Publications by authors named "Beth D Kirkpatrick"

84 Publications

Immunotranscriptomic profiling the acute and clearance phases of a human challenge dengue virus serotype 2 infection model.

Nat Commun 2021 05 24;12(1):3054. Epub 2021 May 24.

Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont, Burlington, VT, USA.

About 20-25% of dengue virus (DENV) infections become symptomatic ranging from self-limiting fever to shock. Immune gene expression changes during progression to severe dengue have been documented in hospitalized patients; however, baseline or kinetic information is difficult to standardize in natural infection. Here we profile the host immunotranscriptome response in humans before, during, and after infection with a partially attenuated rDEN2Δ30 challenge virus (ClinicalTrials.gov NCT02021968). Inflammatory genes including type I interferon and viral restriction pathways are induced during DENV2 viremia and return to baseline after viral clearance, while others including myeloid, migratory, humoral, and growth factor immune regulation factors pathways are found at non-baseline levels post-viremia. Furthermore, pre-infection baseline gene expression is useful to predict rDEN2Δ30-induced immune responses and the development of rash. Our results suggest a distinct immunological profile for mild rDEN2Δ30 infection and offer new potential biomarkers for characterizing primary DENV infection.
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http://dx.doi.org/10.1038/s41467-021-22930-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8144425PMC
May 2021

HLA class I and II associations with common enteric pathogens in the first year of life.

EBioMedicine 2021 May 25;67:103346. Epub 2021 Apr 25.

Department of Medicine, Infectious Diseases and International Health, University of Virginia School of Medicine, Charlottesville, VA, USA.. Electronic address:

Background: genetic susceptibility to infection is mediated by numerous host factors, including the highly diverse, classical human leukocyte antigen (HLA) genes, which are critical genetic determinants of immunity. We systematically evaluated the effect of HLA alleles and haplotypes on susceptibility to 12 common enteric infections in children during the first year of life in an urban slum of Dhaka, Bangladesh.

Methods: a birth cohort of 601 Bangladeshi infants was prospectively monitored for diarrhoeal disease. Each diarrhoeal stool sample was analyzed for enteric pathogens by multiplex TaqMan Array Card (TAC). High resolution genotyping of HLA class I (A and B) and II (DRB1, DQA1, and DQB1) genes was performed by next-generation sequencing. We compared the frequency of HLA alleles and haplotypes between infected and uninfected children.

Findings: we identified six individual allele associations and one five-locus haplotype association. One allele was associated with protection: A*24:02 - EAEC. Five alleles were associated with increased risk: A*24:17 - typical EPEC, B*15:01 - astrovirus, B*38:02 - astrovirus, B*38:02 - Cryptosporidium and DQA1*01:01 - Cryptosporidium. A single five-locus haplotype was associated with protection: A*11:01~B*15:02~DRB1*12:02~DQA1*06:01~DQB1*03:01- adenovirus 40/41.

Interpretation: our findings suggest a role for HLA in susceptibility to early enteric infection for five pathogens. Understanding the genetic contribution of HLA in susceptibility has important implications in vaccine design and understanding regional differences in incidence of enteric infection.

Funding: this research was supported by the National Institute of Health (NIH) and the Bill and Melinda Gates Foundation.
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http://dx.doi.org/10.1016/j.ebiom.2021.103346DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093888PMC
May 2021

A tetravalent live attenuated dengue virus vaccine stimulates balanced immunity to multiple serotypes in humans.

Nat Commun 2021 02 17;12(1):1102. Epub 2021 Feb 17.

Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, NC, USA.

The four-dengue virus (DENV) serotypes infect several hundred million people annually. For the greatest safety and efficacy, tetravalent DENV vaccines are designed to stimulate balanced protective immunity to all four serotypes. However, this has been difficult to achieve. Clinical trials with a leading vaccine demonstrated that unbalanced replication and immunodominance of one vaccine component over others can lead to low efficacy and vaccine enhanced severe disease. The Laboratory of Infectious Diseases at the National Institutes of Health has developed a live attenuated tetravalent DENV vaccine (TV003), which is currently being tested in phase 3 clinical trials. Here we report, our study to determine if TV003 stimulate balanced and serotype-specific (TS) neutralizing antibody (nAb) responses to each serotype. Serum samples from twenty-one dengue-naive individuals participated under study protocol CIR287 (ClinicalTrials.gov NCT02021968) are analyzed 6 months after vaccination. Most subjects (76%) develop TS nAbs to 3 or 4 DENV serotypes, indicating immunity is induced by each vaccine component. Vaccine-induced TS nAbs map to epitopes known to be targets of nAbs in people infected with wild type DENVs. Following challenge with a partially attenuated strain of DENV2, all 21 subjects are protected from the efficacy endpoints. However, some vaccinated individuals develop post challenge nAb boost, while others mount post-challenge antibody responses that are consistent with sterilizing immunity. TV003 vaccine induced DENV2 TS nAbs are associated with sterilizing immunity. Our results indicate that nAbs to TS epitopes on each serotype may be a better correlate than total levels of nAbs currently used for guiding DENV vaccine development.
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http://dx.doi.org/10.1038/s41467-021-21384-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7889627PMC
February 2021

Stimulation of B Cell Immunity in Flavivirus-Naive Individuals by the Tetravalent Live Attenuated Dengue Vaccine TV003.

Cell Rep Med 2020 Dec 22;1(9):100155. Epub 2020 Dec 22.

Department of Microbiology and Molecular Genetics, Vaccine Testing Center, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA.

The tetravalent live attenuated dengue vaccine candidate TV003 induces neutralizing antibodies against all four dengue virus serotypes (DENV1-DENV4) and protects against experimental challenge with DENV2 in humans. Here, we track vaccine viremia and B and T cell responses to this vaccination/challenge model to understand how vaccine viremia links adaptive immunity and development of protective antibody responses. TV003 viremia triggers an acute plasmablast response that, in combination with DENV-specific CD4 T cells, correlates with serum neutralizing antibodies. TV003 vaccinees develop DENV2-reactive memory B cells, including serotype-specific and multivalent specificities in line with the composition of serum antibodies. There is no post-challenge plasmablast response in vaccinees, although stronger and earlier post-TV003 plasmablast responses associate with sterile humoral protection from DENV2 challenge. TV003 vaccine triggers plasmablasts and memory B cells, which, with support from CD4 T cells, functionally link early vaccine viremia and the serum antibody responses.
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http://dx.doi.org/10.1016/j.xcrm.2020.100155DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7762770PMC
December 2020

Kinetics and isotype assessment of antibodies targeting the spike protein receptor-binding domain of severe acute respiratory syndrome-coronavirus-2 in COVID-19 patients as a function of age, biological sex and disease severity.

