Candidate genes and proteins regulating bull semen quality: a review.

Poor semen profile reflected by suboptimum fertility statistics is a concern in bulls reared for breeding purpose. A critical review of research on candidate genes and proteins associated with semen quality traits will be useful to understand the progress of molecular marker development for bull semen quality traits. Here, we have tabulated and classified candidate genes and proteins associated with bull semen quality based on a literature survey. A total of 175 candidate genes are associated with semen quality traits in various breeds of cattle. Several studies using candidate gene approach have identified 26 genes carrying a total of 44 single nucleotide polymorphisms. Furthermore, nine genome-wide association studies (GWASes) have identified 150 candidate genes using bovine single nucleotide polymorphisms (SNP) chips. Three genes, namely membrane-associated ring-CH-type finger 1 (MARCH1), platelet-derived growth factor receptor beta, and phosphodiesterase type 1, were identified commonly in two GWASes, which, especially MARCH1, are required to explore their regulatory roles in bull semen quality in in-depth studies. With the advancement of high-throughput-omic technologies, more candidate genes associated with bull semen quality may be identified in the future. Therefore, the functional significance of candidate genes and proteins need to be delved further into future investigations to augment bull semen quality.

Parametrical Function Describing Influences of the Redistribution of Incorporated Oil for Rupture Process Reconstruction in Rubber.

The present work is focused on finding (i) the tearing energy at rupture and (ii) the redistribution of incorporated paraffin oil on the ruptured surfaces as functions of (a) the initial oil concentration and (b) the speed of deformation to the total rupture in a uniaxially induced deformation to rupture on an initially homogeneously oil incorporated styrene butadiene rubber (SBR) matrix. The aim is to understand the deforming speed of the rupture by calculating the concentration of the redistributed oil after rupture using infrared (IR) spectroscopy in an advanced continuation of a previously published work. The redistribution of the oil after tensile rupture for samples that have three different initial oil concentrations with a control sample that has no initial oil has been studied at three defined deformation speeds of rupture along with a cryo-ruptured sample. Single-edge notched tensile (SENT) specimens were used in the study. Parametric fittings of data at different deformation speeds were used to relate the concentration of the initial oil against the concentration of the redistributed oil. The novelty of this work is in the use of a simple IR spectroscopic method to reconstruct a fractographic process to rupture in relation to the speed of the deformation to rupture.

Evidence of linear and cubic Rashba effect in non-magnetic heterostructure.

TheLaAlO3/KTaO3system serves as a prototype to study the electronic properties that emerge as a result of spin-orbit coupling (SOC). In this article, we have used first-principles calculations to systematically study two types of defect-free (0 0 1) interfaces, which are termed as Type-I and Type-II. While the Type-I heterostructure produces a two dimensional (2D) electron gas, the Type-II heterostructure hosts an oxygen-rich 2D hole gas at the interface. Furthermore, in the presence of intrinsic SOC, we have found evidence of both cubic and linear Rashba interactions in the conduction bands of the Type-I heterostructure. On the contrary, there is spin-splitting of both the valence and the conduction bands in the Type-II interface, which are found to be only linear Rashba type. Interestingly, the Type-II interface also harbors a potential photocurrent transition path, making it an excellent platform to study the circularly polarized photogalvanic effect.

Influence of Ultraviolet Radiation on Mechanical Properties of a Photoinitiator Compounded High Vinyl Styrene-Butadiene-Styrene Block Copolymer.

Ultraviolet curing of elastomers is a special curing technique that has gained importance over the conventional chemical crosslinking method, because the former process is faster, and thus, time-saving. Usually, a suitable photoinitiator is required to initiate the process. Ultraviolet radiation of required frequency and intensity excites the photoinitiator which abstracts labile hydrogen atoms from the polymer with the generation of free radicals. These radicals result in crosslinking of elastomers via radical-radical coupling. In the process, some photodegradation may also take place. In the present work, a high vinyl (~50%) styrene-butadiene-styrene (SBS) block copolymer which is a thermoplastic elastomer was used as the base polymer. An attempt was made to see the effect of ultraviolet radiation on the mechanical properties of the block copolymer. The process variables were time of exposure and photoinitiator concentration. Mechanical properties like tensile strength, elongation at break, modulus at different elongations and hardness of the irradiated samples were studied and compared with those of unirradiated ones. In this S-B-S block copolymer, a relatively low exposure time and low photoinitiator concentration were effective in obtaining optimized mechanical properties. Infrared spectroscopy, contact angle and scanning electron microscopy were used to characterize the results obtained from mechanical measurements.

