Nonavalent Vaccine Research Articles

An anal cancer screening program for MSM in Italy: Prevalence of multiple HPV types and vaccine-targeted infections

BackgroundElevated HPV infection rates have been described in HIV-positive males, placing these subjects at high risk of anal neoplasia. Bivalent, quadrivalent, and nonavalent vaccines to prevent HPV infection have been developed, and recently proposed for gender-neutral immunization programs. ObjectivesIn order to estimate the benefit that could be obtained by vaccination of HIV-positive men who have sex with men (MSM), we aimed at describing the frequency of multiple and vaccine-targeted HPV infections in MSM enrolled in an anal cancer screening program. Study designThe anal cancer screening program was conducted between July 2009 and October 2012. Mucosal anal samples were tested for HPV DNA using MY09/MY11 PCR primers and, if positive, genotyped using the CLART2HPV Clinical Array (35HPV types). ResultsA total of 220 MSM were screened and 88.6% were positive for HPV DNA: in 86.5% at least one high-risk (HR) type was found and in 13% only low-risk (LR) HPV were found. Multiple infections accounted for 84.5% of HPV DNA-positive cases and overall 160 different HPV genotype combinations were recognized (only three combinations were detected in more than one patient each). Based on strain coverage, at least one vaccine-targeted HPV type was found in 38.9%, 64%, and 78.4% of cases when considering bivalent, quadrivalent and nonavalent vaccines, respectively. At least one HR vaccine-targeted strain was found in 39% of MSM for bivalent and quadrivalent vaccines, and in 64% of cases for nonavalent prevention. ConclusionsAnal HPV infections in unvaccinated mostly HIV-infected MSM are highly prevalent. The majority of this population has multiple infections with an extremely heterogeneous number of genotype combinations. The nonavalent vaccine could theoretically have prevented a minimum of one HR HPV type in two thirds of subjects.

O16.4 The estimated impact and cost-effectiveness of nonavalent hpv vaccination in the united states

Introduction The objective of this study was to assess the health impact and cost-effectiveness of human papillomavirus (HPV) vaccination strategies in the United States. Specifically, we examined the incremental costs and benefits of the 9-valent HPV vaccine (9vHPV) compared to the quadrivalent HPV vaccine (4vHPV). Like 4vHPV, 9vHPV protects against HPV types 6, 11, 16, and 18. 9vHPV also protects against 5 additional HPV types 31, 33, 45, 52, and 58. Methods We adapted a previously published model of the impact and cost-effectiveness of 4vHPV to include the five additional HPV types in 9vHPV. The vaccine strategies we examined were (1) 4vHPV for males and females; (2) 9vHPV for females and 4vHPV for males; and (3) 9vHPV for males and females. In the base case, we assumed 9vHPV cost $13 more per dose than 4vHPV. Our model included a wide range of HPV-associated health outcomes that could potentially be averted by vaccination: cervical intraepithelial neoplasia; genital warts; juvenile-onset recurrent respiratory papillomatosis; and cervical, vaginal, vulvar, anal, oropharyngeal, and penile cancers Results Compared to no vaccination, 4vHPV for both sexes cost $5,100 to $22,300 (in 2013 US dollars) per quality-adjusted life year (QALY) depending on assumptions regarding vaccine coverage and 4vHPV cross-protection against HPV 31, 33, 45, 52, and 58. Providing 9vHPV for females instead of 4vHPV was cost-saving in most scenarios we examined. The cost per QALY gained by providing 9vHPV to males instead of 4vHPV varied substantially depending on assumptions such as vaccine coverage and cross-protection of 4vHPV. However, the strategy of 9vHPV for both sexes (compared to the strategy of 4vHPV for both sexes) was cost-saving under most scenarios. Conclusion A vaccination program of 9vHPV for both sexes can save money and improve health outcomes compared to a vaccination program of 4vHPV for both sexes. Disclosure of interest statement The authors have no conflicts to declare. No pharmaceutical grants were received in the development of this study.