Clin Transl Immunology 2020 7;9(10):e1189. Epub 2020 Oct 7.

Department of Microbiology and Molecular Genetics Larner College of Medicine, University of Vermont Burlington VT USA.

Objectives: There is an incomplete understanding of the host humoral immune response to severe acute respiratory syndrome (SARS)-coronavirus (CoV)-2, which underlies COVID-19, during acute infection. Host factors such as age and sex as well as the kinetics and functionality of antibody responses are important factors to consider as vaccine development proceeds. The receptor-binding domain of the CoV spike (RBD-S) protein mediates host cell binding and infection and is a major target for vaccine design to elicit neutralising antibodies.

Methods: We assessed serum anti-SARS-CoV-2 RBD-S IgG, IgM and IgA antibodies by a two-step ELISA and neutralising antibodies in a cross-sectional study of hospitalised COVID-19 patients of varying disease severities. Anti-RBD-S IgG levels were also determined in asymptomatic seropositives.

Results: We found equivalent levels of anti-RBD-S antibodies in male and female patients and no age-related deficiencies even out to 93 years of age. The anti-RBD-S response was evident as little as 6 days after onset of symptoms and for at least 5 weeks after symptom onset. Anti-RBD-S IgG, IgM and IgA responses were simultaneously induced within 10 days after onset, with anti-RBD-S IgG sustained over a 5-week period. Anti-RBD-S antibodies strongly correlated with neutralising activity. Lastly, anti-RBD-S IgG responses were higher in symptomatic COVID-19 patients during acute infection compared with asymptomatic seropositive donors.

Conclusion: Our results suggest that anti-RBD-S IgG reflect functional immune responses to SARS-CoV-2, but do not completely explain age- and sex-related disparities in COVID-19 fatalities.
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http://dx.doi.org/10.1002/cti2.1189DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7541824PMC
October 2020

Direct RT-qPCR detection of SARS-CoV-2 RNA from patient nasopharyngeal swabs without an RNA extraction step.

PLoS Biol 2020 10 2;18(10):e3000896. Epub 2020 Oct 2.

Division of Immunobiology, Department of Medicine, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington, Vermont, United States of America.

The ongoing COVID-19 pandemic has created an unprecedented need for rapid diagnostic testing. The World Health Organization (WHO) recommends a standard assay that includes an RNA extraction step from a nasopharyngeal (NP) swab followed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to detect the purified SARS-CoV-2 RNA. The current global shortage of RNA extraction kits has caused a severe bottleneck to COVID-19 testing. The goal of this study was to determine whether SARS-CoV-2 RNA could be detected from NP samples via a direct RT-qPCR assay that omits the RNA extraction step altogether. The direct RT-qPCR approach correctly identified 92% of a reference set of blinded NP samples (n = 155) demonstrated to be positive for SARS-CoV-2 RNA by traditional clinical diagnostic RT-qPCR that included an RNA extraction. Importantly, the direct method had sufficient sensitivity to reliably detect those patients with viral loads that correlate with the presence of infectious virus. Thus, this strategy has the potential to ease supply choke points to substantially expand COVID-19 testing and screening capacity and should be applicable throughout the world.
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http://dx.doi.org/10.1371/journal.pbio.3000896DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7556528PMC
October 2020

Lewis Blood-group Antigens Are Associated With Altered Susceptibility to Shigellosis.

Clin Infect Dis 2021 06;72(11):e868-e871

Department of Medicine, Division of International Health and Infectious Diseases, University of Virginia School of Medicine, Charlottesville, Virginia, USA.

In a cohort of infants, we found that lack of the Lewis histo-blood group antigen was associated with increased susceptibility to shigellosis. Broadly inhibiting fucosylation in epithelial cells in vitro decreased invasion by Shigella flexneri. These results support a role for fucosylated glycans in susceptibility to shigellosis.
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http://dx.doi.org/10.1093/cid/ciaa1409DOI Listing
June 2021

Kinetics and Isotype Assessment of Antibodies Targeting the Spike Protein Receptor Binding Domain of SARS-CoV-2 In COVID-19 Patients as a function of Age and Biological Sex.

medRxiv 2020 Jul 16. Epub 2020 Jul 16.

SARS-CoV-2 is the newly emerged virus responsible for the global COVID-19 pandemic. There is an incomplete understanding of the host humoral immune response to SARS-CoV-2 during acute infection. Host factors such as age and sex as well the kinetics and functionality of antibody responses are important factors to consider as vaccine development proceeds. The receptor-binding domain of the CoV spike (RBD-S) protein is important in host cell recognition and infection and antibodies targeting this domain are often neutralizing. In a cross-sectional study of anti-RBD-S antibodies in COVID-19 patients we found equivalent levels in male and female patients and no age-related deficiencies even out to 93 years of age. The anti-RBD-S response was evident as little as 6 days after onset of symptoms and for at least 5 weeks after symptom onset. Anti-RBD-S IgG, IgM, and IgA responses were simultaneously induced within 10 days after onset, but isotype-specific kinetics differed such that anti-RBD-S IgG was most sustained over a 5-week period. The kinetics and magnitude of neutralizing antibody formation strongly correlated with that seen for anti-RBD-S antibodies. Our results suggest age- and sex- related disparities in COVID-19 fatalities are not explained by anti-RBD-S responses. The multi-isotype anti-RBD-S response induced by live virus infection could serve as a potential marker by which to monitor vaccine-induced responses.
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http://dx.doi.org/10.1101/2020.07.15.20154443DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7386516PMC
July 2020

DIRECT RT-qPCR DETECTION OF SARS-CoV-2 RNA FROM PATIENT NASOPHARYNGEAL SWABS WITHOUT AN RNA EXTRACTION STEP.

bioRxiv 2020 Apr 6. Epub 2020 Apr 6.

Department of Medicine, Division of Immunobiology, Robert Larner, M.D. College of Medicine, University of Vermont, Burlington VT, 05405, USA.

