| BackgroundRubella is an acute respiratory infection caused by the rubella virus.The main clinical features are fever,rash,and enlarged lymph nodes behind the ears and occipital.Women infected with rubella virus in early pregnancy,the virus can through the placenta and cause chromosomal breaks and aberrations in embryonic cells.It is causing congenital rubella syndrome(CRS),leading to stillbirth,miscarriage or fetal birth with severe disability,puting a serious burden on society and families.CRS is an important public health issue in the world.In 2012,194 WHO member states including our country signed the Global Vaccine Action Plan(GVAP)to eliminate rubella.In 2015,according to the WHO periodic review report,outbreaks occurred from time to time in areas that have been eliminated or are close to elimination,and the incidence in endemic areas is still high.Rubella elimination is facing a huge challenge.In 2017,the incidence of rubella in our country fell to the lowest level in history,with only 0.27 per 100,000.However,there was a sharp rubella rebound nationwide in 2019.Shaanxi Province included rubella containing vaccine(RCV)in its expanded program on immunization in 2008 and implemented the RCV childhood immunization strategy for nearly ten years.However,in recent years,the situation of prevention and control has remained severe,and many problems have not been resolved: such as the epidemiological characteristics of rubella in the province,especially after the implementation of the childhood immunization strategy the characteristics of population and time are still unclear.The baseline data on genotype of epidemic rubella virus is still blank.Whether the current vaccines are effective against the genotypes of the epidemic strains that are constantly changing,and the traceability and transmission dynamics of the epidemic virus strains are not yet known.The population's rubella antibody level changes under high vaccine coverage is not clear.These are of great significance for formulating scientific and effective prevention and control strategies and accurately predicting disease.ObjectivesTo analyze the epidemiological characteristics of rubella in Shaanxi Province and to further analyze the impact of climate influencing factors on the epidemic dynamics of rubella through the mathematical model.To analyze the genotype characteristics,mutations and homology relationships of the epidemic rubella virus and to explore the possible sources and chain of transmission.To analyze the rubella antibody levels and to explore potential high-risk areas and populations through the seroepidemiological survey of people aged 1-59 years old.Methods1.we collected information on reported cases of rubella in Shaanxi Province from2005 to 2018 through the National Infectious Disease Surveillance System,and use descriptive epidemiological methods to analyze the epidemiological characteristics of rubella time,region,and population distribution.On the basis of the weekly time series of the onset of rubella,the wavelet analysis method with Morlet as the mother wavelet is used to accurately analyze the periodicity of the onset of rubella.A two-stage mixed generalized additive model(MGAM)was used to quantitatively analyze the relationship between meteorological factors and the incidence of rubella,and to explore the impact of meteorological factors on the incidence of rubella.In the first stage,Spearman rank correlation was used to determine the meteorological variables,and MGAM was used to quantify the relationship between meteorological factors and rubella incidence in different regions.In the second stage,multiple random effects meta-analysis model was used to evaluate the overall consolidation effect.2.Virus isolation,nucleic acid extraction,and sequence determination were performed on the collected throat swab specimens of rubella cases from 2013 to 2018.MAFFT(v7.205)and Meg Align(v8.1.4)software were using for multiple sequence alignment,amino acids and nucleotides homology analysis to obtain virus type characteristics,nucleotide and amino acid mutations.Download the global representative rubella sequence in Gen Bank and merge the sequence obtained in this study to build a library,and use the neighbor-joining method(NJ)to construct a genetic relationship tree to determine the origin of the virus strain and infer the possible transmission path.3.Stratified multi-stage random sampling method was used to investigate the rubella antibody level based on the sample bank of hepatitis B serum survey.In the first stage,the primary sampling units(PSUs)were selected by sampling method of probability proportional to size(PPS).In the second stage,the survey objects were selected by random sampling method.The single well quantitative method of enzyme linked immunosorbent assay(ELISA)was used to detect IgG antibody in serum samples.The results were estimated according to the sampling weight in different areas and populations.Results1.From 2005 to 2011,the incidence of rubella was relatively high,with an average annual incidence rate of 5.19 per 100,000.The incidence rate dropped sharply from 2012 to 2018,with an average annual incidence rate of 1.34 per 100,000.The incidence is high in spring,accounting for 81.76% of the total number of cases.Rubella cases have been reported in all cities,districts and counties.The top five annual incidence rates are:5.91/100,000 in Tongchuan,4.91/100,000 in Hanzhong,4.81/100,000 in Xi'an,4.14/100,000 in Baoji,4.09/100,000 in Yan'an City.The incidence of males is higher than that of females,and the male-to-female ratio is 1.39:1.Rubella cases are mainly students,and adult cases are mainly farmers.From 2005 to 2018,the age group with high incidence of rubella gradually transferred from the younger age group to the older age group.In the2005-2014,the incidence of children in the 0-14 year old group was significantly higher than that in other age groups.The annual incidence range of age subgroup was18.26-25.53/100,000,and the annual incidence range of other age subgroup was0.18-5.76/100,000.In 2015-2017,the incidence of age group of 10-19 old years was higher than that in other age groups.The annual incidence range of age subgroup was8.35-11.84/100,000,and the average incidence range of the other age subgroups was0.07-4.80/100,000.In 2018,the incidence rate of the 