Safety and immunogenicity of a booster dose of S-268019-b: Interim findings of a Phase 3, open-label clinical study in Japan.

Despite the initial success of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccines in prevention of symptomatic and severe diseases, booster vaccination has become increasingly important with the advent of variants with immune-escaping capacity. Herein, we report the safety and immunogenicity of S-268019-b, comprising SARS-CoV-2 spike protein and a squalene-based adjuvant, as a booster dose. We performed an interim analysis of an open-label, Phase 3 study data until Day 29 following S-268019-b booster in Japanese adults (aged 20-64 years) who had completed primary vaccination with mRNA-1273 and in Japanese elderly (aged ≥ 65 years) who had completed primary vaccination with mRNA-1273 or BNT162b2. Reactogenicity was mild in most participants; no serious treatment-related adverse events were noted. S-268019-b enhanced SARS-CoV-2 neutralizing antibodies, immunoglobulin G antibodies, and predominant T-helper 1-mediated immune reaction in all cohorts, regardless of age, in Japanese participants with prior vaccination with mRNA vaccines.

Results from a preclinical study in rodents and a Phase 1/2, randomized, double-blind, placebo-controlled, parallel-group study of COVID-19 vaccine S-268019-a in Japanese adults.

BACKGROUND: In early 2020, developing vaccines was an urgent need for preventing COVID-19 from a contingency perspective. METHODS: S-268019-a is a recombinant protein-based vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), comprising a modified recombinant spike protein antigen adjuvanted with agatolimod sodium, a Toll-like receptor-9 agonist. In the preclinical phase, it was administered intramuscularly twice at a 2-week interval in 7-week-old mice. Immunogenicity was assessed, and the mice were challenged intranasally with mouse-adapted SARS-CoV-2 at 2 and 8 weeks, respectively, after the second immunization. After confirming the preclinical effect, a Phase 1/2, randomized, parallel-group clinical study was conducted in healthy adults (aged 20-64 years). All participants received 2 intramuscular injections at various combinations of the antigen and the adjuvant (S-910823/agatolimod sodium, in µg: 12.5/250, 25/250, 50/250, 25/500, 50/500, 100/500, 10/500, 100/100, 200/1000) or placebo (saline) in an equivalent volume at a 3-week interval and were followed up until Day 50 in this interim analysis. RESULTS: In the preclinical studies, S-268019-a was safe and elicited robust immunoglobulin G (IgG) and neutralizing antibody responses in mice. When challenged with SARS-CoV-2, all S-268019-a-treated mice survived and maintained weight until 10 days, whereas all placebo- or adjuvant-treated (without antigen) mice died within 6 days. In the Phase 1/2 trial, although S-268019-a was well tolerated in adult participants, was safe up to Day 50, and elicited robust anti-spike protein IgG antibodies, it did not elicit sufficient neutralizing antibody levels. CONCLUSIONS: The S-268019-a vaccine was not sufficiently immunogenic in Japanese adults despite robust immunogenicity and efficacy in mice. Our results exemplify the innate challenges in translating preclinical data in animals to clinical trials, and highlight the need for continued research to overcome such barriers. (jRCT2051200092).

Immunogenicity and safety of booster dose of S-268019-b or BNT162b2 in Japanese participants: An interim report of phase 2/3, randomized, observer-blinded, noninferiority study.

In this randomized, observer-blinded, phase 2/3 study, S-268019-b (n = 101), a recombinant spike protein vaccine, was analyzed for noninferiority versus BNT162b2 (n = 103), when given as a booster ≥6 months after 2-dose BNT162b2 regimen in Japanese adults without prior SARS-CoV-2 infection. Interim results showed noninferiority of S-268019-b versus BNT162b2 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.

Phase 1/2 clinical trial of COVID-19 vaccine in Japanese participants: A report of interim findings.

We initiated a randomized, placebo-controlled, phase 1/2 trial to evaluate the safety and immunogenicity of the S-268019-b recombinant protein vaccine, scheduled as 2 intramuscular injections given 21 days apart, in 60 randomized healthy Japanese adults. We evaluated 2 regimens of the S-910823 antigen (5 µg [n = 24] and 10 µg [n = 24]) with an oil-in-water emulsion formulation and compared against placebo (n = 12). Reactogenicity was mild in most participants. No serious adverse events were noted. For both regimens, vaccination resulted in robust IgG and neutralizing antibody production at days 36 and 50 and predominant T-helper 1-mediated immune reaction, as evident through antigen-specific polyfunctional CD4+ T-cell responses with IFN-γ, IL-2, and IL-4 production on spike protein peptides stimulation. Based on the interim analysis, the S-268019-b vaccine is safe, produces neutralizing antibodies titer comparable with that in convalescent serum from COVID-19-recovered patients. However, further evaluation of the vaccine in a large clinical trial is warranted.

Systemic endotoxin induces gene expression of inducible nitric oxide synthase in fetal rat brain.

BACKGROUND: Few studies have examined the response of the fetus under stress, such as with maternal infection. Recent work has indicated that nitric oxide (NO) modulates corticotropin-releasing hormone (CRH) secretion by the hypothalamus, but details of the action of NO on the fetus remain unclear. Therefore, we investigated the expression of inducible nitric oxide synthase (iNOS) mRNA and the response pattern following lipopolysaccharide (LPS) loading using a rat model of fetal infection. METHODS: Fetuses were delivered by cesarean section on day 20 of gestation and immediately placed in a chamber maintained at 37 degrees C and 100% relative humidity. The LPS group (n=12) was given 400 microg of LPS/100 g body weight, and the physiologic saline group (n=12) was given physiologic saline. Fetuses were then incubated for a further 3 hours. Fetuses were decapitated, the trunk blood was collected immediately after cesarean section or after 3 hours of incubation, and the fetal brains were fixed in formaldehyde and cryopreserved. Coronal cryosections of the brains were prepared, and a (35)S-uridine triphosphate-labeled antisense RNA probe for iNOS was then prepared. In situ hybridization was performed, and iNOS expression was evaluated semiquantitatively on the basis of optical density. In both groups, plasma corticosterone levels were determined with radioimmunoassay. RESULTS: Expression of iNOS mRNA was not noted in the physiologic saline group (3 hours postpartum). In the LPS group, iNOS mRNA expression was observed in the subfornical organ, but not in the paraventricular nucleus. Plasma corticosterone levels were significantly elevated in the LPS group. CONCLUSIONS: In 20-day-old rat fetuses, the hypothalamic-pituitary-adrenal axis was already mobilized in response to LPS-induced stress. These results suggest that iNOS is not involved in the acute response of the hypothalamic-pituitary-adrenal axis to LPS challenge in 20-day-old rat fetuses.

Gasless laparoscopic surgery using a new intra-abdominal fan retractor system: an experience of 500 cases.

AIM: The aim of this study is to report the feasibility of a newly developed intra-abdominal fan retractor system for use in gynecologic laparoscopic surgery. METHODS: Five hundred women undergoing gasless laparoscopic surgery using the abdominal wall lifting device were included in the study. The intraoperative and postoperative courses, and complications were examined. RESULTS: The intra-abdominal retractor system provided adequate exposure in all cases, except for one patient with morbid obesity. Neither the presence of the intra-abdominal retractor blades nor the mechanical arm interfered with the placement of instruments during surgery. No complications related to the use of gasless laparoscopy were encountered in this study period. CONCLUSION: The new intra-abdominal fan retractor system is feasible in gynecologic laparoscopic surgery.