Immune-escape hepatitis B virus (HBV) mutants play an important role in HBV spread. Recently, the multivalent vaccine Bubo^®-Unigep has been developed to protect against both wild-type HBV and the most significant G145R mutant. Here, we compared the effects of recombinant HBsAg antigens, wild-type and mutated at G145R, both included in the new vaccine, on activation of a human high-density culture of peripheral blood mononuclear cells (PBMC) in vitro. The antigens were used either alone or in combination with phytohemagglutinin (PHA). None of the antigens alone affected the expression of CD40, HLA-DR or CD279. Wild-type HBsAg enhanced CD86 and CD69 expression, and induced TNF-α, IL-10, and IFN-γ, regardless of the anti-HBsAg status of donor. In the presence of PHA, wild-type HBsAg had no effect on either of the tested surface markers, but increased IFN-γ and IL-10 and inhibited IL-2. In contrast, the G145R mutant alone did not affect CD86 expression, it induced less CD69, and stimulated IL-2 along with lowering levels of TNF-α, IL-10, and IFN-γ. The G145R mutant also suppressed PHA-induced activation of CD69. The dramatic differences in the immune responses elicited by wild-type HBsAg and the G145R mutant HBsAg suggest distinct adaptive capabilities of the G145R mutant HBV.

Relevance. Currently, there is no registered vaccine against the hepatitis B virus (HBV) mutant G145R worldwide, which justifies the need to develop a new generation of vaccines due to large-scale immunization against hepatitis B and the accumulation of escape mutants of the virus.The aim of the study was a comparative assessment of the immunogenicity, reactogenicity and safety of Bubo®-Unigep (trivalent hepatitis B recombinant yeast vaccine) and the drug Hepatitis B recombinant yeast vaccine.Materials and methods. To assess the main characteristics of the new trivalent vaccine Bubo®-Unigep (CJSC NPC «COMBIOTECH»), a doubleblind, comparative, randomized, multicenter clinical trial was conducted in two parallel groups in previously unvaccinated individuals in an adult healthy population (n = 166) according to a protocol developed by the contract research organization «R&D Pharma».Results. The assessment of hematological and biochemical parameters during screening and the administration of vaccine preparations showed that in the individuals included in the study, the studied indicators were within the boundaries of the normal range. According to the criteria for assessing safety and efficacy, both drugs had low reactogenicity, no serious adverse events were registered. The results of a comparative analysis of the concentrations of antibodies to HBsAg determined after a full course of immunization with Bubo®-Unigep vaccine or recombinant yeast Hepatitis B vaccine showed that both drugs effectively induced a humoral immune response (anti-HBs) with seroprotection rates of 96.3% and 92.6%.Conclusion. The inclusion of the relevant HBV serotypes (ay and ad) and the mutant antigen G145R in the composition of the new polyvalent vaccine Bubo®-Unigep contributes to the expansion of the spectrum of specificity of the immune response, and, consequently, more effective vaccination of hepatitis B.

Relevance. In Russia, phase III of clinical trials of the domestic trivalent vaccine Bubo®-Unigep, containing protective antigens that provide protection against “wild” forms of the hepatitis B virus subtypes ay and ad, as well as the determinant of serotype ay with the G145R mutation, has been completed. Аim. Evaluation of the effect of the new recombinant polyvaccine against hepatitis B «Bubo-Unigep» on vital functions and laboratory parameters in previously unvaccinated individuals in an adult healthy population. Materials and methods. A randomized multicenter clinical study was conducted to assess the reactogenicity, safety and immunogenicity of Bubo®-Unigep (CJSC NPC «COMBIOTECH») in previously unvaccinated healthy adults (n = 166). The study performed according to the protocol developed by the contract research organization «R&D Pharma» at eight clinical centers located in Russian Federation. Results and discussion. Analysis of the studied parameters throughout the study (frequency and severity of adverse events, physical examination data of volunteers with assessment of vital signs, laboratory test results, etc.) made it possible to establish a high safety profile of Bubo®-Unigep vaccine, which turned out to be virtually areactogenic without causing development of targeted local and systemic post-vaccination adverse events. Conclusion. The wide range of specificity of the immune response, along with the high safety and reactogenicity of the Bubo®-Unigep vaccine, the production of which can be carried out through a full technological cycle without the use of imported substances, will increase the effectiveness of hepatitis B prevention.