J Bacteriol Virol.  2015 Sep;45(3):189-199. 10.4167/jbv.2015.45.3.189.

Current and Next-generation Vaccines against Human Papillomaviruses

• Kim YH

• KMID: 2068734
• DOI: http://doi.org/10.4167/jbv.2015.45.3.189

Abstract

Human papillomaviruses (HPVs) infect the squamous epithelium, and cause skin warts, genital warts and cancers, including uterine cervical cancer. Amongst the enormously diverse types of HPVs, HPV16 and HPV18 are most prevalent and responsible for approximately 70% of cervical cancer cases. Current preventive HPV vaccines contain virus-like particles which are composed of L1 major capsid proteins of HPV16 and HPV18. Although bivalent and quadrivalent vaccines exhibit excellent preventive efficacy and safety, they have several limitations. First, since the protection against HPV is type-restricted, the remaining 30% of cervical cancers and warts cannot be prevented. Second, due to the absence of therapeutic activity in the vaccines, people already infected by the HPVs cannot benefit from the current vaccines. Therefore, new preventive and therapeutic vaccines are required for better control of HPV-associated diseases. New developments include a novel nonavalent preventive vaccine that contains five additional cancer-associated HPV types, and it has been tested and approved in 2014. Recently, several groups reported promising clinical results with novel therapeutic HPV vaccines. This review provides an overview of the success of current preventive vaccines and perspectives on the next-generation HPV vaccines.

Keyword

Papillomavirus vaccine; Uterine cervical neoplasm; Sexually transmitted disease

MeSH Terms

Capsid Proteins
Condylomata Acuminata
Epithelium
Humans*
Papillomavirus Vaccines
Sexually Transmitted Diseases
Skin
Uterine Cervical Neoplasms
Vaccines*
Warts
Capsid Proteins
Papillomavirus Vaccines
Vaccines

Reference

1). Forman D, de Martel C, Lacey CJ, Soerjomataram I, Lortet-Tieulent J, Bruni L, et al. Global burden of human papillomavirus and related diseases. Vaccine. 2012; 30:F12–23.

2). de Martel C, Ferlay J, Franceschi S, Vignat J, Bray F, Forman D, et al. Global burden of cancers attributable to infections in 2008: a review and synthetic analysis. Lancet Oncol. 2012; 13:607–15.

3). Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A. Global cancer statistics, 2012. CA Cancer J Clin. 2015; 65:87–108.

4). Doorbar J, Quint W, Banks L, Bravo IG, Stoler M, Broker TR, et al. The biology and life-cycle of human papillomaviruses. Vaccine. 2012; 30:F55–70.

5). Bzhalava D, Eklund C, Dillner J. International standardization and classification of human papillomavirus types. Virology. 2015; 476:341–4.

6). Muñoz N, Bosch FX, de Sanjosé S, Herrero R, Castellsagué X, Shah KV, et al. Epidemiologic classification of human papillomavirus types associated with cervical cancer. N Engl J Med. 2003; 348:518–27.

7). Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD. Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med. 1998; 338:423–8.

8). Giuliano AR, Lee JH, Fulp W, Villa LL, Lazcano E, Papenfuss MR, et al. Incidence and clearance of genital human papillomavirus infection in men (HIM): a cohort study. Lancet. 2011; 377:932–40.

9). Dunne EF, Park IU. HPV and HPV-associated diseases. Infect Dis Clin North Am. 2013; 27:765–78.

10). Ostör AG. Natural history of cervical intraepithelial neoplasia: a critical review. Int J Gynecol Pathol. 1993; 12:186–92.

11). Castle PE, Schiffman M, Wheeler CM, Solomon D. Evidence for frequent regression of cervical intraepithelial neoplasia-grade 2. Obstet Gynecol. 2009; 113:18–25.

12). zur Hausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer. 2002; 2:342–50.

13). Doorbar J. Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond). 2006; 110:525–41.

14). Patel H, Wagner M, Singhal P, Kothari S. Systematic review of the incidence and prevalence of genital warts. BMC Infect Dis. 2013; 13:39.

