Systematic literature review of neutralizing antibody immune responses to non-vaccine targeted high-risk HPV types induced by the bivalent and the quadrivalent vaccines

IntroductionStudies on the cross-protective effect of HPV bivalent and quadrivalent vaccines demonstrated inconsistent findings against additional HPV types covered by the nonavalent vaccine. The objective of this study was to conduct a systematic literature review to assess the consistency and durability of the cross-protective neutralizing antibody immune responses of the currently licensed bivalent and quadrivalent vaccines to non-vaccine HPV types targeted by the nonavalent vaccine (HPV 6, 11, 31, 33, 45, 52, and 58).MethodsPubMed and EMBASE databases were searched from 2008 to 2019 to identify studies reporting antibody/immune response after vaccination with either the bivalent, quadrivalent, or nonavalent vaccine. Key outcomes were seroconversion, seropositivity or geometric mean titers against HPV types 6, 11, 31, 33, 45, 52, and 58.ResultsEighteen publications met inclusion criteria, reporting on 14 interventional and five observational studies. Across all studies, immune responses to non-vaccine high-risk HPV types after bivalent vaccination were higher than baseline or quadrivalent vaccine. Nonavalent vaccine elicited near total seroconversion to HPV types 31, 33, 45, 52, and 58, with seropositivity remaining near 100% up to 24 months post-dose 1. In contrast, bivalent and quadrivalent vaccination resulted in lower seroconversion levels for non-vaccine types, which waned over time.ConclusionsThe cross-protection antibody/immune response among participants having received all three doses of bivalent or quadrivalent vaccine is not comparable to the specific response elicited by HPV vaccine types. Even in cases where a statistically significant cross-reactive immunological response is reported, long-term data on the duration of the response beyond two years are very limited. Further, the lack of a standard for assays limits comparability of results between studies.     

Systematic literature review of cross-protective effect of HPV vaccines based on data from randomized clinical trials and real-world evidence

BackgroundThe extent of cross-protection provided by currently licensed bivalent and quadrivalent HPV vaccines versus direct protection against HPV 31-, 33-, 45-, 52-, and 58-related disease is debated. A systematic literature review was conducted to establish the duration and magnitude of cross-protection in interventional and observational studies.MethodsPubMed and Embase databases were searched to identify randomized controlled trials (RCT) and observational studies published between 2008 and 2019 reporting on efficacy and effectiveness of HPV vaccines in women against non-vaccine types 31, 33, 45, 52, 58, and 6 and 11 (non-bivalent types). Key outcomes of interest were vaccine efficacy against 6- and 12-month persistent infection or genital lesions, and type-specific genital HPV prevalence or incidence. RCT data were analyzed for the according-to-protocol (bivalent vaccine) or negative-for-14-HPV-types (quadrivalent vaccine) efficacy cohorts.ResultsData from 23 RCTs and 33 observational studies evaluating cross-protection were extracted. RCTs assessed cross-protection in post-hoc analyses of small size subgroups. Among fully vaccinated, baseline HPV-naïve women, the bivalent vaccine showed statistically significant cross-protective efficacy, although with wide confidence intervals, against 6-month and 12-month persistent cervical infections and CIN2+ only consistently for HPV 31 and 45, with the highest effect observed for HPV 31 (range 64.6% [95% CI: 27.6 to 83.9] to 79.1% [97.7% CI: 27.6 to 95.9] for 6-month persistent infection; maximal follow-up 4.7 years). No cross-protection was shown in extended follow-up. The quadrivalent vaccine efficacy reached statistical significance for HPV 31 (46.2% [15.3–66.4]; follow-up: 3.6 years). Similarly, observational studies found consistently significant effectiveness only against HPV 31 and 45 with both vaccines.ConclusionsRCTs and observational studies show that cross-protection is inconsistent across non-vaccine HPV types and is largely driven by HPV 31 and 45. Furthermore, existing data suggest that it wanes over time; its long-term durability has not been established.     

