diagnostics

Review
Updates on HPV Vaccination
Ojone Illah * and Adeola Olaitan

Women’s Cancer Department, EGA Institute for Women’s Health, University College London,
London WC1E 6BT, UK
* Correspondence: o.illah@ucl.ac.uk

Abstract: Cervical cancer still poses a significant global challenge. Developed countries have miti-
gated this challenge by the introduction of structured screening programmes and, more recently, the
HPV vaccine. Countries that have successfully introduced national HPV vaccination programmes
are on course for cervical cancer elimination in a few decades. In developing countries that lack
structured screening and HPV vaccination programmes, cervical cancer remains a major cause of
morbidity and mortality. The HPV vaccine is key to addressing the disproportionate distribution
of cervical cancer incidence, with much to be gained from increasing vaccine coverage and uptake
globally. This review covers the history and science of the HPV vaccine, its efficacy, effectiveness
and safety, and some of the considerations and challenges posed to the achievement of global HPV
vaccination coverage and the consequent elimination of cervical cancer.

Keywords: human papillomavirus; HPV; HPV vaccine; cervical cancer

1. History of the HPV Vaccine

One of the most extraordinary stories in medical research is that of Henrietta Lacks,
an African American woman who died from cervical cancer seventy years ago, at the age
of thirty-one. “HeLa cells”, as they are commonly referred to, are the cells which were
collected from her cervix in 1951 shortly before her death; these were the first established
in vitro immortal cancer cell line [1] and have formed the basis for multiple advances in
medical research, including the development of the human papillomavirus (HPV) vaccine.
In the originally biopsied HeLa cells, German virologist Harald zur Hausen in the
Citation: Illah, O.; Olaitan, A. early 1980’s discovered the presence of HPV-18 [2,3]. It is now known that HPV-18 and
Updates on HPV Vaccination. HPV-16 are responsible for 70% of cervical precancers and cancers. This ground-breaking
Diagnostics 2023, 13, 243. https:// discovery, for which zur Hausen won a Nobel prize in 2008, led to the fundamental research
doi.org/10.3390/diagnostics13020243 that is behind our detailed understanding of the natural history of HPV infection and its
induced carcinogenesis [4]. It became established in 1999 that persistent HPV infection was
Academic Editor: Laurent Bélec
a prerequisite for the development of most invasive cervical cancers [5].
Received: 30 September 2022 HPV now forms the basis of both primary and secondary cervical cancer preventative
Revised: 11 December 2022 measures. Most cervical screening programmes worldwide utilise HPV detection as a
Accepted: 19 December 2022 primary screening tool, in keeping with the World Health Organisation (WHO) recommen-
Published: 9 January 2023 dations [6]. HPV vaccine development was initiated in Australia in 1991; Dr Ian Fraser and
Dr Jian Zhou developed viruslike particles (VLPs) based on proteins expressed on the HPV
viral capsid [7]. These VLPs have proven essential for vaccine development.
The combined effect of HPV vaccination and cervical screening should effectively
Copyright: © 2023 by the authors.
make cervical cancer a rare occurrence, yet it remains a leading cause of cancer deaths
Licensee MDPI, Basel, Switzerland.
globally [8]. Worldwide, it is the fourth most common cancer that affects women while in
This article is an open access article
distributed under the terms and
low and low-and-middle-income countries (LLMICs), it is the second most common cancer
conditions of the Creative Commons
affecting women. LLMICs account for 86% of the global cervical cancer burden, bearing
Attribution (CC BY) license (https:// the brunt of this challenge [8].
creativecommons.org/licenses/by/ We review the natural history of HPV infection and its association with cervical cancer,
4.0/). the different types of HPV vaccine and studies looking into their efficacy, effectiveness and

Diagnostics 2023, 13, 243. https://doi.org/10.3390/diagnostics13020243 https://www.mdpi.com/journal/diagnostics

Diagnostics 2023, 13, x FOR PEER REVIEW 2 of 24

Diagnostics 2023, 13, 243 We review the natural history of HPV infection and its association with cervical 2 of 22can-
cer, the different types of HPV vaccine and studies looking into their efficacy, effectiveness
and safety. We also review the implementation of the HPV vaccine globally, with a focus
on the We
safety. barriers faced by
also review the countries with aoflow
implementation thevaccine uptake.
HPV vaccine globally, with a focus on the
barriers faced by countries with a low vaccine uptake.
2. HPV and Cervical Carcinogenesis
2. HPV and
HPV isCervical Carcinogenesis
a double-stranded DNA virus which belongs to the Papillomaviridae family. It
is theHPV
mostis acommon
double-stranded
sexually DNA virus which
transmitted belongs
infection to the Papillomaviridae
worldwide and it is estimatedfamily.that
most sexually active individuals will be infected with HPV at least once in their that
It is the most common sexually transmitted infection worldwide and it is estimated lifetime
most sexually active individuals will be infected with HPV at least once in their lifetime
[9]. Infection is most prevalent in young individuals following the onset of sexual activity [9].
Infection is most prevalent in young individuals following the onset of sexual activity
and in most countries, declines after the age of 35 [9] (Figure 1). Over 90% of exposed
and in most countries, declines after the age of 35 [9] (Figure 1). Over 90% of exposed
individuals will achieve immune-mediated spontaneous clearance of the virus within two
individuals will achieve immune-mediated spontaneous clearance of the virus within two
years of exposure [10].
years of exposure [10].

1. Prevalence
Figure 1.
Figure Prevalenceofof
HPV worldwide
HPV by age
worldwide by (reproduced with permission
age (reproduced from de Sanjosé
with permission from deetSanjosé
al. [11]).et al.
[11]).
There are over 100 subtypes of HPV, characterised into high-risk and low-risk sub-
types depending on oncogenic potential. Low-risk HPV subtypes include HPV-6, HPV-11,
There are over 100 subtypes of HPV, characterised into high-risk and low-risk sub-
HPV-42, HPV-43 and HPV-44 [12]. HPV-6 and HPV-11 are the most prevalent nononco-
types depending on oncogenic potential. Low-risk HPV subtypes include HPV-6, HPV-
genic subtypes and are responsible for over 90% of all cases of genital warts [13]. The
11, HPV-42, HPV-43include
oncogenic subtypes and HPV-44
HPV16,[12]. HPV-6
HPV-18, and HPV-11
HPV-33, HPV-35, are the most
HPV-45 andprevalent
HPV-58, andnonon-
cogenic
these havesubtypes and are
the potential responsible
to cause cervical,for over 90% of all
oropharyngeal, casesvulvar,
vaginal, of genital warts
penile and[13].
anal The
oncogenic
cancers [12,14]. Cervical cancer is by far the most prevalent HPV-associated cancer, and and
subtypes include HPV16, HPV-18, HPV-33, HPV-35, HPV-45 and HPV-58,
these
HPV 16have themost
is the potential
common to cause cervical,
causative oropharyngeal,
subtype, followed by vaginal, vulvar,
HPV-18 [14]. penile
Jointly and anal
HPV-16
cancers
and HPV-18[12,14]. Cervical
account cancer is by far
for approximately 70%the most
of all prevalent
cervical cancerHPV-associated
cases [9]. cancer, and
HPVThere
16 is the
maymost common
be racial and causative subtype,in
ethnic differences followed by HPV-18
age at peak [14]. Jointly
HPV incidence, HPV-16
degree
of HPV persistence and prevalence of high-risk HPV subtypes
and HPV-18 account for approximately 70% of all cervical cancer cases [9]. [14–16] and a number of
studies have looked into these differences by region. Some recent studies
There may be racial and ethnic differences in age at peak HPV incidence, degree ofhave suggested
a higher
HPV burden of
persistence andnon-HPV-16
prevalenceor of HPV-18
high-risk inHPV
Blacksubtypes
and African women
[14–16] and awith cervical
number of stud-
cancer [17,18]. While this requires further studies, HPV-16 and HPV-18
ies have looked into these differences by region. Some recent studies have suggested aremain the most
common
higher high-risk
burden subtypes associated
of non-HPV-16 or HPV-18with in
cervical
Black cancer worldwide
and African women[14,19].
with cervical can-
cer [17,18]. While
HPV-Induced thisCarcinogenesis
Cervical requires further studies, HPV-16 and HPV-18 remain the most com-
mon high-risk subtypes associated with cervical cancer worldwide [14,19].
The HPV genome consists of three regions. The long control region (LCR) regulates
gene expression and replication, the early (E) region encodes for proteins which are required
for HPV gene expression, replication and survival, and the late (L) region encodes for viral
structural proteins [14]. The virus gains access to host cells by infecting the basal epithelial
 HPV-Induced Cervical Carcinogenesis
The HPV genome consists of three regions. The long control region (LCR) regulates
gene expression and replication, the early (E) region encodes for proteins which are re-
Diagnostics 2023, 13, 243 quired for HPV gene expression, replication and survival, and the late (L) region 3 of 22
encodes
for viral structural proteins [14]. The virus gains access to host cells by infecting the basal
epithelial layer of the cervix. Following infection, early proteins E1, E2, E4, E5, E6 and E7
arelayer of the cervix.
produced; E6 and Following
E7 are the infection, early proteins
key oncoproteins which E1,promote
E2, E4, E5,
viralE6DNA
and E7 are
replication
produced; E6 and E7 are the key oncoproteins which promote viral DNA replication
and prevent apoptosis via interactions with tumour suppression proteins [9,14]. Subse- and
prevent apoptosis via interactions with tumour suppression proteins [9,14]. Subsequently,
quently, late capsid proteins L1 and L2 are produced, which allow the formation of prog-
late capsid proteins L1 and L2 are produced, which allow the formation of progeny virions
enyinvirions in host nuclei cells—these replicate the viral life cycle [9] (Figure 2).
host nuclei cells—these replicate the viral life cycle [9] (Figure 2).

