| Varicella-Zoster Virus(VZV)infection results in varicella mostly in children.Reactivation of the virus causes Herpes Zoster(HZ)mostly in adults.Varicella and HZ can be effectively controlled and prevented by immunization with vaccines.Varicella vaccine is a live attenuated vaccine and several varicella live attenuated vaccines(VarV)based on the Oka strain are currently available worldwide.In China,VarV has been introduced and used more than two decades.Since the original vaccine stock from Biken was never cloned,the current vaccine product contains several vaccine virus variants or subspecies.There is a consensus that SNPs in the IE62 gene(coding ORF62)contribute to attenuation,but are not sufficient.Efforts to define the SNPs required for attenuation in other ORFs remain a subject of controversy.In addition,varicella break through cases and fatal cases in immunocompromised patients highlight the challenge of a safe administration of live VZV vaccine.HZ subunit vaccine,glycoprotein E(gE)as main contents,is without the disadvantages of live attenuated vaccine,and its immunogenicity and protection both are greatly improved as reported.Currently,VZV subunit vaccine is not available in China.The aim of this study was to analysis of the SNPs of a varicella vaccine in China and to study on the effect of gE with different adjuvants(Alum,MPL and QS21)immunized in mice.In this study,we analyzed the WGS of vOka-BK produced by Changchun BCHT Biotechnology also known as Baike.vOka-BK WGS was compared against the genomic sequence of 4 other Oka strains:pOka,vOka-Biken,vOka-Varilrix from GlaxoSmithKline(GSK)and vOka-Varivax from Merck&Co..A previous study identified 137 Single Nucleotide Polymorphisms(SNPs)shared by all vOkas.The current analysis used this data as a reference to compare with vOka-BK WGS and focused on 54 SNPs located in the unique regions of the genome.Twenty-eight non-synonymous substitutions were identified,ORF62 and ORF55 featuring the most amino acid changes with 9 and 3 respectively.Among the 54 SNPs,(i)Twenty-two nucleotide positions that featured a similar mutation profile,either mutated or wild type in all vOkas and was likely to be core vaccine positions.A change at these positions might be detrimental for the vaccine potential.A comparison with the Clade 3 strain Ellen,known to be attenuated,identified 3 shared amino acid changes,*130R in ORFO,R958G and S628G in ORF62.(ii)SNPs that featured a different profile in vOka-Varilrix(17 SNPs)and vOka-Varivax(5 SNPs)and could be associated with differences in vaccine efficacy.(iii)Finally,ten positions that had a unique profile in vOka-BK and could affect the vaccine efficacy of the Chinese vaccine.In this study,the extracellular domain of gE was expressed by CHO and immunized it with different adjuvants(Alum,MPL and QS21)in mice.The results showed that after immunization with MPL+QS21+gE mice could induce higher IgG antibody response compared with other groups,and could induce a stronger cell-specific immune response.The secretory cells of Thl lymphocytes with IFN-y were proliferated obviously.MPL+QS21+gE also could produce a certain humoral immune response,and the IL-4 secretion cells of Th2 lymphocytes were moderately increased.At the same time,the ratio of CD8+T and Treg was highest in all groups,and the number of CD8+T cells increased.However,the number of inhibitory Treg cells decreased.The number of CD8+TCM cells also increased,so the immune memory function enhanced.In addition,VZV-IgG level in mice remained stable and obvious adverse reaction was not observed within 28 weeks.In conclusion,this study provides the first comparison of a Chinese varicella vaccine to the other vaccines available worldwide and identifies sites potentially critical for VZV vaccine efficacy.It makes an important contribution to study on varicella vaccine attenuation.Besides,this study also reveals that the MPL+QS21+gE has good safety and immunogenicity in mice.It provides significance for the development of Chinese VZV subunit vaccine. |
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