Dengue NS1 antibodies are associated with clearance of viral NS1.

BACKGROUND: Dengue vascular permeability syndrome is the primary cause of death in severe dengue infections. The protective versus potentially pathogenic role of dengue NS1 antibodies are not well understood. The main goal of this analysis was to characterize the relationship between free NS1 concentration and NS1 antibody titers in primary and secondary dengue infection in order to better understand the presence and duration of NS1 antibody complexes in clinical dengue infections. METHODS: Hospitalized participants with acute dengue infection were recruited from Northern Colombia between 2018 to 2020. Symptom assessment including dengue signs and symptoms, chart review and blood collection was performed. Primary versus secondary Dengue was assessed serologically. NS1 titers and anti-NS1 antibodies were measured daily. RESULTS: Patients with secondary infection have higher antibody titers than those in primary infection, and we find a negative correlation between anti-NS1 antibody titer and NS1 protein. We demonstrate that in a subset of secondary infection, there are indeed NS1 antibody-antigen complexes at the admission day during the febrile phase that are not detectable by the recovery phase. Furthermore, dengue infection status is associated with higher circulating sialidases. DISCUSSION: The negative correlation between antibody and protein suggests that antibodies may play a role in clearing this viral protein.

Understanding immunological origins of atopic dermatitis through multi-omic analysis.

BACKGROUND: The pathophysiology of atopic dermatitis (AD) is multifactorial, impacted by individual medical, demographic, environmental, and immunologic factors. This study used multi-omic analyses to assess how host and microbial factors could contribute to infant AD development. METHODS: This longitudinal cohort study included 129 term infants, identified as AD (n = 37) or non-AD (n = 92) using the Infant Feeding Practices-II survey and review of medical records. Standardized surveys were used to assess medical and demographic traits (gestational age, sex, race, maternal AD, and atopy family history), and environmental exposures (delivery method, maternal tobacco use, pets, breastfeeding duration, and timing of solid food introduction). Saliva was collected at 6 months for multi-omic assessment of cytokines, microRNAs, mRNAs, and the microbiome. The contribution of each factor to AD status was assessed with logistic regression. RESULTS: Medical, demographic, and environmental factors did not differ between AD and non-AD infants. Five "omic" factors (IL-8/IL-6, miR-375-3p, miR-21-5p, bacterial diversity, and Proteobacteria) differed between groups (p < .05). The severity of AD was positively associated with levels of miR-375-3p (R = .17, p = .049) and Proteobacteria (R = .22, p = .011), and negatively associated with levels of miR-21-5p (R = .20, p = .022). Multi-omic features accounted for 17% of variance between groups, significantly improving an AD risk model employing medical, demographic, and environmental factors (X2  = 32.47, p = .006). CONCLUSION: Interactions between the microbiome and host signaling may predispose certain infants to AD by promoting a pro-inflammatory environment.

Is Dengue Vaccine Protection Possible?

In tropical and subtropical countries, 4 dengue viruses (DENVs) produce mild disease and a potentially fatal vascular permeability syndrome. Unique antigenic and biological properties of DENVs contribute to vaccine development delays. Three tissue culture-based tetravalent candidate dengue vaccines have advanced to phase 3 clinical testing. Sanofi-Pasteur's chimeric yellow fever tetravalent dengue vaccine, Dengvaxia, licensed in 19 dengue-endemic countries, Europe, and the United States, partially protects seropositives but sensitizes some seronegatives to severe hospitalized dengue. During 2 years of phase 3, Takeda's TAK-003, a chimeric DENV 2 tetravalent vaccine, protected against DENV 2 but was less protective against other DENVs. In seronegative adults, 1 dose of a tetravalent nonstructural deletion mutant vaccine in late phase developed by the US National Institutes of Health protected seronegative humans against challenge with DENVs 2 and 3. This experience suggests nearly whole DENV genomes are required to achieve balanced and sustained protective immunity.

Vaccine-Associated Enhanced Viral Disease: Implications for Viral Vaccine Development.