The ongoing COVID-19 pandemic has caused an unprecedented need for rapid diagnostic testing. The Centers for Disease Control and Prevention (CDC) and the World Health Organization (WHO) recommend a standard assay that includes an RNA extraction step from a nasopharyngeal (NP) swab followed by reverse transcription-quantitative polymerase chain reaction (RT-qPCR) to detect the purified SARS-CoV-2 RNA. The current global shortage of RNA extraction kits has caused a severe bottleneck to COVID-19 testing. We hypothesized that SARS-CoV-2 RNA could be detected from NP samples via a direct RT-qPCR assay that omits the RNA extraction step altogether, and tested this hypothesis on a series of blinded clinical samples. The direct RT-qPCR approach correctly identified 92% of NP samples (n = 155) demonstrated to be positive for SARS-CoV-2 RNA by traditional clinical diagnostic RT-qPCR that included an RNA extraction. Thus, direct RT-qPCR could be a front-line approach to identify the substantial majority of COVID-19 patients, reserving a repeat test with RNA extraction for those individuals with high suspicion of infection but an initial negative result. This strategy would drastically ease supply chokepoints of COVID-19 testing and should be applicable throughout the world.
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http://dx.doi.org/10.1101/2020.03.20.001008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7239058PMC
April 2020

Immunogenicity and Safety of a Tetravalent Recombinant Subunit Dengue Vaccine in Adults Previously Vaccinated with a Live Attenuated Tetravalent Dengue Vaccine: Results of a Phase-I Randomized Clinical Trial.

Am J Trop Med Hyg 2020 08 7;103(2):855-863. Epub 2020 May 7.

Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland.

New dengue vaccines are needed to prevent this globally expanding vector-borne disease. The V180 vaccine candidate consists of four recombinant, soluble, dengue virus envelope glycoproteins and has been previously evaluated in two clinical trials for safety and immunogenicity in -naive participants (NCT01477580 and NCT0093642). Here, we report on a randomized, placebo-controlled, double-blind study of the safety and immunogenicity of the V180 vaccine in subjects who have previously received the live attenuated tetravalent vaccine (LATV) developed by the National Institute of Allergy and Infectious Diseases (protocol #V180-002 [CIR-301]). The study was designed to evaluate whether this recombinant subunit vaccine could boost the neutralizing antibody responses induced by dengue LATV. Twenty participants who had previously received one or two doses of dengue LATV were randomized and received a single dose of V180 nonadjuvanted ( = 8), V180 adjuvanted with Alhydrogel™ (aluminum hydroxide gel, Brenntag Biosector, Frederikssund, Denmark) ( = 8), or placebo ( = 4). Immunogenicity was measured using a plaque reduction neutralization test at days 1, 15, 28, and 180 after vaccination. In addition, vaccine safety (solicited and unsolicited adverse events) was assessed using a vaccination report card for 28 days following vaccination, and serious adverse events were captured from the time of informed consent through the final study visit at 6 months after vaccination. The results of the study demonstrate that the V180 vaccine is generally well tolerated and immunogenic in these dengue-seropositive volunteers.
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http://dx.doi.org/10.4269/ajtmh.20-0042DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7410446PMC
August 2020

Rapid Induction and Maintenance of Virus-Specific CD8 T and CD4 T Cells Following Protective Vaccination Against Dengue Virus Challenge in Humans.

Front Immunol 2020 24;11:479. Epub 2020 Mar 24.

Department of Microbiology and Molecular Genetics, Larner College of Medicine, University of Vermont, Burlington, VT, United States.

Dengue virus (DENV) is a mosquito-borne flavivirus that causes serious human disease. The current lack of an effective vaccine to simultaneously protect against the four serotypes of DENV in seronegative individuals is a major unmet medical need. Further, the immunological basis for protective immunity in the setting of DENV infection or vaccination is not fully understood. Our team has developed a live attenuated tetravalent dengue virus vaccine that provides complete protection in a human model of dengue virus challenge. The goal of this study was to define, in the context of protective human vaccination, the quality of vaccine-induced DENV-specific CD8 and CD4 T cells and the temporal dynamics associated with their formation and maintenance. Multifunctional, DENV-specific CD8 and CD4 T cells developed 8-14 days after vaccination and were maintained for at least 6 months. Virus-specific CD8 T cells were a mixture of effector memory T cells (T) and effector memory T cells re-expressing CD45RA (T), with T cells predominating until day 21 post-vaccination and T cells thereafter. The majority of virus-specific CD4 T cells were T with a small fraction being T. The frequency of virus-specific CD8 and CD4 T cells were further skewed to the T phenotype following either a second dose of the tetravalent vaccine or challenge with a single serotype of DENV. Collectively, our study has defined the phenotypic profile of antiviral CD8 and CD4 T cells associated with protective immunity to DENV infection and the kinetics of their formation and maintenance.
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http://dx.doi.org/10.3389/fimmu.2020.00479DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7105617PMC
March 2021

New strategies for profiling and characterization of human milk oligosaccharides.

Glycobiology 2020 09;30(10):774-786

Complex Carbohydrate Research Center, The University of Georgia, Athens, GA 30602, USA.

Human breast milk is an incredibly rich and complex biofluid composed of proteins, lipids and complex carbohydrates, including a diverse repertoire of free human milk oligosaccharides (HMOs). Strikingly, HMOs are not digested by the infant but function as prebiotics for bacterial strains associated with numerous benefits. Considering the broad variety of beneficial effects of HMOs, and the vast number of factors that affect breast milk composition, the analysis of HMO diversity and complexity is of utmost relevance. Using human milk samples from a cohort of Bangladeshi mothers participating in a study on malnutrition and stunting in children, we have characterized breast milk oligosaccharide composition by means of permethylation followed by liquid chromatography coupled with high-resolution tandem mass spectrometry (LC-MS/MS) analysis. This approach identified over 100 different glycoforms and showed a wide diversity of milk composition, with a predominance of fucosylated and sialylated HMOs over nonmodified HMOs. We observed that these samples contain on average 80 HMOs, with the highest permethylated masses detected being >5000 mass units. Here we report an easily implemented method developed for the separation, characterization and relative quantitation of large arrays of HMOs, including higher molecular weight sialylated HMOs. Our ultimate goal is to create a simple, high-throughput method, which can be used for full characterization of sialylated and/or fucosylated HMOs. These results demonstrate how current analytical techniques can be applied to characterize human milk composition, providing new tools to help the scientific community shed new light on the impact of HMOs during infant development.
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http://dx.doi.org/10.1093/glycob/cwaa028DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7526734PMC
September 2020

Maternal Secretor Status Affects Oral Rotavirus Vaccine Response in Breastfed Infants in Bangladesh.

