Influenza vaccination reveals sex dimorphic imprints of prior mild COVID-19

Abstract

Acute viral infections can have durable functional impacts on the immune system long after recovery, but how they affect homeostatic immune states and responses to future perturbations remain poorly understood [1][2][3][4] . Here we use systems immunology approaches, including longitudinal multimodal single cell analysis (surface proteins, transcriptome, and V(D)J sequences), to comparatively assess baseline immune statuses and responses to influenza vaccination in 33 healthy individuals after recovery from mild, non-hospitalized COVID-19 (mean: 151 days after diagnosis) and 40 age-and sex-matched controls who never had COVID-19. At baseline and independent of time since COVID-19, recoverees had elevated T-cell activation signatures and lower expression of innate immune genes in monocytes.COVID-19-recovered males had coordinately higher innate, influenza-specific plasmablast, and antibody responses after vaccination compared to healthy male and COVID-19-recovered females, partly because male recoverees had monocytes with higher IL-15 responses early after vaccination coupled with elevated pre-vaccination frequencies of "virtual memory" like CD8+ T-cells poised to produce more IFNγ upon IL-15 stimulation. In addition, the expression of the repressed innate immune genes in monocytes increased by day 1 through day 28 post-vaccination in recoverees, thus moving towards the pre-vaccination baseline of healthy controls. In contrast, these genes decreased on day 1 and returned to the baseline by day 28 in controls. Our study reveals sex-dimorphic impacts of prior mild COVID-19 and suggests that viral infections in humans can establish new set-points impacting future immune responses in an antigen-agnostic manner.

Long COVID manifests with T cell dysregulation, inflammation, and an uncoordinated adaptive immune response to SARS-CoV-2

“…The presence of cytotoxic T cells has been associated with gastrointestinal LC symptoms 12 and it will be of interest in future studies to establish whether biological sex impacts LC-associated cytotoxic T cell function. Intriguingly, biological sex was recently shown to manifest in the context of differential responses to influenza vaccines after COVID-19 convalescence 45 , although individuals with LC were not examined therein.…”

SARS-CoV-2 spike antigen-specific B cell and antibody responses in pre-vaccination period COVID-19 convalescent males and females with or without post-covid condition

“…Thus, the differences seen following natural infection in convalescent males and females with PCC were probably overshadowed/minimized by the effect of adjuvants in the vaccine. Omics based systems biology approach indicated that males who recovered from COVID-19 showed a better coordinated innate, B cell and antibody responses to subsequent influenza vaccination (Sparks et al, 2023). While the history of infections and influenza vaccinations are not known in the participants involved in this study, nevertheless it suggests that immune responses are continually being shaped by past infections.…”

Multiscale integration of human and single-cell variations reveals unadjuvanted vaccine high responders are naturally adjuvanted

“…Assessing tissues such as lymph nodes would give a more comprehensive picture of vaccination response variations across individuals. Despite logistical challenges of human tissue profiling, recent pioneering work using fine needle aspirates or biopsies from lymph nodes [88][89][90] following influenza vaccination 91 both men and women had a temporally stable altered baseline immune state compared to matching controls, and men tended to mount more robust innate and adaptive responses to the seasonal influenza vaccine 93 . As future work we can assess whether and how the monocyte and DC naturally adjuvanted phenotypes overlap with those stably modified by prior infections in the same cells.…”