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Accurate and precise point-of-care (POC) testing for C-reactive protein (CRP) can help support healthcare providers in the clinical management of patients. Here, we compared the analytical performance of 17 commercially available POC CRP tests to enable more decentralized use of the tool. The following CRP tests were evaluated. Eight quantitative tests: QuikRead go (Aidian), INCLIX (Sugentech), Spinit (Biosurfit), LS4000 (Lansionbio), GS 1200 (Gensure Biotech), Standard F200 (SD Biosensor), Epithod 616 (DxGen), IFP-3000 (Xincheng Biological); and nine semi-quantitative tests: Actim CRP (ACTIM), NADAL Dipstick (nal von minden), NADAL cassette (nal von minden), ALLTEST Dipstick (Hangzhou Alltest Biotech), ALLTEST Cassette cut-off 10-40-80 (Hangzhou Alltest Biotech), ALLTEST Cassette cut-off 10–30 (Hangzhou Alltest Biotech), Biotest (Hangzhou Biotest Biotech), BTNX Quad Line (BTNX), BTNX Tri Line (BTNX). Stored samples (n = 660) had previously been tested for CRP using Cobas 8000 Modular analyzer (Roche Diagnostics International AG, Rotkreuz, Switzerland (reference standards). CRP values represented the clinically relevant range (10–100 mg/L) and were grouped into four categories (<10 mg/L, 10–40 mg/L or 10–30 mg/L, 40–80 mg/L or 30–80 mg/L, and > 80mg/L) for majority of the semi-quantitative tests. Among the eight quantitative POC tests evaluated, QuikRead go and Spinit exhibited better agreement with the reference method, showing slopes of 0.963 and 0.921, respectively. Semi-quantitative tests with the four categories showed a poor percentage agreement for the intermediate categories and higher percentage agreement for the lower and upper limit categories. Analytical performance varied considerably for the semi-quantitative tests, especially among the different categories of CRP values. Our findings suggest that quantitative tests might represent the best choice for a variety of use cases, as they can be used across a broad range of CRP categories.

New broadly acting and readily available antiviral agents are needed to combat existing and emerging viruses. Defective interfering particles (DIPs) of influenza A virus (IAV) are regarded as promising options for the prevention and treatment of IAV infections. Interestingly, IAV DIPs also inhibit unrelated viral infections by stimulating antiviral innate immunity. Here, we tested the ability of IAV DIPs to suppress respiratory syncytial, yellow fever and Zika virus infections in vitro. In human lung (A549) cells, IAV DIP co-infection inhibited the replication and spread of all three viruses. In contrast, we observed no antiviral activity in Vero cells, which are deficient in the production of interferon (IFN), demonstrating its importance for the antiviral effect. Further, in A549 cells, we observed an enhanced type-I and type-III IFN response upon co-infection that appears to explain the antiviral potential of IAV DIPs. Finally, a lack of antiviral activity in the presence of the Janus kinase 1/2 (JAK1/2) inhibitor ruxolitinib was detected. This revealed a dependency of the antiviral activity on the JAK/signal transducers and activators of transcription (STAT) signaling pathway. Overall, this study supports the notion that IAV DIPs may be used as broad-spectrum antivirals to treat infections with a variety of IFN-sensitive viruses, particularly respiratory viruses.

SARS-CoV-2 variants accumulating immune escape mutations provide a significant risk to vaccine-induced protection against infection. The novel variant of concern (VoC) Omicron BA.1 and its sub-lineages have the largest number of amino acid alterations in its Spike protein to date. Thus, they may efficiently escape recognition by neutralizing antibodies, allowing breakthrough infections in convalescent and vaccinated individuals in particular in those who have only received a primary immunization scheme. We analyzed neutralization activity of sera from individuals after vaccination with all mRNA-, vector- or heterologous immunization schemes currently available in Europe by in vitro neutralization assay at peak response towards SARS-CoV-2 B.1, Omicron sub-lineages BA.1, BA.2, BA.2.12.1, BA.3, BA.4/5, Beta and Delta pseudotypes and also provide longitudinal follow-up data from BNT162b2 vaccinees. All vaccines apart from Ad26.CoV2.S showed high levels of responder rates (96–100%) towards the SARS-CoV-2 B.1 isolate, and minor to moderate reductions in neutralizing Beta and Delta VoC pseudotypes. The novel Omicron variant and its sub-lineages had the biggest impact, both in terms of response rates and neutralization titers. Only mRNA-1273 showed a 100% response rate to Omicron BA.1 and induced the highest level of neutralizing antibody titers, followed by heterologous prime-boost approaches. Homologous BNT162b2 vaccination, vector-based AZD1222 and Ad26.CoV2.S performed less well with peak responder rates of 48%, 56% and 9%, respectively. However, Omicron responder rates in BNT162b2 recipients were maintained in our six month longitudinal follow-up indicating that individuals with cross-protection against Omicron maintain it over time. Overall, our data strongly argue for booster doses in individuals who were previously vaccinated with BNT162b2, or a vector-based primary immunization scheme.

