Promise of reduced HPV associated

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1 HPV accounts for ~500,000 cases of cancer annually across the globe Promise of reduced HPV associated cancers in AIAN communities NAOMI LEE, PHD NIH IRACDA POSTDOCTORAL FELLOW UNIVERSIT OF NEW MEXICO Human papillomavirus (HPV) is the most common STI Greater than >150 known HPV genotypes Persistent infection with some HPV types can cause genital warts and cancer Low risk HPV (LrHPV) genotypes cause genital warts High risk HPV (HrHPV) genotypes are detected in certain cancers DEPARTMENT OF MOLECULAR GENETICS AND MICROBIOLOG CHACKERIAN LAB CDC HPV statistics Smith JS, et al Human papillomavirus type distribution in invasive cervical cancer and high grade cervical lesions: a meta analysis update. International journal of cancer Aug 1; 121(3): HrHPV genotypes 16 and 18 account for most HPV cancer cases 14 high risk HPV genotypes identified Detected in nearly all cervical cancer cases Men are susceptible to HPV associated cancers HrHPV genotypes 16 and 18 account for ~70% of cervical cancers >90% of other HPV cancer cases Prevalence of HrHPV in AIAN women varies between communities ~25% of women aged years in the general population test positive for at least one HrHPV AIAN populationsare not sufficiently over sampled in national data Few studies have determined HPV prevalence in AIAN communities Only ~8% AI women ages years tested positive for at least one HrHPV from the Northern Plains (pre vaccine) ~30% of AI women tested positive for HrHPV vs. 16% for white women ages years in South Dakota ( ) 22.2% of Hopi women ages years tested positive ( ) 34.8% of AI women ages years tested positive ( ) CDC HPV statistics Lowy DR, Schiller JT. Reducing HPV associated cancer globally. Cancer Prev Res (Phila). 2012;5(1): ) Bell, M.C. et al. (2007) Gynecol Oncol, 107(2): ) Schmidt Grimminger, D.C. et al. (2011). Bmc Infectious Diseases, 11. 3) Winer, R.L. et al. J Community Health. 2016;41(5): ) Lee, N. R. et al (2017) unpublished. 1

2 Prophylactic vaccines only protect uninfected individuals Vaccines are comprised of virus like particles (VLPs) HPV protein monomers spontaneouslyself assemble into non infectiousviral mimic Repetitive display results in high antibody titers Vaccines do not protect against existing infections No or very little antibody Protein monomer Assemble into pentamers Pentamers self assemble Non infectious HPV VLP Antibodies against HPV Most recent vaccine protects against 9 HPV genotypes in uninfected individuals Three vaccines available since 2006 Gardasil 4 HPV 6, 11, 16 and 18 Cervarix HPV16 and18 (females only) Gardasil 9 HPV 6, 11, 16, 18, 31, 33, 45, 52, and 58 Femalesandmalesages9 26 years Estimated that Gardasil 9 should prevent 90% of genital warts and 90% of all cervical cancers 90% of genital warts Cervarix Gardasil Gardasil 4 90% of cervical cancer Higher uptake of HPV vaccines in AIAN young males and females Vaccine coverage varies between genders 57% versus 35% in males aged years received 1 dose IHS data reports higher uptake of HPV vaccines for both females (82%) and males (62%) Decreased prevalence in females aged years types 6, 11, 16, & % in the pre vaccine era ( ) to 4.3% in the vaccine era ( ) Data not yet available to assess the impact of Gardasil 9 Older AI women are at high risk for cervical cancer (%) HrHPV Prevalence Prevalence, (%) % , 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68 16, 18, 31, 33, 45, 52, Age, years 14 high risk genotypes Overall 34.8% positive Prevalence of HPV genotypes covered by different HPV vaccines Cervarix (16, 18) Gardasil 4 (6, 11, 16, 18) Gardasil 9 (31, 33, 45, 52, 58) HrHPV prevalence is 4 fold higher for older women (50 65 years) compared to a large study in NM CDC HPV statistics Available at 8 2