15). Schmitt M, de Koning MN, Eekhof JA, Quint WG, Pawlita M. Evaluation of a novel multiplex human papillomavirus (HPV) genotyping assay for HPV types in skin warts. J Clin Microbiol. 2011; 49:3262–7.

16). Mulhem E, Pinelis S. Treatment of nongenital cutaneous warts. Am Fam Physician. 2011; 84:288–93.

17). Mammas IN, Spandidos DA, Sourvinos G. Genomic diversity of human papillomaviruses (HPV) and clinical implications: an overview in adulthood and childhood. Infect Genet Evol. 2014; 21:220–6.

18). Park HS. Systemic Review for Efficacy of Human Papillomavirus Vaccines. J Bacteriol Virol. 2011; 41:313–8.

19). Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT. Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci U S A. 1992; 89:12180–4.

20). Schiller JT, Lowy DR. Understanding and learning from the success of prophylactic human papillomavirus vaccines. Nat Rev Microbiol. 2012; 10:681–92.

21). Lehtinen M, Paavonen J, Wheeler CM, Jaisamrarn U, Garland SM, Castellsagué X, et al. Overall efficacy of HPV-16/18 AS04-adjuvanted vaccine against grade 3 or greater cervical intraepithelial neoplasia: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012; 13:89–99.

22). Herrero R, Hildesheim A, Rodríguez AC, Wacholder S, Bratti C, Solomon D, et al. Rationale and design of a community-based double-blind randomized clinical trial of an HPV 16 and 18 vaccine in Guanacaste, Costa Rica. Vaccine. 2008; 26:4795–808.

23). McCormack PL. Quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine (gardasil(®)): a review of its use in the prevention of premalignant anogenital lesions, cervical and anal cancers, and genital warts. Drugs. 2014; 74:1253–83.

24). Muñoz N, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez-Avila M, Wheeler CM, et al. Impact of human papillomavirus (HPV)-6/11/16/18 vaccine on all HPV-associated genital diseases in young women. J Natl Cancer Inst. 2010; 102:325–39.

25). Roden RB, Greenstone HL, Kirnbauer R, Booy FP, Jessie J, Lowy DR, et al. In vitro generation and type-specific neutralization of a human papillomavirus type 16 virion pseudotype. J Virol. 1996; 70:5875–83.

26). GlaxoSmithKline Vaccine HPVSG, Romanowski B, de Borba PC, Naud PS, Roteli-Martins CM, De Carvalho NS, et al. Sustained efficacy and immunogenicity of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine: analysis of a randomised placebo-controlled trial up to 6.4 years. Lancet. 2009; 374:1975–85.

27). Breitburd F, Kirnbauer R, Hubbert NL, Nonnenmacher B, Trin-Dinh-Desmarquet C, Orth G, et al. Immunization with viruslike particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection. J Virol. 1995; 69:3959–63.

28). Suzich JA, Ghim SJ, Palmer-Hill FJ, White WI, Tamura JK, Bell JA, et al. Systemic immunization with papillomavirus L1 protein completely prevents the development of viral mucosal papillomas. Proc Natl Acad Sci U S A. 1995; 92:11553–7.

29). Villa LL, Costa RL, Petta CA, Andrade RP, Paavonen J, Iversen OE, et al. High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up. Br J Cancer. 2006; 95:1459–66.

30). Roteli-Martins CM, Naud P, De Borba P, Teixeira JC, De Carvalho NS, Zahaf T, et al. Sustained immunogenicity and efficacy of the HPV-16/18 AS04-adjuvanted vaccine: up to 8.4 years of follow-up. Hum Vaccin Immunother. 2012; 8:390–7.

31). Naud PS, Roteli-Martins CM, De Carvalho NS, Teixeira JC, de Borba PC, Sanchez N, et al. Sustained efficacy, immunogenicity, and safety of the HPV-16/18 AS04-adjuvanted vaccine: final analysis of a long-term follow-up study up to 9.4 years post-vaccination. Hum Vaccin Immunother. 2014; 10:2147–62.

32). Lehtinen M, Dillner J. Clinical trials of human papillomavirus vaccines and beyond. Nat Rev Clin Oncol. 2013; 10:400–10.

