COVID-19 continues to damage populations, communities and economies worldwide. Vaccines have reduced COVID-19-related hospitalisations and deaths, primarily in developed countries. Persisting infection rates, and highly transmissible SARS-CoV-2 Variants of Concern (VOCs) causing repeat and breakthrough infections, underscore the ongoing need for new treatments to achieve a global solution. Based on ADDomer, a self-assembling protein nanoparticle scaffold, we created ADDoCoV, a thermostable COVID-19 candidate vaccine displaying multiple copies of a SARS-CoV-2 receptor binding motif (RBM)-derived epitope. In vitro generated neutralising nanobodies combined with molecular dynamics (MD) simulations and electron cryo-microscopy (cryo-EM) established authenticity and accessibility of the epitopes displayed. A Gigabody comprising multimerized nanobodies prevented SARS-CoV-2 virion attachment with picomolar EC50. Antibodies generated by immunising mice cross-reacted with VOCs including Delta and Omicron. Our study elucidates nasal administration of ADDomer-based nanoparticles for active and passive immunisation against SARS-CoV-2 and provides a blueprint for designing nanoparticle reagents to combat respiratory viral infections.
To characterize species of viral mRNA transcripts generated during respiratory syncytial virus (RSV) infection, human fibroblast-like MRC-5 lung cells were infected with subgroup A RSV for 6, 16 and 24 hours. In addition, we characterised the viral transcriptome in infected Calu-3 lung epithelial cells at 48 hours post infection. Total RNA was harvested and polyadenylated mRNA was enriched and sequenced by direct RNA sequencing using an Oxford nanopore device. This platform yielded over 450,000 direct mRNA transcript reads which were mapped to the viral genome and analysed to determine the relative mRNA levels of viral genes using our in-house ORF-centric pipeline. We examined the frequency of polycistronic readthrough mRNAs were generated and assessed the length of the polyadenylated tails for each group of transcripts. We show a general but non-linear decline in gene transcript abundance across the viral genome, as predicted by the model of RSV gene transcription. However, the decline in transcript abundance is not uniform. The polyadenylate tails generated by the viral polymerase are similar in length to those generated by the host polyadenylation machinery and broadly declined in length for most transcripts as the infection progressed. Finally, we observed that the steady state abundance of transcripts with very short polyadenylate tails less than 20 nucleotides is less for N, SH and G transcripts in both cell lines compared to NS1, NS2, P, M, F and M2 which may reflect differences in mRNA stability and/or translation rates within and between the cell lines.
To characterize species of viral mRNA transcripts generated during respiratory syncytial virus (RSV) infection, human fibroblast-like MRC5 lung cells were infected with subgroup A RSV for 6, 16 and 24 hours. Total RNA was harvested and polyadenylated mRNA was enriched and sequenced by direct RNA sequencing on an Oxford nanopore device. This yielded over 150,000 direct mRNA transcript reads which were mapped to the viral genome and analysed to determine relative mRNA levels of viral genes using our in-house ORF-centric pipeline. We were also able to examine frequencies with which polycistronic readthrough mRNAs were generated and to assess the length of the polyadenylated tails for each group of transcripts. We show that there is a general but non-linear decline in gene transcript abundance across the viral genome, as predicted by the model of RSV gene transcription. However, the decline in transcript abundance is not consistent. We show that the polyadenylate tails generated by the viral polymerase are similar in length to those generated by the host cells polyadenylation machinery and broadly declined in length for most transcripts as infection progressed. Finally, we observed that the steady state abundance of transcripts with very short polyadenylate tails is much less for N, SH and G transcripts compared to NS1, NS2, P, M, F and M2 which may reflect differences in mRNA stability and/or translation rates.
Throughout a 20 year biosurveillance period, viral hemorrhagic septicemia virus was isolated in low titers from only 6/7355 opportunistically sampled adult Pacific herring, reflecting the typical endemic phase of the disease when the virus persists covertly. However, more focused surveillance efforts identified the presence of disease hot spots occurring among juvenile life history stages from certain nearshore habitats. These outbreaks sometimes recurred annually in the same temporal and spatial patterns and were characterized by infection prevalence as high as 96%. Longitudinal sampling indicated that some epizootics were relatively transient, represented by positive samples on a single sampling date, and others were more protracted, with positive samples occurring throughout the first 10 weeks of the juvenile life history phase. These results indicate that viral hemorrhagic septicemia (VHS) epizootics in free-ranging Pacific herring C. pallasii are more common than previously appreciated; however, they are easily overlooked if biosurveillance efforts are not designed around times and locations with high disease potential.
We characterized a natural sea louse epizootic of Caligus clemensi and the effects of parasitism on Pacific herring Clupea pallasii in Port Angeles Harbor, WA, USA. Infestation prevalence on newly metamorphosed age 0 Pacific herring reached 100% prevalence by mid-August. At this time, the mean louse intensity was 4.6 lice / fish, and a positive correlation occurred between louse intensity and herring body length. The epizootic then waned, with infestation prevalence decreasing to less than 25% and the mean parasite intensity falling below 1 louse. While skin injuries were not detected, motile lice preferentially aggregated around head and anterior dorsal areas. However, louse tropism became evenly distributed over the body as the parasite intensity increased. Louse-induced mortality in herring was negligible in controlled experiments. These results indicate that C. clemensi epizootics reach high prevalence, but also fade from mid-summer to early fall. The predominant presence of motile copepod stages suggests that the epizootic fades because lice complete their life cycle and dislodge from the host; however, multiple explanations for epidemic fading are possible.
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