Analysis Of The Causes Of Influenza Virus Infection After Immunization

Objective:To analyze the seroprotection rate of the influenza vaccine 30 days after single dose in people aged 3 years and over,and to explore the causes of influenza virus infection after vaccination.Method:Based on a randomized,double-blind,positive controlled Phase Ⅲ clinical trial of QIV in people aged 3 years and older,a total of 1344 participants were divided into four age groups:3-8 years old,9-17 years old,18-59 years old,60 years old and above,and were allocated to the randomly allocated(2:1:1)to receive one-dose of QIV,TIV-Victoria and TIV-Yamagata.Blood was collected on days 0 and days 30 after single dose,HI antibody detection was performed to calculate the seroprotection rate.To establish the influenza case surveillance system in the clinical trial site,monitor the influenza-like illness and collect nasopharyngeal swab samples.RT-PCR was used to confirm the influenza cases,and then isolate the virus;MEGAalign was uesd to analyze the variation sites of the amino acid sequence of influenza virus and MEGA 7.0 was used to construct a phylogenetic tree;To collect the acute and convalescent serum to detect the HI antibodies against different influenza virus,a 1:4 matched case-control study was designed to analyze the difference of antibody levels between the case and control after immunization,and Cox regression was used to calculate the RR and 95%CI.ROC curve was used to predict the threshold of protective antibody against variant strains after immunization;A case-control design was to compare the antibodies levels in acute phase against epidemic strains between the test-negative cases and test-positive influenza-like cases,and Logistic regression was used to calculate the OR and 95%CI.Results:The results of immunogenicity of influenza vaccine showed that the seroprotection rate of antibodies against the A/H1N1 serotype in each age group was about 94%-100%,and that against the A/H3N2 serotype was about 85%-100%;the seroprotection rates of antibodies against the A/H1N1 A/H3N2 serotypes 30 days after immunization were statistically significant between susceptible,non-susceptible groups and different age groups(P<0.05);To compare the antigenicity of the infected strain and the vaccine strain,between October 2018 and April 2019,a total of 42 influenza-like cases were observed and 18 were confirmed as influenza case,seven of which were A/H1N1,eight of which were A/H3N2 and three were B/Victoria.Among them,six A(H1N1)pdm09 strains and four B/H3N2 strains were isolated.Compared with the amino acid sequence of H1 and H3 vaccine strain,two or more mutations and four or more mutations at the neutralization sites were occurred in six A(H1N1)pdm09 and four A/H3N2 virus samples.To compare the serum antibodies levels against different strains in different periods,the GMT of the antibodies against H1 vaccine strain in A/H1N1 case group after vaccination was significantly higher than that in control group(RR=0.028,95%CI:0.001-0.574,P=0.020);The GMT of the antibodies against H3 vaccine strain in A/H3N2 case group after vaccination was higher than that in control group(RR=0.131(95%CI:0.012-1.440,P=0.097);the ROC curve predicted the antibody titers against H1 and H3 vaccine strain of 1:57 and 1:120 as a threshold for the protective antibodies against the pathogenic variants of the same type influenza after immunization;The GMT of acute serum antibodies against A/Jiangsu Suining/2019/0440(H1N1)and A/Jiangsu Suining/2019/0520(H1N1)in A/H1N1 test-negative group were significantly higher than those in test-positive group(OR=0.103,95%CI:0.018-0.576,P=0.010;OR=0.163,95%CI:0.043-0.624,P=0.008));the GMT of acute serum antibodies against A/Jiangsu Suining/2019/0603(H3N2)and A/Jiangsu Suining/2019/1900(H3N2)in A/H3N2 test-negative group were significantly higher than those in test-positive group(OR=0.040,95%CI:0.003-0.571,P=0.018;OR=0.096,95%CI:0.008-1.095,P=0.059);For A/H1N1 cases,the GMT of acute serum antibodies against A/Jiangsu Suining/2019/0440(H1N1)and A/Jiangsu Suining/2019/0520(H1N1)were 11.04 and 18.11,and that of convalescent antibodies increased to 113.14 and 285.09;for A/H3N2 cases,the GMT of acute serum antibodies against A/Jiangsu Suining/2019/0603(H3N2)and A/Jiangsu Suining/2019/1900(H3N2)were 73.37 and 61.66,and that of convalescent antibodies increased to 269.09 and 640.00.Conclusion:(1)The seroprotection rate after immunizating influenza vaccine varies among different groups population.The failure to reach the level of antibody protection titers after immunization is the direct cause of getting influenza after immunization.(2)The reason for getting influenza after immunization is firstly considered the mismatch of the local epidemic influenza strain and vaccine strain;low antibodies level induced by vaccine combined with lower cross-reactive antibodies level against the variant strain contribute to be attacked by the mutant pathogenic influenza strain.(3)Due to individual differences,consider to increase the dosage or prime-booster immunization to formulate a personalized precision influenza vaccine immunization strategy.