3 Many answers are needed to decrease HPV associated cancers in AIAN communities Is there a genetic or immunologic factor that prevents viral clearance in older women? Do mutations in the viral genome increase carcinogenicity in men and women? What is the efficacy of HPV vaccines in AIAN communities? What are the most prevalent HPV genotypes in cervical malignancies? HrHPV Prevalence, (%) % , 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, Age, years Current progress to decrease HPV cancers in AIAN communities Vaccinate with Gardasil 9 HPV 51 is most prevalent but not covered by current vaccines Develop new prophylactic and therapeutic vaccines to increase protection Include men in future studies 3 fold disparity in HPV oropharyngeal cancer No FDA approved test for men; validating urine based test Increased representation in clinical trials HPV antigen inserted into VLP Protein monomer Tribal Community Self assembly Antigen displayed on VLP Conclusion: reduction of HPV cancers is achievable with continued research HPV causes cancer in men and women Prevalence varies across racial/ethnic subpopulations and AIAN communities HPV vaccines are comprised of VLPs and protect against 9 HPV genotypes Vaccine uptake is higher in IHS facilities than the general population Gardasil 9 needs to be widely distributed Steps are being taken to development vaccines for AIAN communities Acknowledgements CHACKERIAN LAB 1 NIDP 2 Bryce Chackerian, PhD Jason Umans, MD, PhD Kathryn Frietze, PhD Lonnie Nelson, PhD Julianne Peabody Carolyn Noonan, MS Susan Core Dedra Buchwald, MD Spero Manson, PhD Rachel Winer, PhD Staff and faculty OTHERS Angela Wandinger Ness, PhD Sherry Rogers, PhD ASERT fellows Cosette Wheeler, PhD 1 Institutional Research and Academic Career Development Award (IRACDA) NIGMS grant 5K12GM and EPIC STI grant U19 AI (NIAID) at the University of New Mexico 2 Native Investigator Development Program is funded through the Resource Centers for Minority Aging Research program of the National Institute on Aging P30 AG

4 First vaccine licensed nearly 25 years after Vaccine HPV discovery HPV 16 discovered Vaccine Development licensure VLP clinical 1 st report 1 st vaccine: (males) Gardasil 9 1 st VLPs produced trials start of efficacy females only licensure Molecular Pathogenesis Case/control cervical cancer studies Animal HPV causes cervical cancer studies Prospective HPV neoplasia studies Cervical cancer is one of the most common cancers in women worldwide In 2015, ~12,900 cases were diagnosed and ~4,000 die annually within the US Risk for cervical cancer increases with age in HPV infected women American Indian and Alaska Native (AIAN) women had a 2 3 times increased incidence rate and mortality rate compared non Hispanic white women Highest rates (~4 5 fold) were in the Northern Plains HPV vaccinations and cervical cancer detection at early stage can decrease mortality rates Watson, M., et al. (2014) Cervical cancer incidence and mortality disparities among American Indians and Alaska Natives, Cancer Epidemiology Biomarkers & Prevention, 23(11). Unique HrHPV genotype profile National Data Tribal Community 4 of 5 most prevalent genotypes are covered by newest vaccine 1) Shi R. et al NHANES BMC Res Notes. 2014;7:544. 2) Lee, N. R. et al (2017) unpublished. 4

5 Public Health Health Insurance Factors Access to health care Vaccination Genetics 1st degree relative with cervical cancer Oncogenic HPV is the Main Risk Factor Oncogenic HPV Sociodemographics Sexual history Lifestyle Health behaviors Factors Immune Response HPV Associated Cancer Co infections (HIV and Chlamydia) Immunomodulatory therapies (chemo) Conceptual Framework Socio Lifestyle Biological demographics Variables Variables Outcome Virus like particles (VLPs) can increase the immunogenicity of antigens VLPs are flexible platforms for vaccines Age Education Income Marital Status Drug and Alcohol Use Age at first vaginal intercourse # sexual partners Condom use STI history Antibiotic use Access to care Exposure to infected person Efficiency of transmission Duration of infectivity Treatment options Any STI VLP Modify with Antigen Ng antigen Multivalent display of Ng antigen No or very little antibody Antibodies to Ng antigen 19 Frietze, K.M., D.S. Peabody, and B. Chackerian (2016) Engineering virus like particles as vaccine platforms. Curr Opin Virol, 18:

6 Multivalent display of Ng antigen on VLP via chemical conjugation Antigen inserted into Ab loop Self-assembly SMPH bifunctional crosslinker Synthetic Ng peptide MS2 single chain dimer MS2 VLP Qβ VLP Surface exposed lysines highlighted in yellow Antigens are displayed on VLPs using two methods 1. Chemical conjugation of target molecules M NH3 D V Q S S P T D I D T S E C P SMPH Antigen with an accessible sulfhydryl Qß phage Surface lysine residues are shown in red 2. Genetic insertion of target peptides into viral structural proteins insert plasmid coat transcription & translation assembly VLP with foreign peptide on surface 6