Reduction of HPV16/18 prevalence in young women after eight years of three- and two-dose vaccination schemes

BackgroundRecommendations for human papillomavirus vaccination have relied on immunogenicity studies and efficacy results derived from adult women. Insufficient information exists regarding HPV effectiveness in vaccinated girls as they become sexually active, regardless of dose scheme. We aimed to compare the prevalence of high-risk HPV between unvaccinated and vaccinated young women eight years after immunization.MethodsAfter eight years, we recontacted women who received two-dose of bivalent or three-dose—either bivalent or quadrivalent—, HPV vaccine when aged 9–10 years-old as part of a clinical trial. Additionally, we recruited a contemporaneous unvaccinated woman group for comparison. Only those sexually active were included. High-risk HPV DNA was determined in urine samples and compared across groups.ResultsThe prevalence of HPV16/18 types was 6.8% (95 %CI 3.2–14.1%) in the unvaccinated (n = 6/88), 1.1% (95 %CI 0.2–5.8%) in the three-dose (n = 1/93), and 0.0% (95 %CI 0.0–7.0%) in the two-dose group (n = 0/51).ConclusionHPV vaccination, with two-dose of bivalent or three-dose schemes—either with the bivalent or quadrivalent vaccine—, was associated with a lower prevalence of HPV16/18 types eight years after primary immunization.     

Safety and immunogenicity of a pichia pastoris-expressed bivalent human papillomavirus (types 16 and 18) L1 virus-like particle vaccine in healthy Chinese women aged 9–45 years: A randomized,double-blind,placebo-controlled phase 1 clinical trial

BackgroundWe evaluated the safety and immunogenicity of high and low doses of a novel pichia pastoris-expressed bivalent (types 16 and 18) human papillomavirus (HPV) virus-like particle vaccine.MethodsIn this randomized, double-blind, placebo-controlled phase 1 trial, we enrolled 160 healthy females aged 9–45 years in Guangxi, China who were randomized (1:1:2) to receive either low (0.5 mL) or high (1.0 mL) dosages of bivalent HPV vaccine, or placebo (aluminum adjuvant) in a 0, 2, 6 months schedule. Adverse events and other significant conditions that occurred within 30 days after each vaccination were recorded throughout the trial. Sera were collected at days 0, 60, 180 and 210 to measure anti-HPV 16/18 neutralizing antibodies.ResultsA total of 160 participants received at least one dose of the HPV vaccine and 152 completed the three dose vaccination series. Reporting rates of adverse events in placebo, low dose (0.5 mL) and high dose (1.0 mL) groups were 47.5 %, 55.0 % and 55.0 %, respectively. No serious adverse events occurred during this trial. 100 % of the participants who received three doses of the HPV vaccine produced neutralizing antibodies against HPV 16/18 vaccine. For HPV 16 and HPV 18, the geometric mean titers (GMTs) were similar between the low dose group (GMT_{HPV 16} = 10816 [95 % CI: 7824–14953]), GMT_{HPV 18} = 3966 [95 % CI: 2693–5841]) and high dose group (GMT _{HPV 16} = 14482 [95 % CI: 10848–19333], GMT _{HPV 18} = 3428 [95 % CI: 2533–4639]).ConclusionThe pichia pastoris-expressed bivalent HPV vaccine was safe and immunogenic in Chinese females aged 9–45 years. The low dosage (0.5 mL) was selected for further immunogenicity and efficacy study.     

Efficacy of quadrivalent human papillomavirus vaccine against persistent infection and genital disease in Chinese women: A randomized,placebo-controlled trial with 78-month follow-up

BackgroundA quadrivalent human papillomavirus vaccine (qHPV; HPV6/11/16/18) has demonstrated efficacy and effectiveness worldwide. We report qHPV vaccine efficacy for up to 6.5 years after first administration among Chinese women 20–45 years of age.MethodsIn this randomized, double-blind, placebo-controlled, multicenter, Phase 3 study (NCT00834106), women were randomized 1:1 to receive 3 doses of qHPV vaccine or placebo (Day 1, Month 2, Month 6). Endo-ecto-cervical and external genital swabs were collected for HPV testing and gynecologic examinations, and cervical cytology testing were performed at Day 1 and Months 7, 12, 18, 24, 30, 42, 54, 66, and 78. Any abnormality in cytology testing would trigger colposcopy examination and cervical biopsy, if necessary. Efficacy against genital disease, persistent infection, and the composite endpoint was assessed. Primary efficacy analyses were conducted in the per-protocol efficacy (PPE) population.ResultsOf 3006 participants randomized, 2759 (91.8%) and 2374 (79%) completed the Month 30 and Month 78 visits, respectively. At Month 78, efficacy among women aged 20–45 years was 100% (95% CI: 32.3, 100; 0 vs 7 cases) and 100% (95% CI: 70.9, 100; 0 vs 14 cases) against HPV16/18-related cervical intraepithelial neoplasia Grade 2 or 3, adenocarcinoma in situ, and cervical cancer (CIN 2+) and HPV6/11/16/18-related CIN 1+, respectively, in the PPE population. The efficacy against cervical 6-month and 12-month persistent infection was 91.6% (95% CI: 66.0, 99.0) and 97.5% (95% CI: 85.1, 99.9) at Month 30 and Month 78, respectively, in the PPE population. The vaccine also reduced the rate of cervical cytology abnormalities associated with HPV6/11/16/18, with an efficacy of 94.0% (95% CI: 81.5, 98.8). The vaccine was generally well tolerated (reported separately).ConclusionThe qHPV vaccine is efficacious against endpoints of persistent infection and genital precancerous lesions in Chinese women aged 20–45 years.     

