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Background: MERS-CoV is a respiratory pathogen with a case-fatality rate of 36%, and for which no vaccines are currently licensed. MVA-MERS-S is a candidate vaccine based on recombinant modified vaccinia virus Ankara (MVA). In this study, the safety, immunogenicity, and optimal dose schedule of MVA-MERS-S was assessed in individuals with previous exposure to SARS-CoV-2 infections and vaccines., Methods: We conducted a multicentre, double-blind, randomised controlled phase 1b clinical trial at two university medical centres in Germany and the Netherlands. Healthy volunteers aged 18-55 years were assigned by computer randomisation to receive three intramuscular injections of 10 7 or 10 8 plaque-forming units (PFU) of MVA-MERS-S, with two treatment groups each of either 28-day or 56-day intervals between the initial two doses, and one control arm that received only placebo, at a ratio of 2:2:2:2:1. The third dose was given after 224 days. The sponsor, clinical and laboratory staff, and participants were masked to both vaccine dose and dosing interval. The primary outcome was safety, assessed in the all participants who had received at least one injection; daily solicited vaccine reactions were recorded after each dose for 7 days, unsolicited adverse events for 28 days, and serious adverse events throughout the study. The secondary outcome was humoral immunogenicity, measured with vaccine-induced geometric mean antibody concentrations and seroconversion rates, analysed in all participants who received at least three allocated treatments. This study is registered at ClinicalTrials.gov (NCT04119440) and is completed., Findings: Between 26 July, 2021, and 3 March, 2022, 244 volunteers were screened, 177 of whom were eligible and 140 were randomly assigned either to the 28-day 10 7 PFU group (n=32), 56-day 10 7 PFU group (n=31), 28-day 10 8 PFU group (n=31), 56-day 10 8 PFU group (n=30), or placebo group (n=16). In total, 178 doses were administered of 10 7 PFU of MVA-MERS-S, 174 of 10 8 PFU, and 164 doses of placebo, and 139 participants received at least one injection. 73 (53%) were female and 66 (48%) were male. No serious vaccine-related adverse events occurred. Solicited local reactions were mild in 288 (93%, 95% CI 90-96) of 309 reports and consisted primarily of pain or tenderness. Pain or tenderness (of any severity) occurred after 69 (39%, 32-46) of 178 10 7 PFU injections, 138 (79%; 73-85) of 174 10 8 PFU injections, and 18 (11%; 7-11) of 164 placebo injections. Of 595 reported solicited systemic reactions, 479 (81%, 77-83) were graded as mild. Systemic reactions of any grade occurred after 77 (43%; 36-51) 10 7 PFU injections, 102 (59%; 51-66) 10 8 PFU injections, and 67 (41%; 34-49) of 164 placebo injections. At 28 days after the second dose, MERS-CoV neutralising antibodies were highest for participants assigned to 56-day 10 8 PFU, with geometric mean ratios of 7·2 (95% CI 3·9-13·3) for the 56-day 10 8 PFU group versus the 28-day 10 8 PFU group (p<0·0001), 3·9 (2·1-7·2) for the 56-day 10 8 PFU group versus the 56-day 10 7 PFU group (p=0·0031), and 5·4 (2·9-10·0) for the 56-day 10 8 PFU group versus the 28-day 10 7 PFU group (p=0·0003)., Interpretation: MVA-MERS-S was safe and immunogenic in individuals with previous and concurrent SARS-CoV-2 exposure. The second vaccination with the 10 8 PFU dose of MVA-MERS-S elicited a stronger humoral immune response when administered 56 days after the first dose than a 28-day interval. Further studies are needed to verify these findings in groups at risk for MERS-CoV exposure, and at risk of severe disease, including older individuals and those with relevant comorbidities., Funding: Coalition for Epidemic Preparedness Innovations, the German Centre for Infection Research, and the German Research Foundation., Competing Interests: Declaration of interests AF became a full-time employee of BioNTech in January, 2024, after completion of this study. CD has been the translational immunology lead at the Coalition for Epidemic Preparedness Innovations (CEPI) since November, 2022, with responsibilities separate from her role in the present study. BLH is named as an inventor on a patent related to MERS-CoV. SB and GS are named as inventors on a patent for a novel MERS-CoV vaccine. All other authors declare no competing interests., (Copyright © 2024 Elsevier Ltd. All rights reserved, including those for text and data mining, AI training, and similar technologies.)

