VIOLIN Logo
VO Banner
Search: for Help
About
Introduction
Statistics
VIOLIN News
Your VIOLIN
Register or Login
Submission
Tutorial
Vaccine & Components
Vaxquery
Vaxgen
VBLAST
Protegen
VirmugenDB
DNAVaxDB
CanVaxKB
Vaxjo
Vaxvec
Vevax
Huvax
Vaccine Mechanisms
Vaximmutordb
Vaxism
Vaxar
Vaccine Literature
VO-SciMiner
Litesearch
Vaxmesh
Vaxlert
Vaccine Design
Vaxign
Community Efforts
Vaccine Ontology
ICoVax 2012
ICoVax 2013
Advisory Committee
Vaccine Society
Vaxperts
VaxPub
VaxCom
VaxLaw
VaxMedia
VaxMeet
VaxFund
VaxCareer
Data Exchange
V-Utilities
VIOLINML
Help & Documents
Publications
Documents
FAQs
Links
Acknowledgements
Disclaimer
Contact Us
UMMS Logo

Human Papillomavirus

Table of Contents
  1. General Information
    1. NCBI Taxonomy ID
    2. Disease
    3. Introduction
    4. Microbial Pathogenesis
  2. Vaccine Related Pathogen Genes
    1. Calreticulin from humans (Protective antigen)
    2. E6 (Protective antigen)
    3. E7 (Protective antigen)
    4. L1 (Protective antigen)
    5. L2 (Protective antigen)
  3. Vaccine Information
    1. Cervarix
    2. Gardasil
    3. Gardasil 9
    4. Human papillomavirus DNA vaccine CRT/E7 DNA
    5. Human papillomavirus DNA vaccine E7IR
    6. Human papillomavirus DNA vaccine E7SH DNA
    7. Human papillomavirus DNA vaccine hCRTE6E7L2 DNA encoding CRT linked to E6, E7 and L2
    8. Human papillomavirus DNA vaccine pC16-L1 encoding L1
    9. Human papillomavirus DNA vaccine Pe7(pcDNA3-Sig/sE7/LAMP) encoding E7
    10. Human papillomavirus DNA vaccine pNGVL4a-E6/opt
    11. Human papillomavirus DNA vaccine VlJns-Ll encoding L1
    12. Human papillomavirus E7 protein vaccine
    13. Human papillomavirus L2 protein vaccine
    14. LM1-2-E7
  4. References
I. General Information
1. NCBI Taxonomy ID:
10566
2. Disease:
HPV infection
3. Introduction
Human Papilloma Virus (HPV) is a sexually transmitted virus. It is usually found in the genital tract and causes various lesions at the mucosae of both men and women. It is considered as a causative factor of cervical cancer even if all women infected by HPV will not develop the disease (Panagiotis et al., 2008). HPV) infection is the most common sexually transmitted infection in the USA. It has been estimated suggest that more than 80% of sexually active women will have acquired genital HPV by age 50 years (Huang, 2008).
4. Microbial Pathogenesis
HPV infection is limited to the basal cells of stratified epithelium, the only tissue in which they replicate.The virus can not bind to live tissue; instead it infects epithelial tissues through micro-abrasions or other epithelial trauma that exposes segments of the basement membrane.The infectious process is slow, taking 12–24 h for initiation of transcription. It's believed that involved antibodies play a major neutralizing role while the virions still reside on the basement membrane and cell surfaces (Wiki: HPV).
1. Calreticulin from humans
  • Gene Name : Calreticulin from humans
  • Sequence Strain (Species/Organism) : Homo sapiens
  • NCBI Protein GI : 1905911
  • Other Database IDs : CDD:189477
  • Taxonomy ID : 9606
  • Gene Strand (Orientation) : ?
  • Protein Name : calreticulin
  • Protein Length : 417
  • Protein Note : constructed at LLNL from flow-sorted chromosomes from hybrid 5HL2-B, which carries chromosome 19 as its only human chromosome
  • Protein Sequence : Show Sequence
    >gi|1905911|gb|AAB51176.1| calreticulin [Homo sapiens]
    MLLSVPLLLGLLGLAVAEPAVYFKEQFLDGDGWTSRWIESKHKSDFGKFVLSSGKFYGDEEKDKGLQTSQ
    DARFYALSASFEPFSNKGQTLVVQFTVKHEQNIDCGGGYVKLFPNSLDQTDMHGDSEYNIMFGPDICGPG
    TKKVHVIFNYKGKNVLINKDIRCKDDEFTHLYTLIVRPDNTYEVKIDNSQVESGSLEDDWDFLPPKKIKD
    PDASKPEDWDERAKIDDPTDSKPEDWDKPEHIPDPDAKKPEDWDEEMDGEWEPPVIQNPEYKGEWKPRQI
    DNPDYKGTWIHPEIDNPEYSPDPSIYAYDNFGVLGLDLWQVKSGTIFDNFLITNDEAYAEEFGNETWGVT
    KAAEKQMKDKQDEEQRLKEEEEDKKRKEEEEAEDKEDDEDKDEDEEDEEDKEEDEEEDVPGQAKDEL
  • Molecule Role : Protective antigen
  • Related Vaccine(s): Human papillomavirus DNA vaccine hCRTE6E7L2 DNA encoding CRT linked to E6, E7 and L2
2. E6
  • Gene Name : E6
  • Sequence Strain (Species/Organism) : Human papillomavirus type 16
  • VO ID : VO_0011107
  • NCBI Gene ID : 1489078
  • NCBI Protein GI : 9627104
  • Locus Tag : HpV16gp1
  • Genbank Accession : AY686584
  • Protein Accession : NP_041325
  • Taxonomy ID : 333760
  • Gene Starting Position : 82
  • Gene Ending Position : 558
  • Gene Strand (Orientation) : ?
