SYSTEMATIC REVIEW AND META-ANALYSIS OF HPV VACCINES

REACTOGENICITY AMONG ADULTS AGE 27 TO 45 YEARS OLD

In partial fulfillment of the requirements for

the subject,Introduction to Medical Laboratory
Science Research

DELA MERCED, RONIEL DAVE A.

TOLENTINO, CRIS LOVIANNE S.

LICONG, RUBY CIELO B.

ROVILLOS, CRISTINE A.

ORO, JUNICHI C.

FABROS, GUIAN PAULA M.

MANTILE, APRIL JOY B.

May 12, 2022

Page 1 of 32
 AUTHORS:

Roniel Dave A. Dela Merced

ronieldavedelamerced@gmail.com
San Jose Del Monte, Bulacan, Philippines
+639212863265
New Era University Center for Medical and Allied Health Sciences

Cris Lovianne S. Tolentino

loviannetolentino@gmail.com
Real, Quezon, Philippines
+639636699437
New Era University Center for Medical and Allied Health Sciences

Ruby Cielo B. Licong

licongrubycielo@gmail.com
San Jose Del Monte, Bulacan, Philippines
+639560567432
New Era University Center for Medical and Allied Health Sciences

Cristine A. Rovillos
Snkcristine@gmail.com
Antioch, California, United States
+1 (925)968-5535
New Era University Center for Medical and Allied Health Sciences

Page 2 of 32
 Junichi C. Oro
johnjunpau@gmail.com
+8109081363123
Toyohashi, Japan Aichi
New Era University Center for Medical and Allied Health Sciences

Guian Paula M. Fabros

guianpaula@gmail.com
Cuyapo, Nueva Ecija, Philippines
New Era University Center for Medical and Allied Health Sciences

April Joy B. Mantile

ajoymantile@gmail.com
+639503753817
San Jose, Occidental Mindoro, Philippines
New Era University Center for Medical and Allied Health Sciences

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 CHAPTER I
Introduction

Human Papillomavirus (HPV) is the most common sexually transmitted infection

globally. It is a virus that is potentially to cause a long-term health risk, since its
infection may result to an abnormal change in cell which will lead to a number of
cancers. There are more than a hundred types of HPV, and at least 14 are known to be
cancer- causing (also known as high-risk type). An intervention recommended by the
Advisory Committee on Immunization Practices (ACIP) to prevent and lower the cases
of HPV infection is through routine HPV vaccination at age 11 or 12 years and catch-up
vaccination through age 26 years.

Despite the effort, the number of HPV infection cases is high. The overall genital HPV
infection prevalence among men aged 18 to 59 years was 45.2%, and the infection
prevalence with at least 1 high-risk HPV subtype defined by DNA testing was 25.1% [1]
This shows HPV infection being widespread among all age groups of men, still the
current recommendation of the primary intervention only applies to certain age group.

Center for Disease Control and Prevention (CDC) recommends that 11 to 12 years old
receive two doses of Human Papillomavirus vaccine 6 to 12 months apart while 15 through
26 years old receive three doses.

Rationale

In this meta-analysis, important outcomes to the individuals involved were considered.

With the continuous spread of the infection among adults, it is necessary to provide the
policy developers and consumers an information and basis for the optimal dose allocation
based on the reactogenicity of the HPV vaccines to guide them in their decisions. To date,
there has been

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no study reviewing the HPV vaccines with regard to its reactogenicity among adults
ages 27 through 45 and the associated effective allocation based on clinical outcome and
immune response.

Objectives

In this research we deliberately analyzed the reactogenicity of the three types of Human
Papillomavirus vaccines to the age group 27 through 45. Together with all the studies
and reviews done, this research aims to evaluate the reactogenicity of Human
Papillomavirus vaccines to the older age group that is not recommended by the Center
on Disease Control and Prevention; thus, it is expected that the possible optimal- dose-
allocation of the HPV vaccines based on its effect measured from the reactogenicity
responses from the participants will be identified and explained.

At the end of this study, we aim to answer the following review questions:

1. What are the general effects of HPV vaccines doses on reactogenicity among adults ages
27 to 45 years old?

2. What are the effects of one month HPV vaccines dose-timing on reactogenicity among
adults ages 27 to 45 years old?

3. What are the effects of two months of HPV vaccines dose-timing on reactogenicity
among adults ages 27 to 45 years old?

4. What are the effects of six months of HPV vaccines dose-timing on reactogenicity
among adults ages 27 to 45 years old?

