Structure-selected RBM immunogens prime polyclonal memory responses that neutralize SARS-CoV-2 variants of concern

Successful control of the COVID-19 pandemic depends on vaccines that prevent transmission. The full-length Spike protein is highly immunogenic but the majority of antibodies do not target the virus: ACE2 interface. In an effort to affect the quality of the antibody response focusing it to the receptor-binding motif (RBM) we generated a series of conformationally-constrained immunogens by inserting solvent-exposed RBM amino acid residues into hypervariable loops of an immunoglobulin molecule. Priming C57BL/6 mice with plasmid (p)DNA encoding these constructs yielded a rapid memory response to booster immunization with recombinant Spike protein. Immune sera antibodies bound strongly to the purified receptor-binding domain (RBD) and Spike proteins. pDNA primed for a consistent response with antibodies efficient at neutralizing authentic WA1 virus and three variants of concern (VOC), B.1.351, B.1.617.2, and BA.1. We demonstrate that immunogens built on structure selection can be used to influence the quality of the antibody response by focusing it to a conserved site of vulnerability shared between wildtype virus and VOCs, resulting in neutralizing antibodies across variants

A therapy for suppressing canonical and noncanonical SARS-CoV-2 viral entry and an intrinsic intrapulmonary inflammatory response

The prevalence of "long COVID" is just one of the conundrums highlighting how little we know about the lung's response to viral infection, particularly to syndromecoronavirus-2 (SARS-CoV-2), for which the lung is the point of entry. We used an in vitro human lung system to enable a prospective, unbiased, sequential single-cell level analysis of pulmonary cell responses to infection by multiple SARS-CoV-2 strains. Starting with human induced pluripotent stem cells and emulating lung organogenesis, we generated and infected three-dimensional, multi-cell-type-containing lung organoids (LOs) and gained several unexpected insights. First, SARS-CoV-2 tropism is much broader than previously believed: Many lung cell types are infectable, if not through a canonical receptor-mediated route (e.g., via Angiotensin-converting encyme 2(ACE2)) then via a noncanonical "backdoor" route (via macropinocytosis, a form of endocytosis). Food and Drug Administration (FDA)-approved endocytosis blockers can abrogate such entry, suggesting adjunctive therapies. Regardless of the route of entry, the virus triggers a lung-autonomous, pulmonary epithelial cell-intrinsic, innate immune response involving interferons and cytokine/chemokine production in the absence of hematopoietic derivatives. The virus can spread rapidly throughout human LOs resulting in mitochondrial apoptosis mediated by the prosurvival protein Bcl-xL. This host cytopathic response to the virus may help explain persistent inflammatory signatures in a dysfunctional pulmonary environment of long COVID. The host response to the virus is, in significant part, dependent on pulmonary Surfactant Protein-B, which plays an unanticipated role in signal transduction, viral resistance, dampening of systemic inflammatory cytokine production, and minimizing apoptosis. Exogenous surfactant, in fact, can be broadly therapeutic

Halting SARS‐CoV‐2: lung organoids step up to the plate

Defining the pulmonary cell types infected by SARS-CoV-2 and finding ways to prevent subsequent tissue damage are key goals for controlling COVID-19. Recent work establishing a human lung organoid-derived air-liquid interface model permissive to SARS-CoV-2 infection identifies alveolar type II cells as the primary cell type infected, reports an infection-induced interferon response and demonstrates the effectiveness of interferon lambda 1 treatment in dampening lung infection

COVID-19 in Early Life: Infants and Children Are Affected Too

Compared with adults, children are less likely infected with SARS-CoV-2 and are often asymptomatic when infected. However, infection in children can lead to severe disease. The pandemic affects the lives of all children, especially those with lower socioeconomic status. This review highlights the physiological impacts of COVID-19 in early life. </jats:p

Immune-Mediated Neonatal Thrombocytopenia

Immune-mediated thrombocytopenia in neonates is caused by the transplacental passage of maternally derived antiplatelet antibodies. The 2 most common causes include neonatal alloimmune thrombocytopenia, which leads to significant thrombocytopenia and risk of intracranial hemorrhage, and autoimmune thrombocytopenia, which is generally less severe. No specific guidelines for prenatal management exist for either disease; however, intravenous immune globulin treatments and systemic steroids for women with at-risk pregnancies can be useful in both diseases. In this review, we discuss the current literature and management strategies for both pregnant women and newborns with immune-mediated thrombocytopenia.</jats:p

Chronic lung disease in preterm infants receiving various modes of noninvasive ventilation at ≤30 weeks’ postmenstrual age

Objective: To determine the incidence of chronic lung disease (CLD) in mechanically ventilated infants who were born at Study design: Retrospective cohort study of infants born at Results: Of the 2378 eligible infants, 1091 (46%) were on CPAP/NIPPV alone, 173 (7.3%) were on HHHFNC alone, and 1114 (47%) were on a combination of CPAP/NIPPV and HHHFNC at ≤30 weeks’ PMA until weaned to room air or low flow nasal cannula. After adjustment for confounders, infants in both the CPAP/NIPPV (odds ratio [95% confidence interval]; 2.37 [1.18, 4.79]) and Combination (3.47 [2.06, 5.86]) groups had higher odds of developing CLD than infants in the HHHFNC group. Conclusions: Our results demonstrate that infants transitioned to HHHFNC ≤30 weeks’ PMA after extubation to CPAP/NIPPV were associated with a lower odds of CLD than infants maintained on CPAP/NIPPV or a combination of CPAP/NIPPV and HHHFNC.</p