Meningococcal Serogroup ACYWX Conjugate Vaccine in Comparison With MenACWY-TT Conjugate Vaccine

Study Overview
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Brief Summary
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Infants aged 9 months will be randomized to receive a meningococcal vaccine at 9 months or 15 months. Infants randomized to the 9-month age group will be further randomized in a 2:1 ratio to receive a single dose of the experimental meningococcal vaccine (NmCV-5) or a single dose of the comparator meningococcal vaccine (MenACWY-TT). Prospectively identified and consented infants randomized to the 15-month age group will return when aged 15 months and will be randomized in a 2:1 ratio to receive a single dose of NmCV-5 or a single dose of MenACWY-TT.

Detailed Description
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Meningococcal meningitis, caused by invasive strains of Neisseria meningitidis, is a major public health concern because of its considerable morbidity and mortality in sub-Saharan Africa. Case fatality during meningococcal meningitis epidemics can surpass 15%, and rates of permanent sequelae among meningitis survivors in Africa are twice as high as they are in high income countries. Because of the fulminant clinical course of invasive bacterial meningitis and difficulties in access to care in the African meningitis belt, prevention by vaccination is the optimal way to reduce meningococcal meningitis morbidity and mortality. Before 2010, serogroup A meningococcal strains were routinely responsible for the majority (70-96%) of invasive meningococcal disease in sub-Saharan Africa. And annual epidemic could be associated with an incidence of meningococcal disease which could range between 100-1000 cases per 100,000 persons in any given year. Progressive introduction of MenAfriVac since 2010 has resulted in a substantial reduction in cases of serogroup A meningococcal disease. However, regular large-scale epidemics due to serogroups C, W and X remain common in the African meningitis belt. An affordable and scalable pentavalent meningococcal conjugate vaccine (NmCV-5) has been developed by Serum Institute of India Pvt. Ltd. (SIIPL), the manufacturer of MenAfriVac. NmCV-5 is designed to protect against serogroups A, C, W, Y and X. The immediate goal for the clinical development of NmCV-5 is for WHO Pre-Qualification (WHO-PQ), to enable the vaccine to be used in the Meningitis Belt of sub-Saharan Africa. This trial will evaluate a single dose of NmCV-5 administered at either 9 months or 15 months of age, time points in the Expanded Program on Immunization (EPI) schedule when meningococcal vaccine is most likely to be administered. Infants aged 9 months will be randomized to receive a meningococcal vaccine at 9 months or 15 months. Infants aged 9 months (eligibility 9-11 months) and randomized to the 9-month age group will be randomized in a 2:1 ratio to receive a single dose of NmCV-5 or a single dose of MenACWY-TT. Prospectively identified and consented infants randomized to the 15-month age group will return when aged 15 months (eligibility 15-17 months) and will be randomized in a 2:1 ratio to receive a single dose of NmCV-5 or a single dose of MenACWY-TT. Enhanced EPI vaccines will be co-administered and will consist of 2-doses of a measles-containing vaccine administered at 9 months and 15 months and a single dose of yellow fever vaccine administered at 9 months. This study protocol is designed to provide evidence that concomitant vaccination with NmCV-5 will not significantly affect the immune responses of infants to their normally scheduled EPI vaccines. This study has been specifically designed to provide information at two distinct timepoints, 9 months and 15 months. The current Mali EPI schedule consists of a measles only vaccine, yellow fever vaccine, and MenA vaccine at 9 months of age; there is no 15 months of age EPI vaccine visit and typically only a single dose of a measles-containing vaccine is administered. However, to satisfy the conditions for WHO-PQ, study participants will receive two doses of a measles-containing vaccine, at 9-months and 15-months. Furthermore, the noninferiority evaluation must include an assessment of the rubella vaccine responses. These modifications to the standard Malian EPI schedule provide a level-of-care that is higher than the current standard-of-care for the general population. Within the context of this study, the researchers will refer to this as an enhanced EPI schedule.

