A Systematic Review And Meta-analysis Of Cross-reactivity Of Antibodies Induced By H7 Influenza Vaccine

Objective:Systematic evaluation and meta-analysis were used to analyze the cross-reactivity between H7 influenza virus and different subtypes of H7 influenza virus between H7N9,and provide evidence-based evidence for H7 subtype and H7N9 virus prevention.Methods:Database search was conducted in China Biological Med icine Database(CBM),Wanfang Database,PubMed,EMbase,MEDLINE and Cochrane Library up through December 1,2018.We collected Cohort study,randomized controlled trials(RCTs)and clinical controlled trial(CCTs)for H7 subtype influenza vaccine cross-reactivity.Outcomes include influenza infection rate,incidence of influenza-like symptoms,serological changes of cross-reactive antibodies after vaccination(SCR,SPR,GMT and MGI,etc.).Two reviewers independently screened literature and extracted data.Methodological quality evaluation was performed in RevMan 5.3 software using the?offset risk assessment tool?developed by the Cochrane Collaboration Group.Firstly,all the studies included were systematically evaluated,and then meta-analyzed the extractable data using R-3.5.2,Stata12.0 and RevMan 5.3 software.To select the cross-reactivity of antibodies at the highest time points for SCR and SPR selection,we analyzed the specific SCR and SPR of H7 subtype influenza vaccine at different time points,and calculated the RR to compare the SCR and SPR of specific antibodies at different time points.Further analyze the SCR and SPR of cross-reaction between H7subtype,H7 subtype against H7N9 at the time of optimal immune effect.Heterogeneity test was performed using chi-square test and I~2 value.Publication bias evaluation was performed by Egger‘s test and calculation of the safety factor of?of 0.05.The protocol of the study has been registered with PROSPERO(No.CRD42018109974).Results:A total of 9 articles were included,each document only detects serological indicators,and does not describe the rate of influenza infection and the occurrence of flu-like symptoms.All included literature shows that the cross-reaction between the H7 subtype vaccine and the non-H7 subtype was low,and the cross-reaction that H7 subtype vaccine against the first group of H1 subtype influenza virus was not as strong as other subtypes of influenza virus located in the second group;there was a good cross-reaction between H7 subtype influenza vaccines,and the cross-reaction of the adjuvant vaccine is higher than the non-adjuvant vaccine.A meta-analysis of the six articles that the data can be extracted,the total number of studies was 738.The specific antibodies produced by the H7 subtype influenza vaccine were SCR=0.19[0.13,0.25],SPR=0.19[0.13,0.26]after 3 to 4 weeks of the first dose;SCR=0.74[0.65,0.82],SPR=0.81[0.78,0.83]after3 to 4 weeks of the second dose;SCR=0.20[0.16,0.24],SPR=0.21[0.11,0.26]after 6months;SCR=0.07[0.03,0.11],SPR=0.07[0.03,0.12]after 12 months.It can be seen that the level of specific antibody produced after 3 to 4 weeks of the second dose is the highest,much higher than the first dose(SCR 42/56D vs 21/48D:RR=3.83;SPR42/56D vs 21/48D:RR=4.20),6 months(SCR 42/56D vs 6M:RR=3.86;SPR 42/56D vs 6M:RR=3.80)and 12 months(SCR 42/56D vs 12M:RR=11.01;SPR 42/56D vs12M:RR=10.83).The antibody of cross-reaction between H7 subtypes influenza vaccines after 3 to 4 weeks were 0.62[0.41,0.82]and 0.68[0.49,0.87],and the SCR and SPR of cross-reaction between H7N1 influenza vaccine and H7 subtype after the addition of adjuvant were 0.88[0.85,0.91]and 0.75[0.51,0.98],meeting the vaccine production license standards for CHMP and CBER;The SCR and SPR of H7 subtype influenza vaccine cross-reacting to H7N9 virus were 0.63[0.38,0.88]and 0.72[0.55,0.89],and the SCR and SPR of the cross-reaction between H7N1 influenza vaccine and H7N9supplemented with adjuvant were 0.88[0.85,0.91]and 0.75[0.56,0.93],both reached the CBER and CHMP standards.Publication bias was assessed by Egger,s test(p=0.841,>0.05)and The Fail-Safe Number calculation(1071,>5k+10),showing no publication bias.Conclusion:1.All H7 subtype influenza vaccines produce higher titers of specific antibodies,and booster immunization provides better immunoprotection and recommends to use for the prevention of the corresponding H7 influenza virus.2.There was a good cross-reaction between different H7 subtype influenza vaccines.When a certain H7 subtype influenza outbreak,and there was no specific vaccine,recommended to prevent by inoculation of other H7 subtype vaccine.3.There was a cross-reaction between the non-H7N9 influenza vaccine and the H7N9 virus,and the H7 subtype influenza vaccine can be used for the prevention of H7N9 avian influenza.