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Immunogenicity and HPV infection after one, two, and three doses of quadrivalent HPV vaccine in girls in India: a multicentre prospective cohort study.

ABSTRACT:

Background

An increase in worldwide HPV vaccination could be facilitated if fewer than three doses of vaccine are as effective as three doses. We originally aimed to compare the immunogenicity and frequency of persistent infection and cervical precancerous lesions caused by vaccine-targeted HPV after vaccination with two doses of quadrivalent vaccine on days 1 and 180 or later, with three doses on days 1, 60, and 180 or later, in a cluster-randomised trial. Suspension of the recruitment and vaccination due to events unrelated to our study meant that some enrolled girls could not be vaccinated and some vaccinated girls received fewer than the planned number of vaccinations by default. As a result, we re-analysed our data as an observational cohort study.

Methods

Our study was designed to be done in nine locations (188 clusters) in India. Participants were unmarried girls aged 10-18 years vaccinated in four cohorts: girls who received three doses of vaccine on days 1, 60, and 180 or later, two doses on days 1 and 180 or later, two doses on days 1 and 60 by default, and one dose by default. The primary outcomes were immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity after vaccination for the vaccine-targeted HPV types 16, 18, 6, and 11 and incident and persistent infections with these HPVs. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702.

Findings

Vaccination of eligible girls was initiated on Sept 1, 2009, and continued until April 8, 2010. Of 21 258 eligible girls identified at 188 clusters, 17 729 girls were recruited from 178 clusters before suspension. 4348 (25%) girls received three doses, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses at days 1 and 60, and 4950 (28%) received one dose. Immune response in the two-dose HPV vaccine group was non-inferior to the three-dose group (median fluorescence intensity ratio for HPV 16 1·12 [95% CI 1·02-1·23] and for HPV 18 1·04 [0·92-1·19]) at 7 months, but was inferior in the two-dose default (0·33 [0·29-0·38] for HPV 16 and 0·51 [0·43-0·59] for HPV 18) and one-dose default (0·09 [0·08-0·11] for HPV 16 and 0·12 [0·10-0·14] for HPV 18) groups at 18 months. The geometric mean avidity indices after fewer than three doses by design or default were non-inferior to those after three doses of vaccine. Fewer than three doses by design and default induced detectable concentrations of neutralising antibodies to all four vaccine-targeted HPV types, but at much lower concentration after one dose. Cervical samples from 2649 participants were tested and the frequency of incident HPV 16, 18, 6, and 11 infections was similar irrespective of the number of vaccine doses received. The testing of at least two samples from 838 participants showed that there was no persistent HPV 16 or 18 infections in any study group at a median follow-up of 4·7 years (IQR 4·2-5·1).

Interpretation

Despite the limitations imposed by the suspension of the HPV vaccination, our findings lend support to the WHO recommendation of two doses, at least 6 months apart, for routine vaccination of young girls. The short-term protection afforded by one dose of HPV vaccine against persistent infection with HPV 16, 18, 6, and 11 is similar to that afforded by two or three doses of vaccine and merits further assessment.

Funding

Bill & Melinda Gates Foundation.

SUBMITTER: Sankaranarayanan R

PROVIDER: S-EPMC5357737 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:BackgroundA randomised trial designed to compare three and two doses of quadrivalent human papillomavirus (HPV) vaccine in adolescent girls in India was converted to a cohort study after suspension of HPV vaccination in trials by the Indian Government. In this Article, the revised aim of the cohort study was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years post vaccination.MethodsIn the randomised trial, unmarried girls aged 10-18 years were recruited from nine centres across India and randomly assigned to either two doses or three doses of the quadrivalent HPV vaccine (Gardasil [Merck Sharp & Dohme, Whitehouse Station, NJ, USA]; 0·5 mL administered intramuscularly). After suspension of recruitment and vaccination, the study became a longitudinal, prospective cohort study by default, and participants were allocated to four cohorts on the basis of the number vaccine doses received per protocol: the two-dose cohort (received vaccine on days 1 and 180 or later), three-dose cohort (days 1, 60, and 180 or later), two-dose default cohort (days 1 and 60 or later), and the single-dose default cohort. Participants were followed up yearly. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Married participants were screened for cervical cancer as they reached 25 years of age. Unvaccinated women age-matched to the married vaccinated participants were recruited to serve as controls. Vaccine efficacy against persistent HPV 16 and 18 infections (the primary endpoint) was analysed for single-dose recipients and compared with that in two-dose and three-dose recipients after adjusting for imbalance in the distribution of potential confounders between the unvaccinated and vaccinated cohorts. This trial is registered with ISRCTN, ISRCTN98283094, and ClinicalTrials.gov, NCT00923702.FindingsVaccinated participants were recruited between Sept 1, 2009, and April 8, 2010 (date of vaccination suspension), and followed up over a median duration of 9·0 years (IQR 8·2-9·6). 4348 participants had three doses, 4980 had two doses (0 and 6 months), and 4949 had a single dose. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95·4% (95% CI 85·0-99·9) in the single-dose default cohort (2135 women assessed), 93·1% (77·3-99·8) in the two-dose cohort (1452 women assessed), and 93·3% (77·5-99·7) in three-dose recipients (1460 women assessed).InterpretationA single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and 18, the genotypes responsible for nearly 70% of cervical cancers, to that provided by two or three doses.FundingBill & Melinda Gates Foundation.

