Human Papillomavirus 10566 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). HPV infection 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). Baboon Papio cynocephalus 9556 Bank vole Clethrionomys glareolus 447135 Bear Ursus americanus 9643 Birds Passeroidea 175121 Brown Trout Salmo trutta 8032 Buffalo Bison bison 9901 Carnivores Vulpes 9625 Cat Felis catus 9685 Catfishes Siluriformes 7995 Cattle Bos taurus 9913 Chicken Gallus gallus 9031 Chimpanzee Pan troglodytes 9598 chinchillas Chinchillidae 10150 Copper Pheasant Syrmaticus soemmerringii 9067 Deer Cervus elaphus 9860 Deer mouse Peromyscus maniculatus 10042 Dog Canis familiaris 9615 Ducks Anas 8835 Ferret Mustela putorius furo 9669 Fish Hyperotreti 117565 Gerbil Gerbillina 10045 Goat Capra hircus 9925 Gray wolf Canis lupus 9612 Guinea pig Cavia porcellus 10141 Hamster Mesocricetus auratus 10036 Horse Equus caballus 9796 Human Homo sapiens 9606 Macaque Macaca fascicularis 9541 Mongolian Gerbil Meriones unguiculatus 10047 Monkey Platyrrhini 9479 Mouse Mus musculus 10090 None None Parrot Psittacidae 9224 Pig Sus scrofa 9823 Rabbit Oryctolagus cuniculus 9986 Rainbow trout Oncorhynchus mykiss 8022 Rat Rattus 10114 Raven Corvus corax 56781 sei whale Balaenoptera borealis 9768 Sheep Ovis aries 9940 Squirrel Spermophilus richardsonii 37591 Tree shrew Tupaiidae 9393 Trouts, salmons & chars Salmoninae 504568 Turkey Meleagris gallopavo 9103 Vole Microtus ochrogaster 79684 Water buffalo Bubalus bubalis 391902 11-valent recombinant human papilloma virus vaccine (Hansenula polymorpha) ChinaVaccineSerum Virus Like Particle Clinical trial Intramuscular injection (i.m.) Intramuscular injection (i.m.) Recombinant protein preparation (Liu et al., 2015)According to the 0, 2, and 6 months immunization program, intramuscular injection of the upper arm deltoid muscle, 3 doses of the experiment vaccine AAVLP(HPV16/31L2) Recombinant vector vaccine Clinical trial Intramuscular injection (i.m.) Insertion of a neutralizing epitope (amino acids 17–36) from L2 of HPV16 and HPV31 into VP3 at positions 587 and 453, respectively, permitted assembly into empty AAV particles (AAVLP(HPV16/31L2)) (Nieto et al., 2012). Generated AAVLPs displaying HPV16 L2 epitopes in position 587 and HPV31 L2 epitopes in position 453. (Nieto et al., 2012). Intramuscular injection (i.m.) Adeno-associated virus serotype 2 (AAV2) capsids Recombinant protein preparation L2 proteins harbors several regions that can be targeted by neutraliizing antibodies (Nieto et al., 2012). Recombinant protein preparation Insertion of L2 HPV31 into VP3 at positions 583 and 453. Balb/c and C57BL/6 Immunized C57BL/6 mice either with a low dose (LD) (1E+11 particles equivalent to 0.6 µg of protein) or high dose (HD) (5E+12 particles equivalent to 30 µg) with or without adjuvant (+M) (montanide ISA 51). (Nieto et al., 2012). Mice immunized with LD+M or HD+M developed 25 and 50 fold higher HPV16 L2-specific antibodies titers, respectively, than mice immunized with a LD of particles without adjuvant. There was little difference between the mice immunized with LD+M and mice immunized with