Explore the vast range of titles available.

Despite preventive vaccines for oncogenic human papillomaviruses (HPVs), cervical intraepithelial neoplasia (CIN) is common, and current treatments are ablative and can lead to long-term reproductive morbidity. We assessed whether VGX-3100, synthetic plasmids targeting HPV-16 and HPV-18 E6 and E7 proteins, delivered by electroporation, would cause histopathological regression in women with CIN2/3. Efficacy, safety, and immunogenicity of VGX-3100 were assessed in CIN2/3 associated with HPV-16 and HPV-18, in a randomised, double-blind, placebo-controlled phase 2b study. Patients from 36 academic and private gynaecology practices in seven countries were randomised (3:1) to receive 6 mg VGX-3100 or placebo (1 mL), given intramuscularly at 0, 4, and 12 weeks. Randomisation was stratified by age (<25 vs ≥25 years) and CIN2 versus CIN3 by computer-generated allocation sequence (block size 4). Funder and site personnel, participants, and pathologists were masked to treatment. The primary efficacy endpoint was regression to CIN1 or normal pathology 36 weeks after the first dose. Per-protocol and modified intention-to-treat analyses were based on patients receiving three doses without protocol violations, and on patients receiving at least one dose, respectively. The safety population included all patients who received at least one dose. The trial is registered at ClinicalTrials.gov (number NCT01304524) and EudraCT (number 2012-001334-33). Between Oct 19, 2011, and July 30, 2013, 167 patients received either VGX-3100 (n=125) or placebo (n=42). In the per-protocol analysis 53 (49·5%) of 107 VGX-3100 recipients and 11 (30·6%) of 36 placebo recipients had histopathological regression (percentage point difference 19·0 [95% CI 1·4–36·6]; p=0·034). In the modified intention-to-treat analysis 55 (48·2%) of 114 VGX-3100 recipients and 12 (30·0%) of 40 placebo recipients had histopathological regression (percentage point difference 18·2 [95% CI 1·3–34·4]; p=0·034). Injection-site reactions occurred in most patients, but only erythema was significantly more common in the VGX-3100 group (98/125, 78·4%) than in the placebo group (24/42, 57·1%; percentage point difference 21·3 [95% CI 5·3–37·8]; p=0·007). VGX-3100 is the first therapeutic vaccine to show efficacy against CIN2/3 associated with HPV-16 and HPV-18. VGX-3100 could present a non-surgical therapeutic option for CIN2/3, changing the treatment outlook for this common disease. Inovio Pharmaceuticals.

Multidose human papillomavirus (HPV) vaccination is efficacious, yet the vaccine has been underused globally. Emerging data suggest that a single dose may provide protection. Whether a single dose of HPV vaccine would provide similar protection to two doses is uncertain. In this trial, we assessed whether one dose of an HPV vaccine was noninferior to two doses. Girls 12 to 16 years of age were randomly assigned, in a 1:1:1:1 ratio, to receive one or two doses of a bivalent HPV vaccine or one or two doses of a nonavalent HPV vaccine. The primary end point was new HPV type 16 or 18 infection occurring from month 12 to month 60 and persisting for at least 6 months. The prespecified noninferiority margin was 1.25 infections per 100 participants. We also assessed vaccine effectiveness by comparing HPV16 or HPV18 infection among the trial participants with that among girls and women enrolled in a nonrandomized survey. A total of 20,330 participants were enrolled and underwent randomization, and 3005 unvaccinated participants were enrolled in the survey. The noninferiority analysis showed that one vaccine dose was noninferior to two doses in preventing HPV16 or HPV18 infection. The rate difference between one and two doses of the bivalent vaccine was -0.13 infections per 100 participants (95% confidence interval [CI], -0.45 to 0.15; P<0.001 for noninferiority), and the difference between one and two doses of the nonavalent vaccine was 0.21 infections per 100 participants (95% CI, -0.09 to 0.51; P<0.001 for noninferiority). The vaccine effectiveness was at least 97% in each of the four trial groups. No safety concerns were identified. One dose of either a bivalent or nonavalent HPV vaccine provided protection against HPV16 or HPV18 infection and was not inferior to two doses. (Funded by the National Cancer Institute and others; ESCUDDO ClinicalTrials.gov number, NCT03180034.).