HPV prophylactic vaccines: Second-generation or first-generation vaccines

High-risk genotypes of human papillomavirus (HPV) are associated with genital cancers especially cervical cancer. United State Food and Drug Administration (USFDA) has recently licensed two first-generation prophylactic vaccines ( i.e. , Gardasil and Cervarix), for control of HPV 16 and 18 infections. Both vaccines are able to generate neutralizing antibodies against major capsid protein L1 assembled as virus-like particles (VLPs). To enhance protection against other HPV genotypes, second-generation vaccines are underway. A HPV L1-based nonavalent vaccine showed is potent and safe in prevention of precancerous lesions associated with HPV types 16/18/31/33/45/52/58, as well as anogenital warts associated with HPV types 6/11. This vaccine is in the advanced stage of phase III clinical trials. Other second-generation vaccines were based on L1-pentameric subunits and also the minor capsid protein L2 that have shown to be effective in preclinical studies. The L2 protein co-assembles with the L1 protein for VLP formation increasing virion aggregation. This mini-review describes two vaccination strategies including first-generation and second-generation vaccines against HPV infections.

Abstract 847: Human papillomavirus (HPV) type distribution in multi-ethnic cohort of women: Implications for vaccination programs

Abstract Introduction: HPV is linked to many genital and oropharyngeal cancers, and current HPV vaccines target 2 oncogenic HPV types (16 and 18), which are estimated to account for 70% of cervical cancer cases. We sought to determine type distributions among a multi-ethnic cohort of women to understand what proportion of infections are covered by current and proposed vaccines. Methods: We analyzed cervical specimens from a cohort of 536 non-pregnant women from four clinical centers in the United States and Canada. HPV genotyping was performed using the Linear Array® HPV Genotyping Test (Roche), which detects 37 HPV types. We calculated prevalence of HPV types (individually and grouped by those types included in the currently approved bivalent and quadrivalent vaccines and the nonavalent vaccine currently being developed) by age, race/ethnicity, and histology. Results: Overall the prevalence of any HPV type in the entire cohort was 57%. More than a quarter of all specimens showed infection with multiple HPV infections with 6 types being the most detected in a single specimen. The prevalence of oncogenic types on the array ranged from 36% among women with normal histology to 88% and 92% among those with low-grade and high-grade lesions, respectively. Among women with high-grade lesions the prevalence of types 16/18 was only 45% while the prevalence of types in the nonavalent vaccine was 85%. Prevalence of oncogenic types decreased by age group with women less than 30 having a prevalence of 63%, while in those over age 50 it was 34%. HPV16 was the most prevalent type among non-Hispanic white women (19%), but not among African-American (0%) or Hispanic (2%) women. HPV58 and HPV58/59 were the most common types among African-American and Hispanic women, respectively. Among non-Hispanic whites, 50% of prevalent oncogenic types were covered by current vaccines, while 81% would be covered by the nonavalent vaccine. In comparison, only 32% of infections among African-American and 29% among Hispanic women were covered by current vaccines, compared to 86% and 75%, respectively, for the nonavalent vaccine. In fact, African American women had 2.5-fold higher prevalence of HPV 58 compared to non-Hispanic white women. Of note, Asian women were more than four-times as likely to be infected with multiple HPV genotypes compared to non-Hispanic white women. Conclusions: Our findings suggest that a nonavalent vaccine would cover more of the prevalent HPV genotypes present across racial/ethnic groups when compared to current vaccines. These results also suggest that even though more infections occur among younger women (<30), a significant proportion of older women (>50) are also infected. Further, 14-25% of currently prevalent HPV types would still not be covered by next generation vaccines. Citation Format: Michael E. Scheurer, Hung N. Luu, Martial Guillaud, Jane Montealegre, Laura M. Dillon, Michele Follen, Karen Adler-Storthz. Human papillomavirus (HPV) type distribution in multi-ethnic cohort of women: Implications for vaccination programs. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 847. doi:10.1158/1538-7445.AM2015-847

Potential impact of a nonavalent HPV vaccine on the occurrence of HPV-related diseases in France.