33). Paavonen J, Jenkins D, Bosch FX, Naud P, Salmerón J, Wheeler CM, et al. Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet. 2007; 369:2161–70.

34). Group FIS. Quadrivalent vaccine against human papillomavirus to prevent high-grade cervical lesions. N Engl J Med. 2007; 356:1915–27.

35). Group FIIS, Dillner J, Kjaer SK, Wheeler CM, Sigurdsson K, Iversen OE, et al. Four year efficacy of prophylactic human papillomavirus quadrivalent vaccine against low grade cervical, vulvar, and vaginal intraepithelial neoplasia and anogenital warts: randomised controlled trial. BMJ. 2010; 341:c3493.

36). Petäjä T, Keränen H, Karppa T, Kawa A, Lantela S, Siitari-Mattila M, et al. Immunogenicity and safety of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in healthy boys aged 10~18 years. J Adolesc Health. 2009; 44:33–40.

37). Giuliano AR, Palefsky JM, Goldstone S, Moreira ED Jr, Penny ME, Aranda C, et al. Efficacy of quadrivalent HPV vaccine against HPV Infection and disease in males. N Engl J Med. 2011; 364:401–11.

38). Angelo MG, David MP, Zima J, Baril L, Dubin G, Arellano F, et al. Pooled analysis of large and long-term safety data from the human papillomavirus-16/18-AS04-adjuvanted vaccine clinical trial programme. Pharmacoepidemiol Drug Saf. 2014; 23:466–79.

39). Block SL, Brown DR, Chatterjee A, Gold MA, Sings HL, Meibohm A, et al. Clinical trial and post-licensure safety profile of a prophylactic human papillomavirus (types 6, 11, 16, and 18) l1 virus-like particle vaccine. Pediatr Infect Dis J. 2010; 29:95–101.

40). Goss MA, Lievano F, Seminack MM, Dana A. No Adverse Signals Observed After Exposure to Human Papillomavirus Type 6/11/16/18 Vaccine During Pregnancy: 6-Year Pregnancy Registry Data. Obstetrics and Gynecology. 2014; 123:93S.

41). Herrero R, González P, Markowitz LE. Present status of human papillomavirus vaccine development and implementation. Lancet Oncol. 2015; 16:e206–16.

42). Block SL, Nolan T, Sattler C, Barr E, Giacoletti KE, Marchant CD, et al. Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics. 2006; 118:2135–45.

43). Pedersen C, Petaja T, Strauss G, Rumke HC, Poder A, Richardus JH, et al. Immunization of early adolescent females with human papillomavirus type 16 and 18 L1 virus-like particle vaccine containing AS04 adjuvant. J Adolesc Health. 2007; 40:564–71.

44). Korean Standrad Immunization Schedule. Korea Centers for Disease Control and Prevention. 2015. [cited 2015 August 12]. Available from:. https://nip.cdc.go.kr/irgd/index.html.

45). Brotherton JM, Fridman M, May CL, Chappell G, Saville AM, Gertig DM. Early effect of the HPV vaccination programme on cervical abnormalities in Victoria, Australia: an ecological study. Lancet. 2011; 377:2085–92.

46). Donovan B, Franklin N, Guy R, Grulich AE, Regan DG, Ali H, et al. Quadrivalent human papillomavirus vaccination and trends in genital warts in Australia: analysis of national sentinel surveillance data. Lancet Infect Dis. 2011; 11:39–44.

47). Tabrizi SN, Brotherton JM, Kaldor JM, Skinner SR, Cummins E, Liu B, et al. Fall in human papillomavirus prevalence following a national vaccination program. J Infect Dis. 2012; 206:1645–51.

48). Paavonen J, Naud P, Salmerón J, Wheeler CM, Chow SN, Apter D, et al. Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet. 2009; 374:301–14.

49). Wheeler CM, Castellsagué X, Garland SM, Szarewski A, Paavonen J, Naud P, et al. Cross-protective efficacy of HPV-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by non-vaccine oncogenic HPV types: 4-year end-of-study analysis of the randomised, double-blind PATRICIA trial. Lancet Oncol. 2012; 13:100–10.

