Safety and Immunogenicity Study of Recombinant Trivalent Rotavirus Subunit Vaccine in Healthy Infants and Toddlers

Study Overview
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Brief Summary
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The purpose of this study is to assess the immunogenicity, safety and immune persistence of recombinant trivalent rotavirus subunit vaccine in healthy infants aged 6-12 weeks and healthy toddlers aged 7-71 months.

Detailed Description
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This clinical trial is aimed to evaluate the immunogenicity, safety and immune persistence of recombinant trivalent rotavirus subunit vaccine in Chinese healthy infants aged 6-12 weeks and healthy toddlers aged 7-71 months.The subjects will be divided into 12 subgroups. Two different immune regimens and two dose levels will be evaluated in each age group. Toddlers aged 7-71 months will receive two intramuscular injections on Day 0 and 28 or three intramuscular injections on Day 0, 28 and 56. Infants aged 6-12 weeks will receive three intramuscular injections on Day 0, 28 and 56 or Day 0, 56 and 112. Two dose (mid dose and high dose) will be included in each age group. To maintain blindness in the trial, in each age group with fixed immune regimen, subjects will be randomized in a 1:1:1 ratio to receive mid dose vaccine, high dose vaccine, or placebo.

Official Title
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A Phase II Randomized, Double-blind, Placebo-controlled Clinical Trial to Evaluate the Safety and Immunogenicity of Recombinant Trivalent Subunit Rotavirus Vaccine in Healthy Infants Aged 6-12 Weeks and Healthy Toddlers Aged 7-71 Months

Conditions
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Rotavirus Infections, Rotavirus Gastroenteritis

Intervention / Treatment
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* Biological: Mid dose Recombinant Trivalent Subunit Rotavirus Vaccine
* Biological: High dose Recombinant Trivalent Subunit Rotavirus Vaccine
* Biological: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Healthy infants aged 6-12 weeks and healthy toddlers aged 7-71 months; Legally acceptable representative (guardian) properly informed about the study and having signed the informed consent form (ICF). Exclusion Criteria: First dose exclusion criteria: Axillary temperature >37.0℃ before vaccination; Recepit of any rotavirus vaccine in the past; History of intussusception or suffering from intussusception or history of any chronic gastrointestinal disease, including congenital malformations of the gastrointestinal tract that are likely to cause intussusception (such as Meckel's diverticulum); Congenital malformations, developmental disorders, genetic defect, severe malnutrition, etc.; Subjects aged 2 years or younger with history of dystocia, suffocation rescue, or nervous system damage; Subjects aged 2 years or younger with history of premature birth (<37 weeks' gestation) or low birth weight (weight at birth of<2500 g); History of convulsions, epilepsy and cerebral palsy, or mental illness and family history; History of severe anaphylactic reaction to vaccination, or allergy to any components of the study vaccine; Acute diseases (such as fever>39.0℃) or acute exacerbation of chronic disease within 3 days before vaccination; Receipt of immune enhancement (including oral or intravenous immunoglobulin, but hepatitis B immunoglobulin is acceptable) or immunosuppressive therapy (continuous oral or intravenous infusion for more than 14 days) within 3 months; Recepit of live attenuated vaccines within 14 days, or other vaccines within 7 days; Congenital or acquired immunodeficiency, HIV infection, lymphoma, leukemia, systemic lupus erythematosus (SLE), juvenile rheumatoid arthritis (JRA), or other autoimmune diseases; History of coagulation abnormalities (such as lack of blood coagulation factors, blood coagulopathy); Primary and secondary impairment of immune function (history of thyroid, pancreas, liver, spleen resection, or treatment due to thyroid disease within the past 12 months); Concurrent participation or plan to participate in another clinical trial throughout the study; According to the judgment of the investigator, the subject has any other factors that are not suitable for participating in the clinical trial. Subsequent vaccination exclusion criteria: Severe allergic reaction after the previous injection of study vaccine; Serious adverse reactions that are causally related to the previous vaccination; After the first vaccination, subjects with newly discovered or newly happened diseases that meet the first dose exclusion criteria will be determined by the investigator whether to continue participating the study; Other reasons for exclusion judged by the investigator.

