How HPV Vaccines with Various Compositions Work for Humans

Sichu Chen

1,†

and Chen Cheng

2,*,†

University of California – Santa Barbara, Santa Barbara, California 93106, U.S.A.

Coe College – Cedar Rapids, Iowa 528400, U.S.A.

Keywords:

HPV, Vaccines, Immunotherapy.

Abstract: Human papillomavirus (HPV) is the main cause of genital infection, which further causes cervical cancer and

other HPV-related diseases. These diseases severely affect the physical and psychosexuals of both males and

females. Cancer vaccines have contributed significantly to cancer prevention or therapy these years, especially

for cervical cancer. In this review, the topics of what HPV is and how the innate immune system fights against

it have been introduced. Furthermore, the mechanisms of three prophylactic HPV vaccines- Gardasil®,

Cervarix® and Gardasil® 9- that contain various virus-like particles (VLP) have also been discussed. In

addition, this paper discusses and compares the composition of each of these HPV vaccines and how effective

they are in prevention of cervarix cancer, how the body reacts to immunization of these vaccines. Lastly, the

achievements and the future of the vaccination programmes are investigated.

1 INTRODUCTION

Over 570,000 women are affected by cervical cancer,

and about 311,000 women pass on each year

worldwide, with almost 90% of them living in low

and middle- low-income countries (Okuhara et al.,

2021). The International Agency for Research on

Cancer has accepted a direct causative association

between HPV and genital infections, such as in the

cervix, penis, vulva, but the severity of the correlation

varies. As a result, HPV is widely regarded as the

most important oncogenic virus affecting humans

and the leading cause of uterine cervical cancer. The

direct relationship between the prevalence of HPV

and women is all around depicted, with rates peaking

in younger women and then steadily declining. HPV

prevalence in males is higher than in women overall

and remains stable over time among different age

groups. In certain male populations, like who have

sex with men,especially those with HIV infection, the

HPV prevalence can be exceedingly high (over 70

percent) and is commonly linked to anal carcinoma

(Mariani et al., 2017).

In recent years, cancer immunotherapy has been

utilizied more frequently, with cancer vaccines

emerging as a novel approach to cancer treatment.

†

These authors contributed equally

The development of therapeutic vaccines capable of

activating cytotoxic T cells or generating antibodies,

so initiating an immunological response, has been

aided by a better understanding of how cancer cells

avoid detection and are targeted by the immune

system. In clinical trials, cancer vaccines are

commonly combined with other forms of therapy,

such as surgery and chemotherapy, to improve

efficacy. Cell immunizations (cancer or safe cell),

protein/peptide antibodies, and hereditary (DNA,

RNA, and viral) immunization are a few of the major

categories of clinical studies (Mannan et al. 2016).

Almost all high-resource nations have been building

HPV vaccination programs since 2007. The Global

Alliance for Vaccines and Immunization (GAVI) is

coordinating and sponsoring several pilot projects in

low- and middle-income countries. Cervical cancer

incidence and death rates are higher in disadvantaged

areas where immunization efforts are almost non-

existent (Mariani et al., 2017).

This review mainly focuses on the mechanisms

and clinical trials of the three prophylactic HPV

vaccines, including their compositions. There is also

including the effect of cancer vaccines on males and

females of all ages.

156

Chen, S. and Cheng, C.

How HPV Vaccines with Various Compositions Work for Humans.

DOI: 10.5220/0012015200003633

In Proceedings of the 4th International Conference on Biotechnology and Biomedicine (ICBB 2022), pages 156-162

ISBN: 978-989-758-637-8

 2023 by SCITEPRESS – Science and Technology Publications, Lda. Under CC license (CC BY-NC-ND 4.0)

2 THE DISCOVERY AND

DEVELOPMENT OF HPV

HPV are double-stranded circular tiny DNA viruses

that infect epithelial tissues such as the basal

epidermis (skin or mucosal) cells and the upper

respiratory and anogenital tract epithelial linings

(Figure 1). HPVs are classified into low-risk and

high-risk types based on their ability to cause

malignant transformation. According to the

international agreement, "high-risk" genotypes such

as 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and

66 have been associated to cervical cancer and other

mucosal anogenital malignancies. Low-risk

infections can cause benign or low-grade cervical

tissue changes and genital warts, which are growths

on the cervix, vagina, vulva, or anus in women and

the penis, scrotum, or anus in men (Cutts et al., 2007).