Public health impact and cost-effectiveness of a nine-valent gender-neutral HPV vaccination program in France

ObjectivesIn France, 9-valent HPV vaccination is recommended routinely for 11–14-years-old girls and as catch-up for 15–19-years-old girls. Recently, recommendation for gender-neutral vaccination (GNV) has been approved. The objectives of the study were to assess the public health impact and cost-effectiveness of a 9-valent GNV compared with girls-only vaccination program (GOV).MethodsA published HPV disease transmission dynamic model accounting for herd protection effects with a 100-year time horizon was adapted and calibrated to French data. Epidemiological and economic outcomes included disease cases averted and quality-adjusted life years (QALY). Costs and incremental cost-effectiveness ratio (ICER) were measured in 2018 Euros (€). A coverage rate of 26.2% among girls and boys was assumed for the GNV program based on the current female coverage rate in France. The base case included genital warts, cervical, vulvar, vaginal, and anal cancers. Scenario analyses included all HPV-related diseases and considered higher vaccination coverage rate (60%). Deterministic sensitivity analyses on key inputs were performed.ResultsOver 100 years, GNV resulted in an additional reduction of 9,519 and 3,037 cervical cancer cases and deaths; 6,901 and 1,166 additional anal cancer cases and deaths; and a reduction of additional 1,284,077 genital warts compared with current GOV and an ICER of 24,763€/QALY. When including all HPV-related diseases, the ICER was 15,184€/QALY. At a higher coverage rate (60%), GNV would prevent 17,430 and 4,334 additional anogenital cancer cases and deaths and over two million genital warts compared with GOV with an ICER of 40,401€/QALY. Results were sensitive to a higher discount rate (6% versus 4%) and a shorter duration of protection (20 years versus lifetime).ConclusionsIn France, GNV has a significant impact in terms of public health benefits and may be considered cost-effective compared with GOV at low and high coverage rates.     

Immunogenicity and safety of a nine-valent human papillomavirus vaccine in women 27–45 years of age compared to women 16–26 years of age: An open-label phase 3 study

BackgroundEfficacy of the nine-valent human papillomavirus (9vHPV; HPV types 6/11/16/18/31/33/45/52/58) vaccine was demonstrated in a phase 3 study in women 16–26 years of age. We present a phase 3 immunogenicity and safety study of the 9vHPV vaccine in women 27–45 versus 16–26 years of age.MethodsThis international, open-label study (NCT03158220) was conducted in women 16–45 years of age. Participants (16–26 years, n = 570 and 27–45 years, n = 642) received a three-dose 9vHPV vaccination regimen (day 1, month 2, month 6). Month 7 geometric mean titers (GMTs) and seroconversion percentages to anti-HPV 6/11/16/18/31/33/45/52/58 were assessed. Participants were followed for safety throughout the study.ResultsAt month 7, anti-HPV 6/11/16/18/31/33/45/52/58 GMTs in women 27–45 years were compared to those in women 16–26 years of age. The primary hypothesis of non-inferiority of anti-HPV 16/18/31/33/45/52/58 GMTs in older versus younger women was met. The lower bound of the GMT ratio 95% confidence interval (27–45 years to 16–26 years) was 0.60–0.67 depending on HPV type, exceeding the non-inferiority margin of 0.5 for all HPV types. Month 7 seroconversion percentages in women 27–45 years of age were >99% for all HPV types. Injection-site and vaccine-related systemic adverse events (AEs) were observed in 87.5% and 25.1% of women 16–26 years, and 85.2% and 24.1% of women 27–45 years of age, respectively; no vaccine-related serious AEs were reported and no deaths occurred during the study.ConclusionsThe 9vHPV vaccine elicited non-inferior anti-HPV GMTs in women 27–45 years compared with women 16–26 years of age for HPV 16/18/31/33/45/52/58. The vaccine was generally well tolerated with a similar AE profile across the age groups. These data support bridging 9vHPV vaccine efficacy findings in women 16–26 years to women 27–45 years of age.Clinical trial registration NCT03158220.     