Ages Eligible for Study
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Minimum Age: 6 Weeks
Maximum Age: 71 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Mid dose in toddlers (7-71 months old, 3 doses)<br>Mid dose recombinant trivalent rotavirus subunit vaccine in toddlers aged 7-71 months on Day 0, 28 and 56, intramuscularly injected. | Biological: Mid dose Recombinant Trivalent Subunit Rotavirus Vaccine<br>* 0.5 mL of vaccine containing a total of 60 µg of protein (20 µg of each P type) adjuvanted with 0.5 mg aluminum hydroxide.<br>|
| Experimental: Mid dose in toddlers (7-71 months old, 2 doses)<br>Mid dose recombinant trivalent rotavirus subunit vaccine in toddlers aged 7-71 months on Day 0 and 28, intramuscularly injected. | Biological: Mid dose Recombinant Trivalent Subunit Rotavirus Vaccine<br>* 0.5 mL of vaccine containing a total of 60 µg of protein (20 µg of each P type) adjuvanted with 0.5 mg aluminum hydroxide.<br>|
| Experimental: High dose in toddlers (7-71 months old, 3 doses)<br>High dose recombinant trivalent rotavirus subunit vaccine in toddlers aged 7-71 months on Day 0, 28 and 56, intramuscularly injected. | Biological: High dose Recombinant Trivalent Subunit Rotavirus Vaccine<br>* 0.5 mL of vaccine containing a total of 90 µg of protein (30 µg of each P type) adjuvanted with 0.5 mg aluminum hydroxide.<br>|
| Experimental: High dose in toddlers (7-71 months old, 2 doses)<br>High dose recombinant trivalent rotavirus subunit vaccine in toddlers aged 7-71 months on Day 0 and 28, intramuscularly injected. | Biological: High dose Recombinant Trivalent Subunit Rotavirus Vaccine<br>* 0.5 mL of vaccine containing a total of 90 µg of protein (30 µg of each P type) adjuvanted with 0.5 mg aluminum hydroxide.<br>|
| Placebo Comparator: Placebo in toddlers (7-71 months old, 3 doses)<br>Placebo in toddlers aged 7-71 months on Day 0, 28 and 56, intramuscularly injected. | Biological: Placebo<br>* 0.5 mL per dose, containing 0.5 mg aluminium hydroxide adjuvant.<br>|
| Placebo Comparator: Placebo in toddlers (7-71 months old, 2 doses)<br>Placebo in toddlers aged 7-71 months on Day 0 and 28, intramuscularly injected. | Biological: Placebo<br>* 0.5 mL per dose, containing 0.5 mg aluminium hydroxide adjuvant.<br>|
| Experimental: Mid dose in infants (6-12 weeks of age, 3 doses at 4-week intervals)<br>Mid dose recombinant trivalent rotavirus subunit vaccine in infants aged 6-12 weeks on Day 0, 28 and 56, intramuscularly injected. | Biological: Mid dose Recombinant Trivalent Subunit Rotavirus Vaccine<br>* 0.5 mL of vaccine containing a total of 60 µg of protein (20 µg of each P type) adjuvanted with 0.5 mg aluminum hydroxide.<br>|
| Experimental: Mid dose in infants (6-12 weeks of age, 3 doses at 8-week intervals)<br>Mid dose recombinant trivalent rotavirus subunit vaccine in infants aged 6-12 weeks on Day 0, 56 and 112, intramuscularly injected. | Biological: Mid dose Recombinant Trivalent Subunit Rotavirus Vaccine<br>* 0.5 mL of vaccine containing a total of 60 µg of protein (20 µg of each P type) adjuvanted with 0.5 mg aluminum hydroxide.<br>|
| Experimental: High dose in infants (6-12 weeks of age, 3 doses at 4-week intervals)<br>High dose recombinant trivalent rotavirus subunit vaccine in infants aged 6-12 weeks on Day 0, 28 and 56, intramuscularly injected. | Biological: High dose Recombinant Trivalent Subunit Rotavirus Vaccine<br>* 0.5 mL of vaccine containing a total of 90 µg of protein (30 µg of each P type) adjuvanted with 0.5 mg aluminum hydroxide.<br>|
