Sylvia Becker-Dreps

Both Lewis and Secretor Status Mediate Susceptibility to Rotavirus Infections in a Rotavirus Genotype–Dependent Manner

BACKGROUND The live oral rotavirus (RV) vaccines have shown a reduced efficacy in Africa. Recent in vitro studies have shown binding of the RV surface protein (VP4) to histo-blood group antigens (HBGAs) in an RV genotype-dependent manner, suggesting them to be putative receptors for RV. The diversity of HBGA phenotypes in different ethnic populations, combined with prevalence/absence of specific RV genotypes, led us to hypothesize whether the genetic variations in HBGAs in a population limit susceptibility to certain RV genotypes, plausibly leading to reduced vaccine efficacy. METHODS Association between HBGAs status and susceptibility to RV P genotypes was investigated in children in Burkina Faso and Nicaragua. In total, 242 children with diarrhea in Burkina Faso and Nicaragua were investigated, 93 of whom were RV positive. RESULTS In Burkina Faso, the P[8] RV strains (n = 27) infected only Lewis- and secretor-positive children (27/27; P < .0001), but no Lewis-negative children. In contrast, the P[6] strains (n = 27) infected predominantly Lewis-negative children (n = 18; P < .0001) but also Lewis-positive children, irrespective of their secretor status. The results from Nicaragua confirmed that all P[8]-infected children (n = 22) were secretor Lewis positive. CONCLUSIONS As VP4 of genotype P[8] is a component of current RV vaccines, our finding that Lewis-negative children are resistant to P[8] strains provides a plausible explanation for the reduced vaccine efficacy in populations with a high percentage of Lewis-negative individuals, such as in Africa. Furthermore, our findings provide a plausible explanation as to why P[6] RV strains are more common in Africa.

HPV vaccine acceptability among Kenyan women

As human papillomavirus (HPV) vaccines become available in less-developed countries, understanding womens attitudes towards HPV vaccines can help guide approaches to immunization programs. We assessed knowledge and interest in prophylactic HPV vaccines among Kenyan women seeking womens health services (N=147). They knew little about cervical cancer or HPV vaccine. Most women (95%, 95% confidence interval [CI]: 92%, 99%), however, were willing to have their daughters vaccinated with a vaccine that would prevent cervical cancer, with preference for an inexpensive vaccine requiring fewer doses.

Etiology of childhood diarrhea after rotavirus vaccine introduction: a prospective, population-based study in Nicaragua.

Background: Nicaragua was the first developing nation to implement routine immunization with the pentavalent rotavirus vaccine (RV5). In this RV5-immunized population, understanding infectious etiologies of childhood diarrhea is necessary to direct diarrhea treatment and prevention efforts. Methods: We followed a population-based sample of children <5 years in León, Nicaragua for diarrhea episodes through household visits. Information was obtained on RV5 history and sociodemographics. Stool samples collected during diarrhea episodes and among healthy children underwent laboratory analysis for viral, bacterial and parasitic enteropathogens. Detection frequency and incidence of each enteropathogen was calculated. Results: The 826 children in the cohort experienced 677 diarrhea episodes during 607.5 child-years of exposure time (1.1 episodes per child-year). At least 1 enteropathogen was detected among 61.1% of the 337 diarrheal stools collected. The most common enteropathogens among diarrheal stools were: norovirus (20.4%), sapovirus (16.6%), enteropathogenic Escherichia coli (11.3%), Entamoeba histolytica/dispar (8.3%), Giardia lamblia (8.0%) and enterotoxigenic E. coli (7.7%), with rotavirus detected among 5.3% of diarrheal stools. Enteropathogenic Escherichia coli and enterotoxigenic E. coli were frequently detected among stools from healthy children. Among children with diarrhea, norovirus was more commonly detected among younger children (< 2 years) and G. lamblia was more commonly detected among older children (2–4 years). The mean age of rotavirus detection was 34.6 months. Conclusions: In this Central American community after RV5 introduction, rotavirus was not commonly detected among children with diarrhea. Prevention and appropriate management of norovirus and sapovirus should be considered to further reduce the burden of diarrheal disease.