Immunogenicity and safety of the quadrivalent human papillomavirus vaccine in Chinese females aged 9 to 26 years: A phase 3, open-label,immunobridging study

BackgroundThe quadrivalent human papillomavirus (qHPV; HPV6/11/16/18) vaccine was approved for use in Chinese women aged 20–45 years in 2017. This Phase 3, open-label study (NCT03493542) aimed to assess immunogenicity and safety of the qHPV vaccine in Chinese girls aged 9–19 years versus Chinese young women aged 20–26 years; we report results from Day 1 through Month 7. The study will continue through Month 60 to assess antibody persistence in Chinese girls aged 9–19 years.MethodsParticipants aged 9–26 years received three doses of the qHPV vaccine (Day 1, Month 2, Month 6). Geometric mean titers (GMTs) and seroconversion percentages for anti-HPV6/11/16/18 antibodies were determined by competitive Luminex immunoassay (cLIA) in serum samples obtained on Day 1 and at Month 7. Injection-site adverse events (AEs) and systemic AEs within 30 days post-vaccination, and serious AEs (SAEs) occurring at any time during the study, were recorded.ResultsIn total, 766 participants (383 aged 9–19 years; 383 aged 20–26 years) were enrolled and received ≥1 vaccine dose. All participants in the per-protocol immunogenicity population of both age groups seroconverted to each of the vaccine HPV types at Month 7. Anti-HPV6/11/16/18 antibody GMTs at Month 7 in participants aged 9–19 years were non-inferior to those in participants aged 20–26 years. Injection-site AEs and systemic AEs were reported by 36.6% and 49.3% of 9–19-year-olds, and 40.7% and 54.8% of 20–26-year-olds, respectively. There were no vaccine-related SAEs. No participants discontinued the vaccine due to an AE and no deaths were reported.ConclusionAntibody responses induced by the 3-dose qHPV vaccination regimen in Chinese girls aged 9–19 years were non-inferior to those in Chinese young women aged 20–26 years. The vaccine was generally well tolerated in the study population.ClinicalTrials.gov Identifier: NCT03493542.     

Human papillomavirus vaccine coverage in Rwanda: A population-level analysis by birth cohort

BackgroundIn 2011, Rwanda became the first African nation to implement a national human papillomavirus (HPV) vaccination program, conceived to protect girls aged <15 years (i.e. born ≥1997). After an initial school-grade-targeted catch-up campaign, there was a transition to routine vaccination of 12 year-olds only. We aimed to produce population-level vaccine coverage estimates.MethodsThe Rwandan Expanded Program on Immunization (EPI) collected data on number of eligible girls and HPV vaccines delivered, stratified by calendar year (2011–2018), girl’s age, district and vaccination round. HPV vaccine coverage was estimated by birth cohort (reconstituted using calendar year and age), as a proportion of (1) eligible target, and (2) the 2012 Rwandan census population.Results1,156,863 girls received first dose of HPV vaccine between 2011 and 2018, corresponding to 98% of the eligible target. Median vaccination age was 15 years (interquartile range [IQR] 13–16) in 2011–2013 (school grade-targeted catch-up), 13 years (IQR 12–14) in 2014 (transition) and 12 years in 2015–2018 (routine). Population-level coverage versus the census increased from 10 to 40% for girls born in 1993–1995 (median vaccination age = 17 years) to 50–65% for 1996–2000 birth cohorts (14 years), and 80–90% for 2001–2006 birth cohorts (12 years). Coverage trends were similar across provinces and in the capital, Kigali. Second and third round coverage suggested most vaccinated girls completed their recommended dosing regimen (which reduced from 3 to 2 doses in 2015).ConclusionsBirth cohorts provide a clear picture of population-level HPV vaccine coverage after a pragmatic catch-up campaign, particularly in Rwanda where eligible school grades included wide age ranges. Whilst the catch-up campaign resulted in some coverage gaps in out-of-school teenagers, coverage remains high in cohorts routinely targeted as 12 year-olds.     

