Leen‐Jan van Doorn

DDL Diagnostic Laboratory

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Wim Quint

DDL Diagnostic Laboratory

Rolando Herrero

Instituto Costarricense de Investigación y Enseñanza en Nutrición y Salud

Carolina Porras

Instituto Costarricense de Investigación y Enseñanza en Nutrición y Salud

Paula González

Complexo Hospitalario Universitario A Coruña

Allan Hildesheim

Division of Cancer Epidemiology and Genetics

Sholom Wacholder

Division of Cancer Epidemiology and Genetics

John T. Schiller

National Institutes of Health

Douglas R. Lowy

National Cancer Institute

Troy J. Kemp

Frederick National Laboratory for Cancer Research

Aimée R. Kreimer

Division of Cancer Epidemiology and Genetics

Cooperative Institutions

National Cancer Institute

Division of Cancer Epidemiology and Genetics

National Institutes of Health

DDL Diagnostic Laboratory

Centre International de Recherche sur le Cancer

Instituto Costarricense de Investigación y Enseñanza en Nutrición y Salud

University of Amsterdam

Radboud University Nijmegen

Albert Einstein College of Medicine

Johns Hopkins University

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The Efficacy of Laboratory Diagnosis of Helicobacter pylori Infections in Gastric Biopsy Specimens Is Related to Bacterial Density and vacA , cagA , and iceA Genotypes

Journal of Clinical Microbiology (2000)

Leen‐Jan van Doorn Yvonne Henskens Nathalie Nouhan Anita Verschuuren Rolf Vreede

ABSTRACT A total of 500 consecutive patients undergoing upper endoscopy were biopsied and tested for H. pylori infection by the Campylobacter -like organism (CLO) test, culture, histology, and PCR. Serum samples were tested by two different serological assays. Patients were considered H. pylori positive if at least two of the four biopsy specimen-based methods yielded positive results. PCR had the highest diagnostic sensitivity (99.4%), followed by histology (92.2%), culture (89.5%), and the CLO test (89.0%). The specificities of all methods were higher than 98%. Of the organisms from the 181 PCR-positive patients, the vacA (s and m regions), cagA , and iceA genotypes were determined by reverse hybridization (line probe assay) or an allele-specific PCR. Organisms that were detected by PCR but that remained undetected by the CLO test were significantly more often vacA s1 ( P = 0.006), m1 ( P = 0.028), and cagA positive ( P = 0.029) than vacA s2, m2, and cagA negative, respectively. Organisms that were detected by PCR but that remained undetected by culture or histology more often contained iceA1 ( P = 0.034 and P = 0.029, respectively) than iceA2 . Higher H. pylori density was associated with vacA s2 ( P = 0.024), vacA m2 ( P = 0.050), and cagA -negative ( P = 0.035) genotypes. Also, the diagnostic results of the CLO test ( P = 0.001) and culture ( P = 0.031) but not those of the PCR ( P = 0.130) were significantly associated with the H. pylori density. The rate of detection by the four biopsy specimen-based tests was lower for patients who used proton pump inhibitors, but this was independent of the H. pylori genotypes. These observations may be explained by different bacterial densities, as established by the distinct genotypes of H. pylori , and confirm that the biologies of strains with such genotypes are considerably different.

CagA

Histology

Spirillaceae

10.1128/jcm.38.1.13-17.2000

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Citations (75)

In Vitro Antiviral Activity and Preclinical and Clinical Resistance Profile of Miravirsen, a Novel Anti-Hepatitis C Virus Therapeutic Targeting the Human Factor miR-122

Antimicrobial Agents and Chemotherapy (2014)

Søren Ottosen Todd B. Parsley Lu Yang Karin Zeh Leen‐Jan van Doorn

ABSTRACT Miravirsen is a β- d -oxy-locked nucleic acid-modified phosphorothioate antisense oligonucleotide targeting the liver-specific microRNA-122 (miR-122). Miravirsen demonstrated antiviral activity against hepatitis C virus (HCV) genotype 1b replicons with a mean 50% effective concentration (EC 50 ) of 0.67 μM. No cytotoxicity was observed up to the highest concentration tested (>320 μM) in different cell culture models, yielding a therapeutic index of ≥297. Combination studies of miravirsen with interferon α2b, ribavirin, and nonnucleoside (VX-222) and nucleoside (2′-methylcytidine) inhibitors of NS5B, NS5A (BMS-790052), or NS3 (telaprevir) indicated additive interactions. Miravirsen demonstrated broad antiviral activity when tested against HCV replicons resistant to NS3, NS5A, and NS5B inhibitors with less than 2-fold reductions in susceptibility. In serial passage studies, an A4C nucleotide change was observed in the HCV 5′ untranslated region (UTR) from cells passaged in the presence of up to 20 μM (40-fold the miravirsen EC 50 concentration) at day 72 of passage but not at earlier time points (up to 39 days of passage). Likewise, a C3U nucleotide change was observed in the HCV 5′UTR from subjects with viral rebound after the completion of therapy in a miravirsen phase 2 clinical trial. An HCV variant constructed to contain the A4C change was fully susceptible to miravirsen. A C3U HCV variant demonstrated overall reductions in susceptibility to miravirsen but was fully susceptible to all other anti-HCV agents tested. In summary, miravirsen has demonstrated broad antiviral activity and a relatively high genetic barrier to resistance. The identification of nucleotide changes associated with miravirsen resistance should help further elucidate the biology of miR-122 interactions with HCV. (The clinical trial study has been registered at ClinicalTrials.gov under registration no. NCT01200420).

