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.

Viral load and timing of infection define neutralization diversity to SARS-CoV-2 infection (preprint)

AbstractImmunity to SARS-CoV-2 in COVID-19 cases has diversified due to complex combinations of exposure to vaccination and infection. Elucidating the drivers for upgrading neutralizing activity to SARS-CoV-2 in COVID-19 cases with pre-existing immunity will aid in understanding immunity to SARS-CoV-2 and improving COVID-19 booster vaccines with enhanced cross-protection against antigenically distinct variants. This study revealed that the magnitude and breadth of neutralization responses to SARS-CoV-2 infection in breakthrough infections are determined by upper respiratory viral load and vaccination-infection time interval, but not by the lineage of infecting viruses. Notably, the time interval, but not the viral load, may play a critical role in expanding the breadth of neutralization to SARS-CoV-2. This illustrates the importance of dosing interval optimization in addition to antigen design in the development of variant-proof booster vaccines. One-Sentence SummaryViral load and infection timing define the magnitude and breadth of SARS-CoV-2 neutralization after breakthrough infection.

Vaccination-infection interval determines cross-neutralization potency to SARS-CoV-2 Omicron after breakthrough infection by other variants (preprint)

Background The immune profile against SARS-CoV-2 has dramatically diversified due to a complex combination of exposure to vaccines and infection by various lineages/variants, likely generating a heterogeneity in protective immunity in a given population. To further complicate this, the Omicron variant, with numerous spike mutations, has emerged. These circumstances have created the need to assess the potential of immune evasion by the Omicron in individuals with various immune histories. Methods The neutralization susceptibility of the variants including the Omicron and their ancestor was comparably assessed using a panel of plasma/serum derived from individuals with divergent immune histories. Blood samples were collected from either mRNA vaccinees or from those who suffered from breakthrough infections by the Alpha/Delta with multiple time intervals following vaccination. Findings The Omicron was highly resistant to neutralization in fully vaccinated individuals without a history of breakthrough infections. In contrast, robust cross-neutralization against the Omicron were induced in vaccinees that experienced breakthrough infections. The time interval between vaccination and infection, rather than the variant types of infection, was significantly correlated with the magnitude and potency of Omicron-neutralizing antibodies. Conclusions Immune histories with breakthrough infections can overcome the resistance to infection by the Omicron, with the vaccination-infection interval being the key determinant of the magnitude and breadth of neutralization. The diverse exposure history in each individual warrants a tailored and cautious approach to understanding population immunity against the Omicron and future variants. Funding This study was supported by grants from the Japan Agency for Medical Research and Development (AMED).

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.