B Cell Response to a Primary and a Booster Course of the Novartis Meningococcal ACWY Conjugate Vaccine in Healthy Infants

Study Overview
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Brief Summary
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This study is aimed to assess whether the frequency of meningococcal serogroup A, C, W-135 and Y specific memory B Cells, measured 1 month after a primary vaccination series of Novartis MenACWY vaccine, predicts the specific serum bactericidal activity using human complement (hSBA) of (respectively) serogroup A, C, W-135 and Y at 12 months of age

Official Title
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A Phase II, Single Center, Open-label, Randomized Study to Investigate Meningococcal Serogroup A, C, W-135 and Y Saccharide Specific B Cell Response to a Primary and a Booster Course of the Novartis Meningococcal ACWY Conjugate Vaccine in Healthy Infants

Conditions
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Meningococcal Disease

Intervention / Treatment
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* Biological: MenACWY-CRM
* Biological: DTaP-Hib-IPV
* Biological: PCV
* Biological: MMR
* Biological: Hib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who were eligible to be enrolled in the study: healthy infants aged 2 months (56 - 83 days old, inclusive); available for the visits scheduled in the study; mother available for blood draw at Visit 1; good health as determined by the clinical judgement of the investigator; whose parents gave written informed consent for the infant to be enrolled in the study. The infant's parents must have been willing for the infant to receive the full primary immunization course. Exclusion Criteria: Subjects who were not eligible for the study were those: whose parents had not given or were unwilling or unable to give written informed consent to their child's participation in the study with known hypersensitivity to any vaccines contained within the routine immunization schedule with unacceptable concurrent illnesses or conditions - e.g.: a severe acute or chronic illness; with any present or suspected serious disease such as metabolic, cardiac or autoimmune disease or insulin dependent diabetes or with any other serious disease (e.g., with signs of cardiac or renal failure or severe malnutrition), including progressive neurological disease; a genetic anomaly, e.g. Down's syndrome; any immunodeficiency, including use of systemic corticosteroids; born at less than 36 weeks gestation; weighing less than 2.5 kg at birth; previous clinical or bacteriological diagnosis of meningitis, or with a history of household contact or intimate exposure to an individual with culture proven Neisseria meningitidis disease; known bleeding diathesis, or any condition associated with a prolonged bleeding time; who have received any prohibited prior or concomitant medications - e.g.: any immunizations within the 30 days prior to enrollment, with the exception of BCG or hepatitis B; immunoglobulin; any blood products; participating in any other clinical trial either currently or in the previous month; unable to adhere to the protocol, including plans to move from the area; Other: Had any condition which, in the opinion of the investigator, might interfere with the evaluation of the study objectives.

Ages Eligible for Study
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Minimum Age: 56 Days
Maximum Age: 83 Days

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: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MenACWY-CRM and Routine Vaccines (Group 1)<br>Infants received 2 doses of MenACWY-CRM (at 2 and 4 months) as a primary course of vaccination and third dose (at 12 months) as a booster. Infants also received routine vaccines - 3 doses of DTaP-Hib-IPV (at 2, 3, and 4 months), 3 doses of PCV (at 2, 4, and 13 months), and 1 dose each of MMR and Hib (booster) at 13 months. | Biological: MenACWY-CRM<br>* One dose (0.5 mL) of MenACWY conjugate vaccine supplied as an extemporaneous mixing just before injection of the lyophilized component (MenA) reconstituted with the liquid component (MenCWY) was administered at 2-, 4-, and 12-months as IM injections in the anterolateral area of the right thigh.