Besides neutralizing antibodies, which are considered an important measure for vaccine immunogenicity, Fc-mediated antibody functions can contribute to antibody-mediated protection. They are strongly influenced by structural antibody properties such as subclass and Fc glycan composition. We here applied a systems serology approach to dissect humoral immune responses induced by MVA-MERS-S, an MVA-vectored vaccine against the Middle East respiratory syndrome coronavirus (MERS-CoV). Building on preceding studies reporting the safety and immunogenicity of MVA-MERS-S, our study highlights the potential of a late boost, administered one year after prime, to enhance both neutralizing and Fc-mediated antibody functionality compared to the primary vaccination series. Distinct characteristics were observed for antibodies specific to the MERS-CoV spike protein S1 and S2 subunits, regarding subclass and glycan compositions as well as Fc functionality. These findings highlight the benefit of a late homologous booster vaccination with MVA-MERS-S and may be of interest for the design of future coronavirus vaccines., Competing Interests: A.F. is an employee of BioNTech SE as of January 2024 (after the completion of this study). All other authors declare no competing interests., (© 2024 The Author(s).)

Monoclonal antibodies are an increasingly important tool for prophylaxis and treatment of acute virus infections like SARS-CoV-2 infection. However, their use is often restricted due to the time required for development, variable yields and high production costs, as well as the need for adaptation to newly emerging virus variants. Here we use the genetically modified filamentous fungus expression system Thermothelomyces heterothallica (C1), which has a naturally high biosynthesis capacity for secretory enzymes and other proteins, to produce a human monoclonal IgG1 antibody (HuMab 87G7) that neutralises the SARS-CoV-2 variants of concern (VOCs) Alpha, Beta, Gamma, Delta, and Omicron. Both the mammalian cell and C1 produced HuMab 87G7 broadly neutralise SARS-CoV-2 VOCs in vitro and also provide protection against VOC Omicron in hamsters. The C1 produced HuMab 87G7 is also able to protect against the Delta VOC in non-human primates. In summary, these findings show that the C1 expression system is a promising technology platform for the development of HuMabs in preventive and therapeutic medicine., (© 2024. The Author(s).)

Vaccine-induced immune thrombotic thrombocytopenia (VITT) is a rare autoimmune condition associated with recombinant adenovirus (rAV)-based COVID-19 vaccines. It is thought to arise from autoantibodies targeting platelet factor 4 (aPF4), triggered by vaccine-induced inflammation and the formation of neo-antigenic complexes between PF4 and the rAV vector. To investigate the specific induction of aPF4 by rAV-based vaccines, we examined sera from rAV vaccine recipients (AZD1222, AD26.COV2.S) and messenger RNA (mRNA) based (mRNA-1273, BNT162b2) COVID-19 vaccine recipients. We compared the antibody fold change (FC) for aPF4 and for antiphospholipid antibodies (aPL) of rAV to mRNA vaccine recipients. We combined two biobanks of Dutch healthcare workers and matched rAV-vaccinated individuals to mRNA-vaccinated controls, based on age, sex and prior history of COVID-19 (AZD1222: 37, Ad26.COV2.S: 35, mRNA-1273: 47, BNT162b2: 26). We found no significant differences in aPF4 FCs after the first (0.99 vs. 1.08, mean difference (MD) = -0.11 (95% CI -0.23 to 0.057)) and second doses of AZD1222 (0.99 vs. 1.10, MD = -0.11 (95% CI -0.31 to 0.10)) and after a single dose of Ad26.COV2.S compared to mRNA-based vaccines (1.01 vs. 0.99, MD = 0.026 (95% CI -0.13 to 0.18)). The mean FCs for the aPL in rAV-based vaccine recipients were similar to those in mRNA-based vaccines. No correlation was observed between post-vaccination aPF4 levels and vaccine type (mean aPF difference -0.070 (95% CI -0.14 to 0.002) mRNA vs. rAV). In summary, our study indicates that rAV and mRNA-based COVID-19 vaccines do not substantially elevate aPF4 levels in healthy individuals.

Modified vaccinia virus Ankara (MVA) is used as a vaccine against monkeypox virus and as a viral vaccine vector. MVA-MERS-S is a vaccine candidate against Middle East respiratory syndrome (MERS)-associated coronavirus. Here, we report that cross-reactive monkeypox virus neutralizing antibodies were detectable in only a single study participant after the first dose of MVA-MERS-S vaccine, in 3 of 10 after the second dose, and in 10 of 10 after the third dose., Competing Interests: Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2023. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

