Immune recall improves antibody durability and breadth to SARS-CoV-2 variants

Abstract

Key features of immune memory are greater and faster antigen-specific antibody responses to repeat infection. In the setting of immune-evading viral evolution, it is important to understand how far antibody memory recognition stretches across viral variants when memory cells are recalled to action by repeat invasions. It is also important to understand how immune recall influences longevity of secreted antibody responses. We analyzed SARS-CoV-2 variant recognition, dynamics of memory B cells and secreted antibody over time after infection, vaccination, and boosting. We find that a two-dose SARS-CoV-2 vaccination regimen given after natural infection generated greater longitudinal antibody stability and induced maximal antibody magnitudes with enhanced breadth across Beta, Gamma, Delta and Omicron variants. A homologous 3 rd mRNA vaccine dose in COVID-naïve individuals conferred greater cross-variant evenness of neutralization potency with stability that was equal to the hybrid immunity conferred by infection plus vaccination. Within unvaccinated individuals who recovered from COVID, enhanced antibody stability over time was observed within a subgroup of individuals that recovered more quickly from COVID and harbored significantly more memory B cells cross-reactive to endemic coronaviruses early after infection. These cross-reactive clones map to the conserved S2 region of SARS-CoV-2 spike with higher somatic hypermutation levels and greater target affinity. We conclude that SARS-CoV-2 antigen challenge histories in humans influence not only the speed and magnitude of antibody responses, but also functional cross-variant antibody repertoire composition and longevity.

Different Neutralization Profiles After Primary SARS-CoV-2 Omicron BA.1 and BA.2 Infections

“…Multiple exposures to pre-Omicron-SARS-CoV-2, via three mRNA vaccinations (Figure 1A) or mixed infectionvaccination scenarios (Figure 1B), led to high titers with efficient neutralization of both Omicron variants. These data are in agreement with other studies that suggested an increase in the magnitude as well as the breadth of neutralizing antibody responses by repeated exposure to the original antigen (26)(27)(28)(29)(30)(31)(32)(33)(34)(35). Previous data (36) suggest that a three-dose vaccination regimen enhances the breadth of antibody responses in that memory B cells are also formed against conserved epitopes.…”

Serial infection with SARS-CoV-2 Omicron BA.1 and BA.2 following three-dose COVID-19 vaccination

“…While it is perhaps unsurprising that COVID-19 vaccines based on ancestral SARS-CoV-2 sequences will not generate sterilizing immunity against Omicron strains that have evolved to evade host immune responses ( 4 , 40 – 44 ), various lines of evidence suggest that “hybrid” immunity resulting from vaccination plus infection nevertheless provides enhanced protection against SARS-CoV-2 variants ( 5 , 45 ), due in part to maturation of Spike-specific antibodies ( 46 – 48 ) and expansion of antiviral T cells ( 49 – 54 ). In light of this, we note that symptomatic BA.1 infection boosted the case participant’s vaccine-induced humoral responses against both BA.1 and BA.2.…”

Serial infection with SARS-CoV-2 Omicron BA.1 and BA.2 following three-dose COVID-19 vaccination

“…While it is perhaps unsurprising that COVID-19 vaccines based on ancestral SARS-CoV-2 sequences will not generate sterilizing immunity against Omicron strains that have evolved to evade host immune responses (4,(38)(39)(40)(41)(42), various lines of evidence suggest that "hybrid" immunity resulting from vaccination plus infection provides greater protection against SARS-CoV-2 variants (5,43), due in part to maturation of Spike-specific antibodies (44)(45)(46) and expansion of antiviral T cells (47)(48)(49)(50)(51)(52). In light of this, we note that symptomatic BA.1 infection boosted vaccine-induced humoral responses against both BA.1 and BA.2 in our case participant, but the heightened response nevertheless failed to prevent subsequent symptomatic infection by BA.2.…”