Changes in childhood pneumonia and infant mortality rates following introduction of the 13-valent pneumococcal conjugate vaccine in Nicaragua.

Background: In 2010, Nicaragua became the first developing nation to add 13-valent pneumococcal conjugate vaccine (PCV-13) to its national immunization schedule, using a “3+0” dosing schedule. We assessed changes in incidence rates of health facility visits for childhood pneumonia and infant mortality after PCV-13 introduction in the Department of León, Nicaragua. Methods: We collected visit diagnoses from all 107 public health facilities in León between 2008 and 2012. We compared rates of pneumonia hospitalizations, ambulatory visits for pneumonia and infant mortality during the prevaccine (2008–2010) and vaccine (2011–2012) periods among different age groups of children using generalized estimating equations, accounting for clustering by municipality. Exposure time was estimated by official municipality population estimates. Results: The adjusted incidence rate ratio for pneumonia hospitalization in the vaccine versus prevaccine period was 0.67 (0.59–0.75) among infants and 0.74 (0.67–0.81) among 1-year olds. The adjusted incidence rate ratio for ambulatory visits for pneumonia was 0.87 (0.75–1.01) among infants, and 0.84 (0.74, 0.95) among 1-year olds. The adjusted incidence rate ratio for infant mortality was 0.67 (0.57–0.80). We also observed lower rates of health facility visits for pneumonia among age groups (2- to 4-year old and 5- to 14-year old) not eligible to receive PCV-13. Conclusions: Within the first 2 years of a PCV-13 immunization program in Nicaragua, we observed lower rates of hospitalizations and ambulatory visits for pneumonia among children of all ages and a lower infant mortality rate. Lower rates of pneumonia among age groups not eligible to receive PCV-13 suggest an indirect effect of the vaccine.

Patterns of rotavirus vaccine uptake and use in privately-insured US infants, 2006-2010.

Rotavirus vaccines are highly effective at preventing gastroenteritis in young children and are now universally recommended for infants in the US. We studied patterns of use of rotavirus vaccines among US infants with commercial insurance. We identified a large cohort of infants in the MarketScan Research Databases, 2006–2010. The analysis was restricted to infants residing in states without state-funded rotavirus vaccination programs. We computed summary statistics and used multivariable regression to assess the association between patient-, provider-, and ecologic-level variables of rotavirus vaccine receipt and series completion. Approximately 69% of 594,117 eligible infants received at least one dose of rotavirus vaccine from 2006–2010. Most infants received the rotavirus vaccines at the recommended ages, but more infants completed the series for monovalent rotavirus vaccine than pentavalent rotavirus vaccine or a mix of the vaccines (87% versus 79% versus 73%, P<0.001). In multivariable analyses, the strongest predictors of rotavirus vaccine series initiation and completion were receipt of the diphtheria, tetanus and acellular pertussis vaccine (Initiation: RR = 7.91, 95% CI = 7.69–8.13; Completion: RR = 1.26, 95% CI = 1.23–1.29), visiting a pediatrician versus family physician (Initiation: RR = 1.51, 95% CI = 1.49–1.52; Completion: RR = 1.13, 95% CI = 1.11–1.14), and living in a large metropolitan versus smaller metropolitan, urban, or rural area. We observed rapid diffusion of the rotavirus vaccine in routine practice; however, approximately one-fifth of infants did not receive at least one dose of vaccine as recently as 2010. Interventions to increase rotavirus vaccine coverage should consider targeting family physicians and encouraging completion of the vaccine series.

Trends in antibiotic treatment of acute otitis media and treatment failure in children, 2000-2011.

