Running head: AN INTEGRATIVE REVIEW: HPV VACCINE 1

An Integrative Review: HPV Vaccine and Cervical Cancer

Autumn Bryan

Bon Secours Memorial College of Nursing

On my honor, I have neither given nor received aid on this assignment or

test, and I pledge that I am in compliance with the BSMCON Honor System
AN INTEGRATIVE REVIEW: HPV VACCINE 2

Abstract

The purpose of this integrative review is to appraise literature pertaining to the

administration of the HPV vaccine in adult women and its effect of reducing the prevalence of

cervical cancer. The burden of cervical cancer in women worldwide emphasizes the need for the

HPV vaccine to decrease the incidence of this disease among this population. Databases such as

EBSCO Discovery Services and PubMed were utilized to locate research articles. The searches

yielded 247 articles, five of which satisfied the specific research criteria set for this topic. The

results of this research clearly identify a correlation between the HPV vaccine and the decreased

prevalence of cervical cancer. The articles depict the effectiveness of the HPV vaccine in adult

women and show the lowered risk of HPV infection, therefore preventing the development of

cervical cancer. A limitation of the review is that it only consists of five articles due to the

expectations set for this assignment; therefore, this review cannot be considered exhaustive.

Another limitation for this review is the limited amount of experience of the researcher

completing this integrated review. Currently, there is research on the association between HPV

infection and cervical cancer, but not on the comparison of women who receive the HPV vaccine

and those who do not. Future research opportunities include implementing more studies that

follow the participants for a longer time period in order to determine long term efficacy of the

HPV vaccine.
AN INTEGRATIVE REVIEW: HPV VACCINE 3

An Integrative Review: HPV Vaccines and Cervical Cancer

The recognition of the strong causal association between HPV infection and cervical

cancer has resulted in the development of HPV assays to detect cervical cancer precursors

(Arbyn, Bryant, Martin-Hirsch, Xu, Simoens, & Markowitz, 2015, p. 2). The aim of this

integrative review is to compile pertinent literature pertaining to the researchers PICOT

question: Does the administration of the HPV vaccine in adult women reduce the prevalence of

cervical cancer compared with women who do not receive the vaccine?. The problem statement

is to determine the efficacy of the HPV vaccine by the prevalence of cervical cancer in women

who receive the vaccine versus women who do not. There is current research on the association

between HPV infection and cervical cancer, but not on the comparison of women who receive

the HPV vaccine and those who do not. The researcher found articles on women who received

the vaccine and the prevalence of cervical cancer, but there is still a gap in the literature

comparing this to cervical cancer in those who did not receive the vaccine. This topic was of

interest to the researcher due to cervical cancer having been a burden in her family.

Research Design, Search Methods, & Search Outcomes

This integrative review focuses on five research articles. EBSCO and PubMed were two

electronic databases that were used to search for articles that fit the criteria set by the researcher.

The terms used in the searches included, HPV vaccine, cervical cancer, effectiveness, and

Human Papilloma Virus. EBSCO yielded 210 articles and PubMed yielded 37 articles.

In order to obtain recent articles, the search was limited to articles from 2011 to 2016. Four

filters were then placed on the search in order to narrow down the results of the search. The

filters used were peer reviewed articles, articles in English, articles that were published in an

academic journal, and articles with full text. After narrowing search criteria used, five articles
AN INTEGRATIVE REVIEW: HPV VACCINE 4

were chosen by the researcher that met all of the specifications needed for the review. Included

in this review are one qualitative studies and four quantitative studies that will be used to answer

the PICOT question previously stated.

Findings/Results

The results and findings of the research clearly identify a correlation between the HPV

vaccine and the decreased prevalence of cervical cancer (Arbyn et al., 2015; Hildesheim et al.,

2014; Naud et al., 2014; Skinner et al., 2014, Zhu et al., 2014). A summary of the research

articles is located in Table 1. This review is structured based on the following categories: HPV

Vaccine Decreases the Prevalence of Cervical Cancer, Frequency of Adverse Events of the HPV

Vaccine, and HPV Types Examined- HPV 16/18.