A randomised trial designed to compare three and two doses of quadrivalent human papillomavirus (HPV) vaccine in adolescent girls in India was converted to a cohort study after suspension of HPV vaccination in trials by the Indian Government. In this Article, the revised aim of the cohort study was to compare vaccine efficacy of single dose to that of three and two doses in protecting against persistent HPV 16 and 18 infection at 10 years post vaccination. In the randomised trial, unmarried girls aged 10–18 years were recruited from nine centres across India and randomly assigned to either two doses or three doses of the quadrivalent HPV vaccine (Gardasil [Merck Sharp & Dohme, Whitehouse Station, NJ, USA]; 0·5 mL administered intramuscularly). After suspension of recruitment and vaccination, the study became a longitudinal, prospective cohort study by default, and participants were allocated to four cohorts on the basis of the number vaccine doses received per protocol: the two-dose cohort (received vaccine on days 1 and 180 or later), three-dose cohort (days 1, 60, and 180 or later), two-dose default cohort (days 1 and 60 or later), and the single-dose default cohort. Participants were followed up yearly. Cervical specimens were collected from participants 18 months after marriage or 6 months after first childbirth, whichever was earlier, to assess incident and persistent HPV infections. Married participants were screened for cervical cancer as they reached 25 years of age. Unvaccinated women age-matched to the married vaccinated participants were recruited to serve as controls. Vaccine efficacy against persistent HPV 16 and 18 infections (the primary endpoint) was analysed for single-dose recipients and compared with that in two-dose and three-dose recipients after adjusting for imbalance in the distribution of potential confounders between the unvaccinated and vaccinated cohorts. This trial is registered with ISRCTN, ISRCTN98283094, and ClinicalTrials.gov, NCT00923702. Vaccinated participants were recruited between Sept 1, 2009, and April 8, 2010 (date of vaccination suspension), and followed up over a median duration of 9·0 years (IQR 8·2–9·6). 4348 participants had three doses, 4980 had two doses (0 and 6 months), and 4949 had a single dose. Vaccine efficacy against persistent HPV 16 and 18 infection among participants evaluable for the endpoint was 95·4% (95% CI 85·0–99·9) in the single-dose default cohort (2135 women assessed), 93·1% (77·3–99·8) in the two-dose cohort (1452 women assessed), and 93·3% (77·5–99·7) in three-dose recipients (1460 women assessed). A single dose of HPV vaccine provides similar protection against persistent infection from HPV 16 and 18, the genotypes responsible for nearly 70% of cervical cancers, to that provided by two or three doses. Bill & Melinda Gates Foundation.

Cervical cancer is caused by human papillomavirus infection. Most human papillomavirus infection is harmless and clears spontaneously but persistent infection with high-risk human papillomavirus (especially type 16) can cause cancer of the cervix, vulva, vagina, anus, penis, and oropharynx. The virus exclusively infects epithelium and produces new viral particles only in fully mature epithelial cells. Human papillomavirus disrupts normal cell-cycle control, promoting uncontrolled cell division and the accumulation of genetic damage. Two effective prophylactic vaccines composed of human papillomavirus type 16 and 18, and human papillomavirus type 16, 18, 6, and 11 virus-like particles have been introduced in many developed countries as a primary prevention strategy. Human papillomavirus testing is clinically valuable for secondary prevention in triaging low-grade cytology and as a test of cure after treatment. More sensitive than cytology, primary screening by human papillomavirus testing could enable screening intervals to be extended. If these prevention strategies can be implemented in developing countries, many thousands of lives could be saved.