Figure 2. HPV
Figure infective
2. HPV infectivecycle
cycleand
and cervical carcinogenesis
cervical carcinogenesis (Source:
(Source: authors).
authors).

TheThe majorityofofwomen
majority womeninfected
infected with
with HPV
HPVwillwillclear
clearit itwithin
within a few years.
a few An An
years. es- esti-
timated 10–20% of women will have persistent HPV infection [20], which
mated 10–20% of women will have persistent HPV infection [20], which if untreated, can if untreated,
leadcan
tolead to cervical
cervical cancercancer
afterafter
15 to1520toyears.
20 years. In immunosuppressedstates
In immunosuppressed states such
such as
aswith
with un-
untreated HIV, cancer can develop in 5 to 10 years [10]. The persistence of HPV infection
treated HIV, cancer can develop in 5 to 10 years [10]. The persistence of HPV infection
occurs via (i) malignant transformation by the HPV oncoprotein-mediated downregulation
occurs via (i) malignant transformation by the HPV oncoprotein-mediated downregula-
of cell cycle control and genetic damage, and (ii) a wide array of immune evasion mecha-
tionnisms
of cell cycle
which controlpapillomaviruses
high-risk and genetic damage, and (ii)[9,21].
have developed a wide array
From of immune
persistent evasion
infection,
mechanisms
cervical dysplasia and cervical intraepithelial neoplasia (CIN) can develop, which may in-
which high-risk papillomaviruses have developed [9,21]. From persistent
fection, cervical
progress dysplasia
to invasive andcancer
cervical cervical intraepithelial
(Figure 2). neoplasia (CIN) can develop, which
may progress to invasive cervical cancer (Figure 2).
3. Prophylactic HPV Vaccine Types and Mechanism of Action
This understanding
3. Prophylactic of HPV-induced
HPV Vaccine Types andcarcinogenesis
Mechanism alongside
of Actionthe availability of VLPs
has allowed various prophylactic HPV vaccines to be developed. The first to be licensed in
This
2006 wasunderstanding
Gardasil® (Merck, of Sharp
HPV-induced carcinogenesis
& Dome (Merck alongside
& Co., Whitehouse the NJ,
Station, availability
USA)), of
VLPs has allowedvaccine
a quadrivalent various prophylactic
which HPV HPV-11,
targets HPV-6, vaccinesHPV-16
to be developed.
and HPV-18, The first to be li-
conferring
censed in 2006 was Gardasil ® (Merck, Sharp & Dome (Merck & Co., Whitehouse Station,
protection against genital warts, which are most commonly caused by HPV-6 and HPV-11.
NJ,InUSA)),
2007, a abivalent
quadrivalent Cervarix®which
vaccine, vaccine targets HPV-6,
(GlaxoSmithKline, HPV-11,
Rixensart, HPV-16
Belgium), was and HPV-18,
licensed,
which targets HPV-16 and HPV-18. Gardasil 9 ® (Merck, Sharp & Dome (Merck & Co.,
conferring protection against genital warts, which are most commonly caused by HPV-6
andWhitehouse
HPV-11. Station,
In 2007,NJ,a USA)) is a nonavalent
bivalent vaccine licensed
vaccine, Cervarix in 2014 that targets
® (GlaxoSmithKline, HPV-6, Bel-
Rixensart,
HPV-11, HPV-16, HPV-18, HPV-31, HPV-33, HPV-45, HPV-52 and
gium), was licensed, which targets HPV-16 and HPV-18. Gardasil 9® (Merck, HPV-58 [21,22]. These
Sharp &
three established vaccines utilise eukaryotic cells as producer cells. More recently, a bivalent
Dome (Merck & Co., Whitehouse Station, NJ, USA)) is a nonavalent vaccine licensed in
vaccine, Cecolin® (Xiamen Innovax Biotechnology, Xiamen, China), was developed, which
Diagnostics 2023, 13, 243 4 of 22

utilises Escherichia coli to produce HPV-16 and HPV-18 L1 VLPs [23]. Cecolin® was licensed
for use in China in 2020 and prequalified by the WHO in 2021. Finally, a recombinant
bivalent HPV vaccine (Shanghai Zerun Biotechnology, subsidiary of Walvax Biotechnology,
Shanghai, China) targeting HPV-16 and HPV-18 was also licensed for use in China in 2022
and prequalified by WHO in 2022 [24]. Table 1 summarises the characteristics of current
WHO-prequalified vaccines, however the HPV vaccine development market remains active,
and a quadrivalent vaccine, Cervavac, was recently launched in India [25].

Table 1. Characteristics of currently licensed prophylactic HPV vaccines.

