Booster vaccination using bivalent DS-5670a/b is safe and immunogenic against SARS-CoV-2 variants in children aged 5-11 years: a phase 2/3, randomized, active-controlled study.

Background: DS-5670 is a messenger ribonucleic acid (mRNA) vaccine platform targeting the receptor-binding domain (RBD) of the spike protein derived from severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2). Booster vaccination against coronavirus disease 2019 (COVID-19) with monovalent DS-5670a (incorporating mRNA encoding the RBD from the original SARS-CoV-2 strain) or bivalent DS-5670a/b (original and omicron BA.4-5 RBD antigens) is effective and safe in adults. Data from a phase 2/3 active-controlled, non-inferiority, pediatric study evaluating a third booster dose of DS-5670a/b are reported here. Methods: Children aged 5-11 years who had completed the two-dose primary vaccination series with monovalent BNT162b2 (original strain) at least 3 months prior to enrolment were randomly assigned to receive DS-5670a/b (20 µg of mRNA) or bivalent BNT1 62b2 (original/omicron BA.4-5; 10 µg of mRNA) on Day 1. The primary efficacy endpoint was blood neutralization geometric mean titer (GMT) against SARS-CoV-2 (omicron variant BA.5.2.1) and immune response rate (≥ 4-fold increase in post-vaccination circulating anti-SARS-CoV-2 neutralizing activity) on Day 29. Results: Among evaluable participants (DS-5670a/b, n = 74; bivalent BNT162b2, n = 75), the adjusted GMT ratio of DS-5670a/b to bivalent BNT162b2 on Day 29 was 1.636 (95% CI, 1.221, 2.190). Immune response rates were ≥ 89% with both study vaccines; adjusted difference 2.6% (95% CI, -7.8, 13.8). The prespecified non-inferiority margins were exceeded, and the study met the primary endpoint. DS-5670a/b also demonstrated broad neutralization activity across recent omicron sublineages and no cases of COVID-19 between Days 8-29 post-administration were reported. There were no novel safety concerns in the pediatric population at data cut-off. Conclusions: Bivalent DS-5670a/b was non-inferior to bivalent BNT162b2 in terms of immunogenicity, and had a manageable safety profile, when administered as a heterologous booster in children aged 5-11 years. Clinical trial registration: https://jrct.niph.go.jp/, identifier jRCT2031220665.

Age-Specific Profiles of Antibody Responses against Respiratory Syncytial Virus Infection.

Respiratory syncytial virus (RSV) is one of the most prevalent causative agents of lower respiratory tract infections worldwide, especially in infants around 3 to 4months old. Infants at such a young age have maternally-transferred passive antibodies against RSV but do not have active immune systems efficient enough for the control of RSV infection. In order to elucidate age-specific profiles of immune responses against RSV protection, antibody responses were examined by using blood samples in both acute and convalescent phases obtained from child patients and adult patients. In addition to the serum neutralization activity, antibody responses to the RSV fusion protein (F protein) were dissected by analyzing levels of total IgG, IgG subclasses, the binding stability, and the levels of antibody for the neutralization epitopes. It was suggested that children's antibody responses against RSV are matured over months and years in at least 5 stages based on 1) levels of the neutralization titer and IgG3 for F protein in the convalescent phase, 2) geometric mean ratios of the neutralization titers and levels of IgG1 and IgG2 for F protein in the convalescent phase compared to those levels in the acute phase, 3) the affinity maturation of IgG for F protein and the cross reactivity of IgG for RSV glycoproteins of groups A and B, 4) levels of neutralization epitope-specific IgG, and 5) augmentation of overall antibody responses due to repetitive RSV infection.

Superior immunogenicity profile of the new intradermal influenza vaccine compared to the standard subcutaneous vaccine in subjects 65 years and older: A randomized controlled phase III study.