The World Health Organization (WHO) urges global administration of at least one dose of the HPV vaccine, particularly for girls aged 9–14, to work towards the elimination of cervical cancer. However, data on the efficacy of a single dose of Cecolin®, a bivalent HPV vaccine, remain quite limited. Therefore, it is crucial to design studies investigating the protective effects of a single dose of Cecolin® in Chinese girls. The randomized clinical trial began on February 23, 2023 (NCT06345885). 198 Chinese girls aged 9–14 received a single dose of Cecolin® or Gardasil®. Seroconversion rates and geometric mean titers (GMTs) for HPV16 and HPV18 were assessed at one and two months post-vaccination. Non-inferiority was declared if the lower limit of the 95 % confidence interval (CI) exceeded −5 %. Safety of vaccine was evaluated in all vaccinated participants. At one month post-vaccination, both the Cecolin® and Gardasil® groups achieved 100 % seroconversion for HPV16 antibodies. The seroconversion rates for HPV18 were 97.9 % (95 % CI: 92.5 %, 99.7 %) in the Cecolin® group and 95.6 % (95 % CI: 89.1 %, 98.8 %) in the Gardasil® group. The GMTs in the Cecolin® group were significantly higher than those in the Gardasil® group for both HPV types, with GMT ratios of 1.5 (1.1, 2.1) for HPV16 and 2.84 (2.0, 4.1) for HPV18. The seroconversion rates and GMT ratios one month after a single dose of Cecolin® were non-inferior to those of Gardasil®, with results remaining consistent at two months. The incidence of adverse events was similar between the two groups throughout the study, with no statistically significant differences. The immunogenicity and safety of a single dose of Cecolin® in Chinese girls aged 9–14 years were comparable to those of Gardasil. These findings support the use of single-dose Cecolin® to enhance HPV vaccination coverage for cervical cancer prevention.

We evaluated the efficacy of the human papillomavirus HPV-16/18 AS04-adjuvanted vaccine against non-vaccine oncogenic HPV types in the end-of-study analysis after 4 years of follow-up in PATRICIA (PApilloma TRIal against Cancer In young Adults). Healthy women aged 15–25 years with no more than six lifetime sexual partners were included in PATRICIA irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to HPV-16/18 vaccine or a control hepatitis A vaccine, via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The study was double-blind. The primary endpoint of PATRICIA has been reported previously; the present analysis evaluates cross-protective vaccine efficacy against non-vaccine oncogenic HPV types in the end-of-study analysis. Analyses were done for three cohorts: the according-to-protocol cohort for efficacy (ATP-E; vaccine n=8067, control n=8047), total vaccinated HPV-naive cohort (TVC-naive; no evidence of infection with 14 oncogenic HPV types at baseline, approximating young adolescents before sexual debut; vaccine n=5824, control n=5820), and the total vaccinated cohort (TVC; all women who received at least one vaccine dose, approximating catch-up populations that include sexually active women; vaccine n=9319, control=9325). Vaccine efficacy was evaluated against 6-month persistent infection, cervical intraepithelial neoplasia grade 2 or greater (CIN2+) associated with 12 non-vaccine HPV types (individually or as composite endpoints), and CIN3+ associated with the composite of 12 non-vaccine HPV types. This study is registered with ClinicalTrials.gov, number NCT00122681. Consistent vaccine efficacy against persistent infection and CIN2+ (with or without HPV-16/18 co-infection) was seen across cohorts for HPV-33, HPV-31, HPV-45, and HPV-51. In the most conservative analysis of vaccine efficacy against CIN2+, where all cases co-infected with HPV-16/18 were removed, vaccine efficacy was noted for HPV-33 in all cohorts, and for HPV-31 in the ATP-E and TVC-naive. Vaccine efficacy against CIN2+ associated with the composite of 12 non-vaccine HPV types (31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, and 68), with or without HPV-16/18 co-infection, was 46·8% (95% CI 30·7–59·4) in the ATP-E, 56·2% (37·2–69·9) in the TVC-naive, and 34·2% (20·4–45·8) in the TVC. Corresponding values for CIN3+ were 73·8% (48·3–87·9), 91·4% (65·0–99·0), and 47·5% (22·8–64·8). Data from the end-of-study analysis of PATRICIA show cross-protective efficacy of the HPV-16/18 vaccine against four oncogenic non-vaccine HPV types—HPV-33, HPV-31, HPV-45, and HPV-51—in different trial cohorts representing diverse groups of women. GlaxoSmithKline Biologicals.