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 CHAPTER II
Review of Related Literature

HPV Infection and Associated Diseases

The human papillomaviruses are a family of DNA viruses which infect the epithelium.
It is the most common sexually transmitted infection (STI) and it can be passed even if
the infected person has no signs or symptoms. Its symptoms usually occur shortly after
initiation of sexual activity but it can also be developed even years after the sexual
interaction with an infected person. HPV types are divided into two, the high risk or
oncogenic which are the cancer-causing type, and the low risk or nononcogenic.

Clinical manifestations of HPV infection include anogenital warts, recurrent respiratory

papillomatosis (RRP), cervical cancer precursors (cervical intraepithelial neoplasia), and
cancers, including cervical, anal, vaginal, vulvar, penile, and oropharyngeal cancer.
There are more than 130 types of known HPV with 20 HPV types identified as cancer-
related [2].

Anogenital warts (condyloma acuminatum) which are caused by infection with low-risk
HPV types appear as a small bump or group of bumps in the genital area. The low-risk
HPV types HPV6 and 11 caused most of the cases of genital warts [3]. These are generally
benign and resolve within 6 months with or without treatment. Recurrent respiratory
papillomatosis is a rare disorder characterized by benign (noncancerous) tumors called
papillomas growth in the air passages leading from the nose and mouth into the lungs
(respiratory tract).

A small proportion of infected persons can become persistently infected. Persistent

infection with human papillomavirus (HPV) is a major health concern and is the most
important risk factor for the development of variety of cancers. Immunocompromised
persons are more susceptible to HPV associated conditions and cancers. These persons
can be those with human immunodeficiency virus (HIV) infection or those who have
undergone transplant.
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Cervical cancer is the fourth deadliest cancer among women and it is one of the diseases
that is induced by human papillomavirus (HPV) infection specifically HPV 16 and 18.
Compiled studies from cytologically healthy women showed that the highest HPV
prevalence was found within Asian regions, where almost half of the Eastern and
Central and Southern Asian regions (57.7% and 44.4% respectively) were carriers. It has
been estimated that 85% of invasive cervical cancers are associated with HPV and 98%
of cervical cancer deaths are attributed to high-risk oncological HPVs. This cancer, as
well as the other cancers associated with HPV (anal, vulvar, vaginal, penile, etc.), are
more prevalent in developing countries where they are responsible for a high death rate
[4]. Risks factors for HPV and cervical cancer include age at first intercourse, multiple
sexual partners, smoking, herpes simplex, HIV, co-infection with other genital
infections, and oral contraceptive use [2].

Epidemiology and Burden of HPV-Related Diseases

The global prevalence of HPV infection is estimated to be 11.7% (95% confidence

interval: 11.6- 11.7), with Africa and Oceania having particularly high rates of infection.
However, the vast majority of HPV infections (70-90%) are asymptomatic and
transitory (resolve spontaneously in 1-2 years). The highest HPV prevalence is seen in
children and adolescents around the world. In Europe and the Americas, there is an
obvious fall with age, while in Africa and Asia, there is no such clear decline with age.
Furthermore, older women in some regions, such as Western Africa and Central and
South America, have a slight second peak of HPV detection. HPV 16 is the most
common oncogenic type in the world, with 3.2 percent of women with normal cytology
having it, followed by HPV18 (1.4 percent), HPV52 (0.9 percent), HPV31 (0.8 percent),
and HPV58 (0.7 percent), in that order [5].

Population-based study for Human Papillomavirus Infection which is a multi-center

study that examines Japanese women aged 16 to 50 for uterine cervical abnormality and
HPV infection using a liquid based-cytology test and a novel HPV test using the CR-
SSOP-Luminex method that identifies 31 HPV genotypes was conducted. In this study,
HPV- 26/39/51/53/56/59/66/68/70/73/82 were defined as the possible high-risk types.
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The prevalence of contraction of any HPV type according to age significantly decrease
with age in the normal population group and abnormal cytology group (P<0.05, Chi-
square test for trend). Both multiple and single HPV type infections decrease with age in
the normal population (P<0.05, Chi-square test for trend) whereas in the abnormal
cytology group, multiple and single HPV type infections decrease with age (P<0.001,
Chi-square test for trend) [4]. It indicates that the prevalence for HPV 16/18 infection was
at 20-24 years of age in both normal population and abnormal cytology group population.
Intriguingly, the peak of the prevalence of HPV 16 in the normal population was in 20-24
years of age whereas in the abnormal cytology group was in 30-34 years of age.