BACKGROUND: Although the elderly are at high risk for influenza, the immunogenicity in the elderly is lower than that in younger adults. We developed the new type of seasonal influenza vaccine with the novel intradermal (ID) injection system. In the previous exploratory phase I/II study of the ID vaccine with a dose of 15 µg HA per strain showed the superior immunogenicity profile to that of the standard subcutaneous (SC) injection vaccine in subjects aged 20 years and older. METHODS: In this multicenter, randomized, double-blind, active controlled study, 900 adults aged 65 years and older were randomized at an equal ratio to either the ID vaccine group or the licensed standard SC vaccine group. Immunogenicity was assessed using serum hemagglutination inhibition (HAI) titers. The co-primary endpoints were the geometrical mean titers (GMT) and the seroconversion rates (SCR) of HAI titers against 3 vaccine strains on Day 21 (21 days after vaccination). To evaluate the early phase immunogenicity, the GMTs and SCRs on Day 7 were also assessed in the same way as the secondary endpoints. RESULTS: The superiority of the ID vaccine in the GMTs and SCRs were demonstrated in all 3 vaccine strains both on Day 7 and Day 21. The frequency of any injection-site reactions was higher in the ID vaccine group, while the severity of injection-site reactions and the frequency of systemic AEs were comparable between the ID and the SC vaccine groups. CONCLUSIONS: A single-dose of the influenza vaccine with the novel ID injection system and a dose of 15 µg HA was suggested as an appropriate regimen for clinical use in influenza prevention and associated disease burden reduction. It was also suggested that the new ID vaccine has the potential to replace the standard influenza vaccine from the view point of immunogenicity and safety. TRIAL REGISTRATION: JAPIC Clinical Trials Information (JapicCTI-142493).

Immunogenicity and safety of the new intradermal influenza vaccine in adults and elderly: A randomized phase 1/2 clinical trial.

BACKGROUND: Recent clinical evidence indicates that an intradermal (ID) delivery of vaccines confers superior immunogenicity as compared to a standard intramuscular or subcutaneous (SC) delivery. METHODS: In this exploratory study, 600 healthy adults were randomized to 6 study groups with subgroups of young adults (20-64 years old) and older adults (65 years and older). The subjects were either injected by a novel ID injection system with a single dose of 6, 9, or 15 µg HA or two doses (21 days apart) of 15 µg HA per strain or injected by an SC injection method with a single or two doses (21 days apart) of 15 µg HA per strain. Immunogenicity was assessed using hemagglutination inhibition (HAI) titer and microneutralization titer on Days 0, 10, 21, and 42. Solicited and unsolicited adverse events were recorded for 7 and 21 days post-vaccination, respectively. RESULTS: In both young adults and older adults groups, the geometric titer (GMT) ratios of HAI in the ID 15 µg HA group were higher than those in the SC 15 µg HA group on both Day 10 and Day 21, while those in the ID 6 and ID 9 µg HA groups were comparable with those in the SC 15 µg HA group. The kinetics of GMTs of HAI suggested that the ID vaccine has the potential to induce the prompt immune response, which is rather hampered in older adults as seen in the SC vaccine groups. The injection-site AEs were generally mild and transient, and did not occur in a dose or dosage-dependent manner. CONCLUSIONS: The results of this study clearly suggest that the immunologic profile of the ID vaccine is better than that of the SC vaccine, while the safety profile of the ID vaccine is similar to that of the SC vaccine. In this exploratory study with almost 100 subjects per each group, single or two-dose administration of the ID vaccine containing 15 µg HA was suggested to be an appropriate regimen in order to prevent influenza and to reduce the associated disease burden. TRIAL REGISTRATION: JAPIC Clinical Trials Information (JapicCTI-132096).

Laninamivir octanoate for post-exposure prophylaxis of influenza in household contacts: a randomized double blind placebo controlled trial.

Laninamivir octanoate, a long-acting neuraminidase inhibitor, is an effective treatment for influenza. However, its effectiveness for the prevention of influenza has not yet been demonstrated. We conducted a double-blind, multicenter, randomized, placebo-controlled trial to determine whether laninamivir octanoate was superior to a placebo for post-exposure prophylaxis of influenza in household contacts. Eligible participants, who were household members who did not have influenza and were in contact with an influenza-infected index patient, were randomly assigned (1:1:1) to one of three groups: 20 mg of laninamivir octanoate once daily for 2 days (LO-2), 20 mg of laninamivir octanoate once daily for 3 days (LO-3), or a placebo. The primary endpoint was the proportion of participants who developed clinical influenza during a 10-day period. A total of 1711 participants were enrolled, and 1451 participants were included in the primary analysis. The proportion of participants with clinical influenza was 3.9 % (19/487) in the LO-2 group, 3.7 % (18/486) in the LO-3 group, and 16.9 % (81/478) in the placebo group (P < 0.001 for each of the laninamivir octanoate group). The relative risk reductions, compared with the placebo group, were 77.0 % [95 % confidence interval (CI) 62.7-85.8] and 78.1 % (95 % CI 64.1-86.7 %) for the LO-2 and LO-3 groups, respectively. The incidences of adverse events in the laninamivir octanoate groups were similar to that in the placebo group. The inhalation of 20 mg of laninamivir octanoate once daily for 2 or 3 days was well tolerated and effectively prevented the development of influenza in household contacts.