HD+M. Sera of all mice vaccinated with TrXL2+M had HPV16 L2-specific antibodies. (Nieto et al., 2012). Three ZIKA hybrid rabbits were immunized four times with AAVLP(HPV16/31L2) particles (2E+12 capsids equivalent to 13.2 µg) adjuvanted with montanide ISA720. Rabbit sera were administered intraperitoneally to naïve mice. Rabbit sera against AAVLP with an epitope of the cholesteryl ester transfer protein (AAVLP TP18) were used to detect the unspecific effect of AAVLP induced antibodies. Vaginal infection of mice is detected three days after challenge as luminescence signal after injection of the challenged mice with luciferin. (Nieto et al., 2012) The passive transfer of AAVLP(HPV16/31L2) sera protected mice from vaginal challenge with HPV16 PsV, whereas the AAVLP TP18 control serum failed to protect the mice. (Nieto et al., 2012) ADXS11-001 Neoadjuvant ADXS11-001 (ADXS-HPV) Advaxis Live, attenuated vaccine Clinical trial [Ref5589:Galicia-Carmona et al., 2021]LM vector Intravenous injection (i.v.) (Galicia-Carmona et al., 2021) LM based vectors infect antigen presenting cells and secrete HPV-LLO fusion proteins with the APC cytoplasm. These proteins are processed and presented to cytotoxic T lymphocytes (CTL), thus generating a new population of CTLs specific to HPV antigens. These HPV-specific CTLs destroy HPV infected cells. (Galicia-Carmona et al., 2021)LLO acts as a potent adjuvant when incorporated into NA vaccines. (Galicia-Carmona et al., 2021)They prepared two recombinant Lm strains, one expressing the HPV-16 E7 protein without attempting to modify the LLO molecule (Lm-E7), and the second expressed E7 as a non-hemolytic LLO-bound fusion protein (Lm-LLO-E7). Intravenous injection (i.v.) (Galicia-Carmona et al., 2021)Antigen presenting cell alert the adaptive immune response of the presence of Lm through the major histocompatibility complex (MHC) molecules by two different routes. LM antigens from bacteria. tumor antigen-specific cytotoxic CD8 Recombinant protein preparation The tumor-associated antigen (HPV16 E7) is expressed via live attenuated Listeria monocytogenes-listeriolysin O (Lm-LLO), which helped stimulate the antigen-specific immune responses (Galicia-Carmona et al., 2021). Cervarix Human Papillomavirus Bivalent (Types 16 and 18) Vaccine, Recombinant Cervarix GlaxoSmithKline Biologicals VO_0011559 Inactivated or "killed" vaccine Licensed Intramuscular injection (i.m.) USA AS04 Store refrigerated between 2º and 8ºC (36º and 46ºF). Do not freeze. 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). Intramuscular injection (i.m.) Gardasil Human Papillomavirus Quadrivalent (Types 6, 11, 16, 18) Vaccine, Recombinant Gardasil Merck & Co., Inc. VO_0000049 Subunit vaccine Licensed Intramuscular injection (i.m.) USA (License #0002) 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). GARDASIL should be refrigerated at 2 to 8 degrees Celcius. Do not freeze. Protect from light. 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). Intramuscular injection (i.m.) Virus-like particles (VLPs) of the major capsid (L1) protein of HPV Types 6, 11, 16, and 18. 