A summary of the post-licensure surveillance initiatives for GARDASIL/SILGARD

GARDASIL^® has been shown to reduce the incidence of pre-cancerous cervical, vulvar, and vaginal lesions, and external genital warts causally related to HPV6/11/16/18. Because of its expected public health benefit on reduction of cervical cancer and other HPV-related diseases, this vaccine has been rapidly implemented in the routine vaccination programs of several countries. It is therefore essential to assess its impact and safety through post-licensure surveillance programs. Here, we present a summary of 16 post-licensure safety and impact studies across 20 countries. These studies address general safety, including autoimmune disorders, long-term effectiveness, and type replacement. A summary of the surveillance efforts of the Unites States Centers for Disease Control and Prevention can be found in the accompanying article by Markowitz et al.     

Support for HPV vaccine school-entry requirements in the United States: The role of exemption policies

In the United States (U.S.), only five states or territories require human papillomavirus (HPV) vaccination for school attendance, even though almost all U.S. jurisdictions have debated adopting this type of policy. In this U.S. based study, we sought to estimate the level of support for HPV vaccine school-entry requirements with varying exemption policies and documentation procedures to obtain exemptions. Between July and August 2019, we conducted a web-based survey with a national sample of 1,109 U.S. parents of 11- to 17-year-olds. The survey assessed support for four school-entry vaccine requirement policies: without exemption or with exemption for medical, religious or philosophical reasons. Analyses used multivariable logistic regression to assess correlates of support for each policy. Overall, 38% of parents agreed with laws requiring HPV vaccination for school attendance without exemptions. When including exemption provisions, agreement increased to 45% for philosophical reasons, 50% for religious reasons, and 59% for medical reasons. Parents more often agreed on requirements without any exemptions if they were female (OR = 1.37, 95% CI:1.01–1.87), their child had initiated HPV vaccination (OR = 2.05, 95% CI:1.50–2.87), reported high levels of vaccine confidence (OR = 2.41, 95% CI:1.77–3.27), or reported having values similar to those of the people in their community (OR = 1.85, 95% CI:1.39–2.47). Parents more often agreed with requirements that included religious or philosophical exemptions if they reported having values similar to their community or high levels of psychological reactance (all p <.05). Many parents also supported requiring a written notice signed by a health care provider (40%) or religious leader (49%) to obtain a medical or religious exemption, respectively. In conclusion, exemption policies greatly increase parent support of school-entry requirements for HPV vaccination but may decrease their impact in practice. A large number of U.S. parents support strict documentation to obtain exemptions, signaling a promising area of policymaking to strengthen vaccine policies for school attendance.     

Modeling the impact of quadrivalent HPV vaccination on the incidence of Pap test abnormalities in the United States

Background

We present data on Pap test results and HPV prevalence from the HPV Sentinel Surveillance project, a multiyear surveillance project enrolling women from a diverse set of 26 clinics throughout the US from 2003 to 2005. We use mathematical modeling to illustrate the potential timing and magnitude of decreases in Pap test abnormalities in sexually transmitted disease (STD), family planning, and primary care clinics in the US as a result of HPV vaccination.

Methods

The probability of an abnormal Pap result was based on three factors: (1) infection with HPV 16/18, or both; (2) infection with high-risk HPV types other than HPV 16/18; and (3) infection with HPV 6/11, or both. We estimated the relative reduction in the probability of an abnormal Pap result over the first 25 years of a female-only, quadrivalent HPV vaccination program, compared to a scenario of no HPV vaccination in which the probability of abnormal Pap results was assumed constant.

Results

The probability of an abnormal Pap result ranged from 7.0% for the lowest risk group (those without any high-risk HPV types and without HPV 6/11) to 45.2% for the highest risk group (those with HPV 16/18 and at least one other high-risk HPV type). Estimated reductions in abnormal Pap results among women in the 21- to 29-year age group were 0.8%, 10.2%, and 11.3% in years 5, 15, and 25 of the vaccine program respectively, in the lower vaccine coverage scenario, and 7.4%, 21.4%, and 22.2%, respectively, in the higher coverage scenario.