HPV16 and 18 are the two most frequent cancer-

causing DNA subtypes, accounting for around 79%

of carcinomas in North America and 68% in Africa,

respectively, whereas HPV 6 and 11 lead to 90% of

recurrent respiratory papillomatosis (RRP). These

papillomaviruses are the only known viral infections

that start spontaneously by interacting with the cell

surface when they assault. From then, HPV requires

a simple 24 hours to thoroughly acclimatize the

nuclear DNA of the basal cell with its own. As a

result, the infectious genetic material is transcribed

and translated, enabling viral proteins to be

synthesized that interact with the infection. The

genome encodes six early regulatory proteins (E1,

E2, E4, E5, E6, and E7), as well as two late structural

proteins (L1 and L2). The early genes code for viral

DNA replication, transcription, and oncogenic

transformation proteins, whereas the late genes code

for virus capsid proteins. The late viral genes L1 and

L2 are translated when the infected basal cells go up

and separate, accordingly provoking the vegetative

phase of the virus life cycle, which is marked by

substantial genome expansion (Ferreira et al., 2020).

When the cell arrives at the peripheral layer of the

epithelium, the recently generated viral DNA is

exemplified to shape new virions, which are

delivered, and the existence cycle is rehashed

(Thomas T. L. 2016).

Figure 1: Illustration of HPV circular dsDNA (Ferreira et al., 2020).

The HPV vaccine is a crucial strategy for

preventing cervical cancer, primarily when used with

a healthy sexual way of life and appropriate

contraception. Scientists started to examine the

possible role of HPV in cervical cancer in the range

of 1974 and 1976. In 1976, Meisels and Fortin found

the presence of Koilocytes in cervical smears, which

demonstrated the presence of papillomavirus disease.

In 1983 and 1984, the scientists secluded cervical

cancer-related HPV type, HPV16, and HPV18, from

cancer biopsies of the cervix, separately. In 1987, de

Villiers et al. led the first epidemiological

investigation of HPV infections. The first virus-like

particles (VLPs), which are collected from

recombinant HPV capsid proteins and are non-

irresistible because of the absence of viral DNA were

produced in 1991. HPV was first proposed as an

important reason for cervical malignant growth

improvement in 1999. Harro et al. revealed the

wellbeing and immunogenicity of VLP

immunizations in people in 2001 (Figure 2) (Wang et

al., 2020). There are three authorized prophylactic

HPV vaccinations available now. In June 2006, a

quadrivalent HPV (4xHPV; Gardasil®) vaccine that

How HPV Vaccines with Various Compositions Work for Humans

157

protects against HPV6, HPV11, HPV16, and HPV18

was authorized in the United States and afterward in

the European Union (September 2006). The Food and

Drug Administration (FDA) approved a bivalent

HPV (2xHPV; Cervarix®) vaccination

(GlaxoSmithKline) in October 2009, which protects

against HPV16 and HPV18. The nonavalent HPV

(9xHPV; Gardasil 9®) vaccine (Merck & Co) was

licensed in 2014 that covers five more HPV types,

which are HPV31, HPV33, HPV45, HPV52, and

HPV58 (Wang et al., 2018).

Figure 2. The research chronology for HPV and HPV vaccines (Wang et al., 2020).

Despite the fact that prophylactic or preventive

HPV vaccinations have been a huge step forward in

preventing HPV infections and diseases, there is such

an unresolved HPV-related infection problem

throughout the world that there are no therapeutic

HPV vaccines approved for use in humans.

Furthermore, the majority of nations having national

HPV inoculation programs are high or upper-middle-

income countries. There is also concern that

traditional expression techniques may result in more

expensive products, making them unavailable to be

utilized in the low-income countries with the most

significant rates. Thus, medications for managing,

controlling and eliminating existing HPV infections

and related diseases are earnestly needed.

