Radha Railkar

Prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in young women: a randomised double-blind placebo-controlled multicentre phase II efficacy trial

BACKGROUND A randomised double-blind placebo-controlled phase II study was done to assess the efficacy of a prophylactic quadrivalent vaccine targeting the human papillomavirus (HPV) types associated with 70% of cervical cancers (types 16 and 18) and with 90% of genital warts (types 6 and 11). METHODS 277 young women (mean age 20.2 years [SD 1.7]) were randomly assigned to quadrivalent HPV (20 microg type 6, 40 microg type 11, 40 microg type 16, and 20 microg type 18) L1 virus-like-particle (VLP) vaccine and 275 (mean age 20.0 years [1.7]) to one of two placebo preparations at day 1, month 2, and month 6. For 36 months, participants underwent regular gynaecological examinations, cervicovaginal sampling for HPV DNA, testing for serum antibodies to HPV, and Pap testing. The primary endpoint was the combined incidence of infection with HPV 6, 11, 16, or 18, or cervical or external genital disease (ie, persistent HPV infection, HPV detection at the last recorded visit, cervical intraepithelial neoplasia, cervical cancer, or external genital lesions caused by the HPV types in the vaccine). Main analyses were done per protocol. FINDINGS Combined incidence of persistent infection or disease with HPV 6, 11, 16, or 18 fell by 90% (95% CI 71-97, p<0.0001) in those assigned vaccine compared with those assigned placebo. INTERPRETATION A vaccine targeting HPV types 6, 11, 16, 18 could substantially reduce the acquisition of infection and clinical disease caused by common HPV types.

High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up

Human papillomavirus (HPV) causes cervical, vulvar, and vaginal cancers, precancerous dysplasia, and genital warts. We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine. In total, 552 women (16–23 years) were enrolled in a randomised, placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0, 2, and 6. At regular intervals through 3 years, subjects underwent gynaecologic examination, cervicovaginal sampling for HPV DNA, serum anti-HPV testing, and Pap testing, with follow-up biopsy as indicated. A subset of 241 subjects underwent two further years of follow-up. At 5 years post enrolment, the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96% (two cases vaccine versus 46 placebo). There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients, and six cases in placebo recipients (efficacy=100%; 95% CI:12–100%). Through 5 years, vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection. In conclusion, a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18. This duration supports vaccination of adolescents and young adults, which is expected to greatly reduce the burden of cervical and genital cancers, precancerous dysplasia, and genital warts.

Natural History of Genital Warts: Analysis of the Placebo Arm of 2 Randomized Phase III Trials of a Quadrivalent Human Papillomavirus (Types 6, 11, 16, and 18) Vaccine

BACKGROUND The placebo arm of human papillomavirus (HPV) vaccine trials helps define the natural history of genital warts (GW). METHODS Women enrolled in the placebo arm (n = 8800) of 2 randomized trials of a quadrivalent vaccine were examined for the presence of GW for up to 9 visits over approximately 4 years. A comprehensive examination of the perianal area, vulva, and vagina prompted biopsy. Biopsy samples were analyzed by a blinded panel of up to 4 histopathologists and tested for 14 HPV genotypes (6, 11, 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, and 59) by use of a polymerase chain reaction-based assay. Risk factors for the development of GW were assessed. RESULTS Women were followed up for an average of 3.6 years (range, 0-4.9 years). Overall, 298 (3.4%) of 8800 participants developed GW related to HPV-6 or HPV-11 (incidence rate, 0.87 cases per 100 person-years-at-risk). In total, 520 distinct lesions were diagnosed as GW. HPV DNA was detected in 472 (90.8%) lesions, with HPV-6 and HPV-11 detected in 447 (86.0%) of these lesions (94.7% of 472 HPV DNA-positive lesions). We found high-risk HPV types in 161 (31.0%) of 520 lesions. Risk factors for HPV-6- and HPV-11-related GW included infection at baseline, acquisition of new sex partners, a higher number of sex partners, and DNA positivity at baseline for a high-risk HPV type. CONCLUSIONS We confirm the major role played by HPV-6 and HPV-11 in GW, as well as associated risk factors. A vaccine that includes these types of HPV could substantially reduce the overall burden of HPV disease.

