Experimental Evaluation of the Protective Efficacy of Tick-Borne Encephalitis (TBE) Vaccines Based on European and Far-Eastern TBEV Strains in Mice and in Vitro

Tick-borne encephalitis (TBE), caused by the TBE virus (TBEV), is a serious public health threat in northern Eurasia. Three subtypes of TBEV are distinguished. Inactivated vaccines are available for TBE prophylaxis, and their efficacy to prevent the disease has been demonstrated by years of implication. Nevertheless, rare TBE cases among the vaccinated have been registered. The present study aimed to evaluate the protective efficacy of 4 TBEV vaccines against naturally circulating TBEV variants. For the first time, the protection was evaluated against an extended number of phylogenetically distinct TBEV strains isolated in different years in different territories. The protective effect did not strongly depend on the infectious dose of the challenge virus or the scheme of vaccination. All vaccines induced neutralizing antibodies in protective titers against the TBEV strains used, although the vaccines varied in the spectra of induced antibodies and protective efficacy. The protective efficacy of the vaccines depended on the individual properties of the vaccine strain and the challenge virus, rather than on the subtypes. The neutralization efficiency appeared to be dependent not only on the presence of antibodies to particular epitopes and the amino acid composition of the virion surface but also on the intrinsic properties of the challenge virus E protein structure

The state of specific immunity of population of the Republic of Tajikistan to measles, rubella, poliomyelitis viruses

Relevance. To achieve the goals of measles and rubella elimination and poliomyelitis eradication programs, immunization coverage of at least 95% of the target population is required. Objective data on the state of specific herd immunity are provided only by the results of serosurveys. In the Republic of Tajikistan, such monitoring is not carried out regularly. Therefore, the purpose of the study was to assess the actual state of the specific herd immunity to measles, rubella, and poliomyelitis viruses. Materials and methods. The blood sera of 563 children and adults collected in 7 cities and 13 districts of Tajikistan in 2020 were investigated. The level of antibodies (ABs) to measles and rubella viruses was determined using enzyme immunoassay. Test systems VectoKor-IgG (VECTOR-BEST, Russia) and Ecolab, Russia were used to determine ABs to measles and rubella virus, respectively. Neutralizing antibodies (nABs) to the 3 types of poliovirus (PV) were determined in 359 sera using a neutralization reaction with Sabin strains of types 1, 2, 3. Results. The conducted serosurvey showed the level of the specific herd immunity to rubella to be 87.9% in total population, including 86.2% in children, 93.1% in adolescents, and 93.5% and adults, that is sufficient to prevent transmission of the rubella virus. The proportion of individuals seropositive to measles was 54.5%, which is not enough to prevent sustained secondary transmission of infection and the resumption of circulation of the endemic strain of measles virus. The children under 15 years of age should be considered a population at risk of the infection, since children accounted for 38% among seronegative individuals. In general, less than 95% of the examined patients had nABs to PV: 94.4% to PV1, 86.1% to PV2, 83.6% to PV3; 3.3% did not have antibodies to all three types of PV. The level of herd immunity varied in the examined groups depending on the vaccination schedule and the composition of the poliovirus vaccines used: nABs to PV2 had 59.6% of children born during the period when vaccines containing PV2 were not used, and 85.7% of children born after the introduction of trivalent IPV. Deficiency in immunity to PV2 was the cause of a polio outbreak in 2021 caused by circulating vaccine-derived PV type 2. Conclusion. A high level of humoral immunity to the rubella virus was determined. Shortcomings of routine immunization against measles and polio associated with insufficient coverage and lack of IPV have been identified. Conducting regular serological monitoring in the Republic of Tajikistan is advisable to obtain objective information about the level of herd immunity, identify vulnerable groups of the population, and plan additional immunization activities

Phenoxazine nucleoside derivatives with a multiple activity against RNA and DNA viruses

Emerging and re-emerging viruses periodically cause outbreaks and epidemics all over the world, eventually leading to global events such as the current pandemic of the novel SARS-CoV-2 coronavirus infection COVID-19. Therefore, an urgent need for novel antivirals is crystal clear. Here we present the synthesis and evaluation of an antiviral activity of phenoxazine-based nucleoside analogs divided into three groups: (1) 8-alkoxy-substituted, (2) acyclic, and (3) carbocyclic. The antiviral activity was assessed against a structurally and phylogenetically diverse panel of RNA and DNA viruses from 25 species. Four compounds (11a-c, 12c) inhibited 4 DNA/RNA viruses with EC ≤ 20 μM. Toxicity of the compounds for the cell lines used for virus cultivation was negligible in most cases. In addition, previously reported and newly synthesized phenoxazine derivatives were evaluated against SARS-CoV-2, and some of them showed promising inhibition of reproduction with EC values in low micromolar range, although accompanied by commensurate cytotoxicity. 50 5