  • Protein Name : transforming protein
  • Protein pI : 8.97
  • Protein Weight : 18789.29
  • Protein Length : 158
  • Protein Note : E6 ORF from 65 to 559; putative
  • DNA Sequence : Show Sequence
    >gi|9627100:82-558 Human papillomavirus type 16, complete genome
    TATGCACCAAAAGAGAACTGCAATGTTTCAGGACCCACAGGAGCGACCCAGAAAGTTACCACAGTTATGC
    ACAGAGCTGCAAACAACTATACATGATATAATATTAGAATGTGTGTACTGCAAGCAACAGTTACTGCGAC
    GTGAGGTATATGACTTTGCTTTTCGGGATTTATGCATAGTATATAGAGATGGGAATCCATATGCTGTATG
    TGATAAATGTTTAAAGTTTTATTCTAAAATTAGTGAGTATAGACATTATTGTTATAGTTTGTATGGAACA
    ACATTAGAACAGCAATACAACAAACCGTTGTGTGATTTGTTAATTAGGTGTATTAACTGTCAAAAGCCAC
    TGTGTCCTGAAGAAAAGCAAAGACATCTGGACAAAAAGCAAAGATTCCATAATATAAGGGGTCGGTGGAC
    CGGTCGATGTATGTCTTGTTGCAGATCATCAAGAACACGTAGAGAAACCCAGCTGTA
  • Protein Sequence : Show Sequence
    >gi|9627104|ref|NP_041325.1| transforming protein [Human papillomavirus type 16]
    MHQKRTAMFQDPQERPRKLPQLCTELQTTIHDIILECVYCKQQLLRREVYDFAFRDLCIVYRDGNPYAVC
    DKCLKFYSKISEYRHYCYSLYGTTLEQQYNKPLCDLLIRCINCQKPLCPEEKQRHLDKKQRFHNIRGRWT
    GRCMSCCRSSRTRRETQL
  • Molecule Role : Protective antigen
  • Molecule Role Annotation : C57BL/6 mice vaccinated with pNGVL4a-E6/opt are able to generate potent protective and therapeutic antitumor effects against challenge with E6-expressing tumor cell line, TC-1 of HPV (Lin et al., 2006).
  • Related Vaccine(s): Human papillomavirus DNA vaccine CRT/E7 DNA , Human papillomavirus DNA vaccine hCRTE6E7L2 DNA encoding CRT linked to E6, E7 and L2 , Human papillomavirus DNA vaccine pNGVL4a-E6/opt
3. E7
4. L1
  • Gene Name : L1
  • Sequence Strain (Species/Organism) : Human papillomavirus type 16
  • VO ID : VO_0011108
  • NCBI Gene ID : 1489082
  • NCBI Protein GI : 9627108
  • Locus Tag : HpV16gp8
  • Genbank Accession : K02718
  • Protein Accession : NP_041332
  • 3D structure: PDB ID : 2R5H
  • Taxonomy ID : 333760
  • Gene Starting Position : 5558
  • Gene Ending Position : 7153
  • Gene Strand (Orientation) : ?
  • Protein Name : major capsid L1 protein
  • Protein pI : 8.11
  • Protein Weight : 55981.2
  • Protein Length : 531
  • Protein Note : major capsid L1 protein; Two structural proteins are involved in papillomavirus capsid formation, a major (L1) and a minor (L2) protein; L1 forms the pentameric assembly unit of the viral shell while L2 mediates several facets of viral entry including endosomal escape after uncoating
  • DNA Sequence : Show Sequence
    >gi|9627100:5558-7153 Human papillomavirus type 16, complete genome
    GATGCAGGTGACTTTTATTTACATCCTAGTTATTACATGTTACGAAAACGACGTAAACGTTTACCATATT
    TTTTTTCAGATGTCTCTTTGGCTGCCTAGTGAGGCCACTGTCTACTTGCCTCCTGTCCCAGTATCTAAGG
    TTGTAAGCACGGATGAATATGTTGCACGCACAAACATATATTATCATGCAGGAACATCCAGACTACTTGC
    AGTTGGACATCCCTATTTTCCTATTAAAAAACCTAACAATAACAAAATATTAGTTCCTAAAGTATCAGGA
    TTACAATACAGGGTATTTAGAATACATTTACCTGACCCCAATAAGTTTGGTTTTCCTGACACCTCATTTT
    ATAATCCAGATACACAGCGGCTGGTTTGGGCCTGTGTAGGTGTTGAGGTAGGTCGTGGTCAGCCATTAGG
    TGTGGGCATTAGTGGCCATCCTTTATTAAATAAATTGGATGACACAGAAAATGCTAGTGCTTATGCAGCA
    AATGCAGGTGTGGATAATAGAGAATGTATATCTATGGATTACAAACAAACACAATTGTGTTTAATTGGTT
    GCAAACCACCTATAGGGGAACACTGGGGCAAAGGATCCCCATGTACCAATGTTGCAGTAAATCCAGGTGA
    TTGTCCACCATTAGAGTTAATAAACACAGTTATTCAGGATGGTGATATGGTTCATACTGGCTTTGGTGCT
    ATGGACTTTACTACATTACAGGCTAACAAAAGTGAAGTTCCACTGGATATTTGTACATCTATTTGCAAAT
    ATCCAGATTATATTAAAATGGTGTCAGAACCATATGGCGACAGCTTATTTTTTTATTTACGAAGGGAACA
    AATGTTTGTTAGACATTTATTTAATAGGGCTGGTACTGTTGGTGAAAATGTACCAGACGATTTATACATT
    AAAGGCTCTGGGTCTACTGCAAATTTAGCCAGTTCAAATTATTTTCCTACACCTAGTGGTTCTATGGTTA
    CCTCTGATGCCCAAATATTCAATAAACCTTATTGGTTACAACGAGCACAGGGCCACAATAATGGCATTTG
    TTGGGGTAACCAACTATTTGTTACTGTTGTTGATACTACACGCAGTACAAATATGTCATTATGTGCTGCC
    ATATCTACTTCAGAAACTACATATAAAAATACTAACTTTAAGGAGTACCTACGACATGGGGAGGAATATG
    ATTTACAGTTTATTTTTCAACTGTGCAAAATAACCTTAACTGCAGACGTTATGACATACATACATTCTAT
    GAATTCCACTATTTTGGAGGACTGGAATTTTGGTCTACAACCTCCCCCAGGAGGCACACTAGAAGATACT
    TATAGGTTTGTAACCCAGGCAATTGCTTGTCAAAAACATACACCTCCAGCACCTAAAGAAGATGATCCCC
    TTAAAAAATACACTTTTTGGGAAGTAAATTTAAAGGAAAAGTTTTCTGCAGACCTAGATCAGTTTCCTTT
    AGGACGCAAATTTTTACTACAAGCAGGATTGAAGGCCAAACCAAAATTTACATTAGGAAAACGAAAAGCT
    ACACCCACCACCTCATCTACCTCTACAACTGCTAAACGCAAAAAACGTAAGCTGTA
  • Protein Sequence : Show Sequence
    >gi|9627108|ref|NP_041332.1| major capsid protein [Human papillomavirus type 16]
