Relationship between Humoral Immune Responses against HPV16, HPV18, HPV31 and HPV45 in 12-15 Year Old Girls Receiving Cervarix? or Gardasil? Vaccine

Background

Human papillomavirus (HPV) vaccines confer protection against the oncogenic genotypes HPV16 and HPV18 through the generation of type-specific neutralizing antibodies raised against virus-like particles (VLP) representing these genotypes. The vaccines also confer a degree of cross-protection against HPV31 and HPV45, which are genetically-related to the vaccine types HPV16 and HPV18, respectively, although the mechanism is less certain. There are a number of humoral immune measures that have been examined in relation to the HPV vaccines, including VLP binding, pseudovirus neutralization and the enumeration of memory B cells. While the specificity of responses generated against the vaccine genotypes are fairly well studied, the relationship between these measures in relation to non-vaccine genotypes is less certain.

Methods

We carried out a comparative study of these immune measures against vaccine and non-vaccine genotypes using samples collected from 12–15 year old girls following immunization with three doses of either Cervarix^® or Gardasil^® HPV vaccine.

Results

The relationship between neutralizing and binding antibody titers and HPV-specific memory B cell levels for the vaccine genotypes, HPV16 and HPV18, were very good. The proportion of responders approached 100% for both vaccines while the magnitude of these responses induced by Cervarix^® were generally higher than those following Gardasil^® immunization. A similar pattern was found for the non-vaccine genotype HPV31, albeit at a lower magnitude compared to its genetically-related vaccine genotype, HPV16. However, both the enumeration of memory B cells and VLP binding responses against HPV45 were poorly related to its neutralizing antibody responses. Purified IgG derived from memory B cells demonstrated specificities similar to those found in the serum, including the capacity to neutralize HPV pseudoviruses.

Conclusions

These data suggest that pseudovirus neutralization should be used as the preferred humoral immune measure for studying HPV vaccine responses, particularly for non-vaccine genotypes.     

安康地区人乳头瘤病毒感染特征及其与宫颈癌的关系研究

目的:调查安康地区女性人乳头瘤病毒(HPV)感染的基因型别及年龄分布特征,分析其与宫颈癌的关系,为宫颈癌防治及HPV疫苗研发提供可靠的依据。方法:收集2010年6月-2012年8月间在本院及安康市部分县级医院妇产科就诊的2736名女性的液基细胞学和组织学标本,分为8个年龄组:16-24岁119例、25-29岁230例、30-34岁343例、35-39岁472例、40-44岁574例、45-49岁512例、50-54岁206例、55-86岁280例,进行病理学分类及HPV分型检测,分析不同年龄组及不同类型宫颈组织中的HPV感染率。结果:2736例女性中发生HPV感染720例(26.32%),共检出21种型别,感染率最高的基因型别是HPV16(25.05%),其他常见型别依次为HPV58、HPV52、HPV6、HPV11。单一感染占76.25%,多重感染占23.75%。HPV感染率在16-24岁、35-39岁和55-86岁三个年龄段出现高峰;而高危型HPV的感染率在35-39岁和55-86岁两个年龄段分别出现高峰。HPV的检出率随着宫颈病变的严重程度而增加,其中正常或炎症人群的HPV感染率显著低于宫颈病变及宫颈鳞状细胞癌患者(均P0.05),且意义未明的不典型鳞状细胞(ASCUS)、CIN1-3及宫颈鳞状细胞癌患者的HPV感染率对比结果存在显著差异(P0.05)。CIN1组、CIN2-CIN3组及宫颈鳞状细胞癌组单一感染率逐渐增加(P0.05),且其二重、三重感染率比较差异均有统计学意义(P0.05)。结论:安康地区HPV16型别感染较广,临床需加强对HPV16型单一感染宫颈病变患者的癌症预防工作。     

Protection of rabbits against challenge with rabbit papillomaviruses by immunization with the N terminus of human papillomavirus type 16 minor capsid antigen L2

