Human papillomavirus genotype distribution in Ethiopia: an updated systematic review

Background Cervical cancer is caused by infection with high-risk human papillomaviruses (HR-HPVs). It is one of the leading causes of cancer-related deaths in Ethiopia and globally. To develop efficient vaccination and HPV-based cervical cancer screening approaches, data on genotype distribution of HPVs is crucial. Hence, the study was aimed to review HPV genotype distribution in Ethiopia. Methods Research articles were systematically searched using comprehensive search strings from PubMed/Medline and SCOPUS. Besides, Google Scholar was searched manually for grey literature. The last search was conducted on 18 August 2021. The first two authors independently appraised the studies for scientific quality and extracted the data using Excel sheet. The pooled HPV genotype distribution was presented with descriptive statistics. Results We have included ten studies that were reported from different parts of the country during 2005 and 2019. These studies included 3633 women presented with different kinds of cervical abnormalities, from whom 29 different HPV genotypes with a sum of 1926 sequences were reported. The proportion of high-risk, possible/probable high-risk and low-risk HPVs were at 1493 (77.5%), 182 (9.4%) and 195 (10.1%), respectively. Of the reported genotypes, the top five were HPV 16 (37.3%; 95% CI 35.2.1–39.5%), HPV 52 (6.8%; 95% CI 5.8–8.0%), HPV 35 (4.8%; 95% CI 3.9–5.8%), HPV 18 (4.4%; 95% CI 3.5–5.3%) and HPV 56 (3.9%: 95% CI 3.1–4.9%). Some of other HR-HPV groups include HPV 31 (3.8%), HPV 45 (3.5%), HPV 58 (3.1%), HPV 59(2.3%), and HPV 68 (2.3%). Among the high-risk types, the combined prevalence of HPV 16/18 was at 53.7% (95% CI 51.2–56.3%). HPV 11 (2.7%: 95% CI 2.1–3.5%), HPV 42 (2.1%: 95% CI 1.5–2.8%) and HPV 6 (2.1%: 95% CI 1.4–2.7%) were the most common low-risk HPV types. Conclusions We noted that the proportion of HR-HPV types was higher and HPV 16 in particular, but also HPV 52, HPV 35 and HPV 18, warrant special attention in Ethiopian’s vaccination and HPV based cervical screening program. Additional data from other parts of the country where there is no previous HPV genotype report are needed to better map the national HPV genotypes distribution of Ethiopia.

Immunogenicity of a Two-Dose Human Papillomavirus Vaccine Schedule in HIV-Infected Adolescents with Immune Reconstitution

HIV-infected patients are at increased risk of human papillomavirus (HPV) acquisition and HPV-associated diseases. This study set out to determine whether a two-dose (2D) HPV vaccination schedule was sufficient in HIV-infected adolescents with immune reconstitution (IR) following antiretroviral treatment. Participants aged 9–15 years who had CD4 cell counts > 500 cells/mm3 and HIV-1 RNA < 40 copies/mL for at least one year were assigned to the 2D schedule, while older participants or those without IR received a three-dose (3D) schedule. Antibodies to HPV-16 and -18 were measured using a pseudovirion-based neutralization assay. A total of 96 subjects were enrolled; 31.3% and 68.7% received the 2D and 3D schedule, respectively. Of these, 66.7% and 57.6% of the 2D and 3D participants, respectively, were male. The seroconversion rates for HPV-16 and HPV-18 were 100% in all cases, except for HPV-18 in males who received the 3D schedule (97.4%). In males, the anti-HPV-16 geometric mean titers (GMTs) were 6859.3 (95% confidence interval, 4394.3–10,707.1) and 7011.1 (4648.8–10,573.9) in the 2D and 3D groups (p = 0.946), respectively, and the anti-HPV-18 GMTs were 2039.3 (1432.2–2903.8) and 2859.8 (1810.0–4518.4) in the 2D and 3D (p = 0.313) groups, respectively. In females, the anti-HPV-16 GMTs were 15,758.7 (8868.0–28,003.4) and 26,241.6 (16,972.7–40,572.3) in the 2D and 3D groups (p = 0.197), respectively, and the anti-HPV-18 GMTs were 5971.4 (3026.8–11,780.6) and 9993.1 (5950.8–16,781.1) in the 2D and 3D groups (p = 0.271), respectively. In summary, a 2D schedule is as immunogenic in young adolescents with IR as a 3D schedule in older subjects and those without IR.