    MQVTFIYILVITCYENDVNVYHIFFQMSLWLPSEATVYLPPVPVSKVVSTDEYVARTNIYYHAGTSRLLA
    VGHPYFPIKKPNNNKILVPKVSGLQYRVFRIHLPDPNKFGFPDTSFYNPDTQRLVWACVGVEVGRGQPLG
    VGISGHPLLNKLDDTENASAYAANAGVDNRECISMDYKQTQLCLIGCKPPIGEHWGKGSPCTNVAVNPGD
    CPPLELINTVIQDGDMVHTGFGAMDFTTLQANKSEVPLDICTSICKYPDYIKMVSEPYGDSLFFYLRREQ
    MFVRHLFNRAGTVGENVPDDLYIKGSGSTANLASSNYFPTPSGSMVTSDAQIFNKPYWLQRAQGHNNGIC
    WGNQLFVTVVDTTRSTNMSLCAAISTSETTYKNTNFKEYLRHGEEYDLQFIFQLCKITLTADVMTYIHSM
    NSTILEDWNFGLQPPPGGTLEDTYRFVTQAIACQKHTPPAPKEDDPLKKYTFWEVNLKEKFSADLDQFPL
    GRKFLLQAGLKAKPKFTLGKRKATPTTSSTSTTAKRKKRKL
  • Molecule Role : Protective antigen
  • Molecule Role Annotation : rAAV5, -8 and -9 vectors expressing an HPV16 L1/E7 fusion gene were generated and applied intranasally for combined prophylactic and therapeutic vaccination of mice. Vaccination with the rAAV vectors led to a significant protection of animals against a challenge with different HPV tumour cell lines (Nieto et al., 2009).
  • Related Vaccine(s): Human papillomavirus DNA vaccine pC16-L1 encoding L1 , Human papillomavirus DNA vaccine VlJns-Ll encoding L1
5. L2
  • Gene Name : L2
  • Sequence Strain (Species/Organism) : Human papillomavirus type 16
  • VO ID : VO_0011106
  • NCBI Gene ID : 1489081
  • NCBI Protein GI : 9627107
  • Locus Tag : HpV16gp7
  • Genbank Accession : K02718
  • Protein Accession : NP_041331
  • Taxonomy ID : 333760
  • Gene Starting Position : 4234
  • Gene Ending Position : 5655
  • Gene Strand (Orientation) : ?
  • Protein Name : minor capsid protein
  • Protein pI : 6.31
  • Protein Weight : 48008.05
  • Protein Length : 473
  • Protein Note : L2 ORF from 4133 to 5656; putative
  • DNA Sequence : Show Sequence
    >gi|9627100:4234-5655 Human papillomavirus type 16, complete genome
    AATGCGACACAAACGTTCTGCAAAACGCACAAAACGTGCATCGGCTACCCAACTTTATAAAACATGCAAA
    CAGGCAGGTACATGTCCACCTGACATTATACCTAAGGTTGAAGGCAAAACTATTGCTGAACAAATATTAC
    AATATGGAAGTATGGGTGTATTTTTTGGTGGGTTAGGAATTGGAACAGGGTCGGGTACAGGCGGACGCAC
    TGGGTATATTCCATTGGGAACAAGGCCTCCCACAGCTACAGATACACTTGCTCCTGTAAGACCCCCTTTA
    ACAGTAGATCCTGTGGGCCCTTCTGATCCTTCTATAGTTTCTTTAGTGGAAGAAACTAGTTTTATTGATG
    CTGGTGCACCAACATCTGTACCTTCCATTCCCCCAGATGTATCAGGATTTAGTATTACTACTTCAACTGA
    TACCACACCTGCTATATTAGATATTAATAATACTGTTACTACTGTTACTACACATAATAATCCCACTTTC
    ACTGACCCATCTGTATTGCAGCCTCCAACACCTGCAGAAACTGGAGGGCATTTTACACTTTCATCATCCA
    CTATTAGTACACATAATTATGAAGAAATTCCTATGGATACATTTATTGTTAGCACAAACCCTAACACAGT
    AACTAGTAGCACACCCATACCAGGGTCTCGCCCAGTGGCACGCCTAGGATTATATAGTCGCACAACACAA
    CAGGTTAAAGTTGTAGACCCTGCTTTTGTAACCACTCCCACTAAACTTATTACATATGATAATCCTGCAT
    ATGAAGGTATAGATGTGGATAATACATTATATTTTTCTAGTAATGATAATAGTATTAATATAGCTCCAGA
    TCCTGACTTTTTGGATATAGTTGCTTTACATAGGCCAGCATTAACCTCTAGGCGTACTGGCATTAGGTAC
    AGTAGAATTGGTAATAAACAAACACTACGTACTCGTAGTGGAAAATCTATAGGTGCTAAGGTACATTATT
    ATTATGATTTAAGTACTATTGATCCTGCAGAAGAAATAGAATTACAAACTATAACACCTTCTACATATAC
    TACCACTTCACATGCAGCCTCACCTACTTCTATTAATAATGGATTATATGATATTTATGCAGATGACTTT
    ATTACAGATACTTCTACAACCCCGGTACCATCTGTACCCTCTACATCTTTATCAGGTTATATTCCTGCAA
    ATACAACAATTCCTTTTGGTGGTGCATACAATATTCCTTTAGTATCAGGTCCTGATATACCCATTAATAT
    AACTGACCAAGCTCCTTCATTAATTCCTATAGTTCCAGGGTCTCCACAATATACAATTATTGCTGATGCA
    GGTGACTTTTATTTACATCCTAGTTATTACATGTTACGAAAACGACGTAAACGTTTACCATATTTTTTTT
    CAGATGTCTCTTTGGCTGCCTA
  • Protein Sequence : Show Sequence
    >gi|9627107|ref|NP_041331.1| minor capsid protein [Human papillomavirus type 16]
    MRHKRSAKRTKRASATQLYKTCKQAGTCPPDIIPKVEGKTIAEQILQYGSMGVFFGGLGIGTGSGTGGRT
    GYIPLGTRPPTATDTLAPVRPPLTVDPVGPSDPSIVSLVEETSFIDAGAPTSVPSIPPDVSGFSITTSTD
    TTPAILDINNTVTTVTTHNNPTFTDPSVLQPPTPAETGGHFTLSSSTISTHNYEEIPMDTFIVSTNPNTV
    TSSTPIPGSRPVARLGLYSRTTQQVKVVDPAFVTTPTKLITYDNPAYEGIDVDNTLYFSSNDNSINIAPD
    PDFLDIVALHRPALTSRRTGIRYSRIGNKQTLRTRSGKSIGAKVHYYYDLSTIDPAEEIELQTITPSTYT
    TTSHAASPTSINNGLYDIYADDFITDTSTTPVPSVPSTSLSGYIPANTTIPFGGAYNIPLVSGPDIPINI
    TDQAPSLIPIVPGSPQYTIIADAGDFYLHPSYYMLRKRRKRLPYFFSDVSLAA
  • Molecule Role : Protective antigen
  • Molecule Role Annotation : Antibody responses of mice (n = 120) and rabbits (n = 23) to vaccination with HPV-16 amino-terminal L2 polypeptides or multitype L2 fusion proteins were compared. 11-200 x 3 formulated in GPI-0100 adjuvant or alum with 1018 ISS protected mice against HPV-16 challenge (reduction in HPV-16 infection vs phosphate-buffered saline control, P < .001) 4 months after vaccination as well as HPV-16 L1 VLPs (Jagu et al., 2009).
