consequence of the ideological shifts of the 1980s, this commitment to stimulating local vaccine production, to ‘vaccine self-sufficiency’, gradually vanished from international policy statements and resolutions.
Today there are growing signs from different regions that low and middle-income countries, concerned to ensure affordable access to vaccines for their growing populations, have a renewed interest in stimulating vaccine self-reliance. In Asia, an initiative to increase regional vaccine security started in 2014 under the auspices of the Association of South East Nations, ASEAN . Also in 2014 the Organization of Islamic Countries (OIC) established a Vaccine Manufacturers Group under a program called “self-reliance in vaccine supply and production “ with a focus on the Middle East and North Africa . In 2015, the African Vaccine Manufacturing Initiative (AVMI) brought together stakeholders to “develop a roadmap to reach a strategy for vaccine manufacturing and procurement in Africa”. This was followed in February 2016 by a declaration by African Ministers at a Ministerial Conference on Immunization in Africa, to increase the use of vaccines by –among other actions- promoting and investing in regional capacity for the development and production of vaccines in line with the African Union Pharmaceutical Manufacturing Plan . In this paper, we analyse a previous comparable initiative, in the hope that the lessons that can be drawn from its ultimate failure will be of value to those planning these initiatives.
Vaccine policy in the 80s
In the 80s, responding to priorities of the new ‘global health’ policy, to the availability of new sources of funds as well as more comprehensive epidemiological data, and to the efforts of the pharmaceutical industry seeking new markets, developing countries acknowledged their need for vaccines beyond the classical vaccines supplied in the context of the EPI.
In 1984 at a conference at the Rockefeller Foundation’s Bellagio Conference Centre, the Taskforce for Child Survival (TFCS) was installed to energize and transform existing international vaccine programs committed to immunizing the world’s children. Antony Robbins, director of the vaccine development and production initiative of the TFCS, initiated a more pro-active public sector role in vaccine development and strongly promoted a research incentive system called frond-end funding. Robbins and others had analyzed obstacles to development, testing, mass production and distribution of vaccines needed in developing countries and observed that whilst the UN was not equipped to produce them, manufacturers had little interest in doing so. They concluded that the impediments to develop new vaccines were chiefly of an economic and political rather than scientific nature. The classic EPI vaccines could be sold cheaply because there were no more development costs. The main obstacle for development of new vaccines with little commercial interest1 was that the decision to develop is left in the hands of a few institutes or commercial manufacturers in the developed world, who consider it necessary to recoup the research and development costs before selling at cost price.
Capitalizing on the new opportunities for vaccine development created by the biotechnology revolution, the TFCS subsequently developed an initiative to accelerate development of new and improved vaccines for use in developing countries through a “front-end” funding program. UNDP had suggested a revolving fund to cover cost of development. EPI buyers were to agree on long-term purchase agreements with a small surcharge to replenish these development costs over a 5 or 10 year period. The TFCS would establish such fund with a Standing Committee to manage and oversee it. WHO would select the vaccines and the TFCS would establish contracts with developers . These plans for frond-end funding were presented at another Bellagio conference entitled “Protecting the World’s Children” in March 1988, which ended in the Declaration of Talloires.
“urging national governments, multi- and bilateral development agencies, United Nation agencies, non-governmental organizations and private and voluntary groups to commit themselves to pursue research and development, including technology transfer, in support of the initiatives to control respiratory infections which hold promise in the years ahead of averting many of the 3 million childhood deaths from acute respiratory infections each year in developing countries and that are currently not prevented by immunization” .
After interacting with the TFCS during the 1988 Bellagio conference, public sector vaccine institutions from the Netherlands and Scandinavia responded actively to this Call for Action, which eventually led to the establishment of a ‘Dutch Nordic Consortium’ (DNC) and the pneumococcal vaccine project described below. The private industry also considered the analysis of Robbins as a step in the right direction but added that more incentives would be needed to get real commitment from industry: increased protection for another product of that company; extended patents or monopolies for certain countries, or higher prices . In July 1989, the TFCS solicited specific proposals from manufacturers who wished to be considered for “front-end” assistance in developing vaccines of high value to the EPI . Independent scientists reviewed proposals on vaccines against Meningococcus A/C and Meningococcus B, cholera, Japanese encephalitis and pneumococcal infections, the latter being submitted from Finland on behalf of the Finnish, Swedish and Dutch institutes. The idea was that the TFCS would commit to seek funds from its members, foundations and bilateral development programs, for one or more selected proposals. The reviewers considered the proposals on conjugate vaccines against Meningitis A/C and S. pneumoniae as most promising and the TFCS subsequently undertook to acquire funds .
