Environmental Science and Pollution Research (2021) 28:47752–47772

https://doi.org/10.1007/s11356-021-15441-w

REVIEW ARTICLE

Physiopathology and effectiveness of therapeutic vaccines

against human papillomavirus
Noor Ayesha 1 & Sara Aboulaghras 2 & Muhammad Jahangeer 3 & Areej Riasat 3 & Rehana Ramzan 3 & Rameen Fatima 1 &
Muhammad Akram 4 & Abdelaali Balahbib 5 & Abdelhakim Bouyahya 6 & Ekaterina Sepiashvili 7 & Gokhan Zengin 8 &
Mohammad Ali Shariati 7

Received: 21 May 2021 / Accepted: 9 July 2021 / Published online: 21 July 2021
# The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature 2021

Abstract
Human papillomavirus (HPV) is a well-known sexually transmitted disorder globally. Human papillomavirus (HPV) is the 3rd
most common cancer that causes cervical carcinoma, and globally it accounts for 275,000 deaths every year. The load of HPV-
associated abrasions can be lessened through vaccination. At present, three forms of prophylactic vaccines, Cervarix, Gadrasil,
and Gardasil 9, are commercially accessible but all these prophylactic vaccines have not the ability to manage and control
developed abrasions or infections. Therefore, a considerable amount of the population is not secured from HPV infectivity.
Consequently, the development of therapeutic HPV vaccines is a crucial requirement of this era, for the treatment of persisting
infections, and to stop the progression of HPV-associated cancers. Therapeutic vaccines are a developing trial approach. Because
of the constitutive expression of E6 and E7 early genes in cancerous and pre-cancerous tissues, and their involvement in
disturbance of the cell cycle, these are best targets for this therapeutic vaccine treatment. For the synthesis and development of
therapeutic vaccines, various approaches have been examined comprising cell-based vaccines, peptide/protein-based vaccines,
nucleic acid–based vaccines, and live-vector vaccines all proceeding towards clinical trials. This review emphasizes the devel-
opment, progress, current status, and future perspective of several vaccines for the cure of HPV-related abrasions and cancers.
This review also provides an insight to assess the effectiveness, safety, efficacy, and immunogenicity of therapeutic vaccines in
the cure of patients infected with HPV-associated cervical cancer.

Keywords Papillomavirus . Pathogenesis . HLA polymorphism . Cervical cancer . Vaccines

Responsible Editor: Lotfi Aleya

* Abdelhakim Bouyahya 5
Laboratory of Zoology and General Biology, Faculty of Sciences,
[email protected] Mohammed V University in Rabat, Rabat, Morocco
* Gokhan Zengin
6
[email protected] Laboratory of Human Pathologies Biology, Department of Biology,
Faculty of Sciences, And Genomic Center of Human Pathologies,
Faculty of Medicine and Pharmacy, Mohammed V University in
1
Department of Biochemistry, University of Agriculture Faisalabad, Rabat, Rabat, Morocco
Faisalabad, Pakistan
2 7
Physiology and Physiopathology Team, Department of Biology, K.G. Razumovsky Moscow State University of Technologies and
Mohammed V University of Rabat, Rabat, Morocco Management (the First Cossack University), Moscow, Russian
3
Department of Biochemistry, Government College University Federation
Faisalabad, Faisalabad, Pakistan
8
4
Department of Eastern Medicine, Government College University Physiology and Biochemistry Laboratory, Department of Biology,
Faisalabad, Faisalabad, Pakistan Selcuk University, Campus, Konya, Turkey
Environ Sci Pollut Res (2021) 28:47752–47772 47753

Introduction accelerate cellular immune response leading to the removal of

infected and malignant cells that express viral proteins
Cancer is the main cause of death worldwide (Chabeda et al. (Vonsky et al. 2019). Research is therefore focused on discov-
2018) and cervical cancer is the 3rd most widely known can- ering substitutive non-invasive curative strategies for the treat-
cer (Mousavi et al. 2020). Human papillomavirus (HPV) is a ment of HPV-associated cervical infection and dysplasia
recognized causative factor of cervical cancer, the 4th well- (Barra et al. 2020).
known female cancer globally. Human papillomavirus is a The development of therapeutic vaccines emphasizes the
typical well known sexually transmitted disorder globally efficacy of precise immunological responses against antigens
(Harper and DeMars 2017). HPV is a small double-stranded to eradicate the developed disease or to ward off the patient
DNA virus, having a genome of nearly 8kbp that encodes for from being reinfected or to neutralize consequent infections
six non-structural proteins (E1, E2, E4, E5, E6, and E7) and a by the same virus. Due to this feature, therapeutic vaccines
major and a minor structural protein (L1 and L2). Genital differ considerably from the existing prophylactic vaccines
intraepithelial neoplasia can also be caused by HPV infection (Gonçalves et al. 2019). Therapeutic vaccination could be
or abrasion, which often proceed towards cancer (Mousavi one of the most efficacious cures for HPV-related cancer.
et al. 2020). Human papillomavirus is accountable for causing The first victory of therapeutic anticancer vaccines has been
93% of the anus, 63% of the oropharynx, 51% of the vulva, attained particularly in the cure of precancerous disorders that
40% of the vagina, and 40% of the penis, and all cases of are caused by infection with HPV types 16 and 18 (Vonsky
cervical cancers (Panahi et al. 2020). et al. 2019). The main aim of this descriptive review is to
Propagation of infected cells is thought to be responsible provide an insight into the function of therapeutic vaccines
for HPV abrasion. All sexually active people are expected to in the cure of pre-invasive abrasions and cervical infections
develop HPV at some stage in their lifetime because it is the caused by HPV. However, this requires huge attempts to cre-
typical sexually transmitted disease (H. J. Kim and Kim ate and launch therapeutic vaccines against HPV and HPV-
2017). A total of 527,624 females are identified with cervical related neoplasia.
cancer globally and 265,672 females are directed towards
death from this disease yearly (Bruni et al. 2016). It is assumed
that 275,000 people die from cervical cancer and new 530,000 Types of HPV
cases of HPV occur every year globally, thus making it a big
problem worldwide and causing loss of life, especially in de- So far, more than 200 various forms of HPV have been re-
veloping countries (Liu et al. 2019). Various investigations ported, almost one-third of that infect epithelial cell lining the
have revealed that genetic factors and lifestyle aspects can genital tract. Depending on their ability to cause malignancy,
considerably increase the chance of acquiring continued the types of HPV that infect the genital tract are categorized as
HPV infection. For example, several researchers have discov- either high-risk or low-risk [12, 13]. HPV forms 6 and 11 have
ered that both smoking and alcohol can be crucial risk factors very little oncogenes capacity and are hardly associated with
for long-term oral and genital HPV abrasion. It has been sug- cancer. These kinds of HPV infection can trigger the produc-
gested that the carcinogens in cigarette smoke raise viral load tion of low-grade cervical cells or benign anomalies, genital
as well as increase the probability of causing cancerous trans- warts, and laryngeal papilloma (Valentino and Poronsky
formation of epithelial cells upon infection of these cells with 2016). HPV types 6 and 11 have been found in 99% of genital
HPV. wart infections and are categorized as low-risk (Mousavi et al.
The prevalence of HPV-related diseases can be decreased 2020), whereas 70% of cervical cancers have been described
through vaccination (Bogani et al. 2018). Preliminary preven- to be not with high-risk categories, such as 16, 18, 33, and 45
tion through vaccination is efficacious in controlling cervical (Landy et al. 2018). The subtypes of HPV, i.e., 16, 18, 31, 33,
cancer. For control and cure of HPV abrasions, several forms 35, 39, 45, 51, 52, 56, 58, 59, 68, 69, 73, and 82, are taken into
of vaccines have been developed. In the management and consideration as high risk. These subtypes can cause several
prevention of about 3 million deaths yearly, prophylactic oropharyngeal, anal, vulvar, vaginal, and penile cancers
and therapeutic vaccines perform a vital function. Cervarix, (Valentino and Poronsky 2016).
Gardasil, and Gardasil 9, three prophylactic vaccines, were
approved in 2006, 2007, and 2014, correspondingly
(Mousavi et al. 2020). However, all these prophylactic HPV Pathogenesis of human papillomavirus
vaccines do not have a curative effect; i.e., before vaccination,
these vaccines do not control the growth of neoplasia in all HPV is a double-stranded non-enveloped circular DNA virus,
those persons affected with HPV. Furthermore, these prophy- having a genome of ~8 kb in size, consisting of three parts: 6
lactic vaccines are only targeted at the production point of early genes (E1, E2, E4, E5, E6, and E7) encoding open read-
virus-neutralizing antibodies. Therapeutic vaccines, however, ing frame (ORF), open reading frame (ORF) of 2 late genes
47754 Environ Sci Pollut Res (2021) 28:47752–47772

(major L1 and minor L2 capsid proteins), and long control by protein E6. The protein E6 further triggers telomerase ac-
region (LCR). The icosahedral capsid of the HPV virus is tivity which leads to prolonged cell life. Tumor repressor ret-
comprised of seventy-two L1 pentamers (total360) accompa- inoblastoma protein (pRb) is destroyed by E7 protein after
nied by varying numbers of L2 submerged within the surface targeting it, and as a result, genomic replication of host cell
of the capsid (Liu et al. 2019). is triggered when the cell life cycle is shifted to the S-phase
Although E1 is a replication factor, E2 is a transcription (Fig. 1). The proteins E6 and E7 are responsible for disturbing
manager of all HPV viral proteins, able to control DNA rep- the regulation of the cell cycle and stimulate the end of ruing
lication and RNA transcription of the virus. E4 governs the life of the host cell, preceding the instability of the genome
cytoskeleton structure of epithelial cells infected with HPV. and ultimately cancer (Chabeda et al. 2018).
E5, E6, and E7 facilitate and help in cellular transformation.
E6 and E7 are particularly significant, as they are oncoproteins
that suppress tumor repressors p53 and pRb, correspondingly, Genetic polymorphism and HPV infection
thus inhibiting the stimulation of apoptotic pathways.
Furthermore, E6 and E7 promote cell propagation, eventually HLA-G polymorphism and HPV infection
leading to the development of HPV-related malignancies.
During the expression of HPV-related cervical cancer, incor- Human papillomavirus (HPV) infections are very common in
poration of the virus into the genome of host cells usually the world, and they are the main causative agents of CIN and
results in the constitutive upregulation of oncogenes E6 and cancer [18, 19]. However, HPV infection is a necessary but
E7 and deletion of viral proteins E2, E4, E5, L1, and L2 insufficient cause for the development of cervical cancer (Tota
(Cheng et al. 2018). et al. 2011) because recent studies show that most high-risk
Basal epithelial cells are the main target of HPV infection HPV infections of the cervix are transient, and only a small
and L1 and L2 capsid proteins bind to the receptors present on percentage of infected women can develop invasive cancer
epithelial cells. Once the process of entrance initiates, it results (Bowden et al. 2021).
in uncoating of the virus in the cytoplasm and viral genome Extensive studies have shown that HPV interacts with oth-
then enters the infected host cell nucleus, where it is first er co-factors, including human leukocyte antigen (HLA) class
replicated and then transcribed. The genome replication and II alleles (Mahmud et al. 2007), which affect the persistence of
pathogenesis of the host cell are controlled by early proteins HPV and the risk of developing cervical cancer. Indeed, HLA
because they are expressed foremost. Late proteinsL1 and L2 gene polymorphism is related to the risk of developing HPV
expression in a cell differentiation–dependent mode are con- and the risk of HPV-related cervical neoplasia (Chan et al.
trolled by early proteins. Developed squamous cells are the 2007). These genes appear to be important determinants of
late protein expression sites. After terminal epithelial cell dif- the risk of persistent HPV infection and disease progression
ferentiation virions, development and maturation occur and (Paaso et al. 2019)
viral discharge overlaps with the senescent cells’ normal shed- Associations between HLA and cervical cancer have been
ding. The immune system can eradicate the majority of infec- associated with precursor lesions and HPV infection in several
tious agents, but some cervical benign abrasions develop into populations (Maciag et al. 2000). Recent data show that indi-
cancer (Chabeda et al. 2018). viduals with certain alleles (HLA-DQB1 * 0602 and HLA-
The clinical phases of cervical premalignancy stem from DRB1 * 1501) are also more susceptible to persistent HPV
increasing dysplasia severities: cervical intraepithelial neopla- infection and are at increased risk for cervical cancer (Leo
sia (CIN) grades 1, 2, and 3 (CIN1, CIN2, and CIN3, corre- et al. 2017).
spondingly). CIN1 is termed as low-grade intraepithelial squa- Several strategies are used by the virus to evade immune
mous abrasions, while CIN2/3 is known as high-grade surveillance, hence the relevance of studying the relationship
intraepithelial squamous abrasions (Cheng et al. 2018). The between HLA-G and HPV in tumor growth and progression
persistent infection leads to low-grade CIN 1 abrasions or (Fahim et al. 2018) because of the fundamental function of
lacerations. The development to high-grade CIN 2/3 is trig- HLA proteins in T cell–mediated adaptive immune responses
gered by high-risk (HR) HPV abrasions leading towards in- as they are essential for antigen presentation. HLA genes play
vasive cervical cancer (ICC). In a typical high-risk HPV car- a crucial role in the viral presentation; these molecules are
cinogenesis, the viral genome is incorporated into the chro- involved in mediating susceptibility to HPV-related diseases
mosome of the host’s DNA, and during the genomic lineari- (de Araujo Souza et al. 2009).
zation, the early protein E2 sequence is disturbed. Numerous studies have investigated the associations be-
The early protein E2 is the transcriptional repressor of E6 tween HLA class I and HLA class II alleles as well as HLA
and E7, and thus, upon E2 disruption, expression from these G and HPV-associated diseases [29, 30,31]. Associations be-
genes E6 and E7 turn out to be constitutive. Consequently, tween HLA-G polymorphisms and HPV infection and squa-
host-apoptotic regulator protein p53 undergoes degradation mous intraepithelial lesions in women in northern Quebec
Environ Sci Pollut Res (2021) 28:47752–47772 47755