Prevalence of human papillomavirus (HPV)-vaccine types by race/ethnicity and sociodemographic factors in women with high-grade cervical intraepithelial neoplasia (CIN2/3/AIS), Alameda County,California, United States

We evaluated racial/ethnic differences in prevalence of oncogenic HPV types targeted by the quadrivalent HPV vaccine (16/18) and nonavalent HPV vaccine (31/33/45/52/58) in women diagnosed with CIN2/3/AIS after quadrivalent HPV vaccine introduction (2008–2015). Typing data from 1810 cervical tissue specimen from HPV-IMPACT (Alameda County, California, US), a population-based CIN2/3/AIS surveillance effort, were analyzed. Using log-binomial regression, we calculated adjusted prevalence ratios (aPR) and 95% confidence intervals (CI) comparing type prevalence by race/ethnicity, adjusted for health insurance, age, CIN2/3/AIS grade, and time period, overall and in the “early vaccine era” (2008–2011) and “later vaccine era” (2012–2015). Overall, oncogenic HPV16/18 prevalence was significantly lower among black (43%) and Hispanic (43%) women compared with white (52%) women (aPR (95% CI): 0.80 (0.70, 0.93) and 0.80 (0.70, 0.91), respectively). In 2008-2011, proportion of HPV16/18 detected was significantly lower in black (47%), Hispanic (46%), and Asian (42%) women compared to white (58%) women (aPR (95% CI): 0.80 (0.67, 0.96), 0.75 (0.63, 0.90), and 0.73 (0.58, 0.90), respectively). There were no significant differences in 2012-2015. Between the two eras, HPV16/18 prevalence declined in white (−11%), black (−9%), and Hispanic (−6%) women, and increased in Asian women (12%). Decreasing HPV 16/18 prevalence in CIN2/3/AIS lesions in white, black, and Hispanic women may suggest benefit from quadrivalent vaccination. In our unadjusted analysis of HPV31/33/45/52/58, prevalence did not differ significantly by race/ethnicity, but was significantly higher among Hispanic women (32%) compared to white women (27%) after adjustment (aPR (95%CI): 1.22 (1.02, 1.47). Prevalence was also non-significantly higher among black (32%) and Asian (33%) women. This analysis suggests that the nonavalent vaccine’s potential for impact against cervical precancers will not be lower in women of color compared to white women. These data underscore the importance of equitable vaccination in facilitating continued declines of vaccine-preventable HPV types among all women.     

Increases in HPV-16/18 antibody avidity and HPV-specific memory B-cell response in mid-adult aged men post-dose three of the quadrivalent HPV vaccine

Strong quantitative and functional antibody responses to the quadrivalent human papillomavirus (HPV) vaccine were reported in mid-adult aged men, but there are limited data on the avidity of the antibody response and the memory B-cell response following vaccination. Although circulating antibodies induced by vaccination are believed to be the main mediators of protection against infection, evaluation of avidity of antibodies and memory B cell responses are critical for a better understanding of the vaccine immunogenicity mechanisms. Both the modified enzyme-linked immunosorbent assay (ELISA) and the enzyme-linked immunosorbent spot (ELISpot) assay are tools to measure the humoral and cellular immune responses post vaccination to characterize vaccine immunogenicity. The avidity of HPV-16 and HPV-18 specific IgG in the serum of mid-adult aged men (N = 126) who received three quadrivalent HPV vaccine doses was examined using a modified ELISA. HPV-16 memory B-cell responses were assessed via ELISpot at month 0 (prior to vaccination) and 1-month post-dose three of the vaccine (month 7). The quadrivalent vaccine induced an increase in HPV-16 and HPV-18 antibody avidity at month 7. HPV-18 avidity levels moderately correlated with anti-HPV-18 antibody titers, but no association was observed for HPV-16 antibody titers and avidity levels. The HPV-16-specific memory B-cell response was induced following three vaccine doses, however, no association with anti-HPV-16 antibody avidity was observed. Three doses of quadrivalent HPV vaccine increased antibody affinity maturation for HPV-16/18 and increased the frequency of anti-HPV-16 memory B-cells in mid-adult aged men.     