Moreover, the prevalence of HPV increases with the severity of the lesion. Based on
data from IARC meta-analyses of HPV prevalence by specific cervical disease and
updated by the ICO/IARC Information Centre on HPV and Cancer until 2015, HPV is
detected in 52.5 % (51.6- 53.3) of ASCUS lesions, 74.8 % (74.3-75.3) of low-grade
cervical lesions (including low-grade squamous intraepithelial lesion and cervical
intraepithelial neoplasia grade 1 (CIN1), and 88.9% (88.5-89.3) of high-grade cervical
lesions (including high-grade squamous intraepithelial lesion and CIN2/CIN3)
worldwide. HPV16 is the most frequently detected genotype in all stages of the disease.
HPV16 is found in 19.3% (18.9-19.7) of low-grade cervical lesions and 45.1 % (44.6-
45.5) of high-grade cervical lesions. The strong enrichment in HPV16 prevalence, but
also in HPV18 and HPV45, from normal cytology to cervical cancer confirms their
increased carcinogenic potential when compared to other HPV types, as well as an
increased long-term cancer risk after infection with these types [5].

HPV prevalence is highest in the penis and lowest in the urethra in men. HPV prevalence
is highest in the cervix and vagina, and lowest in the vulvar epithelium in women.

HPV Infection Intervention

Vaccination is the primary preventive measure against HPV infection. There are three
HPV vaccines that are licensed by the U.S. Food and Drug Administration (FDA)—9-
valent HPV vaccine (Gardasil® 9, 9vHPV), quadrivalent HPV vaccine (Gardasil®,

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4vHPV), and bivalent HPV vaccine (Cervarix®, 2vHPV). It shows that a decrease in
HPV infections was observed since the first recommendation of HPV vaccination was
done.

Cervarix® protects against HPV types 16 and 18. The quadrivalent HPV
vaccine, Gardasil®, protects against HPV types 6, 11, 16 and 18. Gardasil® 9, a nine-
valent HPV vaccine (9vHPV) induces neutralizing antibodies against HPV types 6, 11, 16,
18, 31, 33, 45, 52, and 58.

All three HPV vaccines are based on virus-like particle (VLP) technology derived by
expressing L1, the major protein capsid of the human papillomavirus. VLPs offer
several advantages, primarily its safety. VLPs lack the infectious viral genome and this
distinction makes VLPs safer vaccine as compared to attenuated or inactive viruses which
have the possibility to revert back into infectious form. L1 is able to self-assemble and
form immunogenic but non- infectious VLPs.

However, since all HPV vaccines are L1 VLP vaccines, they are prophylactic, meaning
they protect individual against new HPV infections but does not treat existing HPV
infections or diseases. Considering this characteristic of HPV vaccines to attain its
maximal population effectiveness, it should be administered before any sexual activity
begins.

HPV Vaccination Recommendation

CDC’s Advisory Committee on Immunization Practices (ACIP) recommended routine

vaccination to all preteens, both boys and girls, at age 11-12 years though it can be
started at age 9. ACIP also recommends catch up vaccination for everyone through age 26
years if not adequately vaccinated previously. HPV vaccination is given as a series of
either two or three doses, depending on age at initial vaccination. Two doses with 6 to 12
months apart are recommended to those who started vaccination at age 9 and through age
14. Following the dosage interval is necessary in order to attain the expected outcome of

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the intervention. Failure to do so (adolescents aged 9 through 14 years receiving two
doses of HPV vaccine with less than 5 months apart) will require a third dose. Teens and
young adults who started the series later, at ages 15 through 26 years, are recommended
to have three doses of HPV vaccine with recommended dose schedule of 0, 1–2 and 6
months. Individuals with weakened immune systems are recommended to have three
doses as well even if they are adolescents aged 9 through 14 [6]. Vaccination is not
recommended for everyone older than age 26 years because HPV vaccines will
not protect individuals against types of HPV to which they have already been exposed,
and many sexually active people have been exposed to at least some HPV types by their
late 20s.

Benefits and Importance of HPV Vaccine

HPV vaccines are said to be highly immunogenic. As reported by Centers for Disease
Control and Prevention (CDC) more than 98% of individuals who undergone HPV
vaccination developed an antibody in response to HPV types included in the respective
vaccines. Moreover, HPV vaccine offers long-lasting protection against HPV infection
and its associated disease. All three HPV vaccines protect against HPV types 16 and 18
that cause most of the HPV cancers and these vaccines have the potential to prevent
more than 90% of HPV attributable cancers [7].