15-19 year old group was the highest,the incidence rate was 1.19/100,000,and the incidence range of other age subgroups was0-0.33/100,000.2.The wavelet analysis results showed that there were significant annual periodicity of time scales of 0.4-0.5 years,0.8–1.4 years,3.8–4.8 years in the incidence of rubella in Shaanxi Province from 2005 to 2018.The time scale of 3.8–4.8 years showed the highest global power.According to the results of study on the influence of meteorological factors on the incidence of rubella,below 0°C,as the temperature increases,the accumulative relative risk(ARR)rises rapidly,reaching a peak of 1.22 at 0°C,and above 0°C,as the temperature increases,ARR gradually decreases.When the relative humidity is lower than43%,the ARR gradually increases with the increase of the relative humidity,reaching a peak of 1.38 at 43%.When the relative humidity is higher than 43%,the ARR fluctuates with the increase of the relative humidity.There is a non-linear relationship between average temperature,average relative humidity and the incidence of rubella.3.A total of 52 rubella virus E1 gene sequences were obtained in this study.In 2013,9 strains were 1E genotype,and the remaining 43 strains were 2B genotype.The key amino acid sites of the 1E and 2B genotypes are highly conserved,and the middle N-type glycosylation sites,hemagglutination inhibition sites,neutralization sites and important epitopes have not changed.According to the results of constructing the NJ tree,the 1E genotype that was epidemic in 2013 and the Hong Kong strain in 2012 are in the same branch,and belong to the domestic dominant epidemic clade 1E-L1.The 2B genotype that was epidemic in 2014-2017 and the genotypes that were popular in other provinces in our country during the same period are grouped together,which belongs to the dominant clade2B-L3 of my country's local epidemic.The 2B genotype that was epidemic in 2018 belongs to 2B-L4.This branch is mostly prevalent in the United States,Canada,India and other places.It has not been detected in our country for many years and belongs to the genotype imported from abroad.4.The survey covered 30 counties(districts)in the province,accounting for 25.64%of the total number of counties(districts)in the province.A total number of 6199 people were surveyed.The rubella vaccination rate for people aged 1-59 years in the province was 31.59%(95%CI: 31.04%-32.26%),among which the vaccination rate for people aged1-9 years was 92.89%(95%CI: 92.34%-93.15%),the vaccination rate of other age groups gradually decreases with age.There was no statistically significant difference in RCV vaccination rates among 1-9 year olds among the three regions of the province(?2=4.763,P=0.92).There was no statistically significant difference in RCV vaccination rates between urban and rural children aged 1-9 years(?2=2.201,P= 0.141).The positive rate of IgG antibodies in people aged 20-39 was the highest,followed by those aged 40-59,those aged 1-9,and the lowest was those aged 10-19.The positive rates of antibodies and GMC values in each age group were 83.34%(95%CI:82.65%-84.12%)and 24.77IU/ml(95%CI:23.58 IU/ml-26.02IU/ml),78.17%(95%CI:77.01%-78.64%)and 19.53IU/ml(95%CI:18.62IU/ml-20.48IU/ml),77.85%(95%CI:77.12%-78.83%)and 20.64IU/ml(95%CI:19.28IU/ml-22.11IU/ml),64.28%(95%CI:63.86%-64.90%)and 13.66IU/ml(95%CI:12.56IU/ml-14.87IU/ml).The positive rates of rubella IgG antibody in Guanzhong,Northern and Southern Shaanxi were 78.93%(95%CI: 78.11%-79.64%),77.89%(95%CI:77.03%-79.25%)and 74.92%(95%CI:74.23%-75.31%).The positive rate of antibodies of people in both Northern and Guanzhong was higher than that in southern Shaanxi,and the difference in positive rates between the three regions was statistically significant(?2=8.380,P=0.015).The positive rate of male antibodies was higher than that of females,the difference was not statistically significant(?2=2.867,P=0.094).There was no statistically significant difference in antibody positive rates between urban and rural areas(?2=0.314,P=0.604).Conclusions1.After the rubella vaccine was included in the planned immunization,the overall incidence of rubella in Shaanxi Province has shown a downward trend.The high-incidence age group has shifted from younger to older age groups,and the risk of adult disease will gradually increase with the passage of time.Rubella epidemic has different periodicity.There is a nonlinear relationship between the two main meteorological factors,temperature and humidity,and the incidence of rubella.The precise incidence cycle and the quantitative relationship between meteorological factors and the incidence of rubella provide key parameters for the further development of predictive and early warning models.2.The characteristics of the genotype changes on the rubella epidemic strains in Shaanxi Province are consistent with the replacement of dominant types throughout the country during the same period,but there are cases of non-dominant clade imported from abroad.Although our province has established a certain population rubella immune barrier,it is difficult to block the introduction of new genotypes causing local epidemics,because there are still a large number of immune blank populations.The key antigen epitopes of the epidemic strains of rubella are highly conservative,and BRD-II RCV currently used can provide effective protection against epidemic wild strains.Vaccination is still an effective way for rubella prevention and control.3.The overall level of rubella antibodies in Shaanxi Province is low,and the risk of large-scale rubella outbreaks is still high.People aged 10-19 are at the highest risk of rubella.There are still a large number of susceptible persons with child-bearing age of20-39 years,and the potential CRS risk persists.The RCV vaccination rate of planned immunization meets the requirements of rubella elimination strategy of WHO.In the meantime,the level of planning immunization in various regions are balanced.Antibody of the children produced by rubella vaccine decay rapidly with age.It is recommended to carry out a supplementary rubella vaccine for people aged 10-19 for a long time.On the one hand,it can eliminate the immune gap in the pre-EPI birth cohort,and on the other hand,the antibody weakened ones can be strengthened with RCV. |
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