Disparities in human papillomavirus vaccination coverage in the United States,National Health and Nutrition Examination Survey,January 2017–March 2020

BackgroundWe assessed disparities in HPV vaccination coverage by sociodemographic characteristics in the United States.MethodsUsing 2017-March 2020 National Health and Nutrition Examination Survey data, we estimated vaccination coverage of ≥ 1 dose of HPV vaccine by race/ethnicity and poverty, insurance, and nativity status for females and males aged 9–14, 15–19, and 20–29 years.ResultsAmong those aged 9–14 years, coverage among non-Hispanic Black (NHB), Hispanic, and non-Hispanic Asian (NHA) females (40.0%, 33.6%, 34.0%) and males (27.1%, 35.3%, 30.9%) was higher than non-Hispanic White (NHW) females (26.5%) and males (25.2%). Among those aged 15–19 and 20–29 years, coverage varied among NHB, Hispanic, and NHA compared to NHW females and was lower among NHB, Hispanic, and NHA than NHW males. Coverage was lower among uninsured than insured in most comparisons.ConclusionsHPV vaccination coverage varied by race/ethnicity and other characteristics. Efforts are needed to increase HPV vaccination coverage in all populations.     

Cost-effectiveness analysis of quadrivalent and nonavalent human papillomavirus vaccines in Ethiopia

BackgroundIn Ethiopia, cervical cancer is the second most common cancer among women of the reproductive age group. Since 2018, the quadrivalent human papillomavirus (4vHPV) vaccine targeting four HPV types (6/11/16/18) has been introduced in the national immunization program in Ethiopia. Currently, however, a nonavalent HPV (9vHPV) vaccine which provides broader protection against nine HPV types (?6/11/16/18/31/33/45/52/58) is available for global use. Our study, therefore, aims to estimate the cost-effectiveness of 9vHPV vaccine compared to the current HPV vaccination program in Ethiopia.MethodA static Markov cohort model was used to simulate the progression of HPV infection to cervical cancer for a cohort of 12-years-old girls (N = 100,000) in Ethiopia. The model ran up to the age of 100 years, with a cycle length of 1 year. One-way and probabilistic sensitivity analyses were used to explore the robustness of the model and uncertainties around the parameters included in the model. Cost-effectiveness thresholds of one and three times gross domestic product (GDP) per quality-adjusted life-year (QALY) gained were considered.ResultsAt a price of US$ 6.9, the incremental cost-effectiveness ratio (ICER) per QALY gained for the 9vHPV vaccine was US$ 454 compared to the 4vHPV vaccine, which is less than one times GDP per capita of Ethiopia. The ICER was most sensitive to the change in the discount rate of QALYs. Compared to 4vHPV vaccine, for 9vHPV vaccine to remain very cost-effective and cost-effective, its price per dose should not exceed US$ 8.4 and US$ 15, respectively, at a threshold of one and three times GDP per capita.ConclusionCompared to the 4vHPV vaccine, the 9vHPV vaccine is a cost-effective option in Ethiopia, given that its price per dose does not exceed US$15.     

Evaluation of immune response to single dose of quadrivalent HPV vaccine at 10-year post-vaccination

BackgroundThe recent World Health Organization recommendation supporting single-dose of HPV vaccine will significantly reduce programmatic cost, mitigate the supply shortage, and simplify logistics, thus allowing more low- and middle-income countries to introduce the vaccine. From a programmatic perspective the durability of protection offered by a single-dose will be a key consideration. The primary objectives of the present study were to determine whether recipients of a single-dose of quadrivalent HPV vaccine had sustained immune response against targeted HPV types (HPV 6,11,16,18) at 10 years post-vaccination and whether this response was superior to the natural antibody titres observed in unvaccinated women.MethodsParticipants received at age 10–18 years either one, two or three doses of the quadrivalent HPV vaccine. Serology samples were obtained at different timepoints up to 10 years after vaccination from a convenience sample of vaccinated participants and from age-matched unvaccinated women at one timepoint. The evolution of the binding and neutralizing antibody response was presented by dose received. 10-year durability of immune responses induced by a single-dose was compared to that after three doses of the vaccine and in unvaccinated married women.ResultsThe dynamics of antibody response among the single-dose recipients observed over 120 months show stabilized levels 18 months after vaccination for all four HPV types. Although the HPV type-specific (binding or neutralizing) antibody titres after a single-dose were significantly inferior to those after three doses of the vaccine (lower bounds of GMT ratios < 0.5), they were all significantly higher than those observed in unvaccinated women following natural infections (GMT ratios: 2.05 to 4.04-fold higher). The results correlate well with the high vaccine efficacy of single-dose against persistent HPV 16/18 infections reported by us earlier at 10-years post-vaccination.ConclusionOur study demonstrates the high and durable immune response in single-dose recipients of HPV vaccine at 10-years post vaccination.     

