Influenza
Conditions
Brief summary
This is a single center, multi-site, double-blind, parallel group, placebo-controlled trial of the clinical efficacy of trivalent Serum Institute of India, Ltd. (SIIL)live-attenuated influenza vaccine (LAIV) vaccine among children aged 24 through 59 months in Bangladesh. Background: 1. Burden: Within Bangladesh, community- based influenza surveillance identified 84.5 cases/1000 children-years among children \<5 years, while 10% of clinical pneumonia cases were influenza positive in this age group. 2. Knowledge gap: There has never been a randomized clinical efficacy trial of the SIIL LAIV vaccine conducted among children in a low-income country. 3. Relevance: Another LAIV vaccine (made by MedImmune) has been shown to have high efficacy against laboratory-confirmed influenza among children. The SIIL LAIV has the potential to be an inexpensive intervention to prevent pediatric influenza disease. Primary Hypothesis: In children aged 24 through 59 months in Bangladesh, LAIV is efficacious in reducing rates of symptomatic, laboratory-confirmed influenza (vaccine-matched strains) among children vaccinated with LAIV as compared to children vaccinated with a placebo through the first influenza season following vaccination. Primary Objective: To determine the efficacy of LAIV in reducing rates of symptomatic, laboratory-confirmed influenza virus infection (vaccine-matched strains) among children receiving LAIV as compared to children receiving a placebo through the first influenza season following vaccination (through December 2013). Methods: A total of 1761 children will be enrolled and randomized in a 2:1 ratio of LAIV to placebo beginning in March 2013. After vaccination, all children will be evaluated for reactions with one home visit four days post vaccination. Subsequently, all children will be monitored weekly for safety outcomes and illness signs at weekly field worker home visits through December 2013. An extended surveillance period was added to this study and, for participants consenting to additional follow-up, surveillance will extend through a second season (through September 2014). Participants with illness signs will be referred to the study clinic for evaluation using standardized diagnostic criteria and treatment by a study physician. Children meeting protocol-defined clinical Specimen Collection Criteria will have a nasopharyngeal wash specimen collected. Clinical specimens will be tested by Real time polymerase chain reaction (rRT-PCR) for evidence of influenza virus infection. Primary Outcome measures/variables: Vaccine efficacy will be assessed against symptomatic, laboratory-confirmed influenza for all circulating virus strains.
Interventions
BIOLOGICALSIIL Live Attenuated Influenza Vaccine
A single dose of SIIL Trivalent LAIV--2012/2013 Northern Hemisphere vaccine containing A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), B/Wisconsin/1/2010
BIOLOGICALPlacebo
A single dose of inactive placebo will be identical to reconstituted SIIL LAIV in ingredients and concentrations except A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), B/Wisconsin/1/2010 will be replaced with egg allantoic fluid.
Sponsors
Johns Hopkins University
International Centre for Diarrhoeal Disease Research, Bangladesh
Centers for Disease Control and Prevention
Bill and Melinda Gates Foundation
PATH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
24 Months to 59 Months
Healthy volunteers
Yes
Inclusion criteria
* Healthy male or female child at least 24 months of age and no older than 59 months of age at the time of study vaccination. * A child whose parent or guardian's primary residence, at the time of study vaccinations, is within the Kamalapur surveillance site catchment area or Matlab service area and who intends to be present in the area for the duration of the trial. * A child whose parent or legal guardian is willing to provide written informed consent prior to the participant's study vaccination.
Exclusion criteria
* Has any serious, active, medical conditions, including: a chronic disease of any body system, chronic infections such as tuberculosis, genetic disorders, such as Down's syndrome or other cytogenetic disorder, known or suspected disease of the immune system. * Is receiving immunosuppressive agents, including systemic corticosteroids, during the month prior to study vaccination. * Has a history of documented hypersensitivity to eggs or other components of the vaccine (including gelatin, sorbitol, lactalbumin and chicken protein), or with life-threatening reactions to previous influenza vaccinations. * Has ever received influenza vaccine (LAIV or inactivated). * History of Guillain-Barre syndrome * Is receiving aspirin therapy or aspirin-containing therapy currently or two weeks before. * Lives in household with somebody currently participating in a respiratory vaccination or antiviral study. * Has current or past participation (within 2 months of trial enrollment visit) in any clinical trial involving a drug or biologic with activity against respiratory disease. * History of a previous severe allergic reaction with generalized urticarial, angioedema, or anaphylaxis. * Has any condition determined by investigator as likely to interfere with evaluation of the vaccine or be a significant potential health risk to the child or make it unlikely that the child would complete the study Temporary Inclusion Contraindications: * Concurrent febrile illness (measured temperature 38 degrees C axillary). * Active wheezing illness
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Percentage of Participants With Symptomatic, Laboratory-confirmed Influenza Virus Infection (Vaccine-matched Strains). | Through 7 to 9 months post-vaccination |
Secondary
| Measure | Time frame |
|---|---|