HPV Vaccine Decreases Prevalence of Cervical Cancer

The results of four of the five reviewed studies indicate a positive effect of the HPV

vaccine on the decreased prevalence of cervical cancer in adult women. This was displayed by a

statistical significant outcome in four of the articles (Hildesheim et al, 2014; Naud, 2014;

Skinner et al., 2014; Zhu et al., 2014). Each of the studies purpose was to evaluate the efficacy

of the HPV vaccine. The results in each of the studies are displayed differently but all show

positive outcomes. Some of the studies measured additional outcomes along with efficacy, and

some of the studies only focused on the efficacy of the vaccine.

In the quantitative study by Skinner et al (2015), the results showed significant vaccine

efficacy against the primary combined endpoint of 6-month persistent infection or CIN1+

associated with HPV 16/18 in the overall population and in the 2635 and 3645 year age strata

(p. 2222). The study consisted of 5752 healthy women older than 25 years old who were

included in the total vaccinated cohort. The participants were randomly assigned to the HPV
AN INTEGRATIVE REVIEW: HPV VACCINE 5

16/18 vaccine or control group. There were 2881 women in the vaccine cohort and 2871 in the

control group. Cytology samples were obtained from the women participants every 6 months for

HPV DNA testing and every 12 months for Pap cytology testing. Vaccine efficacy was

calculated using a conditional exact method which took the follow-up time of participants within

both groups into account. The purpose of the study was to assess the efficacy, safety, and

immunogenicity of the HPV 16/18 vaccine in adult women. The results from this study shows

the efficacy of the HPV 16/18 vaccine against abnormalities and possible cancers. This study

will help clinicians in making informed recommendations for women older than 25 years old.

In the quantitative study by Hildesheim et al (2014), Efficacy against incident HPV-

16/18 associated CIN2+ was 89.8% (95% CI = 39.599.5; Rate Reduction =3.4/1,000 women)

(p. 7), which shows statistical significance of this studys results. This quantitative study

sponsored by the US National Cancer Institute (NCI), invited potential participants from a

national census to be a part of the study. This study was a good representation of a broader

population due to the participants being sent the request for participation in a randomized

method. The sample of 7,466 healthy women ages 18-25 years old were enrolled in the study.

Initially, a pelvic exam was performed on the participants, followed by blood testing, and lastly

annual follow-up examinations of the participants. The purpose was to evaluate the efficacy,

safety, impact, and immune mechanisms associated with the HPV vaccine. The results

confirmed immunogenicity and showed that the HPV 16/18 vaccine was safe and effective.

In the quantitative study by Zhu et al. (2014), there were 17 cases in the control group (2

cases of 6-month PI plus CIN11, 13 cases of 6-month PI alone and 2 cases of CIN11 alone) and

1 case in the vaccine group (of 6-month PI) (p. 2619). This shows that the HPV vaccine

decreased the prevalence of cervical cancer because only one participant out of 3026 had a case
AN INTEGRATIVE REVIEW: HPV VACCINE 6

of CIN11+ cervical cancer. This quantitative study made up of Chinese women aged 1825

years at the time of first vaccination were enrolled in the study. The women were randomized to

receive the HPV-16/18 vaccine or aluminum hydroxide as a control. The participants were

blinded to which vaccine was administered to them. The purpose of the study was to assess the

efficacy, immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-

adjuvanted vaccine. Seropositivity rates for each antigen were then calculated. HPV-16/18

related efficacy was 93.8% against cellular abnormalities and 100% against HPV-16/18

associated CIN11 and CIN21. The HPV-16/18 AS04-adjuvanted vaccine was determined to be

effective, immunogenic, and safe in young Chinese women.