J Infect Dis 2020 Mar 11. Epub 2020 Mar 11.

The University of Vermont Vaccine Testing Center, Larner College of Medicine, University of Vermont; Burlington, VT, USA.

Secretor status controls mucosal histoblood group antigen expression and is associated with susceptibility to rotavirus diarrhea, with non-secretors less susceptible to symptomatic infection. The role of breast milk secretor status on oral live-attenuated rotavirus vaccine response in breastfed infants has not been explored. In a monovalent G1P[8] rotavirus vaccine (RotarixTM) trial in Bangladesh, rotavirus-specific plasma IgA antibody seroconversion rates were higher among infants of maternal non-secretors (39% vs 23%, P=0.001). Maternal status remained a significant predictor when correcting for infant status (P=0.002). Maternal secretor status should be considered when interpreting oral rotavirus vaccine responses in low- and middle-income settings.
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http://dx.doi.org/10.1093/infdis/jiaa101DOI Listing
March 2020

Predictors of oral rotavirus vaccine immunogenicity in rural Zimbabwean infants.

Vaccine 2020 03 19;38(13):2870-2878. Epub 2020 Feb 19.

Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe; Centre for Genomics & Child Health, Blizard Institute, Queen Mary University of London, UK; Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address:

Background: Oral rotavirus vaccines (RVV) have poor immunogenicity in low-income countries, for reasons that remain unclear. This study identified the determinants of RVV immunogenicity among infants in rural Zimbabwe.

Methods: Anti-rotavirus IgA titres were measured among a sub-group of infants enrolled in the Sanitation Hygiene Infant Nutrition Efficacy (SHINE) trial (NCT01824940). SHINE was a cluster-randomized trial of improved infant and young child feeding, and improved water, sanitation and hygiene (WASH) in two rural Zimbabwean districts. Infants received RVV as part of the national immunisation programme. Among HIV-unexposed infants in the non-WASH trial arms, we evaluated associations between potential risk factors (vaccine schedule and dose, maternal and infant nutritional status, infant diarrhoea, and household environment) and RVV immunogenicity (seroconversion, seropositivity and geometric mean titres) using multivariable regression.

Results: Among 219 infants with seroconversion data, 43 (20%) successfully seroconverted and 176 (80%) failed to seroconvert to RVV. Seroconversion was positively associated with a higher length-for-age Z-score (LAZ) around the time of vaccination (adjusted RR 1.27 (95% CI 1.04, 1.55), P = 0.021), and negatively associated with concurrent OPV and RVV administration (adjusted RR 0.36 (0.19, 0.71), P = 0.003). Among 472 infants with post-vaccination titres, a higher LAZ score was associated with increased seropositivity (aRR 1.21 (95% CI 1.06, 1.38), P = 0.004), and higher birthweight was associated with increased IgA titres (0.45 (95%CI 0.18, 1.09) U/mL greater per 100 g gain in birthweight; P = 0.001).

Conclusions: Infant ponderal and linear growth were positively associated with RVV immunogenicity, while concurrent administration of OPV was negatively associated with RVV immunogenicity. Together, these findings suggest that improving foetal growth and separating RVV and OPV administration are plausible approaches to increasing RVV immunogenicity.
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http://dx.doi.org/10.1016/j.vaccine.2020.01.097DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7065039PMC
March 2020

Genome-Wide Association Study of Cryptosporidiosis in Infants Implicates .

mBio 2020 02 4;11(1). Epub 2020 Feb 4.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

Diarrhea is a major cause of both morbidity and mortality worldwide, especially among young children. Cryptosporidiosis is a leading cause of diarrhea in children, particularly in South Asia and sub-Saharan Africa, where it is responsible for over 200,000 deaths per year. Beyond the initial clinical presentation of diarrhea, it is associated with long-term sequelae such as malnutrition and neurocognitive developmental deficits. Risk factors include poverty and overcrowding, and yet not all children with these risk factors and exposure are infected, nor do all infected children develop symptomatic disease. One potential risk factor to explain these differences is their human genome. To identify genetic variants associated with symptomatic cryptosporidiosis, we conducted a genome-wide association study (GWAS) examining 6.5 million single nucleotide polymorphisms (SNPs) in 873 children from three independent cohorts in Dhaka, Bangladesh, namely, the Dhaka Birth Cohort (DBC), the Performance of Rotavirus and Oral Polio Vaccines in Developing Countries (PROVIDE) study, and the Cryptosporidiosis Birth Cohort (CBC). Associations were estimated separately for each cohort under an additive model, adjusting for length-for-age Z-score at 12 months of age, the first two principal components to account for population substructure, and genotyping batch. The strongest meta-analytic association was with rs58296998 ( = 3.73 × 10), an intronic SNP and expression quantitative trait locus (eQTL) of protein kinase C alpha (). Each additional risk allele conferred 2.4 times the odds of -associated diarrhea in the first year of life. This genetic association suggests a role for protein kinase C alpha in pediatric cryptosporidiosis and warrants further investigation. Globally, diarrhea remains one of the major causes of pediatric morbidity and mortality. The initial symptoms of diarrhea can often lead to long-term consequences for the health of young children, such as malnutrition and neurocognitive developmental deficits. Despite many children having similar exposures to infectious causes of diarrhea, not all develop symptomatic disease, indicating a possible role for human genetic variation. Here, we conducted a genetic study of susceptibility to symptomatic disease associated with infection (a leading cause of diarrhea) in three independent cohorts of infants from Dhaka, Bangladesh. We identified a genetic variant within protein kinase C alpha () associated with higher risk of cryptosporidiosis in the first year of life. These results indicate a role for human genetics in susceptibility to cryptosporidiosis and warrant further research to elucidate the mechanism.
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http://dx.doi.org/10.1128/mBio.03343-19DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7002356PMC
February 2020

Immune responses to O-specific polysaccharide (OSP) in North American adults infected with Vibrio cholerae O1 Inaba.

PLoS Negl Trop Dis 2019 11 19;13(11):e0007874. Epub 2019 Nov 19.

Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, United States of America.

Background: Antibodies targeting O-specific polysaccharide (OSP) of Vibrio cholerae may protect against cholera; however, little is known about this immune response in infected immunologically naïve humans.