New consortia in the 90s
In September 1990, at the World Summit for Children in New York City, WHO, UNICEF, UNDP, the Rockefeller Foundation and the World Bank launched the Children’s Vaccine Initiative (CVI) as a major new global initiative to connect new technologies to advance childhood immunization. All organizations had come to realize that the manufacture of vaccines cannot be assured without taking into account the prospective development of new vaccines .
Around the same time, with increasingly widespread political commitment to reducing the role of the state, public sector vaccinology institutions in Europe and other regions were facing increasing challenges to their traditional responsibilities. In this context, George Siber from the Massachusetts Biological Public Health Laboratories in the US proposed the establishment of a public sector vaccine consortium. Public sector manufacturers in industrialized and developing countries could share technology for manufacturing existing vaccines and could develop orphan ”low-profit vaccines for diseases occurring mainly in developing countries or for rare or emerging diseases” .
“within the SIREVA consortium, Butantan started with pneumococcal vaccine development; by fermentation of the polysaccharides. Different countries were to make different polysaccharides. The conjugation technology was developed in-house from studying the literature. Butantan in São Paulo and the Oswaldo Cruz Institute in Rio de Janeiro produced the serotypes 23 and 19 respectively. Chile and Cuba joined later. The collaboration failed, because PAHO had no money: not even money to hold meetings, so people did not interact. Then SIREVA continued in terms of surveillance” (Leite, L.,2011, personal communication).
In Geneva, plans to establish a public sector consortium were also made. In January 1995, the CVI Task Force for Situation Analysis (TFSA), held a meeting on fostering partnerships on DPT and DPT based combination vaccines, where several ongoing initiatives were discussed . Julie Milstien from WHO subsequently drafted a strategic background document: “Strengthening Vaccine Production: A Consortium of Public Sector Vaccine Manufacturers” . The WHO had taken part in visits by the TFSA to a series of developing countries that were producing EPI vaccines predominantly in the public sector for their national immunization programs. These visits to manufacturers and the national control authorities and laboratories in those countries had identified significant gaps in quality and quantity of vaccines. The TFSA had noted that technical support to those countries had often not been effective because of “a lack of receptive management structure leading to frustration with donors and countries”. The proposed solution was a three-step process. First, countries should critically look at the cost-effectiveness and viability of vaccine production in the public sector. Second, vaccine manufacturers should develop a receptive organizational structure to be based on elements of viability of local production. Third, a coordinated system at the international level to support these processes in individual countries needed to be set up. This proposed coordinative system of a global consortium of manufacturers would be managed by WHO and would enable the sharing of management expertise and technical knowledge among its members and would ensure that international consultant advice would be consistent. It would also promote partnerships and interactions with public sector manufacturers in industrialized countries.
This global WHO plan concept referred to earlier similar proposals made by the Netherlands Institute of Public health (RIVM)  and the Massachusetts Public Health Laboratories in the US and it aimed to build on the ongoing SIREVA initiative. The emphasis of the proposed activities was on quality, production rationalization, regional national control laboratories, and training in Good Manufacturing Practices (GMP). The plan did not elaborate on specific work plans and research priorities . However, when presented to the Fifth Annual Meeting of CVI’s Consultative Group in São Paulo in October 1995 , it was rejected. Despite support from several developing country producers, such as the Butantan Institute, several experts and representatives from the international vaccine industry were skeptical and expressed doubts about the viability of public sector manufacturing. Soon after, WHO silently shelved the plan. Some public sector supporting participants, such as Isaias Raw from Brazil, later expressed their opinion that the international vaccine industry saw the proposed consortium as a “cartel” (Raw I., 2011, personal communication). Interestingly, about 5 years later, several of the elements and proposed activities of this plan were taken on by the creation of the Developing Countries Vaccine Manufacturer’s Network (DCVMN) in 2001 .