Fig. 1 The life cycle of HPV. Approach to the basal keratinocytes is amplification (Liu et al. 2019). Activation of persistent propagation and
provided by lesions, which proceed towards denudation of the E1- and E2-directed asexual replication of viral genome to a very high
basement membrane (BM) from epithelial cells. The virus attaches to copy number is triggered by early viral proteins E6 and E7. Stimulation of
heparin sulfate proteoglycans (HSPGs) and laminin 5 on the BM through early protein E4 expression and then late proteins L1 and L2 to package
the major capsid protein L1during human papillomavirus (HPV) infec- the very high copy numbers of the viral genome is accompanied by
tion. This activates conformational changes in the capsid that later on infected cells’ terminal differentiation in the upper layers of the epithelial
leads to the exposure of L2minor capsid protein, containing a conserved cells (Roden and Stern 2018). This is for the reason that E4, L1, and L2
site on the N terminus of protein L2 that is vulnerable to breakdown by are frequently exposed in the upper layers of epithelial cells where wrap-
extracellular furin. Various preserved protective epitopes of L2 are ex- ping of viral DNA and assemblage of perpetual virions occur leading
posed after furin breakage of L2, containing 17–36 residues, on the sur- towards genome amplification. The virus is finally discharged in the
face of viral capsid and is crucial to any infectivity. This is preceded by stratified epithelium superficial layers together with the flaking of senes-
viral uptake into the target basal keratinocyte. Various paths have been cent cells (Liu et al. 2019). As E4 breaks the cytokeratin filaments, the
concerned for the uptake of the virus, but not any pathway is effectively virions are discharged, and the keratinocyte remains are sloughed off the
communally absolute. The viral genome undergoes replication in the epithelial surface. Hence, without exactly triggering cell death the viral
basal cells infected with HPV and creates ~50 copies of HPV episomes, life cycle is finished (Roden and Stern 2018). Abbreviations. BM, base-
which then separate into the daughter lineage as the cells experience cell ment membrane; HSPGs, heparin sulfate proteoglycans; HPV, human
division (Roden and Stern 2018). Essential early E proteins proliferate papillomavirus
and multiply in the middle layers upon the initiation of genome

showed that HLA-G*01:01:01 was associated with an in- et al. 2013). A Canadian population–based study showed that
creased risk of period prevalence in the group with HPV 1, the HLA-G∗ 01:01:02 and HLA-G∗ 01:03 genes are associ-
8, 10, and 13 and the group including HPV 3 and 15 (Metcalfe ated with persistent HPV 16 infection risk and persistent HPV
47756 Environ Sci Pollut Res (2021) 28:47752–47772

2, 3, 4, and 15 infections in the Canadian population HLA class II polymorphism and HPV infection
(Ferguson et al. 2011). The HLA-G∗ 01:01:03 and HLA-G∗
01: 01:05 were determined to be a significant predictor of Regarding the association between HLA class II alleles and
cumulative co-infection during follow-up (Smith et al. HPV, several studies have analyzed this correlation. Kunle
2014). The same cohort showed that HLA-G * 01: 01: 02, Odunsi et al. suggested that HLA alleles DQB 1 *03, DRB
HLA-G * 01: 04: 01, and HLA-G * 01: 06 alleles were asso- 1 *04, and DRB 1* 1 1 are strongly associated with suscepti-
ciated with high-grade HG-CIN (Metcalfe et al. 2013). bility to CIN, especially that the haplotypes DRB1*040, 1 -
However, Metcalfe S et al. reported an association between DQB 1*030 1, and DRB 1 * 1 10 1 -DQB 1 *030 1 were
homozygous HLA-G*01:04:01 and a decreased risk of infec- significant and indicated susceptibility (Odunsi et al. 1996).
tion period in the HPV 3 and 15 groups (Metcalfe et al. 2013). The DRB 1 *0101 -DQB 1 *050 1 haplotype showed a weak
The same study suggests that the HLA-G allele is not signif- protective effect (Odunsi et al. 1996). Another previous study
icantly associated with HPV persistence. HLAG*01:01:02, found similar results for HLA DQB1 * 0301 alone and in
G*01:04:01, and G* 01:06 were associated with high-grade combination with the HLA DRB1 * 0401 allele which is as-
squamous intraepithelial lesions (SIL), but the association was sociated with cervical cancer. This association is more pro-
not statistically significant (Metcalfe et al. 2013). Studies con- nounced in cancers positive for HPV types other than HPV16
ducted in Brazil did not observe an association between spe- and also a protective effect on DQB1 * 0501 was found to be
cific HLA-G alleles and HPV infection but found a protective slightly significant. This study shows that HLA-DRB1*1501
effect of the G: 01:01:02 allele against the development of with HLA-DQB1*0602 is not significantly associated with
intraepithelial lesions (Alves et al. 2015). cancer, but this allele is higher in cervical cancer patients with
The impact of HLA-G genotype on mother-to-child HPV HPV type 16 positive but the protective effect on DRB1 *
transmission was studied by Louvanto et al. (2018) and indi- 1301 was not observed (Cuzick et al. 2000).
cates that an HLA-G genotype match of G∗01:01:01/01:04:01 Other individual class II risk alleles that have increased the
increases the risk of high-risk HPV genotype positivity (HR) risk of cervical cancer in recent studies: DQB1*0402 and
in cord blood and infant oral mucosa. The homozygous HLA- DQB1*05(X. Zhang et al. 2015), DQB1*0601(Hu et al.
G*01:01:02/01:01:02 allele between mother-infant pairs 2017), DQB1*0602 (Ivansson et al. 2008), DRB1*04,
showed an increased risk of oral HPV infection; in contrast, DRB1*0401, and DRB*15 (Leo et al. 2017), DRB1*11
HLAG*01:04:01 and HLAG*01:06 have a low risk for HPV (Ivansson et al. 2008), DRB1*1101(Madeleine et al. 2008),
at birth (Louvanto et al. 2018). and DQA1*0102,*03, *0301, and DQB*0602 (Leo et al.
In Brazilian population patients with HLA-G, *0104 hap- 2017).
lotypes, and HPV-16 and HPV-18 co-infection are particular- Associations between HLA class II polymorphism and
ly associated with high-grade SIL, a protective effect of the HPV type 16 have been performed by several previous stud-
HLA-G∗ 01:03 allele was observed against HPV-related cer- ies; the HLA-DQA1*0102 allele is weakly related to cervical
vical lesions (Simoes et al. 2009). Another study conducted neoplasia in HPV 16–positive patients. HLA-DQB1 *0602
also in Brazil concerning HPV-positive pregnant women was very low in all (CIN) patients but was strongly increased
showed a protective effect of the HLA-G∗01:01:02 allele in HPV-16 seropositive (CIN) patients compared to HPV 16
against the occurrence of CIN in a cohort of HPV/HIV co- seropositive controls (Sanjeevi et al. 1996).
infected pregnant women (Alves et al. 2015). HLA-G expres- The association between HLA-DR 15 and disease (CIN)
sion was also significantly higher in patients with CIN and was particularly strong in HPV-16 seropositive subjects. The
cancer with HPV 16/18 than in patients with CIN without DQA1 *0102- DQB1*0602 (DQ6) haplotype is associated
HPV (Dong et al. 2010). with an increased risk of cervical neoplasia in HPVI6-
No spontaneous demethylation event in CIN2/3 cases was positive subjects and DQA 1*0501 -DQB 1 *030 1 (DQ7) is
found in an analysis of the methylation of seven CpGs in the associated with an increased risk of cervical neoplasia in
HLA-G promoter (Gillio-Tos et al. 2012). On the other hand, HPV-16-positive subjects (Sanjeevi et al. 1996). Consistent
93.7% of the patients with cervical lesions were detected as associations across other studies in HPV16-infected women
HPV positive; however, a low expression of HLA-G5 sub- with cervical cancer were observed for HLA-DRB1*15 and
types was observed in all HPV-related cases (Guimarães DRB1*15 DQB1*0602 haplotype compared with control
et al. 2010). women (Hernández-Hernández et al. 2009).
In benign and premalignant lesions, HLA-G expression Regarding HLA polymorphism and cervical squamous cell
increases, and in invasive cancer and corresponding cervical cancer risk, inconsistent results are often observed between
draining lymph nodes, HLA-G expression gradually de- different populations or even within the same population
creases. On the contrary, HLA-E expression increases with (Hildesheim and Wang 2002). The higher risk of cervical
the extent of disease, including increased expression of the squamous cell cancer associated with several HLA alleles
molecules in lymph nodes (Fig. 2) (Silva et al. 2011). has been described, mainly for the DQB1∗03 alleles and the
Environ Sci Pollut Res (2021) 28:47752–47772 47757

Fig. 2 The different HLA-G al-

leles that are associated with HPV
infection or progression to cervi-
cal cancer. Abbreviations. HLA-
G, human leukocyte antigen G;
HPA, human papillomavirus

DRB1∗1501-DQB1∗0602 haplotype. Some studies have sug- * 44 were significantly related to cervical cancer and persis-
gested strong associations of tumors containing a specific tent HPV-16 infection. The HLA-B * 15 genes are negatively
HPV type. However other studies found no associations with related to cervical cancer (Bhaskaran et al. 2019); indeed,
the DQB1∗03 haplotype and an inverse association was HLA-B15 is a protective factor for the prevention of cervical
shown for the DRB1∗1501-DQB1∗0602 haplotype (de intraepithelial neoplasia grade III (CIN III) or invasive cervi-
Araujo Souza and Villa 2003). cal cancer overall (ICC), and CIN III / ICC HPV52 positive.
Many studies in different populations have shown that the However, none of the HLA-B alleles was found to confer an
risk of cervical squamous cell cancer associated with the increased risk of CIN. HLA-B15 is common in Asians for
DRB1 * 01 and DRB1 * 13 alleles or haplotypes is low. whom HPV52, an uncommon type of HPV worldwide, also
Despite these consistent results, it is not known which exists in a relatively high prevalence (Chan et al. 2006). Leo
DRB1 * 13 allele is important, whether only the DRB1 * 13 et al. 2017 recently showed that HLA-B * 07 increases the risk
alleles, only the DQB1 * 0603 allele is associated with a of cervical squamous lesions. A significant association with
reduced risk of disease, or whether it is linked to other persistent HPV infection and the development of cervical can-
disease-related genes for the major histocompatibility com- cer: HLA-A*02 and HLA-A*0201 (Gokhale et al. 2014),
plex (MHC) found in linkage disequilibrium with these HLAA*0301 (Madeleine et al. 2002), HLA-A*3101 and
HLA alleles are important (Fig. 3) (Goodman et al. 2001). HLA-A*3303 (S. S. Wang et al. 2002), HLAB*3501, HLA-
B*37, and B*3701 (Gokhale et al. 2014), HLA-B*3901 (S. S.
HLA class I polymorphism and HPV infection Wang et al. 2002), HLA-B*4402 (Madeleine et al. 2002),
HLA-B*58 and B*5801 (Gokhale et al. 2014),
The association between HLA class I polymorphism and HPV HLACw*0501 (Madeleine et al. 2002), HLA-C*0702 (Leo
was also studied (Fig. 4); HLA-A, B alleles, and persistent et al. 2017), and HLA-Cw*0704 (Madeleine et al. 2002).
HPV-16 infection and cervical cancer in South India HLA-B
47758 Environ Sci Pollut Res (2021) 28:47752–47772