Vaccine Brand Name Valency and VLP Types Manufacturer and Adjuvant Expression System
Licensure Date
Quadrivalent Amorphous aluminium Yeast
Gardasil® HPV-6, HPV-11, Merck & Co. 2006 hydroxyphosphate Saccharomyces cerevisiae
HPV-16, HPV-18 sulphate 225 µg expressing L1
AS04
0.5 mg aluminium Insect cell line infected with
Bivalent
Cervarix® HPV-16, HPV-18 GlaxoSmithKline 2007 hydroxide and 50 µg recombinant baculovirus
3-0-desacyl-4’ encoding L1
monophosphoryl lipid A
Nonavalent
HPV-6, HPV-11, HPV-16, Amorphous aluminium Yeast
Gardasil 9® HPV-18, HPV-31, Merck & Co. 2014 hydroxyphosphate Saccharomyces cerevisiae
HPV-33, HPV-45, sulphate 500 µg expressing L1
HPV-52, HPV-58
Bivalent Xiamen Innovax Aluminium
Cecolin® HPV-16, HPV-18 Biotechnology 2020 hydroxide 208 µg
Escherichia coli expressing L1
Shanghai Zerun
Walvax recombinant Bivalent Yeast
HPV vaccine HPV-16, HPV-18 Biotechnology (Subsidiary of Aluminium phosphate Pichia Pastoris expressing L1
Walvax Biotechnology) 2022

The vaccines have a similar mode of action based on VLPs, a recombinant, non-
infectious assembly of the L1 HPV capsid protein. VLPs are antigenically identical to
infection-causing HPV virions [26], such that exposure to VLPs induces a strong neutralis-
ing antibody response, which halts HPV uptake by the basal epithelial cells of the cervix.
This humoral response is responsible for the efficacy of the vaccine. The vaccine mode
of action also explains why the HPV vaccine is less effective in women with prior HPV
exposure, as HPV infection of the basal cells has already occurred [27,28]. Each vaccine
has subtype-specific VLPs, depending on their targets; however, they all confer a degree of
cross-protection against other, nonvaccine HPV subtypes [29]. It is on this basis that the
WHO considers all vaccines to be equally protective against cervical cancer [10].

4. Prophylactic HPV Vaccine Clinical Trials

Prior to licensure, all HPV vaccines underwent clinical trials to determine efficacy,
effectiveness and safety. A WHO convention in 2003 determined appropriate HPV vaccine
trial endpoints: it was agreed that ethical and time constraints could not allow for cervical
cancer to be an appropriate trial endpoint, given that participants under follow-up during
the trial period would receive treatment of any cervical precancerous lesions detected [30].
Agreed study endpoints included Grade 2 and above CIN (CIN2+), and HPV infection [30],
as these are sufficient to demonstrate vaccine efficacy at reducing persistent HPV infection
and cervical precancer. After licensure, multiple HPV vaccine trials were performed,
summarised in a systematic review published in 2018. This review included 26 randomised
control trials and concluded that the vaccine was highly efficacious at preventing cervical
precancer [31]. The key prelicensure trials are discussed below.

4.1. Clinical Trials in Younger Females

The phase 3 efficacy trials conducted for HPV vaccines all included younger women
aged 15 to 26. These trials were multinational and included thousands of participants, with
the trial design and conduct led by the respective manufacturers. The results from these
trials are summarised in Table 2.
Diagnostics 2023, 13, 243 5 of 22

4.1.1. The Quadrivalent HPV Vaccine—Gardasil®

The FUTURE I and II trials assessed the efficacy of the Gardasil® quadrivalent HPV vac-
cine, with results published in 2007 [32]. Over 12,000 female participants aged 15 to 26 were
randomised to receive either three doses of the quadrivalent vaccine or a placebo. After a
three-year follow-up period, vaccine efficacy against HPV-16- and HPV-18-associated high-
grade cervical disease was 98% in women without prior exposure to HPV-16 or HPV-18.
Vaccine efficacy in all participants, including those with prior HPV-16 or HPV-18 exposure,
was 44% [32].
A subset of European participants from the FUTURE II trial were followed up for four-
teen years, with no cases of HPV-16- or HPV-18-associated high-grade cervical dysplasia
noted in follow-up period (vaccine efficacy of 100%) [33]. Seropositivity for all four HPV
subtypes at the fourteen-year follow-up mark remained high at >90% [33].
A double-blinded randomised trial of the quadrivalent HPV vaccine in a Japanese
population of women aged 18 to 26 similarly found a high efficacy against vaccine-type
high-grade cervical disease [34].

4.1.2. The Bivalent HPV Vaccine—Cervarix®

The PATRICIA trial was the first to assess the efficacy of the Cervarix® bivalent HPV
vaccine [35,36]. Over 18,000 women aged 15 to 25 were recruited and randomised to receive
either three doses of the Cervarix® vaccine or the hepatitis A vaccine. After a three-year
follow-up period, vaccine efficacy against HPV-16 or HPV-18-associated high-grade CIN
was 92.9% [36]. A subgroup analysis showed that the efficacy against vaccine-type CIN3+
was as high as 100% in the HPV-naïve cohort [37].
The Costa Rican Vaccine Trial (CVT) was a second, large prelicensure trial investigating
the efficacy and safety of Cervarix® . After a four-year follow-up period, vaccine efficacy
was 89% against HPV-16- or HPV-18-associated CIN2+ [38]. A longer-term follow-up
at 11 years showed a vaccine efficacy of 100% against HPV-16- or HPV-18- associated
CIN2+ [39].
The Cervarix® vaccine was also studied in a population of >6000 Chinese women aged
18 to 25 showing a vaccine efficacy of 100% in HPV-naïve participants [40].

4.1.3. The Nonavalent HPV Vaccine—Gardasil 9®

The efficacy of the nonavalent Gardasil® 9 vaccine was assessed in a multinational
double-blind trial in women aged 16 to 25 [41]. Over 14,000 participants were recruited, and
unlike the other trials, the control group received the quadrivalent Gardasil® HPV vaccine.
Vaccine efficacy against high-grade cervical disease associated with HPV-31, HPV-33, HPV-
45, HPV-52 and HPV-58 (i.e., HPV subtypes not covered by the quadrivalent vaccine) was
97.1%; the number of cases per 10,000 person-years was 0.5 in the nonavalent group versus
18.1 in the quadrivalent group. The incidence of abnormalities associated with HPV-6,
HPV-11, HPV-16 and HPV-18 (i.e., HPV subtypes covered by the quadrivalent vaccine) was
comparable between both groups of participants. Furthermore, the immunogenicity of the
nonavalent vaccine with respect to HPV-6, HPV-11, HPV-16 and HPV-18 was comparable
to that of the quadrivalent vaccine [41], with antibody response persisting for up to five
years [42]. The authors concluded that the nonavalent vaccine could potentially prevent
more cervical cancer cases by providing a broader coverage with a sustained high efficacy
against all vaccine HPV subtypes.

4.1.4. The Bivalent Cecolin® Vaccine

The efficacy trial for the bivalent Cecolin® vaccine recruited over 7000 female par-
ticipants aged 18 to 45, in multiple centres in China between 2012 and 2013. The control
group received the hepatitis E vaccine. Vaccine efficacy against high-grade genital disease
and persistent infection associated with HPV-16 or HPV-18 were 100% and 97.3%, respec-
tively [43,44]. Participants were age-stratified into two groups: 18–26 and 27–45, allowing a
Diagnostics 2023, 13, 243 6 of 22

subgroup analysis. A phase 3 clinical trial of the Cecolin® vaccine is ongoing in Bangladesh
and Ghana, with results expected in 2023 (NCT04508309).

Table 2. Summary of prelicensure trials on HPV vaccine efficacy in younger females.

