Abstract The challenges of the journey from target identification through development of a prophylactic quadrivalent human papillomavirus (HPV) vaccine have been met in Gardasil® . Cervical cancer is ...the second leading cause of cancer-related death in women worldwide. Approximately 70% of cervical cancer is caused by infection with HPV types 16 and 18 and ∼90% of genital warts are caused by HPV types 6 and 11. The quadrivalent HPV vaccine was generated by expression of the major capsid protein (L1) of HPV types 16, 18, 6 and 11 in yeast. L1 proteins self assemble into pentamer structures and these pentamer structures come together to form virus-like particles (VLPs). The VLPs are antigenically indistinguishable from HPV virions. The VLPs contain no viral DNA and therefore the vaccine is non-infectious. Gardasil® is composed of VLPs of HPV types 16, 18, 6 and 11 conjugated to a proprietary amorphous aluminum hydroxyphosphate sulfate adjuvant. The results of a rigorous clinical program have demonstrated that the vaccine is safe and highly efficacious in preventing dysplasias, cervical intraepithelial neoplasias (CIN 1–3) the precursors of cervical cancer and external genital lesions caused by vaccine-HPV types. In conclusion, Gardasil® addresses a major medical need, that is, reduction of HPV-related disease including cervical cancer as a safe, immunogenic, and highly efficacious vaccine.
•Human papillomavirus virus-like particle vaccine development journey.•Production of VLPs: recombinant protein expression with conformation constraints.•Hand in hand development of the HPV vaccines ...and HPV clinical assays.•HPV VLP vaccination to prevent cancer benefits women and men worldwide.•Increased HPV vaccine coverage: protection against 9 HPV types.
In 2006, the first human papillomavirus (HPV) virus-like particle (VLP) vaccine was licensed. Gardasil®, the quadrivalent HPV 6, 11, 16 and 18 recombinant VLP vaccine (4vHPV), developed by Merck demonstrated remarkable efficacy in prevention of important clinical pre-cursors to cervical cancer and genital warts. The vaccine was designed to protect against HPV 16 and 18 that cause ∼70% of cervical cancers and HPV 6 and 11 that cause ∼90% of genital warts. Initially, Gardasil® was indicated in the United States for women 9–26 years of age for the prevention of HPV 16 and 18-related cervical, vulvar and vaginal cancer, HPV 6, 11, 16 and 18-related genital intraepithelial neoplasia and the prevention of HPV 6 and 11-related genital warts. Subsequently, a bivalent HPV 16 and 18 VLP vaccine, Cervarix (2vHPV) developed by GlaxoSmithKline was licensed. Since the original licensures, the indications for Gardasil® have been expanded to include males and a vaccine with extended HPV coverage, Gardasil 9 (9vHPV), licensed in 2014.
Genetic variation contributes to host responses and outcomes following infection by influenza A virus or other viral infections. Yet narrow windows of disease symptoms and confounding environmental ...factors have made it difficult to identify polymorphic genes that contribute to differential disease outcomes in human populations. Therefore, to control for these confounding environmental variables in a system that models the levels of genetic diversity found in outbred populations such as humans, we used incipient lines of the highly genetically diverse Collaborative Cross (CC) recombinant inbred (RI) panel (the pre-CC population) to study how genetic variation impacts influenza associated disease across a genetically diverse population. A wide range of variation in influenza disease related phenotypes including virus replication, virus-induced inflammation, and weight loss was observed. Many of the disease associated phenotypes were correlated, with viral replication and virus-induced inflammation being predictors of virus-induced weight loss. Despite these correlations, pre-CC mice with unique and novel disease phenotype combinations were observed. We also identified sets of transcripts (modules) that were correlated with aspects of disease. In order to identify how host genetic polymorphisms contribute to the observed variation in disease, we conducted quantitative trait loci (QTL) mapping. We identified several QTL contributing to specific aspects of the host response including virus-induced weight loss, titer, pulmonary edema, neutrophil recruitment to the airways, and transcriptional expression. Existing whole-genome sequence data was applied to identify high priority candidate genes within QTL regions. A key host response QTL was located at the site of the known anti-influenza Mx1 gene. We sequenced the coding regions of Mx1 in the eight CC founder strains, and identified a novel Mx1 allele that showed reduced ability to inhibit viral replication, while maintaining protection from weight loss.
