Non-vaccine Genotypes Research Articles

Genetic characteristics of breakthrough varicella-zoster virus infection during the varicella outbreaks in Minhang District of Shanghai

Objective To analyze the genetic characteristics of breakthrough varicella-zoster virus infection during the varicella outbreaks in Minhang District of Shanghai in 2013-2014. Methods Samples of the varicella-zoster liquid were collected from patients with chickenpox in Minhang District in 2013-2014 and used for the extraction of genomic DNA. The open reading frame (ORF) of 22 and 62 regions were sequenced and further analyzed by using bioinformatics methods. Results A total of 24 samples were successfully collected and sequenced, and all of them were wild strains. Among the 24 varicella-zoster virus strains, 23 strains were highly homologous to the parental strain (P-Oka) and the vaccine strain (V-Oka), indicating that they belonged to J genotype. Only one strain, whose genotype was between M and E, was highly homologous to the mosaic(M)CA123 strain (M1 genotype), indicating that it might belong to M1 genotype. Conclusion The epidemic strains of varicella-zoster virus in Minhang District were mainly J genotype. Local epidemic of M and other genotypes of varicella-zoster virus also existed. There were some gene variations in different strains of J genotype. These varicella-zoster virus strains of non-vaccine genotypes might be one of the reasons causing the breakthrough cases of chicken pox. Key words: Varicella-zoster virus; Breakthrough case; Varicella outbreak; Genetic characteristics; Bioinformatics

Population Impact and Effectiveness of Monovalent Rotavirus Vaccination in Urban Malawian Children 3 Years After Vaccine Introduction: Ecological and Case-Control Analyses.

Background. Rotavirus vaccines have been introduced in many low-income African countries including Malawi in 2012. Despite early evidence of vaccine impact, determining persistence of protection beyond infancy, the utility of the vaccine against specific rotavirus genotypes, and effectiveness in vulnerable subgroups is important.Methods. We compared rotavirus prevalence in diarrheal stool and hospitalization incidence before and following rotavirus vaccine introduction in Malawi. Using case-control analysis, we derived vaccine effectiveness (VE) in the second year of life and for human immunodeficiency virus (HIV)–exposed and stunted children.Results. Rotavirus prevalence declined concurrent with increasing vaccine coverage, and in 2015 was 24% compared with prevaccine mean baseline in 1997–2011 of 32%. Since vaccine introduction, population rotavirus hospitalization incidence declined in infants by 54.2% (95% confidence interval [CI], 32.8–68.8), but did not fall in older children. Comparing 241 rotavirus cases with 692 test-negative controls, VE was 70.6% (95% CI, 33.6%–87.0%) and 31.7% (95% CI, −140.6% to 80.6%) in the first and second year of life, respectively, whereas mean age of rotavirus cases increased from 9.3 to 11.8 months. Despite higher VE against G1P[8] than against other genotypes, no resurgence of nonvaccine genotypes has occurred. VE did not differ significantly by nutritional status (78.1% [95% CI, 5.6%–94.9%] in 257 well-nourished and 27.8% [95% CI, −99.5% to 73.9%] in 205 stunted children; P = .12), or by HIV exposure (60.5% [95% CI, 13.3%–82.0%] in 745 HIV-unexposed and 42.2% [95% CI, −106.9% to 83.8%] in 174 exposed children; P = .91).Conclusions. Rotavirus vaccination in Malawi has resulted in reductions in disease burden in infants <12 months, but not in older children. Despite differences in genotype-specific VE, no genotype has emerged to suggest vaccine escape. VE was not demonstrably affected by HIV exposure or stunting.

Abstract PR06: Racial/ethnic variation in the prevalence of vaccine-preventable human papillomavirus genotypes

