Understanding "Hybrid Immunity": Comparison and Predictors of Humoral Immune Responses to Severe Acute Respiratory Syndrome Coronavirus 2 Infection (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19) Vaccines.

Background: Comparison of humoral responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinees, those with SARS-CoV-2 infection, or combinations of vaccine/ infection ("hybrid immunity") may clarify predictors of vaccine immunogenicity.

Methods: We studied 2660 US Military Health System beneficiaries with a history of SARS-CoV-2 infection-alone (n = 705), vaccination-alone (n = 932), vaccine-after-infection (n = 869), and vaccine-breakthrough-infection (n = 154). Peak anti-spike-immunoglobulin G (IgG) responses through 183 days were compared, with adjustment for vaccine product, demography, and comorbidities.

Maternal Anti-Dengue IgG Fucosylation Predicts Susceptibility to Dengue Disease in Infants.

Infant mortality from dengue disease is a devastating global health burden that could be minimized with the ability to identify susceptibility for severe disease prior to infection. Although most primary infant dengue infections are asymptomatic, maternally derived anti-dengue immunoglobulin G (IgGs) present during infection can trigger progression to severe disease through antibody-dependent enhancement mechanisms. Importantly, specific characteristics of maternal IgGs that herald progression to severe infant dengue are unknown.

A Model to Explain How the Bacille Calmette Guérin (BCG) Vaccine Drives Interleukin-12 Production in Neonates.

The Bacille Calmette Guérin (BCG) vaccine is the only routine vaccination at birth that effectively induces neonatal T-helper 1 (Th1)-polarized immune responses. The primary cytokine that drives CD4+ T-cell Th1 differentiation is interleukin (IL)-12 p70, a heterodimeric cytokine composed of the IL-12 p35 and IL-12 p40 subunits. We therefore examined the mechanisms involved in BCG vaccine stimulation of IL-12 p35 and p40 production from human umbilical cord (neonatal) cells.

The Pattern of Adipose Tissue Accumulation during Early Infancy Provides an Environment for the Development of Dengue Hemorrhagic Fever.

Background: Dengue is the most prevalent arthropod-borne viral illness in humans with half of the world's population at risk. During early infancy, severe dengue can develop after a primary dengue virus infection. There has been a clinical observation that severe dengue during the first year of life is seen only in chubby infants.

Influenza virus infections in the tropics during the first year of life.

Pediatric influenza virus infections in the tropics, particularly during infancy, are not well described. We identified influenza virus infections among infants with non-dengue acute undifferentiated febrile illnesses in San Pablo, Laguna, Philippines, as part of an ongoing clinical study of dengue virus infections during infancy. We found that 31% of infants with non-dengue acute undifferentiated febrile illnesses in San Pablo, Laguna, Philippines, had influenza virus infections.

Anti-dengue virus envelope protein domain III IgG ELISA among infants with primary dengue virus infections.

Dengue is the most prevalent arthropod-borne viral illness in humans. The current gold standard serologic test for dengue virus (DENV) infection is a neutralizing antibody assay. We examined a DENV recombinant (r)E protein domain III IgG ELISA among infants with primary DENV infections.

Circulating levels of soluble MICB in infants with symptomatic primary dengue virus infections.

Dengue is the most prevalent arthropod-borne viral illness in humans. A MHC class I polypeptide-related sequence B (MICB) single nucleotide polymorphism (SNP) was previously associated with symptomatic dengue compared to non-dengue causes of acute febrile illnesses in infants. We measured circulating levels of soluble (s)MICB in the sera of infants with symptomatic primary dengue virus infections.

Neonatal BCG vaccination is associated with enhanced T-helper 1 immune responses to heterologous infant vaccines.

Neonatal Bacille Calmette Guérin (BCG) vaccination has been reported to have beneficial effects beyond preventing infantile tuberculous meningitis and miliary disease. We hypothesized that BCG vaccine given at birth would enhance T-helper 1 (Th1) immune responses to the first vaccines given later in infancy. We conducted a nested case-control study of neonatal BCG vaccination and its heterologous Th1 immune effects in 2-3 months old infants.

