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Article ; Online: Protection against symptomatic dengue infection by neutralizing antibodies varies by infection history and infecting serotype

Sandra Bos / Aaron L. Graber / Jaime A. Cardona-Ospina / Elias M. Duarte / Jose Victor Zambrana / Jorge A. Ruíz Salinas / Reinaldo Mercado-Hernandez / Tulika Singh / Leah C. Katzelnick / Aravinda de Silva / Guillermina Kuan / Angel Balmaseda / Eva Harris

Nature Communications, Vol 15, Iss 1, Pp 1-

2024 Volume 13

Abstract: Abstract Dengue viruses (DENV1–4) are the most prevalent arboviruses in humans and a major public health concern. Understanding immune mechanisms that modulate DENV infection outcome is critical for vaccine development. Neutralizing antibodies (nAbs) are ...

Abstract	Abstract Dengue viruses (DENV1–4) are the most prevalent arboviruses in humans and a major public health concern. Understanding immune mechanisms that modulate DENV infection outcome is critical for vaccine development. Neutralizing antibodies (nAbs) are an essential component of the protective immune response, yet their measurement often relies on a single cellular substrate and partially mature virions, which does not capture the full breadth of neutralizing activity and may lead to biased estimations of nAb potency. Here, we analyze 125 samples collected after one or more DENV infections but prior to subsequent symptomatic or inapparent DENV1, DENV2, or DENV3 infections from a long-standing pediatric cohort study in Nicaragua. By assessing nAb responses using Vero cells with or without DC-SIGN and with mature or partially mature virions, we find that nAb potency and the protective NT50 cutoff are greatly influenced by cell substrate and virion maturation state. Additionally, the correlation between nAb titer and protection from disease depends on prior infection history and infecting serotype. Finally, we uncover variations in nAb composition that contribute to protection from symptomatic infection differently after primary and secondary prior infection. These findings have important implications for identifying antibody correlates of protection for vaccines and natural infections.
Keywords	Science ; Q
Subject code	570
Language	English
Publishing date	2024-01-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Birth cohort relative to an influenza A virus's antigenic cluster introduction drives patterns of children's antibody titers.

Andrew F Brouwer / Angel Balmaseda / Lionel Gresh / Mayuri Patel / Sergio Ojeda / Amy J Schiller / Roger Lopez / Richard J Webby / Martha I Nelson / Guillermina Kuan / Aubree Gordon

PLoS Pathogens, Vol 18, Iss 2, p e

2022 Volume 1010317

Abstract: An individual's antibody titers to influenza A strains are a result of the complicated interplay between infection history, cross-reactivity, immune waning, and other factors. It has been challenging to disentangle how population-level patterns of ... ...

Abstract	An individual's antibody titers to influenza A strains are a result of the complicated interplay between infection history, cross-reactivity, immune waning, and other factors. It has been challenging to disentangle how population-level patterns of humoral immunity change as a function of age, calendar year, and birth cohort from cross-sectional data alone. We analyzed 1,589 longitudinal sera samples from 260 children across three studies in Nicaragua, 2006-16. Hemagglutination inhibition (HAI) titers were determined against four H3N2 strains, one H1N1 strain, and two H1N1pdm strains. We assessed temporal patterns of HAI titers using an age-period-cohort modeling framework. We found that titers against a given virus depended on calendar year of serum collection and birth cohort but not on age. Titer cohort patterns were better described by participants' ages relative to year of likely introduction of the virus's antigenic cluster than by age relative to year of strain introduction or by year of birth. These cohort effects may be driven by a decreasing likelihood of early-life infection after cluster introduction and by more broadly reactive antibodies at a young age. H3N2 and H1N1 viruses had qualitatively distinct cohort patterns, with cohort patterns of titers to specific H3N2 strains reaching their peak in children born 3 years prior to that virus's antigenic cluster introduction and with titers to H1N1 and H1N1pdm strains peaking for children born 1-2 years prior to cluster introduction but not being dramatically lower for older children. Ultimately, specific patterns of strain circulation and antigenic cluster introduction may drive population-level antibody titer patterns in children.
Keywords	Immunologic diseases. Allergy ; RC581-607 ; Biology (General) ; QH301-705.5
Language	English
Publishing date	2022-02-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Combining genotypes and T cell receptor distributions to infer genetic loci determining V(D)J recombination probabilities