Test–retest repeatability of MR elastography for noninvasive liver fibrosis assessment in hepatitis C

To conduct a rigorous evaluation of the repeatability of liver stiffness assessed by MR elastography (MRE) in healthy and hepatitis‐C‐infected subjects.

Immunogenicity and Reactogenicity of a Novel Vaccine for Human Papillomavirus 16: A 2-Year Randomized Controlled Clinical Trial

OBJECTIVE To evaluate the immunogenicity, reactogenicity, and tolerability of a prototype human papillomavirus (HPV) 16 viruslike particle (VLP) vaccine directed against the L1 capsid protein. SUBJECTS AND METHODS We enrolled healthy nonpregnant women aged 18 to 26 years into a 2-year, double-blind, dose-ranging multicenter trial (October 12, 1998, to September 30, 2001). Subjects were assigned to study groups to receive a 3-dose regimen (day 0, month 2, and month 6) of 1 of 4 vaccine doses: 10 microg, 20 microg, 40 microg, or 80 microg or placebo. Serum anti-HPV 16 L1 antibody (sL1Ab) geometric mean titers (GMTs) were measured at day 0, at month 3, at month 7, and every 6 months for a total of 2 years using a radioimmunoassay. The primary immunogenicity analyses evaluated GMTs at month 7 in L1Ab-seronegative subjects at baseline. Vaccine tolerability was also assessed. RESULTS A total of 480 subjects were randomized to receive placebo (n=52) or 10 microg (n=112), 20 microg (n=105), 40 microg (n=104), or 80 microg (n=107) of HPV 16 L1 VLP vaccine. At baseline, 75% of subjects were L1Ab seronegative. All vaccine doses produced a statistically significant sL1Ab response vs placebo (P<.001). At the completion of the vaccination regimen, sL1Ab GMTs in baseline-seronegative subjects were 36- to 78-fold higher than the sL1Ab GMT at day 0 observed in subjects who had mounted an immune response to HPV 16 infection before enrollment. Serum L1Ab GMTs remained high throughout the 1.5-year postvaccination period. Postvaccination sL1Ab GMTs were 1.1- to 2.4-fold higher in women who had detectable sL1Ab levels at enrollment compared with those in baseline-seronegative subjects, particularly in the persistence phase. The vaccine was generally well tolerated with no statistically significant differences in injection site or systemic adverse experiences among treatment groups. CONCLUSION Immunization with this novel HPV 16 L1 VLP vaccine was well tolerated and produced an immunogenic response that persisted for at least 1.5 years after the final dose.

Noninferiority of Antibody Response to Human Papillomavirus Type 16 in Subjects Vaccinated with Monovalent and Quadrivalent L1 Virus-Like Particle Vaccines

ABSTRACT The incorporation of multiple antigens into a single human papillomavirus (HPV) vaccine may induce immune interference. To evaluate whether interference occurs when HPV type 16 (HPV16) virus-like particles are combined in a multivalent vaccine, we conducted a study to evaluate anti-HPV16 responses among subjects receiving three-dose regimens of either a monovalent HPV16 vaccine or a quadrivalent HPV (types 6, 11, 16, and 18) vaccine.

Reproducibility of hepatic fat fraction measurement by magnetic resonance imaging

To evaluate the reproducibility of magnetic resonance imaging (MRI)‐determined hepatic fat fraction (%) across imaging sites with different magnet types and field strength. Reproducibility among MRI platforms is unclear, even though evaluating hepatic fat fractions (FFs) using MRI‐based methods is accurate against MR spectroscopy.

