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Objectives: To study the effect of mycophenolate mofetil (MMF) on various vaccination responses in kidney transplant recipients. Methods: In a randomized controlled trial (EudraCT nr.: 2014-001372-66), low immunologically risk kidney transplant recipients were randomized to TAC/MMF or TAC-monotherapy (TACmono), six months post-transplantation. One year after transplantation, in a pre-specified sub-study, recipients were vaccinated against pneumococcus, tetanus and influenza. Blood was sampled before and 21 days after vaccination. Adequate vaccination responses were defined by international criteria. A post-hoc analysis was conducted on SARS-CoV-2 vaccination responses within the same cohort. Results: Seventy-one recipients received pneumococcal and tetanus vaccines (TAC/MMF: n = 37, TACmono: n = 34), with 29 also vaccinated against influenza. When vaccinated, recipients were 60 (54–66) years old, with median eGFR of 54 (44–67) ml/min, tacrolimus trough levels 6.1 (5.4–7.0) ug/L in both groups and TAC/MMF daily MMF dose of 1000 (500–2000) mg. Adequate vaccination responses were: pneumococcal (TAC/MMF 43%, TACmono 74%, p = 0.016), tetanus (TAC/MMF 35%, TACmono 82%, p < 0.0001) and influenza (TAC/MMF 20%, TACmono 71%, p = 0.0092). Only 7% of TAC/MMF responded adequately to all three compared to 36% of TACmono (p = 0.080). Additionally, 40% of TAC/MMF responded inadequately to all three, whereas all TACmono patients responded adequately to at least one vaccination (p = 0.041). Lower SARS-CoV-2 vaccination antibody responses correlated with lower pneumococcal antibody vaccination responses (correlation coefficient: 0.41, p = 0.040). Conclusions: MMF on top of tacrolimus severely hampers antibody responses to a broad range of vaccinations.

Newcastle Disease virus (NDV) has shown promise as an oncolytic virus for treatment of a wide range of tumours. NDV with a multi-basic cleavage site (MBCS) in the fusion (F) protein (NDV F3aa) has increased oncolytic efficacy in several tumour models, but also increased virulence in chickens compared to non-virulent NDV F0, raising potential environmental safety issues. Previously, we generated a variant of NDV F3aa with a disrupted V protein gene and a substitution of phenylalanine to serine at position 117 of the F protein (NDV F3aa-S-STOPV). Compared to NDV F3aa this virus had decreased virulence in embryonated chicken eggs. In this study, the virulence of the virus was evaluated upon inoculation of six-week-old chickens through a natural infection route and by determination of the intracerebral pathogenicity index (ICPI). Based on these data NDV F3aa-S-STOPV classified as a non-virulent virus. Although NDV F3aa was classified as a virulent virus based on the ICPI, the virus was also less pathogenic than NDV F0 upon inoculation of six-week-old chickens. These data indicate that NDV with a MBCS is not necessarily pathogenic in chickens. In addition, these data show that F3aa-S-STOPV is safe to use in viro-immunotherapies without posing a threat for chickens upon accidental exposure.

Highly pathogenic avian influenza (HPAI) viruses of the A/Goose/Guangdong/1/1996 lineage (GsGd), which threaten the health of poultry, wildlife and humans, are spreading across Asia, Europe, Africa and North America but are currently absent from South America and Oceania. In December 2021, H5N1 HPAI viruses were detected in poultry and a free-living gull in St. John’s, Newfoundland and Labrador, Canada. Our phylogenetic analysis showed that these viruses were most closely related to HPAI GsGd viruses circulating in northwestern Europe in spring 2021. Our analysis of wild bird migration suggested that these viruses may have been carried across the Atlantic via Iceland, Greenland/Arctic or pelagic routes. The here documented incursion of HPAI GsGd viruses into North America raises concern for further virus spread across the Americas by wild bird migration.

The production of type I interferon (IFN) is the hallmark of the innate immune response. Most, if not all, mammalian viruses have a way to circumvent this response. Fundamental knowledge on viral evasion of innate immune responses may facilitate the design of novel antiviral therapies. To investigate how human metapneumovirus (HMPV) interacts with the innate immune response, recombinant viruses lacking G, short hydrophobic (SH), or M2-2 protein expression were assessed for IFN induction in A549 cells. HMPV lacking G or SH protein expression induced similarly low levels of IFN, compared to the wild-type virus, whereas HMPV lacking M2-2 expression induced significantly more IFN than the wild-type virus. However, sequence analysis of the genomes of M2-2 mutant viruses revealed large numbers of mutations throughout the genome. Over 70% of these nucleotide substitutions were A-to-G and T-to-C mutations, consistent with the properties of the adenosine deaminase acting on RNA (ADAR) protein family. Knockdown of ADAR1 by CRISPR interference confirmed the role of ADAR1 in the editing of M2-2 deletion mutant virus genomes. More importantly, Northern blot analyses revealed the presence of defective interfering RNAs (DIs) in M2-2 mutant viruses and not in the wild-type virus or G and SH deletion mutant viruses. DIs are known to be potent inducers of the IFN response. The presence of DIs in M2-2 mutant virus stocks and hypermutated virus genomes interfere with studies on HMPV and the innate immune response and should be addressed in future studies. IMPORTANCE Understanding the interaction between viruses and the innate immune response is one of the barriers to the design of antiviral therapies. Here, we investigated the role of the G, SH, and M2-2 proteins of HMPV as type I IFN antagonists. In contrast to other studies, no IFN-antagonistic functions could be observed for the G and SH proteins. HMPV with a deletion of the M2-2 protein did induce type I IFN production upon infe

The recently raised awareness of the threat of a new influenza pandemic has stimulated interest in the detection of influenza A viruses in human as well as animal secretions. Virus isolation alone is unsatisfactory for this purpose because of its inherent limited sensitivity and the lack of host cells that are universally permissive to all influenza A viruses. Previously described PCR methods are more sensitive but are targeted predominantly at virus strains currently circulating in humans, since the sequences of the primer sets display considerable numbers of mismatches to the sequences of animal influenza A viruses. Therefore, a new set of primers, based on highly conserved regions of the matrix gene, was designed for single-tube reverse transcription-PCR for the detection of influenza A viruses from multiple species. This PCR proved to be fully reactive with a panel of 25 genetically diverse virus isolates that were obtained from birds, humans, pigs, horses, and seals and that included all known subtypes of influenza A virus. It was not reactive with the 11 other RNA viruses tested. Comparative tests with throat swab samples from humans and fecal and cloacal swab samples from birds confirmed that the new PCR is faster and up to 100-fold more sensitive than classical virus isolation procedures.