A longitudinal study on SARS-CoV-2 seroconversion, reinfection and neutralisation spanning several variant waves and vaccination campaigns, Heinsberg, Germany, April 2020 to November 2022.

BackgroundSince its emergence in December 2019, over 700 million people worldwide have been infected with SARS-CoV-2 up to May 2024. While early rollout of mRNA vaccines against COVID-19 has saved many lives, there was increasing immune escape of new virus variants. Longitudinal monitoring of population-wide SARS-CoV-2 antibody responses from regular sample collection irrespective of symptoms provides representative data on infection and seroconversion/seroreversion rates.AimTo examine adaptive and cellular immune responses of a German SARS-CoV-2 outbreak cohort through several waves of infection with different virus variants.MethodsUtilising a 31-month longitudinal seroepidemiological study (n = 1,446; mean age: 50 years, range: 2-103) initiated during the first SARS-CoV-2 superspreading event (February 2020) in Heinsberg, Germany, we analysed acute infection, seroconversion and virus neutralisation at five follow-up visits between October 2020 and November 2022; cellular and cross-protective immunity against SARS-CoV-2 Omicron variants were also examined.ResultsSARS-CoV-2 spike (S)-specific IgAs decreased shortly after infection, while IgGs remained stable. Both increased significantly after vaccination. We predict an 18-month half-life of S IgGs upon infection. Nucleocapsid (N)-specific responses declined over 12 months post-infection but increased (p < 0.0001) during Omicron. Frequencies of SARS-CoV-2-specific TNF-alpha+/IFN-gamma+ CD4+ T-cells declined over 12 months after infection (p < 0.01). SARS-CoV-2 S antibodies and neutralisation titres were highest in triple-vaccinated participants infected between April 2021 and November 2022 compared with infections between April 2020 and January 2021. Cross neutralisation against Omicron BQ.1.18 and XBB.1.5 was very low in all groups.ConclusionInfection and/or vaccination did not provide the population with cross-protection against Omicron variants.

Vaccination impairs de novo immune response to omicron breakthrough infection, a precondition for the original antigenic sin.

Several studies have suggested the imprinting of SARS-CoV-2 immunity by original immune challenge without addressing the formation of the de novo response to successive antigen exposures. As this is crucial for the development of the original antigenic sin, we assessed the immune response against the mutated epitopes of omicron SARS-CoV-2 after vaccine breakthrough. Our data demonstrate a robust humoral response in thrice-vaccinated individuals following omicron breakthrough which is a recall of vaccine-induced memory. The humoral and memory B cell responses against the altered regions of the omicron surface proteins are impaired. The T cell responses to mutated epitopes of the omicron spike protein are present due to the high cross-reactivity of vaccine-induced T cells rather than the formation of a de novo response. Our findings, therefore, underpin the speculation that the imprinting of SARS-CoV-2 immunity by vaccination may lead to the development of original antigenic sin if future variants overcome the vaccine-induced immunity.