In 2022, WHO recommended single-dose human papillomavirus (HPV) vaccination as an alternative schedule to multidose regimens. To provide evidence to support approval of a single-dose indication for the AS04-adjuvanted bivalent HPV vaccine (Cervarix, GlaxoSmithKline), we investigated whether the immune response to a single dose of the bivalent vaccine in girls aged 9–14 years was non-inferior to the immune response to three doses of the quadrivalent HPV vaccine (Gardasil-4, Merck) in women aged 18–25 years, a dose and population combination with demonstrated efficacy. This non-randomised, open-label, immunobridging trial enrolled girls aged 9–14 years and women aged 18–25 years in Guanacaste Province, Costa Rica. Healthy girls aged 9–14 years received one dose of bivalent HPV vaccine, whereas healthy women aged 18–25 years received three doses of quadrivalent HPV vaccine at 0, 2, and 6 months. The primary endpoint was geometric mean concentrations (GMCs) of HPV-specific serum antibodies measured by a validated virus-like-particle-based ELISA assay at 36 months. The per-protocol cohort included participants who received the correct number of doses within the predefined vaccination windows, had blood collected at the 36-month study visit for the final analysis, were seronegative at baseline for the specified HPV type, and did not receive additional HPV vaccine doses outside the study. Non-inferiority was declared when the lower bound of the 96% CI for the GMC ratio was greater than or equal to 0·67 for HPV-16 and HPV-18. Seropositivity was a secondary objective. Safety was analysed in the total vaccinated population. This trial is registered with ClinicalTrials.gov, NCT03728881, and is complete. Between April 1 and Aug 16, 2019, 620 girls and 620 women were enrolled and received their first HPV vaccination. After exclusions, 539 girls and 366 women were HPV-16 seronegative at enrolment and were included in the HPV-16 per-protocol cohort; 523 girls and 373 women were HPV-18 seronegative at enrolment and were included in the HPV-18 per-protocol cohort. At 36 months, the HPV-16 GMC was 21·4 international units (IU)/mL (95% CI 19·7–23·3) in girls in the single-dose bivalent vaccine group and 42·9 IU/mL (95% CI 38·9–47·3) in women in the three-dose quadrivalent vaccine group, resulting in a GMC ratio of 0·50 (96% CI 0·44–0·57); the HPV-18 GMC was 8·0 IU/mL (95% CI 7·4–8·8) in girls in the single-dose bivalent vaccine group and 7·2 IU/mL (95% CI 6·4–8·1) in women in the three-dose quadrivalent vaccine group, resulting in a GMC ratio of 1·11 (96% CI 0·95–1·29). At 36 months, 538 (99·8%, 95% CI 99·1–100) of 539 girls in the single-dose bivalent vaccine group were seropositive for HPV-16 compared with 366 (100%, 99·2–100) of 366 women in the three-dose quadrivalent vaccine group (p=1·00). The proportion of participants who were seropositive for HPV-18 was higher in the single-dose bivalent vaccine group (517 [98·9%, 95% CI 97·6–99·5] of 523 girls) than in the three-dose quadrivalent vaccine group (358 [96·0%, 93·6–97·6] of 373 women; p=0·0065). Two serious adverse events were reported in 620 girls and 13 serious adverse events were reported in 620 women; all serious adverse events were deemed to be unrelated to HPV vaccination. Non-inferior antibody responses for the single-dose bivalent HPV vaccine were seen for HPV-18 but not HPV-16, which would be insufficient evidence to motivate regulatory change, even though seropositivity approached 100% in the follow-up phase and the observed antibody concentrations were similar to protective levels seen in previous trials. Trials that directly evaluate protection afforded by single-dose HPV vaccination against persistent HPV infection will definitively address the level of protection afforded by single-dose HPV vaccination. National Cancer Institute, Cancer Research UK, and the Gates Foundation. For the Spanish translation of the abstract see Supplementary Materials section.