3 NATURE IMMUNE RESPONSE

Cell-mediated immunity (CMI) is an effective

immune response to the genital HPV infections. The

innate immune system detects the damage via local

antigen-presenting cells (APCs), then the pro-

inflammatory cytokines and chemokines move to

part of the lymph nodes to uphold the viral antigen

processing. Activated APCs can stimulate CD4+ T

cells to either help activation of CD8+ T cells.

Effector T cells get response to the early proteins,

mainly E2, E6 and E7, which can attack the virus-

infected cells. Helper T cells that recognize L1 major

capid protein help induce neutralizing antibodies

(nAbs), thereby preventing virus spread and host

reinfection. However, the expressions of E6 and E7

proteins are depressed with HPV persistence. This

may arise from methylation of the E2 promoter but is

usually associated with viral integration that can

drive lesion growth.

4 VLP IMMUNOGENICITY

Virus-like particles (VLPs) are a more effective

technique to develop highly immunogenic

vaccinations. They combine safety, ease of

production, and the presense of both high-density B

cell epitopes and intracellular T cell epitopes to

produce potent humoral and cellular immune

responses. VLPs are similar to native HPV particles.

The VLPs are fully non-infectious and non-

oncogenic due to the lack of viral genes, forming a

structure that resembles the outer shell of the HPV

virus. They activate antibody synthesis in response to

infection and contain conformational epitopes that

contribute in the development of neutralizing

antibodies by limiting target cell uptake (Stanley et

al., 2010) (Dadar et al., 2018).

Antigens from HPV's capsid can trigger a range

of type-specific antibodies, the majority of which can

bind to the local virion, but not all of them can

eradicate the infection by preventing uptake by the

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158

target cell. The non-neutralizing antibodies (non-

nAbs) are unable to directly affect the infectivity of

the virus. The nAbs generated by L1 VLP can,

however, prevent the binding to heparin sulfate

proteoglycans (HSPGs) on the basement membrane

(BM), but they cannot stop the infection completely.

After a conformational shift in the capsid and

cleavage of L2 by extracellular furin, the nAbs

generated by L2 vaccination can neutralize the virion

and deliver L2 defensive epitopes (Figure 3) (Roden

et al., 2018)

The quadrivalent vaccination comprises a

combination of four different VPLs obtained from the

major capsid protein L1 of HPV 6, 11, 16, and 18.

The nonavalent vaccine contains nine VPLs of

HPV6, 11, 16, 18, 31, 33, 45, 52, and 58. These

type specific L1 VLPs are synthesized by

recombinant expression of major capsid antigen L1

in the Saccharomyces cerevisiae (S. cerevisiae) yeast

with the amorphous aluminum hydroxyphosphate

sulfate (AAHS) adjuvant. In females and males aged

9 to 26 years, the quadrivalent HPV vaccination

protects against genital warts, precancerous or

dysplastic lesions, and cervical cancer. The

nonavalent HPV vaccine is prescribed to avoid

genital warts, precancerous lesions, cervical, vulvar,

vaginal, and anal cancer in females and males aged 9

to 45 years. The bivalent vaccine has been authorized

to prevent cervical and anogenital infection against

HPV16 and 18. It is produced in the baculovirus

expression vector system with the AS04 adjuvant

containing aluminum hydroxide and 3-deacylated

monophosphoryl lipid A (MPL) (Wang et al., 2020).

Figure 3: Antibody-mediated protection (Roden et al., 2018).

5 CLINICAL TRIALS

Several clinical investigations have been conducted

to demostrate the advantages of the vaccine. A total

of 14,000 girls aged 16 to 26 years old took part in a

Gardasil 9 HPV vaccination phase III clinical

research study. This study showed the significant

differences between the result of Gardasil that only 1

out of 6,016 females who received three doses of

Gardasil 9 acquired illnesses caused by HPV types

31, 33, 45, 52, and 58, contrasted with 30 out of 6,017

women who received three dosages of Gardasil.