BackgroundHuman Papillomavirus (HPV) infection is known to be associated with a number of conditions including cervical, vaginal, vulvar, penile, anal neoplasias and cancers, oropharynx cancers and genitals warts (GW). Two prophylactic vaccines are currently available: a bivalent vaccine designed to prevent HPV type 16 and 18 infection and a quadrivalent vaccine targeting HPV 6, 11, 16, and 18. In France, HPV vaccination is recommended in 11-14 year-old girls with a catch-up for girls aged 15-19. The objective of this study was to assess the potential impact of an HPV 6/11/16/18/31/33/45/52/58 nonavalent vaccine on anogenital and oropharyngeal HPV-related diseases in France.MethodsHPV genotype distributions from 6 multicentric retrospective studies (EDiTH I to VI) were analyzed including 516 cases of invasive cervical cancers (ICC), 493 high-grade cervical neoplasias (CIN2/3), 397 low-grade squamous intraepithelial lesions (LSIL), 423 GW, 366 anal cancer and 314 oropharyngeal carcinomas. Low and high estimates of HPV vaccine impact were calculated as follows: low estimate: prevalence of HPV 6/11/16/18/31/33/45/52/58 genotypes alone or in association but excluding presence of another HPV type; high estimate: prevalence of HPV 6/11/16/18/31/33/45/52/58 genotypes alone or in association, possibly in presence of another HPV type.ResultsEstimates of potential impact varied from 85% (low estimate) to 92% (high estimate) for ICC, 77% to 90% for CIN2/3, 26% to 56% for LSIL, 69% to 90% for GW, 81% to 93% for anal cancer, and 41% to 44% for oropharyngeal carcinomas. Compared to the quadrivalent vaccine, the proportion of additional cases potentially prevented by the nonavalent vaccine was 9.9%-15.3% for ICC, 24.7%-33.3% for CIN2/3, 12.3%-22.7% for LSIL, 2.1%-5.4% for GW, 8.5%-10.4% for anal cancer, and 0.0%-1.6% for oropharyngeal carcinoma.ConclusionsThe nonavalent HPV vaccine showed significant increased potential impact compared to the HPV 6/11/16/18 quadrivalent vaccine for ICC, CIN2/3 and LSIL. Considering a 100% vaccine efficacy and high vaccine coverage, about 90% of ICC, CIN2/3, GW or anal cancer cases could be prevented by a nonavalent HPV vaccine in France.Electronic supplementary materialThe online version of this article (doi:10.1186/s12889-015-1779-1) contains supplementary material, which is available to authorized users.

Oral human papillomavirus (HPV) infection in men who have sex with men: prevalence and lack of anogenital concordance.

ObjectivesTo estimate the prevalence of oral detectable human papillomavirus (HPV) DNA in HIV-negative men who have sex with men (MSM) attending a sexual health clinic in London and concordance with anogenital HPV infection. Such data are important to improve our understanding of the epidemiology of oral HPV and the potential use of vaccines to prevent oropharyngeal cancers.MethodsPaired oral rinse samples and anogenital samples were available from 151 HIV-negative MSM within a larger cross-sectional survey. All samples were tested in parallel for 21 types of HPV DNA using an in-house assay.ResultsThe median age of participants was 30 (IQR 25–35). The prevalence of any oral HPV and of high-risk HPV (HR-HPV) was 13.7% (n=21; 95% CI 8.7 to 20.2) and 5.9% (n=9; 95% CI 2.7 to 10.9) compared with 64.9% (n=98; 95% CI 56.7 to 72.5) and 34.4% (n=52; 95% CI 26.9 to 42.6) in any anogenital sample, respectively. The prevalence of types prevented by the bivalent (HPV16/18), quadrivalent (HPV6/11/16/18) and nonavalent (HPV6/11/16/18/31/33/45/52/58) vaccines was 1.3% (95% CI 0.2 to 4.7), 2.6% (95% CI 0.7 to 6.6) and 4.6% (95% CI 1.9 to 9.3), respectively. There was no concordance between HPV genotypes detected in oral and anogenital sites.ConclusionsHR-HPV DNA, including HPV 16/18, was detected in oral specimens from HIV-negative MSM attending sexual health clinics, suggesting a potential role for vaccination, but is far less common than anogenital infection. How this relates to the risk and natural history of HPV-related head and neck cancers warrants further study. Lack of concordance with anogenital infection also suggests that oral HPV infection should be considered separately when estimating potential vaccine impact.