Cervarix formulated with a proprietary immunostimulatory Adjuvant System 04(AS04)

and a Gardasil formulated with a propriety amorphous aluminum hydroxyphosphate
sulfate (AAHS) adjuvant was used in a 3 phased randomized trial on the long-term
immunogenicity and safety of human papillomavirus (HPV)–16/18 AS04-adjuvanted
vaccine and HPV-6/11/16/18 vaccine in healthy women aged 18 to 45 years. After 5
years of vaccination, data on vaccine-induced antibody responses were presented,
seropositive rates for HPV16 and 18 remained high in Cervarix and Gardasil vaccine
group for ages 18-45, seronegative and DNA- negative analyzed by the kinetics of the
antibody response induced by both vaccines shows similarity in trend. Neutralizing
antibody GMTs peaked at month 7, declined, and reached a plateau beyond 18–24-month
post-vaccination.The antibody plateau levels induced by Cervarix appeared to be higher
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than those induced by the Gardasil vaccine up to 60 months across all age strata.
Regardless of the type of vaccine and age, the results still show immunogenicity in terms
of serum nAb responses to HPV 16 and 18 of the two vaccines that were sustained up to
month 60 [8]. A study regarding the persistence of immune responses to the HPV-16/18
AS04- adjuvanted vaccine in women aged 15–55 years was conducted as well [9].
Samples of blood for immunogenicity assessment were collected at 0, 2, 7, 12, 18, 24, 36,
48, 60 (year 5), and 72 months, along with chorionic villus sampling (CVS) samples from
women who volunteered were collected at 18, 24, 60 and 72 months. In the study, the
author assessed samples collected at year 5 and year 6. Anti-HPV–16 and anti-HPV–18
antibody titers in serum and CVS samples were measured by ELISA using type-specific
VLPs as coating antigens and total immunoglobin G (IgG) levels were measured for
variation during the menstrual cycles. The results showed that over 70% were
seronegative for both anti-HPV-16 and anti-HPV-18; among women in the age groups
15–25, 26– 45, and 46– 55 years, 82.5, 67.4, and 66.3% were seronegative for both
HPV–16 and HPV–18, respectively, and only 6% were seropositive for both HPV–16
and HPV–18. In conclusion, the HPV-16/18 AS04-adjuvanted vaccine was well tolerated
and induced sustained immune responses in women aged 15-55 years. It reveals that a
strong correlation between anti-HPV-16/18 levels in serum and CVS samples 6 years
after vaccination indicates long-lasting transudation of serum antibodies across the
cervical epithelium, this suggests that an addition to the routine vaccination, sexually
active mature women can potentially benefit from vaccination with HPV-16/18 AS04-
adjuvanted vaccine on an individual basis [9].

Furthermore, a phase 3 immunogenicity and safety research of the 9vHPV vaccination

in women 27–45 versus 16–26 years old was presented [10]. Anti-HPV
6/11/16/18/31/33/45/52/58 GMTs in women 27–45 years old were compared to those in
women 16–26 years old at the end of month 7. This was a 7-month international
immunogenicity and safety study of the 9vHPV vaccine in women aged 16–45. It was
carried out at 24 study sites spread across six countries (Austria, Belgium, Finland,
Germany, Italy and Spain). Participants were healthy women who had never received an
aprophylactic HPV vaccine, had no history of abnormal Papanicolaou test or cervical
biopsy results, genital warts, or a positive HPV test. Participants were enrolled into the
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study in two age groups: women aged 16–26 years and women aged 27–45 years. This
study aimed to demonstrate the non-inferiority in geometric mean titers (GMTs) for
serum anti-HPV 16/18/31/33/45/52/58 of the administration of the 9vHPV vaccine in
women aged 27–45 years compared with women aged 16– 26 years at 4 weeks after
vaccine Dose 3. The result of this study showed that, at month 7, the 9vHPV vaccine
induced anti-HPV responses for all nine HPV types (6/11/16/18/31/33/45/52/58) in both
women aged 16–26 years and women aged 27–45 years. Antibody responses to the
seven high-risk HPV types (16/18/31/33/45/52/58) were non-inferior in women aged 27–
45 years versus women aged 16–26 years in the primary noninferiority analysis.
Depending on the HPV types, the estimated fold differences for GMT ratios (women aged
27–45 years versus women aged 16–26 years) varied from 0.66 to 0.73, and the lower
bound of the 95 percent confidence interval for GMT ratios ranged from 0.60 to 0.67.
Because the lower bound of the 95 percent CI of the GMT ratio was >0.5 for each of
HPV 16, 18, 31, 33, 45, 52, and 58, the non-inferiority hypothesis was fulfilled (p 0.001).
While HPV 6 and 11 were excluded from the non-inferiority analysis, the estimated fold
differences in GMTs between older and younger women were 0.81 and 0.76,
respectively. The 9vHPV vaccine could provide broad protection against HPV infection
in adult women [10].

Additionally, it was proven that HPV vaccines are effective among people with HIV
infections as well and even shows cross-protection against frequent oncogenic non-
vaccine serotypes. In a study which includes 91 HIV infected participants that received
vaccination with Cervarix® or Gardasil®, it showed that both licensed HPV-vaccines
induced cross-neutralizing antibodiesagainst HPV-31, -33, and -45 in participants who
were seronegative and HPV-DNA negative HIV-infected individuals [11].

