Chikungunya
Conditions
Brief summary
This was a prospective, randomized, double-blinded, multicenter, pivotal study evaluating the full dose of VLA1553 (1 x10E4 TCID50 per dose) in comparison to a placebo control. The dose of VLA1553 or control was administered as single vaccination on Day 1. Overall, approximately 750 male and female participants aged 12 years to \<18 years were enrolled into the study. After completion of the trial, a Post Trial Access program was performed to offer the VLA1553 vaccine to all placebo recipients.
Detailed description
This was a prospective, double-blinded, multicenter, randomized, pivotal Phase 3 study comprising 754 participants aged 12 years to \<18 years randomized in a 2:1 ratio to the live-attenuated CHIKV vaccine candidate (VLA1553) or placebo. The dose of lyophilized VLA1553 or placebo was administered as a single intramuscular vaccination. Subjects in this study were stratified by baseline serostatus. The primary objective of the study was to evaluate the immunogenicity and safety of the full dose of VLA1553 28 days following the single vaccination. Immunogenicity evaluations in the immunogenicity subset included the proportion of subjects with neutralizing CHIKV antibody titers above the seroresponse threshold. The surrogate of protection reasonably likely to predict clinical benefit has been established in non-human primate passive transfer studies using human sera from the Phase 1 study. Safety data collection and immunogenicity were assessed until Month 12.
Interventions
BIOLOGICALActive
Single intramuscular vaccination on Day 1 with VLA1553, a lyophilized live-attenuated Chikungunya vaccine candidate 1x10E4 TCID50 per dose (0.5 mL)
BIOLOGICALPlacebo
Single intramuscular vaccination on Day 1 with Phosphate-Buffered Saline (PBS) as placebo (0.5 mL)
Sponsors
Butantan Institute
Valneva Austria GmbH
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Years to 17 Years
Healthy volunteers
Yes
Inclusion criteria
1. male or female adolescents from the 12th birthday to the last day before the 18th birthday at the time of vaccination; 2. written informed consent by the subject's legal representative(s), and written informed assent of the subject; 3. generally healthy as determined by the Investigator's clinical judgement based on medical history, physical examination and screening laboratory tests; 4. seropositive for previous CHIKV exposure (i.e. IgM+/IgG+ or IgM-/IgG+) or seronegative (i.e. IgM-/IgG-) as screened by CHIKV-specific ELISA. 5. for women of childbearing potential: 1. negative serum or urine pregnancy test at screening and on Day 1. 2. practiced an adequate method of contraception during 30 days before screening 3. agreed to employ adequate birth control measures for the first three months post-vaccination (i.e. until Day 85).
Exclusion criteria
1. Was taking medication or other treatment for unresolved symptoms attributed to a previous CHIKV infection; or had participated in a clinical study involving an investigational CHIKV vaccine; 2. acute or recent infection; 3. tested positive for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg) or hepatitis C virus (HCV); 4. live virus vaccine within 28 days or inactivated vaccine within 14 days prior to vaccination in this study or planned to receive a vaccine within 28 days or 14 days after vaccination, respectively; 5. abnormal findings in any required study investigations (including medical history, physical examination, and clinical laboratory) considered clinically relevant by the Investigator which pose a risk for participation in the study; 6. medical history of or currently had acute or progressive, unstable or uncontrolled clinical conditions that posed a risk for participation in the study; 7. history of immune-mediated or clinically relevant arthritis / arthralgia; 8. history of malignancy in the past 5 years other than squamous cell or basal cell skin cancer. If there had been surgical excision or treatment more than 5 years ago which was considered to have achieved a cure, the subject could be enrolled; 9. known or suspected defect of the immune system, such as subjects with congenital or acquired immunodeficiency, including infection with HIV, status post organ transplantation or immuno-suppressive therapy within 4 weeks prior to vaccination; 10. history of any vaccine related contraindicating event (e.g., anaphylaxis, allergy to components of the candidate vaccine, other known contraindications); 11. with clinical conditions representing a contraindication to intramuscular vaccination and blood draws; 12. pregnant or lactating at the time of enrollment; 13. received blood-derived products (e.g. plasma) within 90 days prior to vaccination in this study or planned to use blood products until Day 180 of the study; 14. rash, dermatological condition or tattoos that would, in the opinion of the Investigator, interfere with injection site reaction rating; 15. known or suspected problem with alcohol or drug abuse as determined by the Investigator; 16. any condition that, in the opinion of the Investigator, may compromise the subjects well-being, might interfere with evaluation of study endpoints, or would limit the subject's ability to complete the study; 17. committed to an institution (by virtue of an order issued either by the judicial or the administrative authorities); 18. participation in another clinical study involving an investigational medicinal product (IMP) or device within 30 days prior to study enrollment or was scheduled to participate in another clinical study involving an IMP, or device during the course of this trial; 19. member of the team conducting the trial or in a dependent relationship with one of the study team members. Dependent relationships include close relatives (i.e., children, partner/spouse, siblings, parents) as well as employees of the Investigator or site personnel conducting the trial.