Epidemiological research in Europe attempted to

quantify the advantages of the nonavalent

vaccination over the quadrivalent vaccine. According

to the findings, the nonavalent vaccination can

prevent 19% more cervical cancers than the

quadrivalent vaccine, and vaccine coverage for

precancerous lesions of the vagina, vulva, cervix, and

anus is expected to be 75% (Manini et al., 2018). The

result of a long-term bivalent HPV vaccine study that

involved 7466 women aged 18-25 years was

characterized histopathologically affirmed CIN2+ or

cervical intraepithelial neoplasia grade 3 or more

terrible related with HPV 16/18 cervical

contamination distinguished at colposcopy reference.

These vaccines have components that are

manufactured through biochemical synthesis. These

How HPV Vaccines with Various Compositions Work for Humans

159

components are part of the epitope of L1. Gardasil 9

is found to contain more virus-like particles that are

double the amount of the antigens and higher than a

double portion of aluminum hydroxide that is found

in Gardasil. The amount of concentration of virus-

like-particles in Gardasil 9 makes it more efficient in

protection against and treatment of HPV 16 and HPV

18 since it can effectively introduce inferior

responses of the antibodies as compared to Gardasil.

In addition, Cervarix contains antigens of a lower

concentration when compared with these other two

vaccine composition that is highly integrated and of

greater enhancement. These look similar to receptors

that inhibit antigens to stimulate and make an

improvement in the human immune responses and as

a result, long-lasting action of response by antibodies

is built up.

Table 1: Vaccine composition of a 0.5 ml dose of the HPV vaccine (Hildesheim et al., 2020).

Gardasil Gardasil9 Cervarix

Onco

enic

rotein subunit

HPV 16 41 60 21

HPV 18 22 41 20

HPV 31 22

HPV 33 20

HPV 45 23

HPV 52 23

HPV 58 23

Verrucouis

rotein subunit

HPV 6 22 30

HPV 11 40 41

Sodium Chloride 9.55 9.55 4.4

Sodium

orate 34 34

Sodium dih

dro

hos

hate dih

drate 0.625

Amorphous aluminum hydroxyphosphate sulfate 224 224

3-O-Desac

l-4′-mono

hos

hor

l li

(

MPL

)

A adsorbe

on 50

Aluminu

hydroxide 500

The trials that were conducted on women of ages

between 16 and 26 years and the findings showed for

the ones under 16 years, as shown by the standard of

WHO, this lack of superiority is acceptable and

especially at the endpoint. The individuals who were

over 26 years of age showed that the persistent of this

infection can be protected against for utmost 6

months given some specific vaccine and subjected to

a certain certified treatment and attention required

was found fit and accepted to be used in preventing

abnormal growth of cells in the female cervical areas.

The ability of the vaccine to protect against the

disease occurring in the vagina gives it the approval

to be used in the treatment and defined as16/18 HPV

and 2/3 HPV intraepithelial neoplasia.

There is not a clearly defined bare maximum level

regarding protection that antibody titers offer against

the cancer-causing and the disease itself in response

to these studies of how cervical cancer vaccines

define the endpoint of these VLPs. However, since

this HPV-causing cancer is found to be one of the

most dangerous and its treatment is limited, and is

also a long-term disease as shown by the studies. As

a result, they are used in the estimation of the

appropriate amount of time it would take to offer

protection to individuals of a certain age. Therefore,

there timing of a vaccine is very important and very

necessary since it determines the effect on the

antibody titers.

Giving three doses of the vaccine tends to be

considered a complete dose especially in women who

are between the age of 12 and 15 years. The

seropositivity that is realized in the response to the

titers of anti- HPV 16 is seen to be high after

vaccination for Cervarix and Gardasil vaccines

(Kumar et al., 2011). The long-term protection that is

expected for the specific vaccine is most of the time

is affected by the decrease in titers, especially the

Gardasil vaccine. Cervarix has higher retention for

seropositivity when compared with Gardasil and

therefore Cervarix shows an ability to bind serum and

response of the antibody for HPV 16 and HPV 18

than Gardasil. Both Gardasil and Gardasil 9 have

shown similar anti-A HPV 16 and 18 responses. In

terms of geometric mean numbers, Cervarix tends to

be superior when put in comparison with Gardasil.

