The HPV Serology Laboratory is leading a global partnership initiative aiming for standardization and harmonization of current serology assay platforms being used to assess immune responses to HPV ...vaccines. Serology standardization is particularly important given the increasing number of immunobridging trials relying on serology data for approval of new vaccine dosing schedules or vaccine formulations. The initiative was established in 2017 to enable comparisons of data between different vaccines and relevant studies as well as expedite the implementation of new vaccines and vaccine indications. The HPV Serology Laboratory has held or attended several meetings with partnering laboratories, including international meetings in 2017, 2018, and 2021.
In this study, a proficiency panel was created for evaluation of assay performance and inter- and intra-laboratory assay comparisons, especially the ability to accurately measure negative, low, ...intermediate, and high levels of HPV type-specific antibodies. Comprised of 80 deidentified samples, this panel is designed for individual labs to evaluate assay performance characteristics on a biennial basis, to promote standardization of methodology and harmonization of data from human papillomavirus (HPV) serology tests in vaccine trials. The proficiency panel was qualified using 2 types of assays (singleplex Enzyme-Linked Immunosorbent Assays ELISAs or Multiplex antibody-binding assays and Pseudovirion-based neutralization assays PBNAs) in 10 laboratories from 7 countries, monitoring HPV antibody responses for up to 9 HPV types and using 3 different analysis methods. Sensitivity, specificity, and correlations (concordance, accuracy, and precision) were evaluated for each HPV type. In laboratories that tested all 80 samples, results from most (74/80) samples were reported with 100% accuracy across all 9 HPV types. The average sensitivity and specificity for singleplex and multiplex antibody binding assays ranged from 86.7% to 98.3% (sensitivity) and 84.2% to 94.3% (specificity), while the average sensitivity and specificity for the Pseudovirion (PsV)-based neutralization assays (PBNA) ranged from 87.6% to 99.4% (sensitivity) and 52.4% to 94.4% (specificity). This proficiency panel will help with assessing performance characteristics of HPV serology assays used in clinical trial studies and assure the data generated from these assays is harmonized.
A comprehensive characterization of the effects of cigarette smoke on systemic soluble immune/inflammatory markers may provide insight into the mechanisms through which smoking causes disease.
Levels ...of 78 inflammation, immune, and metabolic markers were measured using multiplex immune assays in 1819 Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO) participants aged 55 to 74 years from three existing nested case-control studies. These data were made representative of the entire PLCO screening arm through reweighting with weights estimated in logistic regression models. We assessed associations between smoking status, cigarettes smoked per day, and time since quitting with dichotomized marker levels using adjusted weighted logistic regression models.
Current smoking was associated with 10 inflammation markers after correcting for multiple testing, encompassing several components of the immune/inflammation response. Levels of seven of these markers (interleukin IL-15, IL-1RA, IL-1β, IL-16, stem cell factor, soluble interleukin 6 receptor, and soluble vascular endothelial growth factor receptor 3) were lower among current smokers (n = 414) when compared with never smokers (n = 548), with odds ratios (ORs) ranging from 0.44 to 0.27, while levels of CC motif ligand (CCL)/thymus and activation regulated chemokine (CCL17/TARC) (OR = 4.08, 95% confidence interval CI = 2.01 to 8.25), CCL11/EOTAXIN (OR = 2.57, 95% CI = 1.45 to 4.55), and C-reactive protein (CRP) (OR = 2.54, 95% CI = 1.29 to 4.98) were elevated. These markers were not associated with cigarettes per day among current smokers, but there were trends in IL-15, IL-1RA, IL-1β, CCL17/TARC, CCL11/EOTAXIN, and CRP levels across categories of years since quitting smoking.
Smoking is associated with a broad range of alterations in systemic immune and inflammation marker levels among older, long-term smokers. Smoking cessation may result in marker levels reverting back to those of never smokers over time.
Abstract
Natural variants of human papillomavirus (HPV) are classified into lineages and sublineages based upon whole-genome sequence, but the impact of diversity on protein function is unclear. We ...investigated the susceptibility of 3–8 representative pseudovirus variants of HPV16, HPV18, HPV31, HPV33, HPV45, HPV52, and HPV58 to neutralization by nonavalent vaccine (Gardasil®9) sera. Many variants demonstrated significant differences in neutralization sensitivity from their consensus A/A1 variant but these were of a low magnitude. HPV52 D and HPV58 C variants exhibited >4-fold reduced sensitivities compared to their consensus A/A1 variant and should be considered distinct serotypes with respect to nonavalent vaccine-induced immunity.