Trial Number of Participants Participant Ages Efficacy against Vaccine-Type CIN2+

Gardasil®
FUTURE I and II [33] NCT00092521
12,167 15–26 98%
and NCT00092534
Cervarix®
PATRICIA [37] NCT00122681 18,644 15–25 92.9%
CVT [39] NCT00128661 7466 15–25 89.5%
Gardasil 9®
NCT00543543 [42] 14,215 16–25 97.1%
Cecolin®
NCT01735006 [45] 3723 18–26 100%

4.2. Clinical Trials in Older Females

The quadrivalent Gardasil® vaccine and the bivalent Cervarix® vaccine have both
been trialled in older females, a group likely to have reduced efficacy since vaccine efficacy
declines with prior HPV exposure. The FUTURE III trial evaluated the efficacy of the
quadrivalent vaccine in over 3800 women aged 24 to 45. Vaccine efficacy against vaccine-
type CIN1+ was 88.7% in HPV-naïve women and 30.9% in all women [45,46]. Another
double-blinded trial of the quadrivalent vaccine in Chinese women aged 20 to 45 found
a high vaccine efficacy of 94% [47]. The VIVIANE trial evaluated the bivalent Cervarix®
vaccine’s efficacy in women aged > 25. Vaccine efficacy against combined endpoint of
vaccine-type 6-month persistent infection and CIN1+ was 90.5% in the per protocol group
and 86.5% in the total vaccinated cohort. Estimated vaccine efficacy against vaccine-type
CIN2+ was high but insignificant due to low numbers [48].
While these studies support the use of the HPV vaccine in older females, the effective-
ness of the vaccine in this group is less than in adolescents: because the incidence of HPV
infection declines with age (Figure 1), older females are less likely than adolescent females
to develop new HPV infection which reduces the cost-effectiveness of routine vaccination
in this group. Thus, in the UK, HPV vaccination of women >25 can only be obtained
privately [49], whereas the US recommends shared decision-making with clinicians for
women aged between 27 and 45 [50].

4.3. HPV Vaccine with Previous Known Infection

In many countries, there has been a move to HPV-based cervical screening, meaning
that many women will already be known to have had a previous HPV infection. It is
therefore important to define the efficacy of the HPV vaccine in this group. Most of the
HPV vaccine clinical trials included in the total vaccinated cohort participants who, at the
time of recruitment, were positive for HPV DNA or seropositive for HPV antibodies. Un-
surprisingly, these groups had lower vaccine efficacy compared to HPV-naïve participants.
Vaccine efficacy in seropositive, DNA-negative participants, i.e., those with previous but no
current HPV infection, was summarised in a meta-analysis which pooled data from trials
on the bivalent Cervarix® vaccine and the quadrivalent Gardasil® vaccine [51]. Against
CIN2+, the pooled HPV vaccine efficacy was 85%, and against persistent serotype-specific
HPV infection, the pooled vaccine efficacy was 78% (six months of persistent infection)
and 80% (twelve months of persistent infection) [51]. These findings support the use of the
vaccine in HPV-DNA-negative women, regardless of their serostatus.

4.4. HPV Vaccine in HIV Infection

People with HIV are known to have lower levels of immunity, which make them more
susceptible to persistent HPV infection. A few studies have investigated the efficacy and
Diagnostics 2023, 13, 243 7 of 22

safety of the HPV vaccine in this population, showing a 100% seroconversion rate following
vaccination with no adverse outcomes [52]. However, dedicated HPV vaccine efficacy data
are lacking in this population and require further assessment.

4.5. HPV Vaccination in Males

In males, HPV is associated with a range of anogenital and oropharyngeal diseases—over 90%
of anal cancers, over 70% of oropharyngeal cancers and up to 48% of penile cancers are
associated with HPV [53]. HPV vaccination of males therefore has the potential to reduce
HPV infection and associated lesions. A randomised controlled trial of over 4000 males aged
16 to 26 found a quadrivalent vaccine efficacy of 90.4% against vaccine-type anogenital
lesions and 85.6% against persistent vaccine-type HPV infections. Similar to women,
vaccine efficacy was reduced in participants with HPV infection at baseline [54]. The
long-term follow-up study from this trial was able to assess primary outcomes of genital
warts, vaccine-type external genital lesions and vaccine-type anal intraepithelial neoplasia
or anal cancer in men who have sex with men (MSM) [55]. Vaccine efficacy against vaccine-
type genital warts and external genital lesions was 89.9% and 90.8%, respectively, in the
HPV naïve group. In the intention-to-treat group, vaccine efficacy against vaccine-type
external genital lesions was 66.7% [56]. In MSM, vaccine efficacy against vaccine-type anal
intraepithelial neoplasia and anal cancer was 89.6% in the HPV naïve group and 50.3% in
the intention-to-treat group [56]. Studies have not yet reported on vaccine efficacy against
head and neck cancers and penile cancers.
Unlike the quadrivalent Gardasil® vaccine, the nonavalent Gardasil 9® vaccine did
not undergo clinical trials in men prior to licensure. Rather, immunogenicity studies were
done which showed that the nonavalent vaccine elicited immune responses similar to the
quadrivalent vaccine against HPV-6, HPV-11, HPV-16 and HPV-18 [57]. Based on this and
other safety data, Gardasil 9® has been licensed for use in men [58]. In the US, the FDA
approved its indicated use in the prevention of HPV-associated oropharyngeal and head
and neck cancers; a randomised controlled trial is underway to evaluate the efficacy of the
Gardasil 9® vaccine against persistent oral HPV infection [59].

4.6. Cross-Protection against Nonvaccine HPV Subtypes

The prelicensure HPV vaccine trials explored protection conferred by the vaccines
against nonvaccine subtypes, i.e., cross-protection, with all vaccines demonstrating partial
cross-protection against nonvaccine-type infection and disease. The FUTURE I and II trials
of the quadrivalent vaccine assessed cross-protection against ten other HPV subtypes—31,
33, 35, 39, 45, 51, 52, 56, 58 and 59. These showed some cross-protective effect against HPV
infection and low-grade CIN, most marked against HPV-31, but not against high-grade
CIN [29].
The PATRICIA and Costa Rica trials of Cervarix® also assessed the cross-protective
effects of the bivalent vaccine against nonvaccine-type persistent infection and CIN2+ [60].
A high vaccine efficacy was noted against infection and CIN2+ associated with HPV-31,
HPV-33 (both subtypes closely related to HPV-16), HPV-45 (closely related to HPV-18) and
HPV-51. Vaccine efficacy was higher in women who were HPV-naïve at baseline [60,61].
Long-term follow-up data from Cervarix® trials indicate cross-protective effect lasting at
least 11 years [62,63].

5. HPV Vaccine Safety

As with all vaccines, the safety of the HPV vaccine was evaluated in prelicensure
trials and continues to be evaluated in surveillance systems worldwide following licensure.
Data on HPV vaccine safety are robust and have consistently shown no concerns [64–67].
Injection site reactions such as pain, swelling and redness were the most commonly reported
adverse events following vaccine administration, with a slight increased frequency of
these reactions reported with the use of the bivalent Cervarix® and nonavalent Gardasil®
vaccines [64]. In vaccine clinical trials, the rates of systemic adverse events were similar
Diagnostics 2023, 13, 243 8 of 22

