A Study to Evaluate the Safety and Immunogenicity of GlaxoSmithKline (GSK) Biologicals' Quadrivalent Influenza Candidate Vaccine (GSK2321138A) Manufactured Using a New Process in Adults and Children

Phase 3CompletedNCT02207413

GlaxoSmithKline1,886 enrolled

Overview

The purpose of this trial is to demonstrate the acceptable safety profile and the immunological non-inferiority of the FLU D-QIV vaccine manufactured with this investigational process (FLU D-QIV Investigational Process \[IP\]) compared to FLU D-QIV manufactured with the current licensed process (FLU D-QIV Licensed Process \[LP\]).

This study will enroll 3 age cohorts: Adults: 18-49 years, Children: 3-17 years and 6-35 months of age.

Study Type

INTERVENTIONAL

Allocation

RANDOMIZED

Purpose

PREVENTION

Masking

QUADRUPLE

Enrollment

1,886

Conditions

Influenza

Interventions

Influsplit Tetra™ vaccine produced by investigational process (IP)BIOLOGICAL

Influsplit Tetra™ vaccine using a new manufacturing process administered intramuscularly (IM) in the deltoid region of non-dominant arm (Dose 1) in Adults Group and in non-dominant deltoid or left anterolateral thigh (Dose 1) and dominant deltoid or right anterolateral (Dose 2 - unprimed subjects) in 6-35m and 3-17y Groups.

Influsplit Tetra™ vaccine produced by licensed process (LP)BIOLOGICAL

Influsplit Tetra™ vaccine using a licensed manufacturing process administered IM in the deltoid region of non-dominant arm (Dose 1) in Adults Group and in non-dominant deltoid or left anterolateral thigh (Dose 1) and dominant deltoid or right anterolateral (Dose 2 - unprimed subjects) in 6-35m and 3-17y Groups.

Eligibility

Sex: ALLMin age: 6 MonthsMax age: 49 YearsHealthy volunteers:

Medical Language ↔ Plain English

Inclusion Criteria: Adults 18-49 years cohort: * A male or female between, and including, 18 and 49 years of age at the time of vaccination. * Subjects who the investigator believes that they/their parent(s)/Legally Acceptable Representatives (LAR(s)) can and will comply with the requirements of the protocol. * Written informed consent obtained from the subject/parent(s)/LAR(s) of the subject. * Written informed assent obtained from the subject if/as required by local regulations. * Healthy subjects or those with chronic well-controlled disease as established by medical history and clinical examination before entering into the study. * Female subjects of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current tubal ligation, hysterectomy, ovariectomy. * Female subjects of childbearing potential may be enrolled in the study, if the subject: has practiced adequate contraception for 30 days prior to vaccination, and has a negative pregnancy test on the day of vaccination, and has agreed to continue adequate contraception for 2 months after vaccination. Pediatric cohort: United States: • A male or female subject between, and including, the ages of 3 and 17 years in the United States. Rest of the World: • A male or female subject between, and including, the ages of 6 months to 17 years all countries with the exception of the United States. All participating countries: * Subjects who the investigator believes that they/their parent(s)/Legally Acceptable Representatives (LAR(s)) can and will comply with the requirements of the protocol. * Written informed consent obtained from the subject/parent(s)/LAR(s) of the subject. * Written informed assent obtained from the subject if/as required by local regulations. * Healthy subjects or those with chronic well-controlled disease as established by medical history and clinical examination before entering into the study. * Female subjects of non-childbearing potential may be enrolled in the study. Non-childbearing potential is defined as pre-menarche, current tubal ligation, hysterectomy, ovariectomy. * Female subjects of childbearing potential may be enrolled in the study, if the subject: has practiced adequate contraception for 30 days prior to vaccination, and has a negative pregnancy test on the day of vaccination, and has agreed to continue adequate contraception during the entire treatment period and for 2 months after completion of the vaccination series. Exclusion Criteria: Adults aged 18-49 years cohort: * Child in care. * Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period. * Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical or device). * Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs within 6 months prior to the first vaccine dose. Inhaled and topical steroids are allowed. * Any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination. * Any administration of a long-acting immune-modifying drug within 6 months before study start, or planned administration during the study period. * Administration of an influenza vaccine during the 6 months preceding entry into the study. * Administration of a vaccine not foreseen by the study protocol within 30 days before vaccination or planned administration during the study period. * Administration of immunoglobulins and/or any blood products within the 3 months preceding the first dose of study vaccine or planned administration during the study period. * Any known or suspected allergy to any constituent of influenza vaccines (including egg proteins); a history of anaphylactic-type reaction to consumption of eggs; or a history of severe adverse reaction to a previous influenza vaccine. * Acute or un-controlled, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory tests. * Any history of Guillain-Barré Syndrome. * Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥ 38.0ºC/100.4ºF. * Pregnant or lactating female. * Female planning to become pregnant or planning to discontinue contraceptive precautions. * History of chronic alcohol consumption and/or drug abuse. * Any contra-indication to intramuscular administration of influenza vaccines. * Any other condition which, in the opinion of the investigator, prevents the subject from participating in the study. Pediatric cohort * Child in care. * Use of any investigational or non-registered product (drug or vaccine) other than the study vaccine within 30 days preceding the first dose of study vaccine, or planned use during the study period. * Concurrently participating in another clinical study, at any time during the study period, in which the subject has been or will be exposed to an investigational or a non-investigational product (pharmaceutical or device). * Chronic administration (defined as more than 14 days in total) of immunosuppressants or other immune-modifying drugs within 6 months prior to the first vaccination dose. Inhaled and topical steroids are allowed. * Any confirmed or suspected immunosuppressive or immunodeficient condition based on medical history and physical examination. * Any administration of a long-acting immune-modifying drug within 6 months before study start, or planned administration during the study period. * Administration of an influenza vaccine during the 6 months preceding entry into the study. * Administration of a vaccine not foreseen by the study protocol within 30 days before vaccination or planned administration during the study period. * Administration of immunoglobulins and/or any blood products within the 3 months preceding the first dose of study vaccine or planned administration during the study period. * Any known or suspected allergy to any constituent of influenza vaccines (including egg proteins); a history of anaphylactic-type reaction to consumption of eggs; or a history of severe adverse reaction to a previous influenza vaccine. * Acute or un-controlled, clinically significant pulmonary, cardiovascular, hepatic or renal functional abnormality, as determined by physical examination or laboratory tests. * Any history of Guillain-Barré Syndrome. * Acute disease and/or fever at the time of enrolment. Fever is defined as temperature ≥ 38.0ºC/100.4ºF. * Pregnant or lactating female. * Female planning to become pregnant or planning to discontinue contraceptive precautions. * History of chronic alcohol consumption and/or drug abuse. * Any contra-indication to intramuscular administration of influenza vaccines. * Any other condition which, in the opinion of the investigator, prevents the subject from participating in the study.

Locations (53)

Outcomes

Primary Outcomes

Number of Subjects Aged 18-49 Years Reporting Solicited Local Adverse Events (AEs).

Solicited local symptoms assessed were pain, redness and swelling. Any = occurrence of the specified solicited local symptom regardless of its intensity. Grade 3 pain = significant pain at rest and pain that prevented normal everyday activities. Grade 3 redness and swelling = greater than 100 millimeters (mm) i.e. \>100mm.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Number of Subjects Aged 18-49 Years Reporting Any, Grade 3 and Related Solicited General Symptoms.

