ABSTRACT
Fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) energize the COVID-19 pandemic. B.1.1.7 (VOC-202012/01) has become the predominant variant in many countries and a new lineage (VOC-202102/02) harboring the E484K escape mutation in the B.1.1.7 background emerged in February 20211. This variant is of concern due to reduced neutralizing activity by vaccine-elicited antibodies2,3. However, it is not known whether this single amino acid change leads to an altered immune response. Here, we investigate differences in the immune transcriptome in hospitalized patients infected with either B.1.1.7 (n=28) or B.1.1.7+E484K (n=12). RNA-seq conducted on PBMCs isolated within five days after the onset of COVID symptoms demonstrated elevated activation of specific immune pathways, including JAK-STAT signaling, in B.1.1.7+E484K patients as compared to B.1.1.7. Longitudinal transcriptome studies demonstrated a delayed dampening of interferon-activated pathways in B.1.1.7+E484K patients. Prior vaccination with BNT162b vaccine (n=8 one dose; n=1 two doses) reduced the transcriptome inflammatory response to B.1.1.7+E484K infection relative to unvaccinated patients. Lastly, the immune transcriptome of patients infected with additional variants (B.1.258, B.1.1.163 and B.1.7.7) displayed a reduced activation compared to patients infected with B.1.1.7. Acquisition of the E484K substitution in the B.1.1.7 background elicits an altered immune response, which could impact disease progression.
ABSTRACT
Fast-spreading variants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) energize the COVID-19 pandemic. The B.1.351 variant carrying the escape mutation E484K in the receptor binding domain is of particular concern due to reduced immunological protection following vaccination. Protection can manifest as early as 10 days following immunization with full protection two weeks following the second dose, but the course is not well-characterized for variants. Here, we investigated the immune transcriptome of six elderly individuals (average age 82 yr.) from an old peoples home, who contracted B.1.351, with four having received the first dose of BNT162b eight to 11 days prior to the onset of COVID-19 symptoms. The patients were hospitalized and received dexamethasone treatment. Immune transcriptomes were established from PBMCs approximately 10 and 35 days after the onset of COVID-19 symptomology. RNA-seq revealed a more intensive immune response in vaccinated patients as compared to unvaccinated ones. Specifically, transcription factors linked to the JAK/STAT pathway, interferon stimulated genes, and genes associated with innate antiviral immunity and COVID-19-SARS-CoV-2 infection were highly enriched in vaccinated patients. This rendered the transcriptomes of the older vaccinated group significantly different than older unvaccinated individuals infected at the same institution and more similar to the immune response of younger unvaccinated individuals (age range 48-62) following B.1.351 infection. All individuals in this study whether vaccinated or not were hospitalized due to B.1.351 infection and one vaccinated patient died illustrating that although an enhanced immune response was documented infection it was insufficient to protect from disease. This highlights the need for maintaining physical distancing and prevention measures throughout the time course of vaccination in older adults.
