Evaluation of the bioactivity of influenza vaccine strains in vitro suggests that the introduction of new strains in the 2010 Southern Hemisphere Trivalent Influenza Vaccine is associated with adverse events

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 trivalent influenza vaccine (CSL 2010 SH TIV) compared to previous CSL TIVs and other licensed 2010 SH TIVs. The present study describes the outcomes of a series of in vitro experiments directed at elucidating the root cause. The scientific investigations found that a subset of paediatric donors displayed elevated cytokine/chemokine responses to the CSL 2010 SH TIV but not to previous CSL TIVs nor other 2010 SH TIVs. The induction of elevated cytokines/chemokines in paediatric whole blood correlated with elevated NF-κB activation in a HEK293 cell reporter assay. The data indicate that the introduction of the B/Brisbane/60/2008 strain within the CSL manufacturing process (such as occurred in the preceding 2009/10 NH season) appears to have raised the pyrogenic potential of the CSL 2009/10 NH TIV but that this was insufficient to elicit FS in children <5 years. The 2010 SH season coincided with the first introduction of the H1N1 A/California/07/2009 in combination with the B/Brisbane/60/2008 strain. Our data demonstrates that the introduction of the H1N1 A/California/07/2009 (and to a much lesser degree, H3N2 A/Wisconsin/15/2009) in combination with B/Brisbane/60/2008 (as expressed through the CSL method of manufacture) combined and likely compounded the bioactivity of the CSL 2010 SH TIV. This was associated with stronger immune responses, which in a proportion of children <5 years were associated with FS. The assays and systems developed during these investigations should greatly assist in determining the bioactivity of new influenza strains, and thus aid with the manufacture of CSL TIVs indicated for use in the paediatric population.     

Hemagglutinin Displayed Baculovirus Protects Against Highly Pathogenic Influenza

Baculovirus (BV) replicating in insect cells can express a foreign gene product as part of its genome. The influenza hemagglutinin (HA) can be expressed from BV and displayed on the surface of baculovirus (HA-DBV). In this study we first generated six recombinant baculoviruses that expressed chimeric HAs with segments of the BV glycoprotein (gp64). The signal peptide (SP) and cytoplasmic tail (CT) domains of gp64 can enhance the display of HA from A/PR8/34 on BV surface, while the transmembrane (TM) domain of gp64 impairs HA display. Different doses of either live or β-propiolactone (BPL)-inactivated HA-DBV were administered to BALB/c mice. Live HA-DBV elicited higher hemagglutination-inhibition (HAI) titers than BPL-inactivated HA-DBV, and provided sterilizing protection. A second generation recombinant BV simultaneously displaying four HAs derived from four subclades of H5N1 influenza viruses was constructed. This tetravalent H5N1 HA-DBV vaccine elicited HAI titers against all four homologous H5N1 viruses, significantly decreasing viral lung titers of challenged mice and providing 100% protection against lethal doses of homologous H5N1 viruses. Moreover, mice vaccinated with HA-DBV had high levels of IFNγ-secreting and HA-specific CD8+ T cells. Taken together, this study demonstrates that HA-DBV can stimulate strong humoral, as well as cellular immune responses, and is an effective vaccine candidate for influenza.     

蓝紫光照射对烧伤大鼠免疫功能的影响

目的 研究蓝紫光照射对烧伤大鼠免疫功能的影响。方法 将48只大鼠随机分为正常对照组、烧伤对照组及烧伤蓝紫光照射治疗组(治疗组)，在烧伤对照组及烧伤蓝紫光组背部皮肤造成大鼠体表面积(BSA)20％深Ⅱ度烧伤模型，并用蓝紫光对治疗组进行照射。测定烧伤后3d、12d腹腔吞噬细胞吞噬活性、血清免疫球蛋白含量及肿瘤坏死因子细胞毒性的变化。结果 蓝紫光照射可以显著提高烧伤大鼠腹腔吞噬细胞的吞噬能力，并可提高烧伤大鼠血清IgA含量及调节血清中的TNF水平。结论 蓝紫光照射可通过提高大鼠腹腔吞噬细胞的吞噬能力、调节B-细胞功能、TNF水平来提高机体免疫力，从而促进烧伤创面的愈合。     

The use of intermediate purity factor VIII concentrate BPL 8Y as prophylaxis and treatment in congenital thrombotic thrombocytopenic purpura

This report presents seven children with congenital thrombotic thrombocytopenic purpura (TTP). Six had a history of severe neonatal unconjugated hyperbilirubinaemia and thrombocytopenia. The seventh child had no neonatal problems but has suffered three episodes of acute TTP. The subsequent clinical course of the children varied. Five had a relapsing-remitting course and one had chronic microangiopathic haemolytic anaemia. The five oldest children initially received plasma infusions but, because of viral safety issues and easier administration, they now receive intermediate purity US-sourced plasma-derived factor VIII concentrate: BPL 8Y. Effective prophylaxis and treatment is possible in congenital TTP using BPL 8Y.     