| Safety Profile of LAIV: Protocol Defined Wheezing Illness | Through 7 to 9 months post-vaccination |
| The Clinical Characteristics of Influenza, Including Influenza Co-infections With Other Bacterial and Viral Respiratory Pathogens | Through 16 to 19 months post-vaccination |
| The Viral Etiologies of Acute Respiratory and Febrile Illness | Through 16 to 19 months post-vaccination |
| Percentage of Participants With Symptomatic, Laboratory-confirmed Influenza Virus Infection (Vaccine-matched Strains). | Through 16 to 19 months post-vaccination |
| Safety Profile of LAIV: Solicited and Unsolicited Local and Systemic Reactions | Through one week post-vaccination |
| Safety Profile of LAIV: Immediate Reactions | 30 minutes post-vaccination |
| Safety Profile of LAIV: Serious Adverse Events | Through 7 to 9 months post-vaccination |
| Percentage of Participants With Symptomatic, Laboratory-confirmed, Influenza Virus Infection (All Strains) | Through 7 to 9 months post-vaccination |
Other
| Measure | Time frame |
|---|---|
| Percentage of Participants With Symptomatic, Laboratory-confirmed Influenza Virus Infection (All Strains) Among Children | From approx. 6 months to approximately 19 months post-vaccination |
| Percentage of Participants With Symptomatic, Laboratory-confirmed Influenza Virus Infection (Vaccine-matched Strains) Among Children | From approx. 6 months to approximately 19 months post-vaccination |
| Percentage of Participants With Moderate to Severe, Laboratory-confirmed Influenza Virus Infection Among Children | Through 7 to 9 months post-vaccination |
Countries
Bangladesh
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Vaccine A single dose of SIIL Trivalent LAIV--2012/2013 WHO Northern Hemisphere vaccine containing A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), B/Wisconsin/1/2010 | 1,174 |
| Placebo Inactive placebo will be identical to reconstituted SIIL LAIV in ingredients and concentrations except A/California/7/2009 (H1N1), A/Victoria/361/2011 (H3N2), B/Wisconsin/1/2010 will be replaced with egg allantoic fluid. | 587 |
| Total | 1,761 |
Baseline characteristics
| Characteristic | Vaccine | Placebo | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 1174 Participants | 587 Participants | 1761 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Bangladesh | 1174 participants | 587 participants | 1761 participants |
| Sex: Female, Male Female | 589 Participants | 306 Participants | 895 Participants |
| Sex: Female, Male Male | 585 Participants | 281 Participants | 866 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 68 / 1,174 | 35 / 587 |
| serious Total, serious adverse events | 42 / 1,174 | 19 / 587 |
Outcome results
Primary
Percentage of Participants With Symptomatic, Laboratory-confirmed Influenza Virus Infection (Vaccine-matched Strains).
Time frame: Through 7 to 9 months post-vaccination
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine | Percentage of Participants With Symptomatic, Laboratory-confirmed Influenza Virus Infection (Vaccine-matched Strains). | 6.7 percentage of participants |
| Placebo | Percentage of Participants With Symptomatic, Laboratory-confirmed Influenza Virus Infection (Vaccine-matched Strains). | 15.8 percentage of participants |
p-value: <0.0001Fisher Exact
Secondary
Percentage of Participants With Symptomatic, Laboratory-confirmed, Influenza Virus Infection (All Strains)
Time frame: Through 7 to 9 months post-vaccination
Secondary
Percentage of Participants With Symptomatic, Laboratory-confirmed, Influenza Virus Infection (All Strains)
Time frame: Through 16 to 19 months post-vaccination
Secondary
Percentage of Participants With Symptomatic, Laboratory-confirmed Influenza Virus Infection (Vaccine-matched Strains).
Time frame: Through 16 to 19 months post-vaccination
Secondary
Safety Profile of LAIV: Immediate Reactions
Time frame: 30 minutes post-vaccination
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Vaccine | Safety Profile of LAIV: Immediate Reactions | 0 participants |
| Placebo | Safety Profile of LAIV: Immediate Reactions | 0 participants |
Secondary
Safety Profile of LAIV: Protocol Defined Wheezing Illness
Time frame: Through 7 to 9 months post-vaccination
Secondary
Safety Profile of LAIV: Protocol Defined Wheezing Illness
Time frame: Through 16 to 19 months post-vaccination
Secondary
Safety Profile of LAIV: Serious Adverse Events
Time frame: Through 16 to 19 months post-vaccination
Secondary
Safety Profile of LAIV: Serious Adverse Events
Time frame: Through 7 to 9 months post-vaccination
Secondary
Safety Profile of LAIV: Solicited and Unsolicited Local and Systemic Reactions
Time frame: Through one week post-vaccination
Secondary
The Clinical Characteristics of Influenza, Including Influenza Co-infections With Other Bacterial and Viral Respiratory Pathogens
Time frame: Through 16 to 19 months post-vaccination
Secondary
The Viral Etiologies of Acute Respiratory and Febrile Illness
Time frame: Through 16 to 19 months post-vaccination
Other Pre-specified
Percentage of Participants With Moderate to Severe, Laboratory-confirmed Influenza Virus Infection Among Children
Time frame: Through 7 to 9 months post-vaccination
Other Pre-specified
Percentage of Participants With Moderate to Severe, Laboratory-confirmed Influenza Virus Infection Among Children
Time frame: Through 16 to 19 months post-vaccination
Other Pre-specified
Percentage of Participants With Symptomatic, Laboratory-confirmed Influenza Virus Infection (All Strains) Among Children
Time frame: From approx. 6 months to approximately 19 months post-vaccination
Other Pre-specified
Percentage of Participants With Symptomatic, Laboratory-confirmed Influenza Virus Infection (Vaccine-matched Strains) Among Children
Time frame: From approx. 6 months to approximately 19 months post-vaccination