Cervical intraepithelial neoplasia grade 2 or greater (CIN2+) is the surrogate endpoint used in licensure trials of human papillomavirus (HPV) vaccines. Vaccine efficacy against CIN3+, the immediate precursor to invasive cervical cancer, is more difficult to measure because of its lower incidence, but provides the most stringent evidence of potential cancer prevention. We report vaccine efficacy against CIN3+ and adenocarcinoma in situ (AIS) in the end-of-study analysis of PATRICIA (PApilloma TRIal against Cancer In young Adults). Healthy women aged 15–25 years with no more than six lifetime sexual partners were included in PATRICIA, irrespective of their baseline HPV DNA status, HPV-16 or HPV-18 serostatus, or cytology. Women were randomly assigned (1:1) to receive an HPV-16/18 AS04-adjuvanted vaccine or a control hepatitis A vaccine via an internet-based central randomisation system using a minimisation algorithm to account for age ranges and study sites. The patients and study investigators were masked to allocated vaccine. The primary endpoint of PATRICIA has been reported previously. In the present end-of-study analysis, we focus on CIN3+ and AIS in the populations of most clinical interest, the total vaccinated cohort (TVC) and the TVC-naive. The TVC comprised all women who received at least one vaccine dose, approximating catch-up populations and including sexually active women (vaccine n=9319; control=9325). The TVC-naive comprised women with no evidence of oncogenic HPV infection at baseline, approximating early adolescent HPV exposure (vaccine n=5824; control=5820). This study is registered with ClinicalTrials.gov, number NCT00122681. Vaccine efficacy against CIN3+ associated with HPV-16/18 was 100% (95% CI 85·5–100) in the TVC-naive and 45·7% (22·9–62·2) in the TVC. Vaccine efficacy against all CIN3+ (irrespective of HPV type in the lesion and including lesions with no HPV DNA detected) was 93·2% (78·9–98·7) in the TVC-naive and 45·6% (28·8–58·7) in the TVC. In the TVC-naive, vaccine efficacy against all CIN3+ was higher than 90% in all age groups. In the TVC, vaccine efficacy against all CIN3+ and CIN3+ associated with HPV-16/18 was highest in the 15–17 year age group and progressively decreased in the 18–20 year and 21–25 year age groups. Vaccine efficacy against all AIS was 100% (31·0–100) and 76·9% (16·0–95·8) in the TVC-naive and TVC, respectively. Serious adverse events occurred in 835 (9·0%) and 829 (8·9%) women in the vaccine and control groups, respectively; only ten events (0·1%) and five events (0·1%), respectively, were considered to be related to vaccination. PATRICIA end-of-study results show excellent vaccine efficacy against CIN3+ and AIS irrespective of HPV DNA in the lesion. Population-based vaccination that incorporates the HPV-16/18 vaccine and high coverage of early adolescents might have the potential to substantially reduce the incidence of cervical cancer. GlaxoSmithKline Biologicals.