Configuration of Novel Experimental Fractographic Reverse Engineering Approach Based on Relationship between Spectroscopy of Ruptured Surface and Fracture Behaviour of Rubber Sample.

A novel fractographic approach based on a combination of (i) mechanical behavior of cured rubber in uniaxial tensile loading and (ii) spectroscopy of fracture on a ruptured surface was experimentally validated. This approach related the migration of paraffin oil from a matrix to the ruptured rubber surface, to the tearing energy related to the deformation speed responsible for total rubber sample rupture, and the approach itself was configured experimentally. It was evaluated on cured natural rubber (NR) for two different paraffin oil concentrations. Single edge notched tensile (SENT) samples were subjected to uniaxial tensile loadings at two different deformation speeds. First, the tearing energy as a function of deformation speed was determined for each defined oil concentration. Secondly, at specific locations on the ruptured surfaces, infrared (IR) spectroscopy was performed to quantify a characteristic absorbance peak height of migrated paraffin oil during the rupture process. The results of the IR analyses were related to the deformation speed to understand the relation between the amount of migrated paraffin oil during the fracture process and the deformation speed which brought about such a fracture. This novel approach enhanced the reverse engineering process of rubber fracture related to the cause of tearing energies during critical failure.

Immunogenicity and safety of the AS04-HPV-16/18 and HPV-6/11/16/18 human papillomavirus vaccines in asymptomatic young women living with HIV aged 15-25 years: A phase IV randomized comparative study.

BACKGROUND: Women living with HIV (WLWH) are at higher risk of acquisition and progression of human papillomavirus (HPV) infection. Evidence on effect of HPV vaccination in this population is limited. METHODS: This phase IV randomized controlled observer-blind study assessed immunogenicity and safety of two HPV vaccines (AS04-HPV-16/18 vs. 4vHPV) given in WLWH (stage 1) and HIV- females aged 15-25 years. Co-primary endpoints were to demonstrate, in WLWH subjects, non-inferiority (and if demonstrated, superiority) of AS04-HPV-16/18 vs. 4vHPV for HPV-16 and HPV-18 by pseudovirion-based neutralization assay (PBNA) at month 7 and safety. Non-inferiority criteria was lower limit (LL) of the 95% confidence interval (CI) of the GMT ratio AS04-HPV-16/18/4vHPV above 0.5, in the according to protocol population. NCT01031069. FINDINGS: Among 873 subjects recruited between 26-Oct-2010 and 14-May-2015, 546 were randomized (1:1) and received at least one vaccine dose (total vaccinated cohort, TVC): 257 were WLWH (129 AS04-HPV-16/18; 128 4vHPV) and 289 were subjects without HIV (144 AS04-HPV-16/18; 145 4vHPV). Baseline CD4 cell count in WLWH was at least 350 cells/mm3.At month 7, AS04-HPV-16/18 showed immunological superiority to 4vHPV in WLWH. Neutralizing anti-HPV-16 and HPV-18 antibody GMTs were 2·74 (95% CI: 1·83; 4·11) and 7·44 (95% CI: 4·79; 11·54) fold higher in AS04-HPV-16/18 vs. 4vHPV (LL of the GMT ratio >1 in TVC, p<0·0001), respectively. Similar results were observed by ELISA up to month 24.Solicited local and general symptoms were in line with product labels. The number of reported serious adverse events (SAEs) was balanced throughout the study. INTERPRETATION: Both vaccines showed an acceptable safety profile in all subjects. Despite the absence of an immunological correlate of protection for HPV, differences in immune responses elicited by the vaccines especially for HPV-18 may translate into longer lasting or more robust protection against cervical cancer with the AS04-HPV-16/18 vaccine in WLWH.

Impact of vaccines on antimicrobial resistance.