The Dutch Nordic Consortium (DNC)
“the SIREVA initiative is committed to improve the scientific and technological infrastructure and management of science for public health in Latin America; that the DNC is committed to the joint development of new vaccines and to transfer its expertise to developing countries and that regional cooperation needs to be promoted in the CVI”.
“The new set of initiatives (such as CVI) share a recognition that public institutions must assume a central role in managing decisions about vaccine research, development, production, and distribution”.
However, when the CVI’s strategic plan was finally published in 1993, none of these proposals had been adopted. The public sector institutions were not seen as an essential part of CVI’s strategy neither individually nor acting as regional networks.
The tetravalent pneumococcal conjugate vaccine project
The DNC embarked on the development of a conjugate vaccine project because it was thought that the pooled scientific and technical experience and expertise in the five institutions would ensure a reasonable chance of success. The Swedish and the Dutch institutes had in earlier projects [25, 26] accumulated pioneering experience in the innovative conjugation technology , and with the added capacity of the other Scandinavian institutes on serotyping, animal assays and clinical study design, the consortium basically possessed all knowledge and infrastructure to succeed. S. pneumoniae was chosen as a vaccine target, because of its high morbidity and mortality in developing countries.
Of the 8.8 million global annual deaths amongst children under 5 years of age in 2008, WHO estimated in 2012 that 476 000 were caused by pneumococcal infections. Disease rates and mortality are higher in developing than in industrialized settings, with the majority of deaths occurring in Africa and Asia. Although there existed a polysaccharide vaccine against the bacterium, it appeared not to be effective in children under 2 years of age. There was evidence that a conjugated vaccine, made by attaching a poorly immunogenic (polysaccharide) antigen to a carrier protein, would stimulate a more vigorous immune response and would effectively protect young children.
This choice for a, in itself rather complex,2 conjugation-technology approach for a vaccine against pneumococcal infections proved to be correct as shown by the subsequent emergence of a highly profitable global market for pneumococcal conjugate vaccines (PCVs) in developing countries, now shared between Pfizer and GSK [27–29].
After the signing of the DNC Letter of Intent, it still took a long time before start-up grants from the respective governments and the European Union were in place and the project could take off. Detailed bilateral collaboration agreements were made in advance to describe each partner’s specific contributions and responsibilities in proportion to the financial reimbursements from received grants.
Initially a vaccine was envisaged with the four serotypes that were globally the most frequent cause of pneumococcal disease in children under 2 years of age (6B, 14, 19 F and 23 F). When successful, another four serotypes, with specificity for developing countries would be added to make it an eight-valent vaccine.
The laboratory scale development of saccharide-protein conjugates started at the RIVM in the Netherlands and at the Swedish Bacteriological Laboratory (SBL) in the second half of 1993. RIVM and SBL had both independently developed different conjugation technologies.3 The DNC management committee decided to use the Swedish technology for the DNC vaccine and chose tetanus toxoid from RIVM as the carrier protein. Norway would apply an animal model to test experimental conjugate vaccines. The SSI in Denmark, that housed the WHO Reference Laboratory on pneumococcal isolates and typing, was to develop assays to measure the immune response in animals against each of the specific pneumococcal serotypes that were to be in the DNC vaccine. Finland’s National Institute would take responsibility for the design and operational activities needed for the clinical studies.
The challenges that faced the DNC
Financial and managerial constraints
Funding was a major challenge throughout the project, as it had to be obtained from different sources each with tedious and time-consuming application procedures. In addition to the Institutes’ own financial contribution, the DNC managed to obtain grants from the European Commission, the Netherlands Ministry of Development Cooperation and the Scandinavian Development Agencies for the development, testing and its production at RIVM. The European Commission initially contributed with a grant for a 5 year period (1993–1997) for the vaccine development. This was followed by a second 5 year grant (1997- April 2002), later extended to October 2003. The second EU grant served to clinically test the DNC vaccine in Finland and Vietnam and formed part of another EU funded project (ARIVAC2), coordinated by the Finnish DNC Partner, which was to test an eleven-valent pneumococcal conjugate vaccine developed by Pasteur Merieux Vaccines (now Sanofi Pasteur) in the Philippines.