Safety and Risk of HPV Vaccine

There are evidence showing that the HPV vaccines are safe. A study which demonstrates
safety of the quadrivalent HPV vaccine was conducted wherein a total of 3006
individuals were chosen at random and received the same treatment [12]. A minimum of

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one dose was administered. The base study and extension study was completed by 2759
and 2602 respectively. 1499 participants in the qHPV vaccine group and 1498 people in
the placebo group who were vaccinated and had available safety follow-up data were
evaluated for safety. They used the AE grading scale issued by the China Food and
Drug Administration to assess all the abnormalities, signs and symptoms that are
associated with the administration of the said HPV vaccine. Injection-site and systemic
adverse events (AEs) were collected using vaccination report cards (VRCs) for 15
days following each vaccination. Serious AEs (SAEs), pregnancy outcomes, new
medical conditions, and fetal/infant SAEs were collected during the entire study. Within
15 days of any vaccination, injection-site AEs prompted for on the VRC were more
common among qHPV vaccine recipients (37.6 % vs 27.8%), whereas systemic AEs
prompted for on the VRC were comparable in frequency between the qHPV vaccine and
placebo groups (46.8% vs 45.1%). In the qHPV vaccine and placebo groups, 38 and 43
participants, reported SAEs respectively. There were no qHPV vaccine-related SAEs.
Pregnancy outcomes, fetal/infant SAEs, and new medical conditions were generally
similar and within normal ranges in the qHPV vaccine and placebo groups. This study
lead to the conclusion that the qHPV vaccine was well tolerated and had a favorable
safety profile in Chinese women aged 20–45, which was consistent with findings from
global trials and safety surveillance studies. It was proven that the safety profile of the 9-
valent HPV vaccine was similar between women 16– 26 years of age and women 27–45
years of age [10]. The 9vHPV vaccine was generally well tolerated, and there were no
serious side effects. There were no vaccine-related SAEs, no study discontinuations due
to a vaccine-related AE, and no deaths occurred during the study. Ultimately, their study
supports the vaccine's favorable safety profile in people up to the age of 45.

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 CHAPTER III

Methodology

Search Strategy and Information Sources

We attempted to identify the relevant studies including published, unpublished, in press

and in progress. We accessed the studies that was reviewed in this meta-analysis through
the major scientific databases: PubMed and ClinicalTrials.gov. We used the following
search terms: "hpv vaccine"; "human papillomavirus"; “quadrivalent”; “gardasil”;
“bivalent”.

All relevant papers, bibliographies, including reviews, were searched for further references.

Eligibility Criteria

The inclusion criteria used were: all HPV vaccines’ randomized clinical trial reports
published in English language; conducted in human subjects which are 27 through 45
years old; published until September 20, 2021.

The exclusion criteria used were: studies published solely in abstract; editorials, case
reports, commentaries; overlap in subjects within the same analysis.

Study Selection

In this review, R.C.L. and R.D.D.M. will randomly review, evaluate, and select the
preliminary list of included studies. Three authors (R.D.A.D.M, C.L.S.T, and R.C.L) will
work independently on the screening and evaluation of the preliminary included studies
whether they met the inclusion criteria necessary for the systematic review. After
discussion among the three authors, the final inclusion of the studies will be agreed. These

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processes follow the PRISMA 2020 criteria for systematic review reporting.

Data Collection and Data Items

For every study that met the inclusion criteria, four authors (J.C.O., G.P.M.F., A.J.B.M.
and R.D.D.M.) extracted the data and transferred them to standardized data extraction
sheets. Any discrepancies between the authors will be discussed until consensus is reached
or in consultation with a third reviewer. (C.L.S.T.).

Outcomes and Prioritization

Reactogenicity responses including the solicited and unsolicited reaction. Relative risk
measured in reactogenicity responses.

Risk of Bias Individual Studies

The Cochrane Risk of Bias Tool will be used by the authors to investigate the risk of
bias of the studies included.

Data Synthesis and Meta-biases

Outcome regarding the reactogenicity responses was summarized as Risk Ratios (RR).
95% confidence intervals were estimated on the basis of the extracted data. The possibility
of publication bias was assessed using the funnel plot method.

The evidence quality and the quality of the included studies was assessed using the
Grading of Recommendations Assessment, Development and Evaluation (GRADE)
working group guidelines.

Study Budget

The review has not been funded or sponsored by any persons, organizations, groups,
firms, or other legal entities.

