The effect of Omicron breakthrough infection and extended BNT162b2 booster dosing on neutralization breadth against SARS-CoV-2 variants of concern

Abstract

COVID-19 vaccines are playing a vital role in controlling the COVID-19 pandemic. As SARS-CoV-2 variants encoding mutations in the surface glycoprotein, Spike, continue to emerge, there is increased need to identify immunogens and vaccination regimens that provide the broadest and most durable immune responses. We compared the magnitude and breadth of the neutralizing antibody response, as well as levels of Spike-reactive memory B cells, in individuals receiving a second dose of BNT126b2 at a short (3–4 week) or extended interval (8–12 weeks) and following a third vaccination approximately 6–8 months later. We show that whilst an extended interval between the first two vaccinations can greatly increase the breadth of the immune response and generate a higher proportion of Spike reactive memory B cells, a third vaccination leads to similar levels between the two groups. Furthermore, we show that the third vaccine dose enhances neutralization activity against omicron lineage members BA.1, BA.2 and BA.4/BA.5 and this is further increased following breakthrough infection during the UK omicron wave. These findings are relevant for vaccination strategies in populations where COVID-19 vaccine coverage remains low.

Durable reprogramming of neutralising antibody responses following breakthrough Omicron infection

“…Epidemiological studies have indicated that hybrid immunity confers stronger and more durable protection against infection compared to vaccine- or infection-elicited immunity alone ( 14-17 ). In line with other reports ( 6, 18 ), our data suggest that BA.1 and BA.2 breakthrough infection confers neutralisation breadth that extend to the more immune evasive BA.4 variant. Studies of a third dose of an ancestral spike vaccine have similarly demonstrated expansion of Omicron-specific B cells and enhancement of neutralisation breadth ( 19, 20 ), although not to the same extent as breakthrough infection with BA.1 ( 6 ).…”

“…Epidemiological studies have indicated that hybrid immunity confers stronger and more durable protection against infection compared to vaccine-or infection-elicited immunity alone (14)(15)(16)(17). In line with other reports (6,18), our data suggest that BA.1 and BA. Repeated, sequential waves of Omicron outbreaks have driven significant breakthrough infections and conferred "hybrid" immunity to much of the global population.…”

“…While the isolation of receptor binding domain (RBD)-specific monoclonal antibodies (mAbs) specific for the BA.It remains unclear if there is something unique about "hybrid immunity" (vaccination then infection) in terms of durable reprogramming of the antibody response.Epidemiological studies have indicated that hybrid immunity confers stronger and more durable protection against infection compared to vaccine-or infection-elicited immunity alone(14)(15)(16)(17). In line with other reports(6,18), our data suggest that BA.1 and BA.2 breakthrough infection confers neutralisation breadth that extend to the more immune evasive BA.4 variant. Studies of a third dose of an ancestral spike vaccine have similarly demonstrated expansion of Omicron-specific B cells and enhancement of neutralisation breadth(19,20), although not to the same extent as breakthrough infection with BA.1 (6).…”

Comparison of SARS-CoV-2 entry inhibitors based on ACE2 receptor or engineered Spike-binding peptides

“…In particular, early studies reported a diminished ability of vaccine-induced antibodies to neutralize the Beta and Gamma variants [6,7] and recent studies have shown similar escape from vaccine-elicited antibodies by Omicron subvariants [8]. More recently, viruses in the Omicron lineage have been shown to be capable of causing breakthrough infections in both previously vaccinated or infected individuals [9], and the extensive mutations present in the Omicron Spike protein have prevented the effectiveness of antibody therapies [10][11][12]. This underscores the need for alternate, broadly-acting vaccines and therapeutics with activity against both current and future viral variants [13].…”

Broad and potent neutralizing mAbs are elicited in vaccinated individuals following Delta/BA.1 breakthrough infection

“…; https://doi.org/10.1101/2023.03. 30.534872 doi: bioRxiv preprint 4 to increase neutralization breadth against VOCs, in particular against omicron/BA.1 8,19,29,30 . However, whether a SARS-CoV-2 variant infection in vaccinated individuals leads to a de novo response specific for the infecting VOC or whether pre-existing memory B cells are activated upon VOC exposure is not fully understood.…”