Heterologous booster immunization with SARS-CoV-2 spike protein after mRNA vaccine elicits durable and broad antibody responses (preprint)

Although mRNA vaccines are more immunogenic than other vaccine modalities in primary series vaccination, their immunogenicity has not been well compared to different vaccine modalities in additional boosters. Here the longitudinal analysis reveals more sustained RBD-binding IgG titers and RBD-ACE2 binding inhibitory activities with the breadth to antigenically distinct Beta and Omicron BA.1 variants by the S-268019-b spike protein booster vaccination compared to BNT162b2 mRNA homologous booster on mRNA vaccinees. The differences in the durability and breadth of plasma antibodies between BNT162b2 and S-268019-b groups are pronounced in those without systemic adverse events and were associated with different trends in the number and breadth of memory B cells. High-dimensional immune profiling identifies early CD16 + natural killer cell dynamics with CCR3 upregulation, as one of the correlates for the distinct antibody responses by the S-268019-b booster. Our results illustrate the combinational effects of heterologous booster on the immune dynamics and the durability and breadth of recalled antibody responses against emerging virus variants.

Two doses of mRNA vaccine elicit cross-neutralizing memory B-cells against SARS-CoV-2 Omicron variant (preprint)

SARS-CoV-2 Beta and Omicron variants have multiple mutations in the receptor-binding domain (RBD) allowing antibody evasion. Despite the resistance to circulating antibodies in those who received two doses of mRNA vaccine, the third dose prominently recalls cross-neutralizing antibodies with expanded breadth to these variants. Herein, we longitudinally profiled the cellular composition of persistent memory B-cell subsets and their antibody reactivity against these variants following the second vaccine dose. The vaccination elicited a memory B-cell subset with resting phenotype that dominated the other subsets at 4.9 months. Notably, most of the resting memory subset retained the ability to bind the Beta variant, and the memory-derived antibodies cross-neutralized the Beta and Omicron variants at frequencies of 59% and 29%, respectively. The preservation of cross-neutralizing antibody repertoires in the durable memory B-cell subset likely contributes to the prominent recall of cross-neutralizing antibodies following the third dose of the vaccine. One Sentence Summary Fully vaccinated individuals preserve cross-neutralizing memory B-cells against the SARS-CoV-2 Omicron variant.

Distinct immune cell dynamics mark adverse events and antibody responses of SARS-CoV-2 mRNA vaccine (preprint)

Pfizer/BioNTec BNT162b2 mRNA vaccine robustly elicits neutralizing antibodies against SARS-CoV-2 in clinical trials and real-world settings. However, booster vaccinations are frequently associated with self-limited adverse events. Here, by applying a high-dimensional immune profiling approach to peripheral blood, we linked early vaccine-induced immune dynamics with adverse events and neutralizing antibody responses. The dynamics of two dendritic cell subsets (DC3s and AS-DCs) were identified as the specific correlates for adverse events; the combination of these cell dynamics stratified the vaccinees with severe reactogenicity, while the stratification did not affect the neutralizing antibody titers. Furthermore, the NKT-like cell dynamics that correlated with adverse events and antibody titers were accounted for distinct magnitudes of both events by sex and age. The identified immune correlates for adverse events and antibody responses may pave the way for a rational vaccine strategy for reducing the reactogenicity of mRNA vaccines without compromising the immunogenicity.

Myeloid cell dynamics correlate with clinical outcomes of severe coronavirus disease 2019 (preprint)

An expanded myeloid cell compartment is a hallmark of severe coronavirus disease 2019 (COVID-19); however, it remains unclear whether myeloid cells are beneficial or detrimental to the clinical outcome. Here, we tracked cellular dynamics of myeloid-derived suppressor cell (MDSC) subsets and examined whether any of them correlate with disease severity and prognosis by flow cytometric analysis of blood samples from COVID-19 patients. We observed that polymorphonuclear (PMN)-MDSCs, rather than other MDSC subsets, transiently expanded in severe cases but not in mild or moderate cases. Notably, this subset was selectively expanded in survivors of severe cases and diminished during recovery. Analysis of plasma cytokines/chemokines revealed that interleukin-8 increased prior to PMN-MDSC expansion in survivors and returned to basal levels during the recovery phase. In contrast, interleukin-6 and interferon-γ-induced protein 10 were abundantly induced in non-survivors, suggesting possible downstream targets for the immunosuppressive effects of the MDSC subset. Our data indicate that increased cellularity of PMN-MDSCs might be beneficial for the clinical outcome and could be useful as a possible predictor of prognosis in cases of severe COVID-19.