Human papillomavirus (HPV) types 16 and 18 cause 70% of cervical cancer cases globally. The nonavalent HPV vaccine (9vHPV) was licensed in 2014 and protects against the next five most common cancer-causing HPV types (HPV 31/33/45/52/58) after HPV 16/18. Phase III clinical studies have demonstrated high vaccine efficacy (>90%) against cervical, vulvar, and vaginal precancers caused by these additional types, and have shown comparable immunogenicity to the shared genotypes to quadrivalent HPV vaccine (4vHPV). Vaccine efficacy and antibody responses for 9vHPV are found to persist for at least five years while longer-term observational studies are ongoing to monitor long-term vaccine effectiveness. The implementation of 9vHPV has the potential to prevent up to 93% of cervical cancer cases, as well as a significant proportion of other HPV-related anogenital cancers. This review article summarizes the current evidence for 9vHPV in terms of vaccine efficacy against HPV infection and related anogenital precancers, safety, and immunogenicity, as well as discussing the potential impact of this vaccine on the cervical cancer burden globally.

The duration of cross-neutralising antibody responses (cross-NAb) following HPV immunisation is unknown. We compared cross-NAb responses in cohort of girls who were either unimmunised or had received immunisation with one, two or three doses of 4vHPV (Gardasil®, Merck Inc., Kenilworth, NJ, USA) six years earlier, before and one month after a booster dose of 2vHPV (Cervarix®, GSK, Brentford, UK). NAb to potentially cross-reactive HPV genotypes 31, 33, 45, 52 and 58 were measured using a HPV pseudovirion-based neutralisation assay. Girls who had previously received at least one dose of 4vHPV had significantly higher NAb titres for HPV31 when compared with unimmunised girls, whereas no difference in NAb titre was observed for four other genotypes (33, 45, 52 and 58). Following a single further immunisation with 2vHPV, NAb titres to each of the five tested HPV genotypes were comparable for girls who previously received one, two or three doses of 4vHPV, and were significantly higher than for previously unimmunised girls. Immunisation with one, two or three doses of 4vHPV induced NAb to HPV31 that persisted for six years, but there was no persistence of NAb to HPV33, 45, 52 or 58. Our results suggest that one or two doses of 4vHPV may provide long-term protection against HPV31.

BackgroundThe identification of biomarkers predicting a better outcome to adoptive T cell therapy is an emerging, still nascent field. We previously completed a phase 2 clinical trial of autologous adoptive EBV-specific cytotoxic T lymphocyte (CTL) immunotherapy following gemcitabine + carboplatin chemotherapy as first line treatment in 35 advanced incurable stage 4c nasopharyngeal carcinoma (NPC) patients. Here, we aim 1) to evaluate exosome proteins for potential specific predictive biomarkers of benefit to adoptive T cell therapy and 2) to investigate if a specific immunophenotype of our generated EBV targeting CTLs correlates with survival benefit.MethodsWe isolated exosome from plasma samples by size exclusion chromatography and magnetic-based isolation technology, followed by fluorescence-activated cell sorting (FACS) analysis, Western blot analysis for immune-related checkpoint molecules, or mass spectrometry for exosomal peptide detection. All the generated CTLs were analysed by gene expression microarray as well as a FACS system with the use of T cell-specific 23-antibody panel for comprehensive immunophenotyping. The representative CTL samples were also subject to single-cell (sc) RNA-Seq with DNA barcoded antibodies for comprehensive integrated transcriptomics and immunophenotyping analysis.ResultsPatients with overall survival longer than 2 years were grouped as long survivors and the remaining patients were grouped as short survivors. Differentially expressed immune-related checkpoint molecules, such as PD1, ICOS, and CD137, were detected in in pre-treatment exosome of long and short survivors. Furthermore, more than 13,000 high confident and unique peptides which belong to 1,500 unique proteins were identified and quantified by mass spectrometry from the purified plasma exosome. Pathway enrichment analysis further showed that plasma exosome of the short survivors had significantly higher innate immune response-activating signal transduction-related peptides detected (p-value = 4.81 x 10-5). The transcriptomic analysis revealed that statistically lower expressions of SELL (CD62L) and LEF1 were found in the EBV CTL of the short survivors, suggesting that the EBV CTL of short survivors were characterized by a lesser central memory T cell phenotype.ConclusionsOur data reports that specific pre-treatment plasma exosome proteins, and separately, transcriptomic profile of the generated baseline EBV CTLs prior to infusion into the patients correlate with patient survival, suggesting that they could be used together as biomarkers to predict outcome in the advanced NPC patients treated with this chemo-immunotherapy combination. More in-depth analysis of the immunophenotyping of all the CTLs and the representative CTLs’ scRNA-Seq data will be presented at the meeting.AcknowledgementsThis work was supported by Singapore government funding (National Medical Research Council (NMRC) – Open Fund - Large Collaborative Grant (OF-LCG) and National Cancer Centre Singapore Block Grant as well as in part by Tessa Therapeutics Ltd.