  • Related Vaccine(s): Human papillomavirus DNA vaccine hCRTE6E7L2 DNA encoding CRT linked to E6, E7 and L2 , Human papillomavirus L2 protein vaccine
III. Vaccine Information
1. Cervarix
a. Product Name:
Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant
b. Tradename:
Cervarix
c. Manufacturer:
GlaxoSmithKline Biologicals
d. Vaccine Ontology ID:
VO_0011559
e. CDC CVX code:
118
f. Type:
Inactivated or "killed" vaccine
g. Status:
Licensed
h. Location Licensed:
USA
i. Host Species for Licensed Use:
Human
j. Adjuvant: AS04 vaccine adjuvant
k. Preparation
prepared by combining the adsorbed VLPs of each HPV type together with the AS04 adjuvant system in sodium chloride, sodium dihydrogen phosphate dihydrate, and water for Injection (FDA: Cevarix).
l. Immunization Route
Intramuscular injection (i.m.)
m. Storage
Store refrigerated between 2º and 8ºC (36º and 46ºF). Do not freeze.
n . Approved Age for Licensed Use
Females ages 10 to 25
2. Gardasil
a. Product Name:
Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant
b. Tradename:
Gardasil
c. Manufacturer:
Merck & Co., Inc.
d. Vaccine Ontology ID:
VO_0000049
e. CDC CVX code:
62
f. Type:
Subunit vaccine
g. Status:
Licensed
h. Location Licensed:
USA (License #0002)
i. Host Species for Licensed Use:
Human
j. Antigen
Virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18.
k. Adjuvant: amorphous aluminum hydroxyphosphate sulfate adjuvant (AAHSA)
l. Preparation
GARDASIL is a non-infectious recombinant quadrivalent vaccine prepared from the purified virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18. The L1 proteins are produced by separate fermentations in recombinant Saccharomyces cerevisiae and self-assembled into VLPs. The fermentation process involves growth of S. cerevisiae on chemically-defined fermentation media which include vitamins, amino acids, mineral salts, and carbohydrates. The VLPs are released from the yeast cells by cell disruption and purified by a series of chemical and physical methods. The purified VLPs are adsorbed on preformed aluminum-containing adjuvant (Amorphous Aluminum Hydroxyphosphate Sulfate). The quadrivalent HPV VLP vaccine is a sterile liquid suspension that is prepared by combining the adsorbed VLPs of each HPV type and additional amounts of the aluminum-containing adjuvant and the final purification buffer. GARDASIL is a sterile suspension for intramuscular administration (FDA: Gardasil).
m. Immunization Route
Intramuscular injection (i.m.)
n. Storage
GARDASIL should be refrigerated at 2 to 8 degrees Celcius. Do not freeze. Protect from light.
o . Approved Age for Licensed Use
Females ages 9-26
p. Contraindication
Hypersensitivity, including severe allergic reactions to yeast (a vaccine component), or after a previous dose of GARDASIL.
q. Description
Indication: Vaccination in females 9 to 26 years of age for prevention of the following diseases caused by Human Papillomavirus (HPV) Types 6, 11, 16, and 18: cervical cancer, and genital warts (condyloma acuminata), and the following precancerous or dysplastic lesions: cervical adenocarcinoma in situ (AIS), cervical intraepithelial neoplasia (CIN) grade 2 and grade 3, vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3, vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3, cervical intraepithelial neoplasia (CIN) grade 1 (FDA: Gardasil). In June 2006, the US Food and Drug Administration licensed this first vaccine to prevent cervical cancers and other diseases in women. This quadrivalent vaccine protects against HPV-6, HPV-11, HPV-16, and HPV-18, which are responsible for 70% of cervical cancers and 90% of genital warts (Huang, 2008).
r. Human Response
  • Vaccination Protocol: In 5 clinical trials, subjects were administered with GARDASIL or AAHS (Amorphous Aluminum Hydroxyphosphate) control or saline placebo. The subjects included 5088 girls and women ages 9 to 26 years (FDA: Gardasil).
  • Immune Response: In clinical studies it was discovered that around 99% of girls and women who were immunized with GARDASIL became anti-HPV 6, anti-HPV 11, anti-HPV 16 and anti-HPV 18 seropositive by 1 month after the third and final dose(FDA: Gardasil).
  • Side Effects: Most common side effect of immunization was headache. Other side effects include: fever, nausea, dizziness, injection site pain and swelling.