Conclusions

Our results suggest that HPV vaccination will have a discernable impact on the probability of Pap abnormalities, but the timing and magnitude of the reduction will depend substantially on vaccine coverage and the degree of cross-protection against high risk HPV types other than HPV 16/18.     

Declines in HPV vaccine type prevalence in women screened for cervical cancer in the United States: Evidence of direct and herd effects of vaccination

BackgroundHuman papillomavirus (HPV) vaccine has been recommended in the United States since 2006 for routine vaccination of girls at age 11–12 years and through age 26 years for women not previously vaccinated. Changes in vaccine-type HPV (VT) prevalence can be used to evaluate vaccine impact, including herd effects.MethodsWe determined type-specific HPV in cytology specimens from women aged 20–29 years screened for cervical cancer at Kaiser Permanente Northwest in 2007 and in two vaccine era periods: 2012–2013 and 2015–2016. Detection and typing used L1 consensus PCR with hybridization for 37 types, including quadrivalent vaccine types (HPV 6/11/16/18).ResultsAmong 20–24 year-olds in 2012–2013 and 2015–2016, 44% and 64% had a history of ≥1-dose vaccination. VT prevalence decreased from 13.1% in 2007 to 2.9% in 2015–2016 (prevalence ratio [PR] = 0.22; 95% confidence interval [CI] 0.17–0.29). HPV 31 prevalence was also lower in the vaccine periods compared with 2007. VT prevalence in 2015–2016 among 20–24 year-olds was lower in both vaccinated, 1.3% (PR = 0.10; 95% CI 0.06–0.16), and unvaccinated women, 5.8% (PR = 0.45; 95% CI 0.33–0.61). Among 25–29 year-olds, 21% and 32% had a history of ≥1-dose vaccination. VT prevalence decreased from 8.1% in 2007 to 5.0% in 2015–2016 (PR = 0.62; 95% CI 0.50–0.78). Non-VT high risk prevalence was higher in the vaccine periods compared with the pre-vaccine era in both age groups, however, not in 2015–2016 compared with 2012–2013.ConclusionWithin 9–10 years of vaccine introduction, VT prevalence decreased 78% among 20–24 year-olds and 38% in 25–29 year-olds. There were declines in both vaccinated and unvaccinated women, showing evidence of direct and herd protection.     

西安市妇科门诊患者HPV和HPV疫苗的认知调查

目的 了解西安市妇科门诊患者对人乳头瘤病毒(HPV)的认知情况及其接种HPV疫苗的态度,为推广HPV疫苗的接种提供依据. 方法 在西安市第四医院妇科门诊单纯随机抽取前来就诊的患者1 000人,采用自行设计的问卷,进行调查.问卷内容主要包括患者的基本资料(年龄、婚姻、学历、职业)、对HPV的认知、对HPV疫苗的认知及态度. 结果 32.5％患者知晓HPV,不同年龄、教育程度、职业的女性在HPV知晓率上差异均有统计学意义.30＜年龄≤40岁年龄段的女性对HPV的知晓率(49％)明显高于21≤年龄≤30岁(34.4％)和60＜年龄≤71岁(17.6％)年龄段的女性,大学及以上学历的女性对HPV的知晓率(44.3％)明显高于初高中组,未受过教育的女性对HPV的知晓率(29.7％)最低;干部/职员/技术人员对HPV的知晓率(41.7％)最高,而工人、农民、个体户/服务人员对HPV的知晓率普遍偏低.76.0％患者愿意接种HPV疫苗,担心会感染HPV(32.1％)或患宫颈癌(26.1％)的女性有较强的接种意愿.56.6％的患者能接受的疫苗价格在50 ～ 100元,有49.9％的患者更愿意接受政府提供的疫苗,40.8％的患者更愿意接受医疗机构提供的疫苗. 结论 西安市门诊患者对HPV及其疫苗的知晓率较低,应加强公众健康教育宣传力度,普及HPV疫苗相关知识.     

Post-licensure surveillance of trivalent adjuvanted influenza vaccine (aIIV3; Fluad), Vaccine Adverse Event Reporting System (VAERS), United States,July 2016–June 2018

Background

Trivalent adjuvanted influenza vaccine (aIIV3; Fluad®) was approved in the United States (U.S.) in 2015 for adults aged ≥65?years and has been in use since the 2016–17 influenza season.