NS5B

NS5A

NS3

Telaprevir

Replicon

Therapeutic index

10.1128/aac.04220-14

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Citations (197)

Data from Durable Antibody Responses Following One Dose of the Bivalent Human Papillomavirus L1 Virus-Like Particle Vaccine in the Costa Rica Vaccine Trial

Mahboobeh Safaeian Carolina Porras Yuanji Pan Aimée R. Kreimer John T. Schiller

<div>AbstractThe Costa Rica HPV16/18 Vaccine Trial (CVT) showed that four-year vaccine efficacy against 12-month HPV16/18 persistent infection was similarly high among women who received one, two, or the recommended three doses of the bivalent HPV16/18 L1 virus-like particle (VLP) vaccine. Live-attenuated viral vaccines, but not simple-subunit vaccines, usually induce durable lifelong antibody responses after a single dose. It is unclear whether noninfectious VLP vaccines behave more like live-virus or simple-subunit vaccines in this regard. To explore the likelihood that efficacy will persist longer term, we investigated the magnitude and durability of antibodies to this vaccine by measuring HPV16- and HPV18-specific antibodies by VLP-ELISA using serum from enrollment, vaccination, and annual visits through four years in four vaccinated groups; one-dose (n = 78), two-doses separated by one month (n = 140), two doses separated by six months (n = 52), and three scheduled doses (n = 120, randomly selected). We also tested enrollment sera from n = 113 HPV16- or HPV18 L1-seropositive women prevaccination, presumably from natural infection. At four years, 100% of women in all groups remained HPV16/18 seropositive; both HPV16/18 geometric mean titers (GMT) among the extended two-dose group were non-inferior to the three-dose group, and ELISA titers were highly correlated with neutralization titers in all groups. Compared with the natural infection group, HPV16/18 GMTs were, respectively, at least 24 and 14 times higher among the two-dose and 9 and 5 times higher among one-dose vaccinees. Antibody levels following one-dose remained stable from month 6 through month 48. Results raise the possibility that even a single dose of HPV VLPs will induce long-term protection. Cancer Prev Res; 6(11); 1242–50. ©2013 AACR.</div>

Bivalent (engine)

Human papillomavirus vaccine

Antibody response

10.1158/1940-6207.c.6544847.v1

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The importance of vacA, cagA, and iceA genotypes of Helicobacter pylori infection in peptic ulcer disease and gastroesophageal reflux disease

The American Journal of Gastroenterology (2001)

N. L. A. Arents Anton A. van Zwet Jacob C. Thijs Anne M.D. Kooistra-Smid K. R. van Slochteren

To study the relationship between the presence of H. pylori virulence factors and clinical outcome in H. pylori infected patients.DNA was isolated from an antral biopsy sample and vacA, cagA, and iceA genotype were determined by PCR and a reverse hybridization technique in 183 patients with culture-proven H. pylori infection: 51 with peptic ulcer disease (PUD), 62 with gastroesophageal reflux disease (GERD), and 70 with a normal endoscopy (gastritis only; GO).Forty-four samples (24%) showed more than one allelic variant in the vacA s- or in-region and/or both iceA1 and iceA2 genotypes, indicating multiple strain infection. These were excluded from statistical analysis. vacA s1 and cagA were significantly more common in PUD than in GERD and GO. Logistic regression analysis showed that GERD patients were more often infected with strains lacking both cagA and iceA than GO patients (OR = 0.36; CI = 0.15-0.89). Trend analysis showed that GERD patients were most often infected with less virulent strains (p < 0.002).Multiple strain infection is common. H. pylori strains possessing the vacA s1 genotype and/or cagA are associated with PUD. GERD patients, infected with H. pylori, mostly carry less virulent strains possessing neither cagA nor iceA1. Our findings support the hypothesis that virulent strains protect against the development of GERD.