Despite growing recognition of an etiologic role for inflammation in lung carcinogenesis, few prospective epidemiologic studies have comprehensively investigated the association of circulating ...inflammation markers with lung cancer.
We conducted a nested case-control study (n = 526 lung cancer patients and n = 592 control subjects) within the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Control subjects were matched to lung cancer case patients on age, sex, follow-up time (median = 2.9 years), randomization year, and smoking (pack-years and time since quitting). Serum levels of 77 inflammation markers were measured using a Luminex bead-based assay. Conditional logistic regression and weighted Cox models were used to estimate odds ratios (ORs) and cumulative risks, respectively.
Of 68 evaluable markers, 11 were statistically significantly associated with lung cancer risk (P trend across marker categories < .05), including acute-phase proteins (C-reactive protein CRP, serum amyloid A SAA), proinflammatory cytokines (soluble tumor necrosis factor receptor 2 sTNFRII), anti-inflammatory cytokines (interleukin 1 receptor antagonist IL-1RA), lymphoid differentiation cytokines (interleukin 7 IL-7), growth factors (transforming growth factor alpha TGF-A), and chemokines (epithelial neutrophil-activating peptide 78 ENA 78/CXCL5, monokine induced by gamma interferon MIG/CXCL9, B cell-attracting chemokine 1 BCA-1/CXCL13, thymus activation regulated chemokine TARC/CCL17, macrophage-derived chemokine MDC/CCL22). Elevated marker levels were associated with increased lung cancer risk, with odds ratios comparing the highest vs the lowest group ranging from 1.47 (IL-7) to 2.27 (CRP). For IL-1RA, elevated levels were associated with decreased lung cancer risk (OR = 0.71; 95% confidence interval = 0.51 to 1.00). Associations did not differ by smoking, lung cancer histology, or latency. A cross-validated inflammation score using four independent markers (CRP, BCA-1/CXCL13, MDC/CCL22, and IL-1RA) provided good separation in 10-year lung cancer cumulative risks among former smokers (quartile Q 1 = 1.1% vs Q4 = 3.1%) and current smokers (Q1 = 2.3% vs Q4 = 7.9%) even after adjustment for smoking.
Some circulating inflammation marker levels are associated with prospective lung cancer risk.
A single dose of human papillomavirus (HPV) vaccine would simplify logistics and reduce costs of vaccination programs worldwide. We conducted a phase IIa trial to determine the stability of HPV ...type-specific antibody responses after a single dose of the nonavalent HPV vaccine, Gardasil9.
Two hundred-and-one healthy 9 to 11-year-old girls and boys were enrolled at 2 centers in the United States to receive a prime dose of the nonavalent vaccine at baseline, a delayed dose at month 24, and an optional third dose at month 30. Blood samples were collected to measure HPV type-specific antibodies at baseline and at 6, 12, 18, 24, and 30 months after the prime dose. The primary outcomes were serum HPV16 and HPV18 antibody responses.
In both girls and boys, geometric mean concentrations of HPV16 and HPV18 antibodies increased at 6 months, declined between months 6 to 12, and then remained stable and high (at 20- and 10-times those at baseline for HPV16 and HPV18, respectively) throughout months 12, 18, and 24 (prebooster) visits. Both HPV16 and HPV18 antibody responses demonstrated anamnestic boosting effect at 30-months after the delayed (24-month) booster dose.
A single dose of the nonavalent HPV vaccine induced persistent and stable HPV16 and HPV18 antibody responses up to 24 months. This study contributes important immunogenicity data to inform feasibility of the single dose HPV vaccination paradigm. Further research is needed to assess the long-term antibody stability and individual clinical and public health benefit of the single dose schedule.
•The licensed HPV prophylactic vaccines have demonstrated extraordinary immunogenicity and efficacy.•Standardized measurement and reporting of immunogenicity are now extremely critical as HPV ...serology measurements are being proposed as endpoints in vaccine trials evaluating single-dose immunogenicity and efficacy and immunobridging studies.•Continued collective efforts to standardize and harmonize assays and reagents, implement a uniform reporting system, and coordinate research efforts will inform public health decisions and help accelerate reductions the HPV burden globally.