In the fourth quantitative study by Naud et al. (2014), the results stated that During the

entire 36-mo period of HPV-023, no incident HPV-16/18 infection occurred in the vaccine group

whereas 9 cases occurred in the placebo group, resulting in 100% VE (95% CI: 66.1 to 100) (p.

2150). Therefore, the results of the study showed that the HPV vaccine decreased the prevalence

of the HPV strain that causes cervical cancer by 100%. In the study, 437 women, aged 1525

years were randomized to receive 3 doses of either the HPV-16/18 vaccine or placebo at 0, 1,

and 6 months. Cervical samples were tested every 6 months, examinations were performed

annually, and blood samples were collected at 0, 7, 12, and 18 months and on a yearly basis. The

results were significant in that there were no cases cervical lesions or signs of cancer in the

vaccinated cohort for the entire length of the study.

Frequency of Adverse Events of the HPV Vaccine

The results of four of the five reviewed studies displayed a variety of adverse events that

occurred in the studies due to the administration of the HPV vaccine in adult women. This was
AN INTEGRATIVE REVIEW: HPV VACCINE 7

displayed in table format in the four articles (Hildesheim et al, 2014; Naud, 2014; Skinner et al.,

2014; Zhu et al., 2014).

In the quantitative study by Skinner et al (2015), Table 4 displays that in the vaccine

group 10% of participants in the vaccine group experienced a serious adverse event. This

however, can be compared to the control group who had a total of 9% of participants that

experienced a serious adverse event. It should also be mentioned that less than 1% of these

adverse events in both the vaccine and control group were attributed to the vaccine.

In the quantitative study by Hildesheim et al (2014), Table 3 displays that in the vaccine

group 24.5% of participants in the vaccine group experienced a serious adverse event. However,

this can be compared to the control group who had a total of 23.8% of participants that

experienced a serious adverse event. The number of adverse events is slightly higher in the

vaccinated group, but is not significantly higher than the control group. It should also be

mentioned that 1.4% of these adverse events in the vaccine group and 1% in the control group

were attributed to the vaccine. From these findings, we can conclude that the vaccine did not

pose a significantly greater threat than that of the control injection.

In the quantitative study by Naud et al. (2014), Table 4 displays that in the vaccine group

26.8% of participants in the vaccine group experienced a serious adverse event. However, this

can be compared to the control group who had a total of 17.8% of participants that experienced a

serious adverse event. From this data we can conclude that there was a noticeably higher

incidence of adverse events in those that had been vaccinated when compared to the control

group. It should also be mentioned that 1.4% of these adverse events in the vaccine group and

1% in the control group were attributed to the vaccine.

AN INTEGRATIVE REVIEW: HPV VACCINE 8

In the quantitative study by Zhu et al. (2014), Table 4 displays that in the vaccine group

29% of participants in the vaccine group experienced a serious adverse event. However, this can

be compared to the control group who had a total of 55% of participants that experienced a

serious adverse event. The number of adverse events is significantly higher in the control group.

It should also be mentioned that 1% of these adverse events in the vaccine group and 1% in the

control group were attributed to the vaccine. From these findings, we can conclude that the

vaccine did not pose a significantly greater threat than that of the control injection, but that the

control posed a greater risk due to having more significant adverse events.

HPV Types Examined- HPV 16/18

All of the studies included in this review of the HPV vaccines effect on the prevalence of

cervical cancer (Arbyn et al., 2015; Hildesheim et al., 2014; Naud et al., 2014; Skinner et al.,

2014, Zhu et al., 2014) examined two types of HPV. These two types of HPV are types 16 and

18. HPV types 16 and 18 are what is shown to cause cervical cancer in women, therefore, these

types were the focus for this review.