An increase in worldwide HPV vaccination could be facilitated if fewer than three doses of vaccine are as effective as three doses. We originally aimed to compare the immunogenicity and frequency of persistent infection and cervical precancerous lesions caused by vaccine-targeted HPV after vaccination with two doses of quadrivalent vaccine on days 1 and 180 or later, with three doses on days 1, 60, and 180 or later, in a cluster-randomised trial. Suspension of the recruitment and vaccination due to events unrelated to our study meant that some enrolled girls could not be vaccinated and some vaccinated girls received fewer than the planned number of vaccinations by default. As a result, we re-analysed our data as an observational cohort study. Our study was designed to be done in nine locations (188 clusters) in India. Participants were unmarried girls aged 10–18 years vaccinated in four cohorts: girls who received three doses of vaccine on days 1, 60, and 180 or later, two doses on days 1 and 180 or later, two doses on days 1 and 60 by default, and one dose by default. The primary outcomes were immunogenicity in terms of L1 genotype-specific binding antibody titres, neutralising antibody titres, and antibody avidity after vaccination for the vaccine-targeted HPV types 16, 18, 6, and 11 and incident and persistent infections with these HPVs. Analysis was per actual number of vaccine doses received. This study is registered with ISRCTN, number ISRCTN98283094; and with ClinicalTrials.gov, number NCT00923702. Vaccination of eligible girls was initiated on Sept 1, 2009, and continued until April 8, 2010. Of 21 258 eligible girls identified at 188 clusters, 17 729 girls were recruited from 178 clusters before suspension. 4348 (25%) girls received three doses, 4979 (28%) received two doses on days 1 and 180 or later, 3452 (19%) received two doses at days 1 and 60, and 4950 (28%) received one dose. Immune response in the two-dose HPV vaccine group was non-inferior to the three-dose group (median fluorescence intensity ratio for HPV 16 1·12 [95% CI 1·02–1·23] and for HPV 18 1·04 [0·92–1·19]) at 7 months, but was inferior in the two-dose default (0·33 [0·29–0·38] for HPV 16 and 0·51 [0·43–0·59] for HPV 18) and one-dose default (0·09 [0·08–0·11] for HPV 16 and 0·12 [0·10–0·14] for HPV 18) groups at 18 months. The geometric mean avidity indices after fewer than three doses by design or default were non-inferior to those after three doses of vaccine. Fewer than three doses by design and default induced detectable concentrations of neutralising antibodies to all four vaccine-targeted HPV types, but at much lower concentration after one dose. Cervical samples from 2649 participants were tested and the frequency of incident HPV 16, 18, 6, and 11 infections was similar irrespective of the number of vaccine doses received. The testing of at least two samples from 838 participants showed that there was no persistent HPV 16 or 18 infections in any study group at a median follow-up of 4·7 years (IQR 4·2–5·1). Despite the limitations imposed by the suspension of the HPV vaccination, our findings lend support to the WHO recommendation of two doses, at least 6 months apart, for routine vaccination of young girls. The short-term protection afforded by one dose of HPV vaccine against persistent infection with HPV 16, 18, 6, and 11 is similar to that afforded by two or three doses of vaccine and merits further assessment. Bill & Melinda Gates Foundation.

Concerns about vaccine safety are an important reason for vaccine hesitancy, however, limited information is available on whether common adverse reactions following vaccination affect the immune response. Data from three clinical trials of recombinant vaccines were used in this post hoc analysis to assess the correlation between inflammation-related solicited adverse reactions (ISARs, including local pain, redness, swelling or induration and systematic fever) and immune responses after vaccination. In the phase III trial of the bivalent HPV-16/18 vaccine (Cecolin®), the geometric mean concentrations (GMCs) for IgG anti-HPV-16 and -18 (P<0.001) were significantly higher in participants with any ISAR following vaccination than in those without an ISAR. Local pain, induration, swelling and systemic fever were significantly correlated with higher GMCs for IgG anti-HPV-16 and/or anti-HPV-18, respectively. Furthermore, the analyses of the immunogenicity bridging study of Cecolin® and the phase III trial of a hepatitis E vaccine yielded similar results. Based on these results, we built a scoring model to quantify the inflammation reactions and found that the high score of ISAR indicates the strong vaccine-induced antibody level. In conclusion, this study suggests inflammation-related adverse reactions following vaccination potentially indicate a stronger immune response.