The HPV Serology Laboratory in the Frederick National Laboratory for Cancer Research is working in partnership with the scientific community with the goal of standardizing and harmonizing current HPV serology assay platforms in response to the increasing number of immunobridging trials relying on serology data for approval of new vaccine dosing schedules and new formulations. A virtual meeting was held on June 29–30, 2021, to review the progress of the standardization initiative thus far and to bridge scientific gaps and outstanding questions. The main aims and outcomes of the meeting were to discuss: 1) standardization of assays and reagents; 2) International Standard calibration procedures; 3) assay cut-off values; 4) current immunobridging clinical trials; and 5) gaps and challenges in standardization of HPV serology.
Oncogenic human papillomavirus (HPV) infections cause most cases of cervical cancer. Here, we report long-term follow-up results for the Costa Rica Vaccine Trial (publicly funded and initiated before ...licensure of the HPV vaccines), with the aim of assessing the efficacy of the bivalent HPV vaccine for preventing HPV 16/18-associated cervical intraepithelial neoplasia grade 2 or worse (CIN2+).
Women aged 18–25 years were enrolled in a randomised, double-blind, controlled trial in Costa Rica, between June 28, 2004, and Dec 21, 2005, designed to assess the efficacy of a bivalent vaccine for the prevention of infection with HPV 16/18 and associated precancerous lesions at the cervix. Participants were randomly assigned (1:1) to receive an HPV 16/18 AS04-adjuvanted vaccine or control hepatitis A vaccine. Vaccines were administered intramuscularly in three 0·5 mL doses at 0, 1, and 6 months and participants were followed up annually for 4 years. After the blinded phase, women in the HPV vaccine group were invited to enrol in the long-term follow-up study, which extended follow-up for 7 additional years. The control group received HPV vaccine and was replaced with a new unvaccinated control group. Women were followed up every 2 years until year 11. Investigators and patients were aware of treatment allocation for the follow-up phase. At each visit, clinicians collected cervical cells from sexually active women for cytology and HPV testing. Women with abnormal cytology were referred to colposcopy, biopsy, and treatment as needed. Women with negative results at the last screening visit (year 11) exited the long-term follow-up study. The analytical cohort for vaccine efficacy included women who were HPV 16/18 DNA-negative at vaccination. The primary outcome of this analysis was defined as histopathologically confirmed CIN2+ or cervical intraepithelial neoplasia grade 3 or worse associated with HPV 16/18 cervical infection detected at colposcopy referral. We calculated vaccine efficacy by year and cumulatively. This long-term follow-up study is registered with ClinicalTrials.gov, NCT00867464.
7466 women were enrolled in the Costa Rica Vaccine Trial; 3727 received the HPV vaccine and 3739 received the control vaccine. Between March 30, 2009, and July 5, 2012, 2635 women in the HPV vaccine group and 2836 women in the new unvaccinated control group were enrolled in the long-term follow-up study. 2635 women in the HPV vaccine group and 2677 women in the control group were included in the analysis cohort for years 0–4, and 2073 women from the HPV vaccine group and 2530 women from the new unvaccinated control group were included in the analysis cohort for years 7–11. Median follow-up time for the HPV group was 11·1 years (IQR 9·1–11·7), 4·6 years (4·3–5·3) for the original control group, and 6·2 years (5·5–6·9) for the new unvaccinated control group. At year 11, vaccine efficacy against incident HPV 16/18-associated CIN2+ was 100% (95% CI 89·2–100·0); 34 (1·5%) of 2233 unvaccinated women had a CIN2+ outcome compared with none of 1913 women in the HPV group. Cumulative vaccine efficacy against HPV 16/18-associated CIN2+ over the 11-year period was 97·4% (95% CI 88·0–99·6). Similar protection was observed against HPV 16/18-associated CIN3—specifically at year 11, vaccine efficacy was 100% (95% CI 78·8–100·0) and cumulative vaccine efficacy was 94·9% (73·7–99·4). During the long-term follow-up, no serious adverse events occurred that were deemed related to the HPV vaccine. The most common grade 3 or worse serious adverse events were pregnancy, puerperium, and perinatal conditions (in 255 10% of 2530 women in the unvaccinated control group and 201 10% of 2073 women in the HPV vaccine group). Four women in the unvaccinated control group and three in the HPV vaccine group died; no deaths were deemed to be related to the HPV vaccine.