Human Papillomavirus (HPV) Infections and the Importance of HPV Vaccination.

HPV persistence is necessary for the development of anogenital cancer. Studies show that cervical and anal HPV infections in women and in men who have sex with men are common. Clearance of HPV infection is similarly common; few individuals show persistence unless they are HIV-infected. HIV strongly influences the development of cervical and anal cancer, as well as their pre-malignant counterparts. Women with cervical and vulvar HPV-associated lesions have higher rates of anal cancer than the general population. HPV also plays an important role in pathogenesis of head and neck cancers, particularly oropharyngeal cancer. Two commercially available HPV vaccines have been proven to be safe and efficacious against cervical HPV16/18 infections and associated precancerous lesions; one of these has also been shown to prevent HPV16/18-associated anal lesions. The FDA has also just approved a new nonavalent HPV vaccine. HPV vaccines will play an important role in prevention of HPV-associated cancers.

Human papillomavirus DNA in men who have sex with men: type-specific prevalence, risk factors and implications for vaccination strategies.

Background:Human papillomavirus (HPV) vaccination of girls will have relatively little effect on HPV-related disease in men who have sex with men (MSM). We determined HPV prevalence and risk factors in MSM to inform the potential effectiveness of vaccinating MSM.Methods:Cross-sectional study of 522 MSM aged 18–40 attending a London sexual health clinic who completed a computer-assisted self-interview. Urine and two swabs (anal and penile/scrotal/perianal) were collected and tested using an in-house Luminex-based HPV genotyping system.Results:Prevalence of DNA of the vaccine-preventable HPV types in ano-genital specimens of men was 87/511 (17.0%), 166/511 (32.5%) and 232/511 (45.4%) for the bivalent (HPV16/18), quadrivalent (HPV6/11/16/18) and nonavalent (HPV6/11/16/18/31/33/45/52/58) vaccine types, respectively. A total of 25.1% had one of the quadrivalent types, and 7.4% had 2+ types. Median age at first anal sex was 19 (IQR 17–23) and at first clinic attendance was 24 (IQR 20–27). The increase in the odds of any HPV infection per year of age was 4.7% (95% CI 1.2–8.4).Conclusions:On the basis of the current infection status, most MSM, even among a high-risk population attending a sexual health clinic, are not currently infected with the vaccine-type HPV. A targeted vaccination strategy for MSM in the UK could have substantial benefits.

Current and Next-generation Vaccines against Human Papillomaviruses

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.

Human papillomavirus genotype-specific prevalence across the continuum of cervical neoplasia and cancer.

The New Mexico HPV Pap Registry was established to measure the impact of cervical cancer prevention strategies in the United States. Before widespread human papillomavirus (HPV) vaccine implementation, we established the baseline prevalence for a broad spectrum of HPV genotypes across the continuum of cervical intraepithelial neoplasia (CIN) and cancer. A population-based sample of 6,272 tissue specimens was tested for 37 HPV genotypes. The number of specimens tested within each diagnostic category was: 541 negative, 1,411 CIN grade 1 (CIN1), 2,226 CIN grade 2 (CIN2), and 2,094 CIN grade 3 (CIN3) or greater. Age-specific HPV prevalence was estimated within categories for HPV genotypes targeted by HPV vaccines. The combined prevalence of HPV genotypes included in the quadrivalent and nonavalent vaccines increased from 15.3% and 29.3% in CIN1 to 58.4% and 83.7% in CIN3, respectively. Prevalence of HPV types included in both vaccines tended to decrease with increasing age for CIN1, CIN2, CIN3, and squamous cell carcinoma (SCC), most notably for CIN3 and SCC. The six most common HPV types in descending order of prevalence were HPV-16, -31, -52, -58, -33, and -39 for CIN3 and HPV-16, -18, -31, -45, -52, and -33 for invasive cancers. Health economic modeling of HPV vaccine impact should consider age-specific differences in HPV prevalence. Population-based HPV prevalence in CIN is not well described, but is requisite for longitudinal assessment of vaccine impact and to understand the effectiveness and performance of various cervical screening strategies in vaccinated and unvaccinated women.