between vaccine and control groups; fever, nausea, headache and dizziness were the most
commonly reported systemic adverse events [64]. Following the recognition that syncope
could occur after vaccination, recommendations were made in the US for adolescents to be
seated during vaccination [68].
In vaccine clinical trials, there was no difference in rates of serious adverse events
between vaccine and control groups [64,67]. National surveillance data following the intro-
duction of the bivalent Cervarix® and quadrivalent Gardasil® vaccines in various countries
showed a low rate of serious adverse events [64]. Most of the available surveillance data
from the nonavalent vaccine are from the US, which have shown that the nonavalent
vaccine has a similar safety profile to the quadrivalent vaccine [68]. There have been no
reported deaths attributable to the HPV vaccine [64,68].
The HPV vaccine is not currently recommended in pregnancy, but safety data from
this group have been obtained from prelicensure trials, clinical trials and surveillance
systems where women were vaccinated during pregnancy or became pregnant shortly
after vaccination. None of these found any association between vaccine administration and
adverse pregnancy outcomes including spontaneous abortion, foetal loss and congenital
abnormalities [64]. Furthermore, the prelicensure trials found similar rates of pregnancy
between vaccinated and unvaccinated groups, and though there have been several case
reports linking the vaccine to primary ovarian insufficiency, the surveillance data to date
have been unable to establish this as a causal association [64].
Finally, the safety of the vaccine with regards to the development of autoimmune
disease, venous thromboembolism and neurological conditions has been studied in various
contexts, with no association found between the HPV vaccine and these conditions [64].
The evidence all points towards the safety of the vaccine, as has been supported by the
WHO [69], the Global Safety Vaccine Advisory Group [70] and various national and
international immunisation advisory committees.
Despite these robust safety data, concerns about vaccine safety have impacted vaccine
uptake in several countries. A notable example of this is Japan, who introduced HPV
vaccination into their routine national immunisation schedule in April 2013. Due to
physical symptoms including pain and motor impairment reported by vaccinated girls, the
vaccination programme was suspended ten weeks later in June 2013. The vaccine remained
available; however, its proactive recommendation was discontinued causing a reduction in
vaccine coverage from 70% to less than 1% [71]. A modelling study showed the effect of
this is an additional (projected) 25,000 preventable cervical cancer cases and 5000 cervical
cancer deaths in Japan [71]. Real-world data have shown the effect of this in 2020 has been
an increase in HPV-16/HPV-18 infection rates compared to the previous years that featured
vaccinated cohorts [72]. After a nine-year hiatus, the Japanese health ministry has reversed
its position on this and, as of April 2022, has restarted the active recommendation of the
vaccine to 12-to-16-year-old girls [73]. It is hoped that with increasing safety data available,
public confidence in the safety of the HPV vaccine will be strengthened.

6. Impact of HPV Vaccination on Populations

In the initial ten years following the HPV vaccine introduction, several population-
level studies assessed the real-world effectiveness of the vaccine on HPV-16/HPV-18 infec-
tion, anogenital warts and high-grade CIN. In 2019, findings from these were summarised
in a systematic review and meta-analysis [74]. Data from 65 studies in 14 countries were
included showing significant age-dependent reductions in HPV-16 and HPV-18 prevalence
(83% reduction in 13-to-19-year-old girls, and 66% reduction in 20-to-24-year-old women),
anogenital warts in both males and females and CIN2+ (51% reduction in 15-to-19-year-old
girls and 31% reduction in 20-to-24-year-old women) [74].
Ultimately, the aim of the HPV vaccine is to reduce the burden of HPV-associated
cancers, and with longer-term population data increasingly emerging, a few studies have
been able to report on this outcome. Sweden introduced the quadrivalent Gardasil® HPV
vaccine nationally in 2009, and was one of the first countries, in 2020, to report on cervical
 Diagnostics 2023, 13, 243 9 of 22

cancer outcomes following vaccine introduction. Their national data showed a remarkable
88% reduction in cervical cancer incidence in women who had been vaccinated prior to age
17, and a 53% reduction in cervical cancer incidence in women vaccinated between the age
of 17 and 30 [75].
In the UK, the bivalent vaccine was introduced in England in 2008, and data on vaccine
effectiveness against cervical cancer were published in 2021. Population data from England
showed an 87% reduction in cervical cancer incidence in women vaccinated at age 12 to
13, a 62% reduction in women vaccinated at age 14 to 16 and a 34% reduction in women
vaccinated at age 16 to 18 [76]. The authors estimated that there were 448 fewer 10
Diagnostics 2023, 13, x FOR PEER REVIEW than
of 24
expected cervical cancers and over 17,000 fewer than expected CIN3 among the vaccinated
cohort in England (Figure 3) [76].

B
Cumulative incidence rate per 100,000

Cumulative incidence rate per 100,000

Figure
Figure3.3.Cumulative
Cumulativeincidence
incidenceofofcervical
cervical cancer and CIN3
cancer and CIN3using
usingdata
datafrom
fromEngland
England showing
showing a a
reduced incidence of cervical cancer and CIN3 in vaccinated cohorts (reproduced with
reduced incidence of cervical cancer and CIN3 in vaccinated cohorts (reproduced with permission permission
from
fromFalcaro
Falcaroetetal.
al. [76]) (A), schematic
[76]) (A), schematicrepresentation
representation of birth
of birth cohorts
cohorts [76] *[76] * Vaccine
Vaccine coverages
coverages includein-
clude (where data are available) mop-up vaccinations (i.e. when females are vaccinated in a later
(where data are available) mop-up vaccinations (i.e. when females are vaccinated in a later year than
year than the one in which they were first offered vaccination [76] (B), Cumulative incidence rates
the one in which they were first offered vaccination [76] (B), Cumulative incidence rates of invasive
of invasive cervical cancer and CIN3 by birth cohort [76].
cervical cancer and CIN3 by birth cohort [76].

Another
Anothernational
nationalstudy
studyin inDenmark
Denmark published
published in in2021,
2021,where
wherethetheHPV
HPVvaccine
vaccine was
was
introduced
introducedinto
intothe
thechildhood
childhood vaccination programme in
vaccination programme in2009,
2009,reported
reporteda ahigh
high vaccine
vaccine
effectiveness
effectivenessagainst cervicalcancer.
against cervical cancer. The
The incidence
incidence rate rate
ratio ratio wasin0.14
was 0.14 in females
females vac-
vaccinated
cinated
under under
the agethe ageand
of 17, of 0.32
17, and 0.32 invaccinated
in females females vaccinated
between age between agewhen
17 and 20, 17 and 20, when
compared
to unvaccinated
compared females. Mirroring
to unvaccinated females. vaccine efficacy
Mirroring data,
vaccine the effectiveness
efficacy of the vaccine of
data, the effectiveness
was
the reduced
vaccine waswhen administered
reduced at an older age
when administered [77].
at an older age [77].

7. Number of Doses
HPV vaccines were initially licensed with a recommended three-dose schedule, and
the prelicensure trial protocols included three vaccine doses, which demonstrated a high
efficacy against vaccine-type CIN2+ and vaccine-type persistent HPV infection. This led
to a three-dose regimen being recommended by the WHO and national governing bodies.
 Diagnostics 2023, 13, 243 10 of 22

7. Number of Doses
HPV vaccines were initially licensed with a recommended three-dose schedule, and
the prelicensure trial protocols included three vaccine doses, which demonstrated a high
efficacy against vaccine-type CIN2+ and vaccine-type persistent HPV infection. This led to
a three-dose regimen being recommended by the WHO and national governing bodies.
The Costa Rica Vaccine trial group, who conducted a prelicensure trial for the Cervarix®
bivalent vaccine, carried out a post hoc analysis investigating the vaccine efficacy in women
who received less than three doses of the bivalent HPV vaccine. Interestingly, they found
that women who received less than three doses of the vaccine had a similar vaccine efficacy
against persistent HPV-16/HPV-18 infection, relative to the women who received the per-
protocol three doses; this protection lasted for up to ten years [78–80]. Although vaccine
efficacy was similar, a lower, albeit stable, antibody response was noticed in the group that
received a single dose of the vaccine [81].
These findings were of huge significance, as a reduced dosing schedule has important
public health implications, easing both financial and logistical barriers to the introduction of
HPV vaccination programmes. A single-dosing schedule would significantly reduce supply
and storage issues and increase compliance. Even with a modest assumed single-dose
vaccine efficacy of 80%, there would be (projected) millions of averted cases of cervical
cancer [82]. Thus, several trials have followed on from the Costa Rica Vaccine trial to
formally investigate HPV vaccine efficacy using two-dose and one-dose schedules.
A group In India, the Indian HPV vaccine study group, designed a randomised
trial to compare vaccine efficacy between one-, two- and three-dosing schedules. Trial
plans were interrupted in 2010 when the Indian government suspended HPV vaccina-
tion. Consequently, the design was changed to an observational cohort study consisting
of >12,000 participants aged 10 to 18. There were over 4000 participants in each dose
category [83]. Early data showed that although a single dose resulted in lower antibody
titres compared to two or three doses, immune response was sustained and stable over a
four-year period [84]. Ten-year follow-up data from the group showed that the vaccine
Diagnostics 2023, 13, x FOR PEER REVIEW 12 of 24
efficacy against HPV-16/HPV-18 infection was similar in participants receiving one, two or
three doses at 95%, 93% and 93%, respectively (Figure 4) [85].
Incidence of HPV 31, 33, and 45 (%)
Incidence of HPV 16 and 18 (%)

