Towards a sustainable, quality and affordable Haemophilus influenzae type b vaccine for every child in the world

Haemophilus influenzae type b (Hib) conjugate vaccine is a safe and effective vaccine that can prevent meningitis and pneumonia caused by Hib disease. Hib vaccine is recommended for all children under 5 years. Despite the availability of safe and effective Hib vaccines since early 1987, Gambia was the only low-income country that had introduced Hib vaccine in its national immunization program. In 2000 it was reported that the disease accounted for about eight million illnesses each year resulting in approximately 400,000 deaths of children aged 1-59 months almost all in low-income countries . The introduction of Hib vaccines in these countries was limited because of the relatively high price of the vaccine and limited availability. Further, many countries lack information on the disease burden and consequently on the costeffectiveness of the vaccine. To address this problem the National Institute for Public Health and the Environment (Rijksinstituut voor Volksgezondheid en Milieu, RIVM, in Bilthoven, The Netherlands) decided in 1998 to help emerging vaccine manufacturers in gaining access to Hib technology through technology transfer and thereby contributing to a sustainable supply of affordable Hib vaccines to low- and middle-income countries and to the United Nations Millennium Development Goals (MDGs) in reducing child mortality. There was no need to develop an in-house Hib vaccine for the Dutch population, as an imported Hib vaccine was already being used for years in the Dutch national immunization program. So the decision to develop a Hib vaccine was solely for technology transfer to local manufacturers (chapter 2). The Hib technology developed by RIVM was successfully transferred to Biological E (BE, India), Serum Institute of India (SII, India), Bio Farma (Indonesia) and Shanghai Institute of Biological Products (SIBP, China). The technology transfer to SIBP was facilitated by Glovax (Korea). All four partners were able to implement the process in their facilities. SII succeeded in obtaining a marketing license for their Hib vaccines in 2007 and BE was able to WHO prequalify a pentavalent vaccine including Hib in 2011. Several Hib vaccines produced by SII are now also WHO prequalified. Bio Farma decided in 2009 to use a different conjugation technology from the one transferred by RIVM/NVI1 and has licensed its Hib vaccine in 2013. Technology transfer to SIBP started in 2006, till date SIBP didn’t commercialize Hib vaccine, as the Chinese authorities decided not to allow clinical studies using this Hib vaccine since there are already sufficient other public institutes producing Hib vaccines locally. RIVM succeeded in developing an innovative, scalable, non-infringing (patents and proprietary technology), simple and affordable process for the production of quality Hib vaccines (chapter 3). The process was developed based on public information and prior knowledge on conjugate vaccines. Further, additional experiments were performed in order to support the choices made during the process development and to decide on the critical quality parameters. Recently a predictive mathematical model was developed for the Hib process. This model helped to evaluate the existing process and to study possibilities for process optimization. Besides the process and all related quality control tests, additional immuno assays were developed in order to support the development of the new Hib conjugate vaccine (chapter 4). The immuno assays developed by RIVM/NVI were very helpful during process development. All these test methods were transferred to the partners as part of the technology transfer package. Besides for the purpose of process implementation and scale up some ELISA methods were used by technology transfer partners for lot release purpose, after proper qualification and validation. The technology transfer package included all documentation related to the process, quality control tests, raw materials and equipment specifications, materials (e.g. seed lot and reference samples) and (pre)clinical data (chapter 5). The preclinical study was performed by RIVM/NVI on a clinical lot produced in close collaboration between Bio Farma (the first Hib technology transfer partner) and RIVM/NVI. Many lessons were learned during the development and technology transfer of the new Hib conjugate vaccine (chapter 6). The technology transfer partners who have used this Hib technology have made a considerable contribution to ensure sustainable supply of affordable Hib vaccines worldwide. Serum Institute of India (SII) made pentavalent vaccine (DTP-HepB-Hib) available to GAVI for $1.75,- per dose starting from 2011 and Biological E (BE) decided to cut the GAVI price to $ 1.19,- per dose starting from 2013. SII and BE are committed to supply about 600 Million doses of this vaccine in the coming years to GAVI. Till 2007, GAVI had only one European supplier and the price of pentavalent vaccine was $3.56,- per dose. The approach followed for the Hib project can be applied to other technology transfer projects. Before starting the project an extensive and detailed feasibility study was performed to evaluate the following aspects: freedom-to-operate, prior knowledge, expected cost price of the vaccine, project continuity including impact on on-going projects, funding, potential partners and available market. Based on the outcome of this feasibility study the product target profile was defined and decisions were made on the approach to be followed during process development and technology transfer. The process developed had to allow freedom-to-operate (noninfringing with existing patents and proprietary rights) and to result in very stable intermediate and final products. Although the product to be produced using this process was a freeze-dried Hib conjugate vaccine, it was taken into consideration that technology transfer partners would eventually be aiming at a liquid formulation of both standalone and combination vaccines. As the developed process was not going to be used for routine production of the Hib vaccine in the Netherlands, all Hib technology transfer partners were advised to invest in a research infrastructure for conjugate technology in order to be able to perform further scaling up and troubleshooting after the finalization of the technology transfer. The scalability and the GMP applicability of the process were taken into consideration during process development. As part of the feasibility study performed by RIVM before being able to start the Hib project the expected cost of goods was calculated (chapter 7). The cost of goods was recalculated at a later stage using a mathematical model. COGs calculated using both methods was in the same range. The availability of a process model for Hib conjugate vaccine is advantageous because it makes it possible to perform a sensitivity analysis if certain decisions are to be taken and/or process optimization is considered. Through this Hib project, Intravacc’s partners were provided with general conjugation knowhow, and related quality control tests, resulting in a broadening of their research and development portfolio with several conjugate vaccines including meningococcal, and pneumococcal vaccine. Further, The Hib technology allowed producing freeze-dried and liquid formulations of several standalone and combination vaccines. The Hib project has also demonstrated the importance of technology transfer to local manufacturers ensuring a sustainable supply of underused vaccines to low- and middle-income countries