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Article: Frequency of Dengue Virus-Specific T Cells is related to Infection Outcome in Endemic Settings.

Gálvez, Rosa Isela / Martínez-Pérez, Amparo / Escarrega, E Alexandar / Singh, Tulika / Zambrana, José Víctor / Balmaseda, Ángel / Harris, Eva / Weiskopf, Daniela

medRxiv : the preprint server for health sciences

2024

Abstract: Dengue is widespread in tropical and subtropical regions globally and leads to a considerable burden of disease. Annually, dengue virus (DENV) causes up to 400 million infections, of which ~25% present with clinical symptoms ranging from mild to fatal. ... ...

Abstract	Dengue is widespread in tropical and subtropical regions globally and leads to a considerable burden of disease. Annually, dengue virus (DENV) causes up to 400 million infections, of which ~25% present with clinical symptoms ranging from mild to fatal. Despite its significance as a growing public health concern, the development of effective DENV vaccines has been highly challenging. One of the reasons is the lack of comprehensive understanding of the influence exerted by prior DENV infections and immune responses with cross-reactive properties. To investigate this, we collected samples from a pediatric cohort study in dengue-endemic Managua, Nicaragua. We characterized T cell responses in a group of 71 healthy children who had previously experienced one or more natural DENV infections and who, within one year after sample collection, had a subsequent DENV infection that was either symptomatic (n=25) or inapparent (n=46, absence of clinical disease). Thus, our study was designed to investigate the impact of pre-existing DENV specific T cell responses on the clinical outcomes of subsequent DENV infection. We assessed the DENV specific T cell responses using an activation-induced marker assay (AIM). Children who had experienced only one prior DENV infection displayed heterogeneous DENV specific CD4
Language	English
Publishing date	2024-02-06
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.05.24302330
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Article ; Online: Effects of boosting and waning in highly exposed populations on dengue epidemic dynamics.

Aogo, Rosemary A / Zambrana, Jose Victor / Sanchez, Nery / Ojeda, Sergio / Kuan, Guillermina / Balmaseda, Angel / Gordon, Aubree / Harris, Eva / Katzelnick, Leah C

Science translational medicine

2023 Volume 15, Issue 722, Page(s) eadi1734

Abstract: Sequential infection with multiple dengue virus (DENV) serotypes is thought to induce enduring protection against dengue disease. However, long-term antibody waning has been observed after repeated DENV infection. Here, we provide evidence that highly ... ...

Abstract	Sequential infection with multiple dengue virus (DENV) serotypes is thought to induce enduring protection against dengue disease. However, long-term antibody waning has been observed after repeated DENV infection. Here, we provide evidence that highly immune Nicaraguan children and adults (
MeSH term(s)	Adult ; Child ; Humans ; Dengue/epidemiology ; Dengue Virus ; Antibodies, Viral ; Cross Reactions ; Zika Virus Infection ; Zika Virus
Chemical Substances	Antibodies, Viral
Language	English
Publishing date	2023-11-15
Publishing country	United States
Document type	Journal Article
ZDB-ID	2518854-9
ISSN	1946-6242 ; 1946-6234
ISSN (online)	1946-6242
ISSN	1946-6234
DOI	10.1126/scitranslmed.adi1734
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Article: Dengue severity by serotype in 19 years of pediatric clinical studies in Nicaragua.

Narvaez, Federico / Montenegro, Carlos / Juarez, Jose Guillermo / Zambrana, Jose Victor / Gonzalez, Karla / Arguello, Sonia / Barrios, Fanny / Ojeda, Sergio / Plazaola, Miguel / Sanchez, Nery / Camprubi, Daniel / Kuan, Guillermina / Bailey, Gabriela Paz / Harris, Eva / Balmaseda, Angel

medRxiv : the preprint server for health sciences

2024

Abstract: Background: Dengue virus, a major global health threat, consists of four serotypes (DENV1-4) that cause a range of clinical manifestations from mild to severe and potentially fatal disease.: Methods: This study, based on 19 years of data from the ... ...

