key: cord-0987776-dy6znohx
authors: Shinkai, M.; Sonoyama, T.; Kamitani, A.; Shibata, R.; Seki, N.; Omoto, S.; Shinoda, M.; Sato, T.; Ishii, N.; Igarashi, K.; Ariyasu, M.
title: 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
date: 2022-03-06
journal: nan
DOI: 10.1101/2022.03.03.22271827
sha: d6df059770638c5e5b160afec0ff50f1194a4b14
doc_id: 987776
cord_uid: dy6znohx

In this randomized, observer-blinded, phase 2/3 study, we assessed S-268019-b, a recombinant spike protein vaccine. We analyzed the noninferiority of S 268019-b (n=103), versus tozinameran (n=103), when given as a booster [≥]6 months after the 2-dose tozinameran regimen in Japanese adults without prior COVID-19 infection. Interim results showed that S-268019-b was noninferior to tozinameran in co-primary endpoints: geometric mean titer (GMT) (126.42 versus 108.20; adjusted-GMT ratio [95% CI], 1.17 [0.96-1.42]; noninferiority P-value, <0.0001) and seroresponse rate (both 100%; noninferiority P-value, 0.0004) for neutralizing antibodies on day 29. Both vaccines elicited anti-spike protein immunoglobulin G antibodies, and produced T-cell response (n=30/group) and neutralized Delta and Omicron pseudovirus variants (n=24/group) in subgroups. Most participants reported low-grade reactogenicity on days 1 and 2, the most frequent being fatigue, fever, myalgia, and injection-site pain. No serious adverse events were reported. S-268019-b safety and robust immunogenicity as a booster, supporting its use as COVID-19 booster vaccine. Keywords: booster, clinical trial, neutralization test, SARS-CoV-2, recombinant spike protein, immunization JRCT ID: jRCT2031210470

This phase 2/3, single-center, randomized, observer-blinded, active-85 controlled, noninferiority trial comprised three periods: screening (day −28 to −1), 86 evaluation (day 1 to 29), and follow-up (day 30 to 365) (Figure 1) . 87

Participants were healthy immunocompetent Japanese adults (aged The study (jRCT2031210470) was conducted in compliance with the protocol, 97 the Declaration of Helsinki and Council for International Organizations of Medical 98 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The primary objective of the study was to assess the noninferiority of 107 S-268019-b versus tozinameran as a booster dose in inducing SARS-CoV-2 108 neutralizing antibodies on day 29. The co-primary endpoints included day 29 109 geometric mean titer (GMT) and seroresponse rate (SRR) for SARS-CoV-2 110 neutralizing antibodies. SRR was defined as the proportion of participants with a 111 post-vaccination antibody titer ≥ 4-fold higher than the baseline. 112

Secondary endpoints comprised other immunogenicity parameters and safety. 113

These included GMT, geometric mean fold rise (GMFR), and SRR for neutralizing 114 antibodies and anti-spike protein immunoglobulin G (IgG) antibodies on days 15 and 115 29. Exploratory analyses in a smaller sample included geometric means of 50% 116 neutralization titer (NT 50 ) against SARS-CoV-2 pseudovirus strains (wildtype 117

[D614G], Delta, and Omicron) on day 29 and T-cell response on day 15. Safety 118 endpoints included incidence of adverse events (AEs), serious AEs, AEs of special 119 interest, treatment-related AEs (TRAEs), medically attended TRAEs, solicited 120

TRAEs, and changes in laboratory test values. Immunogenicity variables with titer 121 values below the lower limit of quantification (LLOQ) were replaced with 0.5 × LLOQ. 122

