Prophylactic cancer vaccines: development and challenges for HBV and HPV vaccines in Latin America.

Vaccines against hepatitis B virus (HBV) and human papillomaviruses (HPV) are two safe and highly effective vaccines that were developed at the end of the 20th century and can prevent human cancer. HBV vaccine prevents liver cancer, and HPV prevents cervical and other HPV-related cancers. Starting with the immunogen identification, 15 years were necessary to reach the industrial production of HBV vaccine, and 20 years, for the HPV vaccines. However, while HBV vaccines have been commercially available for over 40 years and are used in most countries, there are still significant challenges to achieve universal childhood immunization against hepatitis B. Similarly, HPV vaccines have been commercially available for 17 years, and yet, countries with higher cervical cancer still have the lowest HPV vaccination rates. We describe the development of HBV and HPV vaccines and discuss the challenges to reaching equitable access to these vaccines in Latin America.

Prevention and control of HPV and HPV-related cancers in France: the evolving landscape and the way forward - a meeting report.

Misinformation regarding HPV vaccine safety and benefits has resulted in low coverage within the eligible French population. HPV vaccination is safe and efficacious in preventing HPV infections in adolescents. However, reaching optimal coverage in countries such as France is challenging due to misinformation, among other factors. Moreover, disparities exist in cervical cancer screening programs. To support the government health promotion policy aimed at improving prevention and control of HPV-related cancers in France, the Human Papillomavirus Prevention and Control Board (HPV-PCB), in collaboration with local experts, held a meeting in Annecy, France (December 2021).HPV-PCB is an independent, multidisciplinary board of international experts that disseminates relevant information on HPV to a broad array of stakeholders and provides guidance on strategic, technical and policy issues in the implementation of HPV control programs.After a one-and-a-half-day meeting, participants concluded that multi-pronged strategies are required to expand vaccination coverage and screening. Vaccine acceptance could be improved by: 1) strenghtening existing trust in clinicians by continuous training of current and upcoming/pre-service healthcare professionals (HCPs), 2) improving health literacy among adolescents and the public through school and social media platforms, and 3) providing full reimbursement of the gender-neutral HPV vaccine, as a strong signal that this vaccination is essential.The discussions on HPV infections control focused on the need to: 1) encourage HCPs to facilitate patient data collection to support performance assessment of the national cervical cancer screening program, 2) advance the transition from cytology to HPV-based screening, 3) improve cancer prevention training and awareness for all HCPs involved in screening, including midwives, 4) identifying patient barriers to invitation acceptance, and 5) promoting urine or vaginal self-sampling screening techniques to improve acceptability, while establishing appropriate follow-up strategies for HPV-positive women. This report covers some critical findings, key challenges, and future steps to improve the status of HPV prevention and control measures in the country.

Detection of variable genotypes in common human papillomavirus-associated invasive penile squamous cell carcinomas: a study of 177 human papillomavirus-positive cases.

Human papillomavirus (HPV) is detected in 30-50% of invasive penile carcinomas, and it is frequently associated with basaloid and warty morphological features. Based on this heterogeneity and different clinical behaviors, we hypothesized a variation in their HPV genotypic composition. To test this, we evaluated 177 HPV-positive cases: basaloid (114), warty-basaloid (28), and warty (condylomatous) (35) invasive carcinomas. HPV DNA detection and genotyping was performed using the SPF-10/DEIA/LiPA25 system. Nineteen HPV genotypes were detected. High-risk HPVs predominated (96%), and low-risk HPVs were rarely present. Most common genotype was HPV16 followed by HPVs 33 and 35. According to the genotypes identified, 93% of the cases would be covered with current vaccination programs. There was a significant variation in the distribution of HPV16 and non-HPV16 genotypes according to histological subtype. HPV16 was significantly frequent in basaloid (87%) and was less frequent in warty carcinomas (61%). This molecular difference, along with their distinctive macro-microscopic and prognostic features, makes basaloid and warty carcinomas unique. The gradual decreasing frequency of HPV16 demonstrated in basaloid, warty-basaloid, and warty carcinomas suggest that the basaloid cell, present in those types in decreasing proportions, may be responsible for the differences.

Phylogenetic origin of Helicobacter pylori pathogenicity island and risk of stomach cancer and high-grade premalignant gastric lesions.