Global genomic diversity of human papillomavirus 6 based on 724 isolates and 190 complete genome sequences.

Human papillomavirus type 6 (HPV6) is the major etiological agent of anogenital warts and laryngeal papillomas and has been included in both the quadrivalent and nonavalent prophylactic HPV vaccines. This study investigated the global genomic diversity of HPV6, using 724 isolates and 190 complete genomes from six continents, and the association of HPV6 genomic variants with geographical location, anatomical site of infection/disease, and gender. Initially, a 2,800-bp E5a-E5b-L1-LCR fragment was sequenced from 492/530 (92.8%) HPV6-positive samples collected for this study. Among them, 130 exhibited at least one single nucleotide polymorphism (SNP), indel, or amino acid change in the E5a-E5b-L1-LCR fragment and were sequenced in full. A global alignment and maximum likelihood tree of 190 complete HPV6 genomes (130 fully sequenced in this study and 60 obtained from sequence repositories) revealed two variant lineages, A and B, and five B sublineages: B1, B2, B3, B4, and B5. HPV6 (sub)lineage-specific SNPs and a 960-bp representative region for whole-genome-based phylogenetic clustering within the L2 open reading frame were identified. Multivariate logistic regression analysis revealed that lineage B predominated globally. Sublineage B3 was more common in Africa and North and South America, and lineage A was more common in Asia. Sublineages B1 and B3 were associated with anogenital infections, indicating a potential lesion-specific predilection of some HPV6 sublineages. Females had higher odds for infection with sublineage B3 than males. In conclusion, a global HPV6 phylogenetic analysis revealed the existence of two variant lineages and five sublineages, showing some degree of ethnogeographic, gender, and/or disease predilection in their distribution. This study established the largest database of globally circulating HPV6 genomic variants and contributed a total of 130 new, complete HPV6 genome sequences to available sequence repositories. Two HPV6 variant lineages and five sublineages were identified and showed some degree of association with geographical location, anatomical site of infection/disease, and/or gender. We additionally identified several HPV6 lineage- and sublineage-specific SNPs to facilitate the identification of HPV6 variants and determined a representative region within the L2 gene that is suitable for HPV6 whole-genome-based phylogenetic analysis. This study complements and significantly expands the current knowledge of HPV6 genetic diversity and forms a comprehensive basis for future epidemiological, evolutionary, functional, pathogenicity, vaccination, and molecular assay development studies.

The road ahead for cervical cancer prevention and control.

Since the early 1950s, Papanicolaou ("Pap") cytology screening has dramatically reduced cervical cancer mortality in most high-income settings. Currently, human papillomavirus (hpv) vaccination has the greatest potential to reduce the global burden of cervical cancer and precancerous lesions. However, as the prevalence of precancerous lesions declines, maintaining cytology as the primary screening test in settings with established programs might become less efficient. A reduction in test performance (sensitivity, specificity, and positive predictive value) would lead to an increase in unnecessary colposcopy referrals. Fortunately, hpv dna testing has emerged as a suitable candidate to replace cytology. Compared with the Pap test, hpv testing is less specific but much more sensitive in detecting high-grade precancerous lesions, less prone to human error, and more reproducible across settings. Linkage of hpv vaccination and screening registries could serve the added role of monitoring vaccine efficacy. As a triage test, cytology is expected to perform with sufficient accuracy because most hpv-positive smears would contain relevant abnormalities. This approach and others-for example, hpv testing followed by genotyping-are being evaluated in large population studies and have already been recommended in some settings. Other specific biomarkers that might perform well for screening and triage include hpv E6/E7 messenger rna testing, methylation of host or viral genes, and p16(INK4a) staining. Considering the rapid pace of major discoveries and the anticipated arrival of a nonavalent hpv vaccine (currently in phase iii trials), the evidence base in this field has become an elusive target and will continue to be an obstacle for policymakers.