3. Gardasil 9
a. Product Name:
Human Papillomavirus 9-valent Vaccine, Recombinant
b. Tradename:
Gardasil 9
c. Manufacturer:
Merck & Co., Inc.
d. CDC CVX code:
165
e. Type:
Subunit vaccine
f. Status:
Licensed
g. Location Licensed:
USA, Canada
h. Host Species for Licensed Use:
Human
i. Allergen:
Yeast
j. Immunization Route
Intramuscular injection (i.m.)
k . Approved Age for Licensed Use
9-26 years
l. Description
9-valent derivative of Gardasil
4. Human papillomavirus DNA vaccine CRT/E7 DNA
a. Vaccine Ontology ID:
VO_0004331
b. Type:
DNA vaccine
c. Status:
Research
d. Host Species as Laboratory Animal Model:
Mouse
e. Gene Engineering of E7
  • Type: DNA vaccine construction
  • Description: Vector pCDNA3 expressed E7 protein of HPV 16 and 18 (Cheng et al., 2001).
  • Detailed Gene Information: Click here.
f. Vector:
pCDNA3 (Cheng et al., 2001)
g. Immunization Route
Intramuscular injection (i.m.)
h. Mouse Response
  • Vaccine Immune Response Type: VO_0000286
  • Efficacy: 100% of mice receiving CRT/E7 DNA vaccination remained tumor-free 60 days after TC-1 challenge. In contrast, all of the unvaccinated mice and mice receiving plasmid without insert, CRT, or E7 DNA developed tumors within 15 days after tumor challenge (Cheng et al., 2001).
5. Human papillomavirus DNA vaccine E7IR
a. Vaccine Ontology ID:
VO_0004332
b. Type:
DNA vaccine
c. Status:
Research
d. Host Species as Laboratory Animal Model:
Mouse
e. Gene Engineering of E7
f. Vector:
APL023 (Brinkman et al., 2007)
g. Immunization Route
Gene gun
h. Mouse Response
  • Vaccine Immune Response Type: VO_0000286
  • Efficacy: Vaccination with the modified E7IR construct was able to significantly reduce tumor volume and enhance survival in both prophylactic and therapeutic experiments in mice compared to the WT E7 gene. Vaccination with E7IR also prevented tumor formation; after challenge with tumor cells, by day 33 all naïve and vector vaccinated mice were tumor bearing, 3/5 mice vaccinated with the WT construct were tumor bearing and none of the animals vaccinated with the E7IR construct were tumor bearing. As a result, vaccination with the E7IR construct promoted 100% survival in these mice to 57 days (Brinkman et al., 2007).
6. Human papillomavirus DNA vaccine E7SH DNA
a. Vaccine Ontology ID:
VO_0004333
b. Type:
DNA vaccine
c. Status:
Research
d. Host Species as Laboratory Animal Model:
Mouse
e. Gene Engineering of E7
  • Type: DNA vaccine construction
  • Description: Vector pCDNA3 expressed the E7 oncogene of the human papillomavirus type 16 (HPV 16) (Osen et al., 2001).
  • Detailed Gene Information: Click here.
f. Vector:
pCDNA3 (Osen et al., 2001)
g. Immunization Route
Intramuscular injection (i.m.)
h. Mouse Response
  • Vaccine Immune Response Type: VO_0000286
  • Efficacy: Immunization of C57BL/6 mice with E7SH DNA induced E7-specific CTL and also conveyed protection against E7-positive syngeneic tumor cells. Mice were challenged with 2 doses of TC-1 cells 100 days apart, and there was no tumor growth in any of the mice up to 80 days post-rechallenge, showing that a single injection of E7SH DNA had induced a long-lasting protective immunity (Osen et al., 2001).
7. Human papillomavirus DNA vaccine hCRTE6E7L2 DNA encoding CRT linked to E6, E7 and L2
a. Vaccine Ontology ID:
VO_0004475
b. Type:
DNA vaccine
c. Status:
Research
d. Host Species as Laboratory Animal Model:
Mouse
e. Gene Engineering of E6
  • Type: DNA vaccine construction
  • Description: Vector pNGVL4a vector (National Gene Vector lab) expressed human calreticulin (CRT) linked to HPV16 early proteins, E6 and E7 and the late protein L2 (hCRTE6E7L2) (Kim et al., 2008).
  • Detailed Gene Information: Click here.
f. Gene Engineering of E7
  • Type: DNA vaccine construction
  • Description: Vector pNGVL4a vector (National Gene Vector lab) expressed human calreticulin (CRT) linked to HPV16 early proteins, E6 and E7 and the late protein L2 (hCRTE6E7L2) (Kim et al., 2008).
  • Detailed Gene Information: Click here.
g. Gene Engineering of L2
  • Type: Recombinant protein preparation
  • Description: Vector pNGVL4a vector (National Gene Vector lab) expressed human calreticulin (CRT) linked to HPV16 early proteins, E6 and E7 and the late protein L2 (hCRTE6E7L2) (Kim et al., 2008).
  • Detailed Gene Information: Click here.
h. Gene Engineering of Calreticulin from humans
  • Type: DNA vaccine construction
  • Description: Vector pNGVL4a vector (National Gene Vector lab) expressed human calreticulin (CRT) linked to HPV16 early proteins, E6 and E7 and the late protein L2 (hCRTE6E7L2) (Kim et al., 2008).
  • Detailed Gene Information: Click here.
i. Vector:
pNGVL4a vector (National Gene Vector lab) (Kim et al., 2008)
j. Immunization Route
Gene gun
k. Mouse Response
  • Vaccine Immune Response Type: VO_0000286
  • Efficacy: Immunization with DNA vaccines expressing hCRTE6E7 and hCRTE6E7L2 induced a higher percentage of tumor-free mice compared to immunization with the other DNA vaccines (Kim et al., 2008).
8. Human papillomavirus DNA vaccine pC16-L1 encoding L1
a. Vaccine Ontology ID:
VO_0004330
b. Type:
DNA vaccine
c. Status:
Research
d. Gene Engineering of L1
e. Vector:
pCDNA3 (Rocha-Zavaleta et al., 2002)
f. Immunization Route
Intramuscular injection (i.m.)
g. Mouse Response
  • Vaccine Immune Response Type: VO_0000286
  • Efficacy: Mice were challenged with a syngeneic melanoma cell line, engineered to express the HPV16-L1 protein, tumours in vaccinated animals showed slower growth rate, correlated directly with a longer survival of mice. The results suggest that the L1-based DNA vaccine may be useful for the prevention of primary infections by HPV16 (Rocha-Zavaleta et al., 2002).