COVID-19 convalescent plasma (CCP) with high neutralizing antibodies has been suggested in preventing disease progression in COVID-19. In this study, we investigated the relationship between clinical donor characteristics and neutralizing anti-SARS-CoV-2 antibodies in CCP donors. COVID-19 convalescent plasma donors were included into the study. Clinical parameters were recorded and anti-SARS-CoV-2 antibody levels (Spike Trimer, Receptor Binding Domain (RBD), S1, S2 and nucleocapsid protein) as well as ACE2 binding inhibition were measured. An ACE2 binding inhibition < 20% was defined as an inadequate neutralization capacity. Univariate and multivariable logistic regression analysis was used to detect the predictors of inadequate neutralization capacity. Ninety-one CCP donors (56 female; 61%) were analyzed. A robust correlation between all SARS-CoV-2 IgG antibodies and ACE2 binding inhibition, as well as a positive correlation between donor age, body mass index, and a negative correlation between time since symptom onset and antibody levels were found. We identified time since symptom onset, normal body mass index (BMI), and the absence of high fever as independent predictors of inadequate neutralization capacity. Gender, duration of symptoms, and number of symptoms were not associated with SARS-CoV-2 IgG antibody levels or neutralization. Neutralizing capacity was correlated with SARS-CoV-2 IgG antibodies and associated with time since symptom onset, BMI, and fever. These clinical parameters can be easily incorporated into the preselection of CCP donors.

Background Although anti-SARS-CoV-2 humoral immune responses and epidemiology have been extensively studied, data gaps remain for certain populations such as indigenous people or children especially in low- and middle-income countries. To address this gap, we evaluated SARS-CoV-2 seroprevalence and humoral immunity towards the parental B.1 strain, local SARS-CoV-2 variants, and endemic coronaviruses in children from Colombia from March to April 2021. Methods We performed a cross-sectional seroprevalence study with 80 children from Bogotá and expanded our analysis by comparing results with an independent observational study of 82 children from the Wiwa community living in the north-eastern Colombian territories. Antibody IgG titers towards SARS-CoV-2 and the endemic coronaviruses as well as ACE2 binding inhibition as a proxy for neutralization towards several SARS-CoV-2 variants were analyzed using two multiplex-based immunoassays. Results While we find seroprevalence estimates of 21.3% in children from Bogotá, seroprevalence is higher with 34.1% in Wiwa children. We observe a robust induction of antibodies towards the surface-exposed spike protein, its S1-, S2- and receptor-binding-subdomains in all SARS-CoV-2 seropositive children. Only nucleocapsid-specific IgG is significantly lower in the indigenous participants. ACE2 binding inhibition is low for all SARS-CoV-2 variants examined. We observe a dominance of NL63 S1 IgG levels in urban and indigenous children which suggests an early exposure to this respiratory virus independent of living conditions and geographic location. SARS-CoV-2 seropositivity does not correlate with antibody levels towards any of the four endemic coronaviruses indicating the absence of cross-protective immunity. Conclusions Overall, antibody titers, but in particular ACE2 binding inhibition are low within Colombian samples, requiring further investigation to determine any potential clinical significance. Plain Language Summary Our knowledge of SARS-CoV-2, the virus causing COVID-19 remains incomplete for certain populations including indigenous people and younger age groups. Here, we aim to understand the extent to which children from urban and indigenous populations of Colombia were previously infected with SARS-CoV-2 and the related common cold coronaviruses. By measuring antibodies, protective proteins produced by the immune system, we find higher levels of previous SARS-CoV-2 infections in indigenous children of the Wiwa community (34.1%) compared to children from urbanized Bogotá (21.3%). Antibody levels towards the common cold coronaviruses were similar in SARS-CoV-2 infected and uninfected children suggesting immune responses to one coronavirus do not automatically protect against closely-related viruses. Further, we find low levels of protective immunity against SARS-CoV-2 in both populations. This finding warrants further investigation as it relates to reinfection risk and future vaccination strategies in these populations. Fernández Villalobos, Marsall et al. analyzed seroprevalence and antibody responses to SARS-CoV-2 variants and endemic coronaviruses in Colombian children from urban and indigenous populations. They find high SARS-CoV-2 seroprevalence with comparable antibody titers but low neutralizing capacity and limited cross-protective immunity.

Purpose Respiratory syncytial virus (RSV) is one of the leading causes of severe respiratory disease in infants and adults. While vaccines and monoclonal therapeutic antibodies either are or will shortly become available, correlates of protection remain unclear. For this purpose, we developed an RSV multiplex immunoassay that analyses antibody titers toward the post-F, Nucleoprotein, and a diverse mix of G proteins. Methods A bead-based multiplex RSV immunoassay was developed, technically validated to standard FDA bioanalytical guidelines, and clinically validated using samples from human challenge studies. RSV antibody titers were then investigated in children aged under 2 and a population-based cohort. Results Technical and clinical validation showed outstanding performance, while methodological developments enabled identification of the subtype of previous infections through use of the diverse G proteins for approximately 50% of samples. As a proof of concept to show the suitability of the assay in serosurveillance studies, we then evaluated titer decay and age-dependent antibody responses within population cohorts. Conclusion Overall, the developed assay shows robust performance, is scalable, provides additional information on infection subtype, and is therefore ideally suited to be used in future population cohort studies.