Time since recruitment (years) Time since recruitment (years)

Figure
Figure 4.
4. Incidence of HPV-16
Incidence of HPV-16andandHPV-18
HPV-18 (A)
(A) and
and HPV-31,
HPV-31, HPV-33
HPV-33 and and HPV-45
HPV-45 (B), one,
(B), after aftertwo,
one,
two, three or no doses of the quadrivalent vaccine, showing similar HPV infection incidence in the
three or no doses of the quadrivalent vaccine, showing similar HPV infection incidence in the one-,
one-, two- and three-dose cohorts (reproduced with permission from Basu et al. [84]).
two- and three-dose cohorts (reproduced with permission from Basu et al. [84]).

8. Prophylactic HPVthe
Another study, Vaccine as Adjunct
ESCUDDO Treatment
trial, is forrandomised
an ongoing CIN double-blind design
Even following
comparing the vaccinetreatment
efficacy offor CIN,
a one- women
versus remain schedule
two-dosing susceptible to bivalent
of the reinfection
andwith
the
nonavalent
HPV HPV
and have vaccines
been shown[86]. Over
to be 20,000 participants
at increased were recruited
risk of developing agedCIN
recurrent 12 to 16 HPV-
and with
the primary
associated objectives
cancers of comparing
[94,95]. HPV-16/HPV-18
There is growing evidenceinfection
from a rates betweenthat
few studies the the
one-dose
use of
prophylactic HPV vaccines in women having a treatment for CIN may reduce the risk of
recurrent disease. The SPERANZA study was the first prospective study to assess the ef-
fectiveness of the HPV vaccine for women undergoing surgical management of high-
grade cervical disease. Results showed an 81% reduced risk of HPV-associated high-grade
recurrent disease in vaccinated women [96]. Several other studies followed, including the
Diagnostics 2023, 13, 243 11 of 22

and two-dose groups and estimating vaccine efficacy for a one-dose regimen [86]. For
ethical reasons, a placebo arm was not included, and instead, a survey of unvaccinated
participants was used to estimate vaccine efficacy. Results from this trial are expected
in 2024.
Similar randomised controlled trials are ongoing in various African countries to
investigate the efficacy of a single-dosing vaccine schedule including the DoRIS trial in
Tanzania (NCT02834637), the HANDS trial in Gambia (NCT03832049) and the KEN SHE
trial in Kenya (NCT03675256) [87]. Preliminary results from the KEN SHE trial showed the
high vaccine efficacy of a single dose of the bivalent (97.5%) and nonavalent vaccines (97.5%)
at preventing persistent HPV-16/18 infection after eighteen months [88]. Observational
studies in various countries have additionally shown the high efficacy of single-dose HPV
vaccination schedules [89–91]. Furthermore, data from the Costa Rica vaccine trial group
and the Indian HPV vaccine study group will continue to provide long-term outcomes.
With the evidence pointing towards the high efficacy of a single dose of the HPV
vaccine, the Joint Committee on Vaccination and Immunisation (JCVI) in the UK has recently
recommended a single HPV vaccine dose in their routine adolescent and MSM vaccination
programmes [92]. The WHO Strategic Advisory Group of Experts on Immunisation (SAGE)
also met in April 2022 to review the evidence on single-HPV-vaccine dose efficacy. The
outcome from this was a recommendation for single-dosing schedules for some low-risk
groups; it is likely the WHO will update their recommendation following a review of
this [93]. In the Unites States, the Advisory Committee on Immunization Practices (ACIP)
are yet to change from the current recommended two-dose schedule [50].

8. Prophylactic HPV Vaccine as Adjunct Treatment for CIN

Even following treatment for CIN, women remain susceptible to reinfection with
HPV and have been shown to be at increased risk of developing recurrent CIN and HPV-
associated cancers [94,95]. There is growing evidence from a few studies that the use of
prophylactic HPV vaccines in women having a treatment for CIN may reduce the risk
of recurrent disease. The SPERANZA study was the first prospective study to assess the
effectiveness of the HPV vaccine for women undergoing surgical management of high-
grade cervical disease. Results showed an 81% reduced risk of HPV-associated high-grade
recurrent disease in vaccinated women [96]. Several other studies followed, including the
VENUS study, another observational study which compared outcomes between vaccinated
and unvaccinated women who underwent conization for CIN2-3. Results showed a 59%
reduction in persistent/recurrent CIN2-3 in vaccinated women [97]. Two randomised
control trials also showed reduced CIN recurrence rates in vaccinated women [98,99].
A systematic review was recently published, which evaluated 22 studies reporting
on HPV infection and the risk of HPV-associated disease following surgical management
of HPV-associated genital disease in vaccinated individuals [100]. Although authors con-
cluded that there might be a reduction in the risk of recurrent high-grade cervical disease
with prophylactic HPV vaccination use, they highlighted the requirement for further ade-
quately powered randomised control trials, to establish vaccine use in this setting [100]. The
NOVEL trial (NCT03979014) is an ongoing randomised control trial comparing outcomes
between a group of women receiving local treatment plus vaccination with the nonavalent
HPV vaccine, and a group receiving local treatment only. It is anticipated that results
from this trial will give insight into the effectiveness of the HPV vaccine as an adjunc-
tive treatment in women undergoing surgical excision of HPV-associated premalignant
cervical disease.

9. HPV Vaccination Implementation, Programmes and Coverage

Since HPV vaccines became available in 2006, countries have progressively introduced
the vaccine into their national immunisation schedules. The WHO initially recommended
HPV vaccines in 2009, using a three-dosing schedule to girls aged 9–14 years [101]. In 2014,
this recommendation changed to a two-dosing schedule [102] and further evolved in 2017
Diagnostics 2023, 13, 243 12 of 22