Current L1 virus-like particle (VLP) vaccines provide type-restricted protection against a small subset of the human papillomavirus (HPV) genotypes associated with cervical cancer, necessitating continued cytologic screening of vaccinees. Cervical cancer is most problematic in countries that lack the resources for screening or highly multivalent HPV VLP vaccines, suggesting the need for a low-cost, broadly protective vaccinogen. Here, N-terminal L2 polypeptides comprising residues 1 to 88 or 11 to 200 derived from HPV16, bovine papillomavirus type 1 (BPV1), or cottontail rabbit papillomavirus (CRPV) were produced in bacteria. Rabbits were immunized with these N-terminal L2 polypeptides and concurrently challenged with CRPV and rabbit oral papillomavirus (ROPV). Vaccination with either N-terminal L2 polypeptides of CRPV effectively protected rabbits from CRPV challenge but not from papillomas induced by cutaneous challenge with CRPV genomic DNA. Furthermore, papillomas induced by CRPV genomic DNA deficient for L2 expression grew at the same rate as those induced by wild-type CRPV genomic DNA, further suggesting that the L2 polypeptide vaccines lack therapeutic activity. Neutralizing serum antibody titers of >15 correlated with protection (P < 0.001), a finding consistent with neutralizing antibody-mediated protection. Surprisingly, a remarkable degree of protection against heterologous papillomavirus types was observed after vaccination with N-terminal L2 polypeptides. Notably, vaccination with HPV16 L2 11-200 protected against cutaneous and mucosal challenge with CRPV and ROPV, respectively, papillomaviruses that are evolutionarily divergent from HPV16. Further, vaccination with HPV16 L2 11-200 generates broadly cross-neutralizing serum antibody, suggesting the potential of L2 as a second-generation preventive HPV vaccine antigen.     

Reduced Prevalence of Oral Human Papillomavirus (HPV) 4 Years after Bivalent HPV Vaccination in a Randomized Clinical Trial in Costa Rica

Background

Human papillomavirus (HPV) infection, particularly with type 16, causes a growing fraction of oropharyngeal cancers, whose incidence is increasing, mainly in developed countries. In a double-blind controlled trial conducted to investigate vaccine efficacy (VE) of the bivalent HPV 16/18 vaccine against cervical infections and lesions, we estimated VE against prevalent oral HPV infections 4 years after vaccination.

Methods and Findings

A total of 7,466 women 18–25 years old were randomized (1∶1) to receive the HPV16/18 vaccine or hepatitis A vaccine as control. At the final blinded 4-year study visit, 5,840 participants provided oral specimens (91·9% of eligible women) to evaluate VE against oral infections. Our primary analysis evaluated prevalent oral HPV infection among all vaccinated women with oral and cervical HPV results. Corresponding VE against prevalent cervical HPV16/18 infection was calculated for comparison. Oral prevalence of identifiable mucosal HPV was relatively low (1·7%). Approximately four years after vaccination, there were 15 prevalent HPV16/18 infections in the control group and one in the vaccine group, for an estimated VE of 93·3% (95% CI = 63% to 100%). Corresponding efficacy against prevalent cervical HPV16/18 infection for the same cohort at the same visit was 72·0% (95% CI = 63% to 79%) (p versus oral VE = 0·04). There was no statistically significant protection against other oral HPV infections, though power was limited for these analyses.

Conclusions

HPV prevalence four years after vaccination with the ASO4-adjuvanted HPV16/18 vaccine was much lower among women in the vaccine arm compared to the control arm, suggesting that the vaccine affords strong protection against oral HPV16/18 infection, with potentially important implications for prevention of increasingly common HPV-associated oropharyngeal cancer.ClinicalTrials.gov, Registry number {"type":"clinical-trial","attrs":{"text":"NCT00128661","term_id":"NCT00128661"}}NCT00128661     

Potential Benefits of Second-Generation Human Papillomavirus Vaccines

Background

Current prophylactic vaccines against human papillomavirus (HPV) target two oncogenic types (16 and 18) that contribute to 70% of cervical cancer cases worldwide. Our objective was to quantify the range of additional benefits conferred by second-generation HPV prophylactic vaccines that are expected to expand protection to five additional oncogenic types (31, 33, 45, 52 and 58).

Methods

A microsimulation model of HPV and cervical cancer calibrated to epidemiological data from two countries (Kenya and Uganda) was used to estimate reductions in lifetime risk of cervical cancer from the second-generation HPV vaccines. We explored the independent and joint impact of uncertain factors (i.e., distribution of HPV types, co-infection with multiple HPV types, and unidentifiable HPV types in cancer) and vaccine properties (i.e., cross-protection against non-targeted HPV types), compared against currently-available vaccines.