| Experimental: High dose in infants (6-12 weeks of age, 3 doses at 8-week intervals)<br>High dose recombinant trivalent rotavirus subunit vaccine in infants aged 6-12 weeks on Day 0, 56 and 112, intramuscularly injected. | Biological: High dose Recombinant Trivalent Subunit Rotavirus Vaccine<br>* 0.5 mL of vaccine containing a total of 90 µg of protein (30 µg of each P type) adjuvanted with 0.5 mg aluminum hydroxide.<br>|
| Placebo Comparator: Placebo in infants (6-12 weeks of age, 3 doses at 4-week intervals)<br>Placebo in infants aged 6-12 weeks on Day 0, 28 and 56, intramuscularly injected. | Biological: Placebo<br>* 0.5 mL per dose, containing 0.5 mg aluminium hydroxide adjuvant.<br>|
| Placebo Comparator: Placebo in infants (6-12 weeks of age, 3 doses at 8-week intervals)<br>Placebo in infants aged 6-12 weeks on Day 0, 56 and 112, intramuscularly injected. | Biological: Placebo<br>* 0.5 mL per dose, containing 0.5 mg aluminium hydroxide adjuvant.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| The incidence of adverse events | Incidence of adverse events within 30 minutes after each dose. The severity of solicited and unsolicited adverse events will be graded from grade 1 to grade 4, other adverse events will be graded from grade 1 to grade 5. | Within 30 minutes after each vaccination | 
| The incidence of adverse events | Incidence of adverse events within 14 days after each dose. The severity of solicited and unsolicited adverse events will be graded from grade 1 to grade 4, other adverse events will be graded from grade 1 to grade 5. | Within 14 days after each vaccination | 
| The incidence of adverse events | Incidence of adverse events Day 15 to 28/30 after each dose. The severity of solicited and unsolicited adverse events will be graded from grade 1 to grade 4, other adverse events will be graded from grade 1 to grade 5. | Day 15 to 28/30 after each vaccination | 
| The incidence of adverse events | Incidence of adverse events within 28/30 days after each dose. The severity of solicited and unsolicited adverse events will be graded from grade 1 to grade 4, other adverse events will be graded from grade 1 to grade 5. | Within 28/30 days after each vaccination | 
| Geometric Mean Titers (GMT) of anti-P[4], anti-P[6], anti-P[8] rotavirus Immunoglobulin A (IgA) | Measured by ELISA at baseline and 30 days after the last vaccination. | Day 30 after the last vaccination | 
| Geometric Mean Titers (GMT) of anti-P[4], anti-P[6], anti-P[8] rotavirus Immunoglobulin G (IgG) | Measured by ELISA at baseline and 30 days after the last vaccination. | Day 30 after the last vaccination | 
| Geometric Mean Titers (GMT) of anti-P[4], anti-P[6], anti-P[8] rotavirus neutralizing antibody | Neutralizing antibodies will be measured by Micro serum neutralization test at baseline and 30 days after the last vaccination. | Day 30 after the last vaccination | 
| Seroconversion rates of anti-P[4], anti-P[6], anti-P[8] rotavirus IgA | Seroconversion is defined as a ≥ 4-fold rise in IgA titer compared with Baseline. | Day 30 after the last vaccination | 
| Seroconversion rates of anti-P[4], anti-P[6], anti-P[8] rotavirus IgG | Seroconversion is defined as a ≥ 4-fold rise in IgG titer compared with Baseline. | Day 30 after the last vaccination | 
| Seroconversion rates of anti-P[4], anti-P[6], anti-P[8] rotavirus neutralizing antibody | Seroconversion is defined as a ≥ 2.7-fold rise in neutralizing antibody titer compared with Baseline. | Day 30 after the last vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of serious adverse events (SAE) | Incidence of serious adverse events throughout the study. | From the first vaccination to 12 months after the last vaccination. | 