Considerations for human papillomavirus (HPV) vaccination of mid-adult women in the United States

In the United States, human papillomavirus (HPV) vaccination is recommended for 11 or 12 year old girls, with catch-up vaccination through age 26 years. Data are available for women over the age of 26 years on immunogenicity for both quadrivalent and bivalent HPV vaccines and on efficacy for the quadrivalent HPV vaccine. If HPV vaccines are licensed for use in women over 26 years of age (mid-adult women), recommendations for this age group will need to be considered. This review summarizes vaccine efficacy and immunogenicity data in mid-adult women, and addresses epidemiologic data related to key questions for consideration of vaccine recommendations for women over age 26 years.     

HPV vaccine and adolescent males

In 2009, the United States approved quadrivalent HPV vaccine for males 9-26 years old, but data on vaccine uptake are lacking. We determined HPV vaccine uptake among adolescent males, as well as stage of adoption and vaccine acceptability to parents and their sons. A national sample of parents of adolescent males ages 11-17 years (n = 547) and their sons (n = 421) completed online surveys during August and September 2010. Analyses used multivariate linear regression. Few sons (2%) had received any doses of HPV vaccine, and most parents and sons were unaware the vaccine can be given to males. Parents with unvaccinated sons were moderately willing to get their sons free HPV vaccine (mean = 3.37, SD = 1.21, possible range 1-5). Parents were more willing to get their sons vaccinated if they perceived higher levels of HPV vaccine effectiveness (β = 0.20) or if they anticipated higher regret about their sons not getting vaccinated and later developing an HPV infection (β = 0.32). Vaccine acceptability was also modest among unvaccinated sons (mean = 2.98, SD = 1.13, possible range 1-5). Sons were more willing to get vaccinated if they perceived higher peer acceptance of HPV vaccine (β = 0.39) or anticipated higher regret about not getting vaccinated and later developing an HPV infection (β = 0.22). HPV vaccine uptake was nearly nonexistent a year after permissive national recommendations were first issued for males. Vaccine acceptability was moderate among both parents and sons. Efforts to increase vaccine uptake among adolescent males should consider the important role of peer acceptance and anticipated regret.     

Immunogenicity of next-generation HPV vaccines in non-human primates: Measles-vectored HPV vaccine versus Pichia pastoris recombinant protein vaccine

Human papillomavirus (HPV) infection is the most common sexually transmitted disease worldwide. HPVs are oncogenic small double-stranded DNA viruses that are the primary causal agent of cervical cancer and other types of cancers, including in the anus, oropharynx, vagina, vulva, and penis. Prophylactic vaccination against HPV is an attractive strategy for preventing cervical cancer and some other types of cancers. However, there are few safe and effective vaccines against HPV infections. Current first-generation commercial HPV vaccines are expensive to produce and deliver.The goal of this study was to develop an alternate potent HPV recombinant L1-based vaccines by producing HPV virus-like particles into a vaccine that is currently used worldwide. Live attenuated measles virus (MV) vaccines have a well-established safety and efficacy record, and recombinant MV (rMV) produced by reverse genetics may be useful for generating candidate HPV vaccines to meet the needs of the developing world.We studied in non-human primate rMV-vectored HPV vaccine in parallel with a classical alum adjuvant recombinant HPV16L1 and 18L1 protein vaccine produced in Pichia pastoris. A combined prime-boost approach using both vaccines was evaluated, as well as immune interference due to pre-existing immunity against the MV.The humoral immune response induced by the MV, Pichia-expressed vaccine, and their combination as priming and boosting approaches was found to elicit HPV16L1 and 18L1 specific total IgG and neutralizing antibody titres. Pre-existing antibodies against measles did not prevent the immune response against HPV16L1 and 18L1.     