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). 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). Most common side effect of immunization was headache. Other side effects include: fever, nausea, dizziness, injection site pain and swelling. Gardasil 9 Human Papillomavirus 9-valent Vaccine, Recombinant Gardasil 9 Merck & Co., Inc. VO_0003075 Subunit vaccine Licensed Intramuscular injection (i.m.) USA, Canada 9-valent derivative of Gardasil AAHSA Intramuscular injection (i.m.) Human papillomavirus DNA vaccine CRT/E7 DNA VO_0004331 DNA vaccine Research pCDNA3 [Ref2170:Cheng et al., 2001] Intramuscular injection (i.m.) Intramuscular injection (i.m.) DNA vaccine construction Vector pCDNA3 expressed E7 protein of HPV 16 and 18 (Cheng et al., 2001). VO_0000286 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). Human papillomavirus DNA vaccine E7IR VO_0004332 DNA vaccine Research APL023 [Ref2173:Brinkman et al., 2007] Gene gun Gene gun DNA vaccine construction Vector APL023expressed the E7 gene (Brinkman et al., 2007). VO_0000286 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). Human papillomavirus DNA vaccine E7SH DNA VO_0004333 DNA vaccine Research pCDNA3 [Ref2174:Osen et al., 2001] Intramuscular injection (i.m.) Intramuscular injection (i.m.) DNA vaccine construction Vector pCDNA3 expressed the E7 oncogene of the human papillomavirus type 16 (HPV 16) (Osen et al., 2001). VO_0000286 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). Human papillomavirus DNA vaccine hCRTE6E7L2 DNA encoding CRT linked to E6, E7 and L2 VO_0004475 DNA vaccine Research pNGVL4a vector (National Gene Vector lab) [Ref2412:Kim et al., 2008] Gene gun Gene gun DNA vaccine construction 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). DNA vaccine construction 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). Recombinant protein preparation 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). DNA vaccine construction 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). VO_0000286 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). Human papillomavirus DNA vaccine pC16-L1 encoding L1 VO_0004330 DNA vaccine Research pCDNA3 [Ref2169:Rocha-Zavaleta et al., 2002] Intramuscular injection (i.m.) Intramuscular injection (i.m.) DNA vaccine construction Vector pCDNA3 expressed L1 (Rocha-Zavaleta et al., 2002). VO_0000286 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). Human papillomavirus DNA vaccine Pe7(pcDNA3-Sig/sE7/LAMP) encoding E7 VO_0004329 DNA vaccine Research pcDNA3 [Ref2167:Sin, 2009] Intramuscular injection (i.m.) Intramuscular injection (i.m.) DNA vaccine construction Vector pcDNA3 expressed HPV oncogenic proteins E7 (Sin, 2009). VO_0000286 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). Human papillomavirus DNA vaccine pNGVL4a-E6/opt VO_0011480 DNA vaccine Research pNGVL4a Intradermal injection (i.d.) Intradermal injection (i.d.) Human papillomavirus E6 DNA vaccine construction 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). C57BL/6 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). 