9. Human papillomavirus DNA vaccine Pe7(pcDNA3-Sig/sE7/LAMP) encoding E7
a. Vaccine Ontology ID:
VO_0004329
b. Type:
DNA vaccine
c. Status:
Research
d. Host Species as Laboratory Animal Model:
Mouse
e. Gene Engineering of E7
  • Type: DNA vaccine construction
  • Description: Vector pcDNA3 expressed HPV oncogenic proteins E7 (Sin, 2009).
  • Detailed Gene Information: Click here.
f. Vector:
pcDNA3 (Sin, 2009)
g. Immunization Route
Intramuscular injection (i.m.)
h. Mouse Response
  • Vaccine Immune Response Type: VO_0000286
  • Efficacy: Animals immunized with pE7 alone showed almost complete protection from TC-1 tumour challenge. However, animals immunized with pE7 plus pIL-12 displayed a complete loss of antitumour resistance in a manner similar to control groups (Sin, 2009).
10. Human papillomavirus DNA vaccine pNGVL4a-E6/opt
a. Vaccine Ontology ID:
VO_0011480
b. Type:
DNA vaccine
c. Status:
Research
d. Antigen
Human papillomavirus E6
e. Gene Engineering of E6
  • Type: DNA vaccine construction
  • Description: To generate pNGVL4a-E6, E6 was isolated from pcDNA3-E6 and cloned into pNGVL4a vector. To generate pNGVL4a-E6/opt, codonoptimized E6 synthesized by GenScript Corporation (Piscataway, NJ) was cloned into EcoRI/BamHI of pNGVL4a vector. The DNA and amino acid sequences of the wild-type E6 gene as well as the codon-optimized E6 were fully sequenced (Lin et al., 2006).
  • Detailed Gene Information: Click here.
f. Vector:
pNGVL4a
g. Immunization Route
Intradermal injection (i.d.)
h. Mouse Response
  • Host Strain: C57BL/6
  • Vaccination Protocol: Gold particles coated with pNGVL4a, pNGVL4a-E6 or pNGVL4a-E6/opt were delivered to the shaved abdominal regions of mice by using a helium-driven gene gun (Bio-Rad Laboratories Inc., Hercules, Calif.) with a discharge pressure of 400 lb/in^2. Mice were immunized with 2 lg of the DNA vaccine and received two boosts with the same dose at 1-week interval. Splenocytes were harvested 1 week after the last vaccination (Lin et al., 2006).
  • Challenge Protocol: One week after the last vaccination, mice were challenged with 5 x104 TC-1 tumor cells mouse subcutaneously in the right leg and monitored once a week by inspection and palpation (Lin et al., 2006).
  • Efficacy: C57BL/6 mice vaccinated with pNGVL4a-E6/opt are able to generate potent protective and therapeutic antitumor effects against challenge with E6-expressing tumor cell line, TC-1 of HPV (Lin et al., 2006).
11. Human papillomavirus DNA vaccine VlJns-Ll encoding L1
a. Vaccine Ontology ID:
VO_0004328
b. Type:
DNA vaccine
c. Status:
Research
d. Host Species as Laboratory Animal Model:
Rabbit
e. Gene Engineering of L1
  • Type: DNA vaccine construction
  • Description: Vector VlJns expressed the major viral capsid protein L1 (Donnelly et al., 1996).
  • Detailed Gene Information: Click here.
f. Vector:
VlJns (Donnelly et al., 1996)
g. Immunization Route
Intramuscular injection (i.m.)
h. Rabbit Response
  • Vaccine Immune Response Type: VO_0000286
  • Efficacy: Immunization with plasmid DNA encoding L1 elicited conformationally specific neutralizing antibodies and provided immunity against papilloma formation upon challenge with CRPV (Donnelly et al., 1996).
12. Human papillomavirus E7 protein vaccine
a. Vaccine Ontology ID:
VO_0011395
b. Type:
Subunit vaccine
c. Status:
Research
d. Antigen
Human papillomavirus E7
e. Gene Engineering of E7
  • Type: Recombinant protein preparation
  • Description: An 87-bp DNA fragment coding for the HPV16 E7 peptide38–61 was amplified by PCR from pHPV-16. The E738–61 24-residue peptide, named E7p, and the E749–57 CTL epitope were synthesized in Bioasia Corporation (Shanghai, China). E. coli BL21 (DE3) pLysS cells, transformed with E7p/mcIgG-pET21a, were cultured overnight in 6 ml ZB medium. A 300 ml of LB medium was inoculated with the 6 ml ZB bacteria culture. After a 2-h rotation at 30°C and 200 rpm, chimeric protein expression was induced by the addition of IPTG (isopropyl-β-D-thiogalactopyranoside) to a concentration of 1.0 mM. After a 9-h induction period, the cells were harvested by centrifugation at 5000 rpm for 5 min at 4°C (Qin et al., 2005).
  • Detailed Gene Information: Click here.
f. Adjuvant: incomplete Freunds adjuvant
g. Immunization Route
Subcutaneous injection
h. Mouse Response
  • Host Strain: C57BL/6
  • Vaccination Protocol: Female C57BL/6 mice (8–12 weeks old) were purchased from the Animal Center of Chinese Academy of Medical Science (Beijing, China) and held under specific pathogen-free conditions. Mice were subcutaneously injected either with 200 μg E7p/mIgG. HCCR, 20 μg E7p, 20 μg E7p plus 180 μg mIgG HCCR or 180 μg mIgG HCCR, respectively. All proteins were dissolved in PBS to achieve similar molar levels of E738–61 peptide in all cases. All four immunogens were mixed with an equal volume of Freund's incomplete adjuvant before vaccination. The total injection volume was 200 μl/mouse. All the mice were boosted with the same dose of immunogen solution using the same adjuvant after 3 weeks (Qin et al., 2005).