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 GANNT Chart

Month
Activity August October December January February March April May
2021 2021 2021 2022 2022 2022 2022 2022
Drafting of the
research
proposal
Submission of
initial draft for
checking of
faculty adviser
Revision
period post-
checking with
faculty adviser
Submission of
final draft of
research
proposal
Proposal
presentation
Submission to
the UERM-
RIHS-ERC for
ethical review
and clearance
Finalization of
research
proposal for
UERM-RIHS-
ERC
submission
Data collection
and protocol
development
Allowance for
revision from
UERM-RIHS-
ERC
Preparation
and
finalization of
Chapters 4-5
Submission of
final draft of
research paper
Research
presentation

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 CHAPTER 4
Results and Discussion

Results

This study followed PRISMA guidelines (Figure 1). A search in Clinical Trials.gov and
PubMed databases used pre-determined search criteria, initially generating 84 studies on
Human Papillomavirus vaccines. From the 84 articles, 41 articles were screened and found
eligible for further investigation. Among the 41 studies, 14 was found eligible after
removing duplicates. Only 3 of 14 has the data essential for this study and was included in
the meta-analysis.

Figure 1. PRISMA Flow chart

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 Figure 2. Overall Risk of Bias

Figure 3. Forest plot of included studies

Page 18 of 32
Discussion

Figure 4. Local adverse reaction

Significant portion of what the population has experienced as a result of the HPV
vaccine's side effects was shown in Figure 4, throughout all doses (dose 1, dose 2, and
dose 3). Pain is the most common side effect, accounting for 51.55 % of all dosages;
Pruritus, accounting for 37.5% which simply means itching or itching of the skin.
Redness comes in third with a rate of 21.69 %. Finally, the last adverse effect from all
dosages combined is induration, which is a condition that causes soft tissue stiffening,
with a proportion of 7.7%.

Page 19 of 32
 Figure 5. Systemic adverse effect

The HPV vaccination's systemic detrimental effects on the population are depicted in
Figure 5. The influence of all completed doses, including dosage 1, dose 2, and dose 3,
is represented by these percentages. Pyrexia, a disorder in which the body temperature
rises (leading to fever), has the highest rate of negative consequences, at 18.65%.
Myalgia, a condition that causes muscle pain, affects 12.22% of the population.
Headache makes up 12.20% of the total, while fatigue makes up 10.82%. 6.67 % of
people suffer from nausea. 5.94% of people have diarrhea, 5.60% have cough, 4.40%
have gastrointestinal symptoms, and 3.33% have symptoms of rash. Hypersensitivity is
3.27%, dizziness is 2.22%, fever is 2.20%, vomiting is 1.60%, and urticaria (hives), a
disorder characterized by red itchy welts caused by a skin response, is 0.99%

Page 20 of 32
 Local Adverse Effect
2nd Dose

3%
4%
0%
2 months dose timing
5.80%
5.30%
16.50%

0%
0%
17.17%
1 month dose timing
8.48%
13.71%
38.32%

0.00% 5.00% 10.00% 15.00% 20.00% 25.00% 30.00% 35.00% 40.00% 45.00%

Pruritus Induration Redness Erythema Swelling Pain

Figure 6. Local adverse effect during second dosage.

Figure shows the percentage of the population that experience local adverse effects
during the second dose of the vaccine based on their vaccine dosage interval. Pain
(38.32% on the 1-month dose timing; 16.50 % in 2 months dose timing) has the highest
percentage that is mostly experienced after the injection of the vaccine. Redness (17.7%
it occur and experience only on the 1 month dose timing), swelling (13.71% in 1 month
dose timing; 5.30% in 2 months dose timing), erythema (8.48% in 1 month dose timing;
5.80% in second dose timing) induration (4% in the second month dose timing) it
experienced only on the second dose timing. Those reactions are the naturally occurring
after the injection of the vaccine and it is typically mild

Page 21 of 32
 Local Adverse Effect
3rd Dose
0%
0%
6 months dose timing 0.17%
0%
2.29%
18.68%

0%
0%
5 months dose timing 15.53%
0%
26.70%
41.78%

5%
4%
4 months dose timing 0%
5.90%
5.40%
16.50%

0.00% 5.00% 10.00% 15.00% 20.00% 25.00% 30.00% 35.00% 40.00% 45.00%

Pruritus Induration Redness Erythema Swelling Pain

Figure 7. Local adverse effect during third dosage

The local adverse effect of the 3rd dose of the vaccine which consists of 3 different
months of dosage interval before giving another dosage is shown in Figure 7. Pain is
always experienced in vaccination based on the table it has the highest percentage
(41.78% in 5 months dose timing; 16.50% 4 months dose timing; and 18.68 % in 6
months dose timing). Swelling (5.40% in 4 months dose timing; 26.70% in 5 months
dose timing; and 2.29% in 6 months dose timing). Erythema (5.90% in 4 months dose
timing) is experienced only in the 4 months dose timing the next months of vaccination
they do not experience this reaction. Redness (15.535 in 5 months dose timing and
0.17% in 6 months dose timing). Pruritus and induration are only seen in 4 months dose
timing.