In the systematic review from the Cochrane database by Arbyn et al. (2015), it states that

The HPV type 16, in particular, has a high potential for malignant transformation of infected

cervical cells (p. 2). The purpose of this article is to evaluate the immunogenicity, clinical

efficacy, and safety of prophylactic HPV vaccines in females (Arbyn et al., 2015, p. 3). The

review incorporated studies with females of any age. The women in the studies will be grouped

by age, sexual history, and initial HPV status (Arbyn et al., 2015, p. 3). The sample size is not

stated in this article. This review comprehensively evaluated the impact of vaccination by

categories of age and time since sexual debut. There was no specific sampling strategy in this

study. The goal was to use all available data. This review systematically evaluated evidence for
AN INTEGRATIVE REVIEW: HPV VACCINE 9

cross-protection against HPV types phylogenetically related to HPV-16/18 (Arbyn et al., 2015,

p. 3). The findings were not given in this study due to this review only being a protocol for

further review.

Discussion/Implications

The results of the research articles discussed in this review clearly identify a correlation

between the prevalence of cervical cancer in women who do not receive the HPV vaccine

compared to women who do receive the HPV vaccine. Therefore, the researchers PICOT

question Does the administration of the HPV vaccine in adult women reduce the prevalence of

cervical cancer compared with women who do not receive the vaccine? is supported by the

research in this integrated review. The research showed that the HPV vaccine does in fact

reduce the prevalence of cervical cancer. The vaccine prevents the infection of Human

Papilloma Virus, which prevents further development of cervical cancer in the client. A majority

of the results were statistically significant and displayed a trend towards decreased prevalence of

cervical cancer when the HPV vaccine had been administered to the client. Recently, an IARC

(International Agency for Research on Cancer) expert group reviewed the carcinogenicity of

human papilloviruses and confirmed that for 12 HPV types (HPV 16, 18, 31, 33, 35, 39, 45, 51,

52, 56, 58, and 59) sufficient evidence exists that they are causally linked with the development

of cervical cancer. Type HPV 68 is considered as probably carcinogenic. The specific HPV type

16 has a high potential for malignant transformation of infected cervical cells. The HPV types 16

and 18 jointly cause 70 percent of all the cervical cancers worldwide. (Arbyn et al., 2015, p. 1).

Limitations

There are few limitations of this integrative review, but all need to be further explained.

The articles chosen for this review were within the five-year limit set for this assignment,
AN INTEGRATIVE REVIEW: HPV VACCINE 10

however, there were numerous articles found during the search that were outside of this limit and

could not be used for the purpose of this review. Also, the review only consists of five articles

due to the expectations set for this assignment, therefore, this review cannot be considered

exhaustive. Another limitation for this review is the limited amount of experience of the

researcher completing this integrated review.

The major limitation in most studies on HPV and cervical cancer, including the studies

used in this review, is the length of time the studies are able to continue. As stated in the

protocol by Arbyn et al. (2015), the reduction of the incidence of invasive cervical cancer

would require large and lengthy studies which are unlikely to be undertaken (p. 2). Lastly, the

authors of the studies used in this review did not provide measures of validity and reliability for

the instruments that were used to collect the data.

One of the major strengths of this review is that four out of the five articles used are

randomized control trials and the fifth article used is a systematic review from the Cochrane

database. These types of articles used can be considered the highest level of evidence possible

for an integrated review. This contributes to the validity and reliability of the studies and the

review. The measurement tools were valid and reliable, and the variables were clearly defined as

the HPV vaccine and the prevalence of cervical cancer.

Conclusion

The findings of this integrative review display the importance of adult women receiving

the HPV vaccine to decrease the prevalence of cervical cancer. An important finding from the

review includes statistical significant research data showing the decreased risk of cervical cancer

when given the vaccine versus a higher risk if women dont receive the vaccine. In each of the

four randomized controlled trials, there was a significantly smaller number of participants who
AN INTEGRATIVE REVIEW: HPV VACCINE 11

tested positive for cervical cancer biomarkers in the vaccine group due to the efficacy of the

vaccine. These results display a need for an increased number of vaccines in our population in

order to prevent the development of cervical cancer in adult women.