  • Challenge Protocol: Female C57BL/6 mice (8–12 weeks old) were used for evaluating the protection ability of the chimeric protein against tumor challenge. Four groups (n = 5) of C57BL/6 mice were immunized twice on Day 0 and 21 with 200 μg E7p/mIgG HCCR, 20 μg E7p, 20 μg E7p plus 180 μg mIgG HCCR or 180 μg mIgG HCCR, respectively. After a week, all mice in the four groups were challenged with 5 × 104 TC-1 tumor cells subcutaneously. Following the TC-1 cells challenge, tumor development in mice was monitored every week until the death of mice (Qin et al., 2005).
  • Efficacy: Researchers combined the HPV16 E7 peptide(38-61) with a murine IgG heavy chain constant region to construct a chimeric protein compound. The chimeric vaccine candidate was able to effectively protect mice against the challenge of HPV16-positive tumor cells, and to eradicate HPV16-expressing tumors in mice (Qin et al., 2005).
13. Human papillomavirus L2 protein vaccine
a. Vaccine Ontology ID:
VO_0011397
b. Type:
Subunit vaccine
c. Status:
Research
d. Antigen
Human papillomavirus L2
e. Gene Engineering of L2
  • Type: Recombinant protein preparation
  • Description: The L2 genes were subcloned into the pET28a vector (Novagen, San Diego, CA) and the resulting hexahistidine (6His)-tagged recombinant polypeptides expressed in E coli BL21 (Rosetta cells; Novagen). The recombinant L2 polypeptides were affinity purified by binding to a nickel–nitrilotriacetic acid column (Qiagen, Valencia, CA) in 8 M urea (using the QiaExpressionist standard purification protocol for denaturing conditions) and then dialyzed in cassettes (Pierce, Rockland, NJ) against phosphate-buffered saline (PBS, 137 mM NaCl, 12 mM phosphate, 2.7 mM KCl) (Jagu et al., 2009).
  • Detailed Gene Information: Click here.
f. Adjuvant: aluminum vaccine adjuvant
g. Immunization Route
Subcutaneous injection
h. Mouse Response
  • Host Strain: BALB/c
  • Vaccination Protocol: Balb/c mice (n=120, from NCI, Frederick, MD) were vaccinated in groups of five mice three times at 2-week intervals by subcutaneous injection with 10 μg of HPV-16 or HPV-45 L1 VLP, or the adjuvants alum (1.3 mg), or 1018 ISS alone (10 μg/mouse), or 25 μg of recombinant L2-based antigens including 11-200 × 1, 11-200 × 3, 1-88 × 1, 11-88 × 5, 17-36 × 22, or HPV-16 L2 17-36 peptide prepared by chemical synthesis (Sigma Aldrich, St Louis, MO) in the formulations indicated: PBS alone, or alum alone (1.3 mg), or 1018 ISS alone (10 μg/mouse), or 25 μg 11-200 × 3 alone, or formulated with alum (1.3 mg), or with 1018 ISS (10 μg/mouse), or with GPI-0100 (at either 50 or 200 μg/mouse), or with GPI-0100 (50 μg/mouse) + Tween-40 (1 mg/mouse), or with alum and 1018 ISS (10 μg/mouse) (Jagu et al., 2009).
  • Challenge Protocol: All mice were anesthetized, and a patch of skin on their ventral torso was shaved with an electric razor while taking care not to traumatize the epithelium, before challenge by application of approximately 3 × 109 HPV-16 pseudovirion particles (100 ng protein) that encapsidated pYLUC, a plasmid carrying a luciferase gene that would be expressed upon pseudoinfection (http://home.ccr.cancer.gov/lco/) in 10 μL 0.6% carboxymethylcellulose (Sigma Aldrich) to the patch of shaved skin on each mouse (Jagu et al., 2009).
  • Efficacy: Antibody responses of mice (n = 120) and rabbits (n = 23) to vaccination with HPV-16 amino-terminal L2 polypeptides or multitype L2 fusion proteins were compared. 11-200 x 3 formulated in GPI-0100 adjuvant or alum with 1018 ISS protected mice against HPV-16 challenge (reduction in HPV-16 infection vs phosphate-buffered saline control, P < .001) 4 months after vaccination as well as HPV-16 L1 VLPs (Jagu et al., 2009).
14. LM1-2-E7
a. Vaccine Ontology ID:
VO_0004803
b. Type:
Recombinant vector vaccine
c. Status:
Research
d. Host Species for Licensed Use:
Baboon
e. Gene Engineering of E7
  • Type: Recombinant vector construction
  • Description: The E7 gene is inserted into the vector of Listeria monocytogenes, strain LM1-2 (Jia et al., 2012).
  • Detailed Gene Information: Click here.
f. Preparation
The E7 fragment was amplified with PCR then cloned into the chromosome of L. monocytogenes (Jia et al., 2012).
g. Immunization Route
Intramuscular injection (i.m.)
h. Mouse Response
  • Host Strain: C57BL/6
  • Vaccination Protocol: Mice were vaccinated in both a prophylactic (where the mice were immunized and then presented with a pathogenic challenge) and therapeutic (where the mice already had tumors and then were injected with the vaccine vector) setting (Jia et al., 2012).
  • Vaccine Immune Response Type: VO_0000287
  • Challenge Protocol: In the prophylactic assay, "mice were challenged with TC-1 cells on day 4 after the second immunization and were observed for tumor development" and in the mice vaccinated with LM1-2-E7, 87.5% showed no signs of a tumor until after day 50 (Jia et al., 2012).
  • Efficacy: The LM1-2-E7 vaccine vector was shown to elicit protection against TC-1 tumor cells in the prophylactic challenges (Jia et al., 2012).
IV. References
1. Brinkman et al., 2007: Brinkman JA, Xu X, Kast WM. The efficacy of a DNA vaccine containing inserted and replicated regions of the E7 gene for treatment of HPV-16 induced tumors. Vaccine. 2007; 25(17); 3437-3444. [PubMed: 17241713].
2. Cheng et al., 2001: Cheng WF, Hung CF, Chai CY, Hsu KF, He L, Ling M, Wu TC. Tumor-specific immunity and antiangiogenesis generated by a DNA vaccine encoding calreticulin linked to a tumor antigen. The Journal of clinical investigation. 2001; 108(5); 669-678. [PubMed: 11544272].