Potential cost‐effectiveness of the nonavalent human papillomavirus (HPV) vaccine

Randomized clinical trials are currently examining the efficacy of a nonavalent human papillomavirus (HPV) vaccine, including HPV-types 6/11/16/18/31/33/45/52/58. Evidence on the cost-effectiveness of the nonavalent is required for timely policy-decisions. We compared the potential cost-effectiveness of the nonavalent and quadrivalent HPV vaccines. We used a multi-type individual-based transmission-dynamic model of HPV infection and diseases, 70-year time-horizon, 3% discount rate and healthcare payer perspective. We calibrated the model to Canadian sexual behavior and epidemiologic data, and estimated Quality-Adjusted Life-Years (QALYs) lost and costs ($CAN 2010) from the literature. Under base-case assumptions (vaccinating 10-year-old girls, 80% coverage, 95$/dose, vaccine-type efficacy = 95%, cross-protection for the quadrivalent vaccine, duration of vaccine-type protection (cross-protection) = 20 (10) years), using the quadrivalent and nonavalent vaccines is estimated to cost $15,528 [12,056; 19,140] and $12,203 [9,331; 17,292] per QALY-gained, respectively. At equal price, the nonavalent vaccine is more cost-effective than the quadrivalent vaccine, even when assuming both shorter duration of protection (nonavalent = 20 years vs. quadrivalent = lifelong) and lower vaccine-type efficacy (nonavalent = 85% vs. quadrivalent = 95%). However, the additional cost per dose of the nonavalent vaccine should not exceed $11 to remain more cost-effective than the quadrivalent vaccine, and $24 to represent a cost-effective alternative to the quadrivalent vaccine (using a $40,000/QALY-gained threshold). The nonavalent vaccine can be a cost-effective alternative to the quadrivalent vaccine, even in scenarios where nonavalent vaccine efficacy is 85%. However, because most cervical cancers are caused by HPV-16/18, it is unlikely that the nonavalent would be used if its efficacy against these types is lower than current HPV vaccines.

Preclinical safety and immunogenicity evaluation of a nonavalent PorA native outer membrane vesicle vaccine against serogroup B meningococcal disease

BackgroundAn improved nonavalent PorA native outer membrane vesicle vaccine was developed with intrinsic adjuvating activity due to presence of less-toxic (lpxL1) LPS. In the present study, the safety and immunogenicity of this next-generation NonaMen vaccine were evaluated following repeated vaccination in rabbits and mice. MethodsA repeated–dose toxicology study was performed in rabbits. Immunogenicity of next-generation NonaMen was evaluated by determining the serum bactericidal antibody (SBA) titers against meningococcal serogroup B strains containing several PorA subtypes. Release of the pro-inflammatory cytokine, interleukin-6 (IL-6), by the human monocytic cell line (MM6) was measured to estimate pyrogenic activity. ResultsNo toxicologically relevant findings were noted in vaccinated rabbits receiving plain next-generation NonaMen. In agreement, next-generation NonaMen induced reduced amounts of the pro-inflammatory cytokine, IL-6, released by human monocyte cell line. In both rabbits and mice, next-generation NonaMen induced high SBA titers against all tested MenB strains regardless of whether or not aluminium phosphate adjuvant is used. ConclusionsThe data suggest that next-generation NonaMen is a safe vaccine with the potential to develop a broadly protective immune response and encourage the start of the first clinical studies.

Human papillomavirus genotype attribution and estimation of preventable fraction of anal intraepithelial neoplasia cases among HIV-infected men who have sex with men.