Future research opportunities include implementing more studies that follow the

participants for a longer time period in order to determine long term efficacy of the HPV

vaccine. The longer the study, and the longer the decreased prevalence of cervical cancer, the

more convincing the study will be. The more convincing the study is, the greater the increase in

HPV vaccinations in women. The greater the increase in HPV vaccinations the more decreased

prevalence of women getting a diagnosis of cervical cancer in their lifetime. Nurses that work

with this population are able to educate young and adult women who have not received the HPV

vaccine on how important it is for their health and well-being.

AN INTEGRATIVE REVIEW: HPV VACCINE 12

References

Arbyn, M., Bryant, A., Martin-Hirsch, P., Xu, L., Simoens, C., Markowitz, L. (2015).

Prophylactic vaccination against human papillomaviruses to prevent cervical cancer and

its precursors. Cochrane Database of Systematic Reviews 2013, Issue 12. Art. No.:

CD009069. DOI: 10.1002/14651858.CD009069.pub2.

Coughlan, M., Cronin, P., & Ryan, F. (2007). Step by step guide to critiquing research: Part 1:

Quantitative research. British Journal of Nursing, 16(11), 658-663.

Hildesheim, A., Wacholder, S., Catteau, G., Struyf, F., Dubin, G., Herrero, R., & for the CVT

Group. (2014). Efficacy of the HPV-16/18 vaccine: Final according to protocol results

from the blinded phase of the randomized Costa Rica HPV-16/18 vaccine trial.

Vaccine, 32(39), 50875097. http://doi.org/10.1016/j.vaccine.2014.06.038.

Naud, P., Roteli-Martins, C., De Carvalho, N., Teixeira, J., de Borba, P., Sanchez, N., . . .

Descamps, D. (2014). Sustained efficacy, immunogenicity, and safety of the HPV-16/18

AS04-adjuvanted vaccine: Final analysis of a long-term follow-up study up to 9.4 years

post-vaccination. Human Vaccines & Immunotherapeutics, 10(8), 21472162.

Skinner, S., Szarewski, A., Romanowski, B., Garland, S., Lazcano-Ponce, E., Salmeron, J., . . .

Levin, M. (2015). Efficacy, safety, and immunogenicity of the human papillomavirus

16/18 AS-04-adjuvanted vaccine in women older than 25 years: 4-year interim follow-up

of the phase 3, double-blind, randomized controlled VIVANE study. The Lancet,

384(9961), 2213-2227. http://dx.doi.org/10.1016/SO140-6736(160920-X.

Zhu, F., Chen, W., Hu, Y., Hong, Y., Li, J., Zhang, X., . . . Descamps, D. (2014). Efficacy,

immunogenicity and safety of the HPV-16/18 AS04- adjuvanted vaccine in healthy

AN INTEGRATIVE REVIEW: HPV VACCINE 13

Chinese women aged 1825 years: Results from a randomized controlled trial. Int. J.

Cancer, 135, 26122622.

 Running head: AN INTEGRATIVE REVIEW: HPV VACCINE 14

Running head: AN INTEGRATIVE REVIEW: HPV VACCINES AND CERVICAL CANCER

Table of Evidence

First Author
(Year) Hildesheim (2014) NCI principal investigator, responsible for the design and conduct of the study,
Qualifications wrote the manuscript of the study

Background Problem statement: to determine the efficacy of the HPV vaccine

Problem The purpose of the study was to evaluate the efficacy, safety, impact, and immune mechanisms
Statement associated with the HPV vaccine

Conceptual/
theoretical N/a
Framework
Design/Method Quantitative
/Philosophical Randomized controlled trial
Underpinnings Recorded semi-structured interviews comparing lived experiences of their previous delivery that did not
include immediate SSC with their recent delivery in which they received SSC immediately after delivery.

