Meta Analysis Of The Immune Effect And Adverse Events Of H5N1 Influenza Vaccine

Objective:Systematical evaluation of the immunization effect of adult H5N1 influenza virus vaccine and the comparison of the impact of different doses,adjuvants and vaccine types on the immune effect of H5N1 vaccine as well as the differences in vaccine antibody responses of different ages have been conducted.The occurrence of common adverse events after vaccination of H5N1 influenza vaccine has been analyzed to provide the basis for clinical application of the H5N1 vaccine.Methods:We searched the Chinese biomedical databases,the Vip Journal,Wanfang Database,PubMed,Cochrane Library,and the Embase/MEDLINE database.The search deadline was December 2,2017.The main outcome measures were the influenza infection rate,vaccine protection rate and the occurrence of flu-like symptoms after vaccination.The serological changes of the specific antibodies before and after the H5N1 influenza vaccination were evaluated,namely,the seroconversion rate(SCR)and the seroprotection/positive rate(SPR).Secondary outcomes were the safety,common adverse events.The method used to evaluate the methodological quality was the“offset risk assessment tool”developed by the Cochrane Collaboration Group;the meta-analysis of the study results was executed using Review Manager 5.3 software;the heterogeneity test was done with chi-square test and I~2 value,and the random effect models or fixed effects models were used for analysis based on the heterogeneity;the effect pools adopted relative risk(RR)and its 95%CI and rate difference(RD)and its 95%CI.The publication bias was assessed by plotting the funnel plot and observing the symmetry.(1)The adult group is divided into two parts based on the type of design included in the study:Part1:Randomized controlled study group:Analyzing the effect of randomized controlled studies onH5N1 vaccine immunity;Part 2:All Research on the effects of H5N1 vaccine immunization that meet the inclusion criteria.The immune effects were analyzed from 4 dose groups(?6?g,7.5?g,15?g,and?30?g with or without adjuvant)by using RD(95%CI);and the immune effect between adjacent does was compared with RR(95%)%CI)combined effect amount,the immune effect of different vaccine types was analyzed;besides,the local adverse events analysis of pain,erythema,swelling and induration indicators and the systemic adverse events analysis of fever,headache,myalgia,fatigue,joint pain and shivering indicators adopted the RD(95%CI)combined effect amount.(2)The children and adolescents group,RD(95%CI)was used to analysis of immune effect;the local adverse events analysis of local pain,erythema,swelling,induration indicators and the systemic adverse events analysis of fever,headache,myodynia,fatigue,loss of appetite and irritability(children)indicators were carried out based on the same analysis methods and combined effect amount as(1).(3)The elderly group shares the same immune effect analysis method and effect combination amount with the above.The local adverse events analyzed for local pain,erythema,and swelling,and the systemic adverse events are analyzed for fever,headache,myalgia,arthralgia,fatigue,and shivering with the same analysis method and effect combination amount as(1).Results:(1)A total of 36 studies were included in the adult analysis,including 7 RCTs,23 clinical studies,and 6 non-randomized studies.Only serological antibody changes were included in the outcome indicators of the immune effect included in the study.The results of a randomized controlled trial showed that the adjuvant-free vaccine had a low immune response.The immunization with 2 doses of low-dose(6?g)adjuvant was better,but less than 70%;after analyzing the antibody response before and after immunization of all vaccines in the study,the immunization with 6?g of two doses or even lower doses of non-aluminum adjuvant vaccines can achieve the 70%permission standard for influenza vaccines.There was no statistical significance of the differences in the immune effect between high dose and low dose.The immunization effect of low dose split-virion vaccine was better,and the antibody positive conversion rate could reach 87%.The incidence of local pain,general headache and myalgia was highest.With the increase of dose,the incidence of adverse events increased,but there was no statistical significance of the differences in the incidence of adverse events between high-dose and low-dose vaccine(P<0.05).(2)A total of 8 studies were included in children and adolescents,consisting of 3 RCTs,3 CCTs,and 2 non-randomized studies.The aluminum adjuvant and adjuvant-free vaccine had low immunization efficacy while the positive rate of being vaccinated with 2 doses of 3.75?g or even lower dose of non-aluminum adjuvant vaccines was over 90%,and the rate of positive conversion of higher dose vaccine antibodies didn't increase.When children were vaccinated at the same dose,the immune effect of infants and young children were higher more than 90%.Local pain was most common(23%in the adjuvant-free vaccine group and 32%in the adjuvant vaccine group).The incidence of systemic adverse events was low in the adolescent group,and the incidence of fever and irritability in children was the highest with relatively low incidence of other symptoms while the incidence of adjuvant vaccine adverse events was higher.(3)The elderly group included 7 studies:6 CCT studies,and 2 non-randomized studies.Compared with non-aluminum adjuvanted vaccines,adjuvant-free and aluminum adjuvanted vaccines had a lower immune response.The immune effect 2 doses of 7.5?g with non-aluminum adjuvanted vaccines reaching the standard of 60%,the 15?g was up to 64%.The local pain was the most common symptom and the incidence of non-aluminum adjuvant was higher;and there were relatively high incidences of headache,myalgia and fatigue in systemic adverse events which the incidence of other symptoms was very low(<10%).Conclusion:(1)In the adults,the adjuvant vaccines and aluminum adjuvant vaccines have lower immune effects than the non-aluminum adjuvants.Inoculation with 2 doses of 6?g or even lower doses of non-aluminum adjuvant vaccines can achieve acceptance standard of 70%for the influenza vaccines.Inactivated split-virion vaccines are more effective than other types.There was no significant increase in the effect with higher dose vaccines.The vaccine was safe and there were no serious or even life-threatening adverse events.(2)For children and adolescents,the adjuvant vaccine and aluminum adjuvant vaccine showed lower immune effect than non-aluminum adjuvant;it was necessary to inoculate 2 doses of vaccine.the effect of children and adolescents who received 2 doses of 3.75?g or even lower dose of non-aluminum adjuvant vaccine was above 90%,but the immune effects need further study.There was no significant diffierence in immunization effect between infants and school-age children;in addition,the incidence of adverse events was low.(3)In the elderly,the vaccine without adjuvant or aluminum adjuvant revealed low immune effect,and the positive rate of the inoculation with two doses of 7.5?g non-aluminum adjuvant vaccine antibody could reach 60%,15?g non-aluminum adjuvant vaccine were better.No severe or life-threatening adverse events had been found.