TỶ LỆ NHIỄM HPV VÀ MỐI LIÊN QUAN ĐẾN CÁC BẤT THƯỜNG TẾ BÀO CỔ TỬ CUNG Ở BỆNH NHÂN KHÁM PHỤ KHOA TẠI BỆNH VIỆN K

Mục tiêu: Xác định tỷ lệ nhiễm Human Papillomavirus (HPV) và nhận xét mối liên quan giữa nhiễm HPV nguy cơ cao (NCC) với các tổn thương bất thường tế bào cổ tử cung (CTC) ở những bệnh nhân (BN) đến khám phụ khoa tại bệnh viện K. Đối tượng và phương pháp: Nghiên cứu mô tả cắt ngang được tiến hành trên 2.194 BN đến khám phụ khoa tại bệnh viện K từ tháng 1/5/2019 đến tháng 30/3/2020. Thu thập số liệu qua khám, phỏng vấn BN và các kết quả xét nghiệm từ hồ sơ khám bệnh. Kết quả: Trong tổng số 2.194 BN có 295 trường hợp dương tính chiếm 13,4%. Trong số ca nhiễm thì 12 type HPVNCC(khác type 16, type 18) chiếm 72,9%, chỉ nhiễm 1 type HPV16 là 13,6% và chỉ nhiễm 1 type HPV18 là 7,1%. Có mối liên quan chặt chẽ giữa nguy cơ bất thường tế bào CTC, ung thư cổ tử cung liên quan với nhiễm HPV NCC, đặc biệt là 2 type HPV 16 và HPV 18 (p < 0,01). Kết luận: Tỷ lệ nhiễm HPV ở những BN đến khám phụ khoa tại bệnh viện K trong mức độ trung bình.Việc xác định tỷ lệ nhiễm, định type HPV và mối liên quan đến các tổn thương bất thường tế bào CTC có vai trò quan trọng trong xác định nguy cơung thư cổ tử cung (UTCTC) để hướng dẫn các biện pháp phòng ngừa.

Electrochemical DNA biosensor for the multianalyte detection of HPV-16 and HPV-18 in oral and cervical lesions

Infection with high-risk human papillomavirus (HPV) is a major risk factor for oral and cervical cancers. In this study, we developed an electrochemical DNA biosensor for detection of HPV-16 and HPV-18, which are the 2 most prevalent genotypes for development of oral and cervical cancers. The assay involves the sandwich hybridization of the HPV target to silica-redox dye reporter probe and capture probe, followed by electrochemical detection. The sensor was found to be highly specific and sensitive, with detection limit of 22 fM for HPV-16 and 20 fM for HPV-18, between the range of 1 fM to 1 µM. Evaluation with oral and cervical samples showed that the biosensor result was consistent with the nested PCR /gel electrophoresis detection. The biosensor assay could be completed within 90 minutes. Due to its simplicity, rapidity and high sensitivity, this biosensor could be used as an alternative method for HPV detection in clinical laboratories. [151 words]

Vaccine Strategies for Human Papillomavirus-Associated Head and Neck Cancers

The rising incidence of oropharyngeal squamous cell cancers (OPSCC) in the United States is largely attributed to HPV. Prophylactic HPV vaccines have demonstrated effectiveness against oral infection of HPV 16 and HPV 18. We review the global epidemiology and biology of HPV-related cancers as well as the development of HPV vaccines and their use worldwide. We also review the various strategies and challenges in development of therapeutic HPV vaccines.

Detection and Outcome of Endocervical Atypia in Cytology in Primary HPV Screening Programme

Most endocervical adenocarcinomas (EAC) are associated with high-risk HPV (hrHPV) infection, with HPV genotypes 16, 18 and 45 accounting for >90% of the cases. Among endocervical glandular lesions, screening with hrHPV test has previously shown to predict the outcome better than cytology, although around one-fifth of the EAC remain negative both in hrHPV testing and cytology. The study consists of two consecutive HPV-primary screening rounds, conducted in 2012–2015 and 2017–2020. Of the 87 women aged 35 to 60 years of age diagnosed with Atypical endocervical cells, NOS or Atypical endocervical cells, favor neoplastic cytology during the first screening round, 63 (72.4%) were hrHPV positive and 24 (27.6%) were hrHPV negative. Among hrHPV positive patients, three EAC, two adenocarcinomas in situ (AIS), one AIS + high-grade intraepithelial lesion (HSIL) and 13 HSIL were found. Of the histologically verified lesions, 68.4% (13/19) were purely of squamous origin. All the EAC and AIS were HPV16 or HPV 18 positive. No high-grade histological lesions were found among the hrHPV negative patients with cytological glandular atypia. A later database search revealed one HPV-negative, gastric-type mucinous EAC that was missed by the HPV primary screening.