DRIVERS OF ANTIMICROBIAL RESISTANCE: Antibiotic use drives the development and spread of resistant bacterial infections. Antimicrobial resistance (AMR) has become a prolific global issue, due to significant increases in antibiotic use in humans, livestock and agriculture, inappropriate use (under-dosing and over-prescribing), and misuse of antibiotics (for viral infections where they are ineffective). Fewer new antibiotics are being developed. THE PROBLEM OF AMR: AMR is now considered a key threat to global health, leading to more mortality and increased healthcare costs threatening future conduct of routine medical procedures. Traditional approaches to address AMR include antibiotic stewardship, better hygiene/infection control, promoting antibiotic research and development, and restricting use for agricultural purposes. VACCINES AS A TOOL TO REDUCE AMR: While antibiotic development is declining, vaccine technology is growing. This review shows how vaccines can decrease AMR by preventing bacterial and viral infections, thereby reducing the use/misuse of antibiotics, and by preventing antibiotic-resistant infections. Vaccines are less likely to induce resistance. Some future uses and developments of vaccines are also discussed. CONCLUSIONS: Vaccines, along with other approaches, can help reduce AMR by preventing (resistant) infections and reducing antibiotic use. Industry and governments must focus on the development of novel vaccines and drugs against resistant infections to successfully reduce AMR. A graphical abstract is available online.

Safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in adolescents aged 12-15 years: Interim analysis of a large community-randomized controlled trial.

This community-randomized controlled trial was initiated to assess the overall and herd effects of 2 different human papillomavirus (HPV) immunization strategies in over 80,000 girls and boys aged 12-15 y in 33 communities in Finland (ClinicalTrials.gov NCT00534638). Overall, 14,838 adolescents received HPV-16/18 vaccine (2,440 boys and 12,398 girls) and 17,338 received hepatitis-B virus (HBV) vaccine (9,221 boys and 8,117 girls). In an interim analysis, vaccine safety was assessed by active monitoring and surveillance via health registry linkage. Active monitoring showed that the HPV-16/18 vaccine has acceptable safety and reactogenicity in boys. In all study participants, the observed incidences (per 100,000 person-years) of serious adverse events (SAEs) possibly related to vaccination were 54.3 (95% Confidence Interval [CI]: 34.0-82.1) in the HPV-16/18 group and 64.0 (95% CI: 43.2-91.3) in the HBV group. During the follow-up period for this interim analysis, the most common new-onset autoimmune diseases (NOADs; with incidence rate ≥15 per 100,000) in any group based on hospital discharge registry (HILMO) download were ulcerative colitis, juvenile arthritis, celiac disease, insulin-dependent diabetes mellitus (IDDM) and Crohn's disease. No increased NOAD incidences were observed in HPV-16/18 vaccine recipients compared to HBV vaccine recipients. In both the SAE possibly related- and HILMO-analyses, a lower incidence of IDDM was observed in HPV-16/18 vaccinees compared to HBV vaccinees (relative risks, 0.26 [95% CI: 0.03-1.24] and 0.16 [95% CI: 0.03-0.55], respectively).

Immunogenicity and safety of early vaccination with two doses of a combined measles-mumps-rubella-varicella vaccine in healthy Indian children from 9†months of age: a phase III, randomised, non-inferiority trial.

OBJECTIVE: This study (NCT00969436) compared the immunogenicity and safety of measles-mumps-rubella (MMR) followed by MMR+varicella (V) vaccines to (1) 2 doses of combined MMRV and (2) MMR followed by MMRV, in Indian children. DESIGN: Phase III, open, randomised, non-inferiority study. SETTING: 6 tertiary care hospitals located in India. PARTICIPANTS: Healthy participants aged 9-10 months not previously vaccinated against/exposed to measles, mumps, rubella and varicella or without a history of these diseases. INTERVENTIONS: Participants were randomised (2:2:1) to receive 2 doses of either MMRV (MMRV/MMRV group) or MMR followed by MMRV (MMR/MMRV group) or MMR followed by MMR+V (MMR/MMR+V, control group) at 9 and 15 months of age. Antibody titres against measles, mumps and rubella were measured using ELISA and against varicella using an immunofluorescence assay. MAIN OUTCOME MEASURES: To demonstrate non-inferiority of the 2 vaccination regimens versus the control in terms of seroconversion rates, defined as a group difference with a lower bound of the 95% CI >-10% for each antigen, 43 days postdose 2. Parents/guardians recorded solicited local and general symptoms for a 4-day and 43-day period after each vaccine dose, respectively. RESULTS: Seroconversion rates postdose 1 ranged from 87.5% to 93.2% for measles, 83.3% to 86.1% for mumps and 98.7% to 100% for rubella across the 3 vaccine groups. The seroconversion rates postdose 2 were 100% for measles, mumps and rubella and at least 95.8% for varicella across the 3 vaccine groups. Non-inferiority of MMRV/MMRV and MMR/MMRV to MMR/MMR+V was achieved for all antigens, 43 days postdose 2. The 3 vaccination regimens were generally well tolerated in terms of solicited local and general symptoms. CONCLUSIONS: The immune responses elicited by the MMRV/MMRV and MMR/MMRV vaccination regimens were non-inferior to those elicited by the MMR/MMR+V regimen for all antigens. The 3 vaccination schedules also exhibited an acceptable safety profile in Indian children. TRIAL REGISTRATION NUMBER: NCT00969436.