Low adiposity during early infancy is associated with a low risk for developing dengue hemorrhagic fever: a preliminary model.

Dengue virus (DENV) infections range from asymptomatic or mild illness to a severe and potentially life threatening disease, dengue hemorrhagic fever (DHF). DHF occurs in primary DENV infections during early infancy. A prospective clinical study of DENV infections during infancy was conducted in San Pablo, Philippines.

Breastfeeding During Early Infancy is Associated with a Lower Incidence of Febrile Illnesses.

Human breast milk is known to contain immunoprotective, antimicrobial, and anti-inflammatory agents. In a prospective clinical study of dengue virus infections during infancy, we examined the correlation between breastfeeding and the development of febrile illnesses in an infant population. We found that breastfeeding status and the frequency of breastfeeding during early infancy was associated with a lower incidence of febrile illnesses.

Breastfeeding During Early Infancy is Associated with Higher Weight-Based World Health Organization Anthropometry.

The World Health Organization (WHO) Expert Committee on Physical Status: The Use and Interpretation of Anthropometry established reference anthropometric standards for the growth of healthy infants and children. As part of a prospective clinical study of dengue virus infections in infants, we measured the length and weight of healthy infants in San Pablo, Laguna, Philippines at two scheduled study visits. We examined the correlation between breastfeeding and WHO anthropometric z scores during early infancy in San Pablo, Laguna, Philippines.

Herpes simplex virus bronchiolitis in a cannabis user.

Herpes simplex virus (HSV) lower respiratory tract infections in adults are uncommon. We present a case of HSV bronchiolitis and pneumonitis in an immunocompetent individual, likely linked to chronic habitual marijuana use and a herpetic orolabial ulcer. The case serves as a reminder to consider HSV as a potential unusual cause of lower respiratory tract infection/inflammation in individuals with chronic habitual marijuana use.

Toll-like receptor induced pro-interleukin-1β and interleukin-6 in monocytes are lower in healthy infants compared to adults.

Infants have long been known to have higher infectious diseases morbidity and mortality and suboptimal vaccination responses compared to older children and adults. A variety of differences in innate and adaptive immune responses have been described between these two groups. We compared Toll-like receptor (TLR)-induced production of pro-interleukin (IL)-1β, IL-6, and tumor necrosis factor (TNF)-α between 2-month-old infants and adults.

A shorter time interval between first and second dengue infections is associated with protection from clinical illness in a school-based cohort in Thailand.

Background: Despite the strong association between secondary dengue virus (DENV) infections and dengue hemorrhagic fever (DHF), the majority of secondary infections are subclinical or mild. The determinants of clinical severity remain unclear, though studies indicate a titer-dependent and time-dependent role of cross-protective anti-DENV antibodies.

Methods: Data from 2 sequential prospective cohort studies were analyzed for subclinical and symptomatic DENV infections in schoolchildren in Kamphaeng Phet, Thailand (1998-2002 and 2004-2007).

Dengue viral RNA levels in peripheral blood mononuclear cells are associated with disease severity and preexisting dengue immune status.

Background: Infection with dengue viruses (DENV) causes a wide range of manifestations from asymptomatic infection to a febrile illness called dengue fever (DF), to dengue hemorrhagic fever (DHF). The in vivo targets of DENV and the relation between the viral burden in these cells and disease severity are not known.

Method: The levels of positive and negative strand viral RNA in peripheral blood monocytes, T/NK cells, and B cells and in plasma of DF and DHF cases were measured by quantitative RT-PCR.

The role of MyD88 signaling in heterosubtypic influenza A virus infections.

A mouse model of heterosubtypic influenza A virus infections was used to determine the role of MyD88 signaling in CD4+ T-cell, CD8+ T-cell, and IgG immune responses. We found that MyD88 signaling played an important role in anti-influenza A virus heterosubtypic lung and spleen CD4+ T-cell, and spleen CD8+ T-cell, immune responses. MyD88 dependent signaling was important for T-helper 1 cytokine production in anti-influenza A virus lung and spleen heterosubtypic CD4+ T-cells, but not for their frequencies.