Overall, the DNC program suffered from too little and insufficient upfront funding that had to be collected from different sources, requiring substantial energy and time of investigators. Despite the long-term preparations and hopeful early indications, in the end, neither the TFCS nor the CVI contributed any funds at all. The modest funds that were raised eventually came with many administrative restrictions, making it hard to proceed fast. Moreover, the EU was not interested in financing the collaboration with SIREVA, that the DNC hoped for.
Privatization and patent claims
“Taking into account their simplicity and feasibility for large-scale preparation of pneumococcal polysaccharide conjugate vaccines at costs appropriate for the general use in developing countries, we hope that the described techniques will be further exploited” .
In return, RIVM also decided to independently file a patent application on its own technology with a plan to provide later on exclusive licenses to partners in developing countries.
In retrospect, these cases of unilateral patent applications had a negative impact on the working relations within the consortium.
The project’s leader moves to the private sector
“vaccine development and production is not any longer possible in the public sector due to inadequate resources, lack of infrastructure and too little will to make it a success” (Poolman, J 1997, personal communication).
The DNC was left without a leader during the transition period that followed. Perhaps coincidentally, at around the same time, another advocate of collaborative public sector vaccine development, George Siber from the Massachusetts Public Health Biologicals Laboratory, had come to a similar conclusion and moved as well to private industry. He jointed Wyeth-Lederle in 1996 where he subsequently played a role in the development and commercialization of the world’s first licensed pneumococcal conjugate vaccine, the seven-valent PCV7 (Prevnar).
Vietnam and the Philippines withhold approval for immunogenicity studies in infants
Around mid-1995, DNC members began to consider the region or country where the vaccine could be tested in the field. SIREVA/PAHO with its network in Latin America seemed a logic choice . Bilaterally, RIVM also had good contacts with PAHO on training programs about vaccine quality control and quality assurance. It also had contacts with vaccine manufacturers in Latin America, such as the Butantan Institute, also involved in SIREVA.
The DNC management proposed to the European Commission to field-test the DNC vaccine in the Latin American region, by first building up local capacity for pneumococcal quality control and analytical tests followed by vaccine production technology transfer, for example to the Butantan Institute. However, this did not fit the European Commission policy at that time. The relevant EU working program had prioritized the Asian region over the Latin America region. As a result there were no funds for a SIREVA-DNC collaboration . On top of this, the Butantan management appeared not to be interested in facilitating a field test in Brazil with a DNC vaccine if this vaccine had not been produced in Brazil first. Thus, for its second grant proposal to the EU, the DNC turned its attention to Asia and in Vietnam. The Danish DNC member, SSI, had good contacts there through the Academic Hospital in Copenhagen and a large paediatric hospital in Ho Chi Minh City.
With the second EU grant in place, sites for the clinical studies in infants were prepared in southern Vietnam and Vietnamese staff was sent for training to Denmark, where the serological analysis was to be done. The Vietnamese study investigators submitted a formal application to the regulatory authorities in Hanoi. The application included a protocol for clinical trials and a brochure for clinical investigators, made by the DNC and proposed a field study in southern Vietnam with the tetravalent DNC pneumococcal conjugate vaccine produced by RIVM. However, the regulatory body’s ethical review committee withheld approval. Unaccustomed to authorizing new investigational vaccines not yet licensed in other countries and that had not been produced in Vietnam, their main concern was with the possibility of serious adverse events. This was despite the documented evidence of successful safety testing in Finnish Phase 1 studies. At the time of application, rumors were circulating on adverse events caused by locally made vaccines and the regulatory body did not want to take any risks. [36, 37]. This rejection was a major setback and it necessitated a search for a new study in another country.
By the end of 2002, the consortium management agreed with the European Commission to transfer the site of the Phase 2 trial in infants from Vietnam to the Philippines. By this time RIVM had announced that due to other priorities it would not to continue the clinical development of the vaccine. Nevertheless, the reasoning was that, if the vaccine proved immunogenic, the prototype could be offered for further development by another manufacturer, possibly in a developing country. However, the ethical review board of the partner institute in the Philippines, the RITM, also witheld its approval. Since RIVM would not continue the clinical development, the availability of the vaccine was uncertain. In view of this, the risks of subjecting these infants to an experimental vaccine outweighed its uncertain benefits  . This second refusal marked the end of the DNC pneumococcal vaccine development project.