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). One week after the last vaccination, mice were challenged with 5 x10^4 TC-1 tumor cells mouse subcutaneously in the right leg and monitored once a week by inspection and palpation (Lin et al., 2006). Human papillomavirus DNA vaccine VlJns-Ll encoding L1 VO_0004328 DNA vaccine Research VlJns [Ref2166:Donnelly et al., 1996] Intramuscular injection (i.m.) Intramuscular injection (i.m.) DNA vaccine construction Vector VlJns expressed the major viral capsid protein L1 (Donnelly et al., 1996). VO_0000286 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). Human papillomavirus E7 protein vaccine VO_0011395 Subunit vaccine Research Subcutaneous injection Freund's incomplete adjuvant Subcutaneous injection Human papillomavirus E7 Recombinant protein preparation 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). C57BL/6 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). 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). 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 × 10^4 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). Human papillomavirus L2 protein vaccine VO_0011397 Subunit vaccine Research Subcutaneous injection GPI-0100 adjuvant or alum Subcutaneous injection Human papillomavirus L2 Recombinant protein preparation 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). BALB/c 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). 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). 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 × 10^9 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). licensed Human papillomavirus infection human vaccine Generic Unknown VO_0000667 Subunit vaccine Licensed A generic representation of vaccines utilized to prevent HPV infection in humans, most commonly formulated as subunit vaccines containing recombinant HPV virus-like particles (VLPs) that induce protective immunity. These vaccines target major HPV types responsible for cervical and other anogenital cancers. LM1-2-E7 VO_0004803 Recombinant vector vaccine Research Intramuscular injection (i.m.) The E7 fragment was amplified with PCR then cloned into the chromosome of L. monocytogenes (Jia et al., 2012). Intramuscular injection (i.m.) Recombinant vector construction The E7 gene is inserted into the vector of Listeria monocytogenes, strain LM1-2 (Jia et al., 2012). C57BL/6 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). VO_0000287 The LM1-2-E7 vaccine vector was shown to elicit protection against TC-1 tumor cells in the prophylactic challenges (Jia et al., 2012). 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). MEDI0457 MEDI 0457 CELLECTRA (Inovio Pharmaceuticals, San Diego, CA) DNA vaccine Clinical trial Intramuscular injection (i.m.) (Hasan et al., 2020)MEDI0457 (INO-3112) is a DNA-based vaccine targeting E6 and E7 of HPV-16/18 that is coinjected with an IL-12 plasmid followed by electroporation with the CELLECTRA 5P device. At 2 to 4 weeks after chemoradiation, patients with newly diagnosed stage IB1-IVA (cohort 1) or persistent/recurrent (cohort 2) cervical cancers were treated with 4 immunizations of MEDI0457 every 4 weeks