Abstract Introduction: The bi- and quadrivalent human papillomavirus (HPV) vaccines that have been on the market for ≥ 9 years protect against high-risk HPV types 16 and 18, the two HPV genotypes causally associated with ≥ 70% of cervical cancers. The recent nonavalent vaccine, which became commercially available in 2014, additionally protects against high-risk types 31, 33, 45, 52, and 58. The quadri- and nonavalent vaccines also protect against low-risk HPV types 6 and 11, which cause genital warts. The objective of this analysis is to compare the prevalence of vaccine-preventable HPV genotypes among non-Hispanic white, non-Hispanic black, Hispanic, and Asian women and determine the risk of cervical dysplasia (CIN2+) associated with the genotypes covered by each of the vaccines. Methods: Patients in this analysis represent a subset of those participating in a clinical trial to evaluate new optical technologies for the diagnosis of cervical dysplasia. Trial participants were non-pregnant women, age ≥18 years, with a recent abnormal Pap test and were recruited at participating colposcopy clinics in Houston, El Paso, and Vancouver. As part of the parent trial, a subset of participants provided a biopsy and a cervical swab. Histologic diagnosis was based on biopsies and evaluated by a certified pathologist to represent the histology of the most severe biopsy. HPV genotyping was conducted using the Roche Linear Array. Prevalent HPV types were grouped according to their inclusion in each of the vaccines: bivalent (16, 18), quadrivalent (16, 18, 6, 11), and nonavalent (16, 18, 31, 33, 45, 52, 58, 6, 11). Women were considered to be potentially protected by a particular vaccine if all or some (in the case of multiple infections) type-specific infections were covered by the vaccine. Results for the bi- and quadrivalent vaccines were grouped given the small number of women additionally protected by the quadri- versus bivalent vaccine. Results: The sample for this analysis (n= 419) is comprised of 206 non-Hispanic white, 39 non-Hispanic Black, 142 Hispanic, and 32 Asian women. The prevalence of HPV genotypes covered by the bi- and quadrivalent vaccines was significantly greater among non-Hispanic white (38.3%) and Asian women (37.5%) compared to non-Hispanic black (15.4%) and Hispanic women (19.7%). The increase in the proportion of women potentially protected by the nonavalent vaccine versus the bi-/quadrivalent vaccine was highest among non-Hispanic blacks (33.3% increase) followed by Hispanics (18.3% increase). However, the prevalence of HPV genotypes not covered by any vaccine was also highest among these racial/ethnic groups. Specifically, 42.3% and 35.9% of Hispanic and non-Hispanic black women, respectively, had ≥ 1 genotype not covered by any vaccine, compared to 24.3% and 15.6% among non-Hispanic white and Asian women, respectively. Non-vaccine HPV types were primarily high-risk (68%). Among women with a CIN2+ diagnosis, 37.3% had genotypes included in the bi/quadrivalent vaccine and an additional 46.7% had genotypes included in the nonavalent (but not the bi/quadrivalent) vaccine. However, 16.0% of CIN2+ diagnoses occurred among women with HPV genotypes not covered by any vaccine. Conclusions: Our data suggest racial/ethnic differences in the proportion of women protected by the new nonavalent HPV vaccine. In particular, non-Hispanic black and Hispanic women had the greatest prevalence of HPV types covered by the nonavalent but not the bi-/quadrivalent vaccines. Nonetheless, a large proportion of women from these racial/ethnic groups were infected with genotypes not covered by any vaccine. While HPV 16 and 18 are known to cause most cervical cancers, non-vaccine genotypes were associated with 16% of CIN2+ histology, a diagnosis often requiring significant therapeutic intervention. This abstract is also presented as Poster C38. Citation Format: Indu Varier, Jane R. Montealegre, Christina M. Gutierrez, Laura M. Dillon, Martial Guillaud, Karen A. Storthz, Michele Follen, Andrew G. Sikora, Michael E. Scheurer. Racial/ethnic variation in the prevalence of vaccine-preventable human papillomavirus genotypes. [abstract]. In: Proceedings of the Eighth AACR Conference on The Science of Health Disparities in Racial/Ethnic Minorities and the Medically Underserved; Nov 13-16, 2015; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2016;25(3 Suppl):Abstract nr PR06.

The distribution of Rotavirus G and P genotypes in children with acute gastroenteritis in Cukurova region, Turkey