Infection by Helicobacter pylori (Hp) has been causally linked to risk of gastric cancer (GC). The coevolution of Hp and humans shaped the risk of GC as our species left Africa and migrated to the other continents. Latin America (LatAm) is a high GC incidence region where Hp evolved uniquely in the 500 years since European colonization. Differential virulence of the Hp cagA -pathogenicity island (cagPAI) by ancestral origin has been reported. We hypothesized that Hp phylogenetic origin might play a role in determining GC risk in LatAm. We used genotypes of 50 Hp genetic variants mapping to the Hp cagPAI, studied in 1220 subjects from Venezuela, Colombia, Mexico and Paraguay, who were infected with cagA-positive Hp, including 150 GC, 177 high-grade premalignant lesions (HGPMLs) and 893 low-grade premalignant lesions. We estimated the phylogenetic origin of Hp cagPAI in all study subjects by use of the STRUCTURE software and principal component analysis (PCA) and tested whether the estimated African ancestry percentage was associated with the risk of GC or HGPML. African ancestral component estimates by STRUCTURE and PCA were highly correlated. STRUCTURE-based African origin estimate was not significantly associated with the risk of HGPML, but it was inversely associated with GC risk: the OR associated with the continuous values of African component was 0.09 (95% CI, 0.01-0.85; P = 0.035). Similar trends were observed for GC with PCA-based estimates, but the association was not statistically significant. These results suggest that Hp ancestral origin may play a role in gastric carcinogenesis.

Penile intraepithelial neoplasia: Distribution of subtypes, HPV genotypes and p16INK4a in 84 international cases.

There are few pathologic or molecular studies of penile precancerous lesions, and the majority refers to lesions associated with invasive carcinomas. Penile Intraepithelial Neoplasia (PeIN) is classified in two morphologically and distinctive molecular groups, non-HPV and HPV-related with special subtypes. The primary purpose of this international series was to classify PeIN morphologically, detect HPV genotypes and determine their distribution according to PeIN subtypes. A secondary aim was to evaluate the p16INK4a immunostaining as a possible HPV surrogate for high-risk HPV infection in penile precancerous lesions. Samples consisted of 84 PeIN cases, part of a retrospective cross-sectional analysis of 1095 penile carcinomas designed to estimate the HPV DNA prevalence in penile cancers using PCR and p16INK4a immunostaining. Penile Intraepithelial Neoplasia (PeIN) was classified in HPV-related (basaloid, warty-basaloid, warty, hybrid, and mixed subtypes) and non-HPV-related (differentiated), the former being the most frequent. PeIN subtypes were differentiated (non-HPV-related) and basaloid, warty-basaloid, warty, hybrid and mixed (HPV-related). Basaloid PeIN was the most commonly diagnosed subtype, and HPV16 was the most frequent HPV genotype detected. Warty-basaloid and warty PeIN showed a more heterogeneous genotypic composition. Most HPV genotypes were high-risk but low-risk HPV genotypes were also present in a few cases (4%). A single HPV genotype was detected in 82% of HPV positive cases. In contrast, multiple genotypes were detected in the remaining 18% of cases. The findings in this study support the paradigm that penile in situ neoplasia, like its invasive counterparts, is HPV dependent or independent and has distinctive morphological subtypes readily identified in routine practice. Considering that HPV16 is clearly the predominant type, and that the three available vaccines have HPV16, all of them will be suitable for vaccination programs; the price of the vaccines will be probably the main determinant to choose the vaccine.

Concordance of p16INK4a and E6*I mRNA among HPV-DNA-Positive Oropharyngeal, Laryngeal, and Oral Cavity Carcinomas from the ICO International Study.