Methodology: We measured serum anti-OSP antibodies in adult North American volunteers experimentally infected with V. cholerae O1 Inaba El Tor N16961. We also measured vibriocidal and anti-cholera toxin B subunit (CtxB) antibodies and compared responses to those in matched cholera patients in Dhaka, Bangladesh, an area endemic for cholera.

Principal Findings: We found prominent anti-OSP antibody responses following initial cholera infection: these responses were largely IgM and IgA, and highest to infecting serotype with significant cross-serotype reactivity. The anti-OSP responses peaked 10 days after infection and remained elevated over baseline for ≥ 6 months, correlated with vibriocidal responses, and may have been blunted in blood group O individuals (IgA anti-OSP). We found significant differences in immune responses between naïve and endemic zone cohorts, presumably reflecting previous exposure in the latter.

Conclusions: Our results define immune responses to O-specific polysaccharide in immunologically naive humans with cholera, find that they are largely IgM and IgA, may be blunted in blood group O individuals, and differ in a number of significant ways from responses in previously humans. These differences may explain in part varying degrees of protective efficacy afforded by cholera vaccination between these two populations.

Trial Registration Number: ClinicalTrials.gov NCT01895855.
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http://dx.doi.org/10.1371/journal.pntd.0007874DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6863522PMC
November 2019

Enteropathogens and Rotavirus Vaccine Immunogenicity in a Cluster Randomized Trial of Improved Water, Sanitation and Hygiene in Rural Zimbabwe.

Pediatr Infect Dis J 2019 12;38(12):1242-1248

Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.

Background: Oral rotavirus vaccines (RVVs) are less efficacious in low-income versus high-income settings, plausibly due to more enteropathogen exposure through poor water, sanitation and hygiene (WASH). We explored associations between enteropathogens and RVV immunogenicity and evaluated the effect of improved WASH on enteropathogen carriage.

Methods: We detected stool enteropathogens using quantitative molecular methods and measured anti-rotavirus immunoglobulin A by enzyme-linked immunosorbent assay in infants enrolled to a cluster randomized 2 × 2 factorial trial of improved WASH and improved infant feeding in Zimbabwe (NCT01824940). We used multivariable regression to explore associations between enteropathogens and RVV seroconversion, seropositivity and geometric mean titer. We evaluated effects of improved WASH on enteropathogen prevalence using linear and binomial regression models with generalized estimating equations.

Results: Among 224 infants with enteropathogen and immunogenicity data, 107 (47.8%) had ≥1 pathogen and 39 (17.4%) had ≥2 pathogens detected at median age 41 days (interquartile range: 35-54). RVV seroconversion was low (23.7%). After adjusting for Sabin-poliovirus quantity, pan-enterovirus quantity was positively associated with RVV seroconversion (relative risk 1.61 per 10-fold increase in pan-enterovirus; 95% confidence interval: 1.35-1.91); in the same model, Sabin quantity was negatively associated with RVV seroconversion (relative risk: 0.76; 95% confidence interval: 0.60-0.96). There were otherwise no meaningful associations between individual or total pathogens (bacteria, viruses, parasites or all pathogens) and any measure of RVV immunogenicity. Enteropathogen detection did not differ between randomized WASH and non-WASH groups.

Conclusions: Enteropathogen infections were common around the time of rotavirus vaccination in rural Zimbabwean infants but did not explain poor RVV immunogenicity and were not reduced by a package of household-level WASH interventions.
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http://dx.doi.org/10.1097/INF.0000000000002485DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7205402PMC
December 2019

Increased T Cell Differentiation and Cytolytic Function in Bangladeshi Compared to American Children.

Front Immunol 2019 20;10:2239. Epub 2019 Sep 20.

Department of Microbiology and Immunology, Stanford University, Stanford, CA, United States.

During the first 5 years of life, children are especially vulnerable to infection-related morbidity and mortality. Conversely, the Hygiene Hypothesis suggests that a lack of exposure to infectious agents early in life could explain the increasing incidence of allergies and autoimmunity in high-income countries. Understanding these phenomena, however, is hampered by a lack of comprehensive, direct immune monitoring in children with differing degrees of microbial exposure. Using mass cytometry, we provide an in-depth profile of the peripheral blood mononuclear cells (PBMCs) of children in regions at the extremes of exposure: the San Francisco Bay Area, USA and an economically poor district of Dhaka, Bangladesh. Despite variability in clinical health, functional characteristics of PBMCs were similar in Bangladeshi and American children at 1 year of age. However, by 2-3 years of age, Bangladeshi children's immune cells often demonstrated altered activation and cytokine production profiles upon stimulation with PMA-ionomycin, with an overall immune trajectory more in line with American adults. Conversely, immune responses in children from the US remained steady. Using principal component analysis, donor location, ethnic background, and cytomegalovirus infection status were found to account for some of the variation identified among samples. Within Bangladeshi 1-year-olds, stunting (as measured by height-for-age z-scores) was found to be associated with IL-8 and TGFβ expression in PMA-ionomycin stimulated samples. Combined, these findings provide important insights into the immune systems of children in high vs. low microbial exposure environments and suggest an important role for IL-8 and TGFβ in mitigating the microbial challenges faced by the Bangladeshi children.
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http://dx.doi.org/10.3389/fimmu.2019.02239DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6763580PMC
October 2020

The effect of increased inoculum on oral rotavirus vaccine take among infants in Dhaka, Bangladesh: A double-blind, parallel group, randomized, controlled trial.

Vaccine 2020 01 10;38(1):90-99. Epub 2019 Oct 10.

UVM Vaccine Testing Center and Department of Microbiology and Molecular Genetics, University of Vermont Larner College of Medicine, Burlington, VT 05405, USA.

Background: Oral, live-attenuated rotavirus vaccines suffer from impaired immunogenicity and efficacy in low-income countries. Increasing the inoculum of vaccine might improve vaccine response, but this approach has been inadequately explored in low-income countries.

Methods: We performed a double-blind, parallel group, randomized controlled trial from June 2017 through June 2018 in the urban Mirpur slum of Dhaka, Bangladesh to compare vaccine take (primary outcome) among healthy infants randomized to receive either the standard dose or double the standard dose of oral Rotarix (GlaxoSmithKline) vaccine at 6 and 10 weeks of life. Infants with congenital malformations, birth or enrollment weight <2000 gm, known immunocompromising condition, enrollment in another vaccine trial, or other household member enrolled in the study were excluded. Infants were randomized using random permuted blocks. Vaccine take was defined as detection of post-vaccination fecal vaccine shedding by real-time reverse transcription polymerase chain reaction with sequence confirmation or plasma rotavirus-specific immunoglobulin A (RV-IgA) seroconversion 4 weeks following the second dose.