Solicited general symptoms assessed were fatigue,gastrointestinal symptoms, headache, Joint Pain, myalgia, shivering and fever. Gastrointestinal symptoms included nausea, vomiting, diarrhoea and/or abdominal pain. Any was defined as any solicited general symptom reported irrespective of intensity and relationship to vaccination. Grade 3 was defined as symptoms that prevented normal activities. Related was defined as symptoms assessed by the investigator to have a causal relationship to vaccination. Any fever was defined as subjects with a documented temperature of greater than or equal to (≥) 38°C/100.4°F by any route and all subjects reporting temperature less than (\< )38°C but with missing values (MC) for at least one day during the solicited period. Grade 3 fever was defined as temperature ≥39.0°C.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Duration of Solicited Local and General AEs in Subjects Aged 18-49 Years.

Duration was defined as number of days with any grade of local and general symptoms.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Number of Subjects Aged 18-49 Years Reporting Solicited Oculorespiratory Syndrome (ORS) Like Symptoms.

Oculorespiratory syndrome (ORS) was defined as the occurrence within 24 hours after vaccination of one or more of the following newly onset symptoms: bilateral red eyes, cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, sore throat, facial swelling. Any was defined as any ORS symptom regardless of intensity grade or relationship to vaccination. Grade 3 ORS was defined as ORS symptoms that prevented normal activities. Related ORS was defined as ORS symptom(s) assessed by the investigator as causally related to the vaccination.

Data from ClinicalTrials.gov

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GSK Investigational Site

Wichita, Kansas, United States

GSK Investigational Site

Rochester, New York, United States

GSK Investigational Site

Warwick, Rhode Island, United States

GSK Investigational Site

Nashville, Tennessee, United States

GSK Investigational Site

Dhaka, Bangladesh

GSK Investigational Site

Brno, Czechia

GSK Investigational Site

Chlumec nad Cidlinou, Czechia

GSK Investigational Site

Děčín, Czechia

GSK Investigational Site

Jindřichův Hradec, Czechia

GSK Investigational Site

Liberec, Czechia

...and 43 more locations

Time frame: During the 3-day (Days 0-2) post-vaccination period

Number of Subjects Aged 18-49 Years Reporting the Occurrence of Medically Attended Events (MAEs).

MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Any was defined as any occurrence of MAE(s). Grade 3 was defined as MAE that prevented normal activities. Related was defined as MAE assessed by the investigator to be causally related to the study vaccination.

Time frame: During the entire study period (approximately 21 days following vaccination)

Number of Subjects Aged 3-17 Years Reporting Solicited Local Adverse Events (AEs).

Solicited local symptoms assessed were pain, redness and swelling. Any = occurrence of the specified solicited local symptom regardless of its intensity. Grade 3 pain = Cried when limb was moved/spontaneously painful. Grade 3 redness and swelling = greater than 50 millimeters (mm) i.e. \>50mm.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Number of Subjects Aged 3-4 Years Reporting Any, Grade 3 and Related Solicited General Symptoms.

Solicited general symptoms assessed were drowsiness, irritability/fussiness, loss of appetite and fever. Any was defined as any solicited general symptom reported irrespective of intensity and relationship to vaccination. Related was defined as symptoms assessed by the investigator to have a causal relationship to vaccination. Grade 3 irritability/fussiness was defined as crying that could not be comforted/prevented normal activity. Grade 3 loss of appetite was defined as not eating at all. Grade 3 drowsiness was defined as drowsiness that prevented normal activity. Any fever was defined as subjects with a documented temperature of greater than or equal to (≥) 38°C/100.4°F by any route and all subjects reporting temperature less than (\< )38°C but with missing values (MC) for at least one day during the solicited period. Grade 3 fever was defined as temperature greater than (\>) 39.0°C.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Number of Subjects Aged 5-17 Years Reporting Any, Grade 3 and Related Solicited General Symptoms.

Solicited general symptoms assessed were fatigue, gastrointestinal symptoms, headache, joint pain, myalgia, shivering and fever (Fever = temperature above 38.0 degrees Celsius (°C)). Gastrointestinal symptoms included nausea, vomiting, diarrhoea and/or abdominal pain. Any = any solicited general symptom reported irrespective of intensity and relationship to vaccination. Related = symptoms considered by the investigator to have a causal relationship to vaccination. Grade 3 symptoms = symptoms that prevented normal activity. Any fever = all subjects with a documented temperature of ≥ 38°C/100.4°F by any route and all subjects reporting temperature \< 38°C but with missing values (MC) for at least one day during the solicited period. Grade 3 fever = temperature above 39.0°C.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Duration of Solicited Local AEs in Subjects Aged 3-17 Years.