Fig. 3 The different HLA class II

alleles that are associated with
HPV infection or progression to
cervical cancer. Abbreviations.
HLA, human leukocyte antigen
alleles; HPA, human
papillomavirus; CIN, cervical
intraepithelial neoplasia

HLA polymorphism and HPV E6 and E7 variants HPV E6 overlapping peptide-specific T cell immune re-
sponses have been shown to predict survival in cervical cancer
Many studies have shown an association between HLA poly- patients (Cai et al. 2021). A recent study was performed on the
morphism and E6 and E7 variants. Indeed, an association association between HLA-A alleles as a predictor of prognosis
between HLA class II and E6 variants in Japanese women in patients with cervical squamous cell carcinoma (CSCC)
with HPV16-positive cervical cancer compared to controls. and T cell response to HPV16 E6 and E7. This study shows
Among patients with the HPV16 E6 prototype, the frequency that the level of HPV16 E6 HLA * A02: 07-specific T cell
of DRB1 * 1501 and DQB1 * 0602 was significantly higher response is related to the prognosis of patients with advanced
(Matsumoto et al. 2003). Similar results regarding the associ- CSCC (Cai et al. 2021).
ation between HPV16 E6 variants and HLA class II polymor-
phism in a Chinese population, a significant positive correla-
tion between the DQB1 * 060101 allele and HPV16-positive Therapeutic HPV vaccines
cervical cancer as a variant. A significant positive association
was found in the DQB1 * 060101 allele regarding HPV16 E6 There is a vital requirement to create efficient therapies for
prototype–positive cervical cancers with close results indicat- developed HPV infections and HPV-related disorders, due
ed for DQB1 * 030201 and DPB1 * 1301 (Wu et al. 2007). to the predominance of HPV abrasions globally. One effective
The association between HPV16 E6 variants and HLA- therapeutic strategy includes the use of therapeutic vaccines
DRB1 and DQB1 alleles in young women with cervical can- (Yang et al. 2017). This is because HPV late genes L1 and L2
cer in China showed a low frequency of the DQB1*0501 are lost when HPV incorporates into the genome of host in-
allele in young patients compared with that in older patients fected with HPV high-grade abrasions or HPV-linked malig-
(Hu et al. 2017). nancies. Consequently, late proteins L1 and L2 specific
Environ Sci Pollut Res (2021) 28:47752–47772 47759

Fig. 4 HLA class I alleles that are

associated with HPV infection or
progression to cervical cancer.
Abbreviations. HLA-B, human
leukocyte antigen alleles B; HPA,
human papillomavirus; CIN,
cervical intraepithelial neoplasia

neutralizing antibodies produced by prophylactic vaccines are targeting early viral abrasions and these proteins are
no longer effective against the cells infected with HPV. expressed before viral genome incorporation at very ear-
Therefore, therapeutic HPV vaccines are being developed to ly stages to a higher rate than E6 and E7. These pro-
eradicate HPV abrasions or the previous HPV-linked infec- teins would be the target of ideal therapeutic vaccines
tions (Cheng et al. 2018). because these vaccines stimulate powerful cytotoxic T
Contrary to prophylactic vaccines, therapeutic vac- lymphocyte (CTL) and cancer-specific T cell type 1
cines aim to eradicate the precancerous abrasions and response that can destroy cancerous and infected cells
the continued infection of lesions produced by HPV (Chabeda et al. 2018).
(R. Wang et al. 2020). To eradicate developed abrasions These discoveries have originated several attempts to de-
or lesions, therapeutic vaccines produce T cell–mediated velop an ideal immunotherapeutic cure against HPV lesions
immunity by precisely pointing to HPV early antigens and disorders (Yang et al. 2017). But at present, the use of
that are constitutively exposed around both infected and human therapeutic vaccines for HPV has not been authorized.
malignant cells (Cheng et al. 2018). Consequently, early However, several and broad findings have produced promis-
genes are targeted upon exposure during the viral life ing vaccine contenders checked in clinical trials [61, 62, 5].
cycle and help control the development of HPV-linked Several forms of therapeutic vaccines have been created for
premalignant and malignant abrasions. E6 and E7 pro- the treatment of HPV and checked in clinical and preclinical
teins particularly signify two ideal targets of therapeutic trials, and the main targets of these vaccines are HPV early
HPV vaccine because these two proteins are continuous- proteins E6 and E7 (Yang et al. 2017). These recent therapeu-
ly expressed and implicated in the cancerous transfor- tic strategies against HPV consist of peptide-/protein-based,
mation of HPV-linked cancers (Vici et al. 2016). Other whole cell–based, live vector–based, and nucleic acid–based
proteins E1 (viral helicase) and E2 are beneficial for vaccines (Cheng et al. 2018).
47760 Environ Sci Pollut Res (2021) 28:47752–47772

Fig. 5 Immune response activation by various forms of therapeutic the cell. Furthermore, this transcribed RNA will be translated into anti-
vaccination. Induction of antigen into the body in diverse varieties is genic large peptides or proteins, that can also be engulfed by the dendritic
triggered by the processing of many forms of therapeutic vaccines. (A) cells via process phagocytosis after peptide- or protein-based vaccination
The antigens E6 and E7 encoded by DNA plasmids can be induced into (Yang et al. 2017). (C) Moreover, the protein products can be inducted
DCs either through induction of DNA vaccines directly or through altered into the DC’s directly. However, recombinant protein vaccines are typi-
live vector vaccine indirectly (Yang et al. 2017). Upon transfection of cally comprised of E6 and E7 fusion proteins in the case of HPV
these E6 and E7 HPV antigens directly or through the transmission of (Shanmugasundaram and You 2017). To be introduced to T cell receptors
these antigens indirectly via cross-presentation, antigen-presenting cells (TCR) of CD8+ T cells, processing of antigenic large peptides and pro-
(APCs) are stimulated. Through major histocompatibility complexes teins into shorter peptides occurs by means of the proteasome’s activity,
(MHCs) dendritic cells home towards draining lymph nodes where naive which are encumbered on major histocompatibility complex (MHC I)
T cells can be primed upon introduction of antigenic peptides to T cells. interior to the endoplasmic reticulum (ER) (Yang et al. 2017). (D)
Major histocompatibility complex molecules and the antigens (i.e., MHC: Cultured monocytes taken from the patients in fusion with a specific
antigen [Ag] complex) interact with the T cell receptor and co-stimulatory peptide or antigen are used to prepare dendritic whole cell–based vac-
compounds, such as CD28 present on T cells and B7 present on dendritic cines. These customized DCs are then induced into the patient’s immune
cells assist in this interaction. To activate a cellular immune response system and the same cell-mediated and antibody-mediated immune re-
MHC-I molecules are presented to CD8+ T cells and MHC II molecules sponses are activated through the stimulation of B cells and helper T cells
are presented to CD4+ T cells. CD8+ T cells once stimulated destroy (Shanmugasundaram and You 2017). Abbreviations: APCs, antigen-
cancerous cells directly by provoking apoptosis. CD4+ T cells further presenting cells; MHCs, major histocompatibility complexes; TCR, T cell
assist immune responses, which aid in destroying cancerous cells receptors; MHC I, major histocompatibility complex; ER, endoplasmic
(Cheng et al. 2018). (B)The antigens that encode for DNA will be tran- reticulum
scribed into RNA that can also be induced through RNA vaccination into

Activation mechanism of the immune system cells (APCs) is the main purpose of therapeutic vaccines (Fig.
via therapeutic HPV vaccines 5). Recently, clinical investigations on effectual therapeutic
vaccines are also being carried out, which contrary to prophy-
To reinforce and extend the immune response against HPV, lactic vaccines, fight against HPV abrasions through immuno-
presenting specific antigens to a subset of antigen-presenting therapy (Shanmugasundaram and You 2017). Dissimilar to
Environ Sci Pollut Res (2021) 28:47752–47772 47761

prophylactic vaccines which depend on stimulating memory imiquimod or cidofovir, are essential along with these vac-
B cells and specific antibodies (Hus et al. 2015), therapeutic cines because this adjuvant acts as agonists to several toll-
vaccines attempt to boost the T cell adaptive immune response like receptors as well as enhance the initial immune response
against HPV (Shanmugasundaram and You 2017). E6 and E7 to the vaccine and impart long-term defense
antigens are present in several forms in a majority of thera- (Shanmugasundaram and You 2017).
peutic vaccines, and their purpose is to stimulate antigen pre-
sentation after delivering these antigens to APCs through the Live vector vaccines
MHC class I and MHC class II (Yang et al. 2017).
The vital subset of APCs are dendritic cells, which have Bacterial and viral vector–based vaccines are the main types
been the main target of several therapeutic vaccines and these of live vector–based vaccines (H. J. Kim and Kim 2017).
cells are implicated in capturing and introducing antigens to T Weakened bacteria or viruses are used in live vector vaccines
cells [65, 66]. This is attained through making naive T cells to to carry desired genes into cells (Liu et al. 2019). Live vector
generate cytotoxic T lymphocytes (CTLs) that point cells in- vaccines are genetically modified virus or bacterial vectors
fected with HPV, thus producing CD4+ T cells which gener- that can enable the antigens to propagate by reproducing in-
ate the essential cytokines and reinforce APCs side the host cells. Antigenic expression is triggered then
(Shanmugasundaram and You 2017). MHC class II molecules through both major histocompatibility complex class I and
present helper CD4+T cells while MHC class I molecules class II routes, thus accelerating CD4+ helper T cells and
present CTLs or cytotoxic CD8+ T cells. Amplification of CD8+cytotoxic T cells and, correspondingly, ultimately de-
CTL responses occurs via differentiation of CD4+ T cells into livering a high level of immunogenicity (Chabeda et al. 2018).
TH cells. This differentiation of CD4+ T cells into TH cells
also accelerates humoral B cells to create more neutralizing Bacterial vector–based therapeutic vaccine
antibodies. CTLs facilitate the antigen-targeted destruction of
cancerous cells (Cheng et al. 2018). For the production of live vector therapeutic vaccines, bacteria
For the CD8+ T cell response activation, processing of E6 have been extensively analyzed (Bogani et al. 2018). Species
and E7 antigens and their digestion into smaller peptides oc- of the bacterial vector comprised of Lactobacillus lactis,
curs by the proteasome present in the antigen-presenting cells, Lactobacillus casein, Listeria monocytogenes, and
before their presentation on the major histocompatibility class Salmonella. Listeria is a guaranteeing vector because of its
I molecule. All peptide fragments cannot be efficaciously characteristics; for instance, it has the capacity to target anti-
identified by antigen-peculiar T cells and encumbered on the gen processing through MHC I and MHC II routes and it has
MHC molecule. The sequence of antigenic fragments the capability to infect macrophages without undergoing
(epitopes) contained in short peptides can attach to the MHC phagocytosis (Chabeda et al. 2018). L. monocytogenes (Lm)
molecule with high specificity and elicit a humoral and cell- is of specific importance and is a promising live vector for
mediated immune response after interacting with the T cell vaccine production. This is because of its ability to serve as
receptor of antigen peculiar T cells (Yang et al. 2017), hence a natural adjuvant, the capacity of infecting macrophages
leading to the death of cancerous cell through the stimulation without phagocytosis, and the capability of enabling antigen
of helper B cells, T cells, and cytotoxic T cells processing through MHC I and MHC II routes [1, 74].
(Shanmugasundaram and You 2017). E7 antigen is well de- GLBL101c (comprising of L. casei expressing E7) was
scribed immunologically than E6 antigen in preclinical trials; given orally (6 capsules per day) to seventeen females having
therefore, therapeutic vaccines emphasized triggering immune a diagnosis of CIN 3 in a phase I/II investigation. Enzyme-
responses against the E7 antigen (Yang et al. 2017). linked immune spot (ELISPOT) assay assessed precise E7
immune response and it was identified in all the patients. In
8 of 27 patients (30%) after 9 weeks of treatment, CIN 1
Efficacy and effectiveness of various histologic regression or less happened and these patients ex-
therapeutic vaccines perienced LEEP; 70% of these patients had a decrease in abra-
sion to CIN 2. Any woman did not experience detrimental side
Several forms of therapeutic vaccines have been established effects. Clear evidence is provided by these findings between
for the cure of cervical malignancies comprising of live vector the recession of disease and HPV E7 cell–mediated immunity
(bacterial or viral)–, protein-/peptide-, nucleic acid–, and (Barra et al. 2020).
whole cell–based vaccines (Yang et al. 2017). HPV DNA LM-LLO-E7, a promising Listeria-based vaccine, is devel-
and protein vaccines appear to be the less effective amongst oped through HPV16 E7 fusion with LLO (Liu et al. 2019).
these several categories of therapeutic vaccines. This is be- An E7-based vaccine, Lm-LLO-E7, is based on these bacteria
cause they are not able to generate an adequate early immune and it has been analyzed for curing advanced cervical mela-
response. Therefore, different types of adjuvant, for example, noma, thus indicating an appropriate safety profile (Barra et al.
47762 Environ Sci Pollut Res (2021) 28:47752–47772