The bivalent HPV vaccine has high efficacy against HPV 16/18-associated precancer for more than a decade after initial vaccination, supporting the notion that invasive cervical cancer is preventable.
US National Cancer Institute.
Through the interaction of T follicular helper (Tfh) cells and B cells, efficacious vaccines can generate high-affinity, pathogen-neutralizing antibodies, and memory B cells. Using CXCR5, CXCR3, ...CCR6, CCR7, PD1, and ICOS as markers, Tfh-like cells can be identified in the circulation and be classified into three functionally distinct subsets that are PD1+ICOS+, PD1+ ICOS-, or PD1-ICOS-. We used these markers to identify different subsets of CXCR5+CD4+ Tfh-like cells in response to highly immunogenic and efficacious vaccines for human papillomaviruses (HPV): Cervarix and Gardasil. In this small study, we used PBMC samples from 11 Gardasil recipients, and 8 Cervarix recipients from the Vaccine Research Center 902 Study to examine the induction of circulating Tfh-like cells and IgD-CD38HiCD27+ memory B cells by flow cytometry. PD1+ICOS+ CXCR3+CCR6-CXCR5+CD4+ (Tfh1-like) cells were induced and peaked on Day (D) 7 post-first vaccination, but not as much on D7 post-third vaccination. We also observed a trend toward increase in PD1+ICOS+ CXCR3-CCR6-CXCR5+CD4+ (Tfh2-like) cells for both vaccines, and PD1+ICOS+ CXCR3-CCR6+CXCR5+CD4+ (Tfh17-like) subset was induced by Cervarix post-first vaccination. There were also minimal changes in the other cellular subsets. In addition, Cervarix recipients had more memory B cells post-first vaccination than did Gardasil recipients at D14 and D30. We found frequencies of memory B cells at D30 correlated with anti-HPV16 and 18 antibody titers from D30, and the induction levels of memory B cells at D30 and PD1+ICOS+Tfh1-like cells at D7 post-first vaccination correlated for Cervarix. Our study showed that induction of circulating CXCR5+CD4+ Tfh-like subsets can be detected following immunization with HPV vaccines, and potentially be useful as a marker of immunogenicity of vaccines. However, further investigations should be extended to different cohorts with larger sample size to better understand the functions of these T cells, as well as their relationship with B cells and antibodies.
Abstract
Background
The Costa Rica HPV Vaccine Trial has documented cross-protection of the bivalent HPV vaccine against HPV31/33/45 up to 7 years after vaccination, even with one dose of the ...vaccine. However, the durability of such protection remains unknown. Here, we evaluate the efficacy of different schedules of the vaccine against HPV31/33/45 out to 11 years postvaccination, expanding to other nontargeted HPV types.
Methods
We compared the rates of HPV infection in vaccinated women with the rates in a comparable cohort of unvaccinated women. We estimated the average vaccine efficacy (VEavg) against incident infections and tested for a change in VE over time.
Results
Among 3-dose women, we observed statistically significant cross-protection against HPV31/33/45 (VEavg = 64.4%, 95% confidence interval CI = 57.7% to 70.0%). Additionally, we observed borderline, statistically significant cross-protection against HPV35 (VEavg = 23.2%, 95% CI = 0.3% to 40.8%) and HPV58 (VEavg = 21.2%, 95% CI = 4.2% to 35.3%). There was no decrease in VE over time (two-sided Ptrend > .05 for HPV31, -33, -35, -45, and -58). As a benchmark, VEavg against HPV16/18 was 82.0% (95% CI = 77.3% to 85.7%). Among 1-dose women, we observed comparable efficacy against HPV31/33/45 (VEavg = 54.4%, 95% CI = 21.0% to 73.7%). Acquisition of nonprotected HPV types was similar between vaccinated and unvaccinated women, indicating that the difference in HPV infection rates was not attributable to differential genital HPV exposure.
Conclusions
Substantial cross-protection afforded by the bivalent vaccine against HPV31/33/45, and to a lesser extent, HPV35 and HPV58, was sustained and remained stable after 11 years postvaccination, reinforcing the notion that the bivalent vaccine is an effective option for protection against HPV-associated cancers.
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