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Distinct roadblocks prevent translating basic findings in viral pathogenesis into therapies and implementing potential solutions in the clinic. An ongoing partnership between the Volkswagen Foundation and Nature Medicine resulted in an interactive meeting in 2012, as part of the "Herrenhausen Symposia" series. Current challenges for various fields of viral research were recognized and discussed with a goal in mind--to identify solutions and propose an agenda to address the translational barriers. Here, some of the researchers who participated at the meeting provide a concise outlook at the most pressing unmet research and clinical needs, identifying these key obstacles is a necessary step towards the prevention and cure of human viral diseases.

BACKGROUND. COVID-19 convalescent plasma (CCP) has been considered a treatment option for COVID-19. This trial assessed the efficacy of a neutralizing antibody containing high-dose CCP in hospitalized adults with COVID-19 requiring respiratory support or intensive care treatment. METHODS. Patients (n = 105) were randomized 1:1 to either receive standard treatment and 3 units of CCP or standard treatment alone. Control group patients with progress on day 14 could cross over to the CCP group. The primary outcome was a dichotomous composite outcome of survival and no longer fulfilling criteria for severe COVID-19 on day 21. RESULTS. The primary outcome occurred in 43.4% of patients in the CCP group and 32.7% in the control group (P = 0.32). The median time to clinical improvement was 26 days in the CCP group and 66 days in the control group (P = 0.27). The median time to discharge from the hospital was 31 days in the CCP group and 51 days in the control group (P = 0.24). In the subgroup that received a higher cumulative amount of neutralizing antibodies, the primary outcome occurred in 56.0% of the patients (vs. 32.1%), with significantly shorter intervals to clinical improvement (20 vs. 66 days, P< 0.05) and to hospital discharge (21 vs. 51 days, P = 0.03) and better survival (day-60 probability of survival 91.6% vs. 68.1%, P = 0.02) in comparison with the control group. CONCLUSION. CCP added to standard treatment was not associated with a significant improvement in the primary and secondary outcomes. A predefined subgroup analysis showed a significant benefit of CCP among patients who received a larger amount of neutralizing antibodies. TRIAL REGISTRATION. ClinicalTrials.gov NCT04433910. FUNDING. Bundesministerium fur Gesundheit (German Federal Ministry of Health): ZMVI1-2520COR802., Introduction COVID-19 convalescent plasma (CCP) from patients who have recovered from a SARS-CoV-2 infection has become one of the treatment options for severe COVID-19 (1, 2). It has been broadly [...]

Most SARS‐CoV‐2 proteins are translated from subgenomic RNAs (sgRNAs). While the majority of these sgRNAs are monocistronic, some viral mRNAs encode more than one protein. One example is the ORF3a sgRNA that also encodes ORF3c, an enigmatic 41‐amino‐acid peptide. Here, we show that ORF3c is expressed in SARS‐CoV‐2‐infected cells and suppresses RIG‐I‐ and MDA5‐mediated IFN‐β induction. ORF3c interacts with the signaling adaptor MAVS, induces its C‐terminal cleavage, and inhibits the interaction of RIG‐I with MAVS. The immunosuppressive activity of ORF3c is conserved among members of the subgenus sarbecovirus, including SARS‐CoV and coronaviruses isolated from bats. Notably, however, the SARS‐CoV‐2 delta and kappa variants harbor premature stop codons in ORF3c, demonstrating that this reading frame is not essential for efficient viral replication in vivo and is likely compensated by other viral proteins. In agreement with this, disruption of ORF3c does not significantly affect SARS‐CoV‐2 replication in CaCo‐2, CaLu‐3, or Rhinolophus alcyone cells. In summary, we here identify ORF3c as an immune evasion factor of SARS‐CoV‐2 that suppresses innate sensing in infected cells. Synopsis: SARS‐CoV‐2‐encoded ORF3c is expressed in infected cells. This small viral protein is conserved among sarbecoviruses and suppresses the induction of IFN‐β by targeting the signaling adaptor protein MAVS.SARS‐CoV‐2 ORF3c is expressed in infected cells and suppresses IFN‐β induction.SARS‐CoV‐2 ORF3c interacts with the signaling adaptor MAVS.SARS‐CoV‐2 ORF3c induces C‐terminal cleavage of MAVS and inhibits its interaction with RIG‐I.The immunosuppressive activity of ORF3c is conserved among sarbecoviruses. [ABSTRACT FROM AUTHOR]

The catastrophic Zika virus outbreak in the Americas has affected millions of persons. Brazil was the most affected country and reported [approximately equal to] 95% of all cases of suspected [...]