Magdalena L Russell / Aisha Souquette / David M Levine / Stefan A Schattgen / E Kaitlynn Allen / Guillermina Kuan / Noah Simon / Angel Balmaseda / Aubree Gordon / Paul G Thomas / Frederick A Matsen IV / Philip Bradley

eLife, Vol

2022 Volume 11

Abstract: Every T cell receptor (TCR) repertoire is shaped by a complex probabilistic tangle of genetically determined biases and immune exposures. T cells combine a random V(D)J recombination process with a selection process to generate highly diverse and ... ...

Abstract	Every T cell receptor (TCR) repertoire is shaped by a complex probabilistic tangle of genetically determined biases and immune exposures. T cells combine a random V(D)J recombination process with a selection process to generate highly diverse and functional TCRs. The extent to which an individual’s genetic background is associated with their resulting TCR repertoire diversity has yet to be fully explored. Using a previously published repertoire sequencing dataset paired with high-resolution genome-wide genotyping from a large human cohort, we infer specific genetic loci associated with V(D)J recombination probabilities using genome-wide association inference. We show that V(D)J gene usage profiles are associated with variation in the TCRB locus and, specifically for the functional TCR repertoire, variation in the major histocompatibility complex locus. Further, we identify specific variations in the genes encoding the Artemis protein and the TdT protein to be associated with biasing junctional nucleotide deletion and N-insertion, respectively. These results refine our understanding of genetically-determined TCR repertoire biases by confirming and extending previous studies on the genetic determinants of V(D)J gene usage and providing the first examples of trans genetic variants which are associated with modifying junctional diversity. Together, these insights lay the groundwork for further explorations into how immune responses vary between individuals.
Keywords	t cell receptor repertoire ; VDJ recombination probabilities ; GWAS ; Artemis ; TdT ; Medicine ; R ; Science ; Q ; Biology (General) ; QH301-705.5
Subject code	616
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	eLife Sciences Publications Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SARS-CoV-2 and endemic coronaviruses

Aaron M. Frutos / John Kubale / Guillermina Kuan / Sergio Ojeda / Nivea Vydiswaran / Nery Sanchez / Miguel Plazaola / May Patel / Roger Lopez / Angel Balmaseda / Aubree Gordon

PLOS Global Public Health, Vol 2, Iss

Comparing symptom presentation and severity of symptomatic illness among Nicaraguan children

2022 Volume 5

Abstract: It has been proposed that as SARS-CoV-2 transitions to endemicity, children will represent the greatest proportion of SARS-Co-V-2 infections as they currently do with endemic coronavirus infections. While SARS-CoV-2 infection severity is low for children, ...

Abstract	It has been proposed that as SARS-CoV-2 transitions to endemicity, children will represent the greatest proportion of SARS-Co-V-2 infections as they currently do with endemic coronavirus infections. While SARS-CoV-2 infection severity is low for children, it is unclear if SARS-CoV-2 infections are distinct in symptom presentation, duration, and severity from endemic coronavirus infections in children. We compared symptom risk and duration of endemic human coronavirus (HCoV) infections from 2011–2016 with SARS-CoV-2 infections from March 2020-September 2021 in a Nicaraguan pediatric cohort. Blood samples were collected from study participants annually in February-April. Respiratory samples were collected from participants that met testing criteria. Blood samples collected in were tested for SARS-CoV-2 antibodies and a subset of 2011–2016 blood samples from four-year-old children were tested for endemic HCoV antibodies. Respiratory samples were tested for each of the endemic HCoVs from 2011–2016 and for SARS-CoV-2 from 2020–2021 via rt-PCR. By April 2021, 854 (49%) cohort participants were ELISA positive for SARS-CoV-2 antibodies. Most participants had antibodies against one alpha and one beta coronavirus by age four. We observed 595 symptomatic endemic HCoV infections from 2011–2016 and 121 symptomatic with SARS-CoV-2 infections from March 2020-September 2021. Symptom presentation of SARS-CoV-2 infection and endemic coronavirus infections were very similar, and SARS-CoV-2 symptomatic infections were as or less severe on average than endemic HCoV infections. This suggests that, for children, SARS-CoV-2 may be just another endemic coronavirus. However, questions about the impact of variants and the long-term effects of SARS-CoV-2 remain.
Keywords	Public aspects of medicine ; RA1-1270
Subject code	572
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: SARS-CoV-2 and endemic coronaviruses