Results

Assuming complete uptake of the second-generation vaccine, reductions in lifetime cancer risk were 86.3% in Kenya and 91.8% in Uganda, representing an absolute increase in cervical cancer reduction of 26.1% in Kenya and 17.9% in Uganda, compared with complete uptake of current vaccines. The range of added benefits was 19.6% to 29.1% in Kenya and 14.0% to 19.5% in Uganda, depending on assumptions of cancers attributable to multiple HPV infections and unidentifiable HPV types. These effects were blunted in both countries when assuming vaccine cross-protection with both the current and second-generation vaccines.

Conclusion

Second-generation HPV vaccines that protect against additional oncogenic HPV types have the potential to improve cervical cancer prevention. Co-infection with multiple HPV infections and unidentifiable HPV types can influence vaccine effectiveness, but the magnitude of effect may be moderated by vaccine cross-protective effects. These benefits must be weighed against the cost of the vaccines in future analyses.     

Detection and Genotyping of Human Papillomavirus in Urine Samples from Unvaccinated Male and Female Adolescents in Italy

The introduction of vaccination against Human Papillomavirus (HPV) in adolescent girls in 2006 has focused virological surveillance on this age group. As few studies have evaluated HPV infections in young populations, further data are needed in order to improve and extend prophylactic policy and to monitor epidemiological changes. The present study aimed at evaluating overall and type-specific HPV prevalence in both female and male adolescents in Italy. HPV DNA detection and genotyping was performed on urine samples collected from 870 unvaccinated adolescents (369 females, 501 males, 11-18 years of age) in five cities in Italy. Following DNA extraction by means of a commercial kit (NucliSENS^®-miniMAG^®, bioMérieux), the L1 gene fragment was PCR amplified and genotyped by restriction fragment length polymorphism analysis. HPV DNA was detected in 1.5% of all samples, and in 3% and 0.4% of samples from females and males, respectively. In approximately 70% of HPV DNA positive adolescents, the infection was due to a single genotype, with 88.9% of genotypes belonging to the HR-clade. The only two HPV-positive boys (14 and 18 years old) had HPV-70 genotype. Only one of the 11 HPV-infected girls was in the 11-14 age-group. HPV prevalence was 4.2% in girls aged 15-18 years and 60% of infections were due to vaccine types HPV-16 or HPV-6/-11. This is one of the few studies, the first conducted in Italy, on HPV infection in adolescents. Urine testing is the easier way of detecting HPV infection in younger populations. Our data revealed a very low HPV prevalence, and no infections were observed in the 12-year-old vaccine target population. The majority of infections were seen in females aged 15-18 years. Overall, more than 50% and 30% of the potentially persistent HPV infections detected in this group could have been prevented by the quadrivalent and the bivalent vaccines, respectively.     

Efficacy of vaccination against HPV infections to prevent cervical cancer in France: present assessment and pathways to improve vaccination policies

Background

Seventy percent of sexually active individuals will be infected with Human Papillomavirus (HPV) during their lifetime. These infections are incriminated for almost all cervical cancers. In France, 3,068 new cases of cervical cancer and 1,067 deaths from cervical cancer occurred in 2005. Two vaccines against HPV infections are currently available and vaccination policies aim to decrease the incidence of HPV infections and of cervical cancers. In France, vaccine coverage has been reported to be low.

Methods

We developed a dynamic model for the heterosexual transmission of Human Papillomavirus types 16 and 18, which are covered by available vaccines. A deterministic model was used with stratification on gender, age and sexual behavior. Immunity obtained from vaccination was taken into account. The model was calibrated using French data of cervical cancer incidence.

Results

In view of current vaccine coverage and screening, we expected a 32% and 83% reduction in the incidence of cervical cancers due to HPV 16/18, after 20 years and 50 years of vaccine introduction respectively. Vaccine coverage and screening rates were assumed to be constant. However, increasing vaccine coverage in women or vaccinating girls before 14 showed a better impact on cervical cancer incidence. On the other hand, performing vaccination in men improves the effect on cervical cancer incidence only moderately, compared to strategies in females only.

