Post-pandemic memory T-cell response to SARS-CoV-2 is durable, broadly targeted and cross-reactive to hypermutated BA.2.86

Abstract

SUMMARYThe COVID-19 post-pandemic period is characterised by infection waves of uncertain size (due to low rates of SARS-CoV-2 testing and notification), as well as limited uptake or global access to updated variant vaccines. Ongoing SARS-CoV-2 evolution has given rise to recombinant Omicron lineages that dominate globally (XBB.1), as well as the emergence of hypermutated variants (BA.2.86). In this context, durable and cross-reactive T-cell immune memory is critical for continued protection against severe COVID-19. We examined T-cell responses to SARS-CoV-2 approximately 1.5 years since Omicron first emerged. We describe sustained CD4+ and CD8+ spike-specific T-cell memory responses in healthcare workers in South Africa (n=39), most of whom had received 2 doses of Ad26.CoV2.S (Johnson & Johnson/Janssen) vaccine and experienced at least one SARS-CoV-2 infection. Spike-specific T cells were highly cross-reactive with all Omicron variants tested, including BA.2.86. Abundant non-spike (nucleocapsid and membrane)-specific T cells were detectable in most participants, augmenting the total T-cell resources available for protection. The bulk of SARS-CoV-2-specific T-cell responses had an early-differentiated phenotype, explaining their persistent nature. Thus, hybrid immunity leads to the accumulation of spike and non-spike T cells evident 3.5 years after the start of the pandemic, with preserved recognition of highly mutated SARS-CoV-2 variants. Long-term T-cell immune memory is likely to provide continued protection against severe outcomes of COVID-19.In BriefNesamariet al.investigate T-cell responses in the context of hybrid immunity 3.5 years after the start of the COVID-19 pandemic. They show that T-cell memory is highly durable and cross-reactive with recombinant variants XBB.1 and hypermutated BA.2.86. Abundant non-spike responses augment the overall T-cell response.

SARS‐CoV‐2‐Spike T‐cell response after receiving one or two Wuhan‐Hu‐1‐based mRNA COVID‐19 vaccine booster doses in elderly nursing home residents

“…Third, we used a Wuhan‐Hu‐1‐S‐based peptide library for T‐cell stimulation; thus, it is uncertain whether our results can be extended to currently dominating Omicron (sub)variants. We believe that it may, to some extent, provided that T‐cell responses generated upon natural infection and vaccination with the ancestral SARS‐CoV‐2 spike are highly cross‐reactive against SARS‐CoV‐2 Omicron (sub)variants, including Omicron BA.2.86 5–11 . Fourth, the study group did not include participants receiving booster shots with Omicron‐adapted vaccine platforms.…”

“…SARS‐CoV‐2 T‐cell immunity is likely involved in protecting against severe COVID‐19 infection in this and other group populations 4 . Remarkably, in contrast to SARS‐CoV‐2 spike (S) neutralising antibodies, SARS‐CoV‐2 S‐reactive T‐cell responses generated upon natural infection and vaccination with the ancestral SARS‐CoV‐2 spike are highly cross‐reactive against SARS‐CoV‐2 Omicron subvariants, including the recently emerged Omicron BA.2.86 5–11 . Elderly nursing home residents with frailty and comorbidities frequently develop less robust and more rapidly waning SARS‐CoV‐2 T‐cell responses following regular vaccination, irrespective of the SARS‐CoV‐2 infection status, compared with seemingly healthy and younger counterparts 12–16 .…”

“…4 Remarkably, in contrast to SARS-CoV-2 spike (S) neutralising antibodies, SARS-CoV-2 S-reactive T-cell responses generated upon natural infection and vaccination with the ancestral SARS-CoV-2 spike are highly cross-reactive against SARS-CoV-2 Omicron subvariants, including the recently emerged Omicron BA.2.86. [5][6][7][8][9][10][11] Elderly nursing home residents with frailty and comorbidities frequently develop less robust and more rapidly waning SARS-CoV-2 T-cell responses following regular vaccination, irrespective of the SARS-CoV-2 infection status, compared with seemingly healthy and younger counterparts. [12][13][14][15][16] Furthermore, the booster effect on SARS-CoV-2 T-cell immunity of a third mRNA vaccine dose was reported to have a minimal impact on the frequency of peripheral blood SARS-CoV-2 S-directed IFNγ-producing CD4 + and CD8 + T cells, 17,18 although this might not be the case for those previously unresponsive.…”