Image_1_Experimental Evaluation of the Protective Efficacy of Tick-Borne Encephalitis (TBE) Vaccines Based on European and Far-Eastern TBEV Strains in Mice and in Vitro.PDF

<p>Tick-borne encephalitis (TBE), caused by the TBE virus (TBEV), is a serious public health threat in northern Eurasia. Three subtypes of TBEV are distinguished. Inactivated vaccines are available for TBE prophylaxis, and their efficacy to prevent the disease has been demonstrated by years of implication. Nevertheless, rare TBE cases among the vaccinated have been registered. The present study aimed to evaluate the protective efficacy of 4 TBEV vaccines against naturally circulating TBEV variants. For the first time, the protection was evaluated against an extended number of phylogenetically distinct TBEV strains isolated in different years in different territories. The protective effect did not strongly depend on the infectious dose of the challenge virus or the scheme of vaccination. All vaccines induced neutralizing antibodies in protective titers against the TBEV strains used, although the vaccines varied in the spectra of induced antibodies and protective efficacy. The protective efficacy of the vaccines depended on the individual properties of the vaccine strain and the challenge virus, rather than on the subtypes. The neutralization efficiency appeared to be dependent not only on the presence of antibodies to particular epitopes and the amino acid composition of the virion surface but also on the intrinsic properties of the challenge virus E protein structure.</p

Exploring of primate models of tick-borne flaviviruses infection for evaluation of vaccines and drugs efficacy.

Tick-borne encephalitis virus (TBEV) is one of the most prevalent and medically important tick-borne arboviruses in Eurasia. There are overlapping foci of two flaviviruses: TBEV and Omsk hemorrhagic fever virus (OHFV) in Russia. Inactivated vaccines exist only against TBE. There are no antiviral drugs for treatment of both diseases. Optimal animal models are necessary to study efficacy of novel vaccines and treatment preparations against TBE and relative flaviviruses. The models for TBE and OHF using subcutaneous inoculation were tested in Cercopithecus aethiops and Macaca fascicularis monkeys with or without prior immunization with inactivated TBE vaccine. No visible clinical signs or severe pathomorphological lesions were observed in any monkey infected with TBEV or OHFV. C. aethiops challenged with OHFV showed massive hemolytic syndrome and thrombocytopenia. Infectious virus or viral RNA was revealed in visceral organs and CNS of C. aethiops infected with both viruses; however, viremia was low. Inactivated TBE vaccines induced high antibody titers against both viruses and expressed booster after challenge. The protective efficacy against TBE was shown by the absence of virus in spleen, lymph nodes and CNS of immunized animals after challenge. Despite the absence of expressed hemolytic syndrome in immunized C. aethiops TBE vaccine did not prevent the reproduction of OHFV in CNS and visceral organs. Subcutaneous inoculation of M. fascicularis with two TBEV strains led to a febrile disease with well expressed viremia, fever, and virus reproduction in spleen, lymph nodes and CNS. The optimal terms for estimation of the viral titers in CNS were defined as 8-16 days post infection. We characterized two animal models similar to humans in their susceptibility to tick-borne flaviviruses and found the most optimal scheme for evaluation of efficacy of preventive and therapeutic preparations. We also identified M. fascicularis to be more susceptible to TBEV than C. aethiops

Unwinding the SARS-CoV-2 Ribosomal Frameshifting Pseudoknot with LNA and G-Clamp-Modified Phosphorothioate Oligonucleotides Inhibits Viral Replication

Ribosomal frameshifting (RFS) at the slippery site of SARS-CoV-2 RNA is essential for the biosynthesis of the viral replication machinery. It requires the formation of a pseudoknot (PK) structure near the slippery site and can be inhibited by PK-disrupting oligonucleotide-based antivirals. We obtained and compared three types of such antiviral candidates, namely locked nucleic acids (LNA), LNA–DNA gapmers, and G-clamp-containing phosphorothioates (CPSs) complementary to PK stems. Using optical and electrophoretic methods, we showed that stem 2-targeting oligonucleotide analogs induced PK unfolding at nanomolar concentrations, and this effect was particularly pronounced in the case of LNA. For the leading PK-unfolding LNA and CPS oligonucleotide analogs, we also demonstrated dose-dependent RSF inhibition in dual luciferase assays (DLAs). Finally, we showed that the leading oligonucleotide analogs reduced SARS-CoV-2 replication at subtoxic concentrations in the nanomolar range in two human cell lines. Our findings highlight the promise of PK targeting, illustrate the advantages and limitations of various types of DNA modifications and may promote the future development of oligonucleotide-based antivirals