Abstract	Background: Dengue virus, a major global health threat, consists of four serotypes (DENV1-4) that cause a range of clinical manifestations from mild to severe and potentially fatal disease. Methods: This study, based on 19 years of data from the Pediatric Dengue Cohort Study and Pediatric Dengue Hospital-based Study in Managua, Nicaragua, investigates the influence of serotype and immune status on dengue severity. Study participants 6 months to 17 years old were followed during their hospital stay or as ambulatory patients, with dengue cases confirmed by molecular, serological, and/or virological methods. Results: We enrolled a total of 14071 participants, of whom 2954 (21%) were positive for DENV infection. Of 2425 cases with serotype result by RT-PCR, 541 corresponded to DENV1, 996 to DENV2, 718 to DENV3 and 170 to DENV4. Severe disease was more prevalent among secondary DENV2 and DENV4 cases, while similar disease severity was observed in both primary and secondary DENV1 and DENV3 cases. According to the 1997 World Health Organization (WHO) severity classification, both DENV2 and DENV3 had a higher proportion of severe disease compared to other serotypes, whereas DENV3 had the greatest percentage of severity under the WHO-2009 classification. DENV2 was associated with pleural effusion and low platelet count, while DENV3 correlated with both hypotensive and compensated shock. Conclusions: These findings emphasize the critical need for a dengue vaccine with balanced efficacy against all four serotypes, particularly as existing vaccines show variable efficacy by serotype and immune status, posing challenges for comprehensive protection, particularly in dengue-naïve individuals.
Language	English
Publishing date	2024-02-13
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.02.11.24302393
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Article: Obesity is associated with increased pediatric dengue virus infection and disease: A 9-year cohort study in Managua, Nicaragua.

Mercado-Hernandez, Reinaldo / Myers, Rachel / Carillo, Fausto Bustos / Zambrana, José Victor / López, Brenda / Sanchez, Nery / Gordon, Aubree / Balmaseda, Angel / Kuan, Guillermina / Harris, Eva

medRxiv : the preprint server for health sciences

2024

Abstract: Background: Obesity is on the rise globally in adults and children, including in tropical areas where diseases such as dengue have a substantial burden, particularly in children. Obesity impacts the risk of severe dengue disease; however, the impact on ... ...

Abstract	Background: Obesity is on the rise globally in adults and children, including in tropical areas where diseases such as dengue have a substantial burden, particularly in children. Obesity impacts the risk of severe dengue disease; however, the impact on dengue virus (DENV) infection and dengue cases remains an open question. Methods: We used 9 years of data from 5,940 children in the Pediatric Dengue Cohort Study in Nicaragua to examine whether pediatric obesity is associated with increased susceptibility to DENV infection and symptomatic presentation. Analysis was performed using Generalized Estimating Equations adjusted for age, sex, and pre-infection DENV antibody titers. Results: From 2011 to 2019, children contributed 26,273 person-years of observation, and we observed an increase in the prevalence of overweight (from 12% to 17%) and obesity (from 7% to 13%). There were 1,682 DENV infections and 476 dengue cases in the study population. Compared to participants with normal weight, participants with obesity had higher odds of DENV infection (Adjusted Odds Ratio [aOR] 1.21, 95% confidence interval [CI] 1.03-1.42) and higher odds of dengue disease given infection (aOR 1.59, 95% CI 1.15-2.19). Children with obesity infected with DENV showed increased odds of presenting fever (aOR 1.46, 95% CI 1.05-2.02), headache (aOR 1.51, 95% CI 1.07-2.14), and rash (aOR 2.26, 95% CI 1.49-3.44) when compared with children with normal weight. Conclusions: Our results indicate that obesity is associated with increased susceptibility to DENV infection and dengue cases in children, independently of age, sex, and pre-infection DENV antibody titers.
Language	English
Publishing date	2024-04-03
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.02.24305219
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Article ; Online: Longitudinal analysis of post-acute chikungunya-associated arthralgia in children and adults: A prospective cohort study in Managua, Nicaragua (2014-2018).

Warnes, Colin M / Bustos Carrillo, Fausto Andres / Zambrana, Jose Victor / Lopez Mercado, Brenda / Arguello, Sonia / Ampié, Oscarlette / Collado, Damaris / Sanchez, Nery / Ojeda, Sergio / Kuan, Guillermina / Gordon, Aubree / Balmaseda, Angel / Harris, Eva

PLoS neglected tropical diseases

2024 Volume 18, Issue 2, Page(s) e0011948

Abstract: Chikungunya can result in debilitating arthralgia, often presenting as acute, self-limited pain, but occasionally manifesting chronically. Little is known about differences in chikungunya-associated arthralgia comparing children to adults over time. To ... ...