50). Brown DR, Kjaer SK, Sigurdsson K, Iversen OE, Hernandez-Avila M, Wheeler CM, et al. The impact of quadrivalent human papillomavirus (HPV; types 6, 11, 16, and 18) L1 virus-like particle vaccine on infection and disease due to oncogenic nonvaccine HPV types in generally HPV-naive women aged 16–26 years. J Infect Dis. 2009; 199:926–35.

51). Schiller JT, Castellsagué X, Garland SM. A review of clinical trials of human papillomavirus prophylactic vaccines. Vaccine. 2012; 30:F123–38.

52). Schiller JT, Müller M. Next generation prophylactic human papillomavirus vaccines. Lancet Oncol. 2015; 16:e217–25.

53). Poljak M. Prophylactic human papillomavirus vaccination and primary prevention of cervical cancer: issues and challenges. Clin Microbiol Infect. 2012; 18:64–9.

54). No authors listed. HPV vaccine works against nine viral types. Cancer Discov. 2014; 4:OF2.

55). Tyler M, Tumban E, Chackerian B. Second-generation prophylactic HPV vaccines: successes and challenges. Expert Rev Vaccines. 2014; 13:247–55.

56). Pastrana DV, Gambhira R, Buck CB, Pang YY, Thompson CD, Culp TD, et al. Cross-neutralization of cutaneous and mucosal Papillomavirus types with anti-sera to the amino terminus of L2. Virology. 2005; 337:365–72.

57). Alphs HH, Gambhira R, Karanam B, Roberts JN, Jagu S, Schiller JT, et al. Protection against heterologous human papillomavirus challenge by a synthetic lipopeptide vaccine containing a broadly cross-neutralizing epitope of L2. Proc Natl Acad Sci U S A. 2008; 105:5850–5.

58). Roden RB, Yutzy WH 4th, Fallon R, Inglis S, Lowy DR, Schiller JT. Minor capsid protein of human genital papillomaviruses contains subdominant, cross-neutralizing epitopes. Virology. 2000; 270:254–7.

59). Day PM, Pang YY, Kines RC, Thompson CD, Lowy DR, Schiller JT. A human papillomavirus (HPV) in vitro neutralization assay that recapitulates the in vitro process of infection provides a sensitive measure of HPV L2 infection-inhibiting antibodies. Clin Vaccine Immunol. 2012; 19:1075–82.

60). Schellenbacher C, Kwak K, Fink D, Shafti-Keramat S, Huber B, Jindra C, et al. Efficacy of RG1-VLP vaccination against infections with genital and cutaneous human papillomaviruses. J Invest Dermatol. 2013; 133:2706–13.

61). Karanam B, Jagu S, Huh WK, Roden RB. Developing vaccines against minor capsid antigen L2 to prevent papillomavirus infection. Immunol Cell Biol. 2009; 87:287–99.

62). Gambhira R, Karanam B, Jagu S, Roberts JN, Buck CB, Bossis I, et al. A protective and broadly cross-neutralizing epitope of human papillomavirus L2. J Virol. 2007; 81:13927–31.

63). Varsani A, Williamson AL, de Villiers D, Becker I, Christensen ND, Rybicki EP. Chimeric human papillomavirus type 16 (HPV-16) L1 particles presenting the common neutralizing epitope for the L2 minor capsid protein of HPV-6 and HPV-16. J Virol. 2003; 77:8386–93.

64). Kondo K, Ochi H, Matsumoto T, Yoshikawa H, Kanda T. Modification of human papillomavirus-like particle vaccine by insertion of the cross-reactive L2-epitopes. J Med Virol. 2008; 80:841–6.

65). McGrath M, de Villiers GK, Shephard E, Hitzeroth II, Rybicki EP. Development of human papillomavirus chimaeric L1/L2 candidate vaccines. Arch Virol. 2013; 158:2079–88.

66). Schellenbacher C, Roden R, Kirnbauer R. Chimeric L1-L2 virus-like particles as potential broad-spectrum human papillomavirus vaccines. J Virol. 2009; 83:10085–95.

67). Smith ML, Lindbo JA, Dillard-Telm S, Brosio PM, Lasnik AB, McCormick AA, et al. Modified tobacco mosaic virus particles as scaffolds for display of protein antigens for vaccine applications. Virology. 2006; 348:475–88.

