A weak immune response to two doses of vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been observed in immunocompromised patients, including solid organ transplant recipients (SOTRs)1,2,3. Studies focused on third dose in SOTRs revealed that the percentage of responders increased even if a large portion of patients remained at risk for COVID-194. More in detail, the humoral response to three doses of vaccine at 1 month after the third dose in SOTRs ranged from ≈50 to ≈70% of patients5,6,7. Therefore at least a third of the patients who have an impaired immune response remain unprotected despite the administration of three doses of anti-SARS-CoV-2 vaccine8,9. Similar data emerged from studies conducted on other categories of immunosuppressed patients: less than 40% of onco-haematological patients develop antibodies after administration of two doses of vaccine and only a quarter of non-responders retrieve a humoral response after the third dose10,11. Likewise, rheumatological diseases induce a known frequent immune dysregulation that compromises an adequate response to the anti-SARS-CoV-2 vaccine12. Additionally, the emergence of the new Omicron variant has posed new issues in terms of vaccine immunogenicity. It has been observed that three doses of vaccine lead to a lower neutralization response against Omicron variant than respect to the other variants (Delta, Wild type), especially in transplanted patients13. The use of monoclonal antibodies in prophylaxis may represent a valuable choice for non-responder subjects after complete vaccination in order to prevent severe COVID-19. In this regard, recent data showed that the long-acting monoclonal antibodies (LAABs) were able to block the binding of the SARS-CoV-2 virus to host cells and protect against infection in cell and animal models of disease14. Evusheld (AZD7442) is a combination of two LAABs- Tixagevimab and Cilgavimab- derived from B-cells donated by convalescent patients after SARS-CoV-2 virus. These human monoclonal antibodies were optimized with half-life extension and reduced Fc receptor and complement C1q binding. The half-life extension more than triples the durability of its action compared to conventional antibodies and could afford up to 12 months of protection from COVID-19 following a single administration15,16. The reduced Fc receptor binding aims to minimize the risk of antibody-dependent enhancement of disease - a phenomenon in which virus-specific antibodies promote, rather than inhibit, infection or disease. Data on the safety and efficacy of Evusheld administered in the context of pre-exposure prophylaxis of Covid-19 can be obtained from the Provent trial that represents the largest study to date conducted in the world setting. PROVENT is a Phase III, randomized, double-blind, placebo-controlled, multi-center trial assessing the efficacy and safety of a single 300mg dose of AZD7442 compared to placebo for the prevention of COVID-19. The trial was conducted in 87 sites in the US, UK, Spain, France and Belgium. 5.197 participants were randomized in a 2:1 ratio to receive a single intramuscular (IM) dose of either 300mg of AZD7442 (n = 3460) or saline placebo (n = 1,737), administered in two separate, sequential IM injections. More than 75% had baseline co-morbidities and other characteristics that are associated with an increased risk for severe COVID-19 should they become infected, including those with immunosuppressive disease or taking immunosuppressive medications. In the Phase III PROVENT trial, Evusheld seems to reduce the risk of developing symptomatic COVID-19 by 77%, (95% confidence interval (CI): 46, 90) compared to placebo with high neutralizing antibody titers for at least six months, although further studies will be needed (AstraZeneca news release. New analyses of two AZD7442 COVID-19 trials in high-risk populations confirm robust efficacy and long-term prevention17. There were no cases of severe COVID-19 or COVID-19-related deaths in those treated with AZD7442. In the placebo arm, there were three cases of severe COVID-19, which included two deaths. The monoclonal antibodies were well-tolerated and preliminary analyses show adverse events were balanced between the placebo and AZD7442 groups18. Other ongoing trials include Storm Chaser and Tackle COVID-19; although they are focused on the post-exposure prevention of severe COVID-19 in subjects already exposed to the viral agent, they confirm the safety and tolerability profile of Evusheld in accordance with what emerged from the Provent trial. In Italy, following the publication of AIFA determination N. 42 of 19.02.2022, starting from 20.02.2022 it is possible to use the combination of Evusheld monoclonal antibodies (Tixagevimab-Cilgavimab) in specific and defined categories of patients who have severe immune system impairment including solid organ transplant recipients. In light of the encouraging data currently available, Evusheld could

Inclusion Criteria:

• Adults >= 18 years-old and over, all sexes,
• Negative SARS-COV2 serology tests befire enrollment,
• Severe impairmentof the immune system induced by documented pathology, weight >= 40 kg at initial screening,
• Written informed consent and any required authorization obtained from the partecipant prior to performing any protocol related procedures.

Exclusion Criteria:

• Any condition that might compromise safety or interfere with study results,
• Pregnant or nursing female.

immunocompromised subjects with no serological response after third dose of mRNA vaccine