Sample/ 7,466 healthy women ages 18-25 years old

Setting/Ethical potential participants from a national census were invited to participate in the study.
Considerations ,the US National Cancer Institute (NCI) was who sponsored the study
Major Variables the prophylactic vaccine against HPV and its efficacy against HPV infection in women
Studied
Measurement Tool A pelvic exam was performed on the participants, followed by a 6-month follow-up visit where blood
Data Collection testing was completed, and lastly annual follow-up examinations consisting of an additional pelvic
Method examination and a blood sample.
 AN INTEGRATIVE REVIEW: HPV VACCINE 15

Data Analysis The risk ratio was calculated for the participants receiving the HPV vaccine and for the control group
who received a Hepatitis A vaccine. The complement of the 95% confidence interval for the risk ratio was
used
Findings the HPV vaccine efficacy was 89.8% for HPV 16/18 CIN2+ and 61.4% for and CIN2+. The researcher
Discussion stated that the results were consistent with previous results regarding the efficacy of the HPV 16/18
vaccine
the results confirmed immunogenicity and showed that the HPV 16/18 vaccine was safe and effective.

Appraisal this study was a good representation of a broader population due to the participants being sent the
Worth to practice request for participation in a randomized way
The study demonstrated that the HPV vaccine significantly prevented cancer in women displayed by the
HPV vaccine efficacy of 89.8% for HPV 16/18 CIN2+.

First Author
(Year) Arbyn (2015) Qualifications not stated. Bryant was responsible for Extraction of data, Checking of
Qualifications eligibility of references, Statistical analysis, and writing of the protocol of the study

Background Problem statement: to determine the clinical effectiveness of the HPV vaccine in women
Problem The purpose of the study was to evaluate the immunogenicity, clinical efficacy, and safety of
Statement prophylactic HPV vaccines in females

Conceptual/
theoretical N/a
Framework
 AN INTEGRATIVE REVIEW: HPV VACCINE 16

Design/Method Qualitative (Protocol)

/Philosophical review of all of the available evidence regarding the HPV vaccine and its effectiveness
Underpinnings
Sample/ studies with females of any age. The women in the studies will be grouped by age, sexual history, and
Setting/Ethical initial HPV status The sample size is not stated in this article.
Considerations
Major Variables the association between human papillomavirus (HPV) infection and cervical cancer and other HPV-
Studied related cancers and their precursors
Measurement Tool This review comprehensively evaluated the impact of vaccination by categories of age and time since
Data Collection sexual debut
Method
Data Analysis There was no specific sampling strategy in this study; instead, all available evidence was used.
A power analysis was also not used in this study because the goal was to use all available data. Due to
this there was also no attrition rate for this study because all of the data used was in the past.
Findings the findings were not supplied in this study due to it only being a protocol
Discussion
Appraisal The objective of this review is to summarize all available (published and unpublished) evidence by
Worth to practice combining outcomes with similar definitions and times of measurement. This review is important in order
to examine the validity and trustworthiness of the design of the clinical trials with regard
to the choice of outcomes as well as the rigour with which these trials were conducted
 AN INTEGRATIVE REVIEW: HPV VACCINE 17

First Author
(Year) Skinner (2014) PhD, one of the Principal/coprincipal investigators
Qualifications
Background Problem statement: adolescent girls are the main population for prophylactic human papillomavirus
Problem (HPV)vaccines, however, adult women who remain at risk of cervical cancer can also be vaccinated
Statement The purpose of the study was to assess the efficacy, safety, and immunogenicity of the
HPV 16/18 AS04-adjuvanted vaccine in adult women.