The prevention of human papillomavirus (HPV)-induced anal cancer in high-risk populations such as human immunodeficiency virus (HIV)-infected men who have sex with men (MSM) remains an urgent priority, given rising incidence rates despite widespread antiretroviral therapy use. HPV genotypes and anal disease prevalence, by cytology and histopathologic findings, were evaluated among 363 HIV-infected MSM. We modeled fractions of high-grade anal intraepithelial neoplasia (HGAIN) attributable to individual carcinogenic HPV genotypes and estimated the range of the proportion of HGAIN cases potentially preventable by prophylactic HPV vaccines. HPV16 was the most common genotype overall (26.4% of cases) and among HGAIN cases (55%). Prevalence of multiple (≥ 2) carcinogenic HPV genotypes increased from 30.9% in cases of AIN grade <1 to 76.3% in cases of AIN grade 3 (P(trend) < .001). The fractions of HGAIN cases attributable to carcinogenic HPV16/18 targeted by currently licensed bivalent and quadrivalent HPV vaccines ranged from 12% to 61.5%, and the fractions attributable to carcinogenic HPV16/18/31/33/45/52/58 targeted by an investigational nonavalent HPV vaccine ranged from 39% to 89.4%. Our analytical framework allows estimation of HGAIN cases attributable to individual HPV genotypes in the context of multiple concurrent HPV infections, which are very common among HIV-infected MSM. Our results suggest that licensed and investigational HPV prophylactic vaccines have the potential to prevent a substantial proportion of HGAIN cases in this population.

Population-Level Impact of the Bivalent, Quadrivalent, and Nonavalent Human Papillomavirus Vaccines: A Model–Based Analysis

Bivalent and quadrivalent human papillomavirus (HPV) vaccines are now licensed in several countries. Furthermore, clinical trials examining the efficacy of a nonavalent vaccine are underway. We aimed to compare the potential population-level effectiveness of the bivalent, quadrivalent, and candidate nonavalent HPV vaccines. We developed an individual-based, transmission-dynamic model of HPV infection and disease in a population stratified by age, gender, sexual activity, and screening behavior. The model was calibrated to highly stratified sexual behavior, HPV epidemiology, and cervical screening data from Canada. Under base case assumptions, vaccinating 12-year-old girls (70% coverage) with the bivalent (quadrivalent) vaccine is predicted to reduce the cumulative incidence of anogenital warts (AGWs) by 0.0% (72.1%), diagnosed cervical intraepithelial neoplasia lesions 2 and 3 (CIN2 and -3) by 51.0% (46.1%), and cervical squamous cell carcinoma (SCC) by 31.9% (30.5%), over 70 years. Changing from a bivalent (quadrivalent) to a nonavalent vaccine is predicted to reduce the cumulative number of AGW episodes by an additional 66.7% (0.0%), CIN2 and -3 episodes by an additional 9.3% (12.5%), and SCC cases by an additional 4.8% (6.6%) over 70 years. Differences in predicted population-level effectiveness between the vaccines were most sensitive to duration of protection and the time horizon of analysis. The vaccines produced similar effectiveness at preventing noncervical HPV-related cancers. The bivalent vaccine is expected to be slightly more effective at preventing CIN2 and -3 and SCC in the longer term, whereas the quadrivalent vaccine is expected to substantially reduce AGW cases shortly after the start of vaccination programs. Switching to a nonavalent vaccine has the potential to further reduce precancerous lesions and cervical cancer.

Human Papillomavirus Vaccines for Cervical Cancer Prevention: Translating Possibility Into Reality

Human Papillomavirus Vaccines for Cervical Cancer Prevention: Translating Possibility Into Reality

86IN - HPV Elimination of Cervical Cancer: The Novel Options in Vaccination and Screening

ABSTRACT The recognition that infection with certain human papillomavirus (HPV) types is a necessary cause of cervical cancer has opened new fronts for the prevention of this disease. Primary prevention is now possible via immunization and secondary prevention has gained impetus with the availability of HPV DNA testing. Although universal vaccination of teenagers and young women is a desirable policy, even with high uptake a substantial reduction in the burden of cervical cancer is unlikely for at least 10–15 years. To achieve cost-effective reductions, screening and immunization must be considered as integrated approaches. Several novel options are possible. If the nonavalent vaccine proves to be effective, a screen and vaccine strategy in older women is attractive, and raises the possibility of virtually eliminating cervix cancer in 5-10 years. New approaches for triage following primary HPV-based screening are also being developed and promise to substantially reduce referrals for non-progressive infections. These include HPV typing, p16 and methylation of viral and human genes. Lastly, the use of self sampling is likely to increase in vaccinated women with less frequent HPV-based tests. New collection devices and transport media will be needed to facilitate this. Disclosure J. Cuzick: Advisory boards for Abbott, Becton-Dickinson, Roche, GenProbe, Qiagen, Glaxo Smith Kline, Merck.