123

The study used a noninferiority design. Noninferiority of S-268019-b to 125 tozinameran is confirmed when the lower limit of 95% CI is >0.67 for GMT ratio 126 for anti-SARS-CoV-2 N-protein antibody at screening. The safety analysis subset 132 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. Per day 29 analysis, both co-primary endpoints were met: as a booster, 151 S-268019-b was noninferior to tozinameran in SARS-CoV-2 neutralization. GMTs 152 (95% CIs) for neutralizing antibodies at baseline were 5.53 (4.87-6.28) for S-153 268019-b group and 6.70 (5.76-7.78) for tozinameran, which increased to 126.42 154 (109.76-145.62) and 108.20 (94.57-123.80), respectively, by day 29 (adjusted-155 GMTR 1.17; 95% CI 0.96-1.42; one-sided P-value for noninferiority, <0.0001). The 156 SRR was 100% for both groups (SRR difference 0.0; 95% CI −5.8 to 5.8; one-sided 157 P-value for noninferiority, 0.0004) (Figure 2A and Table 1 ). The GMTs (95% CIs) for 158 anti-spike protein IgG antibodies at baseline were 1475.9 (1280.1-1701.6) for S-159 268019-b and 1795.9 (1536.9-2098.6) for tozinameran; these were elevated to Furthermore, the geometric mean NT 50 against SARS-CoV-2 pseudovirus 164 variants on day 29 were assessed in a smaller sample of the immunogenicity subset 165 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 6, 2022. ; https://doi.org/10.1101/2022.03.03.22271827 doi: medRxiv preprint (n=24/group). The sampling ensured no significant differences in age and 166 neutralizing antibody titer against live wildtype virus on day 29 compared with the 167 entire cohort (Supplementary Table 3 (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity.

The copyright holder for this preprint this version posted March 6, 2022. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. The booster dose of S-268019-b vaccine was noninferior to tozinameran 264 booster as per the findings of GMT and SRR for SARS-CoV-2 neutralizing 265 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. (which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. immunogenicity and reactogenicity of CoronaVac or ZF2001 booster after two 333 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. participants in the study groups (n=30/group). The 95% CI were constructed using 395 the Clopper-Pearson method for proportion data. 396 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. to the original scale. c The GMTR and its 95% CI were obtained using analysis of 408 covariance model fitted on the log-transformed titers; the model included intervention 409 group as the fixed effect as well as age (continuous) and sex as covariates. d The 410

95% CI were constructed using the Clopper-Pearson method for SRR and the 411 Farrington-Manning method for SRR difference. 412 All rights reserved. No reuse allowed without permission.

(which was not certified by peer review) is the author/funder, who has granted medRxiv a license to display the preprint in perpetuity. 12 (11.7) 7 (6.8) 5 (4.9) -8 (7.8) 6 (5.8) 2 (1.9) -Nausea/vomiting 5 (4.9) 5 (4.9) --5 (4.9) 4 (3.9) 1 (1.0) -Diarrhea 6 (5.8) 4 (3.9) 1 (1.0) 1 (1.0) 4 (3.9) 3 (2.9) 1 (1.0) -Chills 7 (6.8) 3 (2.9) 4 (3.9) -4 (3.9) 2 (1.9) 2 (1.9) -Any local solicited TRAEs 

Safety and immunogenicity of seven COVID-19 vaccines as a third dose 337 (booster) following two doses of ChAdOx1 nCov-19 or BNT162b2 in the UK 338 (COV-BOOST): a blinded, multicentre, randomised, controlled, phase 2 trial

Neutralising antibody titres as predictors of protection against SARS-CoV-2 343 variants and the impact of boosting: a meta-analysis

346 Effectiveness of a third dose of the BNT162b2 mRNA COVID-19 vaccine for 347 preventing severe outcomes in Israel: an observational study

351 Neutralization of SARS-CoV-2 Omicron by BNT162b2 mRNA vaccine-elicited 352 human sera

355 Association between 3 doses of mRNA COVID-19 vaccine and symptomatic 356 infection caused by the SARS-CoV-2 Omicron and Delta variants

T cell 359 and antibody kinetics delineate SARS-CoV-2 peptides mediating long-term 360 immune responses in COVID-19 convalescent individuals

The T cell immune response against SARS-CoV-2

Ancestral 365 SARS-CoV-2-specific T cells cross-recognize the Omicron variant