Hepatotropic viruses as etiological agents of acute liver failure and related-outcomes among children in India: a retrospective hospital-based study.

BACKGROUND: Acute liver failure (ALF) is marked by a sudden loss of hepatic function and is associated with a high mortality rate in children. The etiology of ALF is shown to vary geographically. This study assessed the frequency of hepatotropic viruses as etiological agents of ALF in Indian children. METHODS: This retrospective study enrolled children aged 0-18 years with confirmed ALF admitted to Christian Medical College, Vellore and King Edward Memorial Hospital and Research Center, Pune between January 2003 and December 2005. The frequency of hepatotropic viruses as etiological agents in children with ALF aged ≤18 years was calculated with 95% confidence interval (CI). Descriptive analyses of demographic characteristics, clinical signs and symptoms of ALF, choice of treatment and outcomes were performed. RESULTS: Of 76 children enrolled, 54 were included in the per-protocol analyses. Mean age of children with ALF was 5.43 years (standard deviation = 3.62); 51.9% (28/54) were female. The percentage of children positive for anti-hepatitis A virus (HAV) IgM and hepatitis B surface antigen was 65.9% (27/41; 95% CI 49.4-79.9) and 15.9% (7/44; 95% CI 6.6-30.1), respectively. The final cause of ALF was HAV (36.3%) followed by hepatitis B virus (HBV; 8.8%). Before and during admission, encephalopathy was observed in 77.8% (42/54) and 63.0% (34/54) of children, respectively. A high number of children (46/54; 85.2%) required intensive care and ALF was fatal in 24.1% (13/54). The proportion of deaths due to HAV and HBV was 18.5% (5/27) and 57.1% (4/7), respectively. CONCLUSIONS: HAV and HBV were the most common etiological agents of ALF in Indian children. Primary prevention by vaccination against HAV and HBV in young children may be useful in the prevention of ALF due to viral hepatitis in India.

Exciton-polariton gas as a nonequilibrium coolant.

Using angle-resolved Raman spectroscopy, we show that a resonantly excited ground-state exciton-polariton fluid behaves like a nonequilibrium coolant for its host solid-state semiconductor microcavity. With this optical technique, we obtain a detailed measurement of the thermal fluxes generated by the pumped polaritons. We thus find a maximum cooling power for a cryostat temperature of 50 K and below where optical cooling is usually suppressed, and we identify the participation of an ultrafast cooling mechanism. We also show that the nonequilibrium character of polaritons constitutes an unexpected resource: each scattering event can remove more heat from the solid than would be normally allowed using a thermal fluid with normal internal equilibration.

Characteristics of a cluster-randomized phase IV human papillomavirus vaccination effectiveness trial.

