CROI 2024 Abstract eBook

Abstract eBook

Poster Abstracts

400

Peripheral Immune Progression to Long COVID (LC) Is Driven by Mitochondrial Gene Transcription David P Maison 1 , Vedbar Khadka 2 , Isam Mohd-Ibrahim 2 , Michael J. Peluso 1 , Timothy J. Henrich 1 , Youping Deng 2 , Mariana Gerschenson 2 1 University of California San Francisco, San Francisco, CA, USA, 2 University of Hawaii, Honolulu, HI, USA Background: Long COVID (LC) affects about 10% of persons infected with severe acute respiratory coronavirus 2 (SARS-CoV-2) and can have serious clinical consequences. Whereas the pathophysiology of LC is likely multifactorial, several hypotheses have been proposed, including viral persistence in some individuals for months following the acute phase of COVID-19. Herein, we analyzed existing human RNA transcriptome datasets from people with and without LC to identify unique phenotypic fingerprints of LC. Methods: We analyzed 28 publicly available RNAseq datasets from COVID-19 acute and convalescent studies. Differentially expressed genes and gene ontology analysis between No known COVID (NC) (n = 448), Acute COVID (AC) (n = 694), COVID Recovered (CR) (n = 123), and LC (n = 23) were examined. All samples underwent processing using the STAR Aligner and GRCh38 reference genome. DESeq2 identified differentially expressed genes, and the most significant genes were distilled through Gene Ontology and Reactome to identify pathways. We accounted for batch effects between the studies by including 'study' as a covariate in the DESeq2 analysis. Results: The cohort comparison between NC and AC revealed global changes in nucleosome assembly (p.adj = 1.23e-24), chromatin remodeling (p.adj = 1.39e 13), and defense response to virus (p.adj = 0.0027), among others. Comparisons of AC to CR or LC showed a transcriptome signature enriched in mitochondrial genes. LC differed from CR in an increase in genes explicitly related to the electron transport chain and ATP synthesis. Further, the most significantly over-expressed gene in the comparison of AC to LC was MGAT2 (Log Fold Change [LFC] = 6.02; p.adj. = 3.85e-22); which was considerably less expressed in AC compared to CR (LFC = 1.55; p.adj. = 1.45e-17). Reactome analysis additionally points to inhibited CASP8 activity in LC (p = 0.0358). Conclusion: RNA profiling of peripheral immune cells suggests that recovery from AC is driven by mitochondrial gene transcription. In contrast to recovery, LC correlated with electron transport chain-specific genes. These findings support our previous findings of increased oxygen consumption and ATP production in the peripheral immune cells in people with LC and further implies that host gene transcription drives this phenotype.

