Immunogenicity and safety of a booster dose of a self-amplifying RNA COVID-19 vaccine (ARCT-154) versus BNT162b2 mRNA COVID-19 vaccine: a double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial.

BACKGROUND: Licensed mRNA COVID-19 vaccines require booster doses to sustain SARS-CoV-2-specific responses, creating the need for novel, broadly immunogenic vaccines. We aimed to compare the immunogenicity, safety, and tolerability of ARCT-154-a self-amplifying mRNA vaccine against SARS-CoV-2 D614G variant-with the BNT162b2 (Comirnaty; Pfizer-BioNTech) mRNA vaccine when administered as a fourth-dose booster. METHODS: This double-blind, multicentre, randomised, controlled, phase 3, non-inferiority trial, conducted at 11 outpatient clinical sites in Japan, enrolled healthy adults aged at least 18 years who had previously been immunised with two doses of an mRNA COVID-19 vaccine (BNT162b2 or mRNA-1273 [Spikevax; Moderna]) followed by a third dose of BNT162b2 at least 3 months before enrolment. Participants were randomly assigned, in a 1:1 ratio using an Interactive Response Technology system with a block size of four, and with stratification by age (18-64 years or ≥65 years) and by interval since last COVID-19 vaccination (<5 months or ≥5 months), to receive either ARCT-154 or BNT162b2 as a fourth-dose booster via deltoid intramuscular injection. Participants and investigators assessing outcomes were masked to group assignment. The primary objective, measured in per-protocol set 1 (consisting of participants with no evidence of previous SARS-CoV-2 infection who received their intended injection according to protocol), was to show that the immune response 28 days after the ARCT-154 vaccine was non-inferior to that of the BNT162b2 vaccine, measured in terms of both pseudovirus neutralising antibody geometric mean titre (GMT) ratios and seroresponse rates against the wild-type Wuhan-Hu-1 strain of SARS-CoV-2. Non-inferiority was declared when the lower limit of the 95% CI of the ARCT-154 to BNT162b2 GMT ratio exceeded 0·67, and when the lower limit for the difference in seroresponse rates exceeded -10%. Key secondary endpoints included the immune response against the omicron BA.4/5 subvariant, which was assessed for non-inferiority and superiority in per-protocol set 1. Safety was assessed in the full analysis set. This study was registered on the Japan Registry for Clinical Trials, jRCT 2071220080, and is ongoing. FINDINGS: Between Dec 13, 2022, and Feb 25, 2023, we enrolled and randomly assigned 828 participants to receive ARCT-154 (n=420) or BNT162b2 (n=408) vaccines as a fourth-dose booster. In per-protocol set 1, the GMTs of surrogate neutralising antibodies induced against the Wuhan-Hu-1 SARS-CoV-2 strain in the ARCT-154 group (5641 [95% CI 4321-7363]) were non-inferior to those in the BNT162b2 group (3934 [2993-5169]) when measured at 28 days after boosting, with a GMT ratio of 1·43 (95% CI 1·26-1·63). Seroresponse rates were 65·2% (95% CI 60·2-69·9) in the ARCT-154 group versus 51·6% (46·4-56·8) in the BNT162b2 group, a difference of 13·6% (95% CI 6·8-20·5). GMTs against the omicron BA.4/5 variant on day 29 were 2551 (1687-3859) in the ARCT-154 group and 1958 (1281-2993) in the BNT162b2 group-a GMT ratio of 1·30 (1·07-1·58)-with seroresponse rates of 69·9% (65·0-74·4) and 58·0% (52·8-63·1). Both boosters were equally well tolerated. No treatment-related deaths were reported, nor were there severe or serious adverse events considered to be causally associated related to study vaccination. One serious adverse event, a foot deformity reported in a participant in the BNT162b2 group, was observed but determined not to have a causal relationship to the study vaccination. One severe adverse event, a case of abnormal hepatic function in the ARCT-154 group, was considered to be related to study vaccine. Adverse events of special interest for detection of myocarditis and pericarditis included chest pain (one case in the ARCT-154 group and three cases in the BNT162b2 group) and shortness of breath (two cases in the BNT162b2 group), all of which were considered to have a reasonable possibility of being related to vaccination. Local reactions were reported by 398 (95%) of 420 participants receiving the ARCT-154 vaccine and 395 (97%) of 408 participants receiving the BNT162b2 vaccine, and solicited systemic adverse events by 276 (66%) of those receiving the ARCT-154 vaccine and 255 (63%) of those receiving the BNT162b2 vaccine. Adverse events were mainly mild in severity, occurring and resolving within 3-4 days after vaccination. INTERPRETATION: In adults who had previously received three doses of an mRNA COVID-19 vaccine, immune responses 28 days after an ARCT-154 booster dose were non-inferior to those observed after a BNT162b2 booster dose for the Wuhan-Hu-1 strain of SARS-CoV-2 and superior for the Omicron BA.4/5 variant. Increased immune responses at 28 days might provide increased likelihood of protection against these strains during this period and could also result in longer duration of protection. Further studies will assess the immunogenicity induced against more recent SARS-CoV-2 variants. FUNDING: Japanese Ministry of Health, Labour, and Welfare. TRANSLATION: For the Japanese translation of the abstract see Supplementary Materials section.

