CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

Conclusion: Half dose Tixagevimab/Cilgavimab in 20-<40 kg children and adolescents generated equivalent and significantly higher antibodies than ≥40 kg and healthy children with three vaccinations, respectively. This supports further study of next generation long-acting monoclonal antibodies.

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First-in-Human Phase I Trial of an Adjuvanted SARS-CoV-2 Spike Ferritin Nanoparticle Vaccine Natalie Collins 1 , Brittany Ober Shepherd 2 , Paul T. Scott 1 , Melanie McCauley 2 , Jack Hutter 1 , Christine Lee 1 , Ivelese Guzman 1 , Adrian McDermott 3 , Shelia Peel 1 , M. Gordon Joyce 2 , Merlin L. Robb 2 , Nelson L. Michael 1 , Sandhya Vasan 2 , Kayvon Modjarrad 1 , for the SpFN/ALFQ Study Group 1 Walter Reed Army Institute of Research, Silver Spring, MD, USA, 2 Henry M Jackson Foundation, Bethesda, MD, USA, 3 Sanofi, Marcy L’Etoile, France Background: Next-generation coronavirus (CoV) vaccines must confer broader protection against a range of SARS-CoV-2 variants as well as novel species that may cross over from zoonotic reservoirs in the future. The SARS-CoV-2 recombinant spike ferritin nanoparticle (SpFN) vaccine co-formulated with Army Liposomal Formulation (ALFQ) adjuvant containing monophosphoryl lipid A and QS-21 (SpFN/ALFQ) was previously shown to be immunogenic and protective in challenge experiments in rodents and non-human primates against SARS CoV-2 and variants of concern (VoC). This study reports the first-in-human randomized, double-blind, placebo-controlled clinical trial of SpFN/ALFQ. Methods: Healthy, SARS-CoV-2 seronegative and unvaccinated adults aged 18-55 years, majority male, were randomly assigned to receive either 25μg or 50μg of SpFN/ALFQ or saline placebo intramuscularly at days 1 and 29, with an optional open-label third vaccination at day 181. Local and systemic reactogenicity, adverse events and humoral immunity were quantified and analyzed by Clopper-Pearson. Binding and neutralizing antibody responses against multiple CoV were quantified. To further test breadth of cross protection, IgG antibodies from vaccinees were infused into Syrian Golden hamsters (SGH) prior to SARS-CoV-1 Urbani challenge. Lung tissue was recovered at days 3 and 6 post challenge. Virus detected by quantitative RT-PCR was analyzed by two-way ANOVA, as well as immunohistochemistry staining. Results: Of the 29 participants enrolled, all received 2 doses and a subset who did not receive EUA vaccines received a third vaccination. Local and systemic reactogenicity was mild to moderate, and no participants experienced any adverse events of special interest. Binding and neutralizing antibody responses peaked at day 43. Neutralizing antibody titers against Omicron subvariants and clade 1 sarbecoviruses were detectable after two immunizations and peaked after the subset of volunteers who received a third immunization and were present at day 361. Passive IgG transferred from vaccinated volunteers into hamsters-controlled replication of SARS-CoV-1 post challenge. Conclusion: Individuals vaccinated with SpFN/ALFQ mounted neutralizing antibody responses against multiple clade 1 sarbecoviruses. The results of this first-in-human clinical trial represents a platform upon which to build future sarbecovirus vaccine development. PREVENT: Phase I Clinical Trial of a Q-Griffithsin (Q-GRFT) Nasal Spray for Prevention of SARS-CoV-2 Katherine E Bunge 1 , Lin Wang 2 , Lisa C. Rohan 1 , Sravan Patel 1 , Leslie A. Meyn 2 , Ingrid S. Macio 2 , Catherine A. Chappell 1 , Amanda Lasnik 3 , Kathleen Kitterman 3 , Nobuyuki Matoba 3 , Kenneth Palmer 3 , Sharon L. Hillier 1 1 University of Pittsburgh, Pittsburgh, PA, USA, 2 Magee–Womens Research Institute, Pittsburgh, PA, USA, 3 University of Louisville, Louisville, KY, USA Background: The COVID pandemic highlighted the need to develop vaccine alternatives to prevent the spread of SARS-CoV-2, especially in immunosuppressed people. Q-GRFT, a broad-spectrum viral entry inhibitor, functions by binding oligomannose glycans on viral envelopes and is highly potent, with an IC 90 of 645 ng/mL against the SARS-CoV-2 BA.5 variant. A nasal spray formulation was designed to deliver Q-GRFT to the upper respiratory mucosa for topical prophylaxis. Methods: PREVENT (NCT05180500) was a phase I randomized, double-blind, placebo-controlled study to determine the safety and drug persistence of 14 doses of Q-GRFT intranasal spray (two 100 μL bursts of 7.5 mg/mL Q-GRFT per nostril, 400 μL total). Healthy, SARS-CoV-2 -vaccinated participants aged 18-55 with normal nasal and pharyngeal exams were randomized 2:1 to either Q-GRFT (n=33) or placebo (n=17). Participants initially received one metered dose of the study drug; after establishing initial tolerance at 24 hours, participants self-administered the spray for 13 consecutive days. Grade 2 or higher adverse events (AEs) related to study product were compared between groups using Fisher's exact test. Drug persistence was assessed by measuring Q-GRFT concentrations in nasopharyngeal (NP) and nares swabs. Systemic exposure and immune response were measured by Q-GRFT and antidrug antibody (ADA) concentrations in plasma. Acceptability was assessed by questionnaire.

