Efficacy,immunogenicity And Population-level Impact Of Human Papillomavirus Vaccine And Roll-out Study In China

ObjectivesFocusing on different application stage of prophylactic human papillomavirus(HPV)vaccine,firstly,from the perspective of individual benefit,to investigate vaccine efficacy(VE)against non-infected HPV types and re-infection types in women DNA positive to any other high-risk HPV at first vaccination and describe the immunogenicity after HPV vaccination in women DNA positive for HPV-16/18;secondly,from the perspective of public health benefit,to measure the rates of adverse obstetric outcomes in spontaneous singleton living delivery within Scotland’s HPV vaccine immunisation;thirdly,from the perspective of HPV vaccine roll-out in China,to update the evidence on current knowledge,attitudes and practice on HPV vaccine among general population and health care providers(HCPs)in China’s mainland.Materials and methods1.Efficacy and immunogenicity of the HPV vaccine in young Chinese women with high-risk HPV infection at baseline:Based on the Chinese phase Ⅱ/Ⅲ study for bivalent HPV vaccine(Cervarix(?)),871 women aged 18-25 years and positive for any high-risk HPV types at first vaccination were included to analyze VE against incident infection and re-infection related to non-infected HPV-16/18/31/33/45.Study participants in control group were also selected to analyze the rate ratio of new HPV infections in women DNA positive to any high-risk HPV compared to those negative to all high-risk HPV types.Besides,based on another global phase Ⅲ study for bivalent HPV vaccine(Cervarix(?)),geometric mean titers(GMT)until Month 48 after vaccination were described in women DNA positive to HPV-16/18 at baseline.Initial serostatus was not considered in all analysis sets.2.Impact of HPV immunization programme on obstetric outcomes in spontaneous delivery:With data from the Aberdeen Maternity and Neonatal Databank,Scotland,all spontaneous singleton living delivery records with maternal birth year between 1986～1996 and maternal age between 20～30 years were included for an ecological analysis.HPV vaccination status were defined according to maternal birth cohorts:pre-immunisation cohort(1986～1990),catch-up immunisation cohort(1991～1994)and routine immunisation cohort(1995～1996).Outcomes were defined as preterm birth(PTB),low birth weight(LBW)and pre-labour preterm rupture of membranes(pPROM).Generalized estimating equation(GEE)model were applied for multivariate analysis.3.A nationwide post-marketing survey of knowledge,attitude and practice toward HPV vaccine in China:General female and males aged 18～45 years and HCPs aged 18 years and above in China’s mainland were recruited from seven geographic areas by non-randomized sampling.Sociodemographic factors,HPV and HPV vaccine related awareness,knowledge,attitudes,vaccination or recommendation behavior and potential obstacles were collected in questionnaires.Chi-Squared test and Logistic regression were conducted for statistical analysis.Results1.Efficacy and immunogenicity of the HPV vaccine in young Chinese women with oncogenic HPV infection at baseline:VE against 6-month and 12-month HPV-16/18 persistent infections in women DNA-negative to HPV-16/18 but DNA-positive to any other high-risk HPV types at baseline was 100.0%(95%CI:79.8,100)and 100.0%(95%CI:47.2,100),respectively.VE against HPV-31/33/45 incident infections in women DNA-positive to HPV-16/18 and DNA-negative to the other considered HPV types at baseline was 71.0%(95%CI:27.3,89.8).No significant VE was observed against re-infections of HPV-16/18/31/33/45 in women positive for the corresponding HPV types at baseline and cleared during follow-ups.In HPV-16/18 DNA positive women,GMT to HPV-16/18 peaked at 7 month after vaccination:5701.5(95%CI:4630.5,7020.3)EL.U/ml for HPV-16 and 2934.0(95%CI:2374.7,3625.0)EL.U/ml for HPV-18,which were still far above baseline GMT levels at 48 months after vaccination.Compared with women who were negative for all high-risk HPV types,women positive for at least one high-risk HPV type showed 2.19 times(95%CI:1.64,2.87)higher risks for subsequent 12-month infections to any other high-risk HPV type.2.Impact of HPV immunization programme on obstetric outcomes in spontaneous delivery:A total of 6515 spontaneous singleton living birth were included in final analysis,with 5134 births included in the pre-immunisation cohort,1250 in the catch-up immunisation cohort and 131 in the routine immunisation cohort.Compared with the pre-immunisation cohort,no statistically significant reduction on PTB,LBW or pPROM were observed in either immunised cohorts.The adjusted odds ratio(aOR)on PTB was 0.64(95%CI:0.40,1.03)in the catch-up cohort and 0.71(95%CI:0.28,1.77)in the routine cohort.The corresponding aOR were 0.88(95%CI:0.54,1.45)and 0.51(95%CI:0.16,1.62)for LBW and 1.62(95%CI:0.58,4.54)and 1.51(95%CI:0.21,11.01)for pPROM.3.A nationwide post-marketing survey of knowledge,attitude and practice toward HPV vaccine in China:A total of 4000 female,1000 male and 5270 HCP valid records were included in final analysis.In general adults,less than 1/3 heard of HPV vaccine(female:33.7%;male:22.9%).Knowledge score(correct score/total points)on HPV and HPV vaccine were:3.0 out of 13 and 3.0 out of 6 in female;1.8 out of 13 and 2.0 out of 5 in male.Female with lower education level and income level showed lower awareness and knowledge.The HPV vaccine uptake among female is 2.5%.The main barriers to vaccination include concerns about the quality of the vaccine,lack of perceptions of the vaccine,concerns about adverse reactions after vaccination and high price.The median knowledge score for HPV and HPV vaccine-in HCPs was 9.5 out of16.The lower education level and professional title as well as ethnic minorities HCPs were related to lower knowledge level.74.8%of HCPs had recommended HPV vaccination to others,with knowledge level as a significant determinant(2.74,95%CI:2.34,3.21).ConclusionsWomen infected with high-risk HPV types are at higher risks of subsequent infections to non-infected types,compared to women negative to all high-risk HPV types.They could still benefit from HPV vaccination on non-infected types to different degrees.HPV vaccine also induced strong immunogenicity in HPV-16/18 DNA positive women.With data from AMND,the results did not show significant reduction on PTB,LBW or pPROM among spontaneous singleton living birth in either HPV immunised cohorts,although the additional benefit in improving obstetric outcomes cannot be excluded because of the limitations of sample size and study designs.Three years after HPV vaccine licensure in China,the knowledge about HPV and HPV vaccine among general adults and HCPs remain to be improved.In summary,the study adds additional supportive evidence from the perspective of individual benefit,exploratory evidence from the perspective of public health benefit and practical evidence from the perspective of HPV vaccine roll-out in both self-paid stage and future national immunization in China.These results would facilitate to enhance vaccination confidence and promote the application of HPV vaccine so as to accelerate the path of cervical cancer elimination in China.