Pancreatic ductal adenocarcinoma (PDAC) is one of the leading causes of cancer‐related mortality. Despite significant advances made in the treatment of other cancers, current chemotherapies offer ...little survival benefit in this disease. Pancreaticoduodenectomy offers patients the possibility of a cure, but most will die of recurrent or metastatic disease. Hence, preventing metastatic disease in these patients would be of significant benefit. Using principal component analysis (PCA), we identified a LOX/hypoxia signature associated with poor patient survival in resectable patients. We found that LOX expression is upregulated in metastatic tumors from Pdx1‐Cre KrasG12D/+ Trp53R172H/+ (KPC) mice and that inhibition of LOX in these mice suppressed metastasis. Mechanistically, LOX inhibition suppressed both migration and invasion of KPC cells. LOX inhibition also synergized with gemcitabine to kill tumors and significantly prolonged tumor‐free survival in KPC mice with early‐stage tumors. This was associated with stromal alterations, including increased vasculature and decreased fibrillar collagen, and increased infiltration of macrophages and neutrophils into tumors. Therefore, LOX inhibition is able to reverse many of the features that make PDAC inherently refractory to conventional therapies and targeting LOX could improve outcome in surgically resectable disease.
Synopsis
Lysyl oxidase (LOX) is identified as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC). Inhibition of LOX resulted in increased drug efficacy and stromal changes and reduction in metastasis.
A signature of hazardous and protective genes in PDAC was defined. High expression of hypoxia‐associated genes, including LOX, was associated with poor patient prognosis.
Using transgenic mouse models of PDAC, LOX was found to be overexpressed in metastatic disease and its expression was required for PDAC cell invasion.
Inhibition of LOX in transgenic mice inhibited metastasis, while combination therapy with LOX inhibition and gemcitabine induced stromal alterations, immune cell infiltration and tumor necrosis and improved survival.
Lysyl oxidase (LOX) is identified as a therapeutic target in pancreatic ductal adenocarcinoma (PDAC). Inhibition of LOX resulted in increased drug efficacy and stromal changes and reduction in metastasis.
Prophylactic vaccination of 16- to 23-year-old females with a quadrivalent human papillomavirus (types 6, 11, 16, 18) L1 virus-like particle vaccine has been shown to prevent type-specific human ...papillomavirus infection and associated clinical disease. We conducted a noninferiority immunogenicity study to bridge the efficacy findings in young women to preadolescent and adolescent girls and boys, who represent a primary target for human papillomavirus vaccination.
We enrolled 506 girls and 510 boys (10-15 years of age) and 513 females (16-23 years of age). Participants were vaccinated on day 1, at month 2, and at month 6, and serology testing was performed on day 1 and at months 3 and 7 on blinded samples. Neutralizing antibody concentrations were determined using type-specific immunoassays and summarized as geometric mean titers and seroconversion rates. Vaccine tolerability also was assessed.
By month 7, seroconversion rates were > or = 99% for all 4 human papillomavirus types in each group. By month 7, compared with women, anti-human papilloma virus geometric mean titers in girls or boys were noninferior and were 1.7- to 2.7-fold higher. Most (> 97%) injection-site adverse events were mild to moderate in intensity. Significantly more boys (13.8%) and girls (12.8%) than women (7.3%) reported fevers > or = 37.8 degrees C within 5 days of vaccination. Most (96.4%) fevers were mild (< 39 degrees C).
Noninferior immunogenic responses to all 4 human papillomavirus types in the quadrivalent vaccine permit the bridging of efficacy data that were generated in young women to girls. The results in boys lend support for the implementation of gender-neutral human papillomavirus vaccination programs. This vaccine generally was well tolerated.
