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

Phase 2

Completed

Conditions: Meningococcal Disease

Interventions: Biological: MenACWY-CRM
Biological: DTaP-Hib-IPV
Biological: PCV
Biological: MMR
Biological: Hib

Registration Number: NCT00488683

Lead Sponsor: Novartis Vaccines

Brief Summary: 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

Detailed Description: Not available

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 216

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.:
1. 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;
2. a genetic anomaly, e.g. Down's syndrome;
3. any immunodeficiency, including use of systemic corticosteroids;
4. born at less than 36 weeks gestation;
5. weighing less than 2.5 kg at birth;
6. 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;
7. known bleeding diathesis, or any condition associated with a prolonged bleeding time;
who have received any prohibited prior or concomitant medications - e.g.:
1. any immunizations within the 30 days prior to enrollment, with the exception of BCG or hepatitis B;
2. immunoglobulin;
3. 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
MenACWY-CRM and Routine Vaccines (Group 3)	MMR	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.
MenACWY-CRM and Routine Vaccines (Group 1)	MMR	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.
MenACWY-CRM and Routine Vaccines (Group 1)	PCV	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.
MenACWY-CRM and Routine Vaccines (Group 3)	MenACWY-CRM	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.
MenACWY-CRM and Routine Vaccines (Group 1)	MenACWY-CRM	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.
MenACWY-CRM and Routine Vaccines (Group 2)	DTaP-Hib-IPV	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.
MenACWY-CRM and Routine Vaccines (Group 2)	MMR	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.
MenACWY-CRM and Routine Vaccines (Group 3)	DTaP-Hib-IPV	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.
MenACWY-CRM and Routine Vaccines (Group 1)	DTaP-Hib-IPV	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.
MenACWY-CRM and Routine Vaccines (Group 2)	MenACWY-CRM	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.
MenACWY-CRM and Routine Vaccines (Group 2)	PCV	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.
MenACWY-CRM and Routine Vaccines (Group 3)	Hib	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.