Role of viral RNA and lipid in the adverse events associated with the 2010 Southern Hemisphere trivalent influenza vaccine

In Australia, during the 2010 Southern Hemisphere (SH) influenza season, there was an unexpected increase in post-marketing adverse event reports of febrile seizures (FS) in children under 5 years of age shortly after vaccination with the CSL 2010 SH trivalent influenza vaccine (CSL 2010 SH TIV) compared to previous CSL TIVs and other licensed 2010 SH TIVs. In an accompanying study, we described the contribution to these adverse events of the 2010 SH influenza strains as expressed in the CSL 2010 SH TIV using in vitro cytokine/chemokine secretion from whole blood cells and induction of NF-κB activation in HEK293 reporter cells. The aim of the present study was to identify the root cause components that elicited the elevated cytokine/chemokine and NF-κB signature. Our studies demonstrated that the pyrogenic signal was associated with a heat-labile, viral-derived component(s) in the CSL 2010 SH TIV. Further, it was found that viral lipid-mediated delivery of short, fragmented viral RNA was the key trigger for the increased cytokine/chemokine secretion and NF-κB activation. It is likely that the FS reported in children <5 years were due to a combination of the new influenza strains included in the 2010 SH TIV and the CSL standard method of manufacture preserving strain-specific viral components of the new influenza strains (particularly B/Brisbane/60/2008 and to a lesser extent H1N1 A/California/07/2009). These combined to heighten immune activation of innate immune cells, which in a small proportion of children <5 years of age is associated with the occurrence of FS. The data also demonstrates that CSL TIVs formulated with increased levels of splitting agent (TDOC) for the B/Brisbane/60/2008 strain can attenuate the pro-inflammatory signals in vitro, identifying a potential path forward for generating a CSL TIV indicated for use in children <5 years.     

Maternal influenza vaccination and child mortality: Longitudinal,population-based linked cohort study

Influenza vaccination is recommended to protect mothers and their infants from influenza. Few studies have evaluated the association between maternal influenza vaccination and child mortality. We aimed to evaluate the association between in utero exposure to seasonal inactivated influenza vaccine (IIV) and mortality among young children. This longitudinal, population-based cohort study included 191,247 maternal-child pairs in Western Australia between April 2012 and December 2017. Maternal vaccine information was obtained from a state-wide antenatal vaccination database. Mortality was defined as a record of a death registration. We used Cox proportional hazard models, weighted by the inverse-probability of treatment (vaccination), to estimate the hazard ratio of child mortality associated with in utero exposure to seasonal IIV. This study found no association between in utero exposure to seasonal IIV and mortality through age five years.     

Effects of pregnancy, postpartum lactation, and oral contraceptive use on the lipoprotein cholesterol/triglyceride ratio

Lipoprotein cholesterol/triglyceride ratio changes have been observed previously with sex hormone use. To determine if the lipoprotein cholesterol/triglyceride ratio is similarly changed by pregnancy and postpartum lactation, we examined pregnant subjects at 36 weeks gestation and the same women at 6 weeks postpartum and compared them to age-matched, nonpregnant women using or not using oral contraceptives. The cholesterol/triglyceride ratios were examined as means and medians and as curvilinear functions of increasing triglyceride concentration. Median ratios did not predict all ratio changes identified graphically. At very-low-density lipoprotein (VLDL) triglyceride concentrations below 40 mg/dL, the VLDL ratio is less than control in oral contraceptive users and further reduced in pregnant women. Above triglyceride concentrations of 40-60 mg/dL, the curves in the three groups are indistinguishable. No effect of lactation is observed. The low-density lipoprotein (LDL) cholesterol/triglyceride ratio is comparably lower in pregnant subjects and oral contraceptive users at all concentrations of lipoprotein triglyceride and again there is no effect of lactation. In high-density lipoprotein (HDL), there is no effect of either pregnancy or oral contraceptive use on the cholesterol/triglyceride ratio, while it is significantly higher with lactation. Postpartum decreases in the VLDL and LDL cholesterol/triglyceride ratio are seen at all lipoprotein concentrations independent of lactation. We conclude that triglyceride enriches VLDL at low concentrations and LDL at all concentrations in pregnancy and with oral contraceptive use, suggesting a common, hormonal mechanism. HDL is enriched with cholesterol during postpartum lactation, consistent with decreased transfer of cholesterol to other lipoproteins.(ABSTRACT TRUNCATED AT 250 WORDS)     

Low density lipoprotein receptor activity in freshly isolated human blood monocytes and lymphocytes

Circulating human monocytes and lymphocytes were isolated by counterflow and density gradient centrifugation. Binding and degradation of low density lipoprotein (LDL) occurred predominantly in monocytes and to a much lesser extent in lymphocytes. The findings are consistent with greater LDL receptor activity in freshly isolated monocytes than lymphocytes, in keeping with differences in other cell surface receptors between these two cell types. Therefore, when freshly isolated mixed mononuclear cells are used to study LDL receptor activity in vivo in humans, careful attention needs to be given to the proportions of monocytes and lymphocytes, or alternatively, relatively pure preparations of monocytes should be used.     

A mucopolysaccharide storage disease with involvement of the renal glomerular epithelium

A young child with severe mental retardation, skeletal abnormalities and the phenotypic appearance typical of a mucopolysaccharide disorder was found to have a previously unrecognized form of mucopolysaccharide storage disease. Mucopolysaccharide was found to accumulate in perichondrium, coronary arteries, aorta and the glomerular epithelial cells of the kidney; the reticuloendothelial system remained free of mucopolysaccharide. Lipid accumulation was observed in peripheral neurons but not in central neurons. Skin fibroblast cultures accumulated ³⁵SO₄ to an extent intermediate between normal cell lines and those from patients with classic mucopolysaccharide storage disorders.