Conclusion

While current vaccination policies may significantly decrease cervical cancer incidence, other supplementary strategies in females could be considered in order to improve vaccination efficacy.     

Purification and immunogenicity study of human papillomavirus 58 virus-like particles expressed in Pichia pastoris

Two human papillomavirus (HPV) prophylactic vaccines are currently available in the market: Gardasil and Cervarix. These two vaccines work against tumor high-risk subtypes HPV 16 and HPV 18. However, they do not include other high-risk subtypes such as HPV 58. Epidemiological research in China shows that HPV 58 is a prevalent high-risk subtype, second only to HPV 16 and HPV 18. Thus, for cervical cancer prevention in China, developing a vaccine against HPV 58 is necessary. In this study, HPV 58 virus-like particles (VLPs) were expressed in the Pichia pastoris, and subsequently purified through pretreatment and a three-step purification process consisting of strong cation exchange chromatography, size-exclusion chromatography, and hydroxyapatite chromatography. The highly purified HPV 58 VLPs were confirmed by sodium dodecyl sulfate polyacrylamide gel electrophoresis, electron microscopy, dynamic laser scattering, and ultracentrifugation. The purified VLPs were used to immunize mice to test their ability to induce humoral immunity. Enzyme-linked immunosorbent assays were performed on the sera of the immunized mice and significantly high anti-HPV 58 VLP antibody titers were observed. The immunogenicity study demonstrates that the purified HPV 58 VLPs are HPV vaccine candidates.     

子宫颈癌预防用人乳头瘤病毒疫苗及其展拓

人乳头瘤病毒(HPV)是人子宫颈癌病原体,这一发现奠定了子宫颈癌预防用人乳头瘤病毒疫苗得以问世的科学基础。临床实践证明,默克(Merck)公司的Gardasil和葛兰素史克(GSK)公司的Cervarix这两种疫苗可预防由HPV16和HPV18引起的子宫颈癌,有效率几乎达100%。Gardasil和Cervarix的成功激动了围绕Gardasil和Cervar-ix的展拓研究。     

Prevalence of human papillomavirus and herpes simplex virus type 2 infection in Korean commercial sex workers

In order to investigate the prevalence of sexually transmitted viruses such as human papillomavirus (HPV) and herpes simplex virus (HSV) in Korean commercial sex workers (CSWs), we selected 188 CSWs (age range 20-44 years, median age 24 years) who regularly visited one public health center in Seoul, Korea. HPV genotypes were analyzed by using a HPV DNA chip, and an enzyme-linked immunosorbent assay (ELISA) was used to detect type-specific IgG against HSV2 antibody identifying seropositivity for HSV2 infection. Polymerase chain reaction (PCR) was performed with specific primers to detect HPV and HSV1/2 in cervical swabs from the CSWs. The prevalence of HPV infection was 83.5% in 188 cervical swab specimens and the main high-risk HPV genotypes were HPV16, 18, 56, and 58. The principal low-risk HPV genotypes were HPV6 and 11. The prevalence of HSV1/2 DNA was 13.8% and HSV2 seroprevalence was 86.2%. These results suggest that high frequencies of HPV and HSV2 infection might contribute to the rapid spread of STD viruses in CSWs in Korea. Additionally, an understanding of why high-risk HPV genotypes are so prevalent could provide guidelines for prophylactic vaccine development in Korea.     

Preclinical model to test human papillomavirus virus (HPV) capsid vaccines in vivo using infectious HPV/cottontail rabbit papillomavirus chimeric papillomavirus particles

A human papillomavirus (HPV) vaccine consisting of virus-like particles (VLPs) was recently approved for human use. It is generally assumed that VLP vaccines protect by inducing type-specific neutralizing antibodies. Preclinical animal models cannot be used to test for protection against HPV infections due to species restriction. We developed a model using chimeric HPV capsid/cottontail rabbit papillomavirus (CRPV) genome particles to permit the direct testing of HPV VLP vaccines in rabbits. Animals vaccinated with CRPV, HPV type 16 (HPV-16), or HPV-11 VLPs were challenged with both homologous (CRPV capsid) and chimeric (HPV-16 capsid) particles. Strong type-specific protection was observed, demonstrating the potential application of this approach.     

