Meningococcal Infections, Meningococcal Meningitis
Conditions
Keywords
Central Nervous System Infections, Meningitis, toxoid, Meningococcal vaccine, conjugate vaccines
Brief summary
The purpose of this study is to evaluate the production of antibodies to a new conjugate vaccine, NmVac4-A/C/Y/W-135-DT, as a measure of vaccine effectiveness, compared to the production of antibodies to a similar, licensed meningococcal (Groups A, C, Y, W-135) polysaccharide diphtheria toxoid (DT) conjugate vaccine. The investigators will also evaluate the safety of NmVac4-A/C/Y/W-135-DT™ conjugate vaccine compared to the licensed vaccine. The hypothesis is that the test vaccine is comparable to the licensed active control vaccine.
Detailed description
Meningococcal disease is a potentially life-threatening bacterial infection. The disease most commonly is expressed as either meningococcal meningitis, an inflammation of the membranes surrounding the brain and spinal cord, or meningococcemia, the presence of bacteria in the blood. The most common symptoms include high fever, headache, neck stiffness, confusion, nausea, vomiting, lethargy, and rash. If not treated the disease can progress rapidly and can lead to shock and death, often within hours of the onset of symptoms. The disease is fatal at a rate of 10%. Of patients who recover, 10% have permanent hearing loss or other serious sequelae. Neisseria meningitidis capsular polysaccharides are poor immunogens. However, conjugation of bacterial polysaccharides to immunogenic carrier proteins generally results in conjugates that induce strong anti-polysaccharide T-helper cell dependent immune responses, creating a longer-lasting immune response and thus protection against meningococcal infection. The sponsor's small size Phase 1 clinical trial comprised 60 subjects. Therefore, additional data is needed to confirm the previous data with a statistically powered Phase 2 clinical trial. The present study aims to evaluate subject responses to single doses, administered in adult subjects, to determine further safety and immunogenicity of the vaccine. This study compares safety and antibody production induced by one intramuscular injection of either NmVac4-A/C/Y/W-135-DT or a licensed meningococcal (Groups A, C, Y, W-135) polysaccharide diphtheria toxoid conjugate vaccine. The primary immunogenicity endpoint will be seroresponse, based on antibody titer ≥1:8 for subjects with titer \<1:8 at baseline or a 4-fold rise in antibody levels, 4 weeks after a single injection . The number and proportion of subjects achieving seroresponse will be tabulated by serogroup for each vaccine group. A non-inferiority test will be used to determine if the immune response elicited by NmVac4 A/C/Y/W-135-DT™ is not less than a specified difference in percent seroconversion from the licensed control vaccine. Participants will attend a screening visit up to 6 weeks prior to vaccination (day 0), then will attend study visits for 4 weeks. There will be a study phone call at days 2-3, then a post-study call to subjects to assess safety at 26 weeks.
Interventions
BIOLOGICALTest Vaccine
NmVac4-A/C/Y/W-135-DT™ conjugate is a vaccine in liquid form composed of purified polysaccharides (PS) conjugated to diphtheria toxoid. Single intramuscular 0.5 mL dose contains 4 µg each of Serogroup A, C, W-135, and Y PS conjugated to approximately 26 µg total diphtheria toxoid.
BIOLOGICALUS Licensed Vaccine
Meningococcal (Groups A,C,Y,W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine 0.5 mL dose, intramuscular. Single dose contains 4 µg each Serogroup A, C, W-135 and Y conjugated to approximately 48 µg total diphtheria toxoid.
Sponsors
JN-International Medical Corporation
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
(IC): * Participant is willing and able to give informed consent and comply with all aspects of the evaluation after the nature of the study is explained. * Male or female, aged 18 to 55 years old * In general good health with no significant chronic or acute conditions that would interfere with immune response or expected Adverse Event (AE) evaluation in the opinion of the investigator as determined by Medical history and/or History-directed physical examination * Abstinence or use of effective contraception by the participants or their partners during the trial and continuing for four weeks after vaccination will be required for males or female participants of child bearing potential. * Able (in the opinion of the investigator) to comply with all study requirements.