Background: Tests or test algorithms for diagnosing HPV-driven oral cavity and laryngeal head and neck carcinomas (HNC) have not been yet validated, and the differences among oral cavity and laryngeal sites have not been comprehensively evaluated. We aimed to assess the utility of a diagnostic algorithm for the detection of HPV-driven oral cavity (OCC), oropharyngeal (OPC) and laryngeal (LC) carcinomas using HPV-DNA testing followed by p16INK4a immunohistochemistry, taking E6*I mRNA detection as the reference standard. Methods: Formalin-fixed paraffin-embedded OCC, OPC, and LC carcinomas were collected from pathology archives in 29 countries. All samples were subjected to histopathological evaluation, DNA quality control, and HPV-DNA detection. All HPV-DNA-positive samples (including 78 OCC, 257 OPC, and 51 LC out of 3680 HNC with valid HPV-DNA results) were also tested for p16INK4a immunohistochemistry and E6*I mRNA. Three different cutoffs of nuclear and cytoplasmic staining were evaluated for p16INK4a: (a) >25%, (b) >50%, and (c) ≥70%. The concordance of p16INK4a and E6*I mRNA among HPV-DNA-positive OCC, OPC, and LC cases was assessed. Results: A total of 78 OCC, 257 OPC, and 51 LC were HPV-DNA-positive and further tested for p16INK4a and E6*I mRNA. The percentage of concordance between p16INK4a (cutoff ≥ 70%) and E6*I mRNA among HPV-DNA-positive OCC, OPC, and LC cases was 79.5% (95% CI 69.9−89.1%), 82.1% (95% CI 77.2−87.0%), and 56.9% (95% CI 42.3−71.4%), respectively. A p16INK4a cutoff of >50% improved the concordance although the improvement was not statistically significant. For most anatomical locations and p16INK4a cutoffs, the percentage of discordant cases was higher for HPV16- than HPV-non16-positive cases. Conclusions: The diagnostic algorithm of HPV-DNA testing followed by p16INK4a immunohistochemistry might be helpful in the diagnosis of HPV-driven OCC and OPC, but not LC. A different p16INK4a expression pattern was observed in those cases HPV-DNA-positive for types other than HPV16, as compared to HPV16-positive cases. Our study provides new insights into the use HPV-DNA, p16INK4a, and HPV-E6*I mRNA for diagnosing an HPV-driven HNC, including the optimal HPV test or p16INK4a cutoffs to be used. More studies are warranted to clarify the role of p16INK4a and HPV status in both OPC and non-OPC HNC.

TAS2R38 polymorphisms, Helicobacter pylori infection and susceptibility to gastric cancer and premalignant gastric lesions.

BACKGROUND: Gastric cancer is worldwide the fourth more common cancer type by incidence, and the third by mortality. We analyzed three missense variants of TAS2R38 gene: rs713598 (A49P), rs1726866 (V262A), and rs10246939 (I296V). These variants and their combination in haplotypes (proline, alanine and valine/tasters or alanine, valine and isoleucine/nontasters) and diplotypes are responsible for individual differences in bitter perception. The single-nucleotide polymorphisms and the related phenotypes are known to be associated with susceptibility to Gram-negative bacterial infections, such as Helicobacter pylori , and with risk of various cancer types. An association between intermediate tasters (as defined by TAS2R38 diplotypes) and increased risk of gastric cancer was reported in a Korean population. METHODS: We analyzed 2616 individuals of Latin American origin, representing the whole spectrum of lesions from gastritis to gastric cancer. RESULTS: Comparing cancer cases vs. noncancers we observed a decrease in risk associated with heterozygous carriers of rs10246939 ( P = 0.006) and rs1726866 ( P = 0.003) when compared with homozygotes of the more common allele. Also, the analysis of diplotypes/phenotypes reflected the same association, with super-tasters showing a borderline increased risk of developing gastric cancer compared to medium-tasters [odds ratio (OR) = 1.63; 95% confidence interval (CI), 1.04-2.56; P = 0.033]. Also, nontasters showed an increased risk when compared to medium-tasters although not reaching statistical significance (OR = 1.58; 95% CI, 0.80-2.87; P = 0.203). We also tested the interactions between the TAS2R38 genotypes and H. pylori cagA status in a subset of samples and found no interaction. CONCLUSION: In conclusion, our results suggest only a modest contribution of TAS2R38 gene genetic variability in gastric cancer etiology.

Reduction of HPV16/18 prevalence in young women after eight years of three- and two-dose vaccination schemes.