Vaccine-associated enhanced disease (VAED) is a serious barrier to attaining successful virus vaccines in human and veterinary medicine. VAED occurs as two different immunopathologies, antibody-dependent enhancement (ADE) and vaccine-associated hypersensitivity (VAH). ADE contributes to the pathology of disease caused by four dengue viruses (DENV) through control of the intensity of cellular infection. Products of virus-infected cells are toxic. A partially protective yellow fever chimeric tetravalent DENV vaccine sensitized seronegative children to ADE breakthrough infections. A live-attenuated tetravalent whole virus vaccine in phase III testing appears to avoid ADE by providing durable protection against the four DENV. VAH sensitization by viral vaccines occurred historically. Children given formalin-inactivated measles or respiratory syncytial virus (RSV) vaccines experienced severe disease during breakthrough infections. Tissue responses demonstrated that VAH not ADE caused these vaccine safety problems. Subsequently, measles was successfully and safely contained by a live-attenuated virus vaccine. The difficulty in formulating a safe and effective RSV vaccine is troublesome evidence that avoiding VAH is a major research challenge. VAH-like tissue responses were observed during breakthrough homologous virus infections in monkeys given severe acute respiratory syndrome (SARS) or Middle East respiratory syndrome (MERS) vaccines.

Preparing for the Behavioral Health Impact of COVID-19 in Michigan.

PURPOSE OF REVIEW: As a global pandemic, COVID-19 has profoundly disrupted the lives of individuals, families, communities, and nations. This report summarizes the expected impact of COVID-19 on behavioral health, as well as strategies to address mental health needs during the COVID-19 pandemic and its aftermath. The state of Michigan in the USA is used to illustrate the complexity of the mental health issues and the critical gaps in the behavioral health infrastructure as they pertain to COVID-19. Scoping review was conducted to identify potential mental health needs and issues during the COVID-19 pandemic and its aftermath. RECENT FINDINGS: The ramifications of COVID-19 on mental health are extensive, with the potential to negatively impact diverse populations including healthcare providers, children and adolescents, older adults, the LGBTQ community, and individuals with pre-existing mental illness. Suicide rates, alone, are expected to rise for Michiganders due to the economic downturn, isolation and quarantine, increased substance use, insomnia, and increased access to guns associated with the COVID-19 pandemic. This report promotes awareness of a behavioral health crisis due to COVID-19. Increasing access to behavioral health care should minimize COVID-19's negative influence on mental health in Michigan. We propose a three-prong approach to access: awareness, affordability, and technology. Addressing workforce development and fixing gaps in critical behavioral health infrastructure will also be essential. These actions need to be implemented immediately to prepare for the expected "surge" of behavioral health needs in the ensuing months.

COVID-19 Vaccines: Should We Fear ADE?

Might COVID-19 vaccines sensitize humans to antibody-dependent enhanced (ADE) breakthrough infections? This is unlikely because coronavirus diseases in humans lack the clinical, epidemiological, biological, or pathological attributes of ADE disease exemplified by dengue viruses (DENV). In contrast to DENV, SARS and MERS CoVs predominantly infect respiratory epithelium, not macrophages. Severe disease centers on older persons with preexisting conditions and not infants or individuals with previous coronavirus infections. Live virus challenge of animals given SARS or MERS vaccines resulted in vaccine hypersensitivity reactions (VAH), similar to those in humans given inactivated measles or respiratory syncytial virus vaccines. Safe and effective COVID-19 vaccines must avoid VAH.

Ethics of a partially effective dengue vaccine: Lessons from the Philippines.

Dengvaxia, a chimeric yellow fever tetravalent dengue vaccine developed by SanofiPasteur is widely licensed in dengue-endemic countries. In a large cohort study Dengvaxia was found to partially protect children who had prior dengue virus (DENV) infections but sensitized seronegative children to breakthrough DENV disease of enhanced severity. In 2019, the European Medicines Agency and the US FDA issued licenses that reconciled safety issues by restricting vaccine to individuals with prior dengue infections. Using revised Dengvaxia efficacy and safety data we sought to estimate hospitalized and severe dengue cases among the more than 800,000 9 year-old children vaccinated in the Philippines. Despite an overall vaccine efficacy of 69% during 4 years post-vaccination we project there will be more than one thousand vaccinated seronegative and seropositive children hospitalized for severe dengue. Assisting these children through a program of enhanced surveillance leading to improved care deserves widespread support. Clinical responses observed during breakthrough dengue infections in vaccinated individuals counsel prudence in design of vaccine policies. Recommendations concerning continued use of this dengue vaccine are: (1) obtain a better definition of vaccine efficacy and safety through enhanced phase 4 surveillance, (2) obtain a valid, accessible, sensitive, specific and affordable serological test that identifies past wild-type dengue virus infection and (3) clarify safety and efficacy of Dengvaxia in flavivirus immunes. In the absence of an acceptable serological screening test these unresolved ethical issues suggest Dengvaxia be given only to those signing informed consent.