Background: Rotavirus is the major cause of acute gastroenteritis in infants and young children worldwide. The aim of the study was to determine the frequency of rotavirus infection and the distribution of rotavirus G and P genotype combination among children under 5 years of age with acute gastroenteritis in Cukurova region, Turkey, between October 2009 and June 2010. Material and Methods: The stool specimens (n=846) collected from children with acute gastroenteritis were analyzed by enzyme-linked immunosorbent assay (ELISA) for group A rotavirus antigen. Semi-nested multiplex reverse transcription-polymerase chain reaction (RT-PCR) test was performed for rotavirus G and P genotyping. Results: The rate of rotavirus infection was found to be in 144 patients (17%). The predominant rotavirus genotype was G1P[8] (22.2%), followed by G1P[4] (17.3%), G2P[4] (13.8%), G9P[4] (6.3%), G9P[8] (4.8%), G2P[8] (2.8%), G1P[10] (2.1%) and G4P[8] (1.4%). The most common G genotype was G1 (41.7%), followed by G2 (16.6%), G9 (11.1%) and G4 (1.4%). Rotavirus P[4] genotype was identified in 37.5%, P[8] in 31.2% and P[10] in 2.1% of samples. The prevalence of mixed rotavirus infections was 29.2% (n=42). Conclusion: Although the predominant rotavirus genotypes circulating during the study period in our region are targets of current rotavirus vaccines, uncommon, non-vaccine rotavirus genotype combinations such as G1P[4] and G9P[4], which might appear to be the result of mixed rotavirus infections with high rate (29.2%), were also detected. G1 is included in both recent rotavirus vaccines. The continuous investigation of molecular epidemiology of rotavirus infections is essential to evaluate the effectiveness of rotavirus vaccines.

Pre-clinical immunogenicity of human papillomavirus alpha-7 and alpha-9 major capsid proteins

Human papillomavirus (HPV) vaccines confer protection against the oncogenic genotypes HPV16 and HPV18 through the generation of type-specific neutralizing antibodies raised against the constituent virus-like particles (VLP) based upon the major capsid proteins (L1) of these genotypes. The vaccines also confer a degree of cross-protection against some genetically related types from the Alpha-9 (HPV16-like: HPV31, HPV33, HPV35, HPV52, HPV58) and Alpha-7 (HPV18-like: HPV39, HPV45, HPV59, HPV68) species groups. The mechanism of cross-protection is unclear but may involve antibodies capable of recognizing shared inter-genotype epitopes. The relationship(s) between the genetic and antigenic diversity of the L1 protein, particularly for non-vaccine genotypes, is poorly understood.We carried out a comprehensive evaluation of the immunogenicity of L1 VLP derived from genotypes within the Alpha-7 and Alpha-9 species groups in New Zealand White rabbits and used L1L2 pseudoviruses as the target antigens in neutralization assays.The majority antibody response against L1 VLP was type-specific, as expected, but several instances of robust cross-neutralization were nevertheless observed including between HPV33 and HPV58 within the Alpha-9 species and between HPV39, HPV59 and HPV68 in the Alpha-7 species. Immunization with an experimental tetravalent preparation comprising VLP based upon HPV16, HPV18, HPV39 and HPV58 was capable of generating neutralizing antibodies against all the Alpha-7 and Alpha-9 genotypes. Competition of HPV31 and HPV33 cross-neutralizing antibodies in the tetravalent sera confirmed that these antibodies originated from HPV16 and HPV58 VLP, respectively, and suggested that they represent minority specificities within the antibody repertoire generated by the immunizing antigen. These data improve our understanding of the antigenic diversity of the L1 protein per se and may inform the rational design of a next generation vaccine formulation based upon empirical data.

Dynamics of high-risk nonvaccine human papillomavirus types after actual vaccination scheme.

Human papillomavirus (HPV) has been identified as the main etiological factor in the developing of cervical cancer (CC). This finding has propitiated the development of vaccines that help to prevent the HPVs 16 and 18 infection. Both genotypes are associated with 70% of CC worldwide. In the present study, we aimed to determine the emergence of high-risk nonvaccine HPV after actual vaccination scheme to estimate the impact of the current HPV vaccines. A SIR-type model was used to study the HPV dynamics after vaccination. According to the results, our model indicates that the application of the vaccine reduces infection by target or vaccine genotypes as expected. However, numerical simulations of the model suggest the presence of the phenomenon called vaccine—induced pathogen strain replacement. Here, we report the following replacement mechanism: if the effectiveness of cross-protective immunity is not larger than the effectiveness of the vaccine, then the high-risk nonvaccine genotypes emerge. In this scenario, further studies of infection dispersion by HPV are necessary to ascertain the real impact of the current vaccines, primarily because of the different high-risk HPV types that are found in CC.