BACKGROUND: Recommendations for human papillomavirus vaccination have relied on immunogenicity studies and efficacy results derived from adult women. Insufficient information exists regarding HPV effectiveness in vaccinated girls as they become sexually active, regardless of dose scheme. We aimed to compare the prevalence of high-risk HPV between unvaccinated and vaccinated young women eight years after immunization. METHODS: After eight years, we recontacted women who received two-dose of bivalent or three-dose-either bivalent or quadrivalent-, HPV vaccine when aged 9-10 years-old as part of a clinical trial. Additionally, we recruited a contemporaneous unvaccinated woman group for comparison. Only those sexually active were included. High-risk HPV DNA was determined in urine samples and compared across groups. RESULTS: The prevalence of HPV16/18 types was 6.8% (95 %CI 3.2-14.1%) in the unvaccinated (n = 6/88), 1.1% (95 %CI 0.2-5.8%) in the three-dose (n = 1/93), and 0.0% (95 %CI 0.0-7.0%) in the two-dose group (n = 0/51). CONCLUSION: HPV vaccination, with two-dose of bivalent or three-dose schemes-either with the bivalent or quadrivalent vaccine-, was associated with a lower prevalence of HPV16/18 types eight years after primary immunization.

Prevention and control of HPV infection and HPV-related cancers in Colombia- a meeting report.

The Human Papillomavirus (HPV) Prevention and Control Board is an independent multidisciplinary board of international experts that disseminates relevant information on HPV to a broad array of stakeholders and provides guidance on strategic, technical and policy issues in the implementation of HPV control programs. In response to drastic drop of vaccine coverage following the adverse event crisis in Carmen del Bolivar, Colombia, the HPV Prevention and Control Board in collaboration with the Colombian National Cancer Institute and Colombian League Against Cancer convened a meeting in Bogota, Columbia (November 2018). The goal of the meeting was to bring together national and international group of experts to report the disease burden, epidemiology and surveillance of HPV and HPV-related cancers, to discuss the successes and especially the challenges of HPV vaccination and screening in Colombia, as well as the lessons learnt from neighbouring countries. The meeting provided a platform to confer various stakeholder's perspectives, including the role of the Colombian healthcare system and to catalyse various parts of the public health community in Colombia into effective action. The conclusion of the meeting included following suggestions to strengthen HPV prevention and control: 1) Re-introducing school-based vaccine programs, 2) Integrating primary and secondary prevention programs, 3) Developing an innovative crisis communication plan targeting healthcare workers, teachers and general population, 4) Building trust through efficient and timely communication, 5) Building strong relationship with media to ensure a stable vaccination campaign support, and 6) Promoting empathy among healthcare professionals towards patients to build trust and communicate effectively.

Genetic polymorphisms in the cag pathogenicity island of Helicobacter pylori and risk of stomach cancer and high-grade premalignant gastric lesions.

Helicobacter pylori (Hp) infects the stomach of about half of the human population and is strongly associated with the risk of gastric cancer (GC) and its premalignant precursors. The cag pathogenicity island (cagPAI) is a region of the Hp genome encoding for key molecular machinery involved in the infection process. Following a sequencing study, we selected 50 genetic polymorphisms located in seven cagPAI genes and tested their associations with the risk of advanced gastric premalignant lesions and GC in 1220 subjects from various Latin American populations showing the whole spectrum of phenotypes from gastritis to GC. We found that three polymorphisms of cagA are associated with the risk of advanced gastric premalignant lesions (incomplete intestinal metaplasia [ie, Type 2 and 3] or dysplasia), and that six polymorphisms located in cagA, cagL and cagI were associated with risk of GC. When corrected for multiple testing none of the associations were statistically significant. However, scores built by integrating the individual polymorphisms were significantly associated with the risk of advanced gastric premalignant lesions and GC. These results have the potential of establishing markers for risk stratification in the general population, in view of targeting Hp eradication to high-risk population groups.

The role of healthcare providers in HPV vaccination programs - A meeting report.

The Human Papillomavirus (HPV) Prevention and Control Board convened a meeting in Bucharest, Romania (May 2018), to discuss the role of healthcare providers (HCPs) in prevention programs, with a focus on HPV vaccination and cervical cancer screening. International and local experts discussed the role that HCPs can play to increase the uptake of HPV vaccine and screening. Experts recommended: 1) increasing HCP norms of getting vaccinated; 2) training providers to make effective recommendations; 3) making culturally appropriate materials available, in local languages; and 4) centralizing and coordinating education and information material, to direct both HCPs and the general public to the best material available.

