Johannes A. Bogaards

Long-term impact of human papillomavirus vaccination on infection rates, cervical abnormalities, and cancer incidence.

Background: Vaccination against human papillomavirus (HPV) types 16/18 is being implemented in many countries. There may be indirect benefit of HPV vaccination to nonvaccinated women, who may experience a reduced risk of infection with vaccine-preventable types (herd immunity). We attempt to disentangle the direct and indirect effects of HPV vaccination, while accounting for 14 oncogenic HPV types in a dynamic modeling framework. Methods: On the basis of vaccine uptake among preadolescent girls in the Netherlands, we calculated how heterosexual transmission of HPV-16/18 is expected to change as a result of vaccination, and used these predictions in an individual-based simulation model of cervical carcinogenesis that considers 14 high-risk HPV types. Models were parameterized to match prevaccine data on type-specific HPV infection and cervical disease. Results: At 50% vaccine coverage, the estimated lifetime infection risk in nonvaccinated women dropped from 0.69 (95% credible interval = 0.50–0.85) to 0.49 (0.32–0.68) for HPV-16, and from 0.68 (0.46–0.79) to 0.43 (0.26–0.57) for HPV-18. For the whole population, we calculated an eventual 47% reduction in cervical cancer incidence, with 1 in 4 cases prevented among nonvaccinated women. The number of indirectly averted cancer cases was highest with vaccine coverage between 50% and 70%, approximating 70 cases per 100,000 women born from 2010 onward. Conclusions: HPV-16/18 vaccination of preadolescent girls will markedly lower infection rates among nonvaccinated women. Reduced transmission of vaccine-preventable HPV becomes a prominent aspect of cervical cancer control, especially in populations with moderate vaccine coverage.

Model-Based Estimation of Viral Transmissibility and Infection-Induced Resistance From the Age-Dependent Prevalence of Infection for 14 High-Risk Types of Human Papillomavirus

Viral transmissibility and natural resistance to infection are key determinants in assessing the population impact of human papillomavirus (HPV) vaccination, yet information on these parameters is scarce. Using data from 2 large-scale surveys on sexual behavior in the Netherlands (carried out in 2005-2006), the authors employed a Bayesian framework to fit a transmission model to the cross-sectional age-dependent prevalence of HPV DNA in cervical smears (data collected in 1992-2002), assuming that the prevaccine situation reflected an endemic equilibrium, and calculated type-specific estimates of transmissibility and infection-induced resistance. The posterior median transmission probability per heterosexual partnership covered a range of 0.43-0.94 among the 14 high-risk types of HPV. The transmission probability of HPV-16 was estimated at 0.80 (95% posterior interval: 0.60, 0.99) and that of HPV-18 at 0.93 (95% posterior interval: 0.72, 1). The model predicted that the decrease in HPV prevalence with age could not solely be explained by sexual activity and screening but also by resistance to reinfection, which is lost at a rate of 0.014-0.047 (1%-5%) per year. These results support the notion that HPV infection is highly transmissible, and they suggest a gradual loss of type-specific immunity over time. Because high transmission potential is associated with a low impact of herd immunity, extensive vaccination coverage will be required to substantially reduce cervical cancer incidence.

The health and economic effects of HPV DNA screening in the Netherlands.

We studied the health and economic effects of human papillomavirus (HPV) DNA testing in cervical screening using a simulation model. The key data source was a Dutch longitudinal screening trial. We compared cytological testing with repeat cytology (for borderline/mildly abnormal smears) to HPV testing with cytology triage (for HPV‐positive smears), combination testing (combined HPV and cytology) and cytological testing with HPV triage (for borderline/mildly abnormal smears). We varied the screening interval from 5 to 10 years. The main outcome measures were the number of cervical cancer cases, the number of quality‐adjusted life years (QALYs), and the incremental cost‐effectiveness ratio (ICER). The base‐case estimates were accompanied with ranges across 118 calibrated parameter settings (calibration criteria: cervical intraepithelial neoplasia 2/3, cancer and mortality rates). In comparison to 5‐yearly cytology, 5‐yearly HPV testing with cytology triage gave a reduction in the number of cancer cases of 23% (range, 9–27%). The reduction was 26% (range, 10–29%) for combination testing and 3% (range, −1 to 8%) for cytology with HPV triage. For strategies with primary HPV testing, the model also estimated a reduction in cancer cases when the screening interval was extended to 7.5 years. Five‐yearly cytology with HPV triage and 5 to 7.5‐yearly HPV testing with cytology triage were cost effective for the base‐case settings and the majority of calibrated parameter settings (ICER below Dutch willingness‐to‐pay threshold of €20,000/QALY). Our model indicates that HPV testing with cytology triage is likely to be cost effective. An extension of the screening interval may be considered to control costs.