2020). A phase I analysis of fifteen patients suffering from Since live vectors can replicate themselves in the organism,
recurring, terminal, refractory, and metastatic squamous cell therefore, live vector vaccines produce strong immune re-
cervical carcinoma showed a decrease in tumor size in four sponses to antigen vaccines. Both virus- and bacterial-
patients and increment in the E7-specific T cells identified neutralizing antibodies, obtained from either pre-existing im-
among peripheral blood mononuclear cells (PBMCs) in three munity or vaccination, typically restrict the booster effect pro-
patients. More studies are underway on HPV-related cancers duced by repeated vaccination (H. J. Kim and Kim 2017).
currently (Liu et al. 2019).
L. casei–based vaccine BLS-M07 is an E7 protein express- Peptide-/protein-based vaccines
ing vector and delivered by mouth. Immune response in the
gut-related lymphoid tissues can be stimulated by this vaccine Peptide-based vaccines
and triggers the production of humoral antibodies against an-
tigens having the same homology as HPV E7. This vaccine Peptide vaccines are easier to develop but, for effectual depic-
has been analyzed in HPV-16 patients in open-label dose-in- tion, they must be matched with the patient’s HLA type, and
tensification phase I/II an investigation and CIN 3 diagnosis often they are MHC-specific. Immunogenic epitopes should
was observed along with pathological responses (Barra et al. therefore be recognized for every person that makes it impos-
2020). sible to implement this strategy in mass immunizations
(Chabeda et al. 2018). These vaccines appear to have low
Viral vector–based therapeutic vaccines antigenicity, and to enhance vaccine potential for potent
CD8+T cellular responses, they need to be administrated with
Viral vectors can trigger cellular expression of directed anti- adjuvants such as cytokines, different molecules, and ligands
gens by infecting the host cells (Bogani et al. 2018). In pre- like Toll-like receptor (Khong and Overwijk 2016), (Yang
clinical models, the effectiveness of viral vectors such as et al. 2016). However, peptide vaccines have safety and sta-
alphaviruses, adenoviruses, vaccine viruses, and fowl pox bility benefits (Hancock et al. 2018).
has been studied (Skeate et al. 2016). Delivery of HPV E2, The peptide-based vaccine HPV16-SLP (ISA101) consists
E6, and E7 antigens into vaccines was carried out by adeno- of four synthetic HPV16 E7 large overlying peptides fused to
viruses, adeno-associated viruses, vaccine viruses, and alpha- ISA51 (adjuvant montanide) and nine HPV16 E6. Fifteen out
viruses (H. J. Kim and Kim 2017). of nineteen patients in phase II clinical trial reported a clinical
E6 and E7 oncoproteins of HPV type 16/18 are shown by a response of 79% in patients suffering from HPV16+ having a
genetically modified vaccine virus named TA-HPV. For ana- diagnosis of VIN3 along with a full response in nine patients
lyzing a DNA-based therapeutic vaccine, TAHPV was com- (47%). Furthermore, T cell response stimulated by the vaccine
bined with pNGVL4a-Sig/E7, in a phase II clinical trial in was developed in all patients but the more probable systematic
patients infected by high-grade CIN. In the cervico-vaginal response was obtained in patients with stronger CD8 + T cells
tract, TA-HPV achieved success in developing CD8 antigen- and IFN-γ-linked CD4+. The therapeutic ability of ISA101
specific T cells. A dose of 20μL TA-HPV given by a dermal has also been shown in other studies (Liu et al. 2019).
scarification method has been checked in various studies. A vaccine that is PepCan having four synthetic HPV16 E6
Vaccination was not shown to contribute to severe systemic peptides and Candin as an adjuvant in the clinical study of
adverse outcomes. However, myalgia, malaise, and headache dose-escalation phase 1 of HSIL patients, reported that 50 μg
were the most common. Low to moderate local reaction to dose was the most effective, and among all patients, 45% of
scarification site having swelling and erythema, accompanied histological reversion of illness was reported (Greenfield et al.
by the ulceration, can be settled in 17 days (Barra et al. 2020). 2015).
TG4001 comprises the Ankara virus, a genetically modi- A liposomal nanoparticle vaccine named PDS0101 is com-
fied virus having the sequence those codes for human inter- prised of 6 E6/E7 peptides of human HPV type 16 encapsu-
leukin (IL)-2 gene and HPV-16 early genes E6 and E7 (Barra lated by a cationic lipid. There are no research findings on its
et al. 2020). Forty-eight percent of patients have undergone use in humans. The PDS0101 is currently being tested in
regression of disorder, while 38% of them showed clearance females with biopsy-proven CIN 1 (NTC02065973) and
of HPV DNA in a phase I analysis of 21 cases of high-risk HPV infection in an open-label phase I clinical trial
HPV16+patients with a diagnosis of CIN2/3 (Liu et al. 2019). (Barra et al. 2020).
MVA E2, which comprises the bovine Papillomavirus E2
protein, is based on the vaccine virus Ankara (Santesso et al. Protein-based vaccines
2016). In total, 90% clearance of infection was recorded in
female patients and 100% clearance of infection was recorded The E6 /E7 proteins are used in protein-based vaccines to
in male patients in a phase III analysis of patients having HPV immunize humans. They are comprised of all epitopes and
stimulated genital intraepithelial neoplasia (Liu et al. 2019). exclude MHC restrictions in comparison with peptide-based
Environ Sci Pollut Res (2021) 28:47752–47772 47763

vaccines, but they continue to raise humoral immunity and patients with TVGV-1 or without GPI-0100 adjuvant (0.6
have low immunogenicity due to their exogenous origin, mL±0.6 mg) were tested in phase II clinical trial. The effec-
mainly provided by a pathway named MHC II. Such issues tiveness and safety of TVGV-1 were tested in another clinical
can be solved by the use of fusion protein targeted at dendritic trial against HPV-stimulated cervical HSIL (NCT02576561)
cells and by giving them exposure to the antigen presentation ((Barra et al. 2020).
pathway of MHC I (Liu et al. 2019).
GTL001 (Procervix) was combined by bonding E7 of the Nucleic acid–based vaccines
HPV16 and HPV18 to the Bordetella pertussis cyclase
(CyaA), which was catalytically inactive. An essential DNA-based vaccines These include plasmid DNAs that carry
Bordetella pertussis toxin CyaA insets its N-terminal in the desired genes and transfect host cells for the continued expres-
cytoplasm by attaching to integrins on the cell membrane. sion of antigens (Liu et al. 2019). DNA vaccines are based on
Antigens are transported into the cytoplasm by this feature plasmid DNA injections that aid specialized viral antigens to
of CyaA and the MHC I antigen presentation path is originat- be encoded in the host cells, including myocytes (in case of
ed. HPV16- or HPV18-positive patients demonstrated effica- intramuscular injection) or DCS. However, they require adju-
cy and acceptability but with normal cytology, in a phase I vant because they have low immunogenicity (Bogani et al.
analysis of GTL001 fused to topical imiquimod (Van Damme 2018).
et al. 2016). A ligand of TLR5, flagellin, has been shown by Since DNA-based vaccines can stimulate both humoral-
its anti-cancerous effects in a mouse model and has also re- and cell-mediated immune responses and allow for sustained
cently been found to form a fusion protein with HPV16 E7 antigenic expression, therefore these are desirable tools for
(Lin et al. 2016). therapeutic HPV vaccination. For booster vaccinations,
GTL002 contains customized E7 proteins from HPV16, DNA-based vaccines can be regularly administrated, unlike
18, 45, 31, 33, and 52 and it is an evolving second- live vector–based vaccines because of their non-replicating,
generation vaccine. Models in mice and beagle dogs showed non-living, and less immunogenic nature relative to live vec-
that T cell immune response specific to E7 is triggered against tors and are comparatively reliable. In addition, DNA-based
each of the genotypes. There have been no human data on its vaccines are easily manufactured, and these are cost-effective
use so far (Barra et al. 2020). and reliable. HPV DNA vaccines in clinical trials showed
The therapeutic protein-based vaccine SGN-00101 is a sec- positive therapeutic results (H. J. Kim and Kim 2017).
ond vaccine consisting of the complete sequence of The reliability, effectiveness, and immunogenicity of
E7oncoprotein of HPV type 16 connected to the heat shock pNGVL4a-CRTE7 (detox), a calreticulin-related plasmid
protein BCG. This vaccine acquired an incomplete response DNA vaccine (Barra et al. 2020), were evaluated in 32
in 32 women (55%) in the phase II trial. This vaccine was HPV16-associated CIN2/3 patients in a clinical phase I trial.
given subcutaneously to 58 patients having a diagnosis of This vaccine was given to patients either intramuscularly, in-
CIN 3(500 micrograms/proteins 3X in 1 month separately). tradermally, or directly into the cervical abrasion. Twenty-two
There were only moderate, self-limiting side effects associated out of 32 (69%) patients reported adverse effects linked to
with the injection site. During the observation, no patient had vaccines. Constitutional and local injection sites were the most
significant drug-associated side effects supporting SGN- common vaccine-linked incidents and they were of grade 1 or
00101 tolerability and safety (Barra et al. 2020). less severe (Alvarez et al. 2016). The pNGVL4aCRT-E7 is
E6, E7, and L2 oncoproteins of HPV type 16 are contained currently undergoing clinical studies in many clinical trials for
in the TA-CIN vaccine as a single fusion protein. This vaccine curing women having a diagnosis of CIN 2–3: it is being
stopped the HPV 16 positive tumor cells from growing out tested by an ongoing non-randomized open-label experimen-
and demonstrated good immunogenic responses to both L1 tal study (through gene weapons at weeks 0, 4, and 8 until
and E2in a mouse model (Bogani et al. 2018). In 24 of the 32 their lesion has been therapeutically rejected at week 15).
vaccinated patients, TA-CIN-specific IgG and cell-mediated In addition, the pNGVL4aSig / E7 associated with HSP70
immunity were demonstrated by testing on healthy pa- is being studied with or without TA- HPV in anon randomized
tients.63% abrasion response 1 year after vaccination was re- ongoing open-label clinical phase I multi arms study, and this
ported when VIN 2/3 was combined with TA-CIN and topical nonrandomized clinical phase I multi arms study also tested
imiquimod in patients undergoing phase II clinical trials (Liu topical imiquimod in HPV-16 + patients with a diagnosis of
et al. 2019). CIN 3 (NCT00788164) (Barra et al. 2020).
TVGV-1 is a fusion protein that comprises the E7 peptide E6 and E7oncoproteins of HPV type 16/18 are expressed
sequence of HPV type 16 combined with the exotoxin A of by a genetically modified DNA vaccine named GX-188. To
Pseudomonas aeruginosa (PE) and retention signal of endo- increase the expression of antigens by DCs to T lymphocytes,
plasmic reticulum (ER). Da Silva et al. (2019) reported that these HPV-specific E6 /E7 are bonded to Fms-like tyrosine
after reliable results from in vitro study, all the CIN 2–3 kinase-3 ligand (Flt3L) extracellular domain. Nine patients
47764 Environ Sci Pollut Res (2021) 28:47752–47772

