CROI 2025 Abstract eBook

Abstract eBook

Poster Abstracts

720

Optimal Timing and Immunogenicity of COVID-19 Booster Vaccination: The EU-COVAT-2 BOOSTAVAC Trial Elena Alvarez 1 , Lukas Bütikofer 2 , Alejandro Abner Garcia Leon 1 , Virginie Gautier 1 , Jordi Cano Ochando 3 , Katherine Loens 4 , Amelie Michon 5 , Helena H. Askling 6 , Julia Jakobs 7 , Ilse De Coster 4 , Eoin R. Feeney 1 , Sven Trelle 2 , Pierre Van Damme 4 , Oliver Cornely 8 , Mallon W. G. Paddy 1 , for the VACCELERATE Consortium 1 University College Dublin, Dublin, Ireland, 2 University of Bern, Bern, Switzerland, 3 Instituto de Salud Carlos III, Madrid, Spain, 4 University of Antwerp, Antwerp, Belgium, 5 European Clinical Research Infrastructure Network (ECRIN), Paris, France, 6 Karolinska Institute, Stockholm, Sweden, 7 University of Cologne, Cologne, Germany, 8 Cologne University Hospital, Cologne, Germany Background: Currently, optimal timing and/or number of booster COVID19 vaccinations remains unclear. We compared immunogenicity and safety of mRNA booster vaccination at different time intervals. Methods: In a randomised, controlled, multicentre, phase II trial, adults with >3 prior mRNA COVID19 vaccines, with last vaccine 3 to 7 months (M) prior, were randomized to one of five arms; no booster vaccine (control) or Comirnaty mRNA booster vaccine at M0, 2, 4 or 6. Plasma receptor binding domain (RBD) antibodies (IU/mL) were measured at each visit and 2 weeks post booster, along with solicited adverse events (AE). Composite primary endpoint was a two-fold increase in RBD titre at 2 weeks post boost and/or RBD titre ≥500IU/mL in those with pre-boost RBD<500IU/ml. Efficacy was met if >50% subjects in a booster arm met the primary endpoint using a 1 sample proportion test (adjusted 1-sided alpha 0.0125). We explored optimal booster vaccine timing by logistic regression with best fitting fractional polynomial. Data are mean (SD) unless specified. Results: Of 255 subjects, mean age 52 (14) years, 154 (60%) female, 249 (98%) white, 130 (51%) with prior COVID19, time from last vaccine was 154 (44) days and baseline RBD was 15143 (16088) IU/mL. Arms were well matched. In the trial, 39 (20%) received Original, 125 (62%) Original/Omicron BA4-5 and 32 (16%) Omicron BXX.1.5 specific Comirnaty vaccines. Two weeks post boost, RBD titres increased in all four vaccine arms but then declined rapidly (Fig a). Only M2 booster arm achieved efficacy and no dose-response for time to booster vaccination was found (Fig b). 32 (13%) reported incident COVID19, with no difference in infection rates between vaccine arms and controls. Neither age nor prior COVID-19 were associated with the primary endpoint. However, those with a longer time since last pre-study vaccine and lower pre-boost RBD were more likely to reach a primary endpoint (P=0.005 and P<0.001), regardless of study arm (P=0.79 and P=0.16 for interaction). 144/169 (85%) subjects reported AE post-booster with tiredness, headache and muscle pain each reported in ≥20%. Of 7 serious AE, none causally linked to booster vaccine. Conclusions: Booster COVID19 vaccination provided only short-lived increases in RBD titre but with systemic side effects commonly reported. Lower pre-booster RBD and time since last vaccine but not age was associated with greater likelihood of booster immune responses. These data suggest a saturable humoral response to repeated COVID-19 vaccinations.