A Chimeric 18L1-45RG1 Virus-Like Particle Vaccine Cross-Protects against Oncogenic Alpha-7 Human Papillomavirus Types

Persistent infection with oncogenic human papillomaviruses (HPV) types causes all cervical and a subset of other anogenital and oropharyngeal carcinomas. Four high-risk (hr) mucosal types HPV16, 18, 45, or 59 cause almost all cervical adenocarcinomas (AC), a subset of cervical cancer (CxC). Although the incidence of cervical squamous cell carcinoma (SCC) has dramatically decreased following introduction of Papanicolaou (PAP) screening, the proportion of AC has relatively increased. Cervical SCC arise mainly from the ectocervix, whereas AC originate primarily from the endocervical canal, which is less accessible to obtain viable PAP smears. Licensed (bivalent and quadrivalent) HPV vaccines comprise virus-like particles (VLP) of the most important hr HPV16 and 18, self-assembled from the major capsid protein L1. Due to mainly type-restricted efficacy, both vaccines do not target 13 additional hr mucosal types causing 30% of CxC. The papillomavirus genus alpha species 7 (α7) includes a group of hr types of which HPV18, 45, 59 are proportionally overrepresented in cervical AC and only partially (HPV18) targeted by current vaccines. To target these types, we generated a chimeric vaccine antigen that consists of a cross-neutralizing epitope (homologue of HPV16 RG1) of the L2 minor capsid protein of HPV45 genetically inserted into a surface loop of HPV18 L1 VLP (18L1-45RG1). Vaccination of NZW rabbits with 18L1-45RG1 VLP plus alum-MPL adjuvant induced high-titer neutralizing antibodies against homologous HPV18, that cross-neutralized non-cognate hr α7 types HPV39, 45, 68, but not HPV59, and low risk HPV70 in vitro, and induced a robust L1-specific cellular immune response. Passive immunization protected mice against experimental vaginal challenge with pseudovirions of HPV18, 39, 45 and 68, but not HPV59 or the distantly related α9 type HPV16. 18L1-45RG1 VLP might be combined with our previously described 16L1-16RG1 VLP to develop a second generation bivalent vaccine with extended spectrum against hr HPV.     

Effectiveness of bivalent and quadrivalent human papillomavirus vaccination in Luxembourg

BackgroundIn Luxembourg, the human papillomavirus (HPV) vaccination program introduced in 2008, provided either bivalent (BV) or quadrivalent (QV) vaccines to girls aged 12–17 years. Here, we estimate the effectiveness of BV and QV vaccines combined and separately in reducing type-specific HPV prevalence eight years after the introduction of the vaccination program.MethodsA cross-sectional prevalence study was conducted among women aged 18–29 years in 2015-2017. Seven hundred sixteen participants were recruited at family planning centres or private gynaecology practices in Luxembourg. Vaccination records were verified in the social security database. Cervical samples were tested using the Anyplex II HPV28 assay. Vaccine effectiveness was estimated using logistic regression.ResultsIn total, 363/716 (50.7%) participants were HPV positive with any HPV and 209/716 (29.2%) with carcinogenic HPV genotypes. HPV vaccination offered high protection against HPV16/18 (adjusted odds ratio (AOR) = 0.13; 95% CI 0.03-0.63), HPV6/11 (AOR = 0.16; 95% CI 0.05-0.48) and cross-protection against HPV31/33/45 (AOR = 0.41; 95% CI 0.18-0.94). The AORs were generally enhanced when only considering vaccination before sexual debut corresponding to AORs: 0.05 (95% CI 0.00-0.88), 0.08 (95% CI 0.02-0.36) and 0.20 (0.06-0.65) against HPV16/18, HPV6/11 and HPV31/33/45, respectively. We observed significant protection against carcinogenic genotypes included in nonavalent vaccine for BV (AOR = 0.29; 95% CI 0.13-0.67), but not for QV (AOR = 0.81; 95% CI 0.47–1.40) (heterogeneity Chi² P = 0.04).ConclusionsOur study suggests high effectiveness of HPV vaccination against HPV6/11, HPV16/18 and a cross-protection against HPV31/33/45. Vaccination effectiveness was slightly higher for women vaccinated before sexual debut.     