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Seroprotection | On study Day 29,which is 28 days after single vaccination | Percentage of subjects with a seroprotective CHIKV antibody level determined as µPRNT50\>= 150 (Micro Plaque Reduction Neutralization Test 50%) for baseline negative subjects 28 days post-vaccination. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| CHIKV-specific Antibody Titers as GMTs up to 1 Year | On study Day 1, Day 8, Day 29, Day 85, Day 180 (Month 6) and Day 365 (Month 12) post vaccination | Immune response as measured by CHIKV-specific neutralizing antibody titers on Day 1, Day 8, Day 29, Day 85, Day 180 (Month 6) and Day 365 (Month 12) post vaccination as determined by μPRNT |
| Seroprotection up to 1 Year | On the study Day 8, Day 85, Day 180, and Day 365 (Month 12) after vaccination | Percentage of subjects with seroprotective levels defined as μPRNT50 ≥ 150 for μPRNT baseline negative subjects on Day 8, Day 85, Day 180 and Month 12 post-vaccination as determined by μPRNT. |
| Seroconversion up to 1 Year Defined as > 4-fold Increase of μPRNT50 Compared to Baseline | On study Day 29, Day 180 and Month 12 after vaccination | Percentage of subjects with seroconversion defined as \> 4-fold increase of μPRNT50 compared to baseline at Day 29, Month 6 and Month 12 as determined by μPRNT assay |
| Fold Change in Neutralizing Antibodies Compared to Baseline | On study Day 8, 29, 85, 180 and Month 12 after vaccination | Fold change of CHIKV-specific neutralizing antibody titers determined by μPRNT assay at Days 8, 29, 85, 180 and at Month 12 post-vaccination as compared to baseline |
| X-fold Change in Neutralizing Antibody Titers at Month 12 Compared to Baseline | 365 days (12 months) after vaccination | Percentage of subjects reaching an at least 4-fold, 8-fold, 16-fold or 64-fold change in CHIKV-specific neutralizing antibody titer compared to baseline as measured by μPRNT assay |
| Immunogenicity (GMT) Per Baseline Serostatus | On study Day 1, 8, 29, 85, 180 and Month 12 after vaccination | CHIKV-specific neutralizing antibodies, determined by μPRNT assay at Days 1, 8, 29, 85, 180, and Month 12 post-vaccination stratified by μPRNT baseline serostatus. |
| Number of Participants With Unsolicited Adverse Events | On study Day 29 and Day 180 after vaccination | Frequency of unsolicited AEs at Day 29 and Day 180 (6 months) post-vaccination |
| Number of Participants With Solicited Adverse Events | up to 10 days after vaccination | Frequency of solicited injection site and systemic adverse events within ten days post-vaccination |
| Number of Participants With Adverse Event of Special Interest | until 365 days (12 months) after vaccination | Frequency of any Adverse Event of Special Interest: The following cluster of symptoms with or without remissions or exacerbations received particular consideration and were defined as early onset AESI: 1. Fever (≥37.8°C measured axillary); and 2. Acute (poly)arthralgia/arthritis, myalgia, neurological symptoms (e.g., meningoencephalitis, acute encephalitis, headache, seizures), retinitis/uveitis; or one or more of the following signs and symptoms: macular to maculopapular rash (sometimes with cutaneous pruritus (foot plant)), pigmentary changes, bullous rash/skin blistering, purpura and ecchymosis; and 3. Onset of symptoms 2 to 21 days after vaccination (i.e., Day 3 to Day 22); and 4. Duration of event ≥3 days, Onset of symptoms 22 days post vaccination or later (Day 23 - study end) was defined as late onset AESI. |
| Number of Participants With Serious Adverse Events | until 365 days (12 months) after vaccination | Frequency and relatedness of any Serious Adverse Event (SAE) during the entire study period |
Countries
Brazil
Contacts
STUDY_CHAIRFernanda C Boulos, MD, MSc
Butantan Institute
STUDY_DIRECTORValneva Austria GmbH
Valneva Austria GmbH
Participant flow
Pre-assignment details
33 participants excluded from the Protocol population due to major protocol deviations.
Baseline characteristics
| Characteristic | — |
|---|---|
| Age, Customized 12-<15 years | 129 Participants |
| Age, Customized 15 - <18 years | 381 Participants |
| BMI | 21.63 Kg/square Meter STANDARD_DEVIATION 4.81 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 358 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 219 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 31 Participants |
| Race (NIH/OMB) More than one race | 72 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 69 Participants |
| Race (NIH/OMB) White | 167 Participants |
| Region of Enrollment Brazil | 754 Participants |
| Serostatus (PRNT) Seronegative μPRNT50<=40 | 614 Participants |
| Serostatus (PRNT) Seropositive μPRNT50>40 | 94 Participants |
| Sex: Female, Male Female | 269 Participants |
| Sex: Female, Male Male | 233 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 502 | 0 / 252 |
| other Total, other adverse events | 396 / 502 | 171 / 252 |
| serious Total, serious adverse events | 11 / 502 | 5 / 252 |
Outcome results
None listed