Persistence of Immunity When Using Different Human Papillomavirus Vaccination Schedules and Booster-Dose Effects 5 Years After Primary Vaccination.

Background: There are limited data regarding the duration of immunity induced by different human papillomavirus (HPV) vaccination schedules and the immunogenicity of a booster dose of both bivalent HPV vaccine (bHPV) or quadrivalent HPV vaccine (qHPV). Methods: Follow-up of a nonrandomized clinical trial to evaluate the 5-year antibody persistence of the bHPV in girls (age, 9-10 years) and women (age, 18-24 years). Noninferiority of the 2-dose versus 3-dose schedule among girls was evaluated at months 54 (n = 639) and 64 (n = 990). Girls vaccinated with a 2-dose schedule of bHPV or qHPV received a booster dose of either vaccine at month 61. Immunogenicity was measured using a virus-like particle-based enzyme-linked immunosorbent assay. Geometric mean titers (GMTs) for HPV16/18 were estimated after stratification by vaccination schedule and age group. Results: At months 54 and 64, the 2-dose schedule remained noninferior to the 3-dose schedule. GMTs remained above natural infection levels across all age groups up to 64 months. After the booster, anti-HPV16/18 GMTs increased exponentially with the same pattern, regardless of vaccine administered. No safety concerns were identified with the booster dose. Conclusions: A 2-dose schedule is highly immunogenic in girls, suggesting a high immune memory. Thus, a booster dose is likely to be unprofitable, considering the low global immunization coverage. Clinical Trials Registration: NCT01717118.

HPV vaccine confidence and cases of mass psychogenic illness following immunization in Carmen de Bolivar, Colombia.

We report the case of multiple adverse reactions following HPV vaccination in Colombian adolescents in Carmen de Bolivar. In August 2012, the country introduced a school-based HPV immunization programme which successfully reached over 90% of the target population in the first year. In 2014, between May 29th and June 2nd,15 adolescent girls in one school presented adverse reactions after vaccination and were admitted to the local hospital. Soon, videos of girls fainting, twitching, and arriving unconscious at emergency rooms started to appear in national news media as well as on social media platforms such as YouTube. The viral spread of these videos and disturbing images were followed by the viral spread of symptoms, with over 600 cases reported across Colombia. Thorough epidemiological investigation by Colombian health authorities found no organic association between the teenagers' symptoms and the HPV vaccine, concluding this was a case of mass psychogenic reaction to vaccination. Scientific evidence did not appease the anxious public whose confidence in HPV immunization dropped dramatically. By 2016, HPV vaccine uptake among eligible girls declined to 14% for the first dose and 5% for the complete course, down from 98% and 88%, respectively, in 2012. We document this case and discuss the role of news and social media, particularly YouTube, as a driver of contagious psychogenic reactions. We also discuss the role of health authorities and government, and the importance of acting rapidly and appropriately to contain the spread of such symptoms and maintain public confidence in vaccines.

Follow-up study of HPV58 variants in women with incident HPV58 infection from a Colombian cohort.

Certain variants of human papillomavirus (HPV)type 58 are associated with an increased risk of high grade squamous intraepithelial lesions and cervical cancer. However, little is known about the persistence of HPV58 E6/E7 variants in women with incident HPV58 infections. The aim of the present study was to evaluate the presence and persistence of HPV58 E6/E7 variants in 71 women with incident HPV58 infection throughout their follow-up. These women belonged to a cohort examined in a longitudinal study of 1,610 Colombian women, who were HPV-negative and had normal baseline cytology. E6/E7 DNA regions of HPV58-positive samples were amplified and sequenced using automated direct sequencing. A total of 639 samples were analyzed from the 71 women, and 117 samples (18.3%) were HPV58-positive. HPV58 E6/E7 variants were detected in 85.5% of the samples. The T307/A694/G744/A761 variant was identified in 88% of the samples, the T307/G744 variant was identified in 9% of samples and the T187/T307/A367/G744/G793/T798/A801/T840/C852 was identified in 3% of the samples. Overall, 50% of the HPV58 infections were present after 1 year of follow-up and all infections were cleared after 7 years. Women who had first sexual intercourse at >15 years of age had a lower clearance rate than those who had sexual intercourse for the first time at ≤15 years of age [hazard ratio (HR)=0.29; 95% confidence interval (CI)=0.09-0.92]. Likewise, parous women had a higher clearance rate than nulliparous women (HR=3.43, 95% CI=1.23-9.60). There was no difference in clearance rates between HPV58 E6/E7 variants. In conclusion, HPV58 variants were not associated with persistence of the infection in this group of women.