Duration was defined as number of days with any grade of local symptoms.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Duration of Solicited General AEs in Subjects Aged 3-4 Years.

Duration was defined as number of days with any grade of general symptoms.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Duration of Solicited General AEs in Subjects Aged 5-17 Years.

Duration was defined as number of days with any grade of general symptoms.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Number of Subjects Aged 3-17 Years Reporting Solicited Oculorespiratory Syndrome (ORS) Like Symptoms.

Oculorespiratory syndrome (ORS) was defined as the occurrence within 24 hours after vaccination of one or more of the following newly onset symptoms: bilateral red eyes, cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, sore throat, facial swelling. Any = occurrence of any ORS symptom regardless of intensity grade or relationship to vaccination. Grade 3 = ORS symptoms that prevented normal activities. Related = ORS symptom assessed by the investigator as causally related to the vaccination.

Time frame: During the 3-day (Days 0-2) post-vaccination period

Number of Subjects Aged 3-17 Years Reporting the Occurrence of All Medically Attended Events (MAEs) .

MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Any was defined as any occurrence of MAE(s). Grade 3 was a MAE that prevented normal activities. Related was defined as a MAE assessed by the investigator to be causally related to the study vaccination.

Time frame: During the entire study period (approximately 28 days (primed subjects) and 56 days (unprimed subjects) following vaccination

Number of Subjects Aged 18-49 Years Reporting Any, Grade 3 and Related Unsolicited Adverse Events (AEs)

An unsolicited AE was defined as an untoward medical occurrence in a patient or clinical investigation subject, temporally associated with use of a medicinal product, whether or not considered related to the medicinal product and reported in addition to those solicited during the clinical study and any solicited symptom with onset outside the specified period of follow-up for solicited symptoms. Any was defined as occurrence of any unsolicited symptom regardless of intensity grade or relation to vaccination.

Time frame: During the 21-day (Days 0-20) follow-up period after vaccination

Number of Subjects Aged 3-17 Years Reporting Any, Grade 3 and Related Unsolicited Adverse Events (AEs).

Time frame: During the 28-day (Days 0-27) follow-up period after vaccination

Number of Subjects Aged 6-35 Months Reporting Fever ≥38ºC Across Doses.

Time frame: During 7 days (Days 0-6) post-vaccination

Number of Subjects Aged 18-49 Years, Reporting Any and Related Serious Adverse Events (SAEs)

A serious adverse event was defined as any untoward medical occurrence that: resulted in death, was life threatening, required hospitalization or prolongation of hospitalization, resulted in disability/incapacity or was a congenital anomaly/birth defect in the offspring of a study subject. Any was defined as occurrence of any symptom regardless of intensity grade or relation to vaccination and related was an event assessed by the investigator as causally related to the study vaccination.

Time frame: During the entire study period (approximately 21 days)

Number of Subjects Aged 3-17 Years, Reporting Any and Related Serious Adverse Events (SAEs)

Time frame: During the entire study period [approximately 28 days (primed subjects) and 56 days (unprimed subjects)]

Humoral Immune Response in Terms of Haemagglutination Inhibition (HI) Antibodies in Subjects Aged 3-17 Years by Calculating Serum Antihaemagglutination (HA) Antibody Titers Against the 4 Vaccine Strains.

HI antibody titres were expressed as geometric mean titers (GMTs) and adjusted GMT ratios. The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), FluA/Texas/50/2012 (H3N2), Flu B/Massachusetts/02/2012 (Yamagata) and Flu B/Brisbane/60/2008 (Victoria).