3. Chu et al., 2011: Phase I of Human Papillomavirus (HPV) DNA Plasmid (VGX-3100) + Electroporation for CIN 2 or 3 [http://www.clinicaltrials.gov/ct2/show/NCT00685412?term=vgx&rank=1]
4. Donnelly et al., 1996: Donnelly JJ, Martinez D, Jansen KU, Ellis RW, Montgomery DL, Liu MA. Protection against papillomavirus with a polynucleotide vaccine. The Journal of infectious diseases. 1996; 173(2); 314-320. [PubMed: 8568291].
5. FDA: Cevarix: FDA: Cervarix [http://www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm186957.htm]
6. FDA: Gardasil: FDA: Gardasil information [http://www.fda.gov/Cber/products/gardasil.htm]
7. Henken et al., 2012: Henken FE, Oosterhuis K, Ohlschläger P, Bosch L, Hooijberg E, Haanen JB, Steenbergen RD. Preclinical safety evaluation of DNA vaccines encoding modified HPV16 E6 and E7. Vaccine. 2012; 30(28); 4259-4266. [PubMed: 22554465].
8. Huang, 2008: Huang CM. Human papillomavirus and vaccination. Mayo Clinic proceedings. Mayo Clinic. 2008; 83(6); 701-706; quiz 706-706. [PubMed: 18533087].
9. Jagu et al., 2009: Jagu S, Karanam B, Gambhira R, Chivukula SV, Chaganti RJ, Lowy DR, Schiller JT, Roden RB. Concatenated multitype L2 fusion proteins as candidate prophylactic pan-human papillomavirus vaccines. Journal of the National Cancer Institute. 2009; 101(11); 782-792. [PubMed: 19470949].
10. Jia et al., 2012: Jia Y, Yin Y, Duan F, Fu H, Hu M, Gao Y, Pan Z, Jiao X. Prophylactic and therapeutic efficacy of an attenuated Listeria monocytogenes-based vaccine delivering HPV16 E7 in a mouse model. International journal of molecular medicine. 2012; 30(6); 1335-1342. [PubMed: 23027427].
11. Karanam et al., 2009: Karanam B, Gambhira R, Peng S, Jagu S, Kim DJ, Ketner GW, Stern PL, Adams RJ, Roden RB. Vaccination with HPV16 L2E6E7 fusion protein in GPI-0100 adjuvant elicits protective humoral and cell-mediated immunity. Vaccine. 2009; 27(7); 1040-1049. [PubMed: 19095032].
12. Kim et al., 2008: Kim D, Gambhira R, Karanam B, Monie A, Hung CF, Roden R, Wu TC. Generation and characterization of a preventive and therapeutic HPV DNA vaccine. Vaccine. 2008; 26(3); 351-360. [PubMed: 18096279].
13. Klencke et al., 2002: Klencke B, Matijevic M, Urban RG, Lathey JL, Hedley ML, Berry M, Thatcher J, Weinberg V, Wilson J, Darragh T, Jay N, Da Costa M, Palefsky JM. Encapsulated plasmid DNA treatment for human papillomavirus 16-associated anal dysplasia: a Phase I study of ZYC101. Clinical cancer research : an official journal of the American Association for Cancer Research. 2002; 8(5); 1028-1037. [PubMed: 12006515].
14. Lin et al., 2006: Lin CT, Tsai YC, He L, Calizo R, Chou HH, Chang TC, Soong YK, Hung CF, Lai CH. A DNA vaccine encoding a codon-optimized human papillomavirus type 16 E6 gene enhances CTL response and anti-tumor activity. Journal of biomedical science. 2006; 13(4); 481-488. [PubMed: 16649071].
15. Nieto et al., 2009: Nieto K, Kern A, Leuchs B, Gissmann L, Müller M, Kleinschmidt JA. Combined prophylactic and therapeutic intranasal vaccination against human papillomavirus type-16 using different adeno-associated virus serotype vectors. Antiviral therapy. 2009; 14(8); 1125-1137. [PubMed: 20032542].
16. Ohlschläger et al., 2011: Ohlschläger P, Spies E, Alvarez G, Quetting M, Groettrup M. The combination of TLR-9 adjuvantation and electroporation-mediated delivery enhances in vivo antitumor responses after vaccination with HPV-16 E7 encoding DNA. International journal of cancer. Journal international du cancer. 2011; 128(2); 473-481. [PubMed: 20309939].
17. Osen et al., 2001: Osen W, Peiler T, Ohlschläger P, Caldeira S, Faath S, Michel N, Müller M, Tommasino M, Jochmus I, Gissmann L. A DNA vaccine based on a shuffled E7 oncogene of the human papillomavirus type 16 (HPV 16) induces E7-specific cytotoxic T cells but lacks transforming activity. Vaccine. 2001; 19(30); 4276-4286. [PubMed: 11457555].
18. Panagiotis et al., 2008: Panagiotis C, Efthimios D, Konstantinos P, George C. Human papilloma virus: diagnostic, treatment and preventive issues. Akusherstvo i ginekologiia. 2008; 47(1); 35-38. [PubMed: 18642576].
19. Qin et al., 2005: Qin Y, Wang XH, Cui HL, Cheung YK, Hu MH, Zhu SG, Xie Y. Human papillomavirus type 16 E7 peptide(38-61) linked with an immunoglobulin G fragment provides protective immunity in mice. Gynecologic oncology. 2005; 96(2); 475-483. [PubMed: 15661238].
20. Rocha-Zavaleta et al., 2002: Rocha-Zavaleta L, Alejandre JE, Garcia-Carranca A. Parenteral and oral immunization with a plasmid DNA expressing the human papillomavirus 16-L1 gene induces systemic and mucosal antibodies and cytotoxic T lymphocyte responses. Journal of medical virology. 2002; 66(1); 86-95. [PubMed: 11748663].
21. Sin, 2009: Sin JI. Suppression of antitumour protective cytotoxic T lymphocyte responses to a human papillomavirus 16 E7 DNA vaccine by coinjection of interleukin-12 complementary DNA: involvement of nitric oxide in immune suppression. Immunology. 2009; 128(1 Suppl); e707-717. [PubMed: 19740332].
22. Wiki: HPV: Wiki: Human papillomavirus [http://en.wikipedia.org/wiki/Human_papillomavirus]