Cross-protection elicited by primary and booster vaccinations against Japanese encephalitis: A two-year follow-up study

BackgroundThe inactivated Vero cell-derived vaccine (JE-VC, IXIARO) has replaced the traditional mouse brain-derived preparations (JE-MB) in travelers’ vaccinations against Japanese encephalitis. We showed recently that a single JE-VC dose efficiently boosts immunity in JE-MB-primed vaccinees, and that JE-VC elicits cross-protective immunity against non-vaccine genotypes, including the emerging genotype I. While these studies only provided short-term data, the present investigation evaluates the longevity of seroprotection in the same volunteers. MethodsThe study comprised 48 travelers who had received (1) JE-VC primary series, (2) JE-MB primary series followed by a single JE-VC booster dose, or (3) JE-MB primary series and a single JE-MB booster dose. Serum samples were collected two years after the last vaccine dose, and evaluated with the plaque-reduction neutralization test against seven Japanese encephalitis virus strains representing genotypes I–IV. PRNT50 titers≥10 were considered protective. ResultsTwo years after the primary series with JE-VC, 87–93% of the vaccinees proved to be cross-protected against test strains representing genotypes II-IV and 73% against those of genotype I. After a single homologous or heterologous booster dose to JE-MB-primed subjects, the two-year seroprotection rates against genotype I–IV strains were 89–100%. ConclusionsAfter JE-VC primary series, seroprotection appeared to wane first against genotype I. The first booster should not be delayed beyond two years. In JE-MB-primed subjects, a single JE-VC booster provided cross-protective immunity against genotype I–IV strains in almost all vaccinees, suggesting an interval of two years or even longer for the second booster. These data further support the use of a single JE-VC dose for boosting JE-MB immunity.

Exploring individual HPV coinfections is essential to predict HPV-vaccination impact on genotype distribution: A model-based approach

IntroductionAs for other vaccines that only target a subset of circulating pathogen types, human papillomavirus (HPV) immunization raises the concern of a potential risk of genotype replacement. Potential interactions between HPV types may affect infection acquisition and clearance. However, the existence and the nature of these interactions are still largely unknown. Here, we assess how such interactions might affect the impact of HPV vaccination on genotype distribution in the long term. MethodsWe develop two mathematical models of the transmission of oncogenic HPV infections that include interactions between vaccine and nonvaccine genotypes to examine the influence of different coinfection dynamics (simultaneous vs. sequential clearance of coinfections) on the evolution of nonvaccine prevalences postimmunization. ResultsAfter introducing vaccination, the two models give contrasting genotype-replacement outcomes. When hypothesizing that coinfections clear sequentially, genotype replacement depends on whether vaccine and nonvaccine genotypes reduce or favor the acquisition by one or the other. Interestingly, the hypothesis that coinfections clear simultaneously always leads to genotype replacement, even when infections with vaccine types favor the acquisition of infections with nonvaccine types. ConclusionOur results suggest that predictions regarding HPV genotype replacement strongly depend on the assumptions describing the dynamics (acquisition and clearance) of coinfections. In particular, HPV genotype replacement could be compatible with synergistic interactions between types affecting infections acquisition, contrary to previous suggestions. Understanding better how concurrent infections with multiple types change the acquisition and time to clearance of type-specific infections is essential to be able to predict the impact of vaccination on genotype distribution. Longitudinal data collection in populations, particularly examining infection and coinfection acquisition and clearance, is needed to better predict HPV-vaccine impact.

Humoral, Mucosal, and Cell-Mediated Immunity Against Vaccine and Nonvaccine Genotypes After Administration of Quadrivalent Human Papillomavirus Vaccine to HIV-Infected Children

To characterize the immunogenicity of a quadrivalent human papillomavirus vaccine (QHPV) in human immunodeficiency virus (HIV)-infected children, we studied their immune responses to 3 or 4 doses. HIV-infected children aged 7-12 years with a CD4 cell percentage of ≥15% of lymphocytes, received 3 doses of QHPV with or without a fourth dose after 72 weeks. Type-specific and cross-reactive antibodies and cell-mediated immunity were measured. Type-specific antibodies to HPV6, 11, and 16 were detected in 100% and ≥94% of children at 4 and 72 weeks, respectively, after the third QHPV dose. Corresponding numbers for HPV18 were 97% and 76%, respectively. A fourth QHPV dose increased seropositivity to ≥96% for all vaccine genotypes. Four weeks after the third QHPV dose, 67% of vaccinees seroconverted to HPV31, an HPV16-related genotype not in the vaccine; 69% and 39% of vaccinees developed mucosal HPV16 and 18 immunoglobulin G antibodies, respectively; and 60% and 52% of vaccinees developed cytotoxic T lymphocytes (CTLs) for HPV16 and 31, respectively. Three QHPV doses generated robust and persistent antibodies to HPV6, 11, and 16 but comparatively weaker responses to HPV18. A fourth dose increased antibodies against all vaccine genotypes in an anamnestic fashion. CTLs and mucosal antibodies against vaccine genotypes, as well as cross-reactive antibodies and CTL against nonvaccine genotypes, were detected.