having a diagnosis of CIN 3 abrasions were given GX-188 transfected dendritic cells. To fix this problem, a pre-clinical
through electroporation (EP) in phase I clinical trial. All 9 model described that the anti-apoptotic gene is incorporated
patients having a diagnosis of CIN3 showed a considerable into the suicidal DNA to improve APC persistence.
E6- and E7-specific IFN gamma producing a T cell response. The usage of a Kunjin flavivirus (KUN) vector also permits
Significant increase in proliferative ability and cytolytic activ- and extends the immediate presentation of antigen via
ities, effector molecules secretion resulted in an improved mul- transected DCs. This later approach protected mice with an
tifunctional HPV-specialized CD8 T cell response in 8 out of 9 E7 expressing tumor and led to E7-specific T cell responses.
patients. In addition, seven out of nine patients demonstrated Many RNA vaccines for other HPV-related malignances have
complete reversion of their abrasions and viral prohibition within proceeded to clinical trials; nevertheless, more work needs to
36 weeks of monitoring. Administration of GX-188E does not be done in the production of RNA vaccines for HPV
induce significant adverse effects associated with the vaccine at (Chabeda et al. 2018).
all provided doses (Bogani et al. 2018). On the whole, regardless of promising outcomes shown by
In the case of HPV16/18 + CIN 2/3 patients, VGX-3100, a these vaccines in preclinical investigations and clinical trials
DNA vaccine that encodes for E6 and E7 oncoproteins of HPV against other types of cancer, replica vaccines against HPV
type 16/18, has finished its phase IIb clinical trial and given and HPV related disorders did not yet reach the stage of the
intramuscularly with electroporation. A total of 53/107 (49.5%) clinical trial, except for the genetically modified SFV express-
of VGX-3100 patients in the per-protocol study displayed histo- ing HPV 16 E6 / E7 (Vvax001; ViciniVax BV) (Vonsky et al.
pathological regression, compared with 11/36 (30.6%) of place- 2019). These vaccines seem highly promising for the cure of
bo subjects. In the updated intention-to-treatment study, 55/114 HPV lesions; however, further research needs to be conducted
patients (48.2%) with VGX-3100 treatment had histopathologi- (Liu et al. 2019).
cal relapse compared with 12/40 (30%) with placebo patients
(Trimble et al. 2015). The most frequent adverse responses were Whole cell–based vaccines
site reactions, but in the VGX3100 group (98/125, 78.4%), only
in the injection site erythema was significantly higher than in the These vaccines have been developed as a promising therapeu-
placebo group (24/42, 57.1%). Fatigue, myalgia, nausea, and tic vaccine against disorders related to HPV (Barra et al.
arthralgia were also the other adverse effects. For women having 2020). These vaccines involve isolation and removal of cells
confirmed diagnosis of CIN 2 and 3, a phase III randomized, (such as T lymphocytes or dendrite cells) from the expunged
placebo-controlled study is ongoing to determine the effective- tumors of patients or peripheral blood, propagating and ma-
ness, protection, and resistance of VGX-3100 when given intra- neuvering them ex vivo, and ultimately transmitting the mu-
muscularly superseded by electroporation (NCT03185013) tated and picked cells back to the patients (Liu et al. 2019)
(Barra et al. 2020).
ZYC101 is a vaccine that consists of a human MHC class I DC-based vaccines Dendritic cells are inserted on HPV antigens
antigen (HLA-DRα) residue that is attached with a peptide from for the production of DC-based vaccines. Origination and regu-
the HPV type 16 E7 oncoproteins. This vaccine was examined in lation of T cell responses are greatly demonstrated by these den-
an open-label uncontrolled trial against HPV16-associated cervi- drite cells in vitro. Because they promote the identification of
cal dysplasia and anal dysplasia, in which five out of fifteen CIN specific cancer-related antigens that are not usually found on
diagnosed patients showed complete reversion and three out of human cells, therefore, they are considered hypothetically the
twelve patients (40.0%) demonstrated incomplete reversion with best candidates for immunotherapeutic approaches. The genes
anal intraepithelial neoplasia (Barra et al. 2020). that encode for cytokines such as IL-2, IL-12, and granulocyte-
macrophage colony-stimulating factor (GM-CSF) aid in the
RNA replicon–based DNA vaccines The properties of RNA loading of these cells to enhance the immune response. Such
and DNA vaccines are analogous because they are innocuous therapeutic vaccines were previously studied in the treatment of
and do not produce neutralizing antibodies, and they can be progressive cancers (Barra et al. 2020)
given several epochs. Furthermore, no possibility of cellular DCS has been pulsated with HPV16/18 E7 and then given
transformations or chromosomal fusion is posed by RNA- back to patients with IL-2 in phase I clinical trial. All patients
based replicating forms (Chabeda et al. 2018). However, they have had an E7-specific CD8 + response. Dendrite cells were
are hard to manufacture and cannot proliferate across cells pulsated with HPV16/18 E7 along with peephole limpet he-
(Lundstrom 2015). mocyanin in another phase I clinical trial and it was managed
RNA replicon is encoded in a DNA vaccine in case of in patients with phase Ib or IIa cervical tumor, stimulating DC
suicidal DNA vaccines to solve this problem. In transfected maturation. Consequently, a rise in CD8+ T lymphocytes spe-
cells, genomic integration is prevented by suicidal DNA trans- cific to E7 was shown by 8 of 10 patients (Liu et al. 2019).
lation into RNA that stimulates apoptosis. But this approach A subcutaneous injection was administered to the patient.
has directed to weak immunogenicity due to apoptosis of During or after DC vaccinations, no major local or systemic
Environ Sci Pollut Res (2021) 28:47752–47772 47765

Table 1 Main therapeutic vaccine for the cure of cervical cancer

Names of vaccines Effectiveness Limitations References

Bacterium and virus-based live attenuated vaccines

Lm-LLO-E7 Extremely immune accelerating agents, Preceding immune response against vector, Barra et al.
MVA Huge variety of existing vectors; No frequent processing, Safety hazards (2020)
GLBL101c Antigen-presenting cells can produce both for immune-compromised persons Vonsky
BLS-M07 genetically modified plasmid and et al.
TA-HPV expressed protein, Imitates normal pro- (2019)
gression of infection. Marzi et al.
(2015)
(Hancock
et al.
(2018)
Peptide vaccines
PDS0101 Permanence, protection, easy to produce; HLA limited, minimal immunogenicity, Vonsky
Pep can capability to contain a varied variety of adjuvant needs to be co-administrated, et al.
ISA 101 epitopes; chance of alteration to make compulsory preceding mapping of (2019)
TG4001 better attachment to MHC epitopes as an element of prospective Cheng
immunogenic choice; et al.
(2018)
van
Poelgee-
st et al.
(2016)
Greenfield
et al.
(2015)
Hancock
et al.
(2018)
Protein vaccines
GTL001 Non-MHC limited, (all antigens originate Minimal immunogenicity, adjuvant needs to Hancock
TA-CIN from antigen-presenting cells intracellular be co-administrated, et al.
GTL002 procedure), Harmless, Stabling, and ease Produces antibodies in place of cytotoxic T (2018)
SGN-00101 of manufacturing, not HLA limited lymphocytes Vonsky
TVGV-1 et al.
(2019)
Cheng
et al.
(2018)
DNA vaccines
ZYC 101 Stimulate both humoral and cell-mediated Minimal antigenicity, continued cellular H. J. Kim
GX-188 immune responses, harmless, stabling, gene expression since they have minimal and Kim
pNGVL4a-CRT-E7 have a low price immunogenicity, adjuvant needs to be (2017)
VGX-3100 co-administrated Hancock
et al.
(2018)
Bogani
et al.
(2018)
Alvarez
et al.
(2016)
Y. Zhang
et al.
(2019)
RNA-based vaccines
Vaccines have been manufacturing for Temporary abrasions, several modes of Hard to manufacture and stock, Vonsky
several years. RNA replicon vaccines administrating vaccines, continued non-stability, labor exhaustive, no et al.
against HPV and HPV linked disorders antigenic expression, No possibility of intercellular dispersal, Dose-restrictive (2019)
have not undergone the clinical trial harmfulness, reduced immunogenicity,
47766 Environ Sci Pollut Res (2021) 28:47752–47772

Table 1 (continued)

Names of vaccines Effectiveness Limitations References

phase, apart from for the Vvax001,(a cellular transformation and chromosomal the origination of apoptosis in transfected Kübler
recombinant SFV expressing HPV 16 E6 integration cells, complications in creation, scaling up et al.
and E7) and manufacturing, Various mRNAs (2015)
cannot be amalgamated in the same Cheng
preparation, safer data of humans for et al.
RNA has not been completely established (2018)
Whole cell–based
HPV E6-E7 encumbered monocytes DC-based vaccines: Costly, Labor exhaustive, Safety hazards, Barra et al.
Highly immune-stimulating encompassing Highly engineering task (2020)
several methods of antigen loading Vonsky
Tumor cell vaccines: et al.
Target to enhance the immunogenicity of (2019)
cancer cells by raising the expression of Cheng
immune modulator proteins, for example, et al.
GM-CSF, IL-2, and IL-12 (2018)
H. J. Kim
and Kim
(2017)

reactions were reported (Barra et al. 2020). The disadvantages several other cervical, vulvar, vaginal, anal, penile, and head
of DC-based vaccines are short half-life, problems in acquir- and neck cancers. Subsequently, it is a major public health issue
ing large numbers of antilogous DC from the patient, and lack particularly for youths who are extremely affected. The produc-
of propagation that restricts enduring immune response. tion of HPV vaccines has directed the capability of defending
Furthermore, dendrite cell–based vaccines contributed no and preventing HPV infection and its sequela. Since existing
clinical responses despite being able to stimulate cell- vaccines have no therapeutic impact, therapeutic HPV vaccines
mediated and serological immunity against HPV [61, 5]. In are desperately needed to lessen the risk of cervical cancer.
conclusion, even though progressed incidents of cervical can- Even if the public has been able to control HPV infections with
cer make use of DC vaccines, it is unsuitable these DCs will be prophylactic vaccines like Gardasil, Cervarix, and Gardasil-9,
used in the treatment of CIN abrasions because the processes still, a substantial number of people are also at risk for devel-
involved are expensive and labor-intensive (Barra et al. 2020). oping HPV-related malignancies and cancer with current HPV
infection or HPV-related illnesses. Thus, it is more important
Tumor cell–based vaccine Granulocyte-macrophage colony- than ever to use HPV therapeutic vaccines.
stimulating factors and cytokines like IL-2 and IL-12 are To date, no commercially available therapeutic vaccine for
expressed by designed isolated cancer cells. Tumor cell– HPV infection treatment and related malignancies has been
based vaccines upon re-administration greatly enhance the authorized. Clinical trials of HPV therapeutic vaccines, in-
tumor cells’ immunogenicity, thus stimulating immune re- cluding whole cell–based vaccines, DNA, peptide/protein,
moval of abrasions. Such type of vaccines was studied in DNA, and live vector, indicate that these HPV vaccines have
different types of cancer in clinical trials and ought not to the significant ability for safe, reliable, and non-invasive cure
recognize other cancerous antigens. Vaccines based on tumor of cervical cancer as well as emphasizing deficiencies in their
cells may not be the earliest option for its treatment because functional use. But therapeutic vaccines of each class have
cervical cancer is known to have particular antigens, like E6 their efficacy, benefits, and limitations (Table 1). To date, in
and E7. Nevertheless, tumor cell vaccines are related to the phase I–II clinical studies, most of the HPV therapeutic vac-
disadvantage of establishing new tumors in patients, which cines have been analyzed (Table 2). Further phase III clinical
restricts their clinical applicability, especially in HPV- studies are also required to determine the optimum age and
positive patients with typical cytology or patients with low- gender of the population and for the exact description of the
grade abrasions (Liu et al. 2019). function of therapeutic vaccines for the cure of preinvasive
abrasions and cervical HPV illness.
Nonetheless, several clinical trials show the advancement
Conclusion achieved using numerous vaccine approaches and two vaccine
candidates, ADXS11-001 bacterial vector vaccine and
The most common sexually transmitted infection in the USA is VGX3100 DNA vaccine. Both of these vaccines are in phase
not only human papillomavirus infection, but it is the source of III clinical trials, indicating that the vaccine has promising
Environ Sci Pollut Res (2021) 28:47752–47772 47767