High-risk human papillomaviruses (hrHPV) cause anogenital and oropharyngeal cancers. HPV-16/18 virus-like particle vaccine formulated with an AS04 adjuvant is very efficacious against hrHPV associated precancers but the herd effects of different vaccination scenarios are not known. Our cluster randomized trial (NCT00534638) assesses the overall and herd effects of vaccinating girls vs. girls and boys. In two school-years (2007-2008 and 2008-2009) we invited 80,272 1992-1995 born early adolescents to a CRT in 33 communities a priori stratified by low, intermediate and high HPV-16/18 seroprevalence. In 11 Arm A communities 90% of participating girls and boys were assigned to receive HPV-16/18 vaccine, in 11 Arm B communities 90% of girls were assigned to receive HPV-16/18 vaccine - boys were assigned to receive hepatitis B-virus (HBV) vaccine, and in 11 Arm C communities all were assigned to receive HBV-vaccine. Prevalence of HPV in vaccinated and unvaccinated girls is studied at age 18.5 years. Recruitment resulted in equal enrolment of four birth cohorts (born 1992-1995) comprising altogether 32,175 (40% response) early adolescents: 20,514 girls (50.5-53.0% response by arm) and 11,661 boys (21.9-31.6%% response by arm). At the age of 15 years, 79.3% of the vaccinees completed a questionnaire. Among them >98% were living at, and during the week-ends 1.3-1.6% stayed outside, the study site communities. Smoking habit and alcohol consumption were similar in the different trial arms, also mean-age of menarche (12.4 years) and 1st ejaculation (12.6 years), and sexual behaviour (among those <25%, who had had sexual debut) did not differ by arm: mean-age at the sexual debut 14.3 and 14.4 in girls and boys, and proportions of those with multiple (≥5) life-time sexual partners (6.5-7.5%) at the age of 15 years. Uniform residential, life-style and sexual behaviour characteristics indicate successful randomization/enrolment of the CRT. Our CRT will verify modelled predictions on up to 31% herd effect of vaccinating both girls and boys with moderate vaccine coverage - quantifying overall effectiveness of different strategies which will soon guide how to implement HPV vaccination.

Immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese girls and women aged 9 to 45 years.

Immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine were evaluated in healthy Chinese females aged 9-45 years in 2 phase IIIB, randomized, controlled trials. Girls aged 9-17 years (ClinicalTrials.gov, NCT00996125) received vaccine (n = 374) or control (n = 376) and women aged 26-45 years (NCT01277042) received vaccine (n = 606) or control (n = 606) at months 0, 1, and 6. The primary objective was to show non-inferiority of anti-HPV-16 and -18 immune responses in initially seronegative subjects at month 7, compared with Chinese women aged 18-25 years enrolled in a separate phase II/III trial (NCT00779766). Secondary objectives were to describe the anti-HPV-16 and -18 immune response, reactogenicity and safety. At month 7, immune responses were non-inferior for girls (9-17 years) vs. young women (18-25 years): the upper limit of the 95% confidence interval (CI) for the geometric mean titer (GMT) ratio (women/girls) was below the limit of 2 for both anti-HPV-16 (0.37 [95% CI: 0.32, 0.43]) and anti-HPV-18 (0.42 [0.36, 0.49]). Immune responses at month 7 were also non-inferior for 26-45 year-old women vs. 18-25 year-old women: the upper limit of the 95% CI for the difference in seroconversion (18-25 minus 26-45) was below the limit of 5% for both anti-HPV-16 (0.00% [-1.53, 1.10]) and anti-HPV-18 (0.21% [-1.36, 1.68]). GMTs were 2- to 3-fold higher in girls (9-17 years) as compared with young women (18-25 years). The HPV-16/18 AS04-adjuvanted vaccine had an acceptable safety profile when administered to healthy Chinese females aged 9-45 years.

Baseline prevalence and type distribution of human papillomavirus in healthy Chinese women aged 18-25 years enrolled in a clinical trial.

Baseline human papillomavirus (HPV) prevalence and type distribution were evaluated in young Chinese women enrolled in a clinical trial of an HPV vaccine (ClinicalTrials.gov registration NCT00779766). Cervical specimens and blood samples were collected at baseline from women aged 18-25 years (n = 6,051) from four sites across Jiangsu province. Cervical specimens were tested for HPV DNA by SPF10 PCR-DEIA-LiPA25 version 1, and HPV-16/18 type-specific polymerase chain reaction. Anti-HPV-16 and anti-HPV-18 antibody titres were quantified by enzyme-linked immunosorbent assay. At baseline, 15.3% of women were DNA positive for any of 14 HPV high-risk (hr) types (HPV-16/18/31/33/35/39/45/51/52/56/58/59/66/68). The most commonly detected hrHPV types in cervical specimens were HPV-52 (4.0%) and HPV-16 (3.7%). High-risk HPV DNA-positivity increased with severity of cytological abnormalities: 39.3% in atypical squamous cells of undetermined significance, 85.0% in low-grade squamous intraepithelial lesions and 97.8% in high-grade squamous intraepithelial lesions (HSIL). The hrHPV types most frequently detected in HSIL were HPV-16 (63.0%), HPV-18 (17.4%), HPV-52 (17.4%), HPV-58 (15.2%) and HPV-33 (15.2%). The hrHPV types most frequently detected in cervical intraepithelial neoplasia 2+ were HPV-16 (66.1%), HPV-33 (16.1%), HPV-52 (16.1%), HPV-58 (14.5%) and HPV-51 (11.3%). Multiple hrHPV infections were reported for 24.4% of hrHPV DNA positive women. Regardless of baseline HPV DNA status, 30.5% and 16.0% of subjects were initially seropositive for anti-HPV-16 and anti-HPV-18, respectively. In conclusion, the high baseline seropositivity rate and intermediate prevalence of cervical hrHPV types in Chinese women aged 18-25 years underlines the importance of early HPV vaccination in this population.