西安非医学专业女大学生对HPV和HPV疫苗的认知

目的 了解西安市高校非医学专业女大学生对人乳头瘤病毒(HPV)的认知情况及其对接种HPV疫苗的态度,为制定针对非医学专业大学生健康教育模式,推广HPV疫苗的接种提供依据.方法 采用整群随机抽样的方法,在西安市6所非医学类本科高校中抽取16个专业的大学二、三年级女大学生共2 131名,用自行设计的问卷进行调查,获有效问卷2 096份,有效回收率为98.4％.结果 仅11.3％被调查者知晓HPV,有性生活组大学生对HPV知晓率显著高于无性生活组(x2=20.182,P＜0.05),来自单亲或重组家庭的女大学生对HPV知晓率显著高于来自原生家庭组(x2=4.329,P＜0.05).不同年级间(x2=0.921),来自城市或农村(x2=0.891),是否独生子女(x2 =0.330)组间对HPV知晓率差异无统计学意义(P＞0.05).仅9.7％被调查者知晓HPV疫苗.79.9％的被调查者表示愿意接种HPV疫苗;担心会感染HPV (44.1％)或患宫颈癌(19.3％)的被调查者有较强的接种意愿;公众健康教育(42.2％)及医务人员推荐(34.7％)是女大学生们更愿意接受的疫苗推荐方式.超过半数被调查者(50.1％)能够接受的疫苗价格在50～ 100元.结论 西安非医学专业大学生对HPV及HPV疫苗的知晓率低,但接种意愿强.应加强科普健康教育,普及宫颈癌一级预防、HPV及HPV疫苗相关知识.     

Prevalence and characteristics of HPV vaccine hesitancy among parents of adolescents across the US

BackgroundWhile many clinicians encounter parents or adolescents who refuse HPV vaccine, little is known about the prevalence of hesitancy for HPV vaccine nationally or its association with vaccination.MethodsIn April 2019, we surveyed families with adolescents 11–17 years using a national online panel (Knowledge Panel®) as the sampling frame. We assessed the prevalence of HPV vaccine hesitancy with the validated 9-item Vaccine Hesitancy Scale (VHS). We used multivariate analyses to assess demographic factors associated with HPV vaccine hesitancy. We also assessed practical barriers to receipt of HPV vaccine and the relationship between barriers and hesitancy. Finally, we evaluated the association between both HPV vaccine hesitancy and practical barriers on HPV vaccine receipt or refusal.Results2,177 parents out of 4,185 sampled (52%) completed the survey, 2,020 qualified (lived with adolescent). Using a VHS cut-off score > 3 out of 5 points, 23% of US parents were hesitant about HPV vaccine. Hesitancy was lower among those with Hispanic ethnicity. At least one out of five parents disagreed that the HPV vaccine is beneficial for their adolescent, that the vaccine is effective, protects against HPV-related cancers, or that they followed their adolescent’s health-care provider’s recommendation about the vaccine. Many were concerned about vaccine side effects and the novelty of the vaccine. Adolescents living with vaccine-hesitant parents were less than one-third as likely to have received the vaccine (RR = 0.29, 95% CI 0.24, 0.35) or completed the vaccine series (RR = 0.29, 95% CI 0.23, 0.36), and were 6-fold more likely to have refused the vaccine because of parental vaccine-related concerns (RR = 6.09, 95% CI = 5.26, 7.04). Most practical barriers were independently associated with vaccine receipt but not with vaccine refusal.ConclusionsHPV vaccine hesitancy is common nationally and strongly related to both under-vaccination and vaccine refusal.     

Bivalent AS04-adjuvanted HPV vaccine provides optimal cancer prevention for HPV types not included in the vaccine

All available HPV vaccines contain oncogenic types 16 and 18, most often found in HPV-related cancers and precursor lesions, but they differ in their valence and adjuvant potency. The quadri- and nonavalent HPV vaccines both contain additional types 6 and 11, related to anogenital warts, while the nonavalent vaccine contains another five types that are less frequently found in cancers. The bivalent vaccine is adjuvanted by AS04. Phase-III randomised controlled trials and population-based studies on bi- and quadrivalent vaccines suggest that the two vaccines when administered to HPV-naive persons, are optimally effective in preventing cervical intra-epithelial neoplasia grade 3 or greater, caused by types 16 or 18 (specific protection). In addition, the bivalent vaccine, but not the quadrivalent vaccine, cross-protects against HPV types not contained in the vaccine. The advantage of the quadrivalent vaccine to provide additional protection against anogenital warts, should not be traded for a lower overall efficacy in preventing pre-cancerous lesions and eventually cancer.     