带状疱疹疫苗的研究进展及应用

带状疱疹是由潜伏在体内的水痘-带状疱疹病毒再激活引起的一种急性皮肤病,主要发生于老年人和免疫力低下人群。带状疱疹是一种自限性疾病,临床主要表现为带状、成片的皮疹,而其后遗神经痛为该病中最复杂且最常见的一种不良并发症。带状疱疹的发病机制较为复杂,推测与机体的特异性T细胞免疫水平降低有关。本文就带状疱疹与T细胞之间的关系,最新疫苗研究进展进行综述,为疫苗的研发及带状疱疹的预防提供参考。     

Human papillomavirus (HPV) type distribution in Korean women: a meta-analysis

The aim of the present study is to estimate the overall prevalence and type distribution of human papillomavirus (HPV) in Korean women, through literature review and meta-analysis. We searched published data for the period between 1995 and 2007 using the following inclusion criteria; (1) studies using type-specific HPV tests, (2) data from Korean female, (3) with cytologic or pathologic results, (4) having more than 20 cases for each subgroup classified by cytologic results, and (5) HPV detection including types 16, 18, and at least one other type. In total, 18 studies (13,842 cases) published up to April 2007 were identified and selected. Adjusted overall HPV prevalence was 23.9% (95% CI: 23.8-24.1%) in women with normal cytology and 95.8% (95% CI: 95.4-96.2%) in women with cervical cancer. Type 16 was predominant regardless of cervical disease status, and type 58 occupied a significantly larger proportion in high-grade cervical intraepithelial lesions and cervical cancer in Korean women. HPV types 58, 33, and 52 together accounted for about 20% of infections in cervical cancer and high-grade intraepithelial lesions. After introduction of HPV prophylactic vaccines, extended protection, especially against types 58, 33, and 52, will be an important issue for cervical cancer prevention in Korea. The future dominant genotypes will require follow-up epidemiological studies with a large-scale, multicentered, and prospective design.     

Attenuated Recombinant Influenza A Virus Expressing HPV16 E6 and E7 as a Novel Therapeutic Vaccine Approach

Persistent infection with high-risk human papillomavirus (HPV) types, most often HPV16 and HPV18, causes all cervical and most anal cancers, and a subset of vulvar, vaginal, penile and oropharyngeal carcinomas. Two prophylactic virus-like particle (VLPs)-based vaccines, are available that protect against vaccine type-associated persistent infection and associated disease, yet have no therapeutic effect on existing lesions or infections. We have generated recombinant live-attenuated influenza A viruses expressing the HPV16 oncogenes E6 and E7 as experimental immunotherapeutic vaccine candidates. The influenza A virus life cycle lacks DNA intermediates as important safety feature. Different serotypes were generated to ensure efficient prime and boost immunizations. The immune response to vaccination in C57BL/6 mice was characterized by peptide ELISA and IFN-γ ELISpot, demonstrating induction of cell-mediated immunity to HPV16 E6 and E7 oncoproteins. Prophylactic and therapeutic vaccine efficacy was analyzed in the murine HPV16-positive TC-1 tumor challenge model. Subcutaneous (s.c.) prime and boost vaccinations of mice with recombinant influenza A serotypes H1N1 and H3N2, followed by challenge with TC-1 cells resulted in complete protection or significantly reduced tumor growth as compared to control animals. In a therapeutic setting, s.c. vaccination of mice with established TC-1 tumors decelerated tumor growth and significantly prolonged survival. Importantly, intralesional vaccine administration induced complete tumor regression in 25% of animals, and significantly reduced tumor growth in 50% of mice. These results suggest recombinant E6E7 influenza viruses as a promising new approach for the development of a therapeutic vaccine against HPV-induced disease.     

