Background 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. MethodsIn 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. Findings 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).Interpretation 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.Funding Bill & Melinda Gates Foundation.

No abstract

Gastrointestinal (GI) malignancies are some of the most common cancers worldwide with high rates of morbidity and mortality. Immune checkpoint inhibitors have afforded additional treatment options for patients, but their success has been limited. Conversely, in other tumor types such as lung cancer, melanoma and renal cell carcinoma, treatment strategies with immune checkpoint inhibitors have propelled those agents into the front lines of treatment. Strategies utilized include combining immune checkpoint inhibitors with chemotherapy, other checkpoint inhibitors, and targeted therapy. In this review, we analyze combination strategies employed in other tumor types to help identify current and future approaches toward improving outcomes with immunotherapy in GI malignancies.

Gastric and esopahgeal cancers account for the six most common causes of cancer death worldwide. Locally advanced resectable cancers have a 5-year life expectancy of 30%. Despite use of chemotherapy, median overall survival for stage IV cancer rarely exceeds 1 year. A subset of gastric cancers such as microsatellite-instable tumor and Epstein–Barr virus-positive tumors have a rich immune infiltrate that makes them more responsive to immune-directed therapies. Tumors can evade T-cell-mediated “immune surveillance” by activating the programmed cell death receptor 1 (PD-1)/programmed death ligand 1 (PD-L1) pathway. Targeting PD-1 and thus de-engaging them from its ligands can help restore immunogenicity. Pembrolizumab is the first immunotherapy to be approved by US FDA for PD-L1 expressing gastric and gastroesopahgeal junction (GEJ) cancers after they have progressed on at least two prior lines of treatment. While PD-L1 positivity does not define tumor’s responsiveness to pembrolizumab, PD-L1-positive tumors have better overall response rates. The treatment is usually well tolerated and has a favorable adverse events profile. The exact setting for use of pembrolizumab remains to be determined. Pembrolizumab failed to improve overall survival when administered as second-line treatment for advanced, metastatic gastric and GEJ cancers. There are several ongoing studies with various combinations and different settings not only with pembrolizumab but also with other checkpoint inhibitors.

In context of the ongoing multi-centric HPV vaccine study in India, unvaccinated married women (N = 1484) aged 18–23 years were recruited in 2012–2015 as age-matched controls to the vaccinated women and followed up yearly. We assess type-specific prevalence, natural history and potential determinants of human papillomavirus (HPV) infection in these unvaccinated women. Cervical samples were collected yearly for at least four consecutive years. A Multiplex Type-Specific E7-Based polymerase chain reaction assay was used to detect 21 HPV types. HPV prevalence was 36.4% during 6 years. Most common HPV types were 16 (6.5%) and 31 (6.1%). Highest persistence were observed for HPV 35 (62.5%) and 52 (25%). New HPV acquisition rate was 5.6/1000 person-months of observation (PMO), highest for HPV 16 (1.1/1000 PMO). Type-specific clearance rates ranged between 2.9–5.5/100 PMO. HPV 16 and/or 18 infections were 41% (95% CI 4–63%) lower among women with 2-<3 years between marriage and first cervical sample collection compared to those with <2 years. HPV prevalence and acquisition rates in young Indian women were lower than their Western counterparts. HPV 16 infections being most common shows the importance and potential impact of HPV vaccination in India. Women with 2–3 years exposure had reduced risk possibly due to higher infections clearance.