Efficacy and safety of bivalent RSVpreF maternal vaccination to prevent RSV illness in Japanese infants: Subset analysis from the pivotal randomized phase 3 MATISSE trial.

BACKGROUND: Maternal vaccination with respiratory syncytial virus prefusion F vaccine (RSVpreF) is effective at preventing RSV-associated lower respiratory tract illness (LRTI) in newborns/infants. METHODS: This subgroup analysis from the global, phase 3, randomized, double-blind, placebo-controlled MATISSE (Maternal Immunization Study for Safety and Efficacy) trial evaluated participants enrolled in Japan. Pregnant women 24-36 weeks' gestation were randomized 1:1 to receive RSVpreF or placebo. Maternal safety endpoints included local reactions/systemic events within 7 days, adverse events (AEs) through 1 month, and serious AEs (SAEs) through 6 months after vaccination. In infants born to maternal participants, safety endpoints included specific birth outcomes, AEs through 1 month after birth, and SAEs and newly diagnosed chronic medical conditions through 12 or 24 months after birth. Vaccine efficacy in infants was assessed against RSV-positive, medically attended LRTI (RSV-MA-LRTI) and severe RSV-MA-LRTI through 180 days after birth. RESULTS: In Japan, 230 maternal participants received RSVpreF and 232 received placebo; 218 and 216 infants born to these mothers, respectively, were analyzed. Observed vaccine efficacy (95 % CIs) against infant RSV-MA-LRTI within 90 and 180 days after birth was 100.0 % (30.9, 100.0; RSVpreF, 0 cases; placebo, 7 cases) and 87.6 % (7.2, 99.7; RSVpreF, 1 case; placebo, 8 cases), respectively. Vaccine efficacy (95 % CIs) against severe RSV-MA-LRTI within 90 and 180 days was 100.0 % (-140.9, 100.0; RSVpreF, 0 cases; placebo, 3 cases) and 75.1 % (-151.5, 99.5; RSVpreF, 1 case; placebo, 4 cases), respectively. No safety concerns were identified. AE rates ≤1 month after vaccination/birth were similar in the RSVpreF (maternal, 16.1 %; infant, 48.6 %) and placebo (19.8 %; 50.5 %) groups. Preterm birth rates were also similar (RSVpreF, 3.2 %; placebo, 6.0 %). CONCLUSIONS: Safety and efficacy data in Japanese participants were consistent with overall MATISSE results, supporting the efficacy of maternal RSVpreF vaccination against severe MA-RSV-LRTI/MA-RSV-LRTI in infants, with no safety concerns. NCT04424316.

Phase 3 immunogenicity and safety study of a tick-borne encephalitis vaccine in healthy Japanese participants 1 year of age and older.

BACKGROUND: Tick-borne encephalitis (TBE) virus infects the central nervous system and may lead to severe neurological complications or death. This study assessed immunogenicity, safety, and tolerability of TBE vaccine in Japanese participants 1 year of age and older. METHODS: This phase 3, multicenter, single-arm, open-label study was conducted in Japanese adult (≥ 16 years) and pediatric (1-< 16 years) populations. Participants received a single 0.5-mL (adult) or 0.25-mL (pediatric) dose of TBE vaccine at each of 3 visits. The primary endpoint was the proportion of participants who were seropositive (neutralization test [NT] titer ≥ 1:10) 4 weeks after Dose 3. Secondary and exploratory endpoints included NT seropositivity rates 4 weeks after Dose 2, immunoglobulin G (IgG) seropositivity 4 weeks after Doses 2 and 3, NT geometric mean titers (GMTs), IgG geometric mean concentrations (GMCs), and geometric mean fold rises. Primary safety endpoints were frequencies of local reactions, systemic events, adverse events (AEs), and serious AEs. RESULTS: Among 100 adult and 65 pediatric participants, 99.0 % and 100.0 % completed the study, respectively. NT seropositivity was achieved in 98.0 % adult and 100.0 % pediatric participants after Dose 3; seropositivity after Dose 2 was 93.0 % and 92.3 %, respectively. In both age groups, IgG seropositivity was ≥ 90.0 % and ≥ 96.0 % after Doses 2 and 3, respectively; GMTs and GMCs were highest 4 weeks after Dose 3. Reactogenicity events were generally mild to moderate in severity and short-lived. AEs were reported by 15.0 % (adult) and 43.1 % (pediatric) of participants. No life-threatening AEs, AEs leading to discontinuation, immediate AEs, related AEs, or deaths were reported. No serious AEs were considered related to TBE vaccine. CONCLUSIONS: TBE vaccine elicited robust immune responses in Japanese participants 1 year of age and older. The 3-dose regimen was safe and well tolerated, and findings were consistent with the known safety profile of this TBE vaccine. CLINICALTRIALS: gov: NCT04648241.

