| Mumps is a common and acute respiratory infectious disease caused by mumps virus(MuV),which is currently wide spread in the world.Mumps vaccination is the only effective way to prevent mumps.Since 2008,1 doses of mumps vaccine have been included in the national expanded immunization program,and routine immunization has been carried out for children aged between 18 and 24 months.In order to evaluate the protective effect of mumps vaccine on MuV circulated in China,molecular evolution analysis of MuV strain circulating in China during 1995-2016 was carried out based on hemagglutinin-neuraminidase protein(HN)in this study.Through the study,it is intended to clarify the genetic characterization of MuV,investigate its origin and molecular evolution characteristics,analyze the variation of MuV important antigen sites,and based on this,evaluate the influence of the evolution of MuV on the protective effect of mumps vaccine,which will provide the scientific basis for further improving the immunization strategy of mumps vaccine in china.Through the molecular evolution of MuV strain circulating in China during 1995-2016 in this study,genotype F and G was found to be the prevalent genotypes circulating in mainland China.Among them,genotype F was the predominant and unique genotype.In addition,genotype G was also detected in a few provinces in mainland China since 2011.Due to the limited time for the implementation of mumps vaccine immunization,the transmission of MuV has not yet been effective interrupted.Therefore,MuV in mainland China was currently still in a natural epidemic status,and the multiple transmission chains of genotype F MuV strains were simultaneously co-circulating in different regions of mainland China.The molecular evolution of MuV was also analyzed by Bayesian method.The results showed that the common ancestor of genotype F MuV in mainland China could be traced back to 1980.The evolution rate of MuV was similar to other RNA viruses.The estimated evolutionary rates were about 1.58×10-3 substitutions/site/year for the SH gene,and 0.50×10-3 substitutions/site/year for HN gene.The evolution rate of SH gene is about 3 times higher than that of HN gene.During the evolution of genotype F MuV,at least four different evolutionary lineages were co-circulated.Among them,lineages 1 and 2 Mu Vs were formed in the early period of MuV evolution in mainland China,and the lineages 3 and 4 MuVs were occurred after 2000.There were no year and regional difference among the different lineages,and four lineages were co-circulated in China.In addition,the analysis of Bayesian Skyline Plots showed that the genetic polymorphism of F genotype MuV in China has been up to a stable condition.Based on the variation of the important antigenic sites of MuV,the results of this study indicated that there were some antigenic differences in the epitopes relating to neutralizing antigen and immune escape on the HN,F and N protein between the MuV vaccine strain(genotype A)and the MuV wildtype strains(genotype F and G).And with the MuV evolution,the differences between the wildtype MuV strains and the MuV vaccine strain showed a trend of increasing year by year.The variation frequency of nucleotide or amino acid in some sites increased and some variation tended to be stable situation.The variation in these sites might decrease the cross protection between wildtype MuV strains and MuV vaccine strain.In order to effectively evaluate the effect on MuV vaccine cross protection for wildtype MuV strains,the cross neutralization tests were performed between MuV vaccine strain and wildtype genotype F and G MuV strains,with the paired sera of 1-dose MuV vaccination from the healthy children and the paired sera in acute and convalescent phase serum from clinically confirmed MuV cases.The results indicated that MuV vaccine strain had a protective effect on wildtype MuV strain.However,due to the antigenic differences among different MuV genotypes,the cross protection effect of MuV vaccine for wildtype genotype F and G MuV was limited,and the cross protection of MuV vaccine for genotype F MuV strains was relatively poor.Meanwhile,the neutralization antibody titer induced by 1 dose of MMR vaccine was found to be generally low,which might not meet the requirement of MuV vaccine protection.In addition,we also found that no neutralizing protective antibodies produced among a few healthy children after immunization though the high level of MuV IgG was detected by ELISA,which indicated that the level of MuV IgG antibodies could not truly reflect the level of neutralizing antibodies in the body,so it was inaccurate to evaluate the success rate of MuV vaccine only depending on seroconversion rate of MuV IgG antibody.In conclusion,based on the results of this study,the new F genotype MuV vaccine was very urgent to be developed and applied in order to meet the requirement of the prevention and control of mumps in mainland China;in addition,it was also strongly suggested that the second doses of MuV vaccine should be introduced into preschool children in the whole country to ensure the neutralizing antibody titers of MuV reached a higher level among healthy children;moreover,the cross neutralization test should be used as supplementary method for the evaluation of the protective efficacy of MuV vaccine against the wildtype MuV infection. |
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