For dengue viruses 1 to 4 (DENV1-4), a specific range of antibody titer has been shown to enhance viral replication in vitro and severe disease in animal models. Although suspected, such ...antibody-dependent enhancement of severe disease has not been shown to occur in humans. Using multiple statistical approaches to study a long-term pediatric cohort in Nicaragua, we show that risk of severe dengue disease is highest within a narrow range of preexisting anti-DENV antibody titers. By contrast, we observe protection from all symptomatic dengue disease at high antibody titers. Thus, immune correlates of severe dengue must be evaluated separately from correlates of protection against symptomatic disease. These results have implications for studies of dengue pathogenesis and for vaccine development, because enhancement, not just lack of protection, is of concern.
The four dengue virus serotypes (DENV1–4) are mosquito-borne flaviviruses that infect ∼390 million people annually; up to 100 million infections are symptomatic, and 500,000 cases progress to severe ...disease. Exposure to a heterologous DENV serotype, the specific infecting DENV strains, and the interval of time between infections, as well as age, ethnicity, genetic polymorphisms, and comorbidities of the host, are all risk factors for severe dengue. In contrast, neutralizing antibodies (NAbs) are thought to provide long-lived protection against symptomatic infection and severe dengue. The objective of dengue vaccines is to provide balanced protection against all DENV serotypes simultaneously. However, the association between homotypic and heterotypic NAb titers and protection against symptomatic infection remains poorly understood. Here, we demonstrate that the titer of preinfection cross-reactive NAbs correlates with reduced likelihood of symptomatic secondary infection in a longitudinal pediatric dengue cohort in Nicaragua. The protective effect of NAb titers on infection outcome remained significant when controlled for age, number of years between infections, and epidemic force, as well as with relaxed or more stringent criteria for defining inapparent DENV infections. Further, individuals with higher NAb titers immediately after primary infection had delayed symptomatic infections compared with those with lower titers. However, overall NAb titers increased modestly in magnitude and remained serotype cross-reactive in the years between infections, possibly due to reexposure. These findings establish that anti-DENV NAb titers correlate with reduced probability of symptomatic DENV infection and provide insights into longitudinal characteristics of antibody-mediated immunity to DENV in an endemic setting.
Epidemiologic studies indicate that obesity increases the risk of severe complications and death from influenza virus infections, especially in elderly individuals. This work investigates the effect ...of obesity on the duration of viral shedding within household transmission studies in Managua, Nicaragua, over 3 seasons (2015-2017). Symptomatic obese adults were shown to shed influenza A virus 42% longer than nonobese adults (adjusted event time ratio ETR, 1.42; 95% confidence interval CI, 1.06-1.89); no association was observed with influenza B virus shedding duration. Even among paucisymptomatic and asymptomatic adults, obesity increased the influenza A shedding duration by 104% (adjusted ETR, 2.04; 95% CI, 1.35-3.09). These findings suggest that obesity may play an important role in influenza transmission.
Influenza viruses remain a severe threat to human health, causing up to 650,000 deaths annually
. Seasonal influenza virus vaccines can prevent infection, but are rendered ineffective by antigenic ...drift. To provide improved protection from infection, novel influenza virus vaccines that target the conserved epitopes of influenza viruses, specifically those in the hemagglutinin stalk and neuraminidase, are currently being developed
. Antibodies against the hemagglutinin stalk confer protection in animal studies
. However, no data exist on natural infections in humans, and these antibodies do not show activity in the hemagglutination inhibition assay, the hemagglutination inhibition titer being the current correlate of protection against influenza virus infection
. While previous studies have investigated the protective effect of cellular immune responses and neuraminidase-inhibiting antibodies, additional serological correlates of protection from infection could aid the development of broadly protective or universal influenza virus vaccines
. To address this gap, we performed a household transmission study to identify alternative correlates of protection from infection and disease in naturally exposed individuals. Using this study, we determined 50% protective titers and levels for hemagglutination inhibition, full-length hemagglutinin, neuraminidase and hemagglutinin stalk-specific antibodies. Further, we found that hemagglutinin stalk antibodies independently correlated with protection from influenza virus infection.
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.
The Zika pandemic sparked intense interest in whether immune interactions among dengue virus serotypes 1 to 4 (DENV1 to -4) extend to the closely related Zika virus (ZIKV). We investigated ...prospective pediatric cohorts in Nicaragua that experienced sequential DENV1 to -3 (2004 to 2015), Zika (2016 to 2017), and DENV2 (2018 to 2020) epidemics. Risk of symptomatic DENV2 infection and severe disease was elevated by one prior ZIKV infection, one prior DENV infection, or one prior DENV infection followed by one ZIKV infection, compared with being flavivirus-naïve. By contrast, multiple prior DENV infections reduced dengue risk. Further, although high preexisting anti-DENV antibody titers protected against DENV1, DENV3, and ZIKV disease, intermediate titers induced by previous ZIKV or DENV infection enhanced future risk of DENV2 disease and severity, as well as DENV3 severity. The observation that prior ZIKV infection can modulate dengue disease severity like a DENV serotype poses challenges to development of dengue and Zika vaccines.