vaccination was 10% (-40 to 50) for COVID-19 hospitalization and 30% (-40 to 80) for MIS-C. No cases of myocarditis occurred. The age group 12-17 years included 277,758 vaccinated children and 1,388,790 controls. Over 240 days, the estimated effectiveness (95% CI) of vaccination was 50% (20 to 70) for COVID-19 hospitalization and 50% (-20 to 90) for MIS-C. The risk ratio of myocarditis was 1.1 (95% CI: 0.7, 1,7) for vaccinated vs. controls. Conclusion: In this population-based study, including over 2.8 million children, the estimated effectiveness of mRNA vaccines against COVID-19 hospitalization was modest in the age group 12-17 years and lower in the age group 6-11 years. The absolute risks of MISC-C and myocarditis were small, and under conventional statistical criteria, both increased and decreased risks after vaccination were highly compatible with the data. Heterologous mRNA-1273 Boost After Ad26 CoV2 S Prime in Health Workers in South Africa: SHERPA Trial Nigel Garrett 1 , Tarylee Reddy 2 , Nonhlanhla Yende-Zuma 2 , Azwidihwi Takalani 3 , Kate Anteyi 4 , Kubashni Woeber 2 , Ishen Seocharan 5 , Jackline Odhiambo 3 , Penny Moore 6 , Wendy Burgers 7 , Brett Leav 4 , Linda-Gail Bekker 8 , Glenda Gray 5 , Ameena Goga 2 , for the SHERPA Study Group 1 Centre for the AIDS Programme of Research in South Africa, Durban, South Africa, 2 South African Medical Research Council, Durban, South Africa, 3 Hutchinson Center Research Institute of South Africa, Cape Town, South Africa, 4 Moderna, Inc, Cambridge, MA, USA, 5 South African Medical Research Council, Cape Town, South Africa, 6 University of the Witwatersrand, Johannesburg, South Africa, 7 University of Cape Town, Cape Town, South Africa, 8 Desmond Tutu HIV Foundation, Cape Town, South Africa Background: Given limited data on safety and effectiveness of heterologous Covid-19 vaccine boosting in lower income settings with high HIV prevalence, we evaluated an ancestral strain mRNA-1273 vaccine boost after priming with Ad26.COV2.S in South Africa. Methods: SHERPA was a single-arm, open-label, phase 3 study nested in the national Sisonke implementation trial of 500000 health workers. Sisonke participants were offered mRNA-1273 boosters between May and November 2022, a period of circulating Omicron sublineages. Adverse events (AE) were self-reported. Covid-19 co-primary endpoints (1. SARS-CoV-2 infections, 2. Severe Covid-19 of hospitalizations or deaths) were identified through national databases. We used Cox regression models with mRNA-1273 booster status as a time-varying covariate to determine the relative vaccine effectiveness (rVE) of a mRNA-1273 boost among SHERPA participants compared to Sisonke participants who did not receive the booster. 200 participants contributed to an immunogenicity substudy. Results: Of 11248 SHERPA participants in the rVE analysis cohort (79.3% female, median age 41), 45.4% had previously received one and 54.6% two Ad26.COV2.S vaccines. Self-reported comorbidities included HIV (18.7%), hypertension (12.9%) and diabetes (4.6%). In multivariable analysis including 413161 unboosted Sisonke participants, rVE of the booster was 59% (95%CI 29-76%) against SARS-CoV-2 infection: 77% (95%CI 9–94%) for participants with one, and 52% (95%CI 13-73%) for those with two prior Ad26.COV2.S (Table 1). There were 148 adjudicated severe COVID-19 cases among unboosted participants, and only one among SHERPA participants, a person with severe HIV-related immunosuppression. Of 11798 SHERPA participants in the safety cohort, 271 (2.3%) reported a reactogenicity events or unsolicited AEs, more in those with prior SARS-CoV-2 infections (adjusted odds ratio [aOR] 2.03, 95%CI 1.59-2.59) and less in persons with HIV (PWH) (aOR 0.49, 95%CI 0.34-0.69). No related serious AEs were reported. Antibody functions were higher 4 weeks after boosting regardless of prior Ad26.COV2.S dosing, or HIV status. mRNA-1273 increased T- cell responses and generated spike-specific responses that were durable and cross-reactive against circulating Omicron sublineages, irrespective of HIV status. Conclusion: mRNA-1273 boosters after one or two doses of Ad26.COV2.S were well tolerated, immunogenic and effective against SARS-CoV-2 infections with Omicron sub-lineages in a diverse health worker population and PWH.

399

Poster Abstracts

401

ERAPs Control In Vitro and Ex Vivo SARS-CoV-2 Infection by Triggering Antiviral Immune Response Irma Saulle , Maria Luisa Murno, Fiona Limanaqi, Micaela Garziano, Sergio Strizzi, Claudia Vanetti, Sergio Lo Caputo, Mariacristina Poliseno, Teresa A. Santantonio, Mario Clerici, Mara Biasin University of Milan, Milan, Italy Background: ERAP1 and ERAP2 (ERAPs) are two endoplasmic reticulum aminopeptidases which control susceptibility/progression of different infectious diseases. Beyond their canonical role in antigen processing and presentation,

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CROI 2024