Background Contact behaviour is crucial to assess and predict transmission of respiratory pathogens like SARS-CoV-2. Contact behaviour has traditionally been assessed in cross-sectional surveys and not as part of longitudinal population-based studies which simultaneously measure infection frequency and vaccination coverage. During the COVID-19 pandemic, several studies assessed contact behaviour over longer periods and correlated this to data on immunity. This can inform future dynamic modelling. Here, we assess how contact behaviour varied based on SARS-CoV-2 infection or vaccination status in two large population-based studies in Germany during 2021. Methods We assessed direct encounters, separated into household and non-household contacts, in participants of MuSPAD ( n  = 12,641), a population-based cohort study, and COVIMOD ( n  = 31,260), a longitudinal contact survey. We calculated mean numbers of reported contacts and fitted negative binomial mixed-effects models to estimate the impact of immunity status, defined by vaccination or previous infection, on contact numbers; logistic mixed-effects models were used to examine the relationship between contact behaviour and seropositivity due to infection. Results Contact numbers varied over the course of the pandemic from 7.6 to 10.8 per 24 h in MuSPAD and 2.1 to 3.1 per 24 h in COVIMOD. The number of non-household contacts was higher in participants who reported previous infections and vaccinations (contact ratio (CR) MuSPAD: 1.22 (95%CI 0.94–1.60); COVIMOD: 1.35 (CI 1.12–1.62)) compared to unvaccinated and uninfected individuals. Non-household contact numbers were also higher in fully vaccinated participants (MUSPAD: CR 1.15 (CI 1.05–1.26); COVIMOD: 1.43 (CI 1.32–1.56)) compared to unvaccinated individuals. Compared to individuals without household contacts, the odds for seropositivity due to infection were higher among MuSPAD individuals with three or more household contacts (odds ratio (OR) 1.54 (CI 1.12–2.13)) and eleven or more non-household contacts (OR 1.29 (CI 1.01–1.65)). Conclusions Different contact behaviours based on infection and/or vaccination status suggest that public health policies targeting immunity status may influence the contact behaviour of those affected. A combined assessment of self-reported contacts, infections, and vaccinations as well as laboratory-confirmed serostatus in the population can support modelling of the spread of infections. This could help target containment policies and evaluate the impact of public health measures.

In the past decades, vaccine development has made great strides. Nevertheless, more often than not, vaccine candidates fail in advanced stages of development and clinical trials. A key reason is the poor predictive value of non-clinical in vivo and in vitro models, due to either species-specific differences in the immune response or insufficient reflection of physiological vaccine mechanisms. Reliable modeling of human adaptive immune responses is a prerequisite to understand processes leading to vaccine-induced protective immunization and to drive informed decisions in vaccine development pipelines. Here, we present a centrifugal microfluidics based organ-on-chip approach to generate an organotypic high density lymphoid tissue on-chip. The model enables long-term culture of lymphoid tissue and raised antigen-specific antibody responses against influenza vaccines even after four weeks on-chip. Antibody response of different magnitude and quality could be induced both by direct antigen exposure as well as by recruitment of antigen-presenting cells from the periphery. The model represents an attractive approach to evaluate the impact of the mode of antigen delivery on adaptive immune responses. Beyond applications in vaccine development, the lymphoid-tissue-on-chip provides a platform to study cellular interactions during homeostasis, immune responses and long-term impact of immunomodulators over several weeks.

Respiratory syncytial virus (RSV) is one of the leading causes of severe respiratory disease in infants and adults. RSV exists as two subtypes A and B, which co-circulate throughout the season, although one will usually become dominant. While vaccines and monoclonal therapeutic antibodies either are or will shortly become available, correlates of protection remain unclear. For this purpose, we developed an RSV multiplex immunoassay that analyses antibody titers towards the post-F, Nucleoprotein, and a diverse mix of G proteins. Technical and clinical validation showed outstanding performance, while methodological developments enabled identification of the subtype of previous infections through use of the diverse G proteins for approximately 50% of samples. As a proof of concept to show the suitability of the assay in serosurveillance studies, we then evaluated titer decay and age- dependent antibody responses within population cohorts. Overall, the developed assay shows robust performance, is scalable, provides additional information on infection subtype, and is therefore ideally suited to be used in future population cohort studies. Although respiratory syncytial virus (RSV) is endemic and re-infections are common and harmless to the majority of the population, it is a leading cause of hospitalization in young children, the elderly, or immunocompromised individuals. A better characterization of RSV immunology and spreading dynamics is thus critical for preparedness, especially when interventions aiming to mitigate other diseases (e.g., COVID-19) disturb its endemic cycles. This requires high-throughput information-dense assays. We therefore developed a bead-based multiplex immunoassay that allows measurements of antibodies against multiple RSV antigens simultaneously. We identified antibodies which were strong indicators of previous infection, while others allowed identification of the subtype of the previous infection. The assay itself was shown to be robust and scalable, making it ideal for to keep track of the temporal variation RSV immunity profiles within the population.