A phase 3 randomized study to evaluate safety and immunogenicity of 20-valent pneumococcal conjugate vaccine in healthy Japanese infants.

OBJECTIVES: Safety and immunogenicity evaluation of a 4-dose series with 20-valent pneumococcal conjugate vaccine (PCV20). METHODS: This phase 3, double-blind study randomized healthy Japanese infants to receive 4 doses (3 infant doses, 1 toddler dose) of PCV20 by subcutaneous (SC) or intramuscular (IM) injection or 13-valent PCV (PCV13) SC. A primary immunogenicity objective was to demonstrate noninferiority of PCV20 SC to PCV13 SC for percentages of participants meeting predefined serotype-specific immunoglobulin G concentrations 1 month after Dose 3. The 7 additional PCV20 serotypes were compared with the lowest vaccine serotype result in the PCV13 group. Safety and tolerability were assessed as the primary safety objective. RESULTS: Overall, 668 participants were randomized (PCV20 SC, n = 226; PCV13 SC, n = 224; PCV20 IM, n = 218). The primary noninferiority objective for PCV20 SC to PCV13 SC was met for 11/13 matched and 5/7 additional serotypes. Additional data showed PCV20 SC and IM elicited robust functional opsonophagocytic activity and boosting responses to all 20 vaccine serotypes. PCV20 had a similar safety/tolerability profile to PCV13, although local reactions were less frequent with PCV20 IM. CONCLUSIONS: A 4-dose series of PCV20 SC or IM elicited immune responses expected to be protective against all 20 serotypes in Japanese infants. NCT04530838.

A phase 3 randomized trial of the safety and immunogenicity of 20-valent pneumococcal conjugate vaccine in adults ≥ 60 years of age in Japan, South Korea, and Taiwan.

BACKGROUND: Pneumococcal infections are associated with high disease burden in older individuals in Japan, South Korea, and Taiwan. The 20-valent pneumococcal conjugate vaccine (PCV20) was developed to extend protection beyond earlier pneumococcal vaccines. METHODS: This phase 3 randomized, double-blind study investigated the safety and immunogenicity of PCV20 in participants ≥ 60 years of age from Japan, South Korea, and Taiwan. Participants were randomized to receive PCV20 or 13-valent pneumococcal conjugate vaccine (PCV13). One month after vaccination, PCV20 recipients received a saline injection and PCV13 recipients received 23-valent polysaccharide vaccine (PPSV23). Primary immunogenicity objectives were to demonstrate noninferiority of PCV20 to PCV13 (13 matched serotypes) or PPSV23 (7 additional serotypes) for serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) 1 month after vaccination with PCV20, PCV13, or PPSV23. Noninferiority for each serotype was declared if the lower bound of the 2-sided 95% CI for OPA geometric mean ratio (GMR) was > 0.5. Safety endpoints included local reactions, systemic events, adverse events (AEs), and serious AEs. RESULTS: Overall, 1421‬ participants were vaccinated (median age [range]: 65 [60-85] years). PCV20 was noninferior to PCV13 for all 13 matched serotypes and to PPSV23 for 6 of 7 additional serotypes. Although statistical noninferiority was missed for serotype 8 (lower bound of the 2-sided 95% CI for OPA GMR = 0.5, thus not meeting the statistical noninferiority criterion of > 0.5), secondary immunogenicity endpoints for serotype 8 were supportive of a robust immune response. The incidence of AEs and the frequency and severity of local reactions and systemic events were generally similar after PCV20 and PCV13. No safety concerns were identified. CONCLUSION: PCV20 generated robust immune responses to all vaccine serotypes in older adults in Japan, South Korea, and Taiwan. The safety and tolerability profile was similar to PCV13. PCV20 is expected to help protect against all 20 vaccine serotypes. NCT04875533.

A randomized study to evaluate safety and immunogenicity of the BNT162b2 COVID-19 vaccine in healthy Japanese adults.