Efficacy, immunogenicity and safety of the HPV-16/18 AS04-adjuvanted vaccine in healthy Chinese women aged 18-25 years: results from a randomized controlled trial.

This phase II/III, double-blind, randomized trial assessed the efficacy, immunogenicity and safety of the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine in young Chinese women (ClinicalTrials.gov registration NCT00779766). Women aged 18-25 years from Jiangsu province were randomized (1:1) to receive HPV vaccine (n = 3,026) or Al(OH)3 control (n = 3,025) at months 0, 1 and 6. The primary objective was vaccine efficacy (VE) against HPV-16/18 associated 6-month persistent infection (PI) and/or cervical intraepithelial neoplasia (CIN) 1+. Secondary objectives were VE against virological and clinical endpoints associated with HPV-16/18 and with high-risk HPV types, immunogenicity and safety. Mean follow-up for the according-to-protocol cohort for efficacy (ATP-E) was ∼15 months after the third dose. In the ATP-E (vaccine = 2,889; control = 2,894), for initially HPV DNA negative and seronegative subjects, HPV-16/18 related VE (95% CI) was 94.2% (62.7, 99.9) against 6-month PI and/or CIN1+ and 93.8% (60.2, 99.9) against cytological abnormalities. VE against HPV-16/18 associated CIN1+ and CIN2+ was 100% (-50.4, 100) and 100% (-140.2, 100), respectively (no cases in the vaccine group and 4 CIN1+ and 3 CIN2+ cases in the control group). At Month 7, at least 99.7% of initially seronegative vaccine recipients had seroconverted for HPV-16/18; geometric mean antibody titres (95% CI) were 6,996 (6,212 to 7,880) EU/mL for anti-HPV-16 and 3,309 (2,942 to 3,723) EU/mL for anti-HPV-18. Safety outcomes between groups were generally similar. The HPV-16/18 AS04-adjuvanted vaccine is effective, immunogenic and has a clinically acceptable safety profile in young Chinese women. Prophylactic HPV vaccination has the potential to substantially reduce the burden of cervical cancer in China.

Human papillomavirus prevalence and type-distribution in women with cervical lesions: a cross-sectional study in Sri Lanka.

BACKGROUND: Cervical cancer ranks second among all cancers reported in Sri Lankan women. This study assessed the prevalence and type-distribution of human papillomavirus (HPV) among Sri Lankan women with invasive cervical cancer (ICC) and pre-cancerous lesions. METHODS: 114 women aged 21 years and above, hospitalized in the National Cancer Institute, Sri Lanka with a diagnosis of ICC or cervical intraepithelial neoplasia (CIN) 2/3 were prospectively enrolled between October 2009 and September 2010 (110430/NCT01221987). The cervical biopsy or excision specimens collected during routine clinical procedures were subjected to histopathological review. DNA was extracted from samples with a confirmed histological diagnosis and was amplified using polymerase chain reaction and HPV DNA was detected using Enzyme Immuno Assay. HPV positive samples were typed using reverse hybridization Line Probe Assay. RESULTS: Of the cervical samples collected, 93.0% (106/114) had a histologically confirmed diagnosis of either ICC (98/106) or CIN 2/3 (8/106). Among all ICC cases, squamous cell carcinoma was diagnosed in the majority of women (81.6% [80/98]). HPV prevalence among ICC cases was 84.7% (83/98). The HPV types most commonly detected in ICC cases with single HPV infection (98.8% [82/83]) were HPV-16 (67.3%) and HPV-18 (9.2%). Infection with multiple HPV types was recorded in a single case (co-infection of HPV-16 and HPV-59). CONCLUSIONS: HPV was prevalent in most women with ICC in Sri Lanka; HPV-16 and HPV-18 were the predominantly detected HPV types. An effective prophylactic vaccine against the most prevalent HPV types may help to reduce the burden of ICC disease.