Conceptual/
theoretical N/a
Framework
Design/Method Quantitative
/Philosophical Randomized controlled trial
Underpinnings participants were randomly assigned to the HPV 16/18 vaccine or control (1:1) group. The primary
endpoint was vaccine efficacy against 6-month persistent infection or cervical intraepithelial neoplasia
grade 1 or higher (CIN1+) associated with HPV 16/18.
Sample/ 5752 healthy women older than 25 were included in the total vaccinated cohort
Setting/Ethical (n=2881 vaccine, n=2871 control)
Considerations The colposcopy method varied across the different countries and was done in accordance with local
practices. However, a training and quality assurance program for study colposcopists was implemented to
increase the reliability of colposcopy
Major Variables the prophylactic vaccine against HPV and its efficacy against HPV infection in women
Studied
Measurement Tool cytology samples were obtained for HPV DNA testing every 6 months and Pap cytology testing every
Data Collection 12 months. A broad-spectrum assay was used to test cervical samples and biopsy material for HPV
Method DNA from HPV types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68/73.21 Oncogenic
HPV-positive samples were tested by multiplex type-specific PCR and reverse hybridization assay to
detect HPV types 16, 18, 31, 33, 35, 45, 52, 58, and 59.22.
 AN INTEGRATIVE REVIEW: HPV VACCINE 18

Data Analysis Vaccine efficacy was calculated using a conditional exact method. This method computes an exact CI
around the rate ratio (ratio of the event rates in the vaccine vs control groups) and takes into account the
follow-up time of participants within each group. Vaccine efficacy was defined as 1 minus the rate ratio.
Significance was defined for the combined primary endpoint in the according-to-protocol cohort for
efficacy when the lower limit of the 977% CI around the point estimate was greater than 30%. For all
other endpoints and cohorts, significance was defined by the lower limit of the 977% CI greater than 0%.
Findings vaccine efficacy was significant for the combined primary endpoint of 6-month persistent infection or
Discussion CIN1+ associated with HPV 16/18 (811%, 977% CI 521940) and for 6-month persistent
infection with HPV 16/18 (829%, 538951) in the according-to-protocol cohort for efficacy in women
who were seronegative and DNA-negative for the corresponding HPV type at baseline.
Significant vaccine efficacy was also seen in the total vaccinated cohort
Appraisal the results from this study of the VIVIANE trial shows the efficacy of the HPV 16/18 vaccine against
Worth to practice infection and cytological abnormalities. Understanding the potential benefit for individual women older
than 25 years will aid clinicians in making informed recommendations.

First Author
(Year) Naud (2014) from Hospital de Clinicas de Porto Alegre
Qualifications
Background Problem statement: to determine the efficacy of the HPV vaccine
Problem The purpose of the study was to evaluate the efficacy against human papillomavirus (HPV)-16/18
Statement infection and associated cyto-histopathological abnormalities, persistence of immunogenicity, and safety
of the HPV-16/18 AS04-adjuvanted vaccine.
 AN INTEGRATIVE REVIEW: HPV VACCINE 19

Conceptual/
theoretical N/a
Framework
Design/Method Quantitative
/Philosophical Randomized controlled trial
Underpinnings anti-HPV-16/18 antibodies were measured annually by enzyme-linked immunosorbent assay (ELISA )
and pseudovirion-based neutralisation assay (PBNA). Cervical samples were tested for HPV DNA every 6
months, and cyto-pathological examinations were performed annually

Sample/ 437 women, aged 1525 years

Setting/Ethical
Considerations
Major Variables the prophylactic vaccine against HPV and its efficacy against human papillomavirus (HPV)-16/18
Studied infection and associated cyto-histopathological abnormalities

Measurement Tool Women were randomized(1:1) to receive 3 doses of either the HPV-16/18 vaccine or placebo
Data Collection (Al[OH]3) at 0, 1, and 6 mo as previously described.
Method Blood samples were collected at months 0, 7, 12, and 18 during
HPV-001 and on a yearly basis during the follow-up studies
The follow-up evaluations performed in HPV-023 were conducted in accordance with the Declaration
of Helsinki and the International Conference on Harmonisation Good Clinical Practice Guidelines.