<br>Biological: DTaP-Hib-IPV<br>* IM injections of 3 doses of 0.5 mL each of DTaP-Hib-IPV supplied in prefilled vial were administered at 2-, 3-, and 4-months in the anterolateral area of the left thigh.<br>* Other names: Combined diphtheria, tetanus toxoid, acellular pertussis, Haemophilus influenzae type B and inactivated polio vaccine; Pediacel;Biological: PCV<br>* IM injections of 3 doses of 0.5 mL each of PCV supplied in pre-filled syringe were administered at 2-, 4-, and 12-months (Groups 2 and 3) or 13-months (Group 1) in the anterolateral area of the left thigh.<br>* Other names: Heptavalent Streptoccus pneumonia; Prevnar;Biological: MMR<br>* IM injection of one dose of 0.5 mL of MMR obtained by extemporaneous mixing just before injection of powder and the solvent for solution was administered at 13 months in the anterolateral area of the left thigh.<br>* Other names: Measles, mumps, and rubella vaccine; Priorix;Biological: Hib<br>* IM injection of one dose 0.5 mL of Hib supplied in pre-filled syringe was administered at 13 months in the anterolateral area of the right thigh.<br>* Other names: Vaxem Hib;|
| Experimental: MenACWY-CRM and Routine Vaccines (Group 2)<br>Infants received 2 doses of MenACWY-CRM (at 2 and 4 months) as a primary course of vaccination and third dose (at 12 months) as a booster. Infants also received routine vaccines - 3 doses of DTaP-Hib-IPV (at 2, 3, and 4 months), 3 doses of PCV (at 2, 4, and 12 months), and 1 dose each of MMR and Hib (booster) at 13 months. This group had an additional blood draw at the time of enrollment. | Biological: MenACWY-CRM<br>* One dose (0.5 mL) of MenACWY conjugate vaccine supplied as an extemporaneous mixing just before injection of the lyophilized component (MenA) reconstituted with the liquid component (MenCWY) was administered at 2-, 4-, and 12-months as IM injections in the anterolateral area of the right thigh.<br>Biological: DTaP-Hib-IPV<br>* IM injections of 3 doses of 0.5 mL each of DTaP-Hib-IPV supplied in prefilled vial were administered at 2-, 3-, and 4-months in the anterolateral area of the left thigh.<br>* Other names: Combined diphtheria, tetanus toxoid, acellular pertussis, Haemophilus influenzae type B and inactivated polio vaccine; Pediacel;Biological: PCV<br>* IM injections of 3 doses of 0.5 mL each of PCV supplied in pre-filled syringe were administered at 2-, 4-, and 12-months (Groups 2 and 3) or 13-months (Group 1) in the anterolateral area of the left thigh.<br>* Other names: Heptavalent Streptoccus pneumonia; Prevnar;Biological: MMR<br>* IM injection of one dose of 0.5 mL of MMR obtained by extemporaneous mixing just before injection of powder and the solvent for solution was administered at 13 months in the anterolateral area of the left thigh.<br>* Other names: Measles, mumps, and rubella vaccine; Priorix;Biological: Hib<br>* IM injection of one dose 0.5 mL of Hib supplied in pre-filled syringe was administered at 13 months in the anterolateral area of the right thigh.<br>* Other names: Vaxem Hib;|
| Experimental: MenACWY-CRM and Routine Vaccines (Group 3)<br>Infants received 2 doses of MenACWY-CRM (at 2 and 4 months) as a primary course of vaccination and third dose (at 12 months) as a booster. Infants also received routine vaccines - 3 doses of DTaP-Hib-IPV (at 2, 3, and 4 months), 3 doses of PCV (at 2, 4, and 12 months), and 1 dose each of MMR and Hib (booster) at 13 months of age. This group had an additional blood draw at 6-7 days after third dose of MenACWY-CRM. | Biological: MenACWY-CRM<br>* One dose (0.5 mL) of MenACWY conjugate vaccine supplied as an extemporaneous mixing just before injection of the lyophilized component (MenA) reconstituted with the liquid component (MenCWY) was administered at 2-, 4-, and 12-months as IM injections in the anterolateral area of the right thigh.<br>Biological: DTaP-Hib-IPV<br>* IM injections of 3 doses of 0.5 mL each of DTaP-Hib-IPV supplied in prefilled vial were administered at 2-, 3-, and 4-months in the anterolateral area of the left thigh.