Immune responses in Omicron SARS-CoV-2 breakthrough infection in vaccinated adults

Abstract

The SARS-CoV-2 Omicron variant has more than 15 mutations in the receptor binding domain of the Spike protein enabling increased transmissibility and viral escape from antibodies in vaccinated individuals. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a super-spreader event have robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. Individuals with Omicron SARS-CoV-2 breakthrough infections have significantly increased activated SARS-CoV-2 wild type Spike-specific cytotoxic T cells, activated follicular helper (TFH) cells, functional T cell responses, boosted humoral responses, and rapid release of Spike and RBD-specific IgG+ B cell plasmablasts and memory B cells into circulation. Omicron breakthrough infection affords significantly increased de novo memory T cell responses to non-Spike viral antigens. Concerted T and B cell responses may provide durable and broad immunity.

Vaccine- and BTI-elicited pre-Omicron immunity more effectively neutralizes Omicron sublineages BA.1, BA.2, BA.4 and BA.5 than pre-Omicron infection alone

“…They also indicate that the higher cross-neutralizing ability of BTI sera is likely due to the superior avidity of antibodies (Fig 4E). This may explain, at least partly, the superiority of hybrid immunity over infection or vaccination alone, and is consistent with ongoing affinity maturation after infection and vaccination(37, 40,41,82,84,86,87).…”

“…This observation somehow mirrors the restricted cross-neutralizing ability of BA.1-elicited antibodies against pre-Omicron and other Omicron lineages (3, 20, 30, 42, 50, 63, 66, 73, 75–77, 89), and highlights that BA.1 is antigenically very distant from all other VOCs and triggers strongly imprinted immune responses. Accordingly one study found that BA.1 booster triggers the activation of naïve B-cells rather than memory B-cells (74), while others record a small proportion of naïve B-cell activation (2, 63, 67, 87). This observation also suggests that different antigens (infection or mRNA vaccines) lead to slightly different immune imprints.…”

“…Converging evidence indicates that the time since vaccination/infection as well as the infecting variant dictate the level and quality of immune responses to mRNA boosters vaccination (70, 79). Ongoing affinity maturation shapes immune responses elicited by infection (82, 92–95) and by vaccine boosters, including those based on the original Wuhan strain (37, 40, 41, 82, 84, 86, 87). Accordingly, the time elapsed between vaccination and breakthrough infection is proportional to the breadth of the resulting antibody response (84).…”

“…The ability of multivalent vaccines to overcome the immune evasion potential conferred by these mutations and to trigger memory B-cell affinity maturation will be crucial in breaking this vicious cycle. Indeed, recent studies reported that BA.1 breakthrough infection not only induces broadly NAbs, but also reactivates cross-reactive memory B-cell responses which accumulate somatic mutations and increase the breadth of NAbs (67,87), while another study indicates it induces novel naïve B-cells (74). These two mechanisms are not mutually exclusive and the resulting expansion of the memory B-cell repertoire is consistent with the superiority of hybrid immunity and the cross-reactivity of NAbs conferred by Omicron breakthrough infections.…”

Gene Signatures of T-Cell Activation Can Serve as Predictors of Functionality for SARS-CoV-2-Specific T-Cell Receptors

“…Such global efforts resulted in the quick approval of effective vaccines [ 3 , 4 , 5 ]. However, the rapid emergence of variants, in particular the Omicron strain (B.1.1.529) subvariants BA.1.1 and BA.2, have resulted in countless breakthrough infections in vaccinated individuals [ 6 ] partially as a result of neutralizing antibody escape [ 7 , 8 , 9 , 10 ], whereas T-cell immunity seemed globally preserved [ 11 ]. Alarmingly, a recent study showed a complete loss of neutralization activity against Omicron variants in vitro for some therapeutic antibodies, thus legitimately raising concerns about their clinical relevance [ 12 ].…”