Single-dose vaccine against tick-borne encephalitis

Abstract

Tick-borne encephalitis (TBE) virus is the most important human pathogen transmitted by ticks in Eurasia. Inactivated vaccines are available but require multiple doses and frequent boosters to induce and maintain immunity. Thus far, the goal of developing a safe, live attenuated vaccine effective after a single dose has remained elusive. Here we used a replication-defective (single-cycle) flavivirus platform, RepliVax, to generate a safe, single-dose TBE vaccine. Several RepliVax-TBE candidates attenuated by a deletion in the capsid gene were constructed using different flavivirus backbones containing the envelope genes of TBE virus. RepliVax-TBE based on a West Nile virus backbone (RV-WN/TBE) grew more efficiently in helper cells than candidates based on Langat E5, TBE, and yellow fever 17D backbones, and was found to be highly immunogenic and efficacious in mice. Live chimeric yellow fever 17D/TBE, Dengue 2/TBE, and Langat E5/TBE candidates were also constructed but were found to be underattenuated. RV-WN/TBE was demonstrated to be highly immunogenic in Rhesus macaques after a single dose, inducing a significantly more durable humoral immune response compared with three doses of a licensed, adjuvanted human inactivated vaccine. Its immunogenicity was not significantly affected by preexisting immunity against WN. Immunized monkeys were protected from a stringent surrogate challenge. These results support the identification of a single-cycle TBE vaccine with a superior product profile to existing inactivated vaccines, which could lead to improved vaccine coverage and control of the disease.flavivirus vaccine | prophylaxis | preclinical | nonhuman primate

Synergistic Internal Ribosome Entry Site/MicroRNA-Based Approach for Flavivirus Attenuation and Live Vaccine Development

“…However, in contrast to prM/E genes, reduction in C gene expression would likely cause little effect on induction of antiviral immunity. In agreement with that is an observation that complete deletion of the C gene in single-round (replication-defective) or DNA flavivirus vaccines did not interfere with their immunogenicity (3, 19–23). We, therefore, speculate that the developed genetic configuration will drive the superior immunogenic properties of bicistronic flavivirus vaccines compared to strategies developed earlier.…”

Tick-Borne Flaviviruses, with a Focus on Powassan Virus

“…Other approaches offer replication-defective, chimeric vaccines, in which parts of the TBFV genome are replaced by homologous genomic regions derived from a heterologous (e.g., mosquito-borne) flavivirus. In animal models, these vaccine candidates have been shown to be highly immunogenic even after a single dose (123).…”

Current status and future prospects of yellow fever vaccines

“…Similarly, the ChimeriVax® West Nile virus candidate WNV02 was recently assessed in a dose-ranging, phase II safety trial enrolling 208 healthy adults for three age cohorts, revealing 96 percent seroconversion at 28 days that was correlated with vaccine dose [57, 58]. While these studies with mosquito-borne flaviviruses suggest that the nonstructural protein genes of 17D encode the attenuated phenotype, utilization of the ChimeriVax® technology for a tick-borne encephalitis virus prM/M-E chimera did not produce the desired attenuated phenotype in preclinical studies [59]. …”