Opportunities to improve the prevention and treatment of cervical cancer

Human papillomavirus (HPV) is a causal agent for approximately 5.3% of cancers worldwide, including cervical cancer, and subsets of genital and head and neck cancer. Persistent HPV infection is a necessary, but not sufficient, cause of cervical cancer. Of the >100 HPV genotypes, only about a dozen, termed "high-risk", are associated with cancer. HPV-16 is present in approximately 50% of all cervical cancers and HPV-16, HPV-18, HPV-31 and HPV-45 together account for approximately 80%. Most high-risk HPV infections are subclinical, and are cleared by the host's immune system. The remainder produces low or high-grade squamous intraepithelial lesions (SILs), also called cervical intraepithelial neoplasia (CIN), which also may regress spontaneously. However persistent high grade SIL represents the precursor lesion of cervical cancer and carcinogenic progression is associated with integration of the viral DNA, loss of E2 and upregulation of viral oncogene expression, and chromosomal rearrangements like 3q gain. Cytologic screening of the cervix for SIL and intervention has reduced the incidence of cervical cancer in the US by an estimated 80% and HPV viral DNA and other molecular tests may improve screening further. The licensure of a preventive HPV vaccine ushers in a new era, but issues remain, including: protection restricted to a few oncogenic HPV types, access in low resource settings and impact on current cytologic screening protocols. Importantly, preventive HPV vaccination does not help with current HPV infection or disease. Here we examine the potential of second-generation preventive HPV vaccines and therapeutic HPV vaccination to address these outstanding issues.     

Behavioral and sociodemographic risk factors for serological and DNA evidence of HPV6, 11, 16, 18 infections

Introduction: Risk for HPV6/11/16/18 infections in young sexually active, behaviorally low-risk females is not well described and may inform public policy. Methods: To assess exposure risk for HPV/6/11/16/18 among 16–23 year old low-risk females, data for 2409 female clinical trial participants were evaluated. Baseline visit self-reported sexual, behavioral and demographic characteristics; and results from HPV genotyping and serology, and other clinical laboratory assays were analyzed. All subjects reported <5 lifetime male sexual partners and no prior abnormal cytology at baseline. Results: While 98% (2211/2255) were naïve to HPV16 or 18 and 99.6% (2246/2255) were naïve for 1–3 index HPVs, 27% (616/2255) showed antibody, DNA or both for ≥1 index HPV. While 18% (409/2255) tested HPV16- or -18-antibody- or -DNA-positive, only 2% (44/2255) tested positive for both types. Against this high background, other sexually transmitted infections (STIs) were uncommonly detected, suggesting low sexual risk-taking behavior. The adjusted analyses showed race, age, alcohol consumption, current Chlamydia trachomatis (chlamydia) and Trichamonas vaginalis (trichomoniasis), bacterial vaginosis (BV), number of lifetime male sex partners predicted positive index-HPV antibody test results. However, only the number of male sex partners predicted positivity for HPV6/11- and 16/18-DNA, and chlamydia infection predicted positivity for HPV6/11-DNA alone. Conclusions: Taken together, type-specific HPV-DNA and -antibody evidence of HPV6/11/16/18 infections among behaviorally low-risk 16–23 year old females is high. Since almost all participants would have benefited by either currently available bivalent or quadrivalent vaccine strategies, delaying vaccination beyond menarche may be a missed opportunity to fully protect young females against HPV6/11/16/18 infections and related dysplasias. Early diagnosis and treatment of chlamydia and trichomonas may be important in HPV pathogenesis.     

Possibilities for the treatment of varicella-herpes zoster infections in juvenile leukemia]

Chicken pox and herpes zoster represent afraid complications in patients with malignant diseases which may take a noxious course. During the sequence of two chicken pox epidemias in 1973 in children with acute lymphoblastic leukaemias, the prevention and therapeutic possibilities were checked again. Chicken pox or herpes zoster convalescent sera being compatible for blood groups and zoster-immunoglobulin were not available. At the time of the epidemia the first reports on the effect of cytarabine (Alexan) were published. Moreover, we received an information on the therapeutic application of small pox vaccine inactivated with formaldehyde (vaccinia antigen) in adults with herpes zoster and herpes labialis. From 10 children with leukaemias, who were affected with chicken pox or herpes zoster, 7 received up to 1.0 ml of inactivated small pox vaccine intramuscularly on the first day of manifestation. In 6 of the patients there were no new efflorescences on the third day. A third child died. First of all it seems probable that this influence may be due to an induction of interferon formation. Further studies will have to elucidate to what extent this mechanism will also be efficient in severe cases of immunosuppression.