Aaron M Frutos / John Kubale / Guillermina Kuan / Sergio Ojeda / Nivea Vydiswaran / Nery Sanchez / Miguel Plazaola / May Patel / Roger Lopez / Angel Balmaseda / Aubree Gordon

PLOS Global Public Health, Vol 2, Iss 5, p e

Comparing symptom presentation and severity of symptomatic illness among Nicaraguan children.

2022 Volume 0000414

Abstract	It has been proposed that as SARS-CoV-2 transitions to endemicity, children will represent the greatest proportion of SARS-Co-V-2 infections as they currently do with endemic coronavirus infections. While SARS-CoV-2 infection severity is low for children, it is unclear if SARS-CoV-2 infections are distinct in symptom presentation, duration, and severity from endemic coronavirus infections in children. We compared symptom risk and duration of endemic human coronavirus (HCoV) infections from 2011-2016 with SARS-CoV-2 infections from March 2020-September 2021 in a Nicaraguan pediatric cohort. Blood samples were collected from study participants annually in February-April. Respiratory samples were collected from participants that met testing criteria. Blood samples collected in were tested for SARS-CoV-2 antibodies and a subset of 2011-2016 blood samples from four-year-old children were tested for endemic HCoV antibodies. Respiratory samples were tested for each of the endemic HCoVs from 2011-2016 and for SARS-CoV-2 from 2020-2021 via rt-PCR. By April 2021, 854 (49%) cohort participants were ELISA positive for SARS-CoV-2 antibodies. Most participants had antibodies against one alpha and one beta coronavirus by age four. We observed 595 symptomatic endemic HCoV infections from 2011-2016 and 121 symptomatic with SARS-CoV-2 infections from March 2020-September 2021. Symptom presentation of SARS-CoV-2 infection and endemic coronavirus infections were very similar, and SARS-CoV-2 symptomatic infections were as or less severe on average than endemic HCoV infections. This suggests that, for children, SARS-CoV-2 may be just another endemic coronavirus. However, questions about the impact of variants and the long-term effects of SARS-CoV-2 remain.
Keywords	Public aspects of medicine ; RA1-1270
Subject code	572
Language	English
Publishing date	2022-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: The respiratory microbiome and susceptibility to influenza virus infection.

Kyu Han Lee / Aubree Gordon / Kerby Shedden / Guillermina Kuan / Sophia Ng / Angel Balmaseda / Betsy Foxman

PLoS ONE, Vol 14, Iss 1, p e

2019 Volume 0207898

Abstract: Influenza is a major cause of morbidity and mortality worldwide. However, vaccine effectiveness has been low to moderate in recent years and vaccine coverage remains low, especially in low- and middle-income countries. Supplementary methods of prevention ...

Abstract	Influenza is a major cause of morbidity and mortality worldwide. However, vaccine effectiveness has been low to moderate in recent years and vaccine coverage remains low, especially in low- and middle-income countries. Supplementary methods of prevention should be explored to reduce the high burden of influenza. A potential target is the respiratory tract microbiome, complex microbial communities which envelop the respiratory epithelium and play an important role in shaping host immunity. Using a household transmission study, we examined whether the nose/throat microbiota was associated with influenza susceptibility among participants exposed to influenza virus in the household. Further, we characterized changes in the nose/throat microbiota to explore whether community stability was influenced by influenza virus infection. Using a generalized linear mixed effects model, we found a nasal/oropharyngeal community state type (CST) associated with decreased susceptibility to influenza. The CST was rare and transitory among young children but a prevalent and stable CST among adults. Using boosting and linear mixed effects models, we found associations between the nose/throat microbiota and influenza also existed at the taxa level, specifically with the relative abundance of Alloprevotella, Prevotella, and Bacteroides oligotypes. We found high rates of change between bacterial community states among both secondary cases and household contacts who were not infected during follow up. Further work is needed to separate the effect of influenza virus infection from the considerable short-term changes that occur even in the absence of virus. Lastly, age was strongly associated with susceptibility to influenza and the nose/throat bacterial community structure. Although additional studies are needed to determine causality, our results suggest the nose/throat microbiome may be a potential target for reducing the burden of influenza.
Keywords	Medicine ; R ; Science ; Q
Language	English
Publishing date	2019-01-01T00:00:00Z
Publisher	Public Library of Science (PLoS)
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Homotypic protection against influenza in a pediatric cohort in Managua, Nicaragua