Molecular characterization of high-risk humanpapillomavirus genotypes in women with or without cervical lesions at VIA/VILI in Kara, Togo

Background: Persistent infection with high-risk (HR) papillomavirus (HPV) genotypes plays a central role in the pathogenesis of invasive cervical cancer. Objectives: This study aimed to determine the prevalence and distribution of HR-HPV among women with or without cervical lesions at VIA/VILI in Togo. Methods: Cervical samples were collected from 238 women with or without cervical lesions at VIA / VILI and[c3] DNA [c4]was extracted and analyzed by real-time multiplex PCR. Logistic regression analysis was used to determined risk factors associated with HPV infection. inPietro Annigoni Biomolecular Research Center (CERBA / LABIOGENE) in Burkina Faso. Results: The age of the women ranged from 17 to 61 years old, and most were married (73.5%). The prevalence of HRHPV was 35.71% and this was higher in the age range 35-39 years. The six most common genotypes were HPV 31 (18.7%), HPV 52 (13.82%), HPV 68 (13.01%), HPV 66 (9.76%), HPV 58 (8.13%) and HPV 56 (8.13%). Genotypes HPV 18 (4.07%)and HPV 16 (0.81%) were less frequent.[c5] Married or living with a partner was associated with HPV infection ( OR=2,17, IC [1.20-3.91], p<0,009). Conclusion: This study allowed characterizing for the first time in Togo, HR-HPV genotypes. This will help mappingHR-HPV genotypes circulating in West Africa. Keywords: Human papillomavirus; High-risk; Genotyping; Kara; Togo.

483 Initial safety results and immune responses induced by a novel human papillomavirus (HPV)-specific gorilla adenovirus immunotherapy vaccine, PRGN-2009, in patients with advanced HPV-associated cancers

BackgroundPRGN-2009 is a novel gorilla adenovirus vaccine containing 35 non-HLA-restricted epitopes of HPV 16 and 18 which is being tested in an open-label, NCI-sponsored, single-center Phase I/II study alone and combined with the bifunctional TGF-β ”trap”/anti-PD-L1 fusion protein bintrafusp alfa (BA) (NCT04432597).MethodsFor the Phase I of the trial, eligible patients are adults with previously treated (checkpoint blockade allowed) recurrent/metastatic HPV-associated cancers. Objectives are to assess the safety and determine the recommended phase 2 dose (RP2D) of PRGN-2009 alone and combined with BA. Treatment followed a single-agent 3+3 dose escalation at two dose levels of PRGN-2009 (dose level 1: 1x1011 viral particle units (VPU), dose level 2: 5x1011 VPU) subcutaneously Q2W for 3 times, then Q4W for up to one year in total. After determination of RP2D, a combination cohort of 10 patients treated with PRGN-2009 at the RP2D combined with BA (1200 mg IV Q2W for 52 weeks) opened. Peripheral blood mononuclear cells collected from patients before and after vaccination with PRGN-2009 were stimulated with overlapping peptide pools and assessed by intracellular cytokine staining to identify HPV-16 and HPV-18 specific T-cells, as well as T-cells targeting cascade antigens not encoded by the vaccine.ResultsSix patients were enrolled in the single-agent PRGN-2009 dose-escalation phase (3 with cervical cancer, 2 with anal cancer, 1 with vaginal cancer). Observed adverse events were Grade 1-2 flu-like syndrome (headache, body aches), injection site reactions (erythema, pruritus, soreness, localized edema), fatigue, and rash. There were no dose limiting toxicities, and 5x1011 VPU was selected as RP2D. Four patients had stable disease as best response, (one ongoing, 10 months on treatment).T-cells targeting HPV-16 and/or HPV-18 were increased after vaccination in 100% of patients, with 3/6 (50%) developing HPV-16 T cells and 5/6 (83%) developing HPV-18 T cells. In some patients, the magnitude and breadth of HPV-16 and HPV-18 specific T cells were notably increased after repeated vaccination. T cells that target the cascade antigens brachyury and MUC1 were also increased in all patients evaluated. Multifunctional T-cell responses against all these antigens were also developed after vaccination in the majority of patients. No differences in immunogenicity were noted between the two dose levels. Enrollment is underway in combination with BA. Updated data will be presented.ConclusionsThe Phase 1 results demonstrate the safety of single-agent PRGN-2009 and induction of anti-HPV T-cell immune responses, supporting the hypothesis that PRGN-2009 could potentially induce anti-tumor effects in HPV-associated cancers.AcknowledgementsThis research was supported in part by the Intramural Research Program of the NIH, NCI.Trial RegistrationNCT04432597Ethics ApprovalApproved by the NIH IRB (Ref No 543876). All participants have given informed consent before taking part in the study.