to recommend vaccination of multiage cohorts [69], although this was temporarily paused
in 2019 following vaccine supply issues.
As of March 2022, 60% of WHO member states have introduced the HPV vaccine into
their national immunisation schedule (Figure 5). The majority of these are high-income
and upper-middle-income countries [24], and some of the most populous nations are yet to
introduce HPV vaccination into their immunisation schedules. The consequence of this is
that global coverage of the HPV vaccine remains low at 12% for two doses in females, as of
2020 [103].
Strategies to deliver the HPV vaccine include school-based programmes, healthcare
facility-based programmes, and outreach/campaign programmes. School-based HPV
vaccination programmes have been successful at achieving a high HPV vaccine coverage
as demonstrated in several countries. Australia was one of the first countries to imple-
ment a national HPV vaccination programme in 2007. This was a government-funded,
school-based immunisation programme, offering three doses of the quadrivalent vaccine
to 12-to-13-year-old girls. In 2013, the programme was expanded to include boys, and in
2018, changed to two doses of the nonavalent vaccine [104]. Since the vaccine introduction,
Australia has maintained a high vaccination coverage, and if this is maintained, is projected
to eliminate cervical cancer (age standardised incidence of <4 new cases per 100,000 women)
by 2028 [105].
The UK similarly introduced a government-funded school programme aimed at
12-to-13-year-old girls in 2008. The triple dosing schedule was changed to a two-dose sched-
ule in 2014, and the vaccination of 12-to-13-year-old boys was included in 2019 [92]. Prior
to the COVID-19 pandemic, the HPV vaccine coverage was high at >80%; the COVID-19
pandemic disrupted school-based vaccinations as school attendance dropped, and although
improving, the vaccine coverage is not yet back to prepandemic levels [106].
In the United States, routine HPV vaccination for girls aged 11 to 12 was recommended
as a three-dosing schedule in 2006. This also included catch-up vaccination for women up
to the age of 26. In 2011, routine vaccination was recommended for males aged 11 to 12. In
2016, the standard dosing schedule was reduced to two doses [107]. HPV vaccination in
the United States is delivered mainly in primary care and healthcare facilities; Although a
coverage of 75% has been attained [108], there are significant variations in vaccine coverage
dependent on race, ethnicity and socioeconomic status within the United States [109].
Unsurprisingly, many LLMICs have not been able to introduce the HPV vaccine into
national immunisation schedules, due to financial and infrastructural constraints. As
of March 2022, 114 out of 145 (78.6%) high-income and upper-middle-income countries
have introduced HPV vaccination, whereas only 20 out of 80 (37.5%) low-income and
low-middle-income countries have introduced HPV vaccinations nationally [110]. Many
of these countries consequently have a low HPV vaccination coverage. In these countries
where engagement with healthcare services is often minimal, school-based vaccination
programmes would likely achieve the highest levels of coverage. Unfortunately, this
approach is unsustainable due to funding issues, and the majority of HPV vaccine delivery
has been via campaign approaches [111]. A notable exception to this is Rwanda, an LLMIC
which has been able to introduce a successful national HPV vaccination programme.
Rwanda was the first African country to introduce a national HPV vaccination programme
in 2011, which was via a school-based approach financially supported by Merck. They have
consequently been able to attain a high vaccine coverage of over 90% [112,113].
In Asia, several countries have been able to add HPV vaccination to their national
programmes, such as Thailand, Sri Lanka, Bhutan and the Maldives [25]. In China and
India, the HPV vaccine is licensed and available, and there are plans to introduce the
vaccine to routine national immunisation programmes from 2024 onwards [24].
As of 2022, gender-neutral HPV vaccination schedules are present in 39 WHO member
states, and many high-income countries have shifted/are shifting into an era of equity of
access to HPV vaccination for all genders [110,114]. Due to the HPV vaccine shortage in
recent years, the WHO has not yet endorsed the vaccination of males and have instead
 Diagnostics 2023, 13, 243 13 of 22

Diagnostics 2023, 13, x FOR PEER REVIEW 14 of 24

recommended that the vaccination of boys be suspended temporarily to relieve supply
constraints [115]. Opinions on this are mixed, where on the one hand, the benefit of male
vaccination is evident in the reduction of HPV infection and its associated sequelae. On the
the other hand, however, the health benefit of vaccinating more girls in LLMICs, where
other hand, however, the health benefit of vaccinating more girls in LLMICs, where rates of
rates of cervical cancer are much higher and screening measures less well established, is
cervical cancer are much higher and screening measures less well established, is just as, if
just
notas, if not
more, more, impactful.
impactful.

Figure
Figure5.5.WHO
WHOmember
member states
states with HPV vaccination
with HPV vaccinationininnational
nationalimmunisation
immunisation schedule.
schedule. (Repro-
(Repro-
duced with permission from Bruni et al. [111]).
duced with permission from Bruni et al. [111]).

10.Barriers
10. BarrierstotoHPV
HPVVaccine
Vaccine Uptake
Uptake
Theimpact
The impactof
ofthe
theHPV
HPV vaccine
vaccine on
on cervical
cervicalcancer
cancerincidence
incidencecan only
can bebe
only realised
realisedwith
with
a high vaccine coverage, and several barriers continue to hinder this. Unfortunately,
a high vaccine coverage, and several barriers continue to hinder this. Unfortunately, the the
countrieswith
countries withthe
thehighest
highest cervical
cervical cancer
cancer burden
burdenandandtherefore
thereforeininmost
most need
needof of
thethe
HPVHPV
vaccine face the greatest barriers. Addressing these barriers are key to achieving the full
vaccine face the greatest barriers. Addressing these barriers are key to achieving the full
benefit of the vaccine.
benefit of the vaccine.
10.1. Cost
Vaccine cost is a significant barrier, especially in LLMICs where the introduction of
national HPV vaccination programmes is not financially feasible without external support.
Gavi, the vaccine alliance, is a global public–private partnership which works with manu-
facturers to reduce the cost of vaccines to burdened countries, particularly LLMICs. They
introduced a programme in 2012 to enable Gavi-eligible countries to introduce HPV vacci-
nation programmes nationally at a negotiated cost of <$5 per dose, versus the usual >USD
100 per dose [116]. There were two ways of accessing Gavi’s support for national vaccine
introduction: countries either needed to have experience in the delivery of a multidose
adolescent vaccination programme, or they first had to demonstrate their readiness to
deliver national HPV vaccination via a two-year demonstration project [116,117]. This
unfortunately left very few countries eligible for the introduction of a national HPV vacci-
nation programme, until at least 2015, when the two-year demonstration project would
have been complete. In this period, the national vaccination introductions that occurred in
LLMICs were funded by donations from pharmaceutical companies or nongovernmental
organisation (NGO) support [116]. Gavi changed its policy in 2016, allowing eligible coun-
tries to apply directly for a national HPV vaccination introduction, but shortly after this, a
worldwide vaccine supply issue ensued [118].
Diagnostics 2023, 13, 243 14 of 22

10.2. HPV Vaccine Shortage

Since 2018, there has been a worldwide shortage of HPV vaccines resulting in sig-
nificant supply constraints. This resulted in adjustments to planned vaccine introduction
programmes, which particularly affected LLMICs. The shortages also led WHO’s SAGE
to suspend recommendations to vaccinate males and multiage cohorts, in order to reduce
the impact of the vaccine shortage [24]. These adjustment and suspensions will likely
affect LLMICs for years to come. As previously highlighted, this has also brought into
moral question the addition of males to HPV vaccination programmes, which has been
done successfully in several high-income countries. In 2022, the WHO has prequalified
two additional bivalent vaccines, Innovax’s Cecolin® vaccine and Walvax Biotechnology’s
vaccine, and it is anticipated that this, alongside a ramp-up of production of currently
licenced vaccines, will help reverse vaccine shortages by 2023 [24,118].

10.3. Cold-Chain Requirement

Another huge barrier to HPV vaccination which considerably affects LLMICs is the
requirement for cold-chain preservation for current HPV vaccines, which adds to already
high costs. One way to address this is via lyophilization, which would dehydrate vaccine
components and allow transfer of a frozen powder form at higher temperatures [119]. Alter-
natively, heat-stable capsomer preparations would permit more fluctuation in temperature
and therefore greatly reduce costs [53]. Unfortunately, neither one of these preparations are
available at present.

10.4. Adolescent Age Group

The HPV vaccine is targeted at adolescent/school-age children, who are a harder group
to reach compared to the age group targeted by childhood immunisation programmes.
The use of school-based vaccination programmes helps to circumvent this; however, many
LLMICs do not have funded school health programmes, which require additional costs and
manpower [111]. Furthermore, with school dropout rates higher in LLMICs [111], many
adolescents could get missed from school-based programmes. Adding HPV vaccination
to childhood immunisation programmes and/or coadministration with other vaccines
are proposed solutions to this barrier [120]. Several studies have already shown that the
coadministration of the HPV vaccine with other vaccines is safe and immunogenic [121]
and a study is to begin shortly, investigating the immunogenicity of Gardasil 9® in children
aged 4 to 8 years (NCT05329961).