The Middle East respiratory syndrome (MERS) is a respiratory disease caused by MERS coronavirus (MERS-CoV). In follow up to a phase 1 trial, we perform a longitudinal analysis of immune responses following immunization with the modified vaccinia virus Ankara (MVA)-based vaccine MVA-MERS-S encoding the MERS-CoV-spike protein. Three homologous immunizations were administered on days 0 and 28 with a late booster vaccination at 12 ± 4 months. Antibody isotypes, subclasses, and neutralization capacity as well as T and B cell responses were monitored over a period of 3 years using standard and bead-based enzyme-linked immunosorbent assay (ELISA), 50% plaque-reduction neutralization test (PRNT50), enzyme-linked immunospot (ELISpot), and flow cytometry. The late booster immunization significantly increases the frequency and persistence of spike-specific B cells, binding immunoglobulin G1 (IgG1) and neutralizing antibodies but not T cell responses. Our data highlight the potential of a late boost to enhance long-term antibody and B cell immunity against MERS-CoV. Our findings on the MVA-MERS-S vaccine may be of relevance for coronavirus 2019 (COVID-19) vaccination strategies., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Vaccine development is essential for pandemic preparedness. We previously conducted a Phase 1 clinical trial of the vector vaccine candidate MVA-MERS-S against the Middle East respiratory syndrome coronavirus (MERS-CoV), expressing its full spike glycoprotein (MERS-CoV-S), as a homologous two-dose regimen (Days 0 and 28). Here, we evaluate the safety (primary objective) and immunogenicity (secondary and exploratory objectives: magnitude and characterization of vaccine-induced humoral responses) of a third vaccination with MVA-MERS-S in a subgroup of trial participants one year after primary immunization. MVA-MERS-S booster vaccination is safe and well-tolerated. Both binding and neutralizing anti-MERS-CoV antibody titers increase substantially in all participants and exceed maximum titers observed after primary immunization more than 10-fold. We identify four immunogenic IgG epitopes, located in the receptor-binding domain (RBD, n = 1) and the S2 subunit (n = 3) of MERS-CoV-S. The level of baseline anti-human coronavirus antibody titers does not impact the generation of anti-MERS-CoV antibody responses. Our data support the rationale of a booster vaccination with MVA-MERS-S and encourage further investigation in larger trials. Trial registration: Clinicaltrials.gov NCT03615911., (© 2022. The Author(s).)

Purpose: To study the effect of interferon-α2 auto-antibodies (IFN-α2 Abs) on clinical and virological outcomes in critically ill COVID-19 patients and the risk of IFN-α2 Abs transfer during convalescent plasma treatment., Methods: Sera from healthy controls, cases of COVID-19, and other respiratory illness were tested for IFN-α2 Abs by ELISA and a pseudo virus-based neutralization assay. The effects of disease severity, sex, and age on the risk of having neutralizing IFN-α2 Abs were determined. Longitudinal analyses were performed to determine association between IFN-α2 Abs and survival and viral load and whether serum IFN-α2 Abs appeared after convalescent plasma transfusion., Results: IFN-α2 neutralizing sera were found only in COVID-19 patients, with proportions increasing with disease severity and age. In the acute stage of COVID-19, all sera from patients with ELISA-detected IFN-α2 Abs (13/164, 7.9%) neutralized levels of IFN-α2 exceeding physiological concentrations found in human plasma and this was associated with delayed viral clearance. Convalescent plasma donors that were anti-IFN-α2 ELISA positive (3/118, 2.5%) did not neutralize the same levels of IFN-α2. Neutralizing serum IFN-α2 Abs were associated with delayed viral clearance from the respiratory tract., Conclusions: IFN-α2 Abs were detected by ELISA and neutralization assay in COVID-19 patients, but not in ICU patients with other respiratory illnesses. The presence of neutralizing IFN-α2 Abs in critically ill COVID-19 is associated with delayed viral clearance. IFN-α2 Abs in COVID-19 convalescent plasma donors were not neutralizing in the conditions tested., (© 2021. The Author(s).)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the cause of coronavirus disease 2019 (COVID-19). Little is known about the interplay between preexisting immunity to endemic seasonal coronaviruses and the development of a SARS-CoV-2-specific IgG response. We investigated the kinetics, breadth, magnitude, and level of cross-reactivity of IgG antibodies against SARS-CoV-2 and heterologous seasonal and epidemic coronaviruses at the clonal level in patients with mild or severe COVID-19 as well as in disease control patients. We assessed antibody reactivity to nucleocapsid and spike antigens and correlated this IgG response to SARS-CoV-2 neutralization. Patients with COVID-19 mounted a mostly type-specific SARS-CoV-2 response. Additionally, IgG clones directed against a seasonal coronavirus were boosted in patients with severe COVID-19. These boosted clones showed limited cross-reactivity and did not neutralize SARS-CoV-2. These findings indicate a boost of poorly protective CoV-specific antibodies in patients with COVID-19 that correlated with disease severity, revealing "original antigenic sin."

The COVID-19 pandemic has forced many governments to impose social distancing measures upon its citizens, including in the Netherlands. Motivating adolescents to adhere to measures such as social distancing can be challenging, since adolescents are relatively more affected by them, while experiencing virtually no personal health benefit. In addition, the COVID-19 pandemic seems to impact the social environment of adolescents in schools, as some media sources have reported bullying and stigmatisation of students with an Asian appearance. This study aims to explore the experiences of adolescents regarding their Health-Protective Behaviour (HPB), as well as the prevalence and expression of stigma towards ethnic minorities within the context of the first wave of COVID-19 pandemic. We performed a cross-sectional mixed-methods study, including two independent online questionnaires. An adapted version of the "HPB" questionnaire (n = 528) and the "Measure of Disease-Related Stigma (MDRS)" questionnaire (n = 380), were administered to Dutch adolescents of 10-16 years old, attending primary or secondary school. Furthermore, 15 interviews were held with eight male and seven female adolescents. All data collection took place between March 17 and April 20, 2020. Results show that adolescents perceive COVID-19 as a threat to other peoples' health, rather than their own, and report adherence to public health measures in the interest of older and more vulnerable members of their community. We found no convincing evidence for widespread misinformation or stigmatising of certain ethnic groups among adolescents related to COVID-19 during this study. Participants acknowledged such behaviour happened in the early stages of the pandemic, before this study was initiated. Adolescents are a vital group for public health researchers to engage with during a pandemic, even when reaching them can be challenging., Competing Interests: The authors have declared that no competing interests exist.

Lower respiratory tract (LRT) disease induced by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can deteriorate to acute respiratory distress syndrome (ARDS). Because the release of neutrophil extracellular traps (NETs) is implicated in ARDS pathogenesis, we investigated the presence of NETs and correlates of pathogenesis in blood and LRT samples of critically ill patients with COVID-19. Plasma NET levels peaked early after intensive care unit admission and were correlated with the SARS-CoV-2 RNA load in sputum and levels of neutrophil-recruiting chemokines and inflammatory markers in plasma samples. The baseline plasma NET quantity was correlated with disease severity but was not associated with soluble markers of thrombosis or with development of thrombosis. High NET levels were present in LRT samples and persisted during the course of COVID-19, consistent with the detection of NETs in bronchi and alveolar spaces in lung tissue from deceased patient with COVID-19. Thus, NETs are produced and retained in the LRT of critically ill patients with COVID-19 and could contribute to SARS-CoV-2-induced ARDS disease., (© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Antiviral vaccines have contributed substantially to a reduction in the morbidity and mortality suffered from viral infectious diseases, especially during the second half of the 20th century. The efficacy of traditional live-attenuated and inactivated vaccine formulations, however, has been limited for some viral diseases, due to either virus-specific or host-related challenges. The application of genetic engineering technologies developed in the past decades allows for the creation of novel subunit vaccines, viral vector vaccines and nucleic acid-based vaccines. These vaccines, in some cases complemented by novel adjuvants, elicit a more finely controlled immunological response that more effectively prevents certain viral infections. They can be tailored for immunologically hyporesponsive individuals or rapidly mount protection during an outbreak. This article provides an overview of these technologies and how they have been applied in vaccines that have recently become available.

SARS-CoV-2 has been identified as the causative agent of a global outbreak of respiratory tract disease (COVID-19). In some patients the infection results in moderate to severe acute respiratory distress syndrome (ARDS), requiring invasive mechanical ventilation. High serum levels of IL-6, IL-10 and an immune hyperresponsiveness referred to as a 'cytokine storm' have been associated with poor clinical outcome. Despite the large numbers of COVID-19 cases and deaths, information on the phenotype and kinetics of SARS-CoV-2-specific T cells is limited. Here, we studied 10 COVID-19 patients who required admission to an intensive care unit and detected SARS-CoV-2-specific CD4 + and CD8 + T cells in 10 out of 10 and 8 out of 10 patients, respectively. We also detected low levels of SARS-CoV-2-reactive T cells in 2 out of 10 healthy controls not previously exposed to SARS-CoV-2, which is indicative of cross-reactivity due to past infection with 'common cold' coronaviruses. The strongest T-cell responses were directed to the spike (S) surface glycoprotein, and SARS-CoV-2-specific T cells predominantly produced effector and Th1 cytokines, although Th2 and Th17 cytokines were also detected. Furthermore, we studied T-cell kinetics and showed that SARS-CoV-2-specific T cells are present relatively early and increase over time. Collectively, these data shed light on the potential variations in T-cell responses as a function of disease severity, an issue that is key to understanding the potential role of immunopathology in the disease, and also inform vaccine design and evaluation., (Copyright © 2020, American Association for the Advancement of Science.)