Mutagenic effects of fluphenazine hydrochloride in Drosophila melanogaster

The mutagenic potential of fluphenazine hydrochloride was tested on male germ cells of Drosophila melanogaster. The criterion used was sex-linked recessive lethal mutations. Oregon-K males of D. melanogaster, reared on a medium containing 0.01, 0.02 and 0.03 mg/ml of the drug, were screened for sex-linked recessive lethal mutations. The incidence of sex-linked lethals was significant. The results clearly demonstrate that fluphenazine is capable of inducing recessive lethal mutations in Drosophila especially in pre-meiotic stages of spermatogenesis.     

Inactivated infectious bronchitis virus vaccine encapsulated in chitosan nanoparticles induces mucosal immune responses and effective protection against challenge

Avian infectious bronchitis virus (IBV) is one of the most important viral diseases of poultry. The mucosa of upper respiratory tract, specially the trachea, is the primary replication site for this virus. However, conventional inactivate IBV vaccines usually elicit reduced mucosal immune responses and local protection. Thus, an inactivated IBV vaccine containing BR-I genotype strain encapsulated in chitosan nanoparticles (IBV-CS) was produced by ionic gelation method to be administered by oculo-nasal route to chickens. IBV-CS vaccine administered alone resulted in markedly mucosal immune responses, characterized by high levels of anti-IBV IgA isotype antibodies and IFNγ gene expression at 1dpi. The association of live attenuated Massachusetts IBV and IBV-CS vaccine also induced strong mucosal immune responses, though a switch from IgA isotype to IgG was observed, and IFNγ gene expression peak was late (at 5 dpi). Efficacy of IBV-CS was evaluated by tracheal ciliostasis analysis, histopathology examination, and viral load determination in the trachea and kidney. The results indicated that IBV-CS vaccine administered alone or associated with a live attenuated heterologous vaccine induced both humoral and cell-mediated immune responses at the primary site of viral replication, and provided an effective protection against IBV infection at local (trachea) and systemic (kidney) sites.     

IRF2BPL as a novel causative gene for progressive myoclonus epilepsy

IRF2BPL has recently been described as a novel cause of neurodevelopmental disorders with multisystemic regression, epilepsy, cerebellar symptoms, dysphagia, dystonia, and pyramidal signs. We describe a novel IRF2BPL phenotype consistent with progressive myoclonus epilepsy (PME) in three novel subjects and review the features of the 31 subjects with IRF2BPL-related disorders previously reported. Our three probands, aged 28–40 years, harbored de novo nonsense variants in IRF2BPL (c.370C > T, p.[Gln124*] and c.364C > T; p.[Gln122*], respectively). From late childhood/adolescence, they presented with severe myoclonus epilepsy, stimulus-sensitive myoclonus, and progressive cognitive, speech, and cerebellar impairment, consistent with a typical PME syndrome. The skin biopsy revealed massive intracellular glycogen inclusions in one proband, suggesting a similar pathogenic pathway to other storage disorders. Whereas the two older probands were severely affected, the younger proband had a milder PME phenotype, partially overlapping with some of the previously reported IRF2BPL cases, suggesting that some of them might be unrecognized PME. Interestingly, all three patients harbored protein-truncating variants clustered in a proximal, highly conserved gene region around the “coiled-coil” domain. Our data show that PME can be an additional phenotype within the spectrum of IRF2BPL-related disorders and suggest IRF2BPL as a novel causative gene for PME.     

IRF2BPL gene mutation: Expanding on neurologic phenotypes

Heterozygous loss of function variants in the IRF2BPL are a newly described cause of neurodevelopmental disabilities and epilepsy. As of 2019, fewer than 20 patients have been described in the published literature. This article reports an additional case of a patient with a pathogenic IRF2BPL variant and offers a comprehensive review of the published cases of individuals with IRF2BPL variants, in order to help expand the phenotype. The patient has a history of infantile spasms evolving into drug‐resistant epilepsy with underlying epileptic encephalopathy consistent with Lennox–Gastaut syndrome. While at the extreme end of the spectrum, his phenotype is consistent with those previously described. Our literature review highlights the wide range of phenotypes exhibited by those with diseases related to IRF2BPL gene variants. This article also briefly discusses other comorbidities seen in the patient and those previously reported. While the molecular underpinnings of the role of IRF2BPL gene in the central nervous system are newly established, the specifics of its effects elsewhere have yet to be delineated. Furthermore, its pathogenesis in other organ systems is not yet understood and could be of importance from a management perspective.