Table 2 Summary on therapeutic HPV vaccines clinical trials, studies, and their outcomes

Vaccines Antigens Trial design Trial outcome Side effects References

Bacterial vector–based vaccines

GLBL101c E7oncoprotein of HPV Phase I/IIa clinical trial was The substantial rise in No serious adverse effects Barra et al.
type 16 conducted on 17 HPV16 E7-CMI in the Cervical reported (2020)
positive patients having a tract of the vagina, Yang et al.
diagnosis of CIN3 Disease relapse was (2017)
observed in 9 patients to Kawana
CIN2, and 5 patients et al.
further relapsed to LSIL (2014)
Lm-LLo-E7 E7 oncoproteins of Phase I clinical trial was E7-specific T cells rise was The major side effects Barra et al.
HPV type 16 conducted on 15 patients found in 3 PBMCs reported were vomiting, (2020)
suffering from recalcitrant patients. 4 patients the agony of the skeleton Yang et al.
chronic, metastatic, or experienced a decrease in Pyrexia, chills, anemia, (2017)
progressed squamous cell tumor size and tachycardia, nausea, and
cervical carcinoma. progression. headache.
Viral vector–based vaccines
TA-HPV E6 and E7oncoproteins Phase I/II clinical trial was CTL immune response Adequate and mild toxicity Barra et al.
of HPV type 16/18 conducted on 8 patients specific to HPV triggered was reported after (2020)
suffering from the by vaccination was single-dose administration Yang et al.
progressed stage of cervi- observed in 3 out of 8 (2017)
cal cancer members (almost 28 %
patients),
Two patients were free of
tumors
15-21 months after the
following vaccination
Phase I clinical trial was Cytotoxic T lymphocytes Minor to Barra et al.
conducted on 29 patients specific to HPV were modest (2020)
suffering from Stage Ib or observed in 4 patients after Local toxicity was observed. Yang et al.
IIa cervical cancer a single vaccination. (2017)
Serological responses unique
to HPV were established
in 8 patients (28%).
Phase II clinical trial was At least a 50% decrease in Local response was found Barra et al.
conducted on 12 patients total abrasion span was near the vaccination site (2020)
aged 42–54 suffering from observed in24 weeks in 5 between days 7–10 and 2 Yang et al.
15 years with high-grade out of 12 patients with 1 patients were identified (2017)
HPV-positive patient exhibiting total with momentarily con-
intraepithelial vaginal or reversion of the abrasion. fined movement of the
vulval neoplasia. On the whole, an average arm.
decline in abrasion size of
40% was observed in 83%
of women. An enhanced T
cell and immunoglobulin
Gtiter response to the
vaccinia virus was
observed in all patients.
MVAE2 E2oncoproteins of Phase III clinical trial was 90% removal of abrasion The major adverse effects Barra et al.
HPV type 16 conducted on 180 males was reported in female observed were headache, (2020)
and 1176 females cured patients and 100% symptoms of the flu, Yang et al.
suffering from HPV- removal of abrasion was fever, frost, pain, joint and (2017)
stimulated AGIN reported in male cured abdominal pain were. Rosales et al.
patients. (2014)
All checked patients
experienced antibody and
T cell responses.
BLS-M07 E7oncoproteins of Phase I/IIa clinical trial was Safety and effectiveness No serious adverse effects Barra et al.
HPV type 16 conducted on HPV-16 in- evaluation (primary were reported. (2020)
fected patients having endpoint), development of
CIN3. systemic immunoglobulin
19 patients undergone phase IgG against HPVE7; and
I trial and 8 patients the Reid Colposcopic
47768 Environ Sci Pollut Res (2021) 28:47752–47772

Table 2 (continued)

Vaccines Antigens Trial design Trial outcome Side effects References

undergone phase IIa trial.

Index (RCI) assessed
abrasion-grade change
(secondary end points)
TG4001 E6 and E7oncoproteins 21 patients having HPV16+ Disease relapse was Major adverse effects Barra et al.
of HPV type 16 infection and CIN2/3 di- observed in 10 out of 21 reported were fever, (2020)
agnosis undergone phase I patients (48%). 8 patients headache, pain in bone, Brun et al.
clinical trial showed HPV DNA inflammation, pruritus, (2011)
removal and7 patients edema, lymphadenopathy,
showed mRNA removal. asthenia, vaginal release.
Peptide vaccines
ISA101 E6 and E7oncoproteins Phase II clinical trial was 18 patients out of 34 (53%; The ulceration and Barra et al.
of HPV type 16 conducted on 34 patients 95 % showed clinical inflammation of the skin (2020)
having HPV-16+ response with confidence was observed in patients
Irredeemable solid tumors interval (CI) (35.1 to 70.2) along with local reactions,
(vaginal, cervical, vulvar, at 3 months and 15patients even these adverse effects
penile, and anal cancer out of 29 (52%; 95 %) persisted for 12 months
along with or pharyngeal showed clinical responses
squamous cell carcinoma). with confidence interval
(CI) at 12 months. The
complete histological re-
sponse was shown by 8
patient
PDS0101 E6 and E7oncoproteins A phase I clinical trial is There are no findings in the Barra et al.
of HPV type 16 ongoing in 18 estimated literature on its use in (2020)
female patients having humans.
high-grade HPV infection
or diagnosis of CIN1
Pepcan E6oncoproteins of Phase I clinical trial was A decrease in abrasion rate of Reactions at the injection Barra et al.
HPV type 16 conducted on 24 CIN 2/3 83% was reported. site, no dose-limiting tox- (2020)
diagnosed patients proved Immune responses icities have been encoun- Coleman
by biopsy triggered by vaccines were tered by either patient et al.
observed after 4 (2016)
vaccinations in 65% of
women
A phase II clinical trial is Colposcopy-driven quadrant
ongoing biopsies showed clinical
response
Protein vaccines
SGN-00101 The BCG heat shock Phase II clinical trial was 13 patients (22.5%) showed There were only moderate, Barra et al.
protein associated conducted on 58 patients complete histological self-limiting side effects (2020)
with E7oncoproteins with a diagnosis of CIN 3 response (CR) and 32 associated with the injec-
of HPV type 16 (55%) females showed in- tion site
complete response
TA-CIN + E6/E7/L2oncoproteins Phase I clinical trial was 24 out of 32 vaccinated Adverse effects reported Barra et al.
of HPV type 16 conducted on 40 healthy patients produced were reactions at the (2020)
patients TA-CIN specific injection site, headache,
immunoglobin IgG. CMI tenderness, and fatigue
was produced by 25 out of
32 vaccinated patients
Phase II clinical trial was 63% abrasion response was Imiquimod-related local Barra et al.
conducted on 19 patients shown 1 year after reactions were observed. (2020)
with a diagnosis of vaccination.
VIN2/3
TVGV-1 The E7 peptide Phase IIa clinical trial is Since the trial is ongoing, no Barra et al.
sequence of HPV ongoing on 51 expected findings have yet been (2020)
type 16. patients having a reported.
diagnosis of CIN 2–3
GTL001 E7 Phase I clinical trial was Analyzed GTL00 resistance, Slight to moderate Barra et al.
oncoproteins of HPV conducted on 47 HPV-16 safety, and injection-site reactions in- (2020)
type 16 and 18 or HPV-18 +vepatients immunogenicity clude itching induration, Van Damme
having either usual or et al.
Environ Sci Pollut Res (2021) 28:47752–47772 47769

Table 2 (continued)

Vaccines Antigens Trial design Trial outcome Side effects References

slightly anomalous cervi- pain tenderness, and (2016)

cal cytology swelling.
The most common systemic
reactions were myalgia,
Headache, and fatigue
Imiquimod is an 239 HPV-16 or HPV-18 +ve Between placebo groups and There was no unforeseen Barra et al.
adjuvant that was patient underwent phase II GTL001there was incident reported and (2020)
checked with it clinical trial having either arithmetically substantial vaccination was well
usual or slightly anoma- variance in the removal of tolerated
lous cervical cytology virus and advancement of
abrasions to high-grade
GTL002 HPV type 16, 18, 45, Prototypes of Beagle dogs T cell immune response Barra et al.
31, 33 and and mice. There are no specific to E7 is triggered (2020)
52modified E7 human details on its use so against each of the
proteins far genotypes
DNA vaccines
pNGVL4a-CRT/ E7oncoproteins of 32 HPV16+ patients having Histological relapse to CIN1 Reactions at the injection site Barra et al.
E7(detox) HPV type 16 a diagnosis of CIN2/3 un- or less was experienced in were reported. (2020)
dergone phase I clinical 30% of vaccinated Alvarez et al.
trial patients. (2016)
After vaccination, a rise in
intraepithelial C8+ T cells
in the filtrate was reported.
VGX-3100 E6 and Phase I clinical trial was Antibody-mediated immune Major side effects reported Barra et al.
E7oncoproteinsof conducted on 18 response specific to HPV were reaction at the (2020)
HPV type16,18 HPV16/18 + patients with was detected in all patients injection site, fever, Yang et al.
a diagnosis of CIN2/3 while 78% of patients tenderness, and pain. (2017)
showed HPV-specific
CMI.
167 HPV16/18 + CIN2/3 Relapse was shown by Reaction at the injection site, Barra et al.
patients undergone Phase 49.5% of immunized headache, nausea, (2020)
IIb clinical trial patients compared to arthralgia, myalgia Yang et al.
30.6% in the placebo fatigues erythema (2017)
group. Humoral and T cell
immune responses are
boosted by vaccinations.
GX-188E E6 and E7 Phase I clinical trial was An enhanced HPV-specific Major side effects reported Barra et al.
oncoproteinsof HPV conducted on nine HPV CMI was shown in all pa- were chills, hypoesthesia, (2020)
type16,18 16/18+patients having a tients. Complete regres- swelling, aching at Kim et al.
diagnosis of CIN3 sion in abrasion was injection site nuisance, (2014)
shown by 7 patients at the rhinitis, exhaustion
end of the trial.
Cell vaccines
DC vaccinations Antigens of HPV Phase I clinical trial was There was no substantial rise Major side effects reported Barra et al.
conducted on 14HPV+ in lymphocyte were reaction at the local (2020)
patients having propagation. site, chills, abdominal Ramanathan
progressed, chronic discomfort, fever, nausea et al.
cervical cancer. (2014)

potential shortly. In addition, another important subject is the that are established for the cure of HPV illnesses and HPV-
financial dimension correlated to therapeutic vaccines; one related disorders.
study has attempted to investigate the prospective price of this
HPV therapeutic vaccine for females living in the Netherlands
with cervical abrasions caused by HPV. The cost of the vac- Future perspectives
cine was less than the normal medication price for patients
having a diagnosis of cervical malignancies and CIN 2/3. With the information collected from the current and prior re-
Hence, the main focus of this review was to discuss primarily searches along with sustained efforts in the production of ther-
the therapeutic HPV vaccines presently available and or those apeutic HPV vaccines, we think that these therapeutic
47770 Environ Sci Pollut Res (2021) 28:47752–47772