Results: 220 infants were enrolled and randomized (110 per group). 97 standard-dose and 92 high-dose infants completed the study per-protocol. For the primary outcome, no significant difference was observed between groups: vaccine take occurred in 62 (67%) high-dose infants versus 69 (71%) standard-dose infants (RR 0.92, 95% CI 0.67-1.24). However, in post-hoc analysis, children with confirmed vaccine replication had significantly increased RV-IgA responses, independent of the intervention. No significant adverse events related to study participation were detected.

Conclusions: Administration of double the standard dose of an oral, live-attenuated rotavirus vaccine (Rotarix) did not improve vaccine take among infants in urban Dhaka, Bangladesh. However, improved immunogenicity in children with vaccine replication irrespective of initial inoculum provides further evidence for the need to promote in-host replication and improved gut health to improve oral vaccine response in low-income settings. ClinicalTrials.gov: NCT02992197.
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http://dx.doi.org/10.1016/j.vaccine.2019.09.088DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8199793PMC
January 2020

Association of breast milk gamma-linolenic acid with infant anthropometric outcomes in urban, low-income Bangladeshi families: a prospective, birth cohort study.

Eur J Clin Nutr 2020 05 9;74(5):698-707. Epub 2019 Sep 9.

Division of Infectious Diseases and International Health, Department of Medicine, Charlottesville, VA, 22908, USA.

Background/objectives: Infant linear-growth faltering remains a major public health issue in low- and middle-income countries and suboptimal breast milk composition may be a local, population-specific risk factor. The relationship between early post-natal breast milk fatty acid (FA) composition and infant growth at 1 and 2 years of age was investigated prospectively in 563 families in Dhaka, Bangladesh.

Subjects/methods: A maternal breast milk sample drawn before infant age 6 weeks was analyzed for percentage composition of 26 FAs, and infant length for age Z score (LAZ) was measured longitudinally to infant age 2 years. Individual FAs were tested as predictors of the infant growth outcomes.

Results: Of 26 tested FAs, %gamma-linolenic acid (%GLA) was mostly significantly associated with increase in LAZ from 6 to 52 weeks (ΔLAZ(52-6w)), and also to 104 weeks. The association was consistent over all breast milk stages with estimated effect size of +0.05 ΔLAZ(52-6w) per 20% change in %GLA (p value = 3 × 10), and stronger for ΔLAZ(104-6w) at +0.06 (p value = 8 × 10), explaining 1% of the outcome variance. Infant serum zinc measurements at 6 and 18 weeks of age were included in adjusted analyses, suggesting at least partial independence of infant zinc levels. The association was strongest in 417/563 (74.1%) families with %GLA <0.2%. Breast milk arachidonic acid fraction was within normal range with weaker evidence of association in early breast milk stages.

Conclusions: This study found that %GLA in breast milk was independently associated with infant linear growth, albeit with small effect size, in a predominantly slum-dwelling, low-income, Bangladeshi cohort.
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http://dx.doi.org/10.1038/s41430-019-0498-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7214250PMC
May 2020

Increased Fecal Is Associated With a Positive Glucose Hydrogen Breath Test in Bangladeshi Children.

Open Forum Infect Dis 2019 Jul 1;6(7):ofz266. Epub 2019 Jun 1.

Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, Virginia.

Background: Glucose hydrogen breath testing is a noninvasive test for small intestine bacterial overgrowth (SIBO). A positive glucose hydrogen breath test is common in children from low-income countries and has been found to be associated with malnutrition as measured by stunted growth. The microbiome associated with positive breath testing is relatively unstudied.

Methods: We performed 16 S V4 rDNA microbiome analysis on the stool of 90 Bangladeshi children aged 2 years from an impoverished neighborhood who were tested at the same time for SIBO by glucose hydrogen breath testing. Data were analyzed by linear discriminant analysis effect size with SIBO as the outcome. Any selected genera were tested individually by Wilcoxon's rank-sum test to ensure that linear discriminant analysis effect size results were not outlier-skewed.

Results: Linear discriminant analysis effect size analysis identified (linear discriminate analysis score, 4.59; = .03) as over-represented in 15 out of the 90 children who were SIBO positive.

Conclusions: These results suggest that glucose hydrogen breath test positivity in children from low-income settings may be due to an upper intestinal bloom, potentially explaining the association of SIBO with the gut damage and inflammation that leads to malnutrition.
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http://dx.doi.org/10.1093/ofid/ofz266DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6602902PMC
July 2019

Childhood growth and neurocognition are associated with distinct sets of metabolites.

EBioMedicine 2019 Jun 25;44:597-606. Epub 2019 May 25.

Division of Infectious Diseases and International Health, University of Virginia, Charlottesville, VA, USA. Electronic address:

Background: Undernutrition is a serious global problem that contributes to increased child morbidity and mortality, impaired neurocognitive development, and decreased educational and economic attainment. Current interventions are only marginally effective, and identification of associated metabolic pathways can offer new strategies for intervention.

Methods: Plasma samples were collected at 9 and 36 months from a subset of the PROVIDE child cohort (n = 130). Targeted metabolomics was performed on bile acids, acylcarnitines, amino acids, phosphatidylcholines, and sphingomyelins. Metabolic associations with linear growth and neurocognitive outcomes at four years were evaluated using correlation and penalized-linear regression analysis as well as conditional random forest modeling.

Findings: Different metabolites were associated with growth and neurocognitive outcomes. Improved growth outcomes were associated with higher concentrations of hydroxy-sphingomyelin and essential amino acids and lower levels of acylcarnitines and bile acid conjugation. Neurocognitive scores were largely associated with phosphatidylcholine species and early metabolic indicators of inflammation. All metabolites identified explain ~45% of growth and neurocognitive variation.

Interpretation: Growth outcomes were predominantly associated with metabolites measured early in life (9 months), many of which were biomarkers of insufficient diet, environmental enteric dysfunction, and microbiome disruption. Hydroxy-sphingomyelin was a significant predictor of improved growth. Neurocognitive outcome was predominantly associated with 36 month phosphatidylcholines and inflammatory metabolites, which may serve as important biomarkers of optimal neurodevelopment. The distinct sets of metabolites associated with growth and neurocognition suggest that intervention may require targeted approaches towards distinct metabolic pathways. FUND: Bill & Melinda Gates Foundation (OP1173478); National Institutes of Health (AI043596, CA044579).
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http://dx.doi.org/10.1016/j.ebiom.2019.05.043DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6604877PMC
June 2019

Longitudinal analysis of acute and convalescent B cell responses in a human primary dengue serotype 2 infection model.