CagA

Peptic

10.1111/j.1572-0241.2001.04104.x

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Citations (69)

Estimating human papillomavirus vaccine efficacy from a single-arm trial: Proof-of-principle in the Costa Rica Vaccine Trial

JNCI Journal of the National Cancer Institute (2023)

Brian Befano Nicole G. Campos Didem Egemen Rolando Herrero Mark Schiffman

Abstract Background The World Health Organization recommends a 1- or 2-dose human papillomavirus (HPV) vaccination schedule for females aged 9 to 20 years. Studies confirming the efficacy of a single dose and vaccine modifications are needed, but randomized controlled trials are costly and face logistical and ethical challenges. We propose a resource-efficient single-arm trial design that uses untargeted and unaffected HPV types as controls. Methods We estimated HPV vaccine efficacy (VE) from a single arm by comparing 2 ratios: the ratio of the rate of persistent incident infection with vaccine-targeted HPV 16 and 18 (HPV 16/18) and cross-protected types HPV 31, 33, and 45 (HPV 31/33/45) to vaccine-unaffected types HPV 35, 39, 51, 52, 56, 58, 59, and 66 (HPV 35/39/51/52/56/58/59/66) vs the ratio of prevalence of these types at the time of trial enrollment. We compare VE estimates using only data from the bivalent HPV 16/18 vaccine arm of the Costa Rica Vaccine Trial with published VE estimates that used both the vaccine and control arms. Results Our single-arm approach among 3727 women yielded VE estimates against persistent HPV 16/18 infections similar to published 2-arm estimates from the trial (according-to-protocol cohort: 91.0% , 95% CI = 82.9% to 95.3% [single-arm] vs 90.9% , 95% CI = 82.0% to 95.9% [2-arm]; intention-to-treat cohort: 41.7%, 95% CI = 32.4% to 49.8% [single-arm] vs 49.0% , 95% CI = 38.1% to 58.1% [2-arm]). VE estimates were also similar in analytic subgroups (number of doses received; baseline HPV serology status). Conclusions We demonstrate that a single-arm design yields valid VE estimates with similar precision to a randomized controlled trial. Single-arm studies can reduce the sample size and costs of future HPV vaccine trials while avoiding concerns related to unvaccinated control groups. Trial registration ClinicalTrials.gov Identifier: NCT00128661.

Vaccine efficacy

HPV vaccines

10.1093/jnci/djad064

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Citations (2)

Detection of Helicobacter pylori virulence-associated genes

Expert Review of Molecular Diagnostics (2001)

Leen‐Jan van Doorn

Helicobacter pylori is an important human pathogen and persistent colonization of the human gastric mucosa can cause severe gastrointestinal diseases. The bacterium should not be considered as a uniform organism, but as a population of closely related and yet genetically diverse bacteria. Several genes of H. pylori (such as vacA and cagA) have been identified as being virulence-associated and may have important clinical and epidemiological implications. Assessment of virulence-associated genes of H. pylori should be included in clinical and epidemiological studies as well as therapeutic trials, in order to stratify between patient groups, harboring H. pylori strains with particular virulence genotypes. Molecular determination of antibiotic resistance will be especially useful for treatment studies. Together with our increasing knowledge about the human genome, typing of H. pylori will facilitate the management of gastroenterological pathologies.

CagA

Human pathogen

Pathogenicity island

10.1586/14737159.1.3.290

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Citations (13)

Human Rotavirus Vaccine Is Highly Efficacious When Coadministered With Routine Expanded Program of Immunization Vaccines Including Oral Poliovirus Vaccine in Latin America

The Pediatric Infectious Disease Journal (2011)

Miguel Tregnaghi Héctor Abate Alejandra Valencia Pío López Themis Reverbel da Silveira

Background: The efficacy of a rotavirus vaccine against severe rotavirus gastroenteritis when coadministered with routine Expanded Program on Immunization (EPI) vaccines including oral polio vaccine (OPV) was evaluated in this study. Methods: Double-blind, randomized (2:1), placebo-controlled study conducted across 6 Latin American countries. Healthy infants (N = 6568) 6 to 12 weeks of age received 2 doses of RIX4414 vaccine or placebo following a 0, 1- to 2-month schedule. Routine vaccines including OPV were coadministered according to local EPI schedule. Vaccine efficacy (VE) against severe rotavirus gastroenteritis caused by circulating wild-type rotavirus from 2 weeks post-Dose 2 until 1 year of age was calculated with 95% confidence interval [CI]. Safety was assessed during the entire study period. Immunogenicity of RIX4414 and OPV was also assessed. Results: During the efficacy follow-up period (mean duration = 7.4 months), 7 and 19 cases of severe rotavirus gastroenteritis were reported in the vaccine and placebo groups, respectively, with a VE of 81.6% (95% CI: 54.4–93.5). VE against severe rotavirus gastroenteritis caused by G1 type was 100% (95% CI: <0–100) and 80.6% (95% CI: 51.4–93.2) against the pooled non-G1 rotavirus types, respectively. There was no difference (P = 0.514) in the incidence of serious adverse events reported in the 2 groups. Antirotavirus IgA seropositivity rate at 1 to 2 months post-Dose 2 was 61.4% (95% CI: 53.7–68.6) in the RIX4414 group; similar seroprotection rates (≥96.0%) against the 3 antipoliovirus types was observed 1 month post-Dose 3 of OPV in both groups. Conclusion: RIX4414 was highly efficacious against severe rotavirus gastroenteritis caused by the circulating wild-type rotavirus (G1 and non-G1) when coadministered with routine EPI vaccines including OPV.