Objectives Guidelines to treat acute otitis media (AOM) were published in 2004. Initial declines in prescribing were shown, but its unknown if they were sustained. We examine trends in antibiotic dispensing patterns to treat AOM among a large population of children. We also document trends in antibiotic failure. Study Design Children aged 3 months to 12 years with an AOM diagnosis, enrolled in a commercial claims database between January 1, 2000-December 31, 2011 were included. Pharmacy claims within 7 days of diagnosis were searched for antibiotic prescriptions. Antibiotic failure was defined as a dispensing of a different antibiotic class within 2-18 days after the first prescription. We analyzed trends in antibiotic use and failure by class of antibiotic and year. Results We identified over 4 million children under 13 years with AOM. The proportion of antibiotic dispensing decreased from 66.0% in 2005 to 51.9% in 2007, after which the instances of dispensing rebounded to pre-guideline levels. However, levels began decreasing again in 2010 and the antibiotic use rate in 2011 was 57.6%. Cephalosporin prescriptions increased by 41.5% over eleven years. Antibiotic failure decreased slightly, and macrolides had the lowest proportion of failures, while all other classes had failure rates around 10%. Conclusions In recent years, antibiotic dispensing to treat AOM remains high. In addition, the use of broad-spectrum antibiotics is increasing despite having a high rate of treatment failure. Overprescribing of antibiotics and use of non-penicillin therapy for AOM treatment could lead to the development of antibiotic-resistant infections.

Association of Maternal Immunity with Rotavirus Vaccine Immunogenicity in Zambian Infants.

Introduction Live attenuated oral vaccines against rotavirus (RV) have been shown to be less efficacious in children from developing countries. Reasons for this disparity are not fully understood. We assessed the role of maternal factors including breast milk RV-specific IgA, transplacentally acquired infant serum RV-specific IgG and maternal HIV status in seroconversion among Zambian infants routinely immunized with Rotarix™ (RV1). Methods 420 mother-child pairs were recruited at infant age 6–12 weeks in Lusaka. Clinical information and samples were collected at baseline and at one month following the second dose of RV1. Determination of breast milk RV-specific IgA and serum RV-specific IgA and IgG was done using standardized ELISA. Seroconversion was defined as a ≥ 4 fold rise in serum IgA titre from baseline to one-month post RV1 dose 2, while seropositivity of IgA was defined as serum titre ≥ 40 and antibody variables were modelled on log-base 2. Logistic regression was used to identify predictors of the odds of seroconversion. Results Baseline infant seropositivity was 25.5% (91/357). The seroconversion frequency was 60.2% (130/216). Infants who were IgA seropositive at baseline were less likely to seroconvert compared to their seronegative counterparts (P = 0.04). There was no evidence of an association between maternal HIV status and seroconversion (P = 0.25). Higher titres of breast milk rotavirus-specific IgA were associated with a lower frequency of seroconverson (Nonparametric test for trend Z = -2.84; P<0.01): a two-fold increase in breast milk RV-specific IgA titres was associated with a 22% lower odds of seroconversion (OR = 0.80; 95% CI = 0.68–0.94; P = 0.01). There was seasonal variation in baseline breast milk rotavirus-specific IgA titres, with significantly higher GMTs during the cold dry months (P = 0.01). Conclusion Low immunogenicity of RV1 vaccine could be explained in part by exposure to high antibody titres in breast milk and early exposure to wild-type rotavirus infections. Potential interference of anti-RV specific IgA in breast milk and pre-vaccination serum RV specific-IgA and IgG titres with RV1 seroconversion and effectiveness requires further research.

Direct, Indirect, Total, and Overall Effectiveness of the Rotavirus Vaccines for the Prevention of Gastroenteritis Hospitalizations in Privately Insured US Children, 2007–2010

We demonstrate how direct, indirect, total, and overall effectiveness estimates and absolute benefits of rotavirus vaccines vary through the years following vaccine introduction. Privately insured US children in a large claims database were followed from age 8 months until they 1) experienced a hospitalization for rotavirus or acute gastroenteritis; 2) lost continuous health plan enrollment; 3) turned 20 months of age; or 4) reached the end of the study period. Vaccine effectiveness estimates in preventing rotavirus and acute gastroenteritis hospitalizations were estimated using Cox proportional hazards regression, stratified by calendar year and adjusted for birth month. Incidence rate differences were estimated to determine the absolute number of gastroenteritis hospitalizations prevented in the cohort. Among 905,718 children, 51%, 66%, 80%, and 86% received 1 or more doses of rotavirus vaccine in each year from 2007 to 2010. The direct vaccine effectiveness of 1 or more doses of rotavirus vaccine in preventing rotavirus gastroenteritis hospitalizations ranged from 87% to 92% each year. Accounting for indirect protection increased estimates of vaccine effectiveness by an additional 3%-8% among those vaccinated. Failing to account for population-level vaccine benefits in 2010, when circulation of rotavirus was low, could underestimate the sustained impact of the vaccine program.