Intramuscular injection (i.m.) (Hasan et al., 2020)E6 and E7 serve as non self antigens DNA vaccine construction E6 gene is inserted into a DNA vaccine plasmid, which allows the expression of the E6 protein. Recombinant protein preparation The E7 gene is inserted into a DNA vaccine plasmid, which allows the expression of the E7 protein. V503 Human Papillomavirus 9vHPV (6,11,16,18,31,33,45,52,58) Nonvalent Vaccine, Recombinant Gardasil Merck Sharp & Dohme LLC Recombinant vector vaccine Licensed Intramuscular injection (i.m.) USA Instead of a 4VHPV, this vaccine is a 9 valent HPV vaccine providing more protection. Aluminum hydroxyphosphate sulfate (AAHS) Intramuscular injection (i.m.) Participants (n = 600) were randomized to receive 9vHPV or qHPV vaccines on day 1, month 2 and month 6. immune responses to HPV 31/33/45/52/58, a 3-dose regimen of the 9vHPV vaccine elicited a similar immune response to HPV 6/11/16/18 when compared with the qHPV vaccine in girls aged 9–15 years after month 7 (Vesikari et al., 2015). CRTC Homo sapiens 1905911 CDD:306718 9606 ? calreticulin 4.06 46534.41 464 constructed at LLNL from flow-sorted chromosomes from hybrid 5HL2-B, which carries chromosome 19 as its only human chromosome >AAB51176.1 calreticulin [Homo sapiens] MLLSVPLLLGLLGLAVAEPAVYFKEQFLDGDGWTSRWIESKHKSDFGKFVLSSGKFYGDEEKDKGLQTSQ DARFYALSASFEPFSNKGQTLVVQFTVKHEQNIDCGGGYVKLFPNSLDQTDMHGDSEYNIMFGPDICGPG TKKVHVIFNYKGKNVLINKDIRCKDDEFTHLYTLIVRPDNTYEVKIDNSQVESGSLEDDWDFLPPKKIKD PDASKPEDWDERAKIDDPTDSKPEDWDKPEHIPDPDAKKPEDWDEEMDGEWEPPVIQNPEYKGEWKPRQI DNPDYKGTWIHPEIDNPEYSPDPSIYAYDNFGVLGLDLWQVKSGTIFDNFLITNDEAYAEEFGNETWGVT KAAEKQMKDKQDEEQRLKEEEEDKKRKEEEEAEDKEDDEDKDEDEEDEEDKEEDEEEDVPGQAKDEL Protective antigen E6 HPV 18 Human Papillomavirus AAP20594 CDD:332494 333761 E6 protein 8.56 18681.84 216 Early Protein (E6); cl27673 >AAP20594.1 E6 protein [Human papillomavirus type 18] MARFEDPTRRPYKLPDLCTELNTSLQDIEITCVYCKTVLELTEVFEFAFKDLFVVYRDSIPHAACHKCID FYSRIRELRHYSDSVYGDTLEKLTNTGLYNLLIRCLRCQKPLNPAEKLRHLNEKRRFHNIAGHYRGQCHS CCNRARQERLQRRRETQV Protective antigen [Ref5014:Khan et al., 2017] E6 Type 16 Human papillomavirus type 16 VO_0011107 1489078 9627104 HpV16gp1 AB663688 NP_041325 333760 7124 7600 + transforming protein E6 8.97 18789.29 158 E6 ORF from 65 to 559; putative >NC_001526.4:7124-7600 Human papillomavirus type 16, complete genome TATGCACCAAAAGAGAACTGCAATGTTTCAGGACCCACAGGAGCGACCCAGAAAGTTACCACAGTTATGC ACAGAGCTGCAAACAACTATACATGATATAATATTAGAATGTGTGTACTGCAAGCAACAGTTACTGCGAC GTGAGGTATATGACTTTGCTTTTCGGGATTTATGCATAGTATATAGAGATGGGAATCCATATGCTGTATG TGATAAATGTTTAAAGTTTTATTCTAAAATTAGTGAGTATAGACATTATTGTTATAGTTTGTATGGAACA ACATTAGAACAGCAATACAACAAACCGTTGTGTGATTTGTTAATTAGGTGTATTAACTGTCAAAAGCCAC TGTGTCCTGAAGAAAAGCAAAGACATCTGGACAAAAAGCAAAGATTCCATAATATAAGGGGTCGGTGGAC CGGTCGATGTATGTCTTGTTGCAGATCATCAAGAACACGTAGAGAAACCCAGCTGTA >NP_041325.1 transforming protein E6 [Human papillomavirus type 16] MHQKRTAMFQDPQERPRKLPQLCTELQTTIHDIILECVYCKQQLLRREVYDFAFRDLCIVYRDGNPYAVC DKCLKFYSKISEYRHYCYSLYGTTLEQQYNKPLCDLLIRCINCQKPLCPEEKQRHLDKKQRFHNIRGRWT GRCMSCCRSSRTRRETQL Protective antigen 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 [Ref1121:Lin et al., 2006]. E7 Type 16 Human papillomavirus type 16 VO_0011105 1489079 9627105 HpV16gp2 AB663783 NP_041326 333760 7603 7899 + transforming protein E7 3.97 10624.95 98 E7 ORF from 544 to 858; putative >NC_001526.4:7603-7899 Human papillomavirus type 16, complete genome CATGCATGGAGATACACCTACATTGCATGAATATATGTTAGATTTGCAACCAGAGACAACTGATCTCTAC TGTTATGAGCAATTAAATGACAGCTCAGAGGAGGAGGATGAAATAGATGGTCCAGCTGGACAAGCAGAAC CGGACAGAGCCCATTACAATATTGTAACCTTTTGTTGCAAGTGTGACTCTACGCTTCGGTTGTGCGTACA AAGCACACACGTAGACATTCGTACTTTGGAAGACCTGTTAATGGGCACACTAGGAATTGTGTGCCCCATC TGTTCTCAGAAACCATA >NP_041326.1 transforming protein E7 [Human papillomavirus type 16] MHGDTPTLHEYMLDLQPETTDLYCYEQLNDSSEEEDEIDGPAGQAEPDRAHYNIVTFCCKCDSTLRLCVQ STHVDIRTLEDLLMGTLGIVCPICSQKP Protective antigen 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 [Ref1118:Qin et al., 2005]. L1 HPV 16 Human papillomavirus type 16 VO_0011108 1489082 1046490004 HpV16gp8 K02718 NP_041332 2R5H 333760 4774 6291 + major capsid protein L1 8.38 53132.12 505 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 >NC_001526.4:4774-6291 Human papillomavirus type 16, complete genome GATGTCTCTTTGGCTGCCTAGTGAGGCCACTGTCTACTTGCCTCCTGTCCCAGTATCTAAGGTTGTAAGC ACGGATGAATATGTTGCACGCACAAACATATATTATCATGCAGGAACATCCAGACTACTTGCAGTTGGAC ATCCCTATTTTCCTATTAAAAAACCTAACAATAACAAAATATTAGTTCCTAAAGTATCAGGATTACAATA CAGGGTATTTAGAATACATTTACCTGACCCCAATAAGTTTGGTTTTCCTGACACCTCATTTTATAATCCA GATACACAGCGGCTGGTTTGGGCCTGTGTAGGTGTTGAGGTAGGTCGTGGTCAGCCATTAGGTGTGGGCA TTAGTGGCCATCCTTTATTAAATAAATTGGATGACACAGAAAATGCTAGTGCTTATGCAGCAAATGCAGG TGTGGATAATAGAGAATGTATATCTATGGATTACAAACAAACACAATTGTGTTTAATTGGTTGCAAACCA CCTATAGGGGAACACTGGGGCAAAGGATCCCCATGTACCAATGTTGCAGTAAATCCAGGTGATTGTCCAC CATTAGAGTTAATAAACACAGTTATTCAGGATGGTGATATGGTTGATACTGGCTTTGGTGCTATGGACTT TACTACATTACAGGCTAACAAAAGTGAAGTTCCACTGGATATTTGTACATCTATTTGCAAATATCCAGAT TATATTAAAATGGTGTCAGAACCATATGGCGACAGCTTATTTTTTTATTTACGAAGGGAACAAATGTTTG TTAGACATTTATTTAATAGGGCTGGTACTGTTGGTGAAAATGTACCAGACGATTTATACATTAAAGGCTC TGGGTCTACTGCAAATTTAGCCAGTTCAAATTATTTTCCTACACCTAGTGGTTCTATGGTTACCTCTGAT GCCCAAATATTCAATAAACCTTATTGGTTACAACGAGCACAGGGCCACAATAATGGCATTTGTTGGGGTA ACCAACTATTTGTTACTGTTGTTGATACTACACGCAGTACAAATATGTCATTATGTGCTGCCATATCTAC TTCAGAAACTACATATAAAAATACTAACTTTAAGGAGTACCTACGACATGGGGAGGAATATGATTTACAG TTTATTTTTCAACTGTGCAAAATAACCTTAACTGCAGACGTTATGACATACATACATTCTATGAATTCCA CTATTTTGGAGGACTGGAATTTTGGTCTACAACCTCCCCCAGGAGGCACACTAGAAGATACTTATAGGTT TGTAACATCCCAGGCAATTGCTTGTCAAAAACATACACCTCCAGCACCTAAAGAAGATCCCCTTAAAAAA TACACTTTTTGGGAAGTAAATTTAAAGGAAAAGTTTTCTGCAGACCTAGATCAGTTTCCTTTAGGACGCA AATTTTTACTACAAGCAGGATTGAAGGCCAAACCAAAATTTACATTAGGAAAACGAAAAGCTACACCCAC CACCTCATCTACCTCTACAACTGCTAAACGCAAAAAACGTAAGCTGTA >NP_041332.2 major capsid protein L1 [Human papillomavirus type 16] MSLWLPSEATVYLPPVPVSKVVSTDEYVARTNIYYHAGTSRLLAVGHPYFPIKKPNNNKILVPKVSGLQY RVFRIHLPDPNKFGFPDTSFYNPDTQRLVWACVGVEVGRGQPLGVGISGHPLLNKLDDTENASAYAANAG VDNRECISMDYKQTQLCLIGCKPPIGEHWGKGSPCTNVAVNPGDCPPLELINTVIQDGDMVDTGFGAMDF TTLQANKSEVPLDICTSICKYPDYIKMVSEPYGDSLFFYLRREQMFVRHLFNRAGTVGENVPDDLYIKGS GSTANLASSNYFPTPSGSMVTSDAQIFNKPYWLQRAQGHNNGICWGNQLFVTVVDTTRSTNMSLCAAIST