Exclusion criteria
(EC): * Unwilling or unable to understand study requirements and give written informed consent for the study. * Prisoners. * History of Guillain-Barré syndrome (GBS). * Pregnancy (confirmed by positive pregnancy test) or lactation. * Previous diagnosis of laboratory confirmed meningococcal disease. * Previous meningococcal meningitis vaccination in the last five years * Laboratory abnormalities that are considered Grade 2 or higher (based on AE, ranges as described in the protocol appendix) that in the opinion of the Investigator would raise safety concerns for participation in the study or interfere with evaluation of study objectives, or abnormalities \>2 times the Upper Limit of Normal range (ULN). * Known or suspected autoimmune or connective tissue disorders, including rheumatoid arthritis and congenital or acquired immunodeficiency. Does not include mild to moderate seasonal/perennial allergies treated with over the counter antihistamines. * Use of systemic immunosuppressive drugs or therapy within 6 months prior to study enrollment, not including topical or inhaled steroids/cytotoxic agents. Includes anti-cancer chemotherapy, radiation, and long term systemic corticosteroid therapy. History of anaphylactic shock, severe asthma, urticaria, or other allergic or hypersensitivity reactions following vaccination or known hypersensitivity to any vaccine component. * Received blood, blood products, plasma derivatives or any parenteral immunoglobulin preparation in the past 3 months. * Use of systemic antibiotics within 72 hours prior to study enrollment. * History of cirrhosis or hepatitis. * Known bleeding disorder or condition associated with a prolonged bleeding time. * Positive results of testing for hepatitis B surface antigen (HepBsAg), Hepatitis C or HIV-1 or HIV-2 antibodies. Known or suspected HIV or Hepatitis B or C infection. * Positive results of drug screen that cannot be explained by use of approved prescription medication (amphetamine, tetrahydrocannabinol (THC), cocaine). Current (past 30 days) heavy smokers (greater than or equal 1 pack per day).tetrahydrocannabinol * Received another investigational product within the last 30 days. Investigational product may be a drug, vaccine, medical device or medical procedure. * History of significant head trauma, alcohol or substance abuse or other medical illnesses that could cause a neurological deficit (e.g., cerebro-vascular disease). * Medication or alcohol use that, in the opinion of the Investigator, may influence or bias the clinical outcome of the trial. * History of any serious chronic medical or psychiatric illnesses or condition which, in the opinion of the investigator, might interfere with the evaluation of the study objectives. * History of chronic or severe headaches, myalgia, arthralgia, malaise, fatigue or other systemic disorder commonly observed as AEs for licensed meningococcal vaccines. * Currently experiencing a cold, flu or other acute illness (subject may be deferred until after recovery).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Seroresponse (Percent Seroconversion). | Week 4 after injection | Rise in antibody titers in serum at 4 weeks after vaccination, compared to baseline titer for meningococcal serogroups A, C, Y, and W-135. Serum Bactericidal Assay with human complement: Antibody titer ≥1:8 for subjects with titer \<1:8 at baseline or a 4-fold rise in antibody levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Solicited Adverse Events From Diary Cards | Day 0 to Day 7 after vaccination | Local and systemic rates from Diary Cards filled by the participants. |
| Non Solicited Adverse Events | up to 6 months | Non solicited local and systemic adverse Event (AE) rates throughout the course of the study, based on laboratory test results, vital signs, examination and questioning the subjects. |
Countries
United States
Participant flow
Recruitment details
Participants recruited and were enrolled at three sites in Maryland between October 21, 2013 and May 22, 2014. The sites screened 1086 subjects with 559 screen failures. The majority, 390 subjects (69.8 %), failed due to inclusion or exclusion criteria (IC/EC). The most common failure criterion was Laboratory abnormalities (150 subjects, 26.8 %).
Pre-assignment details
Other common reasons for screen failure were inability to re-schedule within enrollment window after trial start was delayed (101 subjects, 18.1 % of screen failures) and lost to follow up 65 subjects (11.6%). These two reasons account for 166 (29.7%) subjects who met IC/EC, but did not enter the trial.
Participants by arm
| Arm | Count |
|---|---|
| Test Vaccine NmVac4-A/C/Y/W-135-DT™ conjugate vaccine | 266 |
| US Licensed Vaccine Meningococcal (Groups A, C, Y and W-135) Polysaccharide Diphtheria Toxoid Conjugate Vaccine | 261 |
| Total | 527 |
Baseline characteristics
| Characteristic | Test Vaccine | US Licensed Vaccine | Total |
|---|---|---|---|
| Age, Continuous | 37.1 years STANDARD_DEVIATION 11.1 | 36.0 years STANDARD_DEVIATION 10.88 | 36.6 years STANDARD_DEVIATION 11 |
| Race/Ethnicity, Customized American Indian/ Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 1 Participants | 3 Participants | 4 Participants |
| Race/Ethnicity, Customized Black/ African-American | 176 Participants | 160 Participants | 336 Participants |
| Race/Ethnicity, Customized Caucasian | 87 Participants | 89 Participants | 176 Participants |
| Race/Ethnicity, Customized Hispanic or Latino | 2 Participants | 6 Participants | 8 Participants |
| Race/Ethnicity, Customized Native Hawaiian/Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 0 Participants | 1 Participants | 1 Participants |
| Sex: Female, Male Female | 116 Participants | 112 Participants | 228 Participants |
| Sex: Female, Male Male | 150 Participants | 149 Participants | 299 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 173 / 265 | 141 / 260 |
| serious Total, serious adverse events | 0 / 265 | 1 / 260 |
Outcome results
Primary
Seroresponse (Percent Seroconversion).
Rise in antibody titers in serum at 4 weeks after vaccination, compared to baseline titer for meningococcal serogroups A, C, Y, and W-135. Serum Bactericidal Assay with human complement: Antibody titer ≥1:8 for subjects with titer \<1:8 at baseline or a 4-fold rise in antibody levels.