Time frame: At Day 28 post last vaccination

Humoral Immune Response in Terms of Haemagglutination Inhibition (HI) Antibodies in Subjects Aged 6-35 Months by Calculating Serum Antihaemagglutination (HA) Antibody Titers Against the 4 Vaccine Strains.

Time frame: At Day 28 post last vaccination

Secondary Outcomes

Humoral Immune Response in Terms of Haemagglutination Inhibition (HI) Antibodies in Subjects Aged 18-49 Years by Calculating Serum Anti-haemagglutination (HA) Antibody Titers Against the 4 Vaccine Strains

HI antibody titres were expressed as Geometric mean titers (GMTs). The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Massachusetts/02/2012 (Yamagata) and Flu B/Brisbane/60/2008 (Victoria).

Time frame: At Day 0 and Day 21

Number of Seroconverted Subjects Aged 18-49 Years for Anti- Haemagglutination Inhibition (HI) Antibodies Against Each of the Four Vaccine Influenza Strains.

A seroconverted subject was defined as a vaccinated subject with either a pre-vaccination titer less than (\<) 1:10 and a post-vaccination titer greater than or equal to (≥) 1:40, or a pre-vaccination titer ≥ 1:10 and at least a 4-fold increase in post-vaccination titer. The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Massachusetts/02/2012 (Yamagata) and Flu B/Brisbane/60/2008 (Victoria).

Time frame: At Day 21

Number of Subjects Aged 18-49 Years, Who Were Seroprotected for Haemagglutination Inhibition (HI) Antibodies Against Each of the Four Vaccine Influenza Strains.

A seroprotected subject was defined as a vaccinated subject with a serum HI titer greater than or equal to (≥) 1:40 that usually is accepted as indicating protection in adults. The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Massachusetts/02/2012 (Yamagata) and Flu B/Brisbane/60/2008 (Victoria).

Time frame: At Day 0 and Day 21

Mean Geometric Increase (MGI) for Haemagglutination Inhibition (HI) Antibody Titer Against Each of the Four Vaccine Influenza Strains in Subjects Aged 18-49 Years.

MGI was defined as the fold increase in serum haemagglutination inhibition (HI) GMTs post-vaccination compared to pre-vaccination (Day 0). The vaccine strains assessed were Flu A/Christchurch/16/2010 (H1N1), Flu A/Texas/50/2012 (H3N2), Flu B/Massachusetts/02/2012 (Yamagata) and Flu B/Brisbane/60/2008 (Victoria).

Time frame: At Day 21

Number of Subjects Aged 5-17 Years Reporting Myalgia Across Doses.

Any = occurrence of any myalgia symptom regardless of intensity grade or relationship to vaccination.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Humoral Immune Response in Terms of Haemagglutination Inhibition (HI) Antibodies in Subjects Aged 3-17 Years by Calculating Serum Anti-haemagglutination (HA) Antibody Titers Against the 4 Vaccine Strains

Time frame: At Day 0 and Day 28 post last vaccination

Number of Seroconverted Subjects Aged 3-17 Years for Anti- Haemagglutination Inhibition (HI) Antibodies Against Each of the Four Vaccine Influenza Strains.

Time frame: At Day 28 post last vaccination

Number of Subjects Aged 3-17 Years, Who Were Seroprotected for Haemagglutination Inhibition (HI) Antibodies Against Each of the Four Vaccine Influenza Strains.

Time frame: At Day 0 and Day 28 post last vaccination

Mean Geometric Increase (MGI) for Haemagglutination Inhibition (HI) Antibody Titer Against Each of the Four Vaccine Influenza Strains in Subjects Aged 3-17 Years.

Time frame: At Day 28 post last vaccination

Humoral Immune Response in Terms of Haemagglutination Inhibition (HI) Antibodies in Subjects Aged 6-35 Months by Calculating Serum Anti-haemagglutination (HA) Antibody Titers Against the 4 Vaccine Strains

Time frame: At Day 0 and Day 28 post last vaccination

Number of Seroconverted Subjects Aged 6-35 Months for Anti- Haemagglutination Inhibition (HI) Antibodies Against Each of the Four Vaccine Influenza Strains.