Autoantibodies against IFN-[alpha] and IFN-[omega] (type I IFNs) were recently reported as causative for severe COVID-19 in the general population. Autoantibodies against IFN-[alpha] and IFN-[omega] are present in almost all patients with autoimmune polyendocrine syndrome type 1 (APS-1) caused by biallelic deleterious or heterozygous dominant mutations in AIRE. We therefore hypothesized that autoantibodies against type I IFNs also predispose patients with APS-1 to severe COVID-19. We prospectively studied 6 patients with APS-1 between April 1, 2020 and April 1, 2021. Biobanked pre-COVID-19 sera of APS-1 subjects were tested for neutralizing autoantibodies against IFN-[alpha] and IFN-[omega]. The ability of the patients' sera to block recombinant human IFN-[alpha] and IFN-[omega] was assessed by assays quantifying phosphorylation of signal transducer and activator of transcription 1 (STAT1) as well as infection-based IFN-neutralization assays. We describe 4 patients with APS-1 and preexisting high titers of neutralizing autoantibodies against IFN-[alpha] and IFN-[omega] who contracted SARS-CoV-2, yet developed only mild symptoms of COVID-19. None of the patients developed dyspnea, oxygen requirement, or high temperature. All infected patients with APS-1 were females andyoungerthan 26 years of age. Clinical penetrance of neutralizing autoantibodies against type I IFNs for severe COVID-19 is not complete., Introduction Mutations in AIRE (gene encoding the protein autoimmune regulator) cause autoimmune polyendocrine syndrome type 1 (APS-1) (1-3). AIRE is expressed in thymic epithelium and secondary lymphoid organs (4). AIRE [...]

Yellow fever virus (YFV) is a mosquitoborne member of the genus Flavivirus within the family Flaviviridae (online Technical Appendix Figure 1, panel A, https://wwwnc.cdc.gov/EID/article/23/11/17-1131-Techapp1.pdf) that is endemic to Africa and [...]

Hepatitis E virus (HEV; family Hepeviridae, genus Orthohepevirus) is a major cause of acute hepatitis in humans worldwide. Large outbreaks have included waterborne HEV in the tropics and zoonotic infections [...]

Background Healthcare workers (HCWs) have experienced high rates of coronavirus disease 2019 (COVID-19) morbidity and mortality. We estimated COVID-19 2-dose primary series and monovalent booster vaccine effectiveness (VE) against symptomatic severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron (BA.1 and BA.2) infection among HCWs in 3 Albanian hospitals during January–May 2022. Methods Study participants completed weekly symptom questionnaires, underwent polymerase chain reaction (PCR) testing when symptomatic, and provided quarterly blood samples for serology. We estimated VE using Cox regression models (1 – hazard ratio), with vaccination status as the time-varying exposure and unvaccinated HCWs as the reference group, adjusting for potential confounders: age, sex, prior SARS-CoV-2 infection (detected by PCR, rapid antigen test, or serology), and household size. Results At the start of the analysis period, 76% of 1462 HCWs had received a primary series, 10% had received a booster dose, and 9% were unvaccinated; 1307 (89%) HCWs had evidence of prior infection. Overall, 86% of primary series and 98% of booster doses received were BNT162b2. The median time interval from the second dose and the booster dose to the start of the analysis period was 289 (interquartile range [IQR], 210–292) days and 30 (IQR, 22–46) days, respectively. VE against symptomatic PCR-confirmed infection was 34% (95% confidence interval [CI], −36% to 68%) for the primary series and 88% (95% CI, 39%–98%) for the booster. Conclusions Among Albanian HCWs, most of whom had been previously infected, COVID-19 booster dose offered improved VE during a period of Omicron BA.1 and BA.2 circulation. Our findings support promoting booster dose uptake among Albanian HCWs, which, as of January 2023, was only 20%. Clinical Trials Registration. NCT04811391. [ABSTRACT FROM AUTHOR]