approaches will go onto obtain progress. We are assured that therapeutic vaccines for treating human papillomavirus-related cer-
vical intraepithelial neoplasia. J Obstet Gynaecol Res 46(7):989–
soon these therapeutic vaccines will become clinically acces-
1006
sible and these vaccines will commonly use along with other Bhaskaran M, Murali SV, Rajaram B, Krishnasamy S, Devasena CS,
remedies involving surgery, chemotherapy, and radiation ther- Pathak A, Ravi V, Swaminathan K, Ayyappa A, Vedhantham S
apy, for the prevention of HPV and HPV-linked disorders. (2019) Association of HLA-A,-B, DRB, and DQB alleles with per-
Prime-boost treatment and other combinatorial techniques sistent HPV-16 infection in women from Tamil Nadu, India. Viral
Immunol 32(10):430–441
may offer a better therapeutic HPV vaccine approach to boost Bogani G, Maggiore ULR, Signorelli M, Martinelli F, Ditto A, Sabatucci
T cell immune responses. For this reason, increased immuno- I, Mosca L, Lorusso D, Raspagliesi F (2018) The role of human
genicity is the most important criterion for the clinical imple- papillomavirus vaccines in cervical cancer: prevention and treat-
mentation of all therapeutic vaccines. These ongoing efforts to ment. Crit Rev Oncol Hematol 122:92–97
Bowden SJ, Bodinier B, Kalliala I, Zuber V, Vuckovic D, Doulgeraki T,
produce therapeutic vaccines help to manage and control ma- Whitaker MD, Wielscher M, Cartwright R, Tsilidis KK (2021)
lignancies related to HPV along with traditional approaches Genetic variation in cervical preinvasive and invasive disease: a
for treating HPV. Further work is currently needed on the genome-wide association study. The Lancet Oncology 22(4):548–557
effects of integrated methods and their basic mechanisms to Brun J-L, Dalstein V, Leveque J, Mathevet P, Raulic P, Baldauf J-J,
Scholl S, Huynh B, Douvier S, Riethmuller D (2011) Regression
improve various synergistic strategies individually custom-
of high-grade cervical intraepithelial neoplasia with TG4001
ized for each patient. targeted immunotherapy. Am J Obstet Gynecol 204(2):169–1e1
In summary, the organized use of different approaches may Bruni L, Diaz M, Barrionuevo-Rosas L, Herrero R, Bray F, Bosch FX, de
work in conjunction against HPV infection. The fusion of Sanjosé S, Castellsagué X (2016) Global estimates of human papil-
prophylactic vaccines with therapeutic ones, or several forms lomavirus vaccination coverage by region and income level: a
pooled analysis. Lancet Glob Health 4(7):e453–e463
of therapeutic vaccines as in prime-booster approach, anti-vi- Cai H, Feng Y, Fan P, Guo Y, Kuerban G, Chang C, Yao X, Peng Y,
ral, or checkpoint inhibitors, and other similar fusions, may Zheng Wang R (2021). HPV16 E6-specific T cell response and
have a great effect on the cure of HPV infection. HLA-A alleles are related to the prognosis of patients with cervical
cancer. https://doi.org/10.21203/rs.3.rs-209456/v1
Chabeda A, Yanez RJ, Lamprecht R, Meyers AE, Rybicki EP, Hitzeroth
II (2018) Therapeutic vaccines for high-risk HPV-associated dis-
Author contribution NA, SA, MJ, AR, RR, RF, MA, AB, AB, AS, GZ,
eases. Papillomavirus Research 5:46–58
and MAS equally contributed to all stages of preparing, drafting, and
writing as well in this review article. All authors read and approved the Chan PK, Cheung JL, Cheung T-H, Lin C, Tam AO, Chan DP, Zhou DX,
final version of this manuscript. Lo KW, Yim S-F, Siu S-SN (2006) HLA-B alleles, high-risk HPV
infection and risk for cervical neoplasia in southern Chinese women.
Int J Cancer 118(6):1430–1435
Data availability All data presented herein are constant with the pub- Chan PK, Cheung T-H, Lin CK, Siu S-SN, Yim S-F, Lo KW, Cheung JL,
lished literature. Tam AO, Tang JW (2007) Association between HLA-DRB1 poly-
morphism, high-risk HPV infection and cervical neoplasia in south-
Declarations ern Chinese. J Med Virol 79(7):970–976
Cheng MA, Farmer E, Huang C, Lin J, Hung C-F, Wu T-C (2018)
Ethical statement Not applicable. Therapeutic DNA vaccines for human papillomavirus and associat-
ed diseases. Hum Gene Ther 29(9):971–996
Coleman HN, Greenfield WW, Stratton SL, Vaughn R, Kieber A,
Consent to participate Not applicable.
Moerman-Herzog AM, Spencer HJ, Hitt WC, Quick CM,
Hutchins LF (2016) Human papillomavirus type 16 viral load is
Consent for publication Not applicable. decreased following a therapeutic vaccination. Cancer Immunol
Immunother 65(5):563–573
Competing interests The authors declare no competing interests. Cuzick J, Terry G, Ho L, Monaghan J, Lopes A, Clarkson P, Duncan I
(2000) Association between high-risk HPV types, HLA DRB1* and
DQB1* alleles and cervical cancer in British women. Br J Cancer
82(7):1348–1352
References Da Silva DM, Skeate JG, Chavez-Juan E, Lühen KP, Wu J-M, Wu C-M,
Kast WM, Hwang K (2019) Therapeutic efficacy of a human pap-
Alvarez RD, Huh WK, Bae S, Lamb LS Jr, Conner MG, Boyer J, Wang illomavirus type 16 E7 bacterial exotoxin fusion protein adjuvanted
C, Hung C-F, Sauter E, Paradis M (2016) A pilot study of with CpG or GPI-0100 in a preclinical mouse model for HPV-
pNGVL4a-CRT/E7 (detox) for the treatment of patients with associated disease. Vaccine 37(22):2915–2924
HPV16+ cervical intraepithelial neoplasia 2/3 (CIN2/3). Gynecol de Araujo Souza PS, Villa LL (2003) Genetic susceptibility to infection
Oncol 140(2):245–252 with human papillomavirus and development of cervical cancer in
Alves BM, Prellwitz IM, Siqueira JD, Meyrelles ÂR, Bergmann A, women in Brazil. Mutation Research/Reviews in Mutation Research
Seuánez HN, Machado ES, Soares MA, Soares EA (2015) The 544(2–3):375–383
effect of human leukocyte antigen G alleles on human papillomavi- de Araujo Souza PS, Sichero L, Maciag PC (2009). HPV variants and
rus infection and persistence in a cohort of HIV-positive pregnant HLA polymorphisms: the role of variability on the risk of cervical
women from Brazil. Infect Genet Evol 34:339–343 cancer. Future Oncol 5(3):359–70. https://doi.org/10.2217/fon.09.8
Barra F, Della Corte L, Noberasco G, Foreste V, Riemma G, Di Filippo Dong D, Yang H, Li K, Xu G, Song L, Fan X, Jiang X, Yie S (2010)
C, Bifulco G, Orsi A, Icardi G, Ferrero S (2020) Advances in Human leukocyte antigen-G (HLA-G) expression in cervical
Environ Sci Pollut Res (2021) 28:47752–47772 47771

lesions: association with cancer progression, HPV 16/18 infection, Ivansson EL, Magnusson JJ, Magnusson PKE, Erlich HA, Gyllensten
and host immune response. Reprod Sci 17(8):718–723 UB (2008) MHC loci affecting cervical cancer risk: distinguishing
Fahim NM, Shehata IH, Taha SE, Fahmy RA, Elsayed MS (2018) the effects of HLA-DQB1 and non-HLA genes TNF, LTA, TAP1
Human Leukocyte Antigen-G (HLA-G) Expression in precancerous and TAP2. Genes Immun 9(7):613–623
and cancerous cervical lesions: association with human papilloma Kawana K, Adachi K, Kojima S, Taguchi A, Tomio K, Yamashita A,
virus infection and host immune response. The Egyptian J Immunol Nishida H, Nagasaka K, Arimoto T, Yokoyama T (2014) Oral vac-
25(1):125–134 cination against HPV E7 for treatment of cervical intraepithelial
Ferguson R, Ramanakumar AV, Richardson H, Tellier P-P, Coutlée F, neoplasia grade 3 (CIN3) elicits E7-specific mucosal immunity in
Franco EL, Roger M (2011) Human leukocyte antigen (HLA)-E and the cervix of CIN3 patients. Vaccine 32(47):6233–6239
HLA-G polymorphisms in human papillomavirus infection suscep- Khong H, Overwijk WW (2016) Adjuvants for peptide-based cancer
tibility and persistence. Hum Immunol 72(4):337–341 vaccines. Journal for Immunotherapy of Cancer 4(1):1–11
Gillio-Tos A, da Graça Bicalho M, Fiano V, Grasso C, Tarallo V, De Kim HJ, Kim H-J (2017) Current status and future prospects for human
Marco L, Trevisan M, Xavier M, Slowik R, Carvalho NS (2012) papillomavirus vaccines. Arch Pharm Res 40(9):1050–1063
Case–control study of HLA-G promoter methylation status, HPV Kim TJ, Jin H-T, Hur S-Y, Yang HG, Seo YB, Hong SR, Lee C-W, Kim
infection and cervical neoplasia in Curitiba, Brazil: a pilot analysis. S, Woo J-W, Park KS (2014) Clearance of persistent HPV infection
BMC Cancer 12(1):1–10 and cervical lesion by therapeutic DNA vaccine in CIN3 patients.
Gokhale P, Mania-Pramanik J, Sonawani A, Idicula-Thomas S, Kerkar S, Nat Commun 5(1):1–14
Tongaonkar H, Chaudhari H, Warke H, Salvi V (2014) Cervical Kübler H, Scheel B, Gnad-Vogt U, Miller K, Schultze-Seemann W, Vom
cancer in Indian women reveals contrasting association among com- Dorp F, Parmiani G, Hampel C, Wedel S, Trojan L (2015) Self-
mon sub-family of HLA class I alleles. Immunogenetics 66(12): adjuvanted mRNA vaccination in advanced prostate cancer patients:
683–691 a first-in-man phase I/IIa study. Journal for Immunotherapy of
Gonçalves CA, Lopes-Júnior LC, Nampo FK, Zilly A, Mayer PCM, Cancer 3(1):1–14
Pereira-da-Silva G (2019) Safety, efficacy and immunogenicity of Landy R, Windridge P, Gillman MS, Sasieni PD (2018) What cervical
therapeutic vaccines in the treatment of patients with high-grade screening is appropriate for women who have been vaccinated
cervical intraepithelial neoplasia associated with human papilloma- against high risk HPV? A simulation study. Int J Cancer 142(4):
virus: A systematic review protocol. BMJ Open 9(7):e026975 709–718
Goodman MT, McDuffie K, Hernandez B, Bertram CC, Wilkens LR, Leo PJ, Madeleine MM, Wang S, Schwartz SM, Newell F, Pettersson-
Kymmer U, Hemminki K, Hallmans G, Tiews S, Steinberg W
Guo C, Seifried A, Killeen J, Le Marchand L (2001) CYP1A1,
(2017) Defining the genetic susceptibility to cervical neoplasia—a
GSTM1, and GSTT1 polymorphisms and the risk of cervical squa-
genome-wide association study. PLoS Genet 13(8):e1006866
mous intraepithelial lesions in a multiethnic population. Gynecol
Oncol 81(2):263–269 Lin K-H, Chang L-S, Tian C-Y, Yeh Y-C, Chen Y-J, Chuang T-H, Liu S-
J, Leng C-H (2016) Carboxyl-terminal fusion of E7 into Flagellin
Greenfield WW, Stratton SL, Myrick RS, Vaughn R, Donnalley LM,
shifts TLR5 activation to NLRC4/NAIP5 activation and induces
Coleman HN, Mercado M, Moerman-Herzog AM, Spencer HJ,
TLR5-independent anti-tumor immunity. Sci Rep 6(1):1–10
Andrews-Collins NR (2015) A phase I dose-escalation clinical trial
Liu Y, Li H, Pi R, Yang Y, Zhao X, Qi X (2019) Current strategies
of a peptide-based human papillomavirus therapeutic vaccine with
against persistent human papillomavirus infection. Int J Oncol
Candida skin test reagent as a novel vaccine adjuvant for treating
55(3):570–584
women with biopsy-proven cervical intraepithelial neoplasia 2/3.
Louvanto K, Roger M, Faucher M-C, Syrjänen K, Grenman S, Syrjänen
Oncoimmunology 4(10):e1031439
S (2018) HLA-G and vertical mother-to-child transmission of hu-
Guimarães MC, Soares CP, Donadi EA, Derchain SF, Andrade LA, Silva
man papillomavirus infection. Hum Immunol 79(6):471–476
TG, Hassumi MK, Simões RT, Miranda FA, Lira RC (2010) Low
Lundstrom K (2015) RNA-based drugs and vaccines. Expert Review of
expression of human histocompatibility soluble leukocyte antigen-G
Vaccines 14(2):253–263
(HLA-G5) in invasive cervical cancer with and without metastasis,
Maciag PC, Schlecht NF, Souza PS, Franco EL, Villa LL, Petzl-Erler ML
associated with papilloma virus (HPV). J Histochem Cytochem
(2000) Major histocompatibility complex class II polymorphisms
58(5):405–411
and risk of cervical cancer and human papillomavirus infection in
Hancock G, Hellner K, Dorrell L (2018) Therapeutic HPV vaccines. Best Brazilian women. Cancer Epidemiology and Prevention Biomarkers
Practice & Research Clinical Obstetrics & Gynaecology 47:59–72 9(11):1183–1191
Harper DM, DeMars LR (2017) HPV vaccines–a review of the first Madeleine MM, Brumback B, Cushing-Haugen KL, Schwartz SM,
decade. Gynecol Oncol 146(1):196–204 Daling JR, Smith AG, Nelson JL, Porter P, Shera KA, McDougall
Hernández-Hernández DM, Cerda-Flores RM, Juárez-Cedillo T, JK (2002) Human leukocyte antigen class II and cervical cancer risk:
Granados-Arriola J, Vargas-Alarcón G, Apresa-García T, Alvarado- a population-based study. J Infect Dis 186(11):1565–1574
Cabrero I, García-Carrancá A, Salcedo-Vargas M, Mohar-Betancourt Madeleine MM, Johnson LG, Smith AG, Hansen JA, Nisperos BB, Li S,
A (2009) Human leukocyte antigens I and II haplotypes associated Zhao L-P, Daling JR, Schwartz SM, Galloway DA (2008)
with human papillomavirus 16-positive invasive cervical cancer in Comprehensive analysis of HLA-A, HLA-B, HLA-C, HLA-
Mexican women. Int J Gynecol Cancer 19(6):1099–1106 DRB1, and HLA-DQB1 loci and squamous cell cervical cancer risk.
Hildesheim A, Wang SS (2002) Host and viral genetics and risk of cer- Cancer Res 68(9):3532–3539
vical cancer: a review. Virus Res 89(2):229–240 Mahmud SM, Robinson K, Richardson H, Tellier P-P, Ferenczy AS,
Hu Y, Wu J-Z, Zhu H, Zhang S-H, Zhu Y-Y, Wu Y-Y, Shuai C-X (2017) Roger M, Coutlée F, Franco EL (2007) HLA polymorphisms and
Association of HLA-DRB1, HLA-DQB1 polymorphisms with cervical human Papillomavirus infection in a cohort of Montreal
HPV 16 E6 variants among young cervical cancer patients in University students. J Infect Dis 196(1):82–90
China. J Cancer 8(12):2401–2409 Marzi A, Kercher L, Marceau J, York A, Callsion J, Gardner DJ, Geisbert
Hus I, Gonet-Sebastianka J, Surdacka A, Bojarska-Junak A, Roliński J TW, Feldmann H (2015) Stat1-deficient mice are not an appropriate
(2015). Analysis of peripheral blood immune cells after prophylactic model for efficacy testing of recombinant vesicular stomatitis virus–
immunization with HPV-16/18 ASO4-adjuvanted vaccin. Advances based filovirus vaccines. J Infect Dis 212(suppl_2):S404–S409
in Hygiene & Experimental Medicine/Postepy Higieny i Medycyny Matsumoto K, Yasugi T, Nakagawa S, Okubo M, Hirata R, Maeda H,
Doswiadczalnej, 69, p543–548. 6p Yoshikawa H, Taketani Y (2003) Human papillomavirus type 16 E6
47772 Environ Sci Pollut Res (2021) 28:47752–47772