Impact of quadrivalent HPV vaccine dose spacing on immunologic response in women living with HIV

HPV vaccination schedules have changed as evidence has supported reduced dosing and extended intervals. Women living with HIV (WLWH) represent an important population with no data on alternative dosing.Girls and WLWH received quadrivalent HPV (qHPV) vaccine in a pan-Canadian study of immunogenicity and efficacy. Serology was performed at months 0/2/7/12/18/24. Medical and sexual history was collected throughout. Linear regression was used to determine if spacing of doses was associated with peak antibody titer.Multivariable analyses demonstrated significant relationships between peak antibody titer and time to blood draw post last vaccine dose, naivety to the relevant HPV type, and HIV viral load for all qHPV types. There was a significant relationship between peak HPV16/18 antibody titer and age.Taking age, time to serology, CD4 cell count, CD4 nadir, HIV viral load, and HPV naivety into account, spacing of the three qHPV vaccine doses did not significantly impact peak antibody titers.     

WHO meeting on the standardization of HPV assays and the role of the WHO HPV Laboratory Network in supporting vaccine introduction held on 24–25 January 2008, Geneva,Switzerland

In anticipation of the implementation of new prophylactic HPV vaccines, the WHO is supporting the establishment of a global WHO HPV Laboratory Network whose mission is to “contribute to improving the quality of laboratory services for effective surveillance and monitoring of HPV vaccination impact through enhanced, state-of-the-art laboratory support”. WHO convened a meeting at its headquarters, 24–25 January 2008 which placed particular emphasis on the harmonization of HPV Laboratory Network practices and standardization of HPV assays as these are crucial for the success of the HPV Laboratory Network in conducting studies measuring HPV disease burden and vaccine impact. To assist the HPV Laboratory Network in fulfilling its mission, the meeting was attended by all members of the HPV Laboratory Network, representatives of WHO Headquarters and Regional Offices, WHO Collaborating Centres involved in HPV-related work as well as experts from additional HPV laboratories around the world, representatives of national regulatory and control authorities, non-profit organizations and the vaccine industry.     

HPV vaccine for adolescent males: Acceptability to parents post-vaccine licensure

We examined mothers’ willingness to get their adolescent sons HPV vaccine. In December 2009, 2 months after approval of HPV vaccine for males, we surveyed a national sample of mothers with sons aged 9–18 (n = 406). More mothers were definitely or probably willing to get their sons HPV vaccine if the vaccine were free (47%) than if it cost $400 out of pocket (11%). The importance of HPV vaccine possibly protecting their sons’ future female partners from HPV-related disease was the strongest correlate of willingness. These findings are important to increasing acceptability to parents of HPV vaccine for their sons.     

Community-based household assessment of human papillomavirus (HPV) vaccination coverage and acceptability – HPV vaccine demonstration program,Cambodia – 2017

Background

In 2017, the Cambodia Ministry of Health introduced human papillomavirus (HPV) vaccine through primarily school-based vaccination targeting 9-year-old girls. Vaccination with a two-dose series of HPV vaccine took place in six districts in two provinces as a demonstration program, to better understand HPV vaccine delivery in Cambodia.

The Health Technology Assessment of bivalent HPV vaccine Cervarix in Italy

Introduction

Health Technology Assessment (HTA) approach was applied to Human Papilloma Virus (HPV) vaccine in the Italian context.

Methods

Epidemiology and costs of HPV infection and related diseases, vaccine efficacy, clinical and economic impact of the HPV vaccination and women's knowledge and attitudes towards vaccination were assessed.

Results

HPV infections pooled prevalence in Italy was 19% (95%CI: 10–30%) and cervical cancer incidence was 9.8/100,000 per year. The mean costs for in situ and invasive carcinoma hospitalisation were estimated respectively in €1745.87 and €2616.16. HPV vaccines have demonstrated high efficacy and good safety profile. The meta-analysis on efficacy results in preventing persistent cervical infections by HPV16 and 18 for both HPV vaccines resulted in 87% (95%CI: 80–91%) and 78% (95%CI: 62–87%). Modelling the impact of vaccination with bivalent vaccine, it would reduce cancer cases by 67% and be cost-effective, with a cost per Quality Adjusted Life Years (QALYs) gained of €22,055.