We report interim safety and immunogenicity findings from an ongoing phase 1/2 study of BNT162b2 in healthy Japanese adults. Participants were randomized 3:1 to receive 2 intramuscular injections of 30 µg BNT162b2 or placebo 21 days apart. Overall, 160 individuals were randomized: 119 received BNT162b2, and 41 received placebo. Participants were stratified by age: 20-64 years (n = 130) and 65-85 years (n = 30). More than 97% of BNT162b2 recipients received 2 doses. Local reactions and systemic events were generally transient and mild to moderate. Severe adverse events were uncommon; there were no serious adverse events. One month after dose 2, SARS-CoV-2 50% serum neutralizing geometric mean titers were 571 and 366, and geometric mean fold rises were 55.8 and 36.6, in the younger and older age groups, respectively. In summary, BNT162b2 has an acceptable safety profile and produces a robust immune response, regardless of age, in Japanese adults. (ClinicalTrials.gov, NCT04588480).

A phase 3, multicenter, single-arm, open-label study to assess the safety, tolerability, and immunogenicity of a single dose of 13-valent pneumococcal conjugate vaccine in Japanese participants aged 6-64 years who are considered to be at increased risk of pneumococcal disease and who are naive to pneumococcal vaccines.

BACKGROUND: This open-label, single-arm, phase 3 study evaluated safety and immunogenicity of the 13-valent pneumococcal conjugate vaccine (PCV13) in pneumococcal vaccine-naive Japanese individuals aged 6-64 years at increased risk of pneumococcal disease (PD). METHODS: Participants received 1 PCV13 dose. Reactogenicity events were recorded for 7 days (individuals aged 6- to 17-year-old) or 14 days (individuals aged 18 to 64 years old) postvaccination. Adverse events (AEs) were collected for 1 month postvaccination. Opsonophagocytic activity (OPA) and anticapsular immunoglobulin G (IgG) geometric mean concentrations (GMCs) were measured for vaccine serotypes before and 1 month postvaccination. Post hoc analyses compared immunogenicity in participants categorized as at-risk (immunocompetent but having chronic medical conditions associated with increased PD risk) or high-risk (immunocompromised due to diseases/conditions and/or medications). RESULTS: 206 participants aged 6- to 17-year-old (n = 53) and 18 to 64 years old (n = 153) completed the study. Reactogenicity events were generally mild to moderate in severity. AEs were reported in 16% (33/206) of participants; 1.0% (2/206) were severe. Six AEs were vaccine-related; most were associated with local reactions. No serious AEs occurred. Circulating antibody levels for all 13 serotypes increased postvaccination. OPA geometric mean fold rises (GMFRs) from prevaccination to 1 month postvaccination were 5.5-61.7; lower limits of the 2-sided, 95% CI were > 1 for all serotypes. IgG GMFRs were consistent with OPA analyses. In post hoc analyses, 55.8% (115/206) and 44.2% (91/206) of participants were categorized as at risk and at high risk of PD, respectively; OPA GMFRs from prevaccination to 1 month postvaccination were 3.9-635.1, with lower limits of the 2-sided 95% CIs > 1 for all 13 serotypes across these risk groups; IgG GMFRs were consistent with OPA analyses. CONCLUSIONS: PCV13 was well tolerated and immunogenic in Japanese individuals aged 6-64 years considered at increased risk of PD. Results were broadly comparable with past PCV13 studies in other Japanese and non-Japanese populations. Registration number: NCT03571607; JapicCTI-184024.

A phase 1 randomized study assessing safety and immunogenicity of two 3-dose regimens of a Clostridium difficile vaccine in healthy older Japanese adults.