10.5. COVID-19 Pandemic

Globally, the COVID-19 pandemic has affected existing HPV vaccination programmes
and halted the introduction of new programmes via the closure of schools and suspension
of routine immunisation programmes. This has affected other vaccination programmes,
and many are still recovering from the impact of the pandemic [120].

10.6. Vaccine Hesitancy

Vaccine hesitancy has a huge impact on HPV vaccine uptake globally. Misinformation
on safety concerns about the vaccine, and an unfounded association of HPV vaccine use
with sexual promiscuity are common drivers behind vaccine hesitancy [120]. A combination
of culturally sensitive education and government-driven health policies can help improve
public confidence and vaccine acceptance.

11. Therapeutic HPV Vaccines

Despite the high efficacy of prophylactic HPV vaccines, worldwide prevalence of
high-risk HPV infection remains high, mainly due to the low global vaccine uptake and
pre-existing HPV infection. This means the elimination of HPV infections and associated
diseases could take decades still. Due to their mechanism of action, by inducing a humoral
response to prevent an initial HPV infection, prophylactic HPV vaccines cannot have a reli-
Diagnostics 2023, 13, 243 15 of 22

able therapeutic effect [122]. This has led to a huge research effort towards the development
of therapeutic HPV vaccines. These vaccines work by stimulating cell-mediated immunity,
versus humoral-mediated immunity, against existing HPV infections and lesions. Many
of these vaccines target the E6 and E7 oncoproteins, which are continuously expressed
in premalignant and invasive lesions and are essential for cell-cycle arrest and the onset
and progression of malignancy [123]. Vector types for therapeutic vaccine development
have included DNA/RNA-based, peptide-based, protein-based and bacterial and viral
vectors [122].
There are no licensed therapeutic vaccines yet, although several have undergone phase
2 and 3 clinical trials for use in the treatment of CIN and cervical cancer. VGX-3100 is one of
such, a DNA-based therapeutic vaccine targeting the E6 and E7 proteins of HPV-16 and -18.
Results from a phase 2 clinical trial showed histopathological regression from CIN2/3
to CIN 1 in 49% of vaccinated participants at six months [124]. None of the participants
who regressed at six months had high-grade cytology findings eighteen months following
vaccination, and 91% had no detectable HPV-16/18 infection [125]. The VGX-3100 vaccine
is currently in phase 3 clinical trials (NCT03185013 and NCT03721978). Bacterial vector
therapeutic vaccines such as the lactobacilli-based IGMKK16E7 [126] and the Listeria-based
ADXS11-001 [127] are in late clinical trial phases, having shown similar promising results
in earlier phase trials. Of particular note is the ADXS11-001 vaccine, which showed a
12-month survival of 38% when used in the treatment of advanced cervical cancer; this is
significantly higher than historical survival of 25% [127].
In trial settings, therapeutic HPV vaccines have also been combined with other anti-
cancer agents, such as antibodies against programmed death-ligand 1 (PD-L1) and pro-
grammed death-1 receptor (PD-1), in the treatment of advanced and recurrent cervical
cancer. PD-L1 is an immune checkpoint inhibitor peptide which binds to its receptor PD-1.
PD-1 and PD-L1 are expressed by many tumour cells, promoting immune evasion, and they
are thus important immunotherapy targets [128]. A phase 2 trial of an HPV-16 peptide vac-
cine (ISA101) combined with nivolumab, a PD-1 antibody, have shown encouraging results,
with increased immune-mediated tumour suppression [129]. Other similar combinations
have also shown promising results [130,131].
Therapeutic vaccines have shown moderate effectiveness against CIN and HPV-
associated cancers, but this has been less than anticipated, especially given the high
effectiveness of the prophylactic vaccine [132]. One proposed mechanism for increas-
ing effectiveness is by broadening coverage to encompass antigens other than E6 and
E7. E1, for example, is increasingly implicated in carcinogenesis. To explore this, two
therapeutic vaccines ChadOx1-HPV and MVA-HPV, have been developed by Vaccitech
Ltd. using a viral vector. In addition to E6 and E7, these vaccines target E1, E2, E4 and
E5 from five high-risk HPV subtypes [133]. Researchers hope that by targeting additional
oncoproteins, including more HPV subtypes and the use of a viral vector, these vaccines,
which are currently in a clinical trial (NCT04607850), will achieve a higher clinical efficacy
than other developed therapeutic vaccines.

12. Conclusions
We are now 16 years following the licensure of the first prophylactic HPV vaccine, and
the efficacy, effectiveness and safety of the vaccine is no longer in question. The main factor
limiting the vaccine’s impact is a deficient population coverage [134]. The addition of HPV
vaccination to infant vaccination programmes has been widely suggested as one way of
addressing this, given the historic success of paediatric immunisation programmes [135].
This would of course require further studies to determine the appropriate dosing and safety
of the vaccine in a paediatric population, but may indeed help increase vaccine coverage,
particularly in areas with limited resources.
Another interesting concept called FASTER suggests combining HPV vaccination with
HPV-based screening in women aged up to 50 [136]. Using this model, women who test
negative for HPV DNA can expect to benefit from a high vaccine efficacy, as observed in
Diagnostics 2023, 13, 243 16 of 22

the per-protocol HPV-naïve cohorts in the vaccine trials. Women who are HPV-positive will
undergo further triage or screen-and-treat protocols [136]. While this approach will have a
high acceptance rate among patients, infrastructural constraints may make it challenging
to introduce [137].
Equity of access to the HPV vaccine, particularly in LLMICs, is a prerequisite for
advancing sustainable HPV vaccination globally. Affordability, political buy-in and ad-
dressing cold-chain challenges are all ways to achieve this. The local development of
biosimilar vaccines, such as Cecolin® , is already helping to drive vaccine costs down and
increase availability. In the long term, the development of additional cheaper vaccines with
less cold-chain dependence will increase HPV vaccine coverage and success. Furthermore,
the gradual endorsement of single-dosing schedules will further reduce costs and improve
full-dose coverage globally.
From a racial and ethnic perspective, there remain concerns regarding vaccine equity
given ethnic and racial variations in HPV genotype prevalence, which may limit the
effectiveness of the vaccine in certain nonwhite populations [138]. The complexity and cost
of including more subtype VLPs would make addressing this concern challenging using
the current vaccine instrument, and an alternative approach could be to identify a single
antigenic target common to all HPV subtypes [134].
Cervical screening of vaccinated women is still recommended, as there remains the po-
tential for disease caused by nonvaccine oncogenic HPV subtypes. Where it was previously
theorised that vaccination against the common oncogenic HPV subtypes would result in
an increase in the prevalence of the less common, nonvaccine oncogenic subtypes, early
studies indicated that there was no evidence of “type replacement”, i.e., the replacement of
the common oncogenic HPV subtypes with the less common ones [139]. Due to the reduced
prevalence of CIN2+ in vaccinated women, however, cervical screening recommendations
may need to be altered in the long term as vaccine coverage increases, to achieve maximal
cost-effectiveness [134].
The comprehensive approach to cervical cancer control consists of a triad of primary,
secondary and tertiary preventative measures. With the highly efficacious prophylactic
vaccine, existing cervical screening measures and an anticipated effective therapeutic
vaccine, alongside established treatment methods, achieving cervical cancer elimination is
within reach. A focus on increasing the coverage and uptake of the HPV vaccine globally
will certainly accelerate the attainment of this goal.

Author Contributions: Conceptualization, A.O.; writing—original draft preparation, O.I.; writing—

review and editing, A.O. All authors have read and agreed to the published version of the manuscript.
Funding: This research received no external funding.
Institutional Review Board Statement: Not applicable.
Informed Consent Statement: Not applicable.
Data Availability Statement: Not applicable.
Conflicts of Interest: The authors declare no conflict of interest.

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