Rotavirus vaccine

10.1097/inf.0b013e3182138278

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Citations (58)

Precancerous cervical lesions caused by non-vaccine-preventable HPV types after vaccination with the bivalent AS04-adjuvanted HPV vaccine: an analysis of the long-term follow-up study from the randomised Costa Rica HPV Vaccine Trial

The Lancet Oncology (2022)

Jaimie Z. Shing Shangying Hu Rolando Herrero Allan Hildesheim Carolina Porras

Vaccine efficacy

HPV vaccines

10.1016/s1470-2045(22)00291-1

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Citations (24)

Glutathione S-transferase L1 multiplex serology as a measure of cumulative infection with human papillomavirus

BMC Infectious Diseases (2014)

Hilary A. Robbins Yan Li Carolina Porras Michael Pawlita Arpita Ghosh

Several assays are used to measure type-specific serological responses to human papillomavirus (HPV), including the bead-based glutathione S-transferase (GST)-L1 multiplex serology assay and virus-like particle (VLP)-based ELISA. We evaluated the high-throughput GST-L1, which is increasingly used in epidemiologic research, as a measure of cumulative HPV infection and future immune protection among HPV-unvaccinated women. We tested enrollment sera from participants in the control arm of the Costa Rica Vaccine Trial (n = 488) for HPV16 and HPV18 using GST-L1, VLP-ELISA, and two assays that measure neutralizing antibodies (cLIA and SEAP-NA). With statistical adjustment for sampling, we compared GST-L1 serostatus to established HPV seropositivity correlates and incident cervical HPV infection using odds ratios. We further compared GST-L1 to VLP-ELISA using pair-wise agreement statistics and by defining alternate assay cutoffs. Odds of HPV16 GST-L1 seropositivity increased with enrollment age (OR = 1.20 per year, 95%CI 1.03-1.40) and lifetime number of sexual partners (OR = 2.06 per partner, 95%CI 1.49-2.83), with similar results for HPV18. GST-L1 seropositivity did not indicate protection from incident infection over 4 years of follow-up (HPV16 adjusted OR = 1.72, 95%CI 0.95-3.13; HPV18 adjusted OR = 0.38, 95%CI 0.12-1.23). Seroprevalence by GST-L1 (HPV16 and HPV18, respectively) was 5.0% and 5.2%, compared to 19.4% and 23.8% by VLP-ELISA, giving positive agreement of 39.2% and 20.8%. Lowering GST-L1 seropositivity cutoffs improved GST-L1/VLP-ELISA positive agreement to 68.6% (HPV16) and 61.5% (HPV18). Our data support GST-L1 as a marker of cumulative HPV infection, but not immune protection. At lower seropositivity cutoffs, GST-L1 better approximates VLP-ELISA.

Multiplex

Serostatus

Glutathione S-transferase

Seroprevalence

10.1186/1471-2334-14-120

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Citations (26)

Rapid Identification of Thermotolerant Campylobacter jejuni , Campylobacter coli , Campylobacter lari , and Campylobacter upsaliensis from Various Geographic Locations by a GTPase-Based PCR-Reverse Hybridization Assay

Journal of Clinical Microbiology (1999)

Leen‐Jan van Doorn Anita Verschuuren-van Haperen André P. Burnens Michael B. Huysmans Peter Vandamme

ABSTRACT Recently, a gene from Campylobacter jejuni encoding a putative GTPase was identified. Based on two semiconserved GTP-binding sites encoded within this gene, PCR primers were selected that allow amplification of a 153-bp fragment from C. jejuni , C. coli , C. lari , and C. upsaliensis . Sequence analysis of these PCR products revealed consistent interspecies variation, which allowed the definition of species-specific probes for each of the four thermotolerant Campylobacter species. Multiple probes were used to develop a line probe assay (LiPA) that permits analysis of PCR products by a single reverse hybridization step. A total of 320 reference strains and clinical isolates from various geographic origins were tested by the GTP-based PCR-LiPA. The PCR-LiPA is highly specific in comparison with conventional identification methods, including biochemical and whole-cell protein analyses. In conclusion, a simple method has been developed for rapid and highly specific identification of thermotolerant Campylobacter species.

Campylobacter coli

10.1128/jcm.37.6.1790-1796.1999

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Citations (35)