Project description:No immunogenicity data has been reported after a single dose of the quadrivalent HPV vaccine (qHPV-Gardasil®) and no data are available on co-administration of this vaccine with the HAV/HBV vaccine (Twinrix-Junior®). Two pre-licensure studies reported similar anti-HPV but lower anti-HBs titers when co-administering HPV and HBV vaccines.To assess the immunogenicity of the qHPV and HAV/HBV vaccine when co-administered (Group-Co-adm) or given one month apart (Group-Sep) and to measure the persistence of HPV antibodies three years post-second dose of qHPV vaccine in both study groups.416 9-10 year-old girls were enrolled. Vaccination schedule was 0-6 months. Anti-HAV and anti-HBs were measured in all subjects 6 months post-first dose and 1 month post-second dose. Anti-HPV were measured 6 months post-first dose in Group-Co-adm and in all subjects 1 and 36 months post-second dose.Six months post-first dose: 100% of subjects had detectable anti-HAV and 56% and 73% had detectable anti-HBs in Group-Co-Adm and Group-Sep, respectively. In Group-Co-adm 94, 100, 99 and 96% had detectable antibodies to HPV 6, 11, 16 and 18, respectively. One month post-second dose of qHPV and HAV/HBV vaccine, in both study groups 99.5-100% of subjects had an anti-HAV titer ? 20IU/L, 97.5-97.6% an anti-HBs level ? 10IU/L, and 100% had an anti-HPV titer ? 3LU. Thirty-six months post-second dose of qHPV all but four subjects (99%) had antibodies to HPV18 and 100% had antibodies to HPV6, 11 and 16. The great majority (97-100%) had an anti-HPV titer ? 3 LU. Post-second dose administration of qHPV and HAV/HBV, no meaningful difference was observed in the immune response in the two study groups to any component of vaccines.The results indicate that qHPV and HAV/HBV can be given during the same vaccination session. Two doses of of qHPV and HAV/HBV vaccines induce a strong immune response. Three years post-second dose of qHPV, the great majority of subjects had antibodies to HPV types included in the vaccine. A two-dose schedule for pre-adolescents might be a reasonable alternative to the currently approved three-dose schedules.

Project description:BackgroundLimited data is available on the use of different HPV vaccines in the same subjects. We evaluated the immunogenicity and safety of a mixed vaccination schedule with one dose of nonavalent (9vHPV) and one dose of bivalent vaccine (2vHPV) administered in different order versus two doses of 9vHPV vaccine.Methods371 girls and boys aged 9-10 years were randomized (1:1) to receive (I) two doses of 9vHPV or (II) a mixed schedule of 2vHPV + 9vHPV or 9vHPV + 2vHPV with a 6 month interval. Antibodies to HPV were tested by ELISA in blood samples collected one or six months post-first dose and one month post-second dose.ResultsPost-first dose of 9vHPV 99.4-100% of subjects were seropositive to 9 HPV types included in the vaccine. GMTs varied from 5.0 to 73.6 IU(AU)/ml depending on HPV type. Post-first dose of 2vHPV all subjects were seropositive to HPV16 and 18 (GMTs 16.7 and 11.7 IU/ml, respectively) and 50.0-76.7% were seropositive to 7 types not included in 2vHPV (GMTs varied from 0.3 to 17.5 AU/ml depending on type). Post-second dose all subjects, regardless of the study group, were seropositive to 9 HPV types included in 9vHPV. Anti-HPV16 and 18 GMTs were higher in subjects with the mixed schedule and for the other 7 HPV types higher in subjects who received two doses of 9vHPV vaccine. A higher proportion of subjects who received 2vHPV reported local or systemic adverse events than those who received 9vHPV as the first dose. Post-second dose there were no differences in reported adverse events between the two vaccines.ConclusionsThe results show the mixed HPV vaccination schedules used in this study are immunogenic and have an acceptable safety profile. Although the seroprotective threshold of antibodies remains unknown the 100% seropositivity to all 9 HPV types included in 9vHPV and the increase of GMTs observed in all study groups post-second dose administration are reassuring and suggest protection might be achieved regardless of the schedule used.Clinical trials registrationClinicaltrials.gov NCT02567955.

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