Novel phenotype in beagle dogs characterized by skin response to compound 48/80 focusing on skin mast cell degranulation.

Beagle dogs have long been employed in toxicology studies and as skin disease models. Compared with other experimental animal species, they are known to be susceptible to skin responses, such as rashes, from exposure to various chemical compounds. Here, a unique dog phenotype was identified that showed no skin response to compound 48/80, a mast cell degranulating agent. Although the skin responses to intradermal injection of polyoxyethylene castor oil derivative (HCO-60, a nonionic detergent), histamine dihydrochloride, concanavalin A (IgE receptor-mediated stimuli), or calcium ionophore A23187 were comparable in wild-type (WT) dogs and these nonresponder (NR) dogs, only the response to compound 48/80 was entirely absent from NR dogs. The skin mast cell density and histamine content per mast cell were histologically comparable between WT and NR dogs. By checking for skin responses to compound 48/80, NR dogs were found to exist at the proportion of 17-20% among four animal breeders. From retrospective analysis of in-house breeding histories, the NR phenotype appears to conform to the Mendelian pattern of recessive inheritance. The standard skin response in WT dogs developed at 2-4 months of age. In conclusion, this unique phenotype, typified by insensitivity in the compound 48/80-induced degranulation pathway in mast cells, has been widely retained by recessive inheritance in beagle dogs among general experimental animal breeders. The knowledge concerning this phenotype could lead to better utilization of dogs in studies and aid in model development.

Genome-wide association study of SSRI/SNRI-induced sexual dysfunction in a Japanese cohort with major depression.

Sexual dysfunction is a major side effect of selective serotonin reuptake inhibitors (SSRIs) and serotonin-noradrenaline reuptake inhibitors (SNRIs). We conducted a genome-wide association study to identify the genetic factors contributing to the risk of SSRI/SNRI-induced sexual dysfunction by testing 186 320 single nucleotide polymorphism (SNP) markers in a cohort of 201 Japanese major depression patients including 36 with sexual dysfunction induced by SSRI (paroxetine or fluvoxamine) or SNRI (milnacipran). The Cochran-Armitage trend test showed that 11 SNPs, tightly clustered in a distinct region on chromosome 14q21.3, were associated with SSRI/SNRI-induced sexual dysfunction at a genome-wide significance level after false discovery rate (FDR) correction, and the strongest SNP association was with rs1160351 (P=3.04 × 10(-7), risk ratio=2.92, 95% confidence interval (CI)=1.79-4.76). These SNPs mapped to the intronic region of the MDGA2 gene. A Manhattan plot showed that the strong association peak remained in MDGA2 after adjustment for sex and age in a multivariable logistic regression analysis although P values increased slightly and became non-significant. Replication studies with larger sample sizes are required to validate this exploratory study, but our findings may provide insights into the genetic basis of sexual dysfunction induced by SSRI/SNRI.

Protective effect of inactive ingredients against nephrotoxicity of vancomycin hydrochloride in rats.

A generic form of vancomycin for I.V. infusion (MEEK) is more soluble and stable than the brand-name form of vancomycin hydrochloride (VCM) due to the addition of two inactive ingredients: D-mannitol and Macrogol400 (PEG400). The aim of the present study was to compare the nephrotoxicity of MEEK with that of brand-name VCM (S-VCM) and to analyze the pharmacokinetics of these preparations. Following administration to rats at the clinical dose of 40 mg/kg, there was no difference between MEEK and S-VCM with regard to pharmacokinetics and effects on the kidneys, indicating that MEEK should be as effective as S-VCM. When administered at the nephrotoxic dose of 400 mg/kg, S-VCM caused impairment of renal function and kidney damage, and an increase of the plasma concentration due to decreased renal clearance was observed. In contrast, MEEK had virtually no effect on renal function or the kidneys and did not cause a marked change of renal clearance. These findings suggest that the inactive ingredients in MEEK play a role in reducing the nephrotoxicity of VCM.