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Drury, Ruth E., Camara, Susana, Chelysheva, Irina, Bibi, Sagida, Sanders, Katherine, Felle, Salle, Emary, Katherine, Phillips, Daniel, Voysey, Merryn, Ferreira, Daniela 
ORCID: https://orcid.org/0000-0002-0594-0902, Klenerman, Paul, Gilbert, Sarah C., Lambe, Teresa, Pollard, Andrew J. and O’Connor, Daniel
(2024)
'Multi-omics analysis reveals COVID-19 vaccine induced attenuation of inflammatory responses during breakthrough disease'. Nature Communications, Vol 15, Issue 1, e3402.
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Abstract
The immune mechanisms mediating COVID-19 vaccine attenuation of COVID-19 remain undescribed. We conducted comprehensive analyses detailing immune responses to SARS-CoV-2 virus in blood post-vaccination with ChAdOx1 nCoV-19 or a placebo. Samples from randomised placebo-controlled trials (NCT04324606 and NCT04400838) were taken at baseline, onset of COVID-19-like symptoms, and 7 days later, confirming COVID-19 using nucleic amplification test (NAAT test) via real-time PCR (RT-PCR). Serum cytokines were measured with multiplexed immunoassays. The transcriptome was analysed with long, short and small RNA sequencing. We found attenuation of RNA inflammatory signatures in ChAdOx1 nCoV-19 compared with placebo vaccinees and reduced levels of serum proteins associated with COVID-19 severity. KREMEN1, a putative alternative SARS-CoV-2 receptor, was downregulated in placebo compared with ChAdOx1 nCoV-19 vaccinees. Vaccination ameliorates reductions in cell counts across leukocyte populations and platelets noted at COVID-19 onset, without inducing potentially deleterious Th2-skewed immune responses. Multi-omics integration links a global reduction in miRNA expression at COVID-19 onset to increased pro-inflammatory responses at the mRNA level. This study reveals insights into the role of COVID-19 vaccines in mitigating disease severity by abrogating pro-inflammatory responses associated with severe COVID-19, affirming vaccine-mediated benefit in breakthrough infection, and highlighting the importance of clinically relevant endpoints in vaccine evaluation.
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