Immunogenicity of Quadrivalent HPV Vaccine in Adolescent Ghanaian Girls 36 Months After Vaccination

Introduction Available human papillomavirus (HPV) vaccines could have an important primary role in cervical cancer prevention once their long-term immunogenicity and safety are evaluated at the population level. The aim of this study was to optimize an assay to be used in evaluating the long-term durability of HPV vaccine response following a pilot vaccination of adolescent girls in Ghana. Methods A rapid, high-throughput, indirect enzyme-linked immunosorbent assay (ELISA) was evaluated for the detection and quantitation of anti-HPV L1 (late expression protein: types 6, 11, 16 and 18) immunoglobulin G (IgG) in human serum (n = 89). The performance of the assay was evaluated using serum collected from a cohort of pre-adolescent girls (n = 49) previously vaccinated with a quadrivalent vaccine and non-immune serum obtained from age-matched controls (n = 40). Results The seroprevalence of anti-HPV IgG antibodies was significantly higher among vaccinated than unvaccinated girls for both HPV − 16 (63.3% vs. 12.5%; p < 0.001) and HPV − 18 (34.7% vs. 20.0%; p = 0.042), respectively. Thirty-six months after receiving the third dose of vaccine, significantly higher mean anti–HPV-16 (0.618 vs. 0.145), anti–HPV-18 (0.323 vs. 0.309), and anti–HPV-6 (1.371 vs. 0.981) antibody levels were measured, compared to unvaccinated girls (all p < 0.05). A correlation between optical density and antibody activity indicated assay sensitivity to increasing levels of antibody activity. Conclusion We have successfully developed and implemented a robust and sensitive assay for the evaluation of antibody responses among immunized adolescent girls for monitoring future large-scale HPV vaccination studies in low-income settings. Our results demonstrated greater immunoglobulin G antibody activity within serum drawn from adolescent girls immunized 36 months prior.

High-risk human papillomavirus-18 uses an mRNA sequence to synthesize oncoprotein E6 in tumors

Cervical cancer is the fourth most common cause of cancer in women worldwide in terms of both incidence and mortality. Persistent infection with high-risk types of human papillomavirus (HPV), namely 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, and 68, constitute a necessary cause for the development of cervical cancer. Viral oncoproteins E6 and E7 play central roles in the carcinogenic process by virtue of their interactions with cell master proteins such as p53, retinoblastoma (Rb), mammalian target of rapamycin (mTOR), and c-MYC. For the synthesis of E6 and E7, HPVs use a bicistronic messenger RNA (mRNA) that has been studied in cultured cells. Here, we report that in cervical tumors, HPV-18, -39, and -45 transcribe E6/E7 mRNAs with extremely short 5′ untranslated regions (UTRs) or even lacking a 5′ UTR (i.e., zero to three nucleotides long) to express E6. We show that the translation of HPV-18 E6 cistron is regulated by the motif ACCaugGCGCG(C/A)UUU surrounding the AUG start codon, which we term Translation Initiation of Leaderless mRNAs (TILM). This motif is conserved in all HPV types of the phylogenetically coherent group forming genus alpha, species 7, which infect mucosal epithelia. We further show that the translation of HPV-18 E6 largely relies on the cap structure and eIF4E and eIF4AI, two key translation initiation factors linking translation and cancer but does not involve scanning. Our results support the notion that E6 forms the center of the positive oncogenic feedback loop node involving eIF4E, the mTOR cascade, and p53.