Comparison of the immunogenicity of the human papillomavirus (HPV)-16/18 vaccine and the HPV-6/11/16/18 vaccine for oncogenic non-vaccine types HPV-31 and HPV-45 in healthy women aged 18-45 years.

Protection against oncogenic non-vaccine types (cross-protection) offered by human papillomavirus (HPV) vaccines may provide a significant medical benefit. Available clinical efficacy data suggest the two licensed vaccines (HPV-16/18 vaccine, GlaxoSmithKline Biologicals (GSK), and HPV-6/11/16/18 vaccine, Merck & Co., Inc.) differ in terms of protection against oncogenic non-vaccine HPV types -31/45. The immune responses induced by the two vaccines against these two non-vaccine HPV types (cross-reactivity) was compared in an observer-blind study up to Month 24 (18 mo post-vaccination), in women HPV DNA-negative and seronegative prior to vaccination for the HPV type analyzed (HPV-010 [NCT00423046]). Geometric mean antibody titers (GMTs) measured by pseudovirion-based neutralization assay (PBNA) and enzyme-linked immunosorbent assay (ELISA) were similar between vaccines for HPV-31/45. Seropositivity rates for HPV-31 were also similar between vaccines; however, there was a trend for higher seropositivity with the HPV-16/18 vaccine (13.0-16.7%) versus the HPV-6/11/16/18 vaccine (0.0-5.0%) for HPV-45 with PBNA, but not ELISA. HPV-31/45 cross-reactive memory B-cell responses were comparable between vaccines. Circulating antigen-specific CD4+ T-cell frequencies were higher for the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine (HPV-31 [geometric mean ratio [GMR] =2.0; p=0.0002] and HPV-45 [GMR=2.6; p=0.0092]), as were the proportion of T-cell responders (HPV-31, p=0.0009; HPV-45, p=0.0793). In conclusion, immune response to oncogenic non-vaccine HPV types -31/45 was generally similar for both vaccines with the exception of T-cell response which was higher with the HPV-16/18 vaccine. Considering the differences in cross-protective efficacy between the two vaccines, the results might provide insights into the underlying mechanism(s) of protection.

Comparative immunogenicity and safety of human papillomavirus (HPV)-16/18 vaccine and HPV-6/11/16/18 vaccine: follow-up from months 12-24 in a Phase III randomized study of healthy women aged 18-45 years.

In this observer-blind study (NCT00423046), women (N=1,106), stratified by age (18-26, 27-35, 36-45 y), were randomized (1:1) to receive the HPV-16/18 vaccine (Cervarix®, GlaxoSmithKline Biologicals, Months 0, 1, 6) or the HPV-6/11/16/18 vaccine (Gardasil® Merck & Co., Inc., Months 0, 2, 6). Month 7 results were previously reported; we now report Month 24 results. In the according-to-protocol cohort for immunogenicity (seronegative and DNA-negative at baseline for HPV type analyzed), seropositivity rates of neutralizing antibodies (nAbs) [pseudovirion-based neutralization assay] were, across all age strata, 100% (HPV-16/18 vaccine) and 97.5-100% (HPV-6/11/16/18 vaccine) for HPV-16, and 99.0-100% (HPV-16/18 vaccine) and 72.3-84.4% (HPV-6/11/16/18 vaccine) for HPV-18. Corresponding geometric mean titers (GMTs) were 2.4-5.8-fold higher for HPV-16 and 7.7-9.4-fold higher for HPV-18 with the HPV-16/18 vaccine versus the HPV-6/11/16/18 vaccine; HPV-16 and HPV-18 GMTs were significantly higher with the HPV-16/18 vaccine than the HPV-6/11/16/18 vaccine (p< 0.0001) in the total vaccinated cohort (received ≥1 vaccine dose, irrespective of baseline sero/DNA-status). Similar results were obtained using enzyme-linked immunosorbent assay (ELISA). Positivity rates and GMTs of antigen-specific IgG antibodies in cervicovaginal secretions (ELISA) were not significantly different between vaccines. At Month 24, CD4⁺ T-cell responses for HPV-16 and HPV-18 were higher with the HPV-16/18 vaccine; memory B-cell response was higher for HPV-18 with the HPV-16/18 vaccine and similar between vaccines for HPV-16. Both vaccines were generally well tolerated. Although an immunological correlate of protection has not been defined, differences in the magnitude of immune response between vaccines may represent determinants of duration of protection.