Official Title
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A Phase 3 Trial to Evaluate the Safety, Immunogenicity, and Non-Interference With Concomitant Routine Vaccines, of a Meningococcal Serogroup ACYWX Conjugate Vaccine (NmCV-5) in Comparison With MenACWY-TT Conjugate Vaccine in Healthy Malian Infants

Conditions
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Meningitis

Intervention / Treatment
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* Biological: NmCV-5
* Biological: MenACWY-TT


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Male and female children between 9 months and 11 months old inclusive. Parent(s)/legal guardian(s) have provided written informed consent, after the nature of the study has been explained according to local regulatory requirements. The investigator believes that their parent(s)/guardian(s) will be available for all the subjects visits and will comply with the requirements of the protocol (e.g., timely reporting of adverse events). Individual is in good health as determined by medical history, physical examination, and clinical judgement of the investigator. Individual has completed their local infant EPI vaccines, not including 9-month EPI vaccines (at the 9-month visit) or 15- month EPI vaccines (at the 15-month visit). A birth dose of oral polio vaccine is not required. Exclusion Criteria: History of receipt of any meningococcal vaccine. Has received a measles-containing vaccine. Current or previous, confirm or suspected disease caused by N. meningitidis. Household contact with and/or intimate exposure to an individual with any laboratory confirmed N. meningitidis infection within 60 days of enrolment or study vaccination (for the 15-month age group). History of severe allergic reactions after previous vaccinations or hypersensitivity to any study vaccine component including tetanus, diphtheria and mutant diphtheria toxoid (CRM197). Acute or chronic, clinically significant pulmonary, cardiovascular, metabolic, neurological, hepatic, or renal functional abnormality, as determined by medical history or physical examination. Any confirmed or suspected condition with impaired or altered function of the immune system (e.g., immunodeficiency, autoimmune conditions, malnutrition). Have any bleeding disorder which is considered a contraindication to intramuscular injection or blood draw. Severe acute malnutrition. Note: a weight-for-length Z-score of less than -3 satisfies this exclusion criteria. History of either hepatitis B or hepatitis C virus infection, human immunodeficiency virus infection, or hereditary immunodeficiency. Presence of major and clinically significant congenital defects. Chronic administration (defined as more than 14 days) of immunosuppressants or other immune-modifying drugs within three months prior to the study vaccination or planned use throughout the study period (for corticosteroids, this means prednisone, or equivalent, ≥ 0.5 mg/kg per day. Inhaled, intranasal, and topical steroids are allowed). Administration of blood, blood products and/or plasma derivatives or any parenteral immunoglobulin preparation in the past 3 months or planned use throughout the study period. Administration of any vaccine within 14 days prior to enrolment in the study or planned administration of any vaccine within 14 days before or after study vaccination. Use of any investigational or non-registered drug or vaccine within 28 days prior to the administration of study vaccine or planned during the study. Malaria infection as confirmed by a Rapid Diagnostic Test. Note: subjects positive at screening may be treated for malaria as per national guidelines outside of the study, and if the subject remains eligible, vaccinated no earlier than 5 days after completing treatment. Individuals who are close family member* of individuals conducting this study. *defined as a child with direct genetic relationship to a member of the study team. Have experienced a moderate or severe acute infection and/or fever (defined as temperature ≥ 37.5°C) within 3 days prior to enrolment or study vaccination. Have received systemic antibiotic treatment within 3 days prior to enrolment or study vaccination. Non-residence in the study area or intent to move out within six months. Any condition which, in the opinion of the investigator, might post additional risk to the subject due to participation in the study.

