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Longitudinal analysis of B- and T-cell responses to SARS-CoV-2 recombinant S-protein vaccine S-268019-b in phase 1/2 priming and booster study

ABSTRACT: The durability of vaccine-induced immune memory to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is crucial for preventing infection, especially severe disease. This follow-up report after homologous booster vaccination in a phase 1/2 study of S-268019-b (a recombinant spike protein vaccine) confirms the long-term safety, tolerability, and immunogenicity. Booster vaccination of S-268019-b resulted in an enhancement of serum neutralizing antibody (NAb) titers and a broad range of viral neutralization. Single-cell immune profiling revealed persistent and mature antigen-specific memory B cells and T follicular helper cells, with increased B-cell receptor diversity. The expansion of B- and T-cell repertoires and cross-reactive NAbs targeting conserved epitopes within the receptor-binding domain following a booster, accounted for the broad-spectrum neutralizing activity. These finding highlights the potential of S-268019-b to provide broad and robust protection against a range of SARS-CoV-2 variants, addressing a critical challenge in the ongoing fight against coronavirus disease 2019 (COVID-19).

ORGANISM(S): Homo Sapiens (human)

SUBMITTER: Shinya Omoto

PROVIDER: PXD056410 | JPOST Repository | Wed Mar 05 00:00:00 GMT 2025

REPOSITORIES: jPOST

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			Action	DRS
	20231130_RBD_Wuhan_peptidemapping.csv	Csv
	20231204_RBD_Wuhan_peptidemapping.csv	Csv
	20240116_RBD_Wuhan_peptidemapping.csv	Csv
	20240117_RBD_Wuhan_peptidemapping.csv	Csv
	HDX-MS_RBD_Wuhan_Human_monoclonalAb_01_DataAnalysis.zip	Other

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Project description:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)has caused the pandemic of the coronavirus induced disease 2019 (COVID-19) with 216 million cases and 4.5 million deathsas of September 2021.Thathas been exacerbated by mutated variants such as α, β, and with high infection rates and increased breakthroughs,resulting in vaccine inefficiencies and resistance to therapeutic monoclonal antibodies. Itremains urgentto identify novel therapeutics against broad strains of SARS-CoV-2 andfuture emerging corona viruses to protect the immune-compromised, unvaccinated, and even vaccinatedalikefrom evolvinginfectious diseases. Onebig question is whether we can harness power from human antiviral immunity for such broad therapeutic development. Wild-type SARS-CoV-2 and its variants infect human and other host cellsvia the entry receptor angiotensin-converting enzyme 2 (ACE2),triggeringinnate and adaptive immune responses. Herein, we reportan increase in circulating extracellular vesicles (EVs) that express ACE2(evACE2)in plasma ofboth acuteand convalescent COVID-19 patientsas part of innate antiviral responseassociatedwith severe pathogenesis. Furthermore, evACE2 isolated from both human plasma and engineered EV-producing cell lines neutralizes SARS-CoV-2 infection by competingwith cellular ACE2.Notably,evACE2 blocksthe binding of the viral spike (S)protein RBD to ACE2+cells ata135-fold higherpotencythan vesicle-free recombinant human ACE2 (rhACE2). Furthermore, evACE2 preventscellinfections by both pseudotyped and authentic SARS-CoV-2at a 60-to 80-fold higher efficacy than rhACE2; and itprotectsthe hACE2 mice from SARS-CoV-2-induced lung injury and mortality. More importantly, evACE2 inhibitsthe infection of SARS-CoV-2 variants (α, β,and δ)with an equal or even higherpotencythan forthe WT strain, supportingevACE2 as a broad-spectrum antiviral mechanismfor therapeutic developmentto block the infection of existing and future coronaviruses that use ACE2 as a receptor.

Project description:In the last two years, the coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a scientific and social challenge worldwide. Vaccines have been the most effective intervention for reducing virus transmission and disease severity. However, virus genetic variants are still circulating among vaccinated individuals with different symptomatology disease cases. Understanding the protective or disease associated mechanisms in vaccinated individuals is relevant to advance in vaccine development and implementation. To address this objective, serum protein profiles were characterized by quantitative proteomics and data analysis algorithms in four cohorts of vaccinated individuals uninfected and SARS-CoV-2 infected with asymptomatic, nonsevere and severe disease symptomatology. The results showed that immunoglobulins were the most overrepresented proteins in infected cohorts when compared to PCR-negative individuals. The immunoglobulin profile varied between different infected cohorts and correlated with protective or disease associated capacity. Overrepresented immunoglobulins in PCR-positive individuals correlated with protective response against SARS-CoV-2, other viruses, and thrombosis in asymptomatic cases. In nonsevere cases, correlates of protection against SARS-CoV-2 and HBV together with risk of myasthenia gravis and allergy and autoantibodies were observed. Patients with severe symptoms presented risk for allergy, chronic idiopathic thrombocytopenic purpura, and autoantibodies. The analysis of underrepresented immunoglobulins in PCR-positive compared to PCR-negative individuals identified vaccine-induced protective epitopes in various coronavirus proteins including the Spike receptor-binding domain RBD. Non-immunoglobulin proteins were associated with COVID-19 symptoms and biological processes. These results evidence host-associated differences in response to vaccination and the possibility of improving vaccine efficacy against SARS-CoV-2.

Dataset Information

Longitudinal analysis of B- and T-cell responses to SARS-CoV-2 recombinant S-protein vaccine S-268019-b in phase 1/2 priming and booster study

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