68). Cerovska N, Hoffmeisterova H, Moravec T, Plchova H, Folwarczna J, Synkova H, et al. Transient expression of Human papillomavirus type 16 L2 epitope fused to N- and C-terminus of coat protein of Potato virus X in plants. J Biosci. 2012; 37:125–33.

69). Nieto K, Weghofer M, Sehr P, Ritter M, Sedlmeier S, Karanam B, et al. Development of AAVLP (HPV16/31L2) particles as broadly protective HPV vaccine candidate. PLoS One. 2012; 7:e39741.

70). Caldeira Jdo C, Medford A, Kines RC, Lino CA, Schiller JT, Chackerian B, et al. Immunogenic display of diverse peptides, including a broadly cross-type neutralizing human papillomavirus L2 epitope, on virus-like particles of the RNA bacteriophage PP7. Vaccine. 2010; 28:4384–93.

71). Jagu S, Karanam B, Gambhira R, Chivukula SV, Chaganti RJ, Lowy DR, et al. Concatenated multitype L2 fusion proteins as candidate prophylactic pan-human papillomavirus vaccines. J Natl Cancer Inst. 2009; 101:782–92.

72). Rubio I, Bolchi A, Moretto N, Canali E, Gissmann L, Tommasino M, et al. Potent anti-HPV immune responses induced by tandem repeats of the HPV16 L2 (20 – 38) peptide displayed on bacterial thioredoxin. Vaccine. 2009; 27:1949–56.

73). Kalnin K, Tibbitts T, Yan Y, Stegalkina S, Shen L, Costa V, et al. Low doses of flagellin-L2 multimer vaccines protect against challenge with diverse papillomavirus genotypes. Vaccine. 2014; 32:3540–7.

74). Yoon SW, Lee TY, Kim SJ, Lee IH, Sung MH, Park JS, et al. Oral administration of HPV-16 L2 displayed on Lactobacillus casei induces systematic and mucosal cross-neutralizing effects in Balb/c mice. Vaccine. 2012; 30:3286–94.

75). Schiller JT, Castellsagué X, Villa LL, Hildesheim A. An update of prophylactic human papillomavirus L1 virus-like particle vaccine clinical trial results. Vaccine. 2008; 26:K53–61.

76). Ma B, Maraj B, Tran NP, Knoff J, Chen A, Alvarez RD, et al. Emerging human papillomavirus vaccines. Expert Opin Emerg Drugs. 2012; 17:469–92.

77). Doorbar J. The papillomavirus life cycle. J Clin Virol. 2005; 32:S7–15.

78). Lin K, Doolan K, Hung CF, Wu TC. Perspectives for preventive and therapeutic HPV vaccines. J Formos Med Assoc. 2010; 109:4–24.

79). Morrow MP, Yan J, Sardesai NY. Human papillomavirus therapeutic vaccines: targeting viral antigens as immunotherapy for precancerous disease and cancer. Expert Rev Vaccines. 2013; 12:271–83.

80). Stern PL, van der Burg SH, Hampson IN, Broker TR, Fiander A, Lacey CJ, et al. Therapy of human papillomavirus-related disease. Vaccine. 2012; 30:F71–82.

81). Kenter GG, Welters MJ, Valentijn AR, Lowik MJ, Berends-van der Meer DM, Vloon AP, et al. Vaccination against HPV-16 oncoproteins for vulvar intraepithelial neoplasia. N Engl J Med. 2009; 361:1838–47.

82). Kim TJ, Jin HT, Hur SY, Yang HG, Seo YB, Hong SR, et al. Clearance of persistent HPV infection and cervical lesion by therapeutic DNA vaccine in CIN3 patients. Nat Commun. 2014; 5:5317.

83). Rosales R, López-Contreras M, Rosales C, Magallanes-Molina JR, Gonzalez-Vergara R, Arroyo-Cazarez JM, et al. Regression of human papillomavirus intraepithelial lesions is induced by MVA E2 therapeutic vaccine. Hum Gene Ther. 2014; 25:1035–49.