Page 22 of 32
 Systemic Adverse Effect
2nd Dose
1.50%
3.00%
1.00%
3.00%
2.85%
0.00%
2 months dose timing 7.40%
0.00%
0%
0%
0%
7.50%
12.80%
7.25%

0%
0.00%
0.00%
0.00%
0.00%
0.50%
1 month dose timing 2.32%
4.32%
2%
0%
2.17%
7.29%
0.86%
7.43%

0.00% 2.00% 4.00% 6.00% 8.00% 10.00% 12.00% 14.00%

Hypersensitivi ty Cough
Vomiting Nausea
Diarrhea Urticaria
Myalgia Gastrointestinal Symptoms (GSI)
Rash Diziness
Fever Fati gue
Pyrexia Headache

Figure 8. Systemic adverse effect during second dosage.

Figure 8 shows systematic adverse effects for human papillomavirus second dose
vaccines. Most frequently occurring effects include but are not limited to pyrexia at
0.86% at 1st month dose timing; 12.80% in 2nd month dose timing, fatigue at 7.29%;
6.50%, headache at 7.43%;7.25%, and nausea at 4.32%; 3.00% respectively for 1st
month dose timing and 2nd month dose timing. A number of adverse effects are also seen
in 2nd month dose timing such as hypersensitivity and cough which are not experienced
in the 1st month dose timing.

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. Systemic Adverse Effect
3rd Dose
0.00%
0.00%
0.00%
0.00%
0.00%
0.50%
6 months dose timing 3.68%
0.32%
0.00%
0.00%
0.17%
0.29%
0.00%
2.43%

1.80%
2.60%
0.60%
3.70%
3.05%
0.00%
4 months dose timing 7.50%
0.00%
0.00%
0.00%
0.00%
7.81%
12.09%
7.25%

0.00% 2.00% 4.00% 6.00% 8.00% 10.00% 12.00% 14.00%

Hypersensitivi ty Cough
Vomiting Nausea
Diarrhea Urticaria
Myalgia Gastrointestinal Symptoms (GSI)
Rash Diziness
Fever Fati gue
Pyrexia Headache

Figure 9. Systemic adverse effect during third dosage.

Figure 9 shows systematic adverse effects for human papillomavirus third dose
vaccines. Most frequently occurring effects include but are not limited to headache at
7.25% in 4th month dose timing; 2.43% at 6th month dose timing, and fatigue at
7.81%; 0.29% respectively for 4th month, and 6th month dose timing. Moreover, the
4th month dose vaccines garnered the highest number of adverse effects.

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 Frequencies of Occurrence of the Common Adverse Effect HPV Vaccines and Placebo
(Second Dose)
SECOND DOSE VACCINATION LOCAL ADVERSE REACTION
Local Adverse Reaction Vaccine Placebo
Pain 28.30% 13.9%
Swelling 11% 4.12%
Erythema 1.95% 2.88%
Redness 8.18% 7.15%
Induration 1.25% 1.72%
Pruritus 1.22% 2.1%
Table 4.1 Common Local Adverse Effect between HPV Vaccines and Placebo (Second Dose)

The second dose vaccination for local adverse reaction has the side effects of pain, with vaccine
it’s 28.30%, in placebo with a percentage of 13.9. Swelling was 11% with the vaccine and 4.12 %
with the placebo, and Erythema was 1.95 % with the vaccine and 2.88 % with the placebo.
Redness was 8.18 % in the vaccination and 7.15 % in the placebo. Induration was 1.25 % in the
vaccination and 1.72 % in the placebo, while pruritus was 1.22 % in the vaccine and percent in the
placebo.

THIRD DOSE VACCINATION LOCAL ADVERSE REACTION

Local Adverse Reaction Vaccine Placebo
Pain 28.40% 13.92%
Swelling 11.36% 4.36%
Erythema 1% 2%
Redness 8.38% 6.70%
Induration 1.31% 1.62%
Pruritus 1.28% 1.5%
Table 4.2 Common Local Adverse Effect between HPV Vaccines and Placebo (Third Dose)

The third dose immunization causes discomfort in 28.40 % of vaccine recipients and 13.92 % of
placebo recipients, swelling in 11.36 % of vaccine recipients and 4.36 % of placebo recipients, and
erythema in 1% of vaccine recipients and 2% of placebo recipients. Redness was found in 8.38 %
of vaccination recipients and 6.70 % of placebo recipients. 1.31 % vaccine induction and 1.62 %