Time frame: Week 4 after injection
Population: Per Protocol Population
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Test Vaccine | Seroresponse (Percent Seroconversion). | Serogroup A | 70.7 percentage of per protocol participants |
| Test Vaccine | Seroresponse (Percent Seroconversion). | Serogroup C | 66.5 percentage of per protocol participants |
| Test Vaccine | Seroresponse (Percent Seroconversion). | Serogroup Y | 63.1 percentage of per protocol participants |
| Test Vaccine | Seroresponse (Percent Seroconversion). | Serogroup W-135 | 66.2 percentage of per protocol participants |
| US Licensed Vaccine | Seroresponse (Percent Seroconversion). | Serogroup W-135 | 65.9 percentage of per protocol participants |
| US Licensed Vaccine | Seroresponse (Percent Seroconversion). | Serogroup A | 70.1 percentage of per protocol participants |
| US Licensed Vaccine | Seroresponse (Percent Seroconversion). | Serogroup Y | 64.1 percentage of per protocol participants |
| US Licensed Vaccine | Seroresponse (Percent Seroconversion). | Serogroup C | 72.5 percentage of per protocol participants |
Comparison: The hypothesis was that the test vaccine is comparable to the licensed active control vaccine. Differences between treatment groups were described using exact two-sided 95% confidence intervals on differences in % seroconversion between the two treatment groups (test vaccine minus reference vaccine) for each serogroup. If the lower bound of the difference is ≥ -15%, then the test vaccine meets the preliminary criterion for non-inferiority.95% CI: [-7.9, 9.1]
Comparison: The hypothesis was that the test vaccine is comparable to the licensed active control vaccine. Differences between treatment groups were described using exact two-sided 95% confidence intervals on differences in % seroconversion between the two treatment groups (test vaccine minus reference vaccine) for each serogroup. If the lower bound of the difference is ≥ -15%, then the test vaccine meets the preliminary criterion for non-inferiority.95% CI: [-14.6, 2.6]
Comparison: The hypothesis was that the test vaccine is comparable to the licensed active control vaccine. Differences between treatment groups were described using exact two-sided 95% confidence intervals on differences in % seroconversion between the two treatment groups (test vaccine minus reference vaccine) for each serogroup. If the lower bound of the difference is ≥ -15%, then the test vaccine meets the preliminary criterion for non-inferiority.95% CI: [-9.9, 7.9]
Comparison: The hypothesis was that the test vaccine is comparable to the licensed active control vaccine. Differences between treatment groups were described using exact two-sided 95% confidence intervals on differences in % seroconversion between the two treatment groups (test vaccine minus reference vaccine) for each serogroup. If the lower bound of the difference is ≥ -15%, then the test vaccine meets the preliminary criterion for non-inferiority.95% CI: [-8.5, 9.1]
Secondary
Non Solicited Adverse Events
Non solicited local and systemic adverse Event (AE) rates throughout the course of the study, based on laboratory test results, vital signs, examination and questioning the subjects.
Time frame: up to 6 months
Population: Safety Population: All vaccinated participants, grouped by actual vaccine received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Test Vaccine | Non Solicited Adverse Events | Subjects with at least 1 AE | 45 participants |
| Test Vaccine | Non Solicited Adverse Events | Subjects with at least 1 treatment related AE | 1 participants |
| US Licensed Vaccine | Non Solicited Adverse Events | Subjects with at least 1 AE | 54 participants |
| US Licensed Vaccine | Non Solicited Adverse Events | Subjects with at least 1 treatment related AE | 5 participants |
Secondary
Solicited Adverse Events From Diary Cards
Local and systemic rates from Diary Cards filled by the participants.
Time frame: Day 0 to Day 7 after vaccination
Population: Safety Population: All vaccinated participants, grouped by actual vaccine received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Test Vaccine | Solicited Adverse Events From Diary Cards | At least 1 local reaction | 53.6 percentage of participants |
| Test Vaccine | Solicited Adverse Events From Diary Cards | At least 1 systemic reaction | 35.1 percentage of participants |
| US Licensed Vaccine | Solicited Adverse Events From Diary Cards | At least 1 systemic reaction | 37.7 percentage of participants |
| US Licensed Vaccine | Solicited Adverse Events From Diary Cards | At least 1 local reaction | 65.8 percentage of participants |
| US Licensed Vaccine - Male | Solicited Adverse Events From Diary Cards | At least 1 local reaction | 40.8 percentage of participants |
| US Licensed Vaccine - Male | Solicited Adverse Events From Diary Cards | At least 1 systemic reaction | 34.7 percentage of participants |
| US Licensed Vaccine - Female | Solicited Adverse Events From Diary Cards | At least 1 local reaction | 46.5 percentage of participants |
| US Licensed Vaccine - Female | Solicited Adverse Events From Diary Cards | At least 1 systemic reaction | 42.5 percentage of participants |