Little is known about enduring memory B cell (MBC) responses to Zika virus (ZIKV) and their relationship with circulating antibodies. Here we comprehensively assess MBC frequency and specificity ...alongside serum binding and neutralizing antibody responses to ZIKV ~2 weeks and ~8 months postinfection in 31 pediatric subjects with 0, 1 or >1 prior infections with the related dengue virus (DENV). ZIKV infection elicits a robust type-specific MBC response, and the majority of late convalescent anti-ZIKV serum neutralizing activity is attributable to ZIKV-specific antibodies. The number of prior DENV infections does not influence type-specific or cross-reactive MBC responses, although ZIKV has the highest cross-reactivity with DENV3. DENV cross-reactive MBCs expanded by ZIKV infection decline in number and proportion by late convalescence. Finally, ZIKV induces greater cross-reactivity in the MBC pool than in serum antibodies. Our data suggest immunity to DENV only modestly shapes breadth and magnitude of enduring ZIKV antibody responses.
Abstract
Background
Previous studies suggest that the nose/throat microbiome may play an important role in shaping host immunity and modifying the risk of respiratory infection. Our aim is to ...quantify the association between the nose/throat microbiome and susceptibility to influenza virus infection.
Methods
In this household transmission study, index cases with confirmed influenza virus infection and their household contacts were followed for 9–12 days to identify secondary influenza infections. Respiratory swabs were collected at enrollment to identify and quantify bacterial species via high-performance sequencing. Data were analyzed by an individual hazard-based transmission model that was adjusted for age, vaccination, and household size.
Results
We recruited 115 index cases with influenza A(H3N2) or B infection and 436 household contacts. We estimated that a 10-fold increase in the abundance in Streptococcus spp. and Prevotella salivae was associated with 48% (95% credible interval CrI, 9–69%) and 25% (95% CrI, 0.5–42%) lower susceptibility to influenza A(H3N2) infection, respectively. In contrast, for influenza B infection, a 10-fold increase in the abundance in Streptococcus vestibularis and Prevotella spp. was associated with 63% (95% CrI, 17–83%) lower and 83% (95% CrI, 15–210%) higher susceptibility, respectively.
Conclusions
Susceptibility to influenza infection is associated with the nose/throat microbiome at the time of exposure. The effects of oligotypes on susceptibility differ between influenza A(H3N2) and B viruses. Our results suggest that microbiome may be a useful predictor of susceptibility, with the implication that microbiome could be modulated to reduce influenza infection risk, should these associations be causal.
The upper respiratory microbiome may play a role in susceptibility to influenza virus. This study examines the role of the nose/throat microbiome on influenza infection using a household influenza transmission study.
Clinical manifestations of Zika virus, chikungunya virus, and dengue virus infections can be similar. To improve virus detection, streamline molecular workflow, and decrease test costs, we developed ...and evaluated a multiplex real-time reverse transcription PCR for these viruses.
The 4 dengue virus serotypes (DENV1-4) and Zika virus (ZIKV) are related mosquito-borne flaviviruses of major importance globally. While monoclonal antibodies and plasma from DENV-immune donors can ...neutralize or enhance ZIKV in vitro and in small-animal models, and vice versa, the extent, duration, and significance of cross-reactivity in humans remains unknown, particularly in flavivirus-endemic regions.
We studied neutralizing antibodies to ZIKV and DENV1-4 in longitudinal serologic specimens collected through 3 years after infection from people in Latin America and Asia with laboratory-confirmed DENV infections. We also evaluated neutralizing antibodies to ZIKV and DENV1-4 in patients with Zika through 6 months after infection.
In patients with Zika, the highest neutralizing antibody titers were to ZIKV, with low-level cross-reactivity to DENV1-4 that was greater in DENV-immune individuals. We found that, in primary and secondary DENV infections, neutralizing antibody titers to ZIKV were markedly lower than to the infecting DENV and heterologous DENV serotypes. Cross-neutralization was greatest in early convalescence, then ZIKV neutralization decreased, remaining at low levels over time.
Patterns of antibody cross-neutralization suggest that ZIKV lies outside the DENV serocomplex. Neutralizing antibody titers can distinguish ZIKV from DENV infections when all viruses are analyzed simultaneously. These findings have implications for understanding natural immunity and vaccines.
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