The consistency approach for the substitution of in vivo testing for the quality control of established vaccines: practical considerations and progressive vision.

The aim of this letter is to share the discussions and proposals made by the VAC2VAC consortium on how to support the deployment of the "Consistency Approach" for quality control of established vaccines and thus facilitate the substitution of in vivo testing. This work answers specific questions about " what does a control strategy according to the consistency testing look like" and " how to submit a control strategy defined according to the consistency testing". Some topics were answered in a very straightforward manner. This was the case when the deployment of the consistency approach and the corresponding changes in vaccines control strategy was supported by the generic application of procedures already described in regulatory guidelines/requirements and related to the establishment or change in the control strategy of vaccines. The application of other procedures required more specific attention and some were deeply debated before reaching a proposal. The key outcomes of this work are that robust science must be used to develop a substitution strategy and generate supportive data packages. And this good science can best occur with good scientific collaboration between the different parties involved. Therefore, early interaction between manufacturers and competent authorities before and during dossier submission is critical to success. The consistency approach, when approved and in place, will ensure vaccine products of assured quality reach the patient in a more efficient manner than when relying on in vivo testing. Adapting the mindset was one of the major hurdles to a progressive vision but there is now consensus between manufacturers and competent authorities to foster the elimination of in vivo testing for routine vaccine release testing.

Technical Development of a New Meningococcal Conjugate Vaccine.

BACKGROUND: Group A Neisseria meningitidis has been a major cause of bacterial meningitis in the sub-Saharan region of Africa in the meningitis belt. Neisseria meningitidis is an encapsulated pathogen, and antibodies against the capsular polysaccharide are protective. Polysaccharide-protein conjugate vaccines have proven to be highly effective against several different encapsulated bacterial pathogens. Purified polysaccharide vaccines have been used to control group A meningococcal (MenA) epidemics with minimal success. METHODS: A monovalent MenA polysaccharide-tetanus toxoid conjugate was therefore developed. This vaccine was developed by scientists working with the Meningitis Vaccine Project, a partnership between PATH and the World Health Organization. RESULTS: A high-efficiency conjugation method was developed in the Laboratory of Bacterial Polysaccharides in the Center for Biologics Evaluation and Research and transferred to the Serum Institute of India, Ltd, which then developed methods for purification of the group A polysaccharide and used its tetanus toxoid as the carrier protein to produce the now-licensed, highly effective MenAfriVac conjugate vaccine. CONCLUSIONS: Although many years of application of meningococcal polysaccharide vaccines have had minimal success in preventing meningococcal epidemics in the meningitis belt of Africa, our collaborative efforts to develop a MenA conjugate vaccine yielded a safe and highly effective vaccine.

Immunogenicity and safety of a new meningococcal A conjugate vaccine in Indian children aged 2-10 years: a phase II/III double-blind randomized controlled trial.

This study compares the immunogenicity and safety of a single dose of a new meningococcal A conjugate vaccine (PsA-TT, MenAfriVac™, Serum Institute of India Ltd., Pune) against the meningococcal group A component of a licensed quadrivalent meningococcal polysaccharide vaccine (PsACWY, Mencevax ACWY(®), GSK, Belgium) 28 days after vaccination in Indian children. This double-blind, randomized, controlled study included 340 Indian children aged 2-10 years enrolled from August to October 2007; 169 children received a dose of PsA-TT while 171 children received a dose of PsACWY. Intention-to-treat analysis showed that 95.2% of children in PsA-TT group had a ≥4-fold response in serum bactericidal titers (rSBA) 28 days post vaccination as compared to 78.2% in the PsACWY group. A significantly higher rSBA GMT (11,209, 95%CI 9708-12,942) was noted in the PsA-TT group when compared to PsACWY group (2838, 95%CI 2368-3401). Almost all children in both vaccine groups had a ≥4-fold response in group A-specific IgG concentration but the IgG GMC was significantly greater in the PsA-TT group (89.1 µg/ml, 95%CI 75.5-105.0) when compared to the PsACWY group (15.3 µg/ml, 95%CI 12.3-19.2). Local and systemic reactions during the 4 days after immunization were similar for both vaccine groups except for tenderness (30.2% in PsA-TT group vs 12.3% in PsACWY group). None of the adverse events or serious adverse events was related to the study vaccines. We conclude that MenAfriVac™ is well tolerated and significantly more immunogenic when compared to a licensed polysaccharide vaccine, in 2-to-10-year-old Indian children.