Changes in Childhood Diarrhea Incidence in Nicaragua Following 3 Years of Universal Infant Rotavirus Immunization

Background: Although the pentavalent rotavirus vaccine was highly efficacious against rotavirus diarrhea in clinical trials, the effectiveness of vaccine under field conditions in the developing world is unclear. In October 2006, Nicaragua became the first developing nation to implement universal infant immunization with the pentavalent rotavirus vaccine. To assess the effect of the immunization program, we examined the incidence of diarrhea episodes between 2003 and 2009 among children in the state of León, Nicaragua. Methods: We extracted data on diarrhea episodes from health ministry records. We used scaled Poisson regression models to estimate diarrhea incidence rate ratios for the period following the programs implementation to the period before implementation. Results: Following implementation of the immunization program, diarrhea episodes among infants were reduced (incidence rate ratios: 0.85, 95% confidence interval: 0.71–1.02) during the rotavirus season, but appear to have increased during other months. Conclusions: Although the immunization program appears effective in reducing diarrhea episodes during the rotavirus season, a large burden of diarrhea still persists during the remainder of the year.

Rotavirus-specific IgG antibodies from mothers' serum may inhibit infant immune responses to the pentavalent rotavirus vaccine.

© 2014 Lippincott Williams & Wilkins www.pidj.com | 115 Rotavirus-specific IgG Antibodies From Mothers’ Serum May Inhibit Infant Immune Responses to the Pentavalent Rotavirus Vaccine in Exon 2 of the IL2RG gene (c.252C>A, p.Asn84Lys; MIM# 300400) and curative therapy with stem cell transplantation was initiated at our specialized medical center. We identified rotavirus vaccine strain in stool samples by sequencing of 8 different gene segments (VP1, VP2, VP4, VP6, VP7, NSP2, NSP4 and NSP5). In all segments vaccine-associated sequences harboring few new mutations were found, leading to the conclusion that the child’s chronic gastroenteritis was caused by persisting infection with the vaccine rotavirus strain (see Table, Supplemental Digital Content 1, http://links.lww.com/INF/B978). No other pathogen could be identified in multiple stool samples, including uncommon parasites, coccidia and helminths. Notably, all stool, blood and respiratory specimens were also tested by Luminex xTAG respiratory and xTAG gastrointestinal pathogen panel (Abbott Molecular, Wiesbaden, Germany). In samples from the respiratory tract, we detected high copy numbers of human bocavirus (HBoV) and rhinovirus, which most likely subsequently caused respiratory failure in our patient. Despite all intensive supportive care and treatment, the boy’s condition deteriorated and he died on day 1 after stem cell transplantation. In addition to the association with intussusception, shedding of rotavirus for a period of time after oral vaccination and vaccineinduced severe gastroenteritis including infection of healthy siblings have been reported. The observation of acute and chronic infections by vaccine strain rotavirus in immunocompromised children led to the addition of SCID as contraindication for administration of rotavirus vaccine. Our SCID patient presented already with advanced disease and severely reduced general condition. We believe that viral shedding of rotavirus for such a prolonged period of time has not been previously reported and might be explained by the lack of timely adequate medical management. We cannot completely exclude that other gastrointestinal infections and other comorbidities might have been involved, but we propose that vaccine-acquired rotavirus-infection had probably contributed significantly to the fatal outcome. The clinical manifestation and diagnosis of SCID patients might be delayed well into the life period after the recommended vaccination schedule. Therefore, we emphasize the negative effect that rotavirus vaccination might have in these endangered patients and we strongly support efforts of mandatory newborn screening for SCID.