Physician clinical decision support system prompts and administration of subsequent doses of HPV vaccine: A randomized clinical trial

BackgroundHPV vaccine is effective in preventing several cancers and anogenital warts, yet rates of HPV vaccination series completion in the United States are low. A primary reason identified by parents for vaccinating children against HPV is a health care provider’s recommendation. Although most clinicians embrace vaccine recommendations, they are not always carried out evenly and subsequent HPV vaccines are missed.MethodsUsing an electronic health records-based decision support system (CHICA) clinicians were randomized to either usual practice or to receive an automated reminder to recommend the 2nd or 3rd dose of HPV vaccine. The reminder was delivered to clinicians of all intervention group eligible adolescents who had already initiated the vaccine series. Logistic regression models with generalized estimating equations were used for data analysis.ResultsA total of 1285 clinical encounters were observed across 29 randomized pediatric providers over a 13-month time frame (50.7% control group, 49.3% intervention group). Overall, patients were 44.9% female, 59.4% Black, 22.1% Hispanic, and 48.8% were ages 11–12 yrs. Within the control group, 421 (64.7%) received a subsequent HPV vaccine, compared to 481 (75.9%) (OR: 1.72, (95% CI 1.35–2.19)). Adjusted analysis showed no difference between the groups (aOR 1.52 (95% CI 0.88–2.62)) or when examined by age (11-12yrs aOR 1.66, (95% CI 0.79–3.48)) and 13-17yrs (aOR 1.19, (95% CI 0.76–1.85)) or gender female (aOR 1.39 (95% CI 0.71–2.72)) and males (aOR 1.67 (95% CI 0.95–2.92)). When results were stratified by both age and gender, there was similarly no statistically significant effect between the two groups.ConclusionsAutomated physician reminders for subsequent 2nd and 3rd doses of HPV vaccination were used. Despite increased rates of vaccination in the intervention group, the differences did not reach the level of statistical significance. Future studies with multifaceted approaches may be needed to examine the efficacy of computer-based reminders.Clinical Trial Registration: NCT02558803, “HPV Vaccination: Evaluation of Reminder Prompts for Doses 2 & 3”.     

Vaccine coverage among children with epilepsy in two Canadian provinces: A Canadian immunization research network study

ObjectivesChildren with epilepsy are at increased risk of complications from vaccine-preventable infections, yet information on vaccine coverage in these children is scarce. We aimed to compare vaccine coverage among children with epilepsy to children without epilepsy.Study designWe conducted a retrospective cohort study including all 2005–2013 births in Manitoba and Ontario, Canada, creating two cohorts: 2-year-olds and 7-year-olds (followed to age 2 and 7 years). We split each cohort into epilepsy and non-epilepsy subcohorts. We assessed vaccination coverage based on provincial schedules and determined timeliness of MMR (measles, mumps, rubella) dose 1 (recommended at 12 months) and DTaP (diphtheria, tetanus, pertussis) dose 4 (recommended at 18 months). We used logistic regression to calculate adjusted odds ratios (aORs) of the association between epilepsy and vaccination, combining both provincial estimates using random effects meta-analysis.ResultsWe included 16,558 2-year-olds (Manitoba, 653; Ontario, 15,905) and 13,004 7-year-olds (Manitoba, 483; Ontario, 12,521) with epilepsy. At age 2 years, the aOR for up-to-date vaccination among children with versus without epilepsy was 0.9 (95% confidence interval 0.8–1.1); at age 7 years it was 1.0 (0.9–1.1). Infants diagnosed with epilepsy before age 6 months were less likely to be up-to-date at age 2 years (0.9; 0.8–0.9), although this difference disappeared by age 7 years. Vaccine timeliness was similar between children with and without epilepsy for MMR dose 1 and DTaP dose 4.ConclusionsOverall, this study suggests that children with epilepsy are not significantly under-vaccinated compared to their peers without epilepsy. As children with epilepsy are at a higher risk of complications from vaccine-preventable diseases, vaccination in children with epilepsy should be optimized, especially early in life, as these children may not be able to rely on herd protection.     