Abstract	Chikungunya can result in debilitating arthralgia, often presenting as acute, self-limited pain, but occasionally manifesting chronically. Little is known about differences in chikungunya-associated arthralgia comparing children to adults over time. To characterize long-term chikungunya-associated arthralgia, we recruited 770 patients (105 0-4 years old [y/o], 200 5-9 y/o, 307 10-15 y/o, and 158 16+ y/o) with symptomatic chikungunya virus infections in Managua, Nicaragua, during two consecutive chikungunya epidemics (2014-2015). Participants were assessed at ~15 days and 1, 3, 6, 12, and 18 months post-fever onset. Following clinical guidelines, we defined participants by their last reported instance of arthralgia as acute (≤10 days post-fever onset), interim (>10 and <90 days), or chronic (≥90 days) cases. We observed a high prevalence of arthralgia (80-95%) across all ages over the study period. Overall, the odds of acute arthralgia increased in an age-dependent manner, with the lowest odds of arthralgia in the 0-4 y/o group (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.14-0.51) and the highest odds of arthralgia in the 16+ y/o participants (OR: 4.91, 95% CI: 1.42-30.95) relative to 10-15 y/o participants. Females had higher odds of acute arthralgia than males (OR: 1.63, 95% CI: 1.01-2.65) across all ages. We found that 23-36% of pediatric and 53% of adult participants reported an instance of post-acute arthralgia. Children exhibited the highest prevalence of post-acute polyarthralgia in their legs, followed by the hands and torso - a pattern not seen among adult participants. Further, we observed pediatric chikungunya presenting in two distinct phases: the acute phase and the subsequent interim/chronic phases. Thus, differences in the presentation of arthralgia were observed across age, sex, and disease phase in this longitudinal chikungunya cohort. Our results elucidate the long-term burden of chikungunya-associated arthralgia among pediatric and adult populations.
MeSH term(s)	Adult ; Male ; Female ; Humans ; Child ; Chikungunya Fever/complications ; Chikungunya Fever/epidemiology ; Prospective Studies ; Chikungunya virus ; Nicaragua/epidemiology ; Arthralgia/etiology ; Arthralgia/complications ; Fever/complications
Language	English
Publishing date	2024-02-28
Publishing country	United States
Document type	Journal Article
ZDB-ID	2429704-5
ISSN	1935-2735 ; 1935-2735
ISSN (online)	1935-2735
ISSN	1935-2735
DOI	10.1371/journal.pntd.0011948
Database	MEDical Literature Analysis and Retrieval System OnLINE

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Article: Comparative Analysis of SARS-CoV-2 Antibody Responses across Global and Lesser-Studied Vaccines.

Zambrana, José Victor / Saenz, Carlos / Maier, Hannah E / Brenes, Mayling / Nuñez, Andrea / Matamoros, Anita / Hernández, Mabel / Dumas, Keyla / Toledo, Cristhian / Peralta, Leonardo / Gordon, Aubree / Balmaseda, Angel

Vaccines

2024 Volume 12, Issue 3

Abstract: Few data are available on antibody response for some SARS-CoV-2 vaccines, and there is a lack of ability to compare vaccine responses in the same population. This cross-sectional study conducted in Nicaragua examines the SARS-CoV-2 antibody responses in ... ...

Abstract	Few data are available on antibody response for some SARS-CoV-2 vaccines, and there is a lack of ability to compare vaccine responses in the same population. This cross-sectional study conducted in Nicaragua examines the SARS-CoV-2 antibody responses in individuals, previously exposed to high infection rates who have received various vaccines. The vaccines under comparison include well-known ones like Pfizer (BNT162b2) and AstraZeneca (ChAdOx1-S), alongside less-studied vaccines including Soberana (Soberana 02), Abdala (CIGB-66), and Sputnik V/Sputnik Light. Overall, 3195 individuals participated, with 2862 vaccinated and 333 unvaccinated. We found that 95% of the unvaccinated were seropositive, with much lower titers than the vaccinated. Among the vaccinated, we found that Soberana recipients mounted the highest anti-spike response (mean difference (MD) = 36,498.8 [20,312.2, 52,685.5]), followed by Abdala (MD = 25,889.9 [10,884.1, 40,895.7]), BNT162b2 (MD = 12,967.2 [7543.7, 18,390.8]) and Sputnik with AstraZeneca as the reference group, adjusting for age, sex, vaccine status, days after last dose, and self-reported COVID-19. In addition, we found that subjects with complete vaccination series had higher antibody magnitude than those with incomplete series. Overall, we found no evidence of waning in the antibody magnitude across vaccines. Our study supports the conclusion that populations with high infection rates still benefit substantially from vaccination.
Language	English
Publishing date	2024-03-19
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2703319-3
ISSN	2076-393X
ISSN	2076-393X
DOI	10.3390/vaccines12030326
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Article: Inapparent primary dengue virus infections reveal hidden serotype-specific epidemiological patterns and spectrum of infection outcome: a cohort study in Nicaragua.