Time frame: At Day 28 post last vaccination

Number of Subjects Aged 6-35 Months, Who Were Seroprotected for Haemagglutination Inhibition (HI) Antibodies Against Each of the Four Vaccine Influenza Strains.

Time frame: At Day 0 and Day 28 post last vaccination

Mean Geometric Increase (MGI) for Haemagglutination Inhibition (HI) Antibody Titer Against Each of the Four Vaccine Influenza Strains in Subjects Aged 6-35 Months.

Time frame: At Day 28 post last vaccination

Number of Subjects Aged 6-35 Months Reporting Fever ≥38ºC After Dose 1 and After Dose 2.

Any fever = all subjects with a documented temperature of ≥ 38°C/100.4°F by any route and all subjects reporting temperature \< 38°C but with missing values (MC) for at least one day during the solicited period. Fever = temperature of ≥ 38°C/100.4°F by any route

Time frame: During 7 days (Days 0-6) post-vaccination

Number of Subjects Aged 6-35 Months Reporting Solicited Local Adverse Events (AEs).

Time frame: During the 7-day (Days 0-6) post-vaccination period

Number of Subjects Aged 6 Months to <5 Years, Reporting Fever ≥38ºC (100.4°F) and >39.0°C (102.2ºF) Across Doses.

Any fever = all subjects with a documented temperature of ≥ 38°C/100.4°F by any route and all subjects reporting temperature \< 38°C but with missing values (MC) for at least one day during the solicited period. Grade 3 fever = temperature above 39.0°C/102.2ºF. Data of 2 independent groups were pooled.

Time frame: During the 2 days (Day 0-Day 1) post-vaccination period

Number of Subjects Aged 6-35 Months Reporting Any, Grade 3 and Related Solicited General Symptoms.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Duration of Solicited Local AEs in Subjects Aged 6-35 Months.

Duration was defined as number of days with any grade of local symptoms.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Duration of Solicited General AEs in Subjects Aged 6-35 Months.

Duration was defined as number of days with any grade of general symptoms.

Time frame: During the 7-day (Days 0-6) post-vaccination period

Number of Subjects Aged 6-35 Months Reporting Solicited Oculorespiratory Syndrome (ORS) Like Symptoms.

Oculorespiratory syndrome (ORS) was defined as the occurrence within 24 hours after vaccination of one or more of the following newly onset symptoms: bilateral red eyes, cough, wheeze, chest tightness, difficulty breathing, difficulty swallowing, hoarseness, sore throat, facial swelling. Any = occurrence of any ORS symptom regardless of intensity grade or relationship to vaccination. Grade 3 = ORS symptoms that prevented normal activities. Related = ORS symptom assessed by the investigator as causally related to the vaccination.

Time frame: During a 3 day (Days 0-2) follow-up period after vaccination

Number of Subjects Aged 6-35 Months Reporting the Occurrence of All Medically Attended Events (MAEs)

MAEs were defined as adverse events with medically-attended visits that were not routine visits for physical examination or vaccination, such as visits for hospitalization, an emergency room visit, or an otherwise unscheduled visit to or from medical personnel (medical doctor) for any reason. Any was defined as any occurrence of MAE(s). Grade 3 was a MAE that prevented normal activities. Related was defined as a MAE assessed by the investigator to be causally related to the study vaccination.

Time frame: During the entire study period (approximately 28 days (primed subjects) and 56 days (unprimed subjects) following vaccination

Number of Subjects Aged 6-35 Months Reporting Any, Grade 3 and Related Unsolicited Adverse Events (AEs).

Time frame: During the 28-day (Days 0-27) follow-up period after vaccination

Number of Subjects Aged 6-35 Months, Reporting Any and Related Serious Adverse Events (SAEs)

Time frame: During the entire study period [approximately 28 days (primed subjects) and 56 days (unprimed subjects)]