721

The Genetic Barrier to Resistance to LEN Is Not Affected by Non-B Subtypes or Treatment Exposure Chiara Paletti 1 , Niccolò Bartolini 1 , Federica Giammarino 2 , Francesco Saladini 1 , Ilaria Vicenti 1 , Lia Fiaschi 1 , Camilla Biba 1 , Ilenia Varasi 1 , Federico Garcia 3 , Anne Geneviève Marcelin 4 , Maurizio Zazzi 1 , Vincenzo Spagnuolo 5 , Emanuele Focà 6 , Stefano Rusconi 7 , for the PRESTIGIO Registry 1 University of Siena, Siena, Italy, 2 Karolinska Institute, Stockholm, Sweden, 3 Hospital Universitario San Cecilio, Granada, Spain, 4 Assistance Publique – Hôpitaux de Paris, Paris, France, 5 IRCCS San Raffaele Scientific Institute, Milan, Italy, 6 University of Brescia, Brescia, Italy, 7 University of Milan, Milan, Italy Background: Lenacapavir (LEN) is a HIV-1 capsid inhibitor approved for heavily-treatment experienced (HTE) people with HIV (PWH). This in vitro study aimed to evaluate LEN susceptibility and genetic barrier in B and non-B subtypes derived from therapy naïve (TN) and HTE PWH. Methods: Thirty-one NL4-3 based recombinant viruses harbouring clinically derived GAG-PR region were generated from plasma samples collected from TN (n=20) and HTE (n=11) PWH enrolled in the Italian PRESTIGIO registry. LEN IC 50 was measured through a TZM-bl cell-based assay and fold-change (FC) values were calculated with respect to the NL4-3 strain. In vitro resistance selection (IVRS) experiments were performed by exposing MT-2 cells infected with recombinant viruses and the NL4-3 control to increasing concentrations of LEN. Cultures were stopped when viral breakthrough (VB) was observed at approximately 100X LEN IC 50 (2.56 nM) or after 105 days from the start of IVRS. Sanger sequencing of the p24 coding region was performed at each VB to detect emerging mutations. Statistical analyses were performed with GraphPad Prism version 9.0.0. Results: None of the viruses harboured known LEN resistance mutations. Baseline susceptibility to LEN was comparable between HTE vs. TN (median FC 0.9 [IQR 0.3-1.6] vs. 2.0 [0.8-3.2], p=0.101, Mann-Whitney test) and between B (n=14) vs. non-B (n=19; 3 each F1 and CRF02_AG, 2 each C, D, CRF01_AE and CRF06_cpx, 1 each A1, A6, G, CRF40_BF, URF D/B) subtypes (median FC 1.1 [0.3-3.0] vs. 1.8 [0.9-3.0], p=0.171). By Kaplan-Meier survival analysis, the time to VB was comparable among HTE vs. TN PWH but not B vs. non-B subtypes at approximately 10X (p=0.284 and p=0.047, respectively, log-rank test) and 100X LEN IC 50 (p=0.131 and p=0.026, respectively), with lower time to VB observed with B viruses (figure 1). Known LEN resistance mutations emerged in 27/32 cultures including Q67H/R/K+N74D (n=7), Q67H/K+T107N/S (n=6), N74D (n=5), N74D+T107N/D (n=3), Q67H+K70R+T107N (n=2), Q67H+K70R (n=2), and Q67H (n=2), while in 5 cases no emergent mutations were identified. Non-polymorphic substitutions F169L (with Q67H+T107TN), V86M (with Q67H+K70R) and E213D (with Q67H+T107N) were detected in three distinct cases each. Conclusions: The in vitro genetic barrier to resistance to LEN was generally low but not affected by long-time exposure to antiretroviral therapy. Viruses harbouring non-B GAG-PR showed delayed breakthrough compared to fully subtype B viruses. The figure, table, or graphic for this abstract has been removed. Structural and Mechanistic Insights Into Cabotegravir Resistance in HIV-1 Integrase Indrani Choudhuri 1 , Tao Jing 1 , Avik Biswas 1 , Steven J. Smith 2 , Eric O. Freed 3 , Terrence Burke 2 , Stephen H. Hughes 2 , Ronald M. Levy 4 , Dmitry Lyumkis 1 1 Salk Institute for Biological Sciences, La Jolla, CA, USA, 2 National Institutes of Health, Bethesda, MD, USA, 3 National Cancer Institute at Frederick, Frederick, MD, USA, 4 Temple University, Philadelphia, PA, USA Background: HIV-1 infection requires the integration of viral DNA into host chromatin, a process mediated by the viral enzyme integrase (IN). This step is effectively blocked by IN strand transfer inhibitors (INSTIs), a key class of antiretroviral drugs. However, resistance to even the most potent INSTIs is becoming more of a clinical problem and the underlying mechanisms of resistance are not fully understood. Methods: Using cryo-electron microscopy (cryo-EM), we solved new high resolution structures of WT and drug-resistant HIV-1 IN assemblies with Cabotegravir (CAB) bound. We also performed hybrid quantum mechanics molecular mechanics (QM/MM) and high-resolution molecular dynamics-based (MD) simulations and free energy calculations to delineate the mechanism of resistance. Results: Here, we investigated the resistance mechanism caused by combinations of mutations at positions E138K, G140A/S, and Q148H/K/R of IN,

Poster Abstracts

722

CROI 2025 208