臨床研究等提出・公開システム

A Phase 1, Randomized, Double-blind, Multi-center, Placebo-controlled Trial to Evaluate the Safety and Immunogenicity of the Intramuscular Norovirus GI.1/GII.4 Bivalent VLP Vaccine in Healthy Japanese Infants 5 Months of Age at First Trial Vaccine Administration

A Phase 1, Randomized, Double-blind, Multi-center, Placebo-controlled Trial to Evaluate the Safety and Immunogenicity of the Intramuscular Norovirus GI.1/GII.4 Bivalent VLP Vaccine in Healthy Japanese Infants 5 Months of Age at First Trial Vaccine Administration

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Mean (standard deviation, SD) participant age was 151.6 (7.55) days and consistent between trial arms. Participant sex was well balanced between trial arms. Consistent with the planned trial population, all participants were Asian, and none were Hispanic or Latino. Baseline length, weight, and head circumference were also well balanced between trial arms. Overall mean (SD) length, weight, and head circumference were 64.17 (1.99) cm, 7.29 (0.74) kg, and 41.73 (1.67) cm, respectively.

Participants took part in the trial at 4 investigative sites in Japan from 18 August 2023 to 27 May 2024. Participants were enrolled in 1 of 2 treatment arms and received 2 doses of either HIL-214, a norovirus vaccine comprising 50 micro-g GI.1 virus-like particle (VLP) and 150 micro-g GII.4c VLP, adjuvanted with 500 micro-g of aluminum hydroxide, or placebo. Twenty-one participants were randomized into the placebo (7 participants) or HIL-214 (14 participants) trial arms, and all participants completed both the vaccine regimen and the trial. No participants withdrew from the second vaccine dose or discontinued from the trial.

In healthy Japanese infants 5 months of age at first trial vaccine administration, 2 doses of HIL-214 were generally well tolerated (i.e., there were no SAEs related to trial vaccine or procedures), and no new safety signals were identified during the trial. - There were no deaths, AEs that led to withdrawal of trial vaccine, or AEs that led to withdrawal from the trial. - There were no related AEs. - One participant had 2 SAEs (hematochezia and gastroenteritis norovirus) that resulted in hospitalization. - The SAE of gastroenteritis norovirus was considered not related. - The SAE of hematochezia was considered related to trial vaccine by the investigator; however, the sponsor and data monitoring committee (DMC) considered the SAE of hematochezia to be not related to trial vaccine. The participant fully recovered from the SAE with appropriate supportive care. - Most solicited AEs were mild or moderate and solicited AE onset was generally within 3 to 4 days after vaccine administration. - There were no solicited AEs within 30 minutes of vaccination, no severe solicited local AEs, and 1 participant in the HIL-214 arm had a nonserious severe solicited systemic AE of diarrhea. - There was no increase in solicited AE incidence after the second dose of HIL-214. - All participants in both trial arms had unsolicited AEs within 28 days of vaccine administration, most of which were mild except for 1 participant in the HIL-214 arm that had a nonserious severe AE of diarrhea that remained ongoing after the 7-day solicited AE collection period. - Nearly all participants had medically attended AEs; most could be attributed to infections and infestations, which is consistent with the population age under study.

- Anti-norovirus GI.1 HBGA-blocking and pan-Ig antibody concentrations exhibited an approximate 65-fold and 200-fold increase from baseline, respectively, 28 days after the second vaccine dose. These responses persisted, showing sustained elevations of approximately 78-fold and 85-fold, respectively, at 6 months after the second dose. - Anti-norovirus GII.4c HBGA-blocking and pan-Ig antibody responses exhibited an approximate 26-fold and 9-fold increase from baseline, respectively, 28 days following the second vaccine dose. These responses persisted, showing sustained elevations of approximately 13-fold and 25-fold, respectively, at 6 months after the second dose. - In the HIL-214 arm, the HBGA-blocking seroresponse rate (SRR) to GI.1 was 87.5% (95% CI: 47.3, 99.7) at Visit 2 (28 days after dose 1), 100.0% (95% CI: 73.5, 100.0) at Visit 3 (28 days after dose 2), and 100.0% (95% CI: 73.5, 100.0) at Visit 4 (end of trial, ET). - In the HIL-214 arm, the HBGA-blocking SRR to GII.4c was 23.1% (95% CI: 5.0, 53.8) at Visit 2 (28 days after dose 1), 92.3% (95% CI: 64.0, 99.8) at Visit 3 (28 days after dose 2), and 84.6% (95% CI: 54.6, 98.1) at Visit 4 (ET). - In the HIL-214 arm, the HBGA-blocking SRR to both GI.1 and GII.4c was 37.5% (95% CI: 8.5, 75.5) at Visit 2 (28 days after dose 1), 91.7% (95% CI: 61.5, 99.8) at Visit 3 (28 days after dose 2), and 84.6% (95% CI: 54.6, 98.1) at Visit 4 (ET). - In the placebo arm, there was no anti-norovirus GI.1 HBGA-blocking seroresponse at any visit, and an anti-norovirus GII.4c HBGA-blocking seroresponse was only detectable at Visit 4 (SRR of 28.6%, 95% CI: 3.7, 71.0). - In the HIL-214 arm, the pan-Ig SRR to GI.1 was 100.0% (95% CI: 75.3, 100.0) at Visit 2 (28 days after dose 1), 100.0% (95% CI: 73.5, 100.0) at Visit 3 (28 days after dose 2), and 100.0% (95% CI: 73.5, 100.0) at Visit 4 (ET). - In the HIL-214 arm, the pan-Ig SRR to GII.4c was 69.2% (95% CI: 38.6, 90.9) at Visit 2 (28 days after dose 1), 100.0% (95% CI: 73.5, 100.0) at Visit 3 (28 days after dose 2), and 84.6% (95% CI: 54.6, 98.1) at Visit 4 (ET). - In the HIL-214 arm, the pan-Ig SRR to both GI.1 and GII.4c was 69.2% (95% CI: 38.6, 90.9) at Visit 2 (28 days after dose 1), 100.0% (95% CI: 73.5, 100.0) at Visit 3 (28 days after dose 2), and 84.6% (95% CI: 54.6, 98.1) at Visit 4 (ET). - In the placebo arm, there was no anti-norovirus GI.1 pan-Ig seroresponse at any visit, and an anti norovirus GII.4c pan-Ig seroresponse was only detectable at Visit 4 (SRR of 28.6%, 95% CI: 3.7, 71.0).

