Although in vitro studies suggest that neutralization by monoclonal antibodies (mAbs) against SARS CoV2 Omicron sub lineages is reduced, in vivo virological response data are lacking. MONET (EudraCT: 2021-004188-28) was multi-centric phase 4 open-label parallel randomized clinical trial, conducted in Italy over 2022-2023, to assess the efficacy of sotrovimab (SOT), tixagevimab/cilgavimab (TIX/CIL) and Nirmatrelvir/ritonavir (NMV/r), in outpatients at high risk for severe COVID-19. The outcome (secondary in the trial protocol) was SARS-CoV-2 variation in cycle threshold (CT) values over the first 7 days (D1-D7) of the trial. CT variation was compared by trial arms using unadjusted linear regression and after controlling for age. We included 346 individuals: 116 (34%) received SOT, 113 (33%) TIX/CIL, 117 (34%) NMV/r. Main characteristics were balanced across arms. Most of the participants were infected with BA.2 (52%) or BA.4/5 (35.5%). The data carried strong evidence that the mean CT change over D1-D7 was larger in subjects receiving NMV/r vs. the other arms (p<0.001). We found no evidence that viral variant was an effect measure modifier for the contrasts of interest (p=0.14). Our analysis provides strong evidence that NMV/r exerts a greater in vivo antiviral effect than mAbs against Omicron sublineages, confirming previous in vitro data.

We estimated the dynamics of the neutralizing response against XBB sublineages and T cell response in PWH with previous AIDS and/or CD4<200/mm 3 receiving the bivalent original strain/BA.4-5 booster dose (bBD) in fall 2022. Samples were collected before the shot (T0), 15 days (T1), 3 (T3), and 6 months (T6) after. PWH were stratified by immunization status: hybrid immunity (HI; vaccination plus COVID-19) vs. non-hybrid immunity (nHI; vaccination only). At T1, 16% and 30% of PWH were non-responders in terms of anti-XBB.1.16 or anti-EG.5.1 nAbs, respectively. At T3, a significant waning of anti-XBB.1.16, EG.5.1 and -XBB.1 nAbs was observed both in HI and nHI but nAbs in HI were higher than in nHI. At T6 both HI and nHI individuals displayed low mean levels of anti-XBB.1.16 and EG.5.1 nAbs. Regarding T cell response, IFN-γ values were stable over time and similar in HI and nHI. Our data showed that in PLWH, during the prevalent circulation of the XBB.1.16, EG.5.1, and other XBB sublineages, a bBD mRNA vaccine might not confer broad protection against them. With a view to the 2023/2024 vaccination campaign, the use of the monovalent XBB.1.5 mRNA vaccine should be urgently warranted in PWH to provide adequate protection.

We report real world use over time in immunocompromised subjects receiving tixagevimab/cilgavimab (T/C) pre-exposure prophylaxis (PrEP). Observational study on participants receiving T/C PrEP stratified: never had COVID-19 (NoC), hybrids (H) and breakthrough infections (BTIs) if COVID-19 before or after PrEP, respectively. Anti-RBD IgG and BA.5 neutralizing antibodies (nAbs), mucosal IgG, T-cell immunity at the administration of T/C (T0), 3 (T1), 6 (T2), and 9 (T3) months after, were measured. Comparison of markers in each group across timepoints, Poisson regression model for BTIs incidence rate ratios were performed. N=231 participants: median age 63 years (IQR 54.0-73.0), 84% hematological disease, median vaccine dose of three. N=72 NoC, 103 H and 56 (24%) BTIs, mostly mild/moderate, IR 4.2 (95%CI 3.2-5.4) BTIs/100 patients-months, no factors associated with. A significant increase of anti-RBD IgG at T1 was observed in all the groups, with a decline at T2. GMTs of anti-BA.5 nAbs were low at T1 for all the groups and around/below the cut off. No changes of IFN-γ. Overall, a mucosal response was observed at T1. An incidence of 24% of mild/moderate BTIs was observed. Anti-RBD IgG levels persistence was ensured, BA.5 nAbs were low/undetectable, cellular T immunity remained stable.