The decision by the Vietnamese regulatory body is best understood as due to its weak regulatory capacity. At that time it had no procedures for dealing with applications for investigational new vaccines not made in Vietnam. In fact, the weakness of the Vietnamese national regulatory authority has been a concern for many decades, and very recently, after an intensive capacity building program, has it been approved as the Vietnamese NRA has reached the international status of being fully competent to exercise the six essential regulatory functions seen as essential by WHO . The rejection by the ethical review in the Philippines was due in part to the information that RIVM would not continue the vaccine development. It also reflected the availability of a commercial seven-valent vaccine that covered all the serotypes (and more) that were contained in the DNC vaccine. The only justification for continuation, that the technology might be transferred in the future to manufacturers in developing countries, proved not to be a convincing argument. None such manufacturer had been identified.
What can we learn from this experience?
The consortium was not endorsed by the global vaccine community
Despite the initially active interactions between the DNC and the TFCS, and later the CVI, eventually neither concrete collaboration nor front-ending funding materialized from that side. The CVI, once established, became the international forum for UN organizations, policymakers, technical agencies, academia and industry to discuss all matters regarding vaccine development and vaccine supply for developing countries. The DNC was unable to become incorporated into the CVI, one of the reasons being that the Netherlands and the Scandinavian countries, as an important donor countries to WHO’s EPI program expressed concerns that the “US-driven” research driven and technology-focused CVI movement would jeopardize EPI country delivery programs . On several occasions, the RIVM management, emphasizing its international technology transfer experience, reflected in a 1995 RIVM International Vaccine Policy Brochure , called for an action-oriented approach and promoted a stronger role of public sector vaccine manufacturing in the CVI, but the impact remained minimal. Over time, the CVI moved gradually towards more partnerships with the international vaccine industry.
The lack of a recipient vaccine manufacturer proved a major weakness
The attempt to establish a “bridging”” relationship between SIREVA/PAHO and the DNC did not materialize. In retrospect, we argue that it was a major weakness that no developing country partner had been engaged from the early stages onwards. By not including such partner from the beginning, the research-focused consortium was insufficiently able to manage the project from the perspective of either a manufacturing or a regulatory recipient. Little attention was paid to process-upscaling or to preparing a technology transfer package to engage to the Butantan Institute in Brazil. There had been no early interactions with regulatory authorities in Vietnam and the Philippines in anticipation of the clinical studies.
Privatization policies hindered public sector collaboration
“When it suited politically the “Dutch Nordic Consortium” concept was enthusiastically exploited, but real commitment backed with substantial funding, that was an entirely different matter” (Bootsma P.,2015, personal communication).
”The DNC was useful in the beginning because at that time some countries were not yet members of the EU; but it was not so successful with the exception of R&D pneumococcal vaccine development” .
Since meanwhile all DNC countries have now stopped vaccine manufacturing in the public domain, DNC collaboration on vaccine issues has ceased to exist at the policy level. The one common interest in vaccines that has remained is the sharing of best practices on vaccine purchases from industry for their respective national immunization programs of vaccines. Increasingly, such common interests are guarded through mechanisms of joint procurement through the European Union .
In conclusion, collaborative vaccine development on common political grounds, but with insufficient upfront funding and unclear end-goals is a risky undertaking and unlikely to succeed. Although a promising tetravalent pneumococcal prototype vaccine resulted from this effort, it was not taken further due to a variety of policy-related factors described in this case study.
The sobering Dutch Nordic Consortium experience formed the basis within RIVM to design, towards the end of the 90s, a less ambitious and technically simpler development and technology transfer project for a monovalent conjugate vaccine against Haemophilus influenza type b (cHib). The key difference with the DNC program was that this time the management approach was entirely partner- and regulatory driven. The goal of the cHib project was straightforward: transfer of technology for an already licensed vaccine, making it a “me too” product and therefore easier for regulators. Most importantly, the early involvement of future recipient manufacturing partners (who co-financed the research and development) ensured that every decision to be taken was evaluated from a receiving partner’s perspective as well as from a regulatory perspective and possible impact on the time to license [45, 46].