| Geometric Mean Titers (GMT) of anti-P[4], anti-P[6], anti-P[8] rotavirus IgA | Measured by ELISA. | Day 90 after the last vaccination | 
| Geometric Mean Titers (GMT) of anti-P[4], anti-P[6], anti-P[8] rotavirus IgA | Measured by ELISA. | Day 180 after the last vaccination | 
| Geometric Mean Titers (GMT) of anti-P[4], anti-P[6], anti-P[8] rotavirus IgA | Measured by ELISA. | Day 360 after the last vaccination | 
| Geometric Mean Titers (GMT) of anti-P[4], anti-P[6], anti-P[8] rotavirus IgG | Measured by ELISA. | Day 90 after the last vaccination | 
| Geometric Mean Titers (GMT) of anti-P[4], anti-P[6], anti-P[8] rotavirus IgG | Measured by ELISA. | Day 180 after the last vaccination | 
| Geometric Mean Titers (GMT) of anti-P[4], anti-P[6], anti-P[8] rotavirus IgG | Measured by ELISA. | Day 360 after the last vaccination | 
| Geometric Mean Titers (GMT) of anti-P[4], anti-P[6], anti-P[8] rotavirus neutralizing antibody | Neutralizing antibodies will be measured by Micro serum neutralization test. | Day 90 after the last vaccination | 
| Geometric Mean Titers (GMT) of anti-P[4], anti-P[6], anti-P[8] rotavirus neutralizing antibody | Neutralizing antibodies will be measured by Micro serum neutralization test. | Day 180 after the last vaccination | 
| Geometric Mean Titers (GMT) of anti-P[4], anti-P[6], anti-P[8] rotavirus neutralizing antibody | Neutralizing antibodies will be measured by Micro serum neutralization test. | Day 360 after the last vaccination | 
| Seroconversion rates of anti-P[4], anti-P[6], anti-P[8] rotavirus IgA | Seroconversion is defined as a ≥ 4-fold rise in IgA titer compared with Baseline. | Day 90 after the last vaccination | 
| Seroconversion rates of anti-P[4], anti-P[6], anti-P[8] rotavirus IgA | Seroconversion is defined as a ≥ 4-fold rise in IgA titer compared with Baseline. | Day 180 after the last vaccination | 
| Seroconversion rates of anti-P[4], anti-P[6], anti-P[8] rotavirus IgA | Seroconversion is defined as a ≥ 4-fold rise in IgA titer compared with Baseline. | Day 360 after the last vaccination | 
| Seroconversion rates of anti-P[4], anti-P[6], anti-P[8] rotavirus IgG | Seroconversion is defined as a ≥ 4-fold rise in IgG titer compared with Baseline. | Day 90 after the last vaccination | 
| Seroconversion rates of anti-P[4], anti-P[6], anti-P[8] rotavirus IgG | Seroconversion is defined as a ≥ 4-fold rise in IgG titer compared with Baseline. | Day 180 after the last vaccination | 
| Seroconversion rates of anti-P[4], anti-P[6], anti-P[8] rotavirus IgG | Seroconversion is defined as a ≥ 4-fold rise in IgG titer compared with Baseline. | Day 360 after the last vaccination | 
| Seroconversion rates of anti-P[4], anti-P[6], anti-P[8] rotavirus neutralizing antibody | Seroconversion is defined as a ≥ 2.7-fold rise in neutralizing antibody titer compared with Baseline. | Day 90 after the last vaccination | 
| Seroconversion rates of anti-P[4], anti-P[6], anti-P[8] rotavirus neutralizing antibody | Seroconversion is defined as a ≥ 2.7-fold rise in neutralizing antibody titer compared with Baseline. | Day 180 after the last vaccination | 
| Seroconversion rates of anti-P[4], anti-P[6], anti-P[8] rotavirus neutralizing antibody | Seroconversion is defined as a ≥ 2.7-fold rise in neutralizing antibody titer compared with Baseline. | Day 360 after the last vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Rotavirus, Gastroenteritis