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.

Immunogenicity and Safety of Booster Dose of S-268019-b or Tozinameran in Japanese Participants: An Interim Report of Phase 2/3, Randomized, Observer-Blinded, Noninferiority Study (preprint)

In this randomized, observer-blinded, phase 2/3 study, S-268019-b (n=101), a recombinant spike protein vaccine, was analyzed for noninferiority versus tozinameran (n=103), when given as a booster ≥6 months after 2-dose tozinameran regimen in Japanese adults without prior COVID-19 infection. Interim results showed noninferiority of S-268019-b versus tozinameran in co-primary endpoints for neutralizing antibodies on day 29: geometric mean titer (GMT) (124.97 versus 109.70; adjusted-GMT ratio [95% CI], 1.14 [0.94-1.39]; noninferiority P -value, <0.0001) and seroresponse rate (both 100%; noninferiority P -value, 0.0004). Both vaccines elicited anti-spike-protein immunoglobulin G antibodies, and produced T-cell response (n=29/group) and neutralizing antibodies against Delta and Omicron pseudovirus and live virus variants (n=24/group) in subgroups. Most participants reported low-grade reactogenicity on days 1-2, the most frequent being fatigue, fever, myalgia, and injection-site pain. No serious adverse events were reported. In conclusion, S-268019-b was safe and showed robust immunogenicity as a booster, supporting its use as COVID-19 booster vaccine. JRCT ID jRCT2031210470 Highlights Third COVID-19 vaccine dose (booster) enhances immune response Interim phase 2/3 data for booster ≥6 months after the 2nd dose in Japan are shown S-268019-b was noninferior to tozinameran in inducing neutralizing antibodies Sera boosted with either vaccines neutralized Delta and Omicron virus variants S-268019-b was safe, and results support its use as a booster in vaccinated adults

Factors Associated with Low IgG Response to mRNA COVID-19 Vaccine BNT162b2 (preprint)

Amid pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), vaccination is hailed as one of the most effective preventive measures. An mRNA vaccine termed BNT162b2 showed satisfactory safety and efficacy in the clinical trials but several issues including variability in the individual immune response or determination of target antibody titre that exerts sufficient immune protection needs to be assessed for planning a more efficient vaccination strategy. By monitoring IgG titres before and two months after the initial administration of BNT162b2 in 655 healthcare workers by Abbott IgG II quant that detects IgG against the receptor-binding domain in S protein of SARS-CoV-2, we confirmed that hypertension, dyslipidaemia, chronic kidney disease and use of immune suppressant in addition to male gender, advanced age, and absence of previous infection were significantly associated with low antibody response to the vaccination.

Prognostic Predictors For COVID-19 in Daily Clinical Practice in Japan: a Propensity Score-Matched Case-Control Study (preprint)

Introduction: Blood tests and computed tomography (CT) findings at diagnosis are widely used in daily clinical practice and can offer useful prognostic factors for coronavirus disease 2019. Methods: : We retrospectively evaluated 66 patients who underwent a blood test and CT between January 1 and May 31, 2020, and performed a propensity score-matched case-control study. Cases and controls were a severe respiratory failure group (non-rebreather mask, nasal high-flow, positive-pressure ventilation) and a non-severe respiratory failure group, matched at a ratio of 1:3 by propensity scores constructed by age, sex, and medical history. We compared groups for maximum body temperature up to diagnosis, laboratory findings, and CT findings in the matched cohort. Two-tailed P-values <0.05 were considered statistically significant. Results: : Nine cases and 27 controls were included in the matched cohort. Significant differences were seen in maximum body temperature up to diagnosis (p=0.0043), the number of shaded lobes (p=0.0434), amount of ground-glass opacity (GGO) in the total lung field (p=0.0071), amounts of GGO (p=0.0001), and consolidation (p=0.0036) in the upper lung field, and pleural effusion (p=0.0117). Conclusions: : Fever and CT findings (such as GGO and consolidation) may be prognostic indicators that can be easily measured at diagnosis.

Identification, crystallization and epitope determination of public TCR shared and expanded in COVID-19 patients (preprint)

T cells play pivotal roles in protective immunity against SARS-CoV-2 infection. Follicular helper T (Tfh) cells mediate the production of antigen-specific antibodies; however, T cell receptor (TCR) clonotypes used by SARS-CoV-2-specific Tfh cells have not been well characterized. Here, we first identified and crystallized public TCR of Tfh clonotypes that are shared and expanded in unhospitalized COVID-19-recovered patients. These clonotypes preferentially recognized SARS-CoV-2 spike (S) protein epitopes which are conserved among emerging SARS-CoV-2 variants. These clonotypes did not react with S proteins derived from common cold human coronaviruses, but cross-reacted with symbiotic bacteria, which might confer the publicity. Among SARS-CoV-2 S epitopes, S864-882, presented by frequent HLA-DR alleles, could activate multiple public Tfh clonotypes in COVID-19-recovered patients. Furthermore, S864-882-loaded HLA tetramer preferentially bound to CD4+ T cells expressing CXCR5. In this study, we identified and crystallized public TCR for SARS-CoV-2 that may contribute to the prevention of COVID-19 aggravation.