The safety profile of HIL-214 remains acceptable, and vaccination with HIL-214 stimulated measurable immune responses to the norovirus GI.1 and GII.4c antigens present in the vaccine. This immune response was maintained for 6 months following the second HIL-214 vaccination.

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https://jrct.mhlw.go.jp/latest-detail/jRCT2051230076

Takahashi Kazuma

PPD-SNBL K.K.

St. Lukes Tower 12F, 8-1, Akashi-cho, Chuo-ku, Tokyo

ppdsnbl-9-nor-109@ppd.com

Takahashi Kazuma

PPD-SNBL K.K.

St. Lukes Tower 12F, 8-1, Akashi-cho, Chuo-ku, Tokyo

+81-80-6844-3947

ppdsnbl-9-nor-109@ppd.com

Complete

Aug. 15, 2023

Interventional

randomized controlled trial

double blind

placebo control

single assignment

prevention purpose

Male or female subject aged 5 months (-14/+14 days).
Infants who are in good health at the time of entry into the trial as determined by medical history, physical examination (including vital signs) and clinical judgment of the investigator.
The subjects legally acceptable representative (LAR) signs and dates a written, informed consent form (ICF) and any required privacy authorization prior to the initiation of any trial procedures, after the nature of the trial has been explained according to local regulatory requirements.
The subjects LAR is willing and able to comply with trial procedures and is available for the duration of follow-up.

Clinically significant abnormality in growth by length/height, weight, or head circumference (according to national guidelines).
Gastrointestinal abnormalities or any chronic gastrointestinal disease, including any uncorrected congenital malformation of the gastrointestinal tract according to medical history and/or physical examination.
Chronic use of oral corticosteroids (equivalent to 20 mg/day prednisolone for >=12 weeks / >=2 mg/kg body weight /day for >=2 weeks) within 60 days prior to Visit 1 (use of inhaled, intranasal, or topical corticosteroids is allowed).
Use of parenteral corticosteroids (equivalent to 20 mg/day prednisolone for >=12 weeks / >=2 mg/kg body weight /day for >=2 weeks. Use of inhaled, intranasal or topical corticosteroid is allowed) within 60 days prior to Visit 1.
Receipt of immunostimulants within 60 days prior to Visit 1.
Receipt of parenteral, epidural or intra-articular immunoglobulin (Ig) preparations, blood products, and/or plasma derivatives within 90 days prior to Visit 1 or planned during the full duration of the trial.
Receipt of immunosuppressive therapy prior to Visit 1.
Known hypersensitivity or allergy to any of the trial vaccine components (including excipients).
Any clinically significant active infection (as assessed by the investigator) or temperature >= 38.0 C (>100.4 F), regardless of method used, within 3 days prior to intended trial vaccine administration.
Gastroenteritis within 7 days before planned dosing (can warrant delay of trial vaccine administration).
History of, e.g., convulsions/febrile convulsions, or any illness, that, in the opinion of the investigator, might interfere with the results of the trial or pose additional risk to the subjects due to participation in the trial.
Abnormalities of splenic or thymic function.
Known or suspected impairment/alteration of immune function.
Known bleeding diathesis, or any condition that may be associated with a prolonged bleeding time.
Receipt or scheduled receipt of any other approved or authorized vaccines within 14 days (for all non-live vaccines or oral live vaccines) or 28 days (for parenteral live vaccines) before or after trial vaccine administration.
Participation in any clinical trial with another investigational product 30 days prior to first trial visit or intention to participate in another clinical trial at any time during the conduct of this trial.
Seropositive for, or in evaluation for, possible human immunodeficiency virus infection.
Hepatitis B or C infection.
Any heritable immunodeficiency or autoimmune disease.
Subjects LAR or subjects first-degree relatives involved in the trial conduct.

Both

Prevention of norovirus-associated acute gastroenteritis.

0.5 mL of HIL-214 or Placebo is injected twice at an interval of 4 to 8 weeks by the intramuscular (IM) route (anterolateral thigh).

Occurrence and intensity of solicited local reactions up to 7 days after each dose of trial vaccine.
Occurrence, intensity, and relationship of solicited systemic AEs up to 7 days after each dose of trial vaccine.
Occurrence, intensity, and relationship of unsolicited AEs up to 28 days after each dose of trial vaccine.
Occurrence, intensity, and relationship of AEs leading to withdrawal of trial vaccine up to 56 days post-dose 1.

Occurrence, intensity, and relationship of AEs leading to withdrawal from the trial, SAEs and MAAEs throughout the entire trial period
At baseline, pre-dose 2, 28-days post-dose 2 and 6-months post-dose 2:
(1) HBGA blocking antibody titers.
(2) Pan-Ig antibody titers.

June. 19, 2023

June. 19, 2023

June. 19, 2023

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