Abstract
The poliovirus vaccine field is moving towards novel vaccination strategies. Withdrawal of the Oral Poliovirus Vaccine and implementation of the conventional Inactivated Poliovirus Vaccine (cIPV) is imminent. Moreover, replacement of the virulent poliovirus strains currently used for cIPV with attenuated strains is preferred. We generated Cold-Adapted Viral Attenuation (CAVA) poliovirus strains by serial passage at low temperature and subsequent genetic engineering, which contain the capsid sequences of cIPV strains combined with a set of mutations identified during cold-adaptation. These viruses displayed a highly temperature sensitive phenotype with no signs of productive infection at 37°C as visualized by electron microscopy. Furthermore, decreases in infectious titers, viral RNA, and protein levels were measured during infection at 37°C, suggesting a block in the viral replication cycle at RNA replication, protein translation, or earlier. However, at 30°C, they could be propagated to high titers (9.4–9.9 Log10TCID50/ml) on the PER.C6 cell culture platform. We identified 14 mutations in the IRES and non-structural regions, which in combination induced the temperature sensitive phenotype, also when transferred to the genomes of other wild-type and attenuated polioviruses. The temperature sensitivity translated to complete absence of neurovirulence in CD155 transgenic mice. Attenuation was also confirmed after extended in vitro passage at small scale using conditions (MOI, cell density, temperature) anticipated for vaccine production. The inability of CAVA strains to replicate at 37°C makes reversion to a neurovirulent phenotype in vivo highly unlikely, therefore, these strains can be considered safe for the manufacture of IPV. The CAVA strains were immunogenic in the Wistar rat potency model for cIPV, inducing high neutralizing antibody titers in a dose-dependent manner in response to D-antigen doses used for cIPV. In combination with the highly productive PER.C6 cell culture platform, the stably attenuated CAVA strains may serve as an attractive low-cost and (bio)safe option for the production of a novel next generation IPV.
Highlights
There are two vaccines that can effectively protect against poliomyelitis which have been available for more than 60 years and are still used today
An Inactivated Poliovirus Vaccine (IPV) based on attenuated Sabin strains is recommended, as these strains are currently the only option to move to safer manufacturing of IPV
Their lack of pathogenicity was confirmed by intracerebral inoculation of susceptible transgenic mice that subsequently did not develop any symptoms of poliomyelitis
Summary
There are two vaccines that can effectively protect against poliomyelitis which have been available for more than 60 years and are still used today. OPV and IPV have dramatically reduced the incidence of poliomyelitis since their introduction; with only 74 wild-type poliomyelitis cases worldwide in 2015, restricted to Afghanistan and Pakistan, eradication of the disease is extremely close [4]. In OPV vaccinees these reverted neurovirulent strains can cause Vaccine-Associated Paralytic Poliomyelitis (VAPP), and via shedding, circulating Vaccine Derived Polioviruses (cVDPVs) [6] can cause poliomyelitis outbreaks in areas of low vaccination coverage [7]. The cessation of OPV use in routine immunization and full implementation of vaccination with the safer, but more expensive, IPV is required to enable the final stages of eradication and sustain a polio-free status in the years thereafter [8,9]
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