Meningococcal B vaccination coverage among older adolescents in the United States

BackgroundSerogroup B meningococcal (MenB) vaccination recommendations for adolescents in the United States (US) include routine vaccination for all individuals at increased risk and vaccination for individuals not at increased risk aged 16–23 years (preferred age 16–18 years) based on shared clinical decision-making. The two licensed MenB vaccines require administration of ≥2 doses.MethodsThis cross-sectional study analyzed 2017–2018 National Immunization Survey-Teen (NIS-Teen) data to evaluate ≥1 dose and ≥2 dose MenB vaccination coverage among adolescents aged 17 years. Multivariable logistic regression was used to further evaluate determinants of MenB vaccination.ResultsNationally, MenB vaccination coverage among 17-year-olds increased from 14.5% in 2017 to 17.2% in 2018 for ≥1 dose and from 6.3% to 8.4% for ≥2 doses. MenB vaccination coverage (2017–2018) was the lowest in the South (≥1 dose: 14.6%; ≥2 doses: 6.3%) and highest in the Northeast region (18.3% and 9.3%), with variation observed by census division. Adolescents were more likely to have received ≥1 dose of MenB vaccine if they had any Medicaid insurance (odds ratio [OR], 1.77; 95% confidence interval [CI], 1.32–2.39) or had received human papillomavirus (OR, 1.94; 95% CI, 1.41–2.67) or meningococcal A, C, W, and Y (OR, 4.03; 95% CI, 2.92–5.56) vaccinations.ConclusionsMenB first-dose coverage in the US is low, and even lower for a second dose, with regional variation. Being up to date with other routinely administered vaccines increased the likelihood of receiving MenB vaccination.     

Cost-effectiveness of human papillomavirus vaccination in girls living in Latin American countries: A systematic review and meta-analysis

BackgroundCervical cancer is a major public health problem in Latin America. Cost-effectiveness studies help stakeholders with decisions regarding human papillomavirus (HPV) vaccination programs, one of the main prevention measures. Our objective was to synthesize the results of cost-effectiveness studies of HPV vaccination in girls, to understand factors influencing cost-effectiveness in the region.MethodsWe systematically searched databases as well as repositories from conferences, Ministries of Health and Health Technology Assessment offices. Incremental cost-effectiveness ratios (ICERs) were extracted, with data converted to international dollars (I$) and inflated to 2019 values. We used the gross domestic product per capita as threshold for judging the cost-effectiveness of vaccination. We calculated the geometric mean ICER by type of vaccine, whether screening (cytology or HPV test) was used as comparator, effectiveness measure, perspective, source of funding, year of cost, and country.ResultsWe found 24 studies. Despite the methodological differences, most studies concluded that HPV vaccination of girls in Latin American countries was either cost-saving or cost-effective. The mean ICER was I$ 3,804 for the bivalent vaccine, I$ 640 for the quadrivalent and I$ 358 for a generic HPV-16/18 vaccine. The mean ICER was lower in the studies that used HPV DNA test instead of cytology (I$ 122 vs I$ 1,841) as comparator; used the societal perspective (I$ 235 vs. I$ 1,986); were funded by non-profit sources instead of by pharmaceutical industry (I$ 421 vs. I$ 2,676); and used costs obtained prior to 2008 (I$ 365 vs I$ 1,415). We observed great variation in the mean ICERs by effectiveness measure (I$ 402 for per disability adjusted life years, I$ 461 for life year saved, and I$ 1,795 for quality adjusted life years).ConclusionsMost studies concluded that HPV vaccination of girls in Latin America countries was cost-saving or cost-effective, despite heterogeneity between models.     

Importance of human papillomavirus vaccination leaflets focusing on the safety profile targeted pediatricians in Japan

ObjectivesTo investigate the association between providing leaflets to support pediatricians in explaining the safety of the human papillomavirus (HPV) vaccine and mother’s decision to vaccinate their daughters in Japan.MethodsIn this cross-sectional study, we conducted a survey of mothers to evaluate the effect of leaflets that were created to support pediatricians in explaining the safety profile of the HPV vaccine. Mothers who provided consent for vaccination before receiving an explanation were excluded from the study. The primary outcome was the mother’s decision to vaccinate their daughters with the HPV vaccine after receiving an explanation from pediatricians using our leaflets.ResultsAmong 161 eligible mothers, 101 decided on HPV vaccination (decided group) and 60 did not (decided against group). There was no difference in the maternal background between the 2 groups. The decided group had a significantly more positive impression of the leaflets than the undecided group. In multivariable logistic regression analysis, a detailed explanation for possible adverse events and specific solutions to them was associated with the mother's decision to have their daughters vaccinated (odds ratio 2.35, 95% confidence interval 1.02–5.44), but not the pathology of cervical cancer and the HPV vaccination process.ConclusionLeaflets emphasizing an explanation of adverse events may contribute to mothers’ decision making for HPV vaccination.