variants and HLA class II alleles among Japanese women with cer- Montreal university students: the influence of behavioral and bio-
vical cancer. Int J Cancer 106(6):919–922 logic factors. Cancer Epidemiology and Prevention Biomarkers
Metcalfe S, Roger M, Faucher M-C, Coutlée F, Franco EL, Brassard P 23(5):812–822
(2013) The association between human leukocyte antigen (HLA)-G Tota JE, Chevarie-Davis M, Richardson LA, Devries M, Franco EL
polymorphisms and human papillomavirus (HPV) infection in Inuit (2011) Epidemiology and burden of HPV infection and related dis-
women of northern Quebec. Hum Immunol 74(12):1610–1615 eases: implications for prevention strategies. Prev Med 53:S12–S21
Mousavi T, Saravi SS, Valadan R, Haghshenas MR, Rafiei A, Jafarpour Trimble CL, Morrow MP, Kraynyak KA, Shen X, Dallas M, Yan J,
H, Shamshirian A (2020) Different types of adjuvants in prophylac- Edwards L, Parker RL, Denny L, Giffear M (2015) Safety, efficacy,
tic and therapeutic human papillomavirus vaccines in laboratory and immunogenicity of VGX-3100, a therapeutic synthetic DNA
animals: a systematic review. Arch Virol 165(2):263–284 vaccine targeting human papillomavirus 16 and 18 E6 and E7 pro-
Odunsi K, Terry G, Ho L, Bell J, Cuzick J, Ganesan TS (1996) teins for cervical intraepithelial neoplasia 2/3: A randomised, dou-
Susceptibility to human papillomavirus-associated cervical intra- ble-blind, placebo-controlled phase 2b trial. Lancet 386(10008):
epithelial neoplasia is determined by specific HLA DR-DQ alleles. 2078–2088
Int J Cancer 67(5):595–602 Valentino K, Poronsky CB (2016) Human papillomavirus infection and
Paaso A, Jaakola A, Syrjänen S, Louvanto K (2019) From HPV infection vaccination. J Pediatr Nurs 31(2):e155–e166
to lesion progression: The role of HLA alleles and host immunity. Van Damme P, Bouillette-Marussig M, Hens A, De Coster I, Depuydt C,
Acta Cytol 63(2):148–158 Goubier A, Van Tendeloo V, Cools N, Goossens H, Hercend T
Panahi HA, Bolhassani A, Javadi G, Noormohammadi Z, Agi E (2020) (2016) GTL001, A therapeutic vaccine for women infected with
Development of multiepitope therapeutic vaccines against the most human papillomavirus 16 or 18 and normal cervical cytology: re-
prevalent high-risk human papillomaviruses. Immunotherapy 12(7): sults of a phase I clinical trial. Clin Cancer Res 22(13):3238–3248
459–479 van Poelgeest MI, Welters MJ, Vermeij R, Stynenbosch LF, Loof NM,
Ramanathan P, Ganeshrajah S, Raghanvan RK, Singh SS, Thangarajan R Berends-van der Meer DM, Löwik MJ, Hamming IL, van Esch EM,
(2014) Development and clinical evaluation of dendritic cell vac- Hellebrekers BW (2016) Vaccination against oncoproteins of
cines for HPV related cervical cancer-a feasibility study. Asian Pac J HPV16 for noninvasive vulvar/vaginal lesions: lesion clearance is
Cancer Prev 15(14):5909–5916 related to the strength of the T-cell response. Clin Cancer Res
Roden RB, Stern PL (2018) Opportunities and challenges for human pap- 22(10):2342–2350
illomavirus vaccination in cancer. Nat Rev Cancer 18(4):240–254 Vici P, Pizzuti L, Mariani L, Zampa G, Santini D, Di Lauro L, Gamucci
Rosales R, López-Contreras M, Rosales C, Magallanes-Molina J-R, T, Natoli C, Marchetti P, Barba M (2016) Targeting immune re-
Gonzalez-Vergara R, Arroyo-Cazarez JM, Ricardez-Arenas A, del sponse with therapeutic vaccines in premalignant lesions and cervi-
Follo-Valencia A, Padilla-Arriaga S, Guerrero MV (2014) cal cancer: hope or reality from clinical studies. Expert Review of
Regression of human papillomavirus intraepithelial lesions is in- Vaccines 15(10):1327–1336
duced by MVA E2 therapeutic vaccine. Hum Gene Ther 25(12): Vonsky MS, Runov AL, Gordeychuk IV, Isaguliants MG (2019)
1035–1049 Therapeutic vaccines against human papilloma viruses: achieve-
Sanjeevi CB, Hjelmström P, Hallmans G, Wiklund F, Lenner P, ments and prospects. Biochem Mosc 84(7):800–816
Angström T, Dillner J, Lernmark (1996) Different HLA-DR-DO
Wang SS, Hildesheim A, Gao X, Schiffman M, Herrero R, Bratti MC,
haplotypes are associated with cervical intraepithelial neoplasia
Sherman ME, Barnes WA, Greenberg MD, McGowan L (2002)
among human papillomavirus type-16 seropositive and seronegative
Comprehensive analysis of human leukocyte antigen class I alleles
Swedish women. Int J Cancer 68(4):409–414
and cervical neoplasia in 3 epidemiologic studies. J Infect Dis
Santesso N, Mustafa RA, Wiercioch W, Kehar R, Gandhi S, Chen Y,
186(5):598–605
Cheung A, Hopkins J, Khatib R, Ma B (2016) Systematic reviews
Wang R, Pan W, Jin L, Huang W, Li Y, Wu D, Gao C, Ma D, Liao S
and meta-analyses of benefits and harms of cryotherapy, LEEP, and
(2020) Human papillomavirus vaccine against cervical cancer: op-
cold knife conization to treat cervical intraepithelial neoplasia. Int J
portunity and challenge. Cancer Lett 471:88–102
Gynecol Obstet 132(3):266–271
Wu Y, Liu B, Lin W, Xu Y, Li L, Zhang Y, Chen S, Xu A (2007) HPV16
Shanmugasundaram S, You J (2017) Targeting persistent human papil-
E6 variants and HLA class II polymorphism among Chinese women
lomavirus infection. Viruses 9(8):229
with cervical cancer. J Med Virol 79(4):439–446
Silva TG, Crispim JC, Miranda FA, Hassumi MK, de Mello JM, Simões
RT, Souto F, Soares EG, Donadi EA, Soares CP (2011) Expression Yang A, Farmer E, Lin J, Wu T-C, Hung C-F (2017) The current state of
of the nonclassical HLA-G and HLA-E molecules in laryngeal le- therapeutic and T cell-based vaccines against human papillomavi-
sions as biomarkers of tumor invasiveness. Histol Histopathol: ruses. Virus Res 231:148–165
1487–1497 Zhang X, Lv Z, Yu H, Wang F, Zhu J (2015) The HLA-DQB1 gene
Simoes RT, Gonçalves MAG, Castelli EC, Junior CM, Bettini JS, polymorphisms associated with cervical cancer risk: a meta-analy-
Discorde ML, Duarte G, Quintana SM, Simoes AL, Moreau P sis. Biomedicine & Pharmacotherapy = Biomedecine &
(2009) HLA-G polymorphisms in women with squamous Pharmacotherapie 73:58–64. https://doi.org/10.1016/j.biopha.2015.
intraepithelial lesions harboring human papillomavirus. Mod 06.002
Pathol 22(8):1075–1082 Zhang Y, Yang J, Li M, Cui M, Fu ZF, Zhao L, Zhou M (2019) A
Skeate JG, Woodham AW, Einstein MH, Da Silva DM, Kast WM (2016) recombinant rabies virus expressing Fms-like tyrosine kinase 3 li-
Current therapeutic vaccination and immunotherapy strategies for gand (Flt3L) induces enhanced immunogenicity in mice. Virol Sin
HPV-related diseases. Human Vaccines & Immunotherapeutics 34(6):662–672
12(6):1418–1429
Smith MA, Tellier P-P, Roger M, Coutlée F, Franco EL, Richardson H Publisher’s note Springer Nature remains neutral with regard to jurisdic-
(2014) Determinants of human papillomavirus coinfections among tional claims in published maps and institutional affiliations.