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placebo induction. Pruritus was seen in 1.28 % of vaccine recipients and 1.5 % of placebo
recipients.
Frequencies of Occurrence of the Common Adverse Effect HPV Vaccines and Placebo
(Third Dose)
SECOND DOSE VACCINATION SYSTEMIC ADVERSE REACTION
SystemicAdverse Reaction Vaccine Placebo
Headache 3.22% 8.4%
Pyrexia 4.62% 9%
Fatigue 3.81% 2.85%
Rash 0% 0.83%
Gastrointestinal symptoms 0.65% 2.62%
Myalgia 3.56% 3%
Urticaria 0.11% 0.67%
Diarhea 1.13% 1.05%
Nausea 1.11% 1.09%
Vomiting 0.27% 0.12%
Cough 0.96% 1.11%
Hypersensitivity 0.45% 0.36%
Table 4.3 Common Systemic Adverse Effect between HPV Vaccines and Placebo (Second Dose)

The table 4.3 list systemic adverse reaction during second dose of vaccination. It is found out that
pyrexia is the most common reaction that the participants experienced wherein 4.62% was
reported in vaccine group and 9% in placebo. Among all systemic reaction, rash is the only
reaction that was absent in vaccine but precent in the placebo. Vomiting is the reaction with the
lowest percentage in the placebo group with 0.12%.

THIRD DOSE VACCINATION SYSTEMIC ADVERSE REACTION

SystemicAdverse Reaction Vaccine Placebo
Headache 3.28% 8.56%
Pyrexia 4.02% 8%
Fatigue 3.55% 2.95%
Rash 0% 0.83%
Gastrointestinal symptoms 0.69% 2.52%
Myalgia 3.40% 3.06%
Urticaria 0.23% 0.67%
Diarrhea 0.83% 1.01%

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 Nausea 1.13% 1.05%
Vomiting 0.27% 0.18%
Cough 0.9% 1.03%
Hypersensitivity 0.65% 0.5%
Table 4.4 Common Systemic Adverse Effect between HPV Vaccines and Placebo (Third Dose)

Table 4.4 shows the systemic adverse reaction during third dose of the vaccination in the vaccine
and placebo group. Of all the systemic reaction, Pyrexia gain the highest percentage among the
vaccine group with 4.02% while headache was the most experienced reaction in the placebo group
having 8.56%. Rash is the only reaction seen in vaccine group that was absent in the placebo
group. Vomiting gains the lowest percentage among the reactions that was experienced by the
placebo group with only 0.18%.

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 CHAPTER V
Conclusions and Recommendations

Conclusions

This meta-analysis of three studies shows a significant reduction of risk of local adverse
reaction during administration of 2nd dose of the vaccine with 2 months dose timing but
has an increased risk in systematic adverse reaction with RR of 1.0980 (95%-CI
[1.0316; 1.1687]). It also showed a significant reduction of risk in both adverse and
systematic adverse reaction in the administration of the 3rd dose with six months dose
timing.

The major effects of the HPV vaccine doses on reactogenicity includes but are not
limited to pain, pruritus, redness, and swelling for local adverse reaction. Multiple side
effects of the HPV vaccination have been documented in the systemic adverse effect.
The symptoms are Pyrexia, headache, tiredness, fever, dizziness, rash, gastrointestinal
problems, myalgia, urticaria, diarrhea, nausea, vomiting, cough, and hypersensitivity.

In terms of local adverse reactions, the one-month HPV vaccine causes pain, redness,
swelling, erythema, and induration. However, these symptoms are common following
immunization and are usually mild. Pyrexia, tiredness, headache, and nausea were
among the systemic adverse reactions recorded. These outcomes are based on the result
of 3 vaccination studies.

The effects of two months of HPV vaccines dose timing in terms of the local adverse
reactions causes pain, redness, erythema, swelling, induration and pruritus. Those
reactions typically occur after the vaccine injection and they are usually mild. In
systemic adverse effects the reactions are fatigue, headache, vomiting, diarrhea,
myalgia, rash, nausea, hypersensitivity and cough.

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 The effects of six months of HPV vaccines dose timing on reactogenicity in terms of
local adverse reactions causes pain, redness and swelling which are consistently
experienced after the vaccination. Headache, fatigue, fever, nausea, myalgia, and
urticaria are most frequently effects seen in the systemic adverse reaction.

Recommendations

The researchers recommend the following:

1) Use other research databases in screening of relevant studies to be included in the
meta-analysis;
2) People age 27 through 45 to get their 2nd dose of vaccine be administered with 1
month dose timing and the 3rd dose with 6 months dose timing;
3) Future similar studies should include immunogenicity of the HPV vaccine in the same
age group.

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