Objective To examine the diagnostic performance of real-time reverse transcription (RT)-polymerase chain reaction (PCR) assays for Zika virus detection. Methods We compared seven published real-time RT-PCR assays and two new assays that we have developed. To determine the analytical sensitivity of each assay, we constructed a synthetic universal control ribonucleic acid (uncRNA) containing all of the assays' target regions on one RNA strand and spiked human blood or urine with known quantities of African or Asian Zika virus strains. Viral loads in 33 samples from Zika virus-infected patients were determined by using one of the new assays. Findings Oligonucleotides of the published real-time RT-PCR assays, showed up to 10 potential mismatches with the Asian lineage causing the current outbreak, compared with 0 to 4 mismatches for the new assays. The 95% lower detection limit of the seven most sensitive assays ranged from 2.1 to 12.1 uncRNA copies/reaction. Two assays had lower sensitivities of 17.0 and 1373.3 uncRNA copies/reaction and showed a similar sensitivity when using spiked samples. The mean viral loads in samples from Zika virus-infected patients were 5 x 104 RNA copies/mL of blood and 2 x [10.sup.4] RNA coples/mL of urine. Conclusion We provide reagents and updated protocols for Zika virus detection suitable for the current outbreak strains. Some published assays might be unsuitable for Zika virus detection, due to the limited sensitivity and potential incompatibility with some strains. Viral concentrations in the clinical samples were close to the technical detection limit, suggesting that the use of insensitive assays will cause false-negative results. Objectif Etudier la performance diagnostique des tests bases sur l'amplification en chaine par polymerase (PCR) en temps reel apres transcription inverse (RT) pour detecter le virus Zika. Methodes Nous avons compare sept tests publies utilisant la RT-PCR en temps reel et deux nouveaux tests developpes par nos soins. Afin de determiner la sensibilite analytique de chaque test, nous avons concu un acide ribonucleique synthetique de controle universel (ARNcun) contenant toutes les regions ciblees par les tests sur une helice ARN et enrichi de l'urine ou du sang humain de quantites connues de souches africaines ou asiatiques du virus Zika. Les charges virales dans 33 echantillons provenant de patients infectes par le virus Zika ont ete determinees a l'aide de l'un des nouveaux tests. Resultats Les oligonucleotides des tests publies utilisant la RT-PCR en temps reel ont presente jusqu'a TOmauvais apparlements potentiels avec la lignee asiatique provoquant l'epidemie actuelle, alors qu'on a constate de 0 a 4 mauvais appariements dans le cas des nouveaux tests. La limite de detection inferieure a 95% des sept tests les plus sensibles variait de 2,1 a 12,1 copies dARNcun/reaction. Deux tests presentaient des sensibilites plus basses de 17,0 et 1373,3 copies d'ARNcun/reaction et montraient une sensibilite similaire lorsque des echantillons enrichis etaient utilises. Les charges virales moyennes dans les echantillons provenant de patients infectes par le virus Zika etaient de 5 x 104 copies d'ARN/mL de sang et de 2 x 104 copies dARN/mL d'urine. Conclusion Nous proposons pour detecter le virus Zika des reactifs et des protocoles actualises, adaptes aux souches responsables de la flambee actuelle.Tous les tests publies ne permettent pas de detecter le virus Zika en raison d'une sensibilite limitee et d'une incompatibilite potentielle avec certaines souches. Les concentrations virales dans les echantillons cliniques etaient proches de la limite de detection technique, ce qui laisse penser que l'utilisation de tests insensibles donnera des resultats faussement negatifs. Objetivo Examinar el rendimiento del diagnostico de las pruebas de reaccion en cadena de la polimerasa de transcriptasa inversa (RT-PCR) en tiempo real para la deteccion del virus de Zika. Metodos Se compararon siete pruebas de RT-PCR en tiempo real publicadas y dos pruebas nuevas que se han desarrollado. Con el fin de determinar la sensibilidad analitica de cada prueba, se construyo un acido ribonucleico sintetico de control universal (uncRNA) que contenia todas las regiones objetivo de las pruebas en una hebra de RNA y se anadio a sangre u orina humana con cantidades conocidas de cepas de virus de Zika de Asia o Africa. Se determinaron las cargas viricas en 33 muestras procedentes de pacientes infectados por el virus de Zika a traves de una de las pruebas nuevas. Resultados Los oligonucleotidos de las pruebas de RT-PCR en tiempo real publicadas mostraron hasta 10 posibles discordancias con el linaje de Asia causante de los brotes actuales, en comparacion con 0 de 4 discordancias en el caso de las pruebas nuevas. El limite de deteccion inferior del 95% de las siete pruebas mas sensibles abarco de 2,1 a 12,1 copias/reaccion de uncRNA. Dos pruebas mostraron sensibilidades inferiores de 17,0 y 1373,3 copias/reaccion de uncRNA y presentaron una sensibilidad similar al usar muestras Infectadas. Las cargas viricas medias en las muestras procedentes de pacientes infectados por el virus de Zika fueron de 5 x 104 copias de RNA/mL de sangre y de 2 x [10.sup.4] coplas de RNA/ml de orina. Conclusion Se proporcionan reactivos y protocolos actualizados para la deteccion adecuada del virus de Zika en el caso de las cepas de brotes actuales. Algunas pruebas publicadas pueden no ser adecuadas para la deteccion del virus de Zika, debido a la limitada sensibilidad y a la posible incompatibilidad con algunas cepas. Las concentraciones viricas en las muestras clinicas se acercaron al limite de deteccion tecnico, lo que sugeria que el uso de pruebas Intensivas causaria resultados falsos negativos., Introduction The Zika virus is a mosquito-borne flavivirus with an approximately 11 kilobase ribonucleic acid (RNA) genome. (1) The virus usually causes a mild infection in adults, symptoms include fever, [...]