Conclusion

The thoroughness of the evaluation allowed us accounting for all the aspects of HPV infection/diseases. The HTA report on the HPV vaccine demonstrated to be a comprehensive tool for an informed decision making process.     

Health beliefs and attitudes associated with HPV vaccine intention among young gay and bisexual men in the southeastern United States

Gay and bisexual men are at increased risk of anal cancer as a result of human papillomavirus (HPV) infection. Prophylactic vaccination is a potentially effective strategy for preventing anal cancer in this population. The purpose of this study was to identify factors associated with gay and bisexual men's intention to receive HPV vaccine. In the fall of 2010, 179 self-identified gay and bisexual men (mean age 22 years) completed an Internet-based questionnaire assessing beliefs and attitudes toward HPV vaccination. Men were recruited from college-based and Internet venues throughout the southeastern United States. The probability of intent to receive HPV vaccine was modeled using logistic regression. A majority of men (93%) had heard of HPV prior to participation but were generally unaware of the association of HPV with anal, penile, and oral cancers. Only 26% were aware of an HPV vaccine for males. Of the 179 participants, 64 (36%) were likely to be vaccinated. Men most likely to receive HPV vaccine perceived stronger physical and psychological benefits from vaccination and had more positive attitudes toward the vaccine. Conversely, intent to be vaccinated was negatively associated with concern over the financial cost of vaccination. Findings from this study can inform college-based health education programs aimed at increasing vaccine uptake among gay and bisexual men.     

996名门诊部患者对HPV疫苗的认知与评价分析

目的了解公众对HPV疫苗的认知程度和对其有效性与安全性的评价,探索影响公众对该疫苗认知和评价的因素。方法对某门诊部的996名女性患者进行问卷调查,对调查结果进行统计分析。结果受访者对HPV疫苗认知的平均得分为2.25分;不同年龄、居住地、职业、受教育程度和收入水平的受访者对HPV疫苗的认知程度不同,差异有统计学意义(P<0.05);在对HPV疫苗有效性的评价方面,年龄较大、城市、已就业、高学历的受访者高于年龄较小、农村、未就业、低学历的受访者(OR值与95%CI分别为:1.89(1.43～2.35)、2.21(1.78～2.64)、3.36(3.05～3.67)、3.87(3.50～4.24)),高收入的受访者低于低收入的受访者(OR值与95%CI为0.87(0.79～0.95));在对HPV疫苗安全性的评价方面,年龄较大的受访者高于年龄较小的受访者(OR值与95%CI为:2.78(2.53～2.97)),城市、高学历的受访者低于农村、低学历的受访者(OR值与95%CI分别为:0.76(0.58～0.94),0.68(0.50～0.86))。结论受访者对HPV疫苗的认知程度较低,...     

Parents' Internet use for information about HPV vaccine

Purpose

The Internet is an increasingly common source of health-related information. We sought to examine associations between parents’ Internet information-seeking and their knowledge, attitudes and beliefs about human papillomavirus (HPV) vaccine.

Methods

We interviewed parents within a year after approval of HPV vaccine for females and males. Participants were North Carolina parents with daughters ages 10–18 surveyed by telephone in Fall 2007 (n = 773); and a national sample of parents with sons ages 11–17 surveyed online in Fall 2010 (n = 115). We used multivariate regression to examine associations of past and intended Internet seeking for HPV vaccine information with knowledge and health belief model-related constructs.

Results

Among parents of daughters, having heard of HPV vaccine through the Internet (8%) was associated with higher HPV knowledge, perceived likelihood of HPV, and vaccination willingness, and with receiving a doctor's recommendation. It was also associated with lower perceived vaccine harms, uncertainty, and anticipated regret. Parents of sons who heard of HPV vaccine through the Internet (10%) perceived greater barriers to vaccination than parents who learned about HPV vaccine for males through other sources. Intended future Internet information-seeking among parents of daughters (69%) was more likely if they perceived a lower likelihood that their daughters would get HPV if they were vaccinated (all p < .05).

Conclusions

Our findings suggest a positive influence of accessing information on the Internet about HPV vaccine. It was associated with higher knowledge and mostly positive parental attitudes and beliefs.