innovating vaccines

Development of inactivated polio vaccine derived from attenuated Sabin strains

Introduction

Worldwide efforts to eradicate polio recently caused a strategic change in polio vaccination recommendations. A switch from oral polio vaccine, which can cause circulating and virulent vaccine derived polioviruses, to inactivated polio vaccines (IPV) is foreseen shortly.

However, current IPV supply is limited, and the cost price is relatively high when compared with oral polio vaccine. To enhance worldwide production of affordable IPV, a cost-effective manufacturing process using attenuated (Sabin) poliovirus strains, instead of wild-type polioviruses, has been developed in collaboration with the World Health Organization (WHO).

The resulting Sabin-IPV (sIPV) was developed for technology transfer to local manufacturers. By using weakened polioviruses (the attenuated Sabin poliovirus strains) in production, the risk of facilities related outbreaks can be reduced significantly when compared with conventional IPV manufacturing.

Intravacc historyThe first vaccine against poliovirus was developed in the 1950s by Jonas Salk. This vaccine (IPV) consists of an injectable dose of purified and inactivated wild-type polioviruses. Soon after this discovery, at Intravaccs predecessors in Bilthoven, an industrial scale production process for IPV was developed based on several inventions like for example the micro-carrier technology for adherent cell culture. From the substantial history regarding inactivated polio vaccine production in Bilthoven, a valuable dataset has been generated. Data from dozens of batches at two different industrial production scales were analysed using multivariate data analysis. This statistical method is stimulated by regulatory authorities to improve scientific understanding of production processes for troubleshooting and improved process control.

Scale-down approachTo accommodate IPV production process improvement and optimization, a scale-down version of the legacy production process was set-up based on the multivariate data analysis results. The lab-scale unit

Factsheet Polio | July 2016

Vero cell growth supported by microcarrier beads.

Technology transferCurrently, the sIPV technology is transferred to emerging manufacturers in low- and middle-income countries. Intravacc has licensed the sIPV technology to a number of selected industrial partners, and will be providing training and support. The lab-scale sIPV production process is currently being used for hands-on training of our technology transfer partners. In parallel, continued process optimization and improvement can contribute to increase the sIPV quantities available for the post-eradication era.

operations (i.e. cell- and virus culture, clarification, concentration, column chromatographic purification, and inactivation) can now be used separately, as well as sequentially, to study variations and critical product quality attributes in the production process. Also, it has been shown that the scale-down version can be used to prepare trivalent vaccine at lab- and pilot-scale. The resulting IPV was shown to have comparable characteristics with product produced at manufacturing scale.

Sabin-IPV developmentThe same scale-down polio vaccine manufacturing process was recently used for the fast-track development of a new sIPV to meet WHO requirements for a safer-for-production and affordable inactivated polio vaccine for local manufacturing. In this way, analytical methods were developed, and process adaptations and modernizations were implemented prior to Master- and Working Virus Seedlot production, and to define the conditions for large-scale sIPV clinical lot production.

Clinical studiesThree dose levels of sIPV, were produced for clinical evaluation with respect to the safety and immunogenicity. To explore dose-sparing and cost-price reduction opportunities, sIPV was also adjuvanted with aluminium hydroxide. The highest dose level of both plain and adjuvanted sIPV were first evaluated in a phase I trial in healthy adults (both in Poland and in Cuba). After showing safety, this trial was followed by a phase I-IIa trial in new-born infants (in Poland). In both trials, a reference group received conventional IPV. Virus-neutralizing titers against both Sabin- and wild-type strains were determined before and after (the last) vaccination with sIPV.

Seroconversion rates in infants after sIPV vaccination were 95–100% for Sabin- and wild-type strains. Three doses of sIPV or adjuvanted sIPV in infants induced high protective virus titers, both against Sabin- and wild-type strains (i.e. cross-protection was shown), even at a low dose level. In conclusion, sIPV and adjuvanted sIPV were immunogenic and safe both as booster dose in adults (also in tropical settings) and for primary immunization of infants.

Factsheet Polio | July 2016

IntravaccThe Institute for Translational Vaccinology is an experienced, not-for-profit R&D organization. With our unique capabilities and infrastructure, we are able to optimize vaccines, vaccine processes and vaccine technologies. Our aim is to increase equality in access to vaccines throughout the world in order to contribute to public health. We achieve this by transferring our knowledge and technologies to public and private partners worldwide and collaborative R&D. A team of 150 professionals is at your disposal at Science Park Bilthoven in The Netherlands.

ContactDr. Wilfried Bakker Program Manager Polio Vaccines T: +31 (0) 30 7920 405 wilfried.bakker@intravacc.nl Intravacc Antonie van Leeuwenhoeklaan 9 3721 MA BILTHOVEN T: +31 (0) 30 7920 300 info@intravacc.nl www.intravacc.nl

Overview of activities to shift from conventional Salk-IPV to Sabin-IPV.

Multireactor system as scale-down version for fast-track Sabin-IPV process development & hands-on training purposes.