The inactivated NDV-HXP-S COVID-19 vaccine induces a significantly higher ratio of neutralizing to non-neutralizing antibodies in humans as compared to mRNA vaccines

NDV-HXP-S is a recombinant Newcastle disease virus based-vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which expresses an optimized (HexaPro) spike protein on its surface. The vaccine can be produced in embryonated chicken eggs using the same process as that employed for the production of influenza virus vaccines. Here we performed a secondary analysis of the antibody responses after vaccination with inactivated NDV-HXP-S in a Phase I clinical study in Thailand. Please click Download on the upper right corner to see the full abstract

Broadly cross-reactive antibodies dominate the human B cell response against 2009 pandemic H1N1 influenza virus infection

Although scarce after annual influenza vaccination, B cells producing antibodies capable of neutralizing multiple influenza strains are abundant in humans infected with pandemic 2009 H1N1 influenza

High Affinity Antibodies against Influenza Characterize the Plasmablast Response in SLE Patients After Vaccination

We thank Elena Solomaha for advice on SPR experiments, Angela Hayes for clerical support, Christina Helms and Lori Garman for technical assistance, Gillian M. Air for providing influenza viruses; Linda F. Thompson for early involvement in the study and Meghan Sullivan, Irvin Ho and Sarah F. Andrews for helpful comments on the manuscript.Breakdown of B cell tolerance is a cardinal feature of systemic lupus erythematosus (SLE). Increased numbers of autoreactive mature naïve B cells have been described in SLE patients and autoantibodies have been shown to arise from autoreactive and non-autoreactive precursors. How these defects, in the regulation of B cell tolerance and selection, influence germinal center (GC) reactions that are directed towards foreign antigens has yet to be investigated. Here, we examined the characteristics of post-GC foreign antigen-specific B cells from SLE patients and healthy controls by analyzing monoclonal antibodies generated from plasmablasts induced specifically by influenza vaccination. We report that many of the SLE patients had anti-influenza antibodies with higher binding affinity and neutralization capacity than those from controls. Although overall frequencies of autoreactivity in the influenza-specific plasmablasts were similar for SLE patients and controls, the variable gene repertoire of influenza-specific plasmablasts from SLE patients was altered, with increased usage of JH6 and long heavy chain CDR3 segments. We found that high affinity anti-influenza antibodies generally characterize the plasmablast responses of SLE patients with low levels of autoreactivity; however, certain exceptions were noted. The high-avidity antibody responses in SLE patients may also be correlated with cytokines that are abnormally expressed in lupus. These findings provide insights into the effects of dysregulated immunity on the quality of antibody responses following influenza vaccination and further our understanding of the underlying abnormalities of lupus.Yeshttp://www.plosone.org/static/editorial#pee

Studies of molecular events during peripheral B cell differentiation

This thesis focuses on molecular changes occuring during terminal B cell differentiation as well as on somatic hypermutation and the generation and maintenance of B cell memory. During T cell dependent immune responses the average affinity for the eliciting antigen increases with time. This affinity maturation is generated by somatic hypermutation and selection for B cells carrying a high-affinty BCR. A secondary immune response is characterised by rapid differentiation of memory B cells into plasma cells producing high affinty antibodies. However, the V gene repertoire of a secondary response differs from that used in the primary response, called repertoire shift. Analysis of the repertoire shift accuring during the immune response to phOx-OVA showed that the repertoire shift occured already during the memory maintenance phase of the response. While systemic immune responses are abolished in CD28 deficient mice they mount normal IgA responses to oral immunisation with KLH-CT. We have shown that the IgA plasma cells present in the lamina propria have undergone somatic hypermutation and functional experiments indicate that they have also undergone affinity selection. This is in spite of the total absence of germinal center structures both in the PP and in the MLN. Two proteins that is differentially expressed in plasma cells were identified by cDNA subtraction. One of the proteins is Ly6C, a surface protein previously shown to be expressed on T cell subsets. We show that within the B cell lineage it is expressed only on plasma cells. Also, crosslinking of the Ly6C protein might positively modulate Ig secretion. The other protein that was identified is a novel thioredoxin-like protein, PC-TRP, expressed specifically in plasma cells. A functional analysis of the properties of this protein might yield some interesting insight into plasma cell biology

Humoral cross-reactivity between Zika and dengue viruses: implications for protection and pathology

Zika virus (ZIKV) is a re-emerging mosquito-borne flavivirus that has recently caused extensive outbreaks in Central and South America and the Caribbean. Given its association with Guillain–Barré syndrome in adults and neurological and ocular malformities in neonates, ZIKV has become a pathogen of significant public health concern worldwide. ZIKV shares a considerable degree of genetic identity and structural homology with other flaviviruses, including dengue virus (DENV). In particular, the surface glycoprotein envelope (E), which is involved in viral fusion and entry and is therefore a chief target for neutralizing antibody responses, contains regions that are highly conserved between the two viruses. This results in immunological cross-reactivity, which in the context of prior DENV exposure, may have significant implications for the generation of immune responses to ZIKV and affect disease outcomes. Here we address the issue of humoral cross-reactivity between DENV and ZIKV, reviewing the evidence for and discussing the potential impact of this cross-recognition on the functional quality of antibody responses against ZIKV. These considerations are both timely and relevant to future vaccine design efforts, in view of the existing overlap in the distribution of ZIKV and DENV and the likely spread of ZIKV to additional DENV-naive and experienced populations.Emerging Microbes & Infections (2017) 6, e33; doi:10.1038/emi.2017.42; published online 10 May 201

Strong Differential Regulation of Serum and Mucosal IgA Responses as Revealed in CD28-Deficient Mice Using Cholera Toxin Adjuvant.

n this study, we show that costimulation required for mucosal IgA responses is strikingly different from that needed for systemic responses, including serum IgA. Following oral immunization with cholera toxin (CT) adjuvant we found that whereas CTLA4-H{gamma}1 transgenic mice largely failed to respond, CD28-/- mice developed near normal gut mucosal IgA responses but poor serum Ab responses. The local IgA response was functional in that strong antitoxic protection developed in CT-immunized CD28-/- mice. This was in spite of the fact that no germinal centers (GC) were observed in the Peyer’s patches, spleen, or other peripheral lymph nodes. Moreover, significant somatic hypermutation was found in isolated IgA plasma cells from gut lamina propria of CD28-/- mice. Thus, differentiation to functional gut mucosal IgA responses against T cell-dependent Ags does not require signaling through CD28 and can be independent of GC formations and isotype-switching in Peyer’s patches. By contrast, serum IgA responses, similar to IgG-responses, are dependent on GC and CD28. However, both local and systemic responses are impaired in CTLA4-H{gamma}1 transgenic mice, indicating that mucosal IgA responses are dependent on the B7-family ligands, but require signaling via CTLA4 or more likely a third related receptor. Therefore, T-B cell interactions leading to mucosal as opposed to serum IgA responses are uniquely regulated and appear to represent separate events. Although CT is known to strongly up-regulate B7-molecules, we have demonstrated that it acts as a potent mucosal adjuvant in the absence of CD28, suggesting that alternative costimulatory pathways are involved