Safety and immunogenicity of human papillomavirus-16/18 AS04-adjuvanted vaccine in healthy Chinese females aged 15 to 45 years: a phase I trial.

Globally, about 70% of cervical cancers are associated with human papillomavirus (HPV)-16 or HPV-18 infection. A meta-analysis of epidemiologic studies in China showed that HPV was present in 98% of cervical cancer samples. The HPV-16/18 AS04-adjuvanted vaccine Cervarix has shown a high level of protection against HPV-16/18 infections and associated cervical lesions. This phase I trial (NCT00549900) assessed the safety, tolerability, and immunogenicity of the vaccine in Chinese. Thirty healthy Chinese females, aged 15 to 45 years with a median age of 29.5 years, received three doses of Cervarix in Months 0, 1, and 6. Safety was assessed via recording solicited local and systemic symptoms within 7 days and unsolicited symptoms within 30 days after each vaccination. Serious adverse events, new onset of chronic diseases, and other medically significant conditions were recorded throughout this trial. As an exploratory objective, HPV-16/18 antibody titers were determined by enzyme-linked immunosorbent assay in serum samples collected in Months 0 and 7. Pain at the injection site was the most frequently reported local symptom. Two subjects reported medically significant adverse events. Both cases were assessed as unrelated to vaccination by the investigator. In Month 7, 100% seroconversion was observed for both anti-HPV-16 and anti-HPV-18 with high geometric mean antibody titers. HPV-16/18 AS04-adjuvanted vaccine, evaluated for the first time in Chinese females, was generally well tolerated and immunogenic, as previously shown in global studies.

The immunogenicity and safety of a reduced PRP-content DTPw-HBV/Hib vaccine when administered according to the accelerated EPI schedule.

BACKGROUND: Combination vaccines improve coverage, compliance and effectively introduce new antigens to mass vaccination programmes. This was a phase III, observer-blind, randomized study of GSK Biologicals diphtheria-tetanus-whole cell pertussis vaccine combined with hepatitis B and Haemophilus influenzae type b vaccines, containing a reduced amount of polyribosyl-ribitol-phosphate (PRP) and a DTPw component manufactured at a different site (DTPw-HBV/Hib2.5 [Kft]). The primary aim of this study was to demonstrate that DTPw-HBV/Hib2.5 [Kft] was not inferior to the licensed DTPw-HBV/Hib (Tritanrix(tm)-HepB/Hiberix(tm)) vaccine or the DTPw-HBV/Hib2.5 vaccine, also containing a reduced amount of PRP, with respect to the immune response to the PRP antigen, when administered to healthy infants, according to the Expanded Programme for Immunization (EPI) schedule at 6, 10 and 14 weeks of age. METHODS: 299 healthy infants were randomised to receive either DTPw-HBV/Hib2.5 [Kft] DTPw-HBV/Hib2.5 or DTPw-HBV/Hib according to the 6-10-14 week EPI schedule. Blood samples were analysed prior to the first dose of study vaccine and one month after the third vaccine dose for the analysis of immune responses. Solicited local and general symptoms such as pain, redness and swelling at the injection site and drowsiness and fever, unsolicited symptoms (defined as any additional adverse event) and serious adverse events (SAEs) were recorded up to 20 weeks of age. RESULTS: One month after the third vaccine dose, 100% of subjects receiving DTPw-HBV/Hib2.5 [Kft] or DTPw-HBV/Hib and 98.8% of subjects receiving DTPw-HBV/Hib2.5 vaccine had seroprotective levels of anti-PRP antibodies (defined as anti-PRP antibody concentration ≥0.15 µg/ml). Seroprotective antibody concentrations were attained in over 98.9% of subjects for diphtheria, tetanus and hepatitis B. The vaccine response rate to pertussis antigen was at least 97.8% in each group. Overall, the DTPw-HBV/Hib2.5 [Kft] vaccine was well tolerated in healthy infants; no SAEs were reported in any group. CONCLUSIONS: The DTPw-HBV/Hib2.5 [Kft] vaccine was immunogenic and well-tolerated when administered according to the EPI schedule to Indian infants. TRIAL REGISTRATION: http://www.clinicaltrials.gov NCT00473668.