Data Analysis The overall value for all analyses was 005 (two-sided test). Alpha values for the final analysis, =
0049(two-sided). Based on an estimated 6% cervical infection rate, minimum 80% VE, and a 10%
discontinuation rate per year for women enrolled in the trial, the power at the end of the trial was
estimated at 83%.
Findings No breakthrough cases of HPV- 16/18 infection or related cervical lesions occurred in the vaccinated
Discussion cohort over the 36-mo study period
 AN INTEGRATIVE REVIEW: HPV VACCINE 20

Appraisal this study represents the longest follow-up reported for a licensed HPV vaccine
Worth to practice These results should provide confidence in the duration of protection offered by HPV mass vaccination
programs existing in a number of countries around the world.
The protocol and other materials were approved by the Independent Ethics Committee or Institutional
Review Board of each study center and the National Committee of Ethics and Research.

First Author
(Year) Zhu (2014) PhD, one of the Principal/coprincipal investigators
Qualifications
Background Problem statement: to determine the HPV vaccine efficacy (VE) against HPV-16/18 associated 6-month
Problem persistent infection (PI) and/or cervical intraepithelial neoplasia (CIN) 11.
Statement The purpose of the study was to assess the efficacy, immunogenicity and safety of the human
papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in young Chinese women
Conceptual/
theoretical N/a
Framework
Design/Method Quantitative
/Philosophical Randomized controlled trial
Underpinnings participants from Jiangsu province were randomized (1:1) to receive HPV vaccine (n53,026) or
Al(OH)3 control (n53,025) at months 0, 1 and 6.
Sample/ Women aged 1825 years (vaccine 52,889; control 52,894) at the time of first
Setting/Ethical vaccination were enrolled at four sites in Jiangsu Province
Considerations (Binhai, Jintan, Lianshui and Xuzhou CDCs).
 AN INTEGRATIVE REVIEW: HPV VACCINE 21

Major Variables the prophylactic vaccine against HPV and its efficacy against HPV infection in women
Studied
Measurement Tool Women were randomized 1:1 to receive HPV-16/18 AS04- adjuvanted vaccine or aluminum hydroxide
Data Collection as a control. Treatment allocation at the investigator site was performed using a central internet-based
Method randomization system. All participants, investigators and study staff were blinded to individual subject
treatment assignments and results. The vaccine and control were identical in appearance and were
provided in prefilled syringes. 0.5 mL of vaccine or control was administered into the deltoid muscle at 0,
1 and 6 months..

Data Analysis Assuming VE of 85%,6 it was calculated that 17 cases of the primary endpoint (6-month PI
and/or CIN11 associated with HPV-16 and/or HPV-18) were needed to provide at least 90% power to
obtain a significant result (defined as lower limit of the 95% confidence interval [CI] for VE above 0%).
Seropositivity rates and geometric mean antibody titres (GMTs) for each antigen with 95% CI were
calculated. To maintain blinding, all analyses were carried out by an external statistician. Statistical
analyses were performed using SASVR 9.2 and PROC StatXactVR 8.1.
Findings In the ATP-E (vaccine52,889; control52,894), for initially HPV DNA negative and seronegative
Discussion subjects, HPV-16/18 related VE (95% CI) was 94.2% (62.7, 99.9) against 6-month PI and/or CIN11 and
93.8% (60.2, 99.9) against cytological abnormalities. VE against HPV-16/18 associated CIN11 and CIN21
was 100% (250.4, 100) and 100% (2140.2, 100), respectively (no cases in the vaccine group and 4 CIN11
and 3 CIN21 cases in the control group). At Month 7, at least 99.7% of initially seronegative vaccine
recipients had seroconverted for HPV-16/18;
Appraisal The HPV-16/18 AS04-adjuvanted vaccine is effective, immunogenic and has a clinically acceptable
Worth to practice safety profile in young Chinese women. Prophylactic HPV vaccination has the potential to substantially
reduce the burden of cervical cancer in China.