<br>* Other names: Combined diphtheria, tetanus toxoid, acellular pertussis, Haemophilus influenzae type B and inactivated polio vaccine; Pediacel;Biological: PCV<br>* IM injections of 3 doses of 0.5 mL each of PCV supplied in pre-filled syringe were administered at 2-, 4-, and 12-months (Groups 2 and 3) or 13-months (Group 1) in the anterolateral area of the left thigh.<br>* Other names: Heptavalent Streptoccus pneumonia; Prevnar;Biological: MMR<br>* IM injection of one dose of 0.5 mL of MMR obtained by extemporaneous mixing just before injection of powder and the solvent for solution was administered at 13 months in the anterolateral area of the left thigh.<br>* Other names: Measles, mumps, and rubella vaccine; Priorix;Biological: Hib<br>* IM injection of one dose 0.5 mL of Hib supplied in pre-filled syringe was administered at 13 months in the anterolateral area of the right thigh.<br>* Other names: Vaxem Hib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Summary of Memory B Cells Per 2 x 105 LOC by Serogroup A, C, W-135 and Y | The memory B cell response at one month after primary vaccinations (5 months of age) was defined as the mean number of meningococcal serogroup A, C, W-135 and Y specific memory B cells, measured in vitro by ELISpot assay per 2x100000 lymphocytes obtained from culture (LOC) of peripheral blood mononuclear cells (PBMC) circulating in blood incubated for 5.5 days in the presence of polyclonal B cell activators. Serogroup A, C, W-135 and Y geometric mean titers (GMTs) were measured by serum bactericidal assay using human complement (hSBA) at 12 months of age (before third dose). Correlation and linear regression coefficients were determined between memory B cells at 1 month after primary vaccinations with MenACWY-CRM (5 months of age) and hSBA titers at 12 months of age (before third dose) for the serogroups A, C, W-135 and Y. | 1 month after primary vaccination and immediately before third dose at 12 months of age | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Memory B Cells by Serogroup A, C, W-135 and Y | Memory B cell response at 1 month after primary vaccination and immediately before third dose at 12 months of age was measured as mean number of meningococcal serogroup specific memory B cells by ELISpot assay per 2x100000 LOC. The meningococcal serogroup A, C, W-135 and Y specific IgG concentrations immediately before third dose at 12 months of age were measured by ELISA. | 1 month after primary vaccination and immediately before third dose | 
| Memory B Cells Per 2x100000 by Serogroup A,C, W-135 and Y at One Month After Primary MenACWY-CRM Vaccination and Third MenACWY-CRM Vaccination | Memory B cell response at 1 month after MenACWY-CRM primary and booster vaccinations was measured as mean number of meningococcal serogroup specific memory B cells by ELISpot assay per 2x100000 LOC. hSBA GMTs for the serogroup A, C, W-135 and Y were measured one month after the third MenACWY-CRM vaccination. The meningococcal serogroup A, C, W-135 and Y specific IgG concentrations one month after third MenACWY-CRM vaccination were measured by ELISA. | 1 month after primary vaccination and 1 month after third vaccination | 
| Memory B Cells 1 Month After Primary Vaccination and Rise From Pre-third Dose to 1 Month After Third Dose of MenACWY-CRM Vaccination | Memory B cell response at 1 month after MenACWY-CRM primary and third (booster) vaccination was measured as mean number of meningococcal serogroup specific memory B cells by ELISpot assay per 2x100000 LOC. The serogroup A, C, W-135 and Y specific IgG concentrations at 1 month after MenACWY-CRM booster were measured by ELISA. hSBA GMTs were measured by hSBA assay one month after MenACWY-CRM booster vaccination. The rise in serogroup specific IgG, memory B cells and hSBA was calculated by pre/post third dose geometric mean ratios, calculated by the difference in the log10 of the concentrations/titers measured at 13 months to the log10 of the concentrations at 12 months: i.e. rise = log10(x) at 13 months minus log10(x)at 12 months where x is the serogroup specific IgG or memory B cell concentrations or SBA titers. | 1 month after primary and pre-third and 1 month after third vaccination | 