BACKGROUND: Clostridium difficile infection (CDI) is a major global cause of nosocomial and community-acquired infections. Despite potentially severe or fatal complications and frequent recurrence, no preventive vaccine is currently available. This randomized, observer-blinded, placebo-controlled phase 1 study in older Japanese adults evaluated safety and immunogenicity of an investigational C difficile vaccine containing a mixture of genetically detoxified and chemically inactivated toxoids, A and B. METHODS: Healthy Japanese adults aged 65 to 85 years were randomized in a 3:3:2 ratio to receive 100 or 200 µg of C difficile vaccine or placebo, respectively, at 0, 1, and 6 months (month regimen) or 1, 8, and 30 days (day regimen). The primary objective was safety evaluation. Vaccine immunogenicity, the secondary objective, was determined by assessing toxin A- and toxin B-specific neutralizing antibody levels in human sera. RESULTS: Local reactions were reported by up to 33.3% of subjects per dose in the month regimen; percentages were generally higher in the 200-µg group. Such reactions were all mild or moderate in severity and generally transient. No adverse events in the month regimen led to subject withdrawal, and no serious adverse events were considered vaccine related. Further enrollment and dosing in the day regimen were discontinued after 3 subjects in the 100-µg group reported severe redness after dose 2. In the month regimen study arm, immune responses as measured by toxin-neutralizing antibody geometric mean concentrations, geometric mean fold rises, and proportions of subjects achieving prespecified fold rises were generally higher in the 200-µg group, peaked at month 7, and remained elevated at month 12. CONCLUSIONS: The C difficile vaccine candidate was safe, well tolerated, and immunogenic when administered to healthy older Japanese adults at 0, 1, and 6 months. Results support continued development of the vaccine for the prevention of CDI. ClinicalTrials.gov identifier: NCT02725437.

Safety, tolerability, and immunogenicity of a novel 4-antigen Staphylococcus aureus vaccine (SA4Ag) in healthy Japanese adults.

A novel Staphylococcus aureus 4-antigen vaccine (SA4Ag) is under development, comprising capsular polysaccharide serotypes 5 and 8 (CP5 and CP8) conjugated to CRM197, recombinant protein clumping factor A (rmClfA), and recombinant manganese transporter protein C (MntC). We evaluated SA4Ag safety, tolerability, and immunogenicity in Japanese adults aged 20 to 64 and 65 to 85 years. A total of 136 healthy Japanese adults (68 per age group) were randomized 1:1 to receive single-dose SA4Ag or placebo intramuscularly (Day 1). Safety assessments included reactogenicity and adverse events. The ability of the vaccine to induce immune responses that are considered functional due to their ability to facilitate the killing of S. aureus or neutralize S. aureus virulence mechanisms was assessed using 5 different antigen-specific assays. SA4Ag was well tolerated in both age groups, with no safety concerns. At Day 29, > 85% of SA4Ag recipients in each age group achieved predefined thresholds for each antigen. Antibody geometric mean-fold rises from baseline to Day 29 in SA4Ag groups were: > 80 and > 30 for CP5 and CP8 (opsonophagocytic activity assay), > 10 for ClfA (fibrinogen-binding inhibition assay), and > 15 and > 7 for ClfA and MntC (competitive Luminex® immunoassay), respectively. Antibody titers decreased through Month 12 but remained well above baseline and placebo levels. SA4Ag had an acceptable safety profile and induced rapid and robust functional immune responses in both age groups. These results support ongoing development of SA4Ag for the prevention of invasive S. aureus disease in elective-surgery patients in Japan, North America, and Europe.

Immunogenicity and Safety of a 13-Valent Pneumococcal Conjugate Vaccine Given With DTaP Vaccine in Healthy Infants in Japan.

BACKGROUND: 13-Valent pneumococcal conjugate vaccine (PCV13) provides broader protection against pneumococcal disease than 7-valent pneumococcal conjugate vaccine (PCV7). This study performed in Japan compared the safety and immunogenicity of PCV13 with PCV7. METHODS: Healthy Japanese infants received PCV13 and diphtheria, tetanus and acellular pertussis vaccine (DTaP), PCV7 and DTaP or DTaP alone subcutaneously as a 3-dose infant series, with a fourth dose at 12 months of age. Antigen-specific immunoglobulin G (IgG) serum concentrations and opsonophagocytic activity and DTaP antibodies were measured 1 month after doses 3 and 4. RESULTS: After 3 and 4 doses, the proportion of subjects in the PCV13 + DTaP group achieving IgG concentrations ≥0.35 µg/mL to the 7 serotypes common to PCV13 and PCV7 was noninferior to that of the PCV7 + DTaP group. IgG geometric mean concentrations (GMCs) in the PCV13 + DTaP group were lower than but noninferior to the PCV7 + DTaP group GMCs. For the 6 additional pneumococcal serotypes, the proportion of PCV13 + DTaP group responders achieving IgG concentrations ≥0.35 µg/mL and IgG GMCs (except serotype 3 after dose 4) was noninferior to the lowest PCV7 + DTaP group pneumococcal response in PCV7 recipients, and responses to the 6 additional antigens were significantly higher. The majority of the subjects achieved prespecified antibody levels to DTaP antigens. GMCs to DTaP antigens were comparable among groups, except filamentous hemagglutinin (numerically higher in the DTaP alone group after dose 4). CONCLUSIONS: PCV13 + DTaP was as immunogenic as PCV7 for the 7 common pneumococcal antigens and elicited significantly higher responses to the 6 additional antigens. DTaP responses were comparable across groups. PCV13 given with DTaP was safe and well tolerated.

