Induction of humoral and cell-mediated immunity to the NS1 protein of TBEV with recombinant Influenza virus and MVA affords partial protection against lethal TBEV infection in mice

Abstract

IntroductionTick-borne encephalitis virus (TBEV) is one of the most relevant tick-transmitted neurotropic arboviruses in Europe and Asia and the causative agent of tick-borne encephalitis (TBE). Annually more than 10,000 TBE cases are reported despite having vaccines available. In Europe, the vaccines FSME-IMMUN® and Encepur® based on formaldehyde-inactivated whole viruses are licensed. However, demanding vaccination schedules contribute to sub-optimal vaccination uptake and breakthrough infections have been reported repeatedly. Due to its immunogenic properties as well as its role in viral replication and disease pathogenesis, the non-structural protein 1 (NS1) of flaviviruses has become of interest for non-virion based flavivirus vaccine candidates in recent years.MethodsTherefore, immunogenicity and protective efficacy of TBEV NS1 expressed by neuraminidase (NA)-deficient Influenza A virus (IAV) or Modified Vaccinia virus Ankara (MVA) vectors were investigated in this study.ResultsWith these recombinant viral vectors TBEV NS1-specific antibody and T cell responses were induced. Upon heterologous prime/boost regimens partial protection against lethal TBEV challenge infection was afforded in mice.DiscussionThis supports the inclusion of NS1 as a vaccine component in next generation TBEV vaccines.

Poor virus-specific T-cell responses early after tick-borne encephalitis virus infection correlate with disease severity

“…Animal models have demonstrated that virus-specific antibodies contribute to protective immunity against TBEV infections [ 13 , 17–21 ]. Also in humans, TBEV-specific antibodies have been identified as a correlate of protection [ 6 ].…”

“…Upon infection with TBEV, stronger antibody responses to the E and NS1 proteins are induced than after vaccination [ 2 , 32 ]. We recently showed in mice that antibodies against TBEV E and NS1 proteins afford full or partial protection [ 13 , 18 ]. In the present study, we determined virus-specific IgG, IgM levels and antibody responses to the EDIII and NS1 protein and their neutralizing activity in view of disease severity and outcome.…”

“…The same holds true for the virus-specific antibody response. For example, it has been shown in a mouse model that in addition to virus-neutralizing antibodies, antibodies to non-structural protein 1 (NS1) contribute to protective immunity [ 13 , 14 ], but their role in human infections has not been conclusively demonstrated. We hypothesize that virus-specific cellular and possibly humoral responses induced early during TBEV infection determine clinical course of TBE, including its severity and long-term outcome.…”

Immunity to Tick-Borne Encephalitis Virus NS3 Protein Induced with a Recombinant Modified Vaccinia Virus Ankara Fails to Afford Mice Protection against TBEV Infection

“…Recombinant MVA with integrated NS3 sequence in deletion site III (MVA-NS3) was generated by homologous and intragenomic homologous recombination using the modified standard protocol [ 37 ] ( Figure 1 A). MVA-NS3 was propagated in primary CEF cells and concentrated as described previously [ 35 , 36 ].…”

“…Recently, we constructed and tested recombinant MVA candidate vaccines expressing the prM-E and NS1 TBEV proteins, respectively. With these recombinant MVAs, we were able to induce E- and NS1-specific antibody and T cell responses which afforded complete or partial protection, respectively, against lethal challenge infection in mice [ 35 , 36 ].…”