| Memory B Cells 1 Month After Primary Vaccination and 1 Week After Third Vaccination by Serogroup A, C, W-135 and Y | Memory B cell response at 1 month after primary vaccination and at 1 week after third vaccination was measured as mean number of meningococcal serogroup specific memory B cells by ELISpot assay per 2x100000 LOC. Plasma B cell response at 1 week after vaccination was measured as the mean number of cells secreting antibodies specific for meningococcal serogroup A, C, W-135 and Y, measured by ELISpot assay, per 2x100000 PBMC. Serogroup A, C, W-135 and Y specific IgG were measured by ELISA and hSBA GMTs were measured at 1 week after third vaccination. | One month after primary vaccination and 1 week after third vaccination | 
| CRM197 Specific Memory B Cells 1 Month After Primary Vaccination and at 12 Months of Age and One Month After MenACWY-CRM Third Vaccination | CRM197 specific memory B cell response at each time point was measured as mean number of CRM197 specific memory B cells by ELISpot assay per 2x100000 LOC. CRM197 specific IgG concentration was measured by ELISA at 12 months of age and one month after MenACWY-CRM booster vaccination. | 5 months (B cells), 12 months and 13 months (B cells and IgG) of age | 
| Increase in Serogroup A, C, W-135 and Y Specific Memory B Cells Before and 1 Month After MenACWY-CRM Booster Vaccination at 12 Months of Age Administered Concomitantly With Pneumococcal Conjugate Vaccine or Alone | Memory B cell response before and one month after MenACWY-CRM booster vaccination at 12 months of age was measured as mean number of meningococcal serogroup A, C, W-135 and Y specific memory B cells by ELISpot assay per 2x100000 LOC. | Before and one month after booster vaccination | 
| Increase in Serogroup A, C, W-135 and Y Specific hSBA Titers Before and 1 Month After MenACWY-CRM Booster Vaccination at 12 Months of Age Administered Concomitantly With Pneumococcal Conjugate Vaccine or Alone | hSBA GMTs were measured before and one month after MenACWY-CRM booster vaccination at 12 months of age. | Before and one month after booster vaccination | 
| Serogroups A, C, W-135 and Y Specific Memory B Cell Response in Children Lacking a hSBA Titer of ≥1:8 One Month After MenACWY-CRM Primary Vaccination | The memory B cell response in children lacking a hSBA titer ≥1:8 one month after MenACWY-CRM primary vaccination was calculated as the mean number of meningococcal serogroup specific memory B cells, measured by ELISpot assay per 2x100000 LOC. | One month after primary vaccination | 
| Serogroup A, C, W-135 and Y Specific Memory B Cells and Plasma B Cells After MenACWY-CRM Primary Vaccination | To assess the kinetics of serogroup A, C, W-135 and Y specific memory B cells, plasma B cells and IgG concentrations were measured on days 0, 7, 14, 49, 90, and 120 following vaccination with MenACWY-CRM vaccination at month 4 of the study. The memory B cell response at different timepoint was defined as the mean number of meningococcal serogroup A, C, W-135 and Y specific memory B cells, measured in vitro by ELISpot assay per 2x100000 lymphocytes obtained from culture (LOC) of peripheral blood mononuclear cells (PBMC) circulating in blood incubated for 5.5 days in the presence of polyclonal B cell activators in vitro. The B plasma cell response at each time point was defined as the mean number of cells secreting antibodies specific for meningococcal serogroup A, C, W-135 and Y, measured by ELISpot assay, per 2x100000 PBMC. | Day 0, 7, 14, 49, 90, and 120 after MenACWY-CRM vaccination at month 4 | 
| Serogroup A, C, W-135 and Y Specific hSBA Titers After MenACWY-CRM Primary Vaccination | To assess the kinetics of serogroup A, C, W-135 and Y specific hSBA titers, the geometric mean titer was measured on day 0, 7, 14, 30, 49, 90, and 120 following vaccination with MenACWY-CRM vaccination at month 4 of the study. | Day 0, 7, 14, 30, 49, 90,120 after MenACWY-CRM vaccination at month 4 | 
| Correlation and Linear Regression Coefficients Between Serogroup A, C, W-135 and Y Specific Memory B Cells 1 Month After MenACWY-CRM Primary Vaccination and IgG Concentration at Day 1 in the Serum of Mothers of Infants | The serogroup A, C, W-135 and Y specific IgG concentrations were measured in the serum of mothers at the time of their enrollment into the study (Day 1) by ELISA. | Day 1 (IgG) and one month after primary vaccination (B cells) | 
