Update on improving IPV
This is an update to the article entitled “Improving IPV” published in the first issue of the Polio pipeline (Issue 1, Summer 2008). The aim of this project is to make inactivated poliovirus vaccine (IPV) affordable to countries which may choose to use it after oral poliovirus vaccine (OPV) cessation. A five-pronged strategy is being pursued:
1) Schedule and dose-reduction
A number of studies have shown that a routine schedule with IPV given at 2, 4, and 6 months of age provides immunity in >90% of children, also in developing countries. A 2-dose schedule provided at 2 and 4 months is suboptimal (<90% seroconversion to at least some serotypes). Recently, a decision was made to conduct a new 2-dose trial in 2009-2010 to evaluate whether >90% seroconversion could be achieved if the first IPV dose is delayed to later in life (e.g. 4 months) and the interval between the two IPV doses is extended (e.g. by 4 months).
In terms of dose reduction, preliminary results are available from two fractional-dose trials: Cuba and Oman. In both trials, a needle-free device - Biojector®2000 - was used to administer the intradermal fractional doses (1/5th of a full dose). The results are excellent for the 2, 4, and 6-month schedule in Oman, where >95% of children seroconverted to all three poliovirus serotypes. The results in Cuba provides additional evidence that IPV at 6, 10, and 14 weeks is suboptimal in inducing adequate immunity, and furthermore, with this early schedule, the intradermal arm performed substantially inferior compared with the intramuscular arm.
Nevertheless, the data are extremely encouraging and suggest that the fractional dose strategy may provide a viable option for decreasing costs without loss of immunity. Trial results will be submitted for publication in the second quarter of 2009.
2) Adjuvant to decrease antigen requirement per dose
A number of research groups have evaluated traditional adjuvants for IPV and have reported that a 3 to 5-fold reduction in antigen content may be feasible. Recently, the Infectious Disease Research Institute (IDRI) in Seattle, USA, with funding provided through the Polio Research Committee (PRC), has been examining newer adjuvants which could lead to further decreases in antigen needs, including oil and water emulsion. The results of this study should be forthcoming in the first quarter of 2009.
3) Alternative inactivation agents
Given that formalin is quite abrasive to poliovirus and may destroy some of the antigenic sites on the capsid of the virus, a collaboration has been established with the Netherlands Vaccine Institute (NVI) to examine β-propriolactone as an alternative inactivation agent for the inactivation of poliovirus strains used in the IPV. Since β-propriolactone is used to inactivate rabies virus, there is a body of evidence already available for this agent. In addition, a preliminary study suggested that IPV inactivated by β-propriolactone is substantially more immunogenic than IPV inactivated by formalin. The results of this work should be available in 2010.
4) Optimizing production processes
Production processes have been established first in the 1950s (Salk) and then in the 1960s (van Wezel). Since then few improvements were noted. However, increasing the cell densities in the bioreactors to grow poliovirus or examining suspended cells increase the antigen yield, and potentially lower the production costs.
5) Production in developing country settings
Because of the stringent containment requirements after polio has been eradicated, the production of IPV in developing countries must be based on Sabin or other strains. Because of this, WHO has established a collaboration with NVI to develop a Sabin-based IPV. The pharmaceutical development of this product has nearly been completed, and the focus is now on the clinical development of this new vaccine over the next 3 to 5 years. Preliminary results suggest that the immunogenicity of Sabin virus is superior for type 1 polio, inferior for type 2 polio, and roughly equivalent for type 3 polio. Ultimately, through technology transfer, developing country manufacturers should be in a position to produce Sabin-IPV.