EBioMedicine 2019 Mar 8;41:465-478. Epub 2019 Mar 8.

Department of Microbiology and Molecular Genetics, Vaccine Testing Center, Larner College of Medicine, University of Vermont, Burlington, VT 05405, USA. Electronic address:

Background: Acute viral infections induce a rapid and transient increase in antibody-secreting plasmablasts. At convalescence, memory B cells (MBC) and long-lived plasma cells (LLPC) are responsible for long-term humoral immunity. Following an acute viral infection, the specific properties and relationships between antibodies produced by these B cell compartments are poorly understood.

Methods: We utilized a controlled human challenge model of primary dengue virus serotype 2 (DENV2) infection to study acute and convalescent B-cell responses.

Findings: The level of DENV2 replication was correlated with the magnitude of the plasmablast response. Functional analysis of plasmablast-derived monoclonal antibodies showed that the DENV2-specific response was dominated by cells producing DENV2 serotype-specific antibodies. DENV2-neutralizing antibodies targeted quaternary structure epitopes centered on domain III of the viral envelope protein (EDIII). Functional analysis of MBC and serum antibodies from the same subjects six months post-challenge revealed maintenance of the serotype-specific response in both compartments. The serum response mainly targeted DENV2 serotype-specific epitopes on EDIII.

Interpretation: Our data suggest overall functional alignment of DENV2-specific responses from the plasmablast, through the MBC and LLPC compartments following primary DENV2 inflection. These results provide enhanced resolution of the temporal and specificity of the B cell compartment in viral infection and serve as framework for evaluation of B cell responses in challenge models.

Funding: This study was supported by the Bill and Melinda Gates Foundation and the National Institutes of Health.
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http://dx.doi.org/10.1016/j.ebiom.2019.02.060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6444124PMC
March 2019

The Impact of Improved Water, Sanitation, and Hygiene on Oral Rotavirus Vaccine Immunogenicity in Zimbabwean Infants: Substudy of a Cluster-randomized Trial.

Clin Infect Dis 2019 11;69(12):2074-2081

Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe.

Background: Oral vaccines have lower efficacy in developing compared to developed countries. Poor water, sanitation, and hygiene (WASH) may contribute to reduced oral vaccine immunogenicity.

Methods: We conducted a cluster-randomized 2 × 2 factorial trial in rural Zimbabwe. Pregnant women and their infants were eligible if they lived in clusters randomized to (1) standard of care (52 clusters); (2) improved infant feeding (53 clusters); (3) WASH: ventilated improved pit latrine, 2 hand-washing stations, liquid soap, chlorine, infant play space, and hygiene counseling (53 clusters); or (4) feeding plus WASH (53 clusters). This substudy compared oral rotavirus vaccine (RVV) seroconversion (primary outcome), and seropositivity and geometric mean titer (GMT) (secondary outcomes), in WASH vs non-WASH infants by intention-to-treat analysis.

Results: We included 801 infants with documented RVV receipt and postvaccine titer measurements (329 from 84 WASH clusters; 472 from 102 non-WASH clusters); 328 infants with prevaccination titers were included in the primary outcome. Thirty-three of 109 (30.3%) infants in the WASH group seroconverted following rotavirus vaccination, compared to 43 of 219 (19.6%) in the non-WASH group (absolute difference, 10.6% [95% confidence interval {CI}, .54%-20.7%]; P = .031). In the WASH vs non-WASH groups, 90 of 329 (27.4%) vs 107 of 472 (22.7%) were seropositive postvaccination (absolute difference, 4.7% [95% CI, -1.4% to 10.8%]; P = .130), and antirotavirus GMT was 18.4 (95% CI, 15.6-21.7) U/mL vs 14.9 (95% CI, 13.2-16.8) U/mL (P = .072).

Conclusions: Improvements in household WASH led to modest but significant increases in seroconversion to RVV in rural Zimbabwean infants.

Clinical Trials Registration: NCT01824940.
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http://dx.doi.org/10.1093/cid/ciz140DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6880336PMC
November 2019

Human megakaryocytes possess intrinsic antiviral immunity through regulated induction of IFITM3.

Blood 2019 05 5;133(19):2013-2026. Epub 2019 Feb 5.

University of Utah Molecular Medicine Program, Salt Lake City, UT.

Evolving evidence indicates that platelets and megakaryocytes (MKs) have unexpected activities in inflammation and infection; whether viral infections upregulate biologically active, antiviral immune genes in platelets and MKs is unknown, however. We examined antiviral immune genes in these cells in dengue and influenza infections, viruses that are global public health threats. Using complementary biochemical, pharmacological, and genetic approaches, we examined the regulation and function of interferon-induced transmembrane protein 3 (IFITM3), an antiviral immune effector gene not previously studied in human platelets and MKs. IFITM3 was markedly upregulated in platelets isolated from patients during clinical influenza and dengue virus (DENV) infections. Lower IFITM3 expression in platelets correlated with increased illness severity and mortality in patients. Administering a live, attenuated DENV vaccine to healthy subjects significantly increased platelet IFITM3 expression. Infecting human MKs with DENV selectively increased type I interferons and IFITM3. Overexpression of IFITM3 in MKs was sufficient to prevent DENV infection. In naturally occurring, genetic loss-of-function studies, MKs from healthy subjects harboring a homozygous mutation in IFITM3 (rs12252-C, a common single-nucleotide polymorphism in areas of the world where DENV is endemic) were significantly more susceptible to DENV infection. DENV-induced MK secretion of interferons prevented infection of bystander MKs and hematopoietic stem cells. Thus, viral infections upregulate IFITM3 in human platelets and MKs, and IFITM3 expression is associated with adverse clinical outcomes. These observations establish, for the first time, that human MKs possess antiviral functions, preventing DENV infection of MKs and hematopoietic stem cells after local immune signaling.
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http://dx.doi.org/10.1182/blood-2018-09-873984DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6509546PMC
May 2019

Interventions to improve oral vaccine performance: a systematic review and meta-analysis.