| Linear Regression Coefficients (1) Between Serogroup A, C, W-135 and Y Memory B at 5 Months and hSBA Titers at 12 Months, (2) Between Serogroup A, C, W-135 and Y Memory B at 5 Months and IgG at 12 Months, After a 2-Dose Primary Course of MenACWY-CRM | Linear regression analysis between memory B cells at 5 months of age and hSBA titers and IgG at 12 months of age was performed with and without inclusion of demographic factors (subject's household smoking status, number of older children living in subject's household, attendance at daycare and total duration of breast feeding) in the model. | 1 month post primary vaccination (B cells) and 12 months (hSBA titers and IgG) | 
| Linear Regression Coefficients (1) Between Serogroup A, C, W-135 and Y Memory B Cells at 5 Months and Rise in hSBA Titers, (2) Between Serogroup A, C, W-135 and Y Memory B Cells at 5 Months and Rise in IgG, After Third Dose of MenACWY-CRM at 12 Months | The rise in serogroup-specific hSBA and IgG was calculated by pre/post third dose geometric mean ratios, calculated by the difference in the log10 of the concentrations/titers measured at 13 months to the log10 of the concentrations at 12 months: i.e. rise = log10(x) at 13 months minus log10(x) at 12 months where x is the serogroup specific IgG or SBA titers. Linear regression analysis between memory B cells at 5 months of age and rise in hSBA titers or IgG at 12 months of age was performed with and without inclusion of demographic factors (subject's household smoking status, number of older children living in subject's household, attendance at daycare and total duration of breast feeding) in the model. | 1 month post primary vaccination (B cells) and 12 months (hSBA titers and IgG) | 
| Percentage of Subjects Who Reported Injection Site Local Reactions After Each MenACWY-CRM and Routine Infant Vaccinations. | Safety was assessed as the percentage of subjects who reported injection site local reactions during 7-day follow-up period after each MenACWY-CRM and routine infant vaccination administered as a primary course of vaccination. | 7 days post each MenACWY-CRM and routine infant vaccination | 
| Percentage of Subjects Who Reported Solicited Systemic Reactions After MenACWY-CRM and Routine Infants Primary Vaccinations | Safety was assessed as the percentage of subjects who reported systemic reactions during 7-day follow-up period after MenACWY-CRM (2 and 4 months) and routine infant primary vaccinations (2, 3 and 4 months). | 7 days post vaccination at 2, 3, and 4 months of age | 
| Percentage of Subjects Who Reported Injection Site Local Reactions After MenACWY-CRM and PCV Vaccinations at 12 Months of Age | Safety was assessed as the percentage of subjects who reported injection site local reactions during 7-day follow-up period after MenACWY-CRM and PCV vaccinations at 12 months of age. | 7 days post 12 month vaccination | 
| Percentage of Subjects Who Reported Solicited Systemic Reactions After MenACWY-CRM and PCV Vaccination at 12 Months of Age | Safety was assessed as the percentage of subjects who reported systemic reactions during 7-day follow-up period after MenACWY-CRM and PCV vaccination at 12 months of age. | 7 days post 12 months vaccination | 
| Increase in Serogroup A, C, W-135 and Y Specific IgG Concentrations Before and 1 Month After MenACWY-CRM Booster Vaccination at 12 Months of Age Administered Concomitantly With Pneumococcal Conjugate Vaccine or Alone | Serogroup A, C, W-135 and Y specific IgG concentrations were measured before and one month after MenACWY-CRM booster vaccination by ELISA. | Before and one month after booster vaccination | 
| Serogroup A, C, W-135 and Y Specific IgG Concentrations After MenACWY-CRM Primary Vaccination | To assess the kinetics of serogroup A, C, W-135 and Y specific IgG concentrations, the geometric mean concentration was measured on day 0, 7, 14, 30, 49, 90, and 120 following vaccination with MenACWY-CRM vaccination at month 4 of the study. | Day 0, 7, 14, 30, 49, 90,120 after MenACWY-CRM vaccination at month 4 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Meningococcal disease, Prevention, Vaccination