Genetic risk for dengue hemorrhagic fever and dengue fever in multiple ancestries.

BACKGROUND: Genetic risk factors for dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) and dengue fever (DF) are limited, in particular there are sparse data on genetic risk across diverse populations. METHODS: We conducted a genome-wide association study (GWAS) in a derivation and validation sample of 7, 460 participants of Latin American, South Asian, and South East Asian ancestries. We then developed a weighted polygenic risk score (PRS) for each participant in each of the validation cohorts of the three ancestries to predict the risk of DHF/DSS compared to DF, DHF/DSS compared to controls, and, DF compared to controls. FINDINGS: The risk of DHF/DSS was significantly increased, odds ratio [OR] 1.84 (95%CI 1.47 to 2.31) (195 SNPs), compared to DF, fourth PRS quartile versus first quartile, in the validation cohort. The risk of DHF/DSS compared to controls was increased (OR=3.94; 95% CI 2.84 to 5.45) (278 SNPs), as was the risk of DF compared to controls (OR=1.97; 95%CI 1.63 to 2.39) (251 SNPs). Risk increased in a dose-dependent manner with increase in quartiles of PRS across comparisons. Significant associations persisted for PRS built within ancestries and applied to the same or different ancestries as well as for PRS built for one outcome (DHF/DSS or DF) and applied to the other. INTERPRETATION: There is a strong genetic effect that predisposes to risk of DHF/DSS and DF. The genetic risk for DHF/DSS is higher than that for DF when compared to controls, and this effect persists across multiple ancestries.

Travelling arboviruses: A historical perspective.

Chikungunya, dengue, yellow fever and Zika viruses share many attributes. All are complex and widespread zoonoses of subhuman primates that have made successful transitions to the urban Aedes aegypti transmission cycle. More important, they have an established record of travelling, having moved from their place of origin hundreds of years ago, sometimes repeatedly. Understanding their epidemiology requires a knowledge of past behaviors including unexplained restraints to their travel. This is a review of mechanisms that may contribute to invasiveness and pathogenicity of these important human pathogens.

Recent advances in understanding dengue.

This is a selective review of recent publications on dengue clinical features, epidemiology, pathogenesis, and vaccine development placed in a context of observations made over the past half century. Four dengue viruses (DENVs) are transmitted by urban cycle mosquitoes causing diseases whose nature and severity are influenced by interacting factors such as virus, age, immune status of the host, and human genetic variability. A phenomenon that controls the kinetics of DENV infection, antibody-dependent enhancement, best explains the correlation of the vascular permeability syndrome with second heterotypic DENV infections and infection in the presence of passively acquired antibodies. Based on growing evidence in vivo and in vitro, the tissue-damaging DENV non-structural protein 1 (NS1) is responsible for most of the pathophysiological features of severe dengue. This review considers the contribution of hemophagocytic histiocytosis syndrome to cases of severe dengue, the role of movement of humans in dengue epidemiology, and modeling and planning control programs and describes a country-wide survey for dengue infections in Bangladesh and efforts to learn what controls the clinical outcome of dengue infections. Progress and problems with three tetravalent live-attenuated vaccines are reviewed. Several research mysteries remain: why is the risk of severe disease during second heterotypic DENV infection so low, why is the onset of vascular permeability correlated with defervescence, and what are the crucial components of protective immunity?

Dengue infection and advances in dengue vaccines for children.

Dengue viruses are endemic in most tropical and subtropical countries where they produce disease ranging from a mild fever to a severe, potentially fatal vascular permeability syndrome. We reviewed the status of development and testing in children of three vaccines designed to protect against the four dengue viruses. The first dengue virus vaccine, Dengvaxia, now licensed in 20 endemic countries, the EU and the USA, provides protection against severe dengue in seropositive individuals but increases the risk for naive recipients to develop severe dengue and to be hospitalised. We discuss mechanisms and implications of shortcomings of the licensed vaccine and describe the structure and attributes of two other dengue virus vaccines. Based upon human dengue challenge studies, one of these vaccines promises to deliver solid, long-lasting immunity after a single dose. Because dengue virus infections are ubiquitous in residents and visitors to tropical countries, in the absence of a protective vaccine paediatricians should recognise the early signs and clinical presentation of severe dengue, understand its pathophysiology and appropriate management.