Ages Eligible for Study
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Minimum Age: 9 Months
Maximum Age: 11 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: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Vaccination at 9 months of age with NmCV-5<br>Infant participants randomized to receive the NmCV-5 meningococcal vaccination at 9 months of age, while receiving the current Mali EPI schedule of vaccines. | Biological: NmCV-5<br>* NmCV-5 is a pentavalent meningococcal (A, C, Y, W, X) polysaccharideconjugate vaccine composed of capsularpolysaccharides (PS) from Neisseria meningitidis serogroups A, C, Y, W, and X individually conjugated to a protein carrier, either mutant diphtheria toxoid (CRM197) or tetanus toxoid (TT).<br>|
| Active Comparator: Vaccination at 9 months of age with MenACWY-TT<br>Infant participants randomized to receive the MenACWY-TT meningococcal vaccination at 9 months of age, while receiving the current Mali EPI schedule of vaccines. | Biological: MenACWY-TT<br>* MenACWY-TT (the comparator meningococcal vaccine) is a WHO-PQ quadrivalent meningococcal (A, C, Y, W) polysaccharide-conjugate vaccine manufactured by Pfizer.<br>* Other names: Nimenrix;|
| Experimental: Vaccination at 15 months of age with NmCV-5<br>Infant participants randomized to receive the NmCV-5 meningococcal vaccination at 15 months of age, while receiving the current Mali EPI schedule of vaccines. | Biological: NmCV-5<br>* NmCV-5 is a pentavalent meningococcal (A, C, Y, W, X) polysaccharideconjugate vaccine composed of capsularpolysaccharides (PS) from Neisseria meningitidis serogroups A, C, Y, W, and X individually conjugated to a protein carrier, either mutant diphtheria toxoid (CRM197) or tetanus toxoid (TT).<br>|
| Active Comparator: Vaccination at 15 months of age with MenACWY-TT<br>Infant participants randomized to receive the MenACWY-TT meningococcal vaccination at 15 months of age, while receiving the current Mali EPI schedule of vaccines. | Biological: MenACWY-TT<br>* MenACWY-TT (the comparator meningococcal vaccine) is a WHO-PQ quadrivalent meningococcal (A, C, Y, W) polysaccharide-conjugate vaccine manufactured by Pfizer.<br>* Other names: Nimenrix;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Seroprotective Response | The percentage of participants with seroprotective response (defined as rabbit serum bactericidal antibody (rSBA) titers ≥ 8) against each meningococcal serogroup A, C, W, X and Y, 28 days after a single dose of meningococcal vaccine, will be compared between study arms, among participants vaccinated at either 9 months or 15 months of age. | 28 days after meningococcal vaccination | 
| Percentage of Participants with Seroprotective Response to Serogroup X after NmCV-5 | The percentage of participants with seroprotective response to serogroup X in the NmCV-5 arm, to be compared to the percentage of participants with the lowest seroprotective response among serogroups A, C, W and Y in the MenACWY-TT arm. | 28 days after meningococcal vaccination | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants with Seroprotective Response to Serogroup X | The percentage of participants with seroprotective response (rSBA antibody titers ≥ 8) to serogroup X in the NmCV-5 arm compared to the percentage of participants with seroprotective response to serogroup X MenACWY-TT arm, 28 days after a single dose of meningococcal vaccine. | 28 days after meningococcal vaccination | 
| rSBA Titers | Level of rSBA titers (evaluated as geometric mean titers (GMTs)) against meningococcal serogroups A, C, W, X and Y, 28 days after meningococcal vaccine at either 9-11 or 15-17 months of age. | 28 days after meningococcal vaccination | 
| Percentage of Participants with Seroresponse in rSBA Titers | For a subset of participants, the percentage of participants with seroresponse in rSBA titers to meningococcal serogroups A, C, W, X and Y at 28 days after a single dose of meningococcal vaccine at either 9 months or 15 months of age will be examined. Seroresponse is defined as a post-immunization rSBA titer of 32 or greater if the participant's preimmunization (Baseline) rSBA titer was < 8; or a ≥ four-fold increase over baseline at Day 29 post-immunization if the participant's pre-immunization rSBA titer was ≥ 8. | 28 days after meningococcal vaccination | 
| Proportion of Participants with rSBA titers ≥ 128 | The proportion of participants with rSBA titers ≥ 128 at 28 days after a single dose of meningococcal vaccine will be examined. | 28 days after meningococcal vaccination | 
| Number of Serious Adverse Events | The number of serious adverse events reported after meningococcal vaccination will be compared between study arms. | 6 months after meningococcal vaccination | 
| Number of Solicited Adverse Events | The number of solicited adverse events reported after meningococcal vaccination will be compared between study arms. Solicited adverse events following meningococcal vaccination include injection site tenderness, swelling/induration, erythema, irritability, drowsiness, anorexia, and fever. | 7 days after meningococcal vaccination | 
| Number of Unsolicited Adverse Events | The number of unsolicited adverse events following meningococcal vaccination will be compared between study arms. | 28 days after meningococcal vaccination | 
| Proportion of Participants with Seropositive Response for Measles | Proportion of participants with seropositive response for measles vaccine will be compared between study arms. The seropositive response to measles vaccine is defined as achieving anti-measles immunoglobulin G (IgG) concentration ≥ 150 milli-international units per milliliter (mIU/mL). | 28 days after meningococcal vaccination | 
| Proportion of Participants with Seropositive Response for Rubella | Proportion of participants with seropositive response for rubella vaccine will be compared between study arms. The seropositive response to rubella vaccine is defined as achieving anti-rubella IgG concentration ≥ 4 IU/mL. | 28 days after meningococcal vaccination | 
| Proportion of Participants with Seroprotective Titers for Yellow Fever Vaccine | Proportion of participants with seroprotective titers for yellow fever vaccine will be compared between study arms. The seroprotective response to yellow fever vaccine is defined as yellow fever neutralizing antibody titers ≥ 1:8. | 28 days after meningococcal vaccination | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vaccine, meningococcal, Neisseria meningitidis, conjugate meningococcal vaccine, meningococcal serogroup X