A unique human rotavirus (non vaccine) G9P4 genotype infection in a child with gastroenteritis

Group A Rotaviruses with serotypes G1-G4 and G9 are the common Rotavirus types of clinical importance. This study aimed at determining the different Rotavirus genotypes in stool sample of children below 5 years. A total of 300 children with acute gastroenteritis were tested for group specific VP6 antigen of group A Rotaviruses by Enzyme Linked Immunosorbent Assay. 47 of these samples were positive for Rotavirus antigen. Out of these, 20 positive samples were subjected to Reverse Transcriptase Polymerase Chain Reaction for genotyping. The identified genotypes were G9P8, G1P8, G2P4, G9P4 (non-vaccine genotype), G1P6, and G1 (P types not identified in 5 samples).

Frequency and risk factors for prevalent, incident, and persistent genital carcinogenic human papillomavirus infection in sexually active women: community based cohort study

Objective To investigate frequency and risk factors for prevalent, incident, and persistent carcinogenic human papillomavirus (HPV) in young women before the introduction of immunisation against HPV types 16 and 18...

Detection of human papillomavirus infection in women attending a colposcopy clinic

Background Infection by human papillomavirus (HPV) is the main cause of and a necessary factor for cervical cancer. There are more than 100 known HPV genotypes, although HPV genotypes do not all have the same risk of inducing cervical cancer. The main aim of this study is to know the distribution of different types of HPV in women attending a colposcopy clinic for cervical dysplasia. Methods We prospectively identified and enrolled a cohort of women followed for cervical dysplasia who were referred to the colposcopy clinic of University Hospital Sant Joan de Déu in Barcelona, Spain, from April 2003 to April 2007. Two cervical scrape samples from each patient were collected for routine cytology and for identification of HPV DNA. During the study period, 2 techniques (Line Probe assay and microarray assay) were used consecutively. Findings HPV DNA was detected in 68% of patients (338 of 496 women) with statistically significant differences in positive results according to the cytologic category. Overall, the type distribution showed a predominance of genotype HPV-16 (27% of the total patients) followed by HPV-53 (9.4%), HPV-51 (8%), and HPV-51 (8%). Multiple genotype detection was observed in 35.5% of the patients with HPV infection. HPV-16 was mainly associated with the probable high-risk genotypes: HPV-53 and HPV-66. Conclusion The higher prevalence of high-risk nonvaccine genotypes should be considered to increase vaccine efficiency.

Identification of vaccine human papillomavirus genotypes in squamous intraepithelial lesions (CIN2–3)

Objective To identify the prevalence of human papillomavirus vaccine genotypes and non-vaccine genotypes implicated in the appearance of cervical intraepithelial neoplasia (CIN2–3). Methods Prospective study of 519 women with abnormal cytology. All the women underwent a second Papanicolaou test, cervicovaginal sampling for type-specific HPV detection and colposcopy, and women with abnormal colposcopy results were referred to biopsy. Pearson's chi-square test was used for statistical analysis. Results HPV was detected in 340 patients (65.5%), and in 125 (24%) more than one HPV genotype was present. We selected 206 patients with CIN2 or CIN3 confirmed by biopsy. In 88 (42.7%) of these patients, HPV types 16 and 18 were detected, but only 58 (28.2%) without co-infection by other high-risk or probable high-risk HPV types. In 115 (55.8%) women diagnosed with CIN2 or CIN3 high-risk or probable high-risk HPV types other than 16 or 18 were found. High-risk and/or probable high-risk HPV genotypes not included in the vaccine were isolated in this study more frequently than 16 or 18, and this difference was statistically significant ( p = 0.047). Of the 206 women diagnosed with CIN2 or CIN3, 19 tested negative for HPV and 14 tested positive for low-risk HPV types. Conclusion Only 28.2% of women with CIN2 or CIN3 confirmed by biopsy were infected exclusively by HPV type 16 or 18, a finding that places in doubt the degree of protection afforded by HPV vaccination.