When Gardasil 9 is administered in three doses, it

shows a similar reduction in geometric mean number

and an equal loss of seropositivity when taken for

protection against HPV 18 like Gardasil. However, in

22 months after giving the vaccine, a reduction of the

observable titers. In 1.4 years of vaccination, over

ICBB 2022 - International Conference on Biotechnology and Biomedicine

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12% of female individuals showed no presence of

detectable titers while 255 of women could show the

absence of observable titers after 3 years of

vaccination and 35% women after 5 years.

After 24 months of administering the Gardasil 9

vaccine, 15% of women shoed to have lost the

detectable titers for HPV 45. The loss of these

antibody titers for HPV 45 is considerably larger than

the lowest percentage loss shown by the same

vaccine for HPV 16 type and shows direct protection.

The intervals that the doses of the vaccines are taken

are also termed to be very important and help in the

determination of the GMT.

Two doses of Gardasil 9 and Cervarix were given

at an interval of six months thereafter followed by a

booster for the adolescents between 9 and 10 years of

age showed that hat Gardasil maintained a lower

amount of HPV 16 and 18 titers than for the dose of

Cervarix in one month of vaccination.

Three doses of Gardasil when given to pre-

adolescent girls tend to show an absence of

antibodies for different HPV types different from

those administered with Cervarix. A random test was

conducted for three doses of Gardasil 9 that showed

a higher number of HPV titers which was higher than

those administered with Gardasil 9 (Arbyn et al.,

2018). Both Gardasil and Cervarix have similar

antibody titers when administered at an interval of six

months and only two doses given. Women who are

above the age of 25 have inferior antibodies unlike

those who are below 18 years.

Vaccines need to be examined and their safety

determined and create an assurance that they will

provide the maximum protection to the recipients

against the different types of HPVs (Pennella et al.,

2020). Administering the most efficient of these

vaccines to women enhances protection against pre-

cancer infections. Surveillance that was carried out

by the Vaccine Safety Datalink depicted that these

three vaccines are safe for use by the recipients and

offer the most effective protection against these types

of HPV infections. Before any vaccine is licensed and

is accepted to be used, its safety is evaluated. In am

examination to determine how safe these vaccines

are, a similarity in the safety image of Gardasil and

Gardasil 9 which was the earlier version of Gardasil

9. However, the latter was found out to show more

side effects than Gardasil which however disappear

away after some time.

Through the program for vaccination, the

government has attained a significant decrease in the

occurrence of the various HPV causing disease types

that lead to the development of cervical cancer. An

approximately 50% in the go down of appearance of

abnormalities to teenage girls whose age is below 18

years. Through this, society is able to create

assurance to both men and women that vaccination is

important to their health and help them get away from

this dangerous disease. This also helps them to avoid

the expensive treatment of these long-term diseases

by just prevention them by taking a vaccination.

Since cancer is one of the fatal and dangerous and is

becoming a threat in society today by the number of

deaths it contributes to. Due to this, society today

together with the government has enabled individuals

to receive special attention and experienced medical

care by enabling the introduction and inputting the

required equipment for treatment and screening of

cancer cells to help determine early detection and

early treatment and later these have led to the

achievement of a healthy society (Kumar et al.,

2011).

6 FUTURE AND GOALS

The vaccination programs today are working in hands

with the various respective governments to give more

quality care to the individuals who are at a high risk

of contracting the cancer disease. It, therefore, aims

to achieve an educated society with people who are

aware of the danger of these diseases and are aware

of the importance of seeking early checkups and

treatment. Through this, a healthy society and the

number of deaths from this disease is achievable

7 CONCLUSION

In conclusion, cancer vaccines have been realized to

be a very important aspect in both the health sector

and even in the society at large. This is because they

enabled the finding of the solution to one of the

threats to individuals in the world today. Scientists

and research centers through the World Health

Organisation put these vaccines into place to help in

the fight to eradicate this deadly disease. Though the

cure has not yet been found, protection through these

vaccines saves a great deal. Even though these

vaccines bring different side effects to the body and

tend to react with different types of bodies of diverse

ages. More research enables determine which is the

most effective vaccine to administer to what age and

gender will work with their bodies without causing

diverse effects and abnormalities.

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161

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