Sex-specific immunization for sexually transmitted infections such as human papillomavirus: insights from mathematical models

Johannes Bogaards and colleagues use mathematical models to investigate whether vaccinating females only, males only, or both sexes is the best way to achieve the most effective reduction in the population prevalence of sexually-transmitted infections

Population-level impact, herd immunity, and elimination after human papillomavirus vaccination: a systematic review and meta-analysis of predictions from transmission-dynamic models

Summary Background Modelling studies have been widely used to inform human papillomavirus (HPV) vaccination policy decisions; however, many models exist and it is not known whether they produce consistent predictions of population-level effectiveness and herd effects. We did a systematic review and meta-analysis of model predictions of the long-term population-level effectiveness of vaccination against HPV 16, 18, 6, and 11 infection in women and men, to examine the variability in predicted herd effects, incremental benefit of vaccinating boys, and potential for HPV-vaccine-type elimination. Methods We searched MEDLINE and Embase for transmission-dynamic modelling studies published between Jan 1, 2009, and April 28, 2015, that predicted the population-level impact of vaccination on HPV 6, 11, 16, and 18 infections in high-income countries. We contacted authors to determine whether they were willing to produce new predictions for standardised scenarios. Strategies investigated were girls-only vaccination and girls and boys vaccination at age 12 years. Base-case vaccine characteristics were 100% efficacy and lifetime protection. We did sensitivity analyses by varying vaccination coverage, vaccine efficacy, and duration of protection. For all scenarios we pooled model predictions of relative reductions in HPV prevalence (RRprev) over time after vaccination and summarised results using the median and 10th and 90th percentiles (80% uncertainty intervals [UI]). Findings 16 of 19 eligible models from ten high-income countries provided predictions. Under base-case assumptions, 40% vaccination coverage and girls-only vaccination, the RRprev of HPV 16 among women and men was 0·53 (80% UI 0·46–0·68) and 0·36 (0·28–0·61), respectively, after 70 years. With 80% girls-only vaccination coverage, the RRprev of HPV 16 among women and men was 0·93 (0·90–1·00) and 0·83 (0·75–1·00), respectively. Vaccinating boys in addition to girls increased the RRprev of HPV 16 among women and men by 0·18 (0·13–0·32) and 0·35 (0·27–0·39) for 40% coverage, and 0·07 (0·00–0·10) and 0·16 (0·01–0·25) for 80% coverage, respectively. The RRprev were greater for HPV 6, 11, and 18 than for HPV 16 for all scenarios investigated. Finally at 80% coverage, most models predicted that girls and boys vaccination would eliminate HPV 6, 11, 16, and 18, with a median RRprev of 1·00 for women and men for all four HPV types. Variability in pooled findings was low, but increased with lower vaccination coverage and shorter vaccine protection (from lifetime to 20 years). Interpretation Although HPV models differ in structure, data used for calibration, and settings, our population-level predictions were generally concordant and suggest that strong herd effects are expected from vaccinating girls only, even with coverage as low as 20%. Elimination of HPV 16, 18, 6, and 11 is possible if 80% coverage in girls and boys is reached and if high vaccine efficacy is maintained over time. Funding Canadian Institutes of Health Research.

Direct benefit of vaccinating boys along with girls against oncogenic human papillomavirus: bayesian evidence synthesis

Objective To assess the reduction in the vaccine preventable burden of cancer in men if boys are vaccinated along with girls against oncogenic human papillomavirus (HPV). Design Bayesian evidence synthesis approach used to evaluate the impact of vaccination against HPV types 16 and 18 on the burden of anal, penile, and oropharyngeal carcinomas among heterosexual men and men who have sex with men. The reduced transmission of vaccine-type HPV from vaccination of girls was assumed to lower the risk of HPV associated cancer in all men but not to affect the excess risk of HPV associated cancers among men who have sex with men. Setting General population in the Netherlands. Intervention Inclusion of boys aged 12 into HPV vaccination programmes. Main outcome measures Quality adjusted life years (QALYs) and numbers needed to vaccinate. Results Before HPV vaccination, 14.9 (95% credible interval 12.2 to 18.1) QALYs per thousand men were lost to vaccine preventable cancers associated with HPV in the Netherlands. This burden would be reduced by 37% (28% to 48%) if the vaccine uptake among girls remains at the current level of 60%. To prevent one additional case of cancer among men, 795 boys (660 to 987) would need to be vaccinated; with tumour specific numbers for anal, penile, and oropharyngeal cancer of 2162, 3486, and 1975, respectively. The burden of HPV related cancer in men would be reduced by 66% (53% to 805) if vaccine uptake among girls increases to 90%. In that case, 1735 boys (1240 to 2900) would need to be vaccinated to prevent an additional case; with tumour specific numbers for anal, penile, and oropharyngeal cancer of 2593, 29107, and 6484, respectively. Conclusions Men will benefit indirectly from vaccination of girls but remain at risk of cancers associated with HPV. The incremental benefit of vaccinating boys when vaccine uptake among girls is high is driven by the prevention of anal carcinomas, which underscores the relevance of HPV prevention efforts for men who have sex with men.