SETTYKNTNFKEYLRHGEEYDLQFIFQLCKITLTADVMTYIHSMNSTILEDWNFGLQPPPGGTLEDTYRF VTSQAIACQKHTPPAPKEDPLKKYTFWEVNLKEKFSADLDQFPLGRKFLLQAGLKAKPKFTLGKRKATPT TSSTSTTAKRKKRKL Protective antigen 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 [Ref1122:Nieto et al., 2009]. L1 HPV 52 AAY57811.1 GQ472848 ACX32362 CDD:420110 10618 ? L1 5.31 28729.71 324 L1 (late) protein; cl23949 >AAY57811.1 L1, partial [human papillomavirus 52] ACTGLEIGRGQPLGVGISGHPLLNKFDDTETSNKYAGKPGIDNRECLSMDYKQTQLCILGCKPPIGEHWG KGTPCNNNSGNPGDCPPLQLINSVIQDGDMVDTGFGCMDFNTLQASKSDVPIDICSSVCKYPDYLQMASE PYGDSLFFFLRREQMFVRHFFNRAGTLGDPVPGDLYIQGSNSGNTATVQSSAFFPTPSGSMVTSESQLFN KPYWLQRAQGHNNGICWGNQLFVTVVDTTRSTNMTLCAEVKKESTYKNENFKEYLRHGE Protective antigen L2 HPV 16 Human papillomavirus type 16 VO_0011106 1489081 1046490003 HpV16gp7 K02718 NP_041331 333760 3372 4793 ? minor capsid protein L2 6.31 47994.02 473 L2 ORF from 4133 to 5656; putative >NC_001526.4:3372-4793 Human papillomavirus type 16, complete genome AATGCGACACAAACGTTCTGCAAAACGCACAAAACGTGCATCGGCTACCCAACTTTATAAAACATGCAAA CAGGCAGGTACATGTCCACCTGACATTATACCTAAGGTTGAAGGCAAAACTATTGCTGATCAAATATTAC AATATGGAAGTATGGGTGTATTTTTTGGTGGGTTAGGAATTGGAACAGGGTCGGGTACAGGCGGACGCAC TGGGTATATTCCATTGGGAACAAGGCCTCCCACAGCTACAGATACACTTGCTCCTGTAAGACCCCCTTTA ACAGTAGATCCTGTGGGCCCTTCTGATCCTTCTATAGTTTCTTTAGTGGAAGAAACTAGTTTTATTGATG CTGGTGCACCAACATCTGTACCTTCCATTCCCCCAGATGTATCAGGATTTAGTATTACTACTTCAACTGA TACCACACCTGCTATATTAGATATTAATAATACTGTTACTACTGTTACTACACATAATAATCCCACTTTC ACTGACCCATCTGTATTGCAGCCTCCAACACCTGCAGAAACTGGAGGGCATTTTACACTTTCATCATCCA CTATTAGTACACATAATTATGAAGAAATTCCTATGGATACATTTATTGTTAGCACAAACCCTAACACAGT AACTAGTAGCACACCCATACCAGGGTCTCGCCCAGTGGCACGCCTAGGATTATATAGTCGCACAACACAA CAGGTTAAAGTTGTAGACCCTGCTTTTGTAACCACTCCCACTAAACTTATTACATATGATAATCCTGCAT ATGAAGGTATAGATGTGGATAATACATTATATTTTTCTAGTAATGATAATAGTATTAATATAGCTCCAGA TCCTGACTTTTTGGATATAGTTGCTTTACATAGGCCAGCATTAACCTCTAGGCGTACTGGCATTAGGTAC AGTAGAATTGGTAATAAACAAACACTACGTACTCGTAGTGGAAAATCTATAGGTGCTAAGGTACATTATT ATTATGATTTAAGTACTATTGATCCTGCAGAAGAAATAGAATTACAAACTATAACACCTTCTACATATAC TACCACTTCACATGCAGCCTCACCTACTTCTATTAATAATGGATTATATGATATTTATGCAGATGACTTT ATTACAGATACTTCTACAACCCCGGTACCATCTGTACCCTCTACATCTTTATCAGGTTATATTCCTGCAA ATACAACAATTCCTTTTGGTGGTGCATACAATATTCCTTTAGTATCAGGTCCTGATATACCCATTAATAT AACTGACCAAGCTCCTTCATTAATTCCTATAGTTCCAGGGTCTCCACAATATACAATTATTGCTGATGCA GGTGACTTTTATTTACATCCTAGTTATTACATGTTACGAAAACGACGTAAACGTTTACCATATTTTTTTT CAGATGTCTCTTTGGCTGCCTA >NP_041331.2 minor capsid protein L2 [Human papillomavirus type 16] MRHKRSAKRTKRASATQLYKTCKQAGTCPPDIIPKVEGKTIADQILQYGSMGVFFGGLGIGTGSGTGGRT GYIPLGTRPPTATDTLAPVRPPLTVDPVGPSDPSIVSLVEETSFIDAGAPTSVPSIPPDVSGFSITTSTD TTPAILDINNTVTTVTTHNNPTFTDPSVLQPPTPAETGGHFTLSSSTISTHNYEEIPMDTFIVSTNPNTV TSSTPIPGSRPVARLGLYSRTTQQVKVVDPAFVTTPTKLITYDNPAYEGIDVDNTLYFSSNDNSINIAPD PDFLDIVALHRPALTSRRTGIRYSRIGNKQTLRTRSGKSIGAKVHYYYDLSTIDPAEEIELQTITPSTYT TTSHAASPTSINNGLYDIYADDFITDTSTTPVPSVPSTSLSGYIPANTTIPFGGAYNIPLVSGPDIPINI TDQAPSLIPIVPGSPQYTIIADAGDFYLHPSYYMLRKRRKRLPYFFSDVSLAA Protective antigen 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 [Ref1119:Jagu et al., 2009]. L2 HPV31 ALT54672 CDD:332973 10585 ? 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