Steph Wraith / Angel Balmaseda / Fausto Andres Bustos Carrillo / Guillermina Kuan / John Huddleston / John Kubale / Roger Lopez / Sergio Ojeda / Amy Schiller / Brenda Lopez / Nery Sanchez / Richard Webby / Martha I. Nelson / Eva Harris / Aubree Gordon

Nature Communications, Vol 13, Iss 1, Pp 1-

2022 Volume 8

Abstract: Here Wraith et al. report homotypic protection from repeated influenza infection in a prospective pediatric cohort in Nicaragua followed for 9 years. This protection is observed across multiple seasons, subtypes, and lineages and is consistent for older ... ...

Abstract	Here Wraith et al. report homotypic protection from repeated influenza infection in a prospective pediatric cohort in Nicaragua followed for 9 years. This protection is observed across multiple seasons, subtypes, and lineages and is consistent for older and younger children.
Keywords	Science ; Q
Language	English
Publishing date	2022-03-01T00:00:00Z
Publisher	Nature Portfolio
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Influenza Illness and Partial Vaccination in the First Two Years of Life

Abram L. Wagner / Lionel Gresh / Nery Sanchez / Guillermina Kuan / John Kubale / Roger Lopez / Sergio Ojeda / Eduardo Azziz-Baumgartner / Angel Balmaseda / Aubree Gordon

Vaccines, Vol 9, Iss 676, p

2021 Volume 676

Abstract: More information about influenza in low- and middle-income countries could guide the establishment of pediatric influenza vaccine programs. This study (1) characterizes the burden of influenza in infants, and (2) compares signs and symptoms by prior ... ...

Abstract	More information about influenza in low- and middle-income countries could guide the establishment of pediatric influenza vaccine programs. This study (1) characterizes the burden of influenza in infants, and (2) compares signs and symptoms by prior influenza vaccination or influenza illness. Newborns from Managua, Nicaragua, were followed for two years. Data came from primary medical appointments, PCR testing, and parents’ daily symptom diaries. Logistic regression models estimated associations between preceding vaccination or illness and influenza incidence. Linear models compared duration of illness by prior vaccination or influenza illness. Among 833 infants, 31% had PCR-positive influenza, and 28% were vaccinated against influenza. Four (<0.5%) were fully vaccinated. Overall, influenza incidence was 21.0 (95% confidence interval (CI): 18.8, 23.2) per 100 person-years. Incidence was lower among those with prior influenza compared with those without preceding illness or vaccination (OR: 0.64, 95% CI: 0.44, 0.94). Partially vaccinated children had 1 day less fever than those without prior illness or vaccination ( p = 0.049). A large proportion of children <2 years in Nicaragua contract influenza. Illness was attenuated for those partially vaccinated. Since few children were fully vaccinated, future studies will need to consider the effectiveness of a two-dose vaccination schedule.
Keywords	vaccine effectiveness ; human influenza ; fever ; hospitalization ; vaccination ; Medicine ; R
Language	English
Publishing date	2021-06-01T00:00:00Z
Publisher	MDPI AG
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Peptide arrays incubated with three collections of human sera from patients infected with mosquito-borne viruses [version 3; peer review

Maria del Pilar Martinez Viedma / Nurgun Kose / Leda Parham / Angel Balmaseda / Guillermina Kuan / Ivette Lorenzana / Eva Harris / James E. Crowe Jr. / Brett E. Pickett

F1000Research, Vol

2 approved]

2020 Volume 8

Abstract: Background: Global outbreaks caused by emerging or re-emerging arthropod-borne viruses (arboviruses) are becoming increasingly more common. These pathogens include the mosquito-borne viruses belonging to the Flavivirus and Alphavirus genera. These ... ...