Background The impact of the prophylactic vaccine against human papillomavirus (HPV) types 6, 11, 16, and 18 (HPV6/11/16/18) on all HPV-associated genital disease was investigated in a population ...that approximates sexually naive women in that they were “negative to 14 HPV types” and in a mixed population of HPV-exposed and -unexposed women (intention-to-treat group). Methods This analysis studied 17 622 women aged 15–26 years who were enrolled in one of two randomized, placebo-controlled, efficacy trials for the HPV6/11/16/18 vaccine (first patient on December 28, 2001, and studies completed July 31, 2007). Vaccine or placebo was given at day 1, month 2, and month 6. All women underwent cervicovaginal sampling and Papanicolaou (Pap) testing at day 1 and every 6–12 months thereafter. Outcomes were any cervical intraepithelial neoplasia; any external anogenital and vaginal lesions; Pap test abnormalities; and procedures such as colposcopy and definitive therapy. Absolute rates are expressed as women with endpoint per 100 person-years at risk. Results The average follow-up was 3.6 years (maximum of 4.9 years). In the population that was negative to 14 HPV types, vaccination was up to 100% effective in reducing the risk of HPV16/18-related high-grade cervical, vulvar, and vaginal lesions and of HPV6/11-related genital warts. In the intention-to-treat group, vaccination also statistically significantly reduced the risk of any high-grade cervical lesions (19.0% reduction; rate vaccine = 1.43, rate placebo = 1.76, difference = 0.33, 95% confidence interval CI = 0.13 to 0.54), vulvar and vaginal lesions (50.7% reduction; rate vaccine = 0.10, rate placebo = 0.20, difference = 0.10, 95% CI = 0.04 to 0.16), genital warts (62.0% reduction; rate vaccine = 0.44, rate placebo = 1.17, difference = 0.72, 95% CI = 0.58 to 0.87), Pap abnormalities (11.3% reduction; rate vaccine = 10.36, rate placebo = 11.68, difference = 1.32, 95% CI = 0.74 to 1.90), and cervical definitive therapy (23.0% reduction; rate vaccine = 1.97, rate placebo = 2.56, difference = 0.59, 95% CI = 0.35 to 0.83), irrespective of causal HPV type. Conclusions High-coverage HPV vaccination programs among adolescents and young women may result in a rapid reduction of genital warts, cervical cytological abnormalities, and diagnostic and therapeutic procedures. In the longer term, substantial reductions in the rates of cervical, vulvar, and vaginal cancers may follow.
Attempts to develop a vaccine to prevent genital herpes simplex virus 2 (HSV-2) disease have been only marginally successful, suggesting that novel strategies are needed. Immunization with HSV-2 ...glycoprotein C (gC-2) and gD-2 was evaluated in mice and guinea pigs to determine whether adding gC-2 to a gD-2 subunit vaccine would improve protection by producing antibodies that block gC-2 immune evasion from complement. Antibodies produced by gC-2 immunization blocked the interaction between gC-2 and complement C3b, and passive transfer of gC-2 antibody protected complement-intact mice but not C3 knockout mice against HSV-2 challenge, indicating that gC-2 antibody is effective, at least in part, because it prevents HSV-2 evasion from complement. Immunization with gC-2 also produced neutralizing antibodies that were active in the absence of complement; however, the neutralizing titers were higher when complement was present, with the highest titers in animals immunized with both antigens. Animals immunized with the gC-2-plus-gD-2 combination had robust CD4+ T-cell responses to each immunogen. Multiple disease parameters were evaluated in mice and guinea pigs immunized with gC-2 alone, gD-2 alone, or both antigens. In general, gD-2 outperformed gC-2; however, the gC-2-plus-gD-2 combination outperformed gD-2 alone, particularly in protecting dorsal root ganglia in mice and reducing recurrent vaginal shedding of HSV-2 DNA in guinea pigs. Therefore, the gC-2 subunit antigen enhances a gD-2 subunit vaccine by stimulating a CD4+ T-cell response, by producing neutralizing antibodies that are effective in the absence and presence of complement, and by blocking immune evasion domains that inhibit complement activation.
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