Bos, Sandra / Zambrana, Jose Victor / Duarte, Elias / Graber, Aaron L / Huffaker, Julia / Montenegro, Carlos / Premkumar, Lakshmanane / Gordon, Aubree / Balmaseda, Angel / Harris, Eva

medRxiv : the preprint server for health sciences

2024

Abstract: Background: Dengue is the most prevalent mosquito-borne viral disease and a major public health problem worldwide. Most primary infections with the four dengue virus serotypes (DENV1-4) are inapparent; nevertheless, prior research has primarily focused ... ...

Abstract	Background: Dengue is the most prevalent mosquito-borne viral disease and a major public health problem worldwide. Most primary infections with the four dengue virus serotypes (DENV1-4) are inapparent; nevertheless, prior research has primarily focused on symptomatic infections, which has limited our understanding of the epidemiological burden and spectrum of disease of each DENV serotype. Our study addresses this bottleneck in dengue research by providing a new method and a detailed examination of primary inapparent infections. Methods: Here we present (1) the evaluation of a multiplex DENV1-4 envelope domain III multiplex microsphere-based assay (EDIII-MMBA) to serotype inapparent primary infections and (2) its application leveraging 17 years of prospective sample collection from the Nicaraguan Pediatric Dengue Cohort Study. After evaluation, we analyzed 46% (N=574) of total inapparent primary DENV infections with the EDIII-MMBA. Remaining infections were inferred using stochastic imputation, taking year and neighborhood of infection into account. Findings: The EDIII-MMBA demonstrated excellent diagnostic accuracy of symptomatic and inapparent primary DENV infections when evaluated against gold-standard serotyping methods. Significant within- and between-year variation in serotype distribution between symptomatic and inapparent infections and circulation of serotypes undetected in symptomatic cases were observed in multiple years. Our findings reveal that a significant majority of primary infections remained inapparent: 76.8% for DENV1, 79.9% for DENV2, and 63.9% for DENV3. DENV3 exhibited the highest likelihood of symptomatic and severe primary infections (Pooled OR compared to DENV1 = 2.13, 95% CI 1.28-3.56, and 6.75, 2.01-22.62, respectively), whereas DENV2 had similar likelihood to DENV1 in both analyses. Interpretation: Our study indicates that case surveillance skews the perceived epidemiological footprint of DENV and reveals a more complex and intricate pattern of serotype distribution in inapparent infections. Further, the significant differences in infection outcomes by serotype emphasizes the need for serotype-informed public health strategies. Funding: NIH/NIAID P01AI106695, U01AI153416. Research in context: Evidence before this study:
Language	English
Publishing date	2024-04-08
Publishing country	United States
Document type	Preprint
DOI	10.1101/2024.04.05.24305281
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Article ; Online: Protection against symptomatic dengue infection by neutralizing antibodies varies by infection history and infecting serotype.

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

Nature communications

2024 Volume 15, Issue 1, Page(s) 382

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 ... ...

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.
MeSH term(s)	Chlorocebus aethiops ; Animals ; Humans ; Child ; Antibodies, Neutralizing ; Cohort Studies ; Serogroup ; Vero Cells ; Coinfection ; Dengue/prevention & control
Chemical Substances	Antibodies, Neutralizing
Language	English
Publishing date	2024-01-09
Publishing country	England
Document type	Journal Article
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-023-44330-8
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Article: Primary exposure to Zika virus increases risk of symptomatic dengue virus infection with serotypes 2, 3, and 4 but not serotype 1.

Zambrana, Jose Victor / Hasund, Chloe M / Aogo, Rosemary A / Bos, Sandra / Arguello, Sonia / Gonzalez, Karla / Collado, Damaris / Miranda, Tatiana / Kuan, Guillermina / Gordon, Aubree / Balmaseda, Angel / Katzelnick, Leah / Harris, Eva

medRxiv : the preprint server for health sciences

2023

Abstract: Infection with any of the four dengue virus serotypes (DENV1-4) can protect against or enhance subsequent dengue depending on pre-existing antibodies and the subsequent infecting serotype. Additionally, primary infection with the related flavivirus Zika ... ...