Human Papillomavirus Genotypes From Vaginal and Vulvar Intraepithelial Neoplasia in Females 15-26 Years of Age.

OBJECTIVE: To estimate the proportion of vulvar and vaginal low-grade and high-grade squamous intraepithelial lesions (LSILs and HSILs) in females 15-26 years of age attributable to 14 human papillomavirus (HPV) genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59). METHODS: A post hoc analysis of prospectively diagnosed vulvar and vaginal LSILs and HSILs among females 15-26 years of age enrolled in the placebo arms of two phase 3, randomized HPV vaccine trials assessed 14 prespecified HPV genotypes associated with cervical cancers or anogenital warts using a type-specific multiplex polymerase chain reaction assay. The frequency of lesions associated with specific HPV genotypes was estimated by proportional and other attribution methods. RESULTS: During approximately 4 years of follow-up in 8,798 females, 40 vulvar LSILs and 46 vulvar HSILs were diagnosed in 68 females, and 118 vaginal LSILs and 33 vaginal HSILs were diagnosed in 107 females. Females developing vulvar (41.2%) or vaginal (49.5%) lesions also had cervical lesions, whereas 6.5% of females with cervical lesions had vaginal or vulvar lesions. At least 1 of the 14 HPV genotypes was detected in females with vulvar LSIL (72.5%), vulvar HSIL (91.3%), vaginal LSIL (61.9%), and vaginal HSIL (72.7%). Considering only HPV-positive lesions, the nine most common genotypes causing cervical cancer and anogenital warts (6, 11, 16, 18, 31, 33, 45, 52, and 58) were found in 89.4% of vulvar LSILs, 100% of vulvar HSILs, 56.0% of vaginal LSILs, and 78.3% of vaginal HSILs. CONCLUSION: Most vulvar and vaginal lesions were attributable to at least 1 of the 14 HPV genotypes analyzed. Effective immunization programs could potentially prevent substantial numbers of HPV-related vulvar and vaginal LSILs and HSILs. CLINICAL TRIAL REGISTRATION: CLINICALTRIALS.GOV,: NCT00092521 and NCT00092534.

Detection and Genotyping of HPV DNA in a Group of Unvaccinated Young Women from Colombia: Baseline Measures Prior to Future Monitoring Program.

In 2012, Colombia launched human papillomavirus (HPV) vaccination program for girls ages 9 to 12, and in 2013, the target age was expanded to 9 to 17 years. Monitoring the changes of HPV infection prevalence among young women has been proposed as an endpoint for early assessment of HPV vaccination programs. However, the data on HPV prevalence in young ages are very limited. The purpose of this study was to determine the prevalence of HPV infection and the distribution of genotypes in a group of nonvaccinated women ages 18 to 25 years old in three Colombian cities as baseline for the monitoring of the HPV national vaccination program. A total of 1,782 sexually active women were included. Cervical smear samples were collected to perform the Pap smear and HPV DNA detection using a Linear Array HPV assay. Of the 1,782 specimens analyzed, 60.3% were positive for any HPV type; 42.2% were positive for high-risk HPV (HR-HVP) types, and 44.4% for low-risk HPV (LR-HPV) types. Multiple and single infections were identified in 37.1% and 23.2% of samples, respectively. HR-HPV types -16, -52, and -51 were the most predominant with proportions of 11.3%, 7.92%, and 7.9%, correspondingly. The prevalence for HR-HPV 16/18 was 14.4%. HR-HPV prevalence in women with abnormal cytology (75.16%) was higher than in women with normal cytology (38.6%). In conclusion, a high prevalence of HR-HPV was observed among younger women. This HPV type-specific prevalence baseline may be used to monitor postvaccination longitudinal changes and to determine its impact on HPV-related disease incidence in Colombia population. Cancer Prev Res; 11(9); 581-92. ©2018 AACR.