Pneumococcal serogroups and serotypes in severe pneumococcal pneumonia in Belgian children: Theoretical coverage of the 7-valent and 9-valent pneumococcal conjugate vaccines

Although the causative pneumococcal serotypes of invasive diseases are already extensively studied, few data are available about the pneumococcal serotypes additionally isolated from broncho-alveolar lavage samples in childhood pneumonia. To identify the causative pneumococcal serotypes in culture proven childhood community acquired pneumonia (CAP) and to calculate the effectiveness of the heptavalent and nonavalent pneumococcal vaccine (7- and 9-valent PnV) in severe pneumococcal pneumonia. All pneumococcal isolates stored from broncho-alveolar lavage, blood culture and pleural fluid in healthy children with CAP were characterized. Seventy children (median age 2 years 3.5 months) could be included. The most prevalent serotypes were: SGT1 (21.4%), SGT6 (20.0%), SGT19 (12.8%), SGT23 (10.0%), and SGT14 (7.1%). SGT1 was especially prevalent in complicated cases and children >5 years. This first ranking of SGT1 is not reported in invasive pneumococcal disease studies. The overall theoretical coverage of the 7-valent PnV and the 9-valent PnV for pneumococcal pneumonia was 45.7% and 72.8%. The theoretical coverage of both vaccines was equal for non-invasive pneumonia (64%) but the theoretical coverage of the 9-valent PnV for invasive pneumonia was much higher (79% vs. 37.2%). Antibiotic susceptibility to penicillin was 84%, 70% to tetracycline and 61% to erythromycin; however only one strain (MIC = 4 mg/L) was highly resistant to penicillin. Based on this serotyping, the theoretical coverage of the 7-valent PnV for proven pneumococcal pneumonia is good but decreases with age. A 9-valent PnV containing SGT1 could significantly increase the coverage, especially for invasive pneumonia. According to these data, penicillin remains the first choice antibiotic treatment for childhood CAP in Belgium.

Long-term antibody levels and booster responses in South African children immunized with nonavalent pneumococcal conjugate vaccine

Children who had initially received three doses of either a nonavalent pneumococcal conjugate vaccine containing serotypes 1, 4, 5, 6B, 9V, 14, 18C, 19F, and 23F or placebo at 6, 10, and 14 weeks of age were bled at 9 and 18 months for determination of antibody concentrations. The children were then randomized to receive a booster dose of either the 9-valent pneumococcal conjugate vaccine or a 23-valent polysaccharide vaccine and antibody levels determined 1 month later. At 9 months, the geometric mean concentrations (GMCs) were significantly higher for all vaccine serotypes in vaccinated children compared with controls (means varied from 0.49 μg/ml for serotype 4 to 2.37 μg/ml for serotype 14). At 18 months, antibody concentrations remained significantly higher in vaccinated children (means varied from 0.19 μg/ml for serotype 4 to 1.1 μg/ml for serotype 14). In children who had received conjugate vaccine in infancy, the conjugate vaccine at 18 months produced a significant booster response for serotypes 1, 6B, 14, 19F, and 23F (means varied from 2.74 μg/ml for serotype 19F to 15.52 μg/ml for serotype 6B) and produced a comparable response to a first dose of conjugate at this age for serotypes 4, 5, 9V, and 18C. Boosting at 18 months with polysaccharide vaccine produced higher antibody concentrations to all serotypes in children who had previously received conjugate vaccine compared to children who had not received the conjugate vaccine in infancy. In conclusion, the 9-valent pneumococcal conjugate vaccine given in infancy elicits significant and long-lasting antibody responses which can be boosted with either the conjugate or polysaccharide vaccines.