The profile of the RIVM as an advanced European public sector vaccine development and manufacturing institute actively sharing technology with developing countries has faded over the last decades. Despite some notable successes in international vaccine technology capacity building and transfer  and the cHib project, the national mission to develop and produce new vaccines for the Dutch national immunization program, became politically unsustainable. The Institute’s policy to consolidate its national manufacturing task through securing a key global health position in support of a network of public vaccine manufacturers  found insufficient support from the Dutch government, nor from WHO, despite a strong appeal in 1999 by the Dutch Minister of Health for a core-membership in the GAVI Board for RIVM’s Director-General . Difficulties to keep up with high costs, high-risk innovative vaccine development and production in a public sector setting led to the gradual loss of production tasks and to the 2009 decision by the Government to privatize the vaccine production tasks of the Institute.
AMC, advanced market commitment; cHib, conjugate Haemophilus influenzae type b vaccine; CVI, Children’s Vaccine Initiative; DNC, Dutch Nordic Consortium; EPI, Expanded Programme on Immunization; GAVI, Global Alliance for Vaccines and Immunization; GMP, good manufacturing practice; MSF, Médicins Sans Frontières; PAHO, Pan American Health Organization; PCV, Pneumococcal conjugate vaccine; RITM, Research Institute of Tropical Medicine; RIVM, National Institute of Public Health and the Environment, the Netherlands; SBL, State Bacteriological Laboratory, Sweden; SIIDC, Swedish Institute for Infectious Diseases, Sweden; SIREVA, SIstema de REdes de Vigilancia de los Agentes bacterianos responsables de neumonía y meningitis; SSI, Staten Serum Institute, Denmark; TFCS, taskforce for child survival; UNDP, United Nations Development Programme
At that time, a new conjugate vaccine against pneumococcal infections was regarded to be of little commercial interest.
Jan Poolman, who left RIVM in 1996 to join GSK, co-authored a review on the history of pneumococcal conjugate vaccine development in 2013. That paper describes the strategic importance of choosing the right combination of technical factors that illustrate the complexity of manufacturing of polyvalent conjugate vaccines, such as establishing the correct dose, the best carrier-protein for each of the serotypes and the most appropriate conjugation technology .
The Swedish and Dutch conjugation technologies employed in the DNC project differ in the way how the polysaccharide is linked to the carrier protein. The Swedish method used thiolation of polysaccharides with 2-iminothiolane [32, 49], followed by coupling to the bromoacetylated carrier protein to obtain thioether-linked PS-protein conjugates. The advantages are that it is fast and suitable for larger polysaccharides and causes less cross-linking. The RIVM method used reductive amination of polysaccharides with cystamine to obtain thiolated polysaccharides .
For example: a dual strategy for pneumococcal vaccines (national/international) within RIVM, led to a lack of focus and delays: while for developing countries a conjugation strategy was followed in the DNC project, RIVM had simultaneously started research for the Dutch immunization program on a vaccine development approach based on a common pneumococcal protein, “pneumolysin” to which it had acquired a patent. In 1997, the RIVM management expected that the Wyeth Lederle PCV7 vaccine would reach the Dutch market within 2 or 3 years. Negotiations with Lederle were considered to exchange RIVM’s pneumolysoid patent and know-how for access to Lederle’s conjugate product .
The authors would like to thank Andrzej Pawlowski (Sweden), Gunilla Källenius (Sweden), Freddie Karup Pedersen (Denmark), Hanne Nøkleby (Norway), Helena Käythy (Finland), Peter Hoogerhout (the Netherlands), Jan Poolman (the Netherlands) , Ruud van Noort (the Netherlands) and Peter Bootsma (the Netherlands) for comments on an earlier version of the article. Mw Irma Lambregts is acknowledged for assisting in the research in the RIVM archives.
JH was responsible for archival research in the Netherlands and participated in collection and review of secondary sources. SB participated in collection and review of secondary sources and in drafting the article. Both authors read and approved the final manuscript.
The authors declare that they have no competing interests.
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