Abstract	Infection with any of the four dengue virus serotypes (DENV1-4) can protect against or enhance subsequent dengue depending on pre-existing antibodies and the subsequent infecting serotype. Additionally, primary infection with the related flavivirus Zika virus (ZIKV) has been shown to increase DENV2 disease. Here, we measured how prior DENV and ZIKV immunity influenced risk of disease caused by all four serotypes in a pediatric Nicaraguan cohort. Of 3,412 participants in 2022, 10.6% experienced symptomatic DENV infections caused by DENV1 (n=139), DENV4 (n=133), DENV3 (n=54), DENV2 (n=9), or an undetermined serotype (n=39). Longitudinal clinical and serological data were used to define infection histories, and generalized linear and additive models adjusted for age, sex, time since the last infection, cohort year, and repeat measurements were used to predict disease risk. Compared to flavivirus-naïve participants, primary ZIKV infection increased disease risk of DENV4 (relative risk = 2.62, 95% confidence interval: 1.48-4.63) and DENV3 (2.90, 1.34-6.27) but not DENV1 (1.20, 0.72-1.99). Primary DENV infection or a DENV followed by ZIKV infection also increased DENV4 risk. We re-analyzed 19 years of cohort data and demonstrated that prior flavivirus-immunity and pre-existing antibody titer differentially affected disease risk for incoming serotypes, increasing risk of DENV2 and DENV4, protecting against DENV1, and protecting at high titers but enhancing at low titers against DENV3. We thus find that prior ZIKV infection, like prior DENV infection, increases risk of certain DENV serotypes. Cross-reactivity among flaviviruses should be carefully considered when assessing vaccine safety and efficacy.
Language	English
Publishing date	2023-11-30
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.11.29.23299187
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Article: Longitudinal Analysis of the Burden of Post-Acute Chikungunya-Associated Arthralgia in Children and Adults: A Prospective Cohort Study in Managua, Nicaragua (2014-2019).

Warnes, Colin M / Carrillo, Fausto Andres Bustos / Zambrana, Jose Victor / Mercado, Brenda Lopez / Arguello, Sonia / Ampié, Oscarlette / Collado, Damaris / Sanchez, Nery / Ojeda, Sergio / Kuan, Guillermina / Gordon, Aubree / Balmaseda, Angel / Harris, Eva

medRxiv : the preprint server for health sciences

2023

Abstract	Chikungunya can result in debilitating arthralgia, often presenting as acute, self-limited pain, but occasionally manifesting chronically. Little is known about differences in chikungunya-associated arthralgia comparing children to adults over time. To characterize long-term chikungunya-associated arthralgia, we recruited 770 patients (105 0-4 year olds [y/o], 200 5-9 y/o, 307 10-15 y/o, and 158 16+ y/o) with symptomatic chikungunya virus infections in Managua, Nicaragua, during two chikungunya epidemics (2014-2015). Participants were assessed at ~15 days and 1, 3, 6, 12, and 18 months post-fever onset. Following clinical guidelines, we defined participants by their last reported instance of arthralgia as acute (≤10 days post-fever onset), interim (>10 and <90 days), or chronic (≥90 days) cases. We observed a high prevalence of arthralgia (80-95%) across all ages over the study period. Overall, the odds of acute arthralgia increased in an age-dependent manner, with the lowest odds of arthralgia in the 0-4 y/o group (odds ratio [OR]: 0.27, 95% confidence interval [CI]: 0.14-0.51) and the highest odds of arthralgia in the 16+ y/o participants (OR: 4.91, 95% CI: 1.42-30.95) relative to 10-15 y/o participants. Females had a higher odds of acute arthralgia than males (OR: 1.63, 95% CI: 1.01-2.65) across all ages. We found that 23-36% of pediatric and 53% of adult participants reported an instance of post-acute arthralgia. Children exhibited the highest prevalence of post-acute polyarthralgia in their legs, followed by the hands and torso - a pattern not seen among adult participants. Further, we observed pediatric chikungunya presenting in two distinct phases: the acute phase and the associated interim and chronic phases. Differences in the presentation of arthralgia were observed across age, sex, and disease phase in this longitudinal chikungunya cohort. Our results elucidate the long-term burden of chikungunya-associated arthralgia among pediatric and adult populations.
Language	English
Publishing date	2023-05-17
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.05.09.23289726
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