Dengue virus type 2 modulates endothelial barrier function through CD73.

Dengue hemorrhagic fever is characterized by a unique vascular leakage syndrome. The mechanisms of endothelial barrier dysfunction in dengue hemorrhagic fever are not well understood. We examined the modulation of endothelial barrier function in dengue virus type 2 (DENV2) infections using primary human umbilical vein endothelial cells.

Fine scale spatiotemporal clustering of dengue virus transmission in children and Aedes aegypti in rural Thai villages.

Background: Based on spatiotemporal clustering of human dengue virus (DENV) infections, transmission is thought to occur at fine spatiotemporal scales by horizontal transfer of virus between humans and mosquito vectors. To define the dimensions of local transmission and quantify the factors that support it, we examined relationships between infected humans and Aedes aegypti in Thai villages.

Methodology/principal Findings: Geographic cluster investigations of 100-meter radius were conducted around DENV-positive and DENV-negative febrile "index" cases (positive and negative clusters, respectively) from a longitudinal cohort study in rural Thailand.

Plasmacytoid dendritic cell interferon-α production to R-848 stimulation is decreased in male infants.

Background: Sex differences in response to microbial infections, especially viral ones, may be associated with Toll-like receptor (TLR)-mediated responses by plasmacytoid dendritic cells (pDCs).

Results: In this study, we identified sex differences in human infant pDC interferon-α production following challenge with the TLR7/8 agonist R-848. Male pDC responses were significantly lower than those of females during early infancy.

Underrecognized mildly symptomatic viremic dengue virus infections in rural Thai schools and villages.

Background: The understanding of dengue virus (DENV) transmission dynamics and the clinical spectrum of infection are critical to informing surveillance and control measures. Geographic cluster studies can elucidate these features in greater detail than cohort studies alone.

Methods: A 4-year longitudinal cohort and geographic cluster study was undertaken in rural Thailand.

The degree of leukocytosis and urine GATA-3 mRNA levels are risk factors for severe acute kidney injury in Puumala virus nephropathia epidemica.

Puumala hantavirus (PUUV) infection, also known as nephropathia epidemica, is the most common cause of hemorrhagic fever with renal syndrome (HFRS) in Europe. The pathogenesis of PUUV nephropathia epidemica is complex and multifactorial, and the risk factors for severe acute kidney injury (AKI) during acute PUUV infection are not well defined. We conducted a prospective study of hospitalized patients with PUUV infection in Tampere, Finland to identify acute illness risk factors for HFRS severity.

The combination of early and rapid type I IFN, IL-1α, and IL-1β production are essential mediators of RNA-like adjuvant driven CD4+ Th1 responses.

There is a growing need for novel vaccine adjuvants that can provide safe and potent T-helper type 1 (Th1) activity. RNA-like immune response modifiers (IRMs) are candidate T-cell adjuvants that skew acquired immune responses towards a Th1 phenotype. We set out to delineate the essential signaling pathways by which the RNA-like IRMs, resiquimod (R-848) and polyinosinic:polycytidylic acid (poly I:C), augment CD4+ T-helper 1 (Th1) responses.

Preexisting Japanese encephalitis virus neutralizing antibodies and increased symptomatic dengue illness in a school-based cohort in Thailand.

Background: Dengue viruses (DENVs) and Japanese encephalitis virus (JEV) have significant cross-reactivity in serological assays; the clinical implications of this remain undefined. An improved understanding of whether and how JEV immunity modulates the clinical outcome of DENV infection is important as large-scale DENV vaccine trials will commence in areas where JEV is co-endemic and/or JEV immunization is routine.

Methods And Findings: The association between preexisting JEV neutralizing antibodies (NAbs) and the clinical severity of DENV infection was evaluated in a prospective school-based cohort in Thailand that captured asymptomatic, non-hospitalized, and hospitalized DENV infections.