Clinical Progression of High-Grade Cervical Intraepithelial Neoplasia: Estimating the Time to Preclinical Cervical Cancer From Doubly Censored National Registry Data

Little is known about the time span of progression from high-grade cervical intraepithelial neoplasia (CIN2/3) to invasive cervical cancer. Estimation of this duration from longitudinal studies is not permitted, as CIN2/3 should be treated when detected. Cross-sectional data on the age-specific incidence of detected CIN2/3 and cervical cancer cases are readily available in national registries, but these data are difficult to interpret because neither the moment of lesion development nor the onset of invasive cancer is observed. We developed a statistical model for estimating the duration of time between CIN2/3 and preclinical cancer using Dutch national registries for the years 2000-2005. Human papillomavirus (HPV) genotype data were used to separate CIN2/3 and cancer incidences to obtain estimates for HPV-16-positive and HPV-16-negative lesions. The median time from CIN2/3 to cancer was estimated to be 23.5 years (95% confidence interval: 20.8, 26.6), and 1.6% of the lesions progressed to cancer within 10 years. The median duration for HPV-16-positive lesions was similar, but 2.4% of the HPV-16-positive lesions progressed to cancer within 10 years, as compared with 0.6% for HPV-16-negative lesions. Estimated durations of time to cancer are essential for reassessment of the optimal screening interval in light of vaccination and novel screening tests.

Rectal Swabs for Analysis of the Intestinal Microbiota

The composition of the gut microbiota is associated with various disease states, most notably inflammatory bowel disease, obesity and malnutrition. This underlines that analysis of intestinal microbiota is potentially an interesting target for clinical diagnostics. Currently, the most commonly used sample types are feces and mucosal biopsy specimens. Because sampling method, storage and processing of samples impact microbiota analysis, each sample type has its own limitations. An ideal sample type for use in routine diagnostics should be easy to obtain in a standardized fashion without perturbation of the microbiota. Rectal swabs may satisfy these criteria, but little is known about microbiota analysis on these sample types. In this study we investigated the characteristics and applicability of rectal swabs for gut microbiota profiling in a clinical routine setting in patients presenting with various gastro-intestinal disorders. We found that rectal swabs appeared to be a convenient means of sampling the human gut microbiota. Swabs can be performed on demand, whenever a patient presents; swab-derived microbiota profiles are reproducible, whether they are gathered at home by patients or by medical professionals in an outpatient setting and may be ideally suited for clinical diagnostics and large-scale studies.

IS-pro: high-throughput molecular fingerprinting of the intestinal microbiota

The human intestinal microbiota is known to play an important role in human health and disease, and with the advent of novel molecular techniques, disease‐specific variations in its composition have been found. However, analysis of the intestinal microbiota has not yet been applicable in large‐scale clinical research or routine diagnostics because of the complex and expensive nature of the techniques needed. Here, we describe a new PCR‐based profiling technique for high‐throughput analysis of the human intestinal microbiota, which we have termed IS‐pro. This technique combines bacterial species differentiation by the length of the 16S–23S rDNA interspace region with instant taxonomic classification by phylum‐specific fluorescent labeling of PCR primers. We validated IS‐pro in silico, in vitro, and in vivo, on human colonic biopsies and feces, and introduced a standardized protocol for data analysis. IS‐pro is easy to implement in general clinical microbiological laboratories with access to capillary gel electrophoresis, and the high‐throughput nature of the test makes analysis of large numbers of samples feasible. This combination renders IS‐pro ideally suited for use in clinical research and routine diagnostics.—Budding, A. E., Grasman, M. E., Lin, F., Bogaards, J. A., Soeltan‐Kaersenhout, D. J., Vandenbroucke‐Grauls, C. M. J. E., van Bodegraven, A. A., Savelkoul, P. H. M. IS‐pro: high‐throughput molecular fingerprinting of the intestinal microbiota. FASEB J. 24, 4556–4564 (2010). www.fasebj.org

Enrichment broth improved detection of extended-spectrum-beta-lactamase-producing bacteria in throat and rectal surveillance cultures of samples from patients in intensive care units.

ABSTRACT We evaluated the use of a trypticase soy broth (TSB) for improving detection of extended-spectrum-beta-lactamase-producing (ESBL+) bacteria. Preenrichment of throat and rectal swabs in TSB prior to inoculation on solid medium doubled the number of ESBL+ bacteria detected in samples obtained from patients in our intensive care unit.