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Sotrovimab Lacks Efficacy in Treatment of Syrian Golden Hamsters Infected With SARS-CoV-2 BQ 1 1 Lee Tatham , Joanne Sharp, Megan Neary, Joanne Herriott, Edyta Kijak, Eduardo Gallardo-Toledo, Helen Cox, Chloe Bramwell, Anthony Valentijn, Usman Arshad, Henry Pertinez, Paul Curley, Rajith Rajoli, James P. Stewart, Andrew Owen University of Liverpool, Liverpool, United Kingdom Background: Monoclonal antibodies (mAbs) demonstrate diminished neutralisation of Omicron sub-lineages such that continued use of sotrovimab (SOT) is not supported by current pharmacokinetic-pharmacodynamic (PK-PD) understanding. However, SOT is still used in immunocompromised patients in some geographies. Published preclinical studies have shown virological efficacy in prophylaxis for BQ.1.1 but no data are available in treatment. This study investigated the virological efficacy of SOT in healthy and immunocompromised male hamsters infected with Delta or BQ.1.1 variants using experimental designs reflective of prophylaxis and treatment. Methods: Intramuscular SOT (14 mg/kg) was administered 24h before or after intranasal inoculation with 10[4] PFU Delta or BQ.1.1. Control groups were dosed IM with vehicle 24h after inoculation. A subset of hamsters were immunosuppressed using 100 mg/kg IP-administered cyclophosphamide. Hamsters were sacrificed at 3-dpi and viral replication was quantified using qPCR to measure total (N-gene) viral RNA. Data were normalised to 18S for quantitation. Terminal blood samples were taken and ELISAs were used for SOT plasma quantification. Results: Reductions in pulmonary viral RNA were observed in prophylaxis and treatment for Delta in healthy and immunocompromised animals (Table 1.). Smaller and statistically insignificant reductions were observed for BQ.1.1 for prophylaxis and treatment, in healthy and immunocompromised animals. Reduced pulmonary viral RNA was evident in untreated BQ.1.1 inoculated, compared to untreated Delta inoculated, hamsters in healthy and immunocompromised groups (log 10 -3.38; P=0.007, log 10 -1.85; P=<0.0001, respectively). SOT plasma concentrations were comparable across Delta (44.13 ± [SD] 5.40 µg/mL) and BQ.1.1 (47.06 ± [SD] 4.44 µg/mL) inoculated groups and consistent with values reported for prior hamster studies. Conclusion: Consistent with PK-PD understanding from RCTs, SOT did not exert virological efficacy in the treatment of immunocompromised hamsters infected with BQ.1.1. SOT did not block infection of Delta or BQ.1.1 when given in prophylaxis. The relevance of changes in viral RNA at high SOT concentrations, early in the profile, to longer-term prophylaxis are unclear. Analysis of pulmonary viral RNA and compartmental SOT concentrations across an extended experimental design is warranted. Caution should be taken when interpreting preclinical experimental designs that may not be reflective of the clinical use case.

Poster Abstracts

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CROI 2024 194