Background BNT162b2 mRNA and ChAdOx1 nCOV-19 adenoviral vector vaccines have been rapidly rolled out in the UK from December, 2020. We aimed to determine the factors associated with vaccine coverage for both vaccines and documented the vaccine effectiveness of the BNT162b2 mRNA vaccine in a cohort of health-care workers undergoing regular asymptomatic testing. MethodsThe SIREN study is a prospective cohort study among staff (aged ≥18 years) working in publicly-funded hospitals in the UK. Participants were assigned into either the positive cohort (antibody positive or history of infection [indicated by previous positivity of antibody or PCR tests]) or the negative cohort (antibody negative with no previous positive test) at the beginning of the follow-up period. Baseline risk factors were collected at enrolment, symptom status was collected every 2 weeks, and vaccination status was collected through linkage to the National Immunisations Management System and questionnaires. Participants had fortnightly asymptomatic SARS-CoV-2 PCR testing and monthly antibody testing, and all tests (including symptomatic testing) outside SIREN were captured. Data cutoff for this analysis was Feb 5, 2021. The follow-up period was Dec 7, 2020, to Feb 5, 2021. The primary outcomes were vaccinated participants (binary ever vacinated variable; indicated by at least one vaccine dose recorded by at least one of the two vaccination data sources) for the vaccine coverage analysis and SARS-CoV-2 infection confirmed by a PCR test for the vaccine effectiveness analysis. We did a mixed-effect logistic regression analysis to identify factors associated with vaccine coverage. We used a piecewise exponential hazard mixed-effects model (shared frailty-type model) using a Poisson distribution to calculate hazard ratios to compare time-to-infection in unvaccinated and vaccinated participants and estimate the impact of the BNT162b2 vaccine on all PCR-positive infections (asymptomatic and symptomatic). This study is registered with ISRCTN, number ISRCTN11041050, and is ongoing.Findings 23 324 participants from 104 sites (all in England) met the inclusion criteria for this analysis and were enrolled. Included participants had a median age of 46•1 years (IQR 36•0-54•1) and 19 692 (84%) were female; 8203 (35%) were assigned to the positive cohort at the start of the analysis period, and 15 121 (65%) assigned to the negative cohort. Total follow-up time was 2 calendar months and 1 106 905 person-days (396 318 vaccinated and 710 587 unvaccinated). Vaccine coverage was 89% on Feb 5, 2021, 94% of whom had BNT162b2 vaccine. Significantly lower coverage was associated with previous infection, gender, age, ethnicity, job role, and Index of Multiple Deprivation score. During follow-up, there were 977 new infections in the unvaccinated cohort, an incidence density of 14 infections per 10 000 person-days; the vaccinated cohort had 71 new infections 21 days or more after their first dose (incidence density of eight infections per 10 000 person-days) and nine infecti...

Microglia are phagocytic cells that are the main inflammatory response cells of the central nervous system. In Alzheimer's disease brain, activated microglia are concentrated in regions of compact amyloid deposits that contain the 39 -43-amino acid A␤ peptide. We examined the uptake, degradation, and release of small aggregates of fibrillar A␤ (fA␤) or soluble A␤ (sA␤) by microglia. We found that although some degradation of fA␤ was observed over 3 days, no further degradation was observed over the next 9 days. Instead, there was a slow release of intact A␤. The poor degradation was not due to inhibition of lysosomal function, since the rate of ␣2-macroglobulin degradation was not affected by the presence of fA␤ in the late endosomes/lysosomes. In contrast to fA␤, internalization of sA␤ was not saturable. After internalization, sA␤ was released rapidly from microglia, and very little was degraded. These data show that fA␤ and sA␤ interact differently with microglia but that after internalization a large fraction of both are released without degradation.

The endogenous major histocompatibility complex (MHC) class II presentation pathway allows biosynthesized, intracellular antigens access for presentation to MHC class II-restricted T cells. This pathway has been well documented in B cells and fibroblasts, but may not be universally available in all antigen-presenting cell types. This study compares the ability of different antigen-presenting cells, expressing endogenous C5 protein (fifth component of mouse complement) as a result of transfection, to present their biosynthesized C5 to MHC class II-restricted T cells. B cells and fibroblasts expressing C5 were able to present several epitopes of this protein with MHC class II molecules, whereas macrophages were unable to do so, but readily presented C5 from an extracellular source. However, macrophage presentation of endogenous C5 could be achieved when they were treated with low doses of the lysosomotropic agent ammonium chloride. In the presence of an inhibitor of autophagy, presentation of endogenous C5 was abrogated, indicating that biosynthesized C5 is shuttled into lysosomal compartments for degradation before making contact with MHC class II molecules. Taken together, this suggests that proteolytic activity in lysosomes of macrophages may be excessive, compared with fibroblasts and B cells, and destroys epitopes of the C5 protein before they can gain access to MHC class II molecules. Thus, there are inherent differences in presentation pathways between antigen-presenting cell types; this could reflect their specialized functions within the immune system with macrophages focussing preferentially on internalization, degradation, and presentation of extracellular material.

Microglia are macrophage-like immune system cells found in the brain. They are associated with Alzheimer's Disease plaques, which contain fibrillar ␤-amyloid (fA␤) and other components such as complement proteins. We have shown previously that murine microglia bind and internalize fA␤ microaggregates via the type A scavenger receptor, but degradation of internalized fA␤ is significantly slower than normal degradation. In this study, we compared internalization by microglia of fA␤ microaggregates to that of anti-A␤-antibody-coated fA␤ (IgG-fA␤) microaggregates and found that the uptake of the latter is increased by about 1.5-fold versus unmodified fA␤. The endocytic trafficking of IgG-fA␤ is similar to that of fA␤ microaggregates, following an endosomal/ lysosomal pathway. We also compared the internalization of fA␤ microaggregates to that of complement protein, C1q-coated fA␤ microaggregates, and found that the levels of uptake are also increased by about 1.5-fold. Rates of degradation of both types of modified fA␤ microaggregates are unchanged compared with unmodified fA␤ microaggregates. We demonstrated by blocking studies that internalization of IgG-fA␤ is mediated by Fc receptors. These data suggest that, in vivo, several different microglial receptors may play a part in internalizing fA␤, but the involvement of other receptors may not increase the degradation of fA␤.

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