Impact of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle vaccine in a sexually active population of North American women

OBJECTIVE The purpose of this study was to inform policy regarding human papillomavirus (HPV) vaccination in North America. We measured the clinical impact of HPV-6/-11/-16/-18 vaccination in North American women. STUDY DESIGN The study enrolled 21,954 women, the majority aged 16-25, across 5 studies of a quadrivalent HPV vaccine or its HPV-16 vaccine prototype. The North American subjects (n = 5996) were pooled from these trials, and the prevalence of HPV-6/-11/-16/-18 exposure was measured. The impact of vaccination on the burden of anogenital HPV lesions in an intention-to-treat population (regardless of enrollment HPV status) was calculated. RESULTS At enrollment, the median age was 20 years; 13% of the women had had a Papanicolaou test abnormality, and 76% of the women had negative tests results for all 4 vaccine HPV types. With approximately 3 years of follow-up evaluations in the intention-to-treat population (regardless of enrollment HPV status), vaccination reduced the rate of HPV-16- and -18-related precancers and HPV-6/-11/-16/-18-related genital lesions by 66.4% (95% CI, 42.7%-81.1%) and 57.7% (95% CI, 27.3%-76.3%), respectively. CONCLUSION The administration of HPV vaccine to sexually active North American women reduced the burden of HPV-6/-11/-16/-18-related disease. Catch-up vaccination programs in this population are warranted.

Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination

Aging is associated with hyporesponse to vaccination, whose mechanisms remain unclear. In this study hepatitis B virus (HBV)-naive older adults received three vaccines, including one against HBV. Here we show, using transcriptional and cytometric profiling of whole blood collected before vaccination, that heightened expression of genes that augment B-cell responses and higher memory B-cell frequencies correlate with stronger responses to HBV vaccine. In contrast, higher levels of inflammatory response transcripts and increased frequencies of pro-inflammatory innate cells correlate with weaker responses to this vaccine. Increased numbers of erythrocytes and the haem-induced response also correlate with poor response to the HBV vaccine. A transcriptomics-based pre-vaccination predictor of response to HBV vaccine is built and validated in distinct sets of older adults. This moderately accurate (area under the curve≈65%) but robust signature is supported by flow cytometry and cytokine profiling. This study is the first that identifies baseline predictors and mechanisms of response to the HBV vaccine.

Correlation between Circulating Fungal Biomarkers and Clinical Outcome in Invasive Aspergillosis

Objective means are needed to predict and assess clinical response in patients treated for invasive aspergillosis (IA). We examined whether early changes in serum galactomannan (GM) and/or β-D-glucan (BDG) can predict clinical outcomes. Patients with proven or probable IA were prospectively enrolled, and serial GM and BDG levels and GM optical density indices (GMI) were calculated twice weekly for 6 weeks following initiation of standard-of-care antifungal therapy. Changes in these biomarkers during the first 2 and 6 weeks of treatment were analyzed for associations with clinical response and survival at weeks 6 and 12. Among 47 patients with IA, 53.2% (25/47) and 65.9% (27/41) had clinical response by weeks 6 and 12, respectively. Changes in biomarkers during the first 2 weeks were associated with clinical response at 6 weeks (GMI, P = 0.03) and 12 weeks (GM+BDG composite, P = 0.05; GM, P = 0.04; GMI, P = 0.02). Changes in biomarkers during the first 6 weeks were also associated with clinical response at 6 weeks (GM, P = 0.05; GMI, P = 0.03) and 12 weeks (BDG+GM, P = 0.02; GM, P = 0.02; GMI, P = 0.01). Overall survival rates at 6 weeks and 12 weeks were 87.2% (41/47) and 79.1% (34/43), respectively. Decreasing biomarkers in the first 2 weeks were associated with survival at 6 weeks (BDG+GM, P = 0.03; BDG, P = 0.01; GM, P = 0.03) and at 12 weeks (BDG+GM, P = 0.01; BDG, P = 0.03; GM, P = 0.01; GMI, P = 0.007). Similar correlations occurred for biomarkers measured over 6 weeks. Patients with negative baseline GMI and/or persistently negative GMI during the first 2 weeks were more likely to have CR and survival. These results suggest that changes of biomarkers may be informative to predict and/or assess response to therapy and survival in patients treated for IA.