Immunogenicity and safety of 13-valent pneumococcal conjugate vaccine when administered to healthy Japanese adults aged ≥50 years. An open-label trial.

This open-label study was designed to assess immunogenicity and safety of 13-valent pneumococcal conjugate vaccine (PCV13) when administered to Japanese adults aged ≥50 years not previously vaccinated with 23-valent pneumococcal polysaccharide vaccine and to compare this Japanese study population with similar study populations in the United States (US; 50-64 years age group) and European Union (EU; ≥65 years age group). Functional antibody immune responses were measured by opsonophagocytic activity assays. Immune responses in both Japanese age groups showed significant pre/postvaccination fold rises for each serotype. In the Japanese 50-64 years age group, immune responses for the majority of serotypes were significantly lower than in the ≥65 years Japanese age group and generally lower than in the 50-64 years age group in the US study. Immune responses in the Japanese ≥65 years age group were significantly higher for the majority of serotypes compared with the ≥65 years age group in the EU study. The safety profiles across age groups and studies were generally similar. In conclusion, PCV13 elicited robust immune responses in the Japanese study population. The unanticipated higher immune responses observed in the older age group in the Japanese study are of interest and of potential benefit given the higher incidence of pneumococcal disease in older adults. PCV13 was well tolerated and safe.

Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in healthy infants in Japan.

BACKGROUND: A 13-valent pneumococcal conjugate vaccine (PCV13) containing 6 additional serotypes not included in the 7-valent PCV has been developed to broaden protection against Streptococcus pneumoniae, which is responsible for over 500,000 deaths annually worldwide in children <5 years of age. This study in Japanese infants evaluated the immunogenicity and safety of PCV13 given subcutaneously, the standard route for infant vaccination in Japan. METHODS: This phase 3, single-arm, open-label study was conducted at 25 sites. Subjects received PCV13 as a 3-dose infant series and a toddler dose. Parents/legal guardians recorded local reactions and systemic events after each vaccination. The proportion of subjects with serotype-specific antipneumococcal polysaccharide immunoglobulin (Ig)G antibody concentrations ≥0.35 µg/mL was calculated before and 1 month after the infant series and toddler dose. RESULTS: A total of 193 subjects enrolled. The proportion of subjects achieving pneumococcal IgG antibody concentrations ≥0.35 µg/mL was ≥97.2% for all 13 pneumococcal serotypes 1 month after the infant series and 98.9-100% after the toddler dose. IgG geometric mean concentrations were 2.57-14.69 µg/mL after the infant series and 2.06-16.33 µg/mL after the toddler dose. IgG geometric mean concentrations increased from pre- to posttoddler dose by ≥2.8-fold, demonstrating a booster effect. Local reactions and fever were generally mild or moderate in severity. CONCLUSIONS: PCV13 was immunogenic for all serotypes and had a favorable safety profile when administered subcutaneously to Japanese infants. PCV13 should offer broader serotype protection than 7-valent PCV in preventing pneumococcal disease in Japanese children.

SKIP modifies gene expression by affecting both transcription and splicing.

SKIP has been described as a transcriptional coregulator as well as a spliceosome component, but the relationship between these functions is not clear. We found that SKIP activated reporter gene expression from the basal promoters of viral origin. SKIP exhibited more prominent effect on the promoters with stronger activities, in an experiment employing a series of reporter constructs carrying different numbers of GC boxes. We also found that SKIP suppressed aberrant splicing at a cryptic splice donor site in the luciferase reporter gene. In addition, SKIP suppressed splicing of an extra intron created by a beta-thalassemia mutation in the human beta-globin gene. In the transfection experiment, an intronless reporter exhibited a higher level of expression, but was less significantly activated by SKIP, than the intron-containing reporter. These results indicate that SKIP affects gene expression by both transcriptional activation and regulation of pre-mRNA splicing.