Lancet Infect Dis 2019 02 30;19(2):203-214. Epub 2019 Jan 30.

Centre for Genomics & Child Health, Blizard Institute, Queen Mary University of London, London, UK; Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe.

Background: Oral vaccines underperform in low-income and middle-income countries compared with in high-income countries. Whether interventions can improve oral vaccine performance is uncertain.

Methods: We did a systematic review and meta-analysis of interventions designed to increase oral vaccine efficacy or immunogenicity. We searched Ovid-MEDLINE and Embase for trials published until Oct 23, 2017. Inclusion criteria for meta-analysis were two or more studies per intervention category and available seroconversion data. We did random-effects meta-analyses to produce summary relative risk (RR) estimates. This study is registered with PROSPERO (CRD42017060608).

Findings: Of 2843 studies identified, 87 were eligible for qualitative synthesis and 66 for meta-analysis. 22 different interventions were assessed for oral poliovirus vaccine (OPV), oral rotavirus vaccine (RVV), oral cholera vaccine (OCV), and oral typhoid vaccines. There was generally high heterogeneity. Seroconversion to RVV was significantly increased by delaying the first RVV dose by 4 weeks (RR 1·37, 95% CI 1·16-1·62) and OPV seroconversion was increased with monovalent or bivalent OPV compared with trivalent OPV (RR 1·51, 95% CI 1·20-1·91). There was some evidence that separating RVV and OPV increased RVV seroconversion (RR 1·21, 95% CI 1·00-1·47) and that higher vaccine inoculum improved OCV seroconversion (RR 1·12, 95% CI 1·00-1·26). There was no evidence of effect for anthelmintics, antibiotics, probiotics, zinc, vitamin A, withholding breastfeeding, extra doses, or vaccine buffering.

Interpretation: Most strategies did not improve oral vaccine performance. Delaying RVV and reducing OPV valence should be considered within immunisation programmes to reduce global enteric disease. New strategies to address the gap in oral vaccine efficacy are urgently required.

Funding: Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and WHO Polio Research Committee.
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http://dx.doi.org/10.1016/S1473-3099(18)30602-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6353819PMC
February 2019

Neonatal vitamin A supplementation and immune responses to oral polio vaccine in Zimbabwean infants.

Trans R Soc Trop Med Hyg 2019 03;113(3):110-115

Zvitambo Institute for Maternal and Child Health Research, 16 Lauchlan Avenue, Harare, Zimbabwe.

Background: Micronutrient deficiencies may contribute to reduced oral vaccine immunogenicity in developing countries. We hypothesised that neonatal vitamin A supplementation (NVAS) would improve oral vaccine responses.

Methods: We performed a cross-sectional study of infants recruited at birth to the Zimbabwe Vitamin A for Mothers and Babies (ZVITAMBO) trial, a randomised controlled trial of single, high-dose NVAS vs placebo conducted in Zimbabwe between 1997-2001. We measured poliovirus-specific IgA to type 1-3 polio strains by semiquantitative capture ELISA in cryopreserved plasma samples collected at 6 months of age.

Results: A total of 181 infants fulfilled inclusion criteria, of whom 80 were randomised to NVAS and 101 to placebo. There were no significant differences in baseline characteristics between groups. At 6 months of age, median (IQR) vaccine titres for infants randomised to NVAS vs placebo were 932 (421-3001) vs 1774 (711-5431) for Sabin-1 (p=0.04); 1361 (705-3402) vs 2309 (1081-4283) for Sabin-2 (p=0.15); and 1584 (796-4216) vs 2260 (996-5723) for Sabin-3 (p=0.14), respectively. After adjusting for breast feeding status, birth weight, season and infant sex in a linear regression model, there was only weak evidence of difference in log mean titres between vitamin A and placebo groups for Sabin-1 (p=0.08) and no evidence of difference in log mean titres for Sabin-2 and Sabin-3.

Conclusions: NVAS did not augment oral polio vaccine responses in Zimbabwean infants. Further research is required to understand the impact of NVAS on responses to other oral vaccines.The trial is registered with clinicaltrials.gov identifier: NCT00198718.
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http://dx.doi.org/10.1093/trstmh/try126DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6391935PMC
March 2019

Genome-Wide Association Study Reveals Genetic Link between Diarrhea-Associated Entamoeba histolytica Infection and Inflammatory Bowel Disease.

mBio 2018 09 18;9(5). Epub 2018 Sep 18.

Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, USA

is the etiologic agent of amebic dysentery, though clinical manifestation of infection is highly variable ranging from subclinical colonization to invasive disease. We hypothesize that host genetics contribute to the variable outcomes of infection; thus, we conducted a genome-wide association study (GWAS) in two independent birth cohorts of Bangladeshi infants monitored for susceptibility to disease in the first year of life. Children with at least one diarrheal episode positive for (cases) were compared to children with no detectable infection in the same time frame (controls). Meta-analyses under a fixed-effect inverse variance weighting model identified multiple variants in a region of chromosome 10 containing loci associated with symptomatic infection. An intergenic insertion between and (rs58000832) achieved genome-wide significance ( value from meta-analysis [] = 6.05 × 10), and each additional risk allele of rs58000832 conferred 2.42 increased odds of a diarrhea-associated infection. The most strongly associated single nucleotide polymorphism (SNP) within a gene was in an intron of (rs58468612; = 8.94 × 10), which has been implicated as a susceptibility locus for inflammatory bowel disease (IBD). Gene expression resources suggest associated loci are related to the lower expression of Increased expression is also observed in early infection. Further, mice were more susceptible to amebic colitis. These genetic associations reinforce the pathological similarities observed in gut inflammation between infection and IBD. Diarrhea is the second leading cause of death for children globally, causing 760,000 deaths each year in children less than 5 years old. Amebic dysentery contributes significantly to this burden, especially in developing countries. The identification of host factors that control or enable enteric pathogens has the potential to transform our understanding of disease predisposition, outcomes, and treatments. Our discovery of the transcriptional regulator cAMP-responsive element modulator (CREM) as a genetic modifier of susceptibility to amebic disease has implications for understanding the pathogenesis of other diarrheal infections. Further, emerging evidence for CREM in IBD susceptibility suggests that CREM is a critical regulator of enteric inflammation and may have broad therapeutic potential as a drug target across intestinal inflammatory diseases.
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http://dx.doi.org/10.1128/mBio.01668-18DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6143743PMC
September 2018
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