Introduction of Haemophilus influenzae type b (Hib) vaccine in low- and middle-income countries has been limited by cost and availability of Hib conjugate vaccines for a long time. It was previously recognized by the Institute for Translational Vaccinology (Intravacc, originating from the former Vaccinology Unit of the National Institute of Public Health [RIVM] and the Netherlands Vaccine Institute [NVI]) that local production of a Hib conjugate vaccine would increase the affordability and sustainability of the vaccine and thereby help to speed up Hib introduction in these countries. A new affordable and a non-infringing production process for a Hib conjugate vaccine was developed, including relevant quality control tests, and the technology was transferred to a number of vaccine manufacturers in India, Indonesia, and China. As part of the Hib technology transfer project managed by Intravacc, a preclinical toxicity study was conducted in the Netherlands to test the safety and immunogenicity of this new Hib conjugate vaccine. The data generated by this study were used by the technology transfer partners to accelerate the clinical development of the new Hib conjugate vaccine. A repeated dose toxicity and local tolerance study in rats was performed to assess the reactogenicity and immunogenicity of a new Hib conjugate vaccine compared to a licensed vaccine. The results showed that the vaccine was well tolerated and immunogenic in rats, no major differences in both safety and immunogenicity in rats were found between the vaccine produced according to the production process developed by Intravacc and the licensed one. Rats may be useful to verify the immunogenicity of Hib conjugate vaccines and for preclinical evaluation. In general, nonclinical evaluation of the new Hib conjugate vaccine, including this proof of concept (safety and immunogenicity study in rats), made it possible for technology transfer partners, having implemented the original process with no changes in the manufacturing process and vaccine formulation, to start directly with phase 1 clinical trials.
Keywords: ELISA, enzyme-linked immunosorbent assay; EP, European Pharmacopeia; Haemophilus influenzae type b; Hib, Haemophilus influenzae type b; IgG, Immunoglobulin G; Intravacc, Institute for Translational Vaccinology; LCB, Laboratory of Control of Biological Products; NIBSC, National Institute for Biological Standards and Control (UK); NVI, Netherlands Vaccine Institute; OECD, Organization for Economic Cooperation and Development; PRP, poly-ribosylribitol phosphate (Hib capsular polysaccharide); PRP-T, Hib capsular polysaccharide conjugated to Tetanus Toxoid; QC, quality control; RIVM, The National Institute for Public Health and the Environment (Rijksinstituut voor Volksgezondheid en Milieu); SPF, specific pathogen free; WHO, World Health Organization; conjugate; preclinical; rats; technology transfer; vaccine.