Abstract	Background: Global outbreaks caused by emerging or re-emerging arthropod-borne viruses (arboviruses) are becoming increasingly more common. These pathogens include the mosquito-borne viruses belonging to the Flavivirus and Alphavirus genera. These viruses often cause non-specific or asymptomatic infection, which can confound viral prevalence studies. In addition, many acute phase diagnostic tests rely on the detection of viral components such as RNA or antigen. Standard serological tests are often not reliable for diagnosis after seroconversion and convalescence due to cross-reactivity among flaviviruses. Methods: In order to contribute to development efforts for mosquito-borne serodiagnostics, we incubated 137 human sera on individual custom peptide arrays that consisted of over 866 unique peptides in quadruplicate. Our bioinformatics workflow to analyze these data incorporated machine learning, statistics, and B-cell epitope prediction. Results: Here we report the results of our peptide array data analysis, which revealed sets of peptides that have diagnostic potential for detecting past exposure to a subset of the tested human pathogens including Zika virus. These peptides were then confirmed using the well-established ELISA method. Conclusions: These array data, and the resulting peptides can be useful in diverse efforts including the development of new pan-flavivirus antibodies, more accurate epitope mapping, and vaccine development against these viral pathogens.
Keywords	Medicine ; R ; Science ; Q
Subject code	610
Language	English
Publishing date	2020-02-01T00:00:00Z
Publisher	F1000 Research Ltd
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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Article ; Online: Viral genome-based Zika virus transmission dynamics in a paediatric cohort during the 2016 Nicaragua epidemic

Haoyang Sun / Raquel A. Binder / Borame Dickens / Paola Florez de Sessions / Maia A. Rabaa / Eliza Xin Pei Ho / Alex R Cook / Fausto Bustos Carrillo / Jairo Carey Monterrey / Guillermina Kuan / Angel Balmaseda / Eng Eong Ooi / Eva Harris / October M. Sessions

EBioMedicine, Vol 72, Iss , Pp 103596- (2021)

2021

Abstract: Background: Nicaragua experienced a large Zika epidemic in 2016, with up to 50% of the population in Managua infected. With the domesticated Aedes aegypti mosquito as its vector, it is widely assumed that Zika virus transmission occurs within the ... ...

Abstract	Background: Nicaragua experienced a large Zika epidemic in 2016, with up to 50% of the population in Managua infected. With the domesticated Aedes aegypti mosquito as its vector, it is widely assumed that Zika virus transmission occurs within the household and/or via human mobility. We investigated these assumptions by using viral genomes to trace Zika transmission spatially. Methods: We analysed serum samples from 119 paediatric Zika cases participating in the long-standing Paediatric Dengue Cohort Study in Managua, which was expanded to include Zika in 2015. An optimal spanning directed tree was constructed by minimizing the differences in viral sequence diversity composition between patient nodes, where low-frequency variants were used to increase the resolution of the inferred Zika outbreak dynamics. Findings: Out of the 18 houses where pairwise difference in sample collection dates among all the household members was within 30 days, we only found two where viruses from individuals within the same household were up to 10th-most closely linked to each other genetically. We also identified a substantial number of transmission events involving long geographical distances (n=30), as well as potential super-spreading events in the estimated transmission tree. Interpretation: Our finding highlights that community transmission, often involving long geographical distances, played a much more important role in epidemic spread than within-household transmission. Funding: This study was supported by an NUS startup grant (OMS) and grants R01 AI099631 (AB), P01 AI106695 (EH), P01 AI106695-03S1 (FB), and U19 AI118610 (EH) from the US National Institutes of Health.
Keywords	Zika virus ; transmission network ; genomic inference ; Nicaragua ; Medicine ; R ; Medicine (General) ; R5-920
Language	English
Publishing date	2021-10-01T00:00:00Z
Publisher	Elsevier
Document type	Article ; Online
Database	BASE - Bielefeld Academic Search Engine (life sciences selection)

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