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Globally accessible preventive and therapeutic molecules against SARS-CoV-2 are urgently needed. DARPin molecules are an emerging class of novel therapeutics based on naturally occurring repeat proteins (∼15 kDa in size) and can be rapidly produced in bacteria in large quantities. Here, we report the identification of 380 DARPin molecules specifically targeting the SARS-CoV-2 spike protein selected from a naïve library of 1012 DARPin molecules. Using extensive biophysical and biochemical characterization, (pseudo)virus neutralization assays and cryo-EM analysis, 11 mono-DARPin molecules targeting either the receptor binding domain (RBD), the S1 N-terminal-domain (NTD) or the S2 domain of the SARS-CoV-2 spike protein were chosen. Based on these 11 mono-DARPin molecules, 31 anti-SARS-CoV-2 multi-DARPin molecules were constructed which can broadly be grouped into 2 types; multi-paratopic RBD-neutralizing DARPin molecules and multi-mode DARPin molecules targeting simultaneously RBD, NTD and the S2 domain. Each of these multi-DARPin molecules acts by binding with 3 DARPin modules to the SARS-CoV-2 spike protein, leading to potent inhibition of SARS-CoV-2 infection down to 1 ng/ml (12 pM) and potentially providing protection against viral escape mutations. Additionally, 2 DARPin modules binding serum albumin, conferring an expected half-life of about 3 weeks in humans, were included in the multi-DARPin molecules. The protective efficacy of one multi-DARPin molecule was studied in a Golden Syrian hamster SARS-CoV-2 infection model, resulting in a significant reduction in viral load and pathogenesis. In conclusion, the multi-DARPin molecules reported here display very high antiviral potency, high-production yield, and a long systemic half-life, and thereby have the potential for single-dose use for prevention and treatment of COVID-19.

Background In next fall and winter, SARS-CoV-2 could circulate in parallel with seasonal influenza. The dual epidemics will result in considerable morbidity and mortality; therefore, influenza vaccination may be essential. Recent studies found increased risk of coronavirus in individuals receiving influenza vaccination. Aims Our aim is to analyse the association between influenza vaccination and COVID-19 in a population of healthcare workers (HCWs). Methods IgG antibodies against SARS-CoV-2 were detected in 3520 HCWs at a large hospital in Northern Italy. For each participant, we collected data on flu immunization status for the last five flu seasons. Logistic regression was used to test associations between seasonal flu vaccination status and a positive serology tests for COVID-19. Results During the last five flu seasons, 2492 vaccinations were administered. Serology tests were negative for 3196 (91%) HCWs and residents and only 21 (1%) people had an equivocal test (12.0–15.0 AU/mL). Only 128 (4%) people received a diagnosis of COVID-19, with a positive swab test. No flu vaccinations for the last five flu seasons were specifically associated with diagnosis of COVID-19 or with positive results of serology tests. Conclusions Flu vaccinations did not appear to be associated with SARS-CoV-2 infection. Influenza vaccination should continue to be recommended for HCWs and for individuals at increased risk for severe illness from respiratory infection.

Background. COVID-19 has spread widely among health care workers. Oral health care workers have an increased risk of being infected owing to dental practice characteristics. New, effective vaccines against COVID-19 have been approved for use. The authors aim was to evaluate intentions to be vaccinated against COVID-19 in a population of dentists and identify factors associated with their intentions.Methods. The authors conducted an anonymous online survey among 761 dentists enrolled at the Board of Physicians and Dentists of the District of Monza Brianza, Monza, Italy. The authors collected data on demographic characteristics, influenza vaccine uptake, COVID-19 history, vaccine attitudes, and specific reasons for their intentions to be vaccinated against COVID-19 or not.Results. Overall, 421 dentists completed the survey. More than 82% of the participants declared their intention to be vaccinated against COVID-19. The multivariate logistic regression model reported a positive association with receiving the influenza vaccine in the 2020-2021 influenza season (odds ratio, 5.15; 95% CI, 2.14 to 12.39) and a negative association with receiving a diagnosis of COVID-19 previously (odds ratio, 0.32; 95% CI, 0.15 to 0.66). The participants' main reason for supporting vaccination was to protect their family and friends (87%) and their main reason for opposing vaccination was the lack of information (39%).Conclusions. It is fundamental to consider vaccine hesitancy in health care workers and address it properly because they must provide recommendations to patients and promote adherence to vaccination programs.Practical Implications. The vaccination of dental practitioners should be prioritized owing to the high risk related to dental practice.

The emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants with potential resistance to existing drugs emphasizes the need for new therapeutic modalities with broad variant activity. Here we show that ensovibep, a trispecific DARPin (designed ankyrin repeat protein) clinical candidate, can engage the three units of the spike protein trimer of SARS-CoV-2 and inhibit ACE2 binding with high potency, as revealed by cryo-electron microscopy analysis. The cooperative binding together with the complementarity of the three DARPin modules enable ensovibep to inhibit frequent SARS-CoV-2 variants, including Omicron sublineages BA.1 and BA.2. In Roborovski dwarf hamsters infected with SARS-CoV-2, ensovibep reduced fatality similarly to a standard-of-care monoclonal antibody (mAb) cocktail. When used as a single agent in viral passaging experiments in vitro, ensovibep reduced the emergence of escape mutations in a similar fashion to the same mAb cocktail. These results support further clinical evaluation of ensovibep as a broad variant alternative to existing targeted therapies for Coronavirus Disease 2019 (COVID-19).

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Background The COVID-19 pandemic has spread widely among healthcare workers. Recently, new effective vaccines against COVID-19 have begun to be administered to healthcare workers in several countries, including Italy. Purpose Our aim was to evaluate the intentions to be vaccinated against COVID-19 in a population of nursing students, identifying factors associated with the intentions. Method We conducted an anonymous online survey among 728 nursing students. The questionnaire collected data on demographic and academic characteristics, health status, vaccine attitudes, and specific reasons regarding the intention to get or not get the COVID-19 vaccination. Results A total of 422 nursing students completed the survey. Almost 81% of participants wanted to take the vaccine against coronavirus. The intention to adhere to the vaccination program was associated with male gender, a previous flu vaccine uptake, and high school education. The main reason in favor of taking the vaccine was to protect family and friends. The main reason for opposition was the fear of adverse events. Conclusion It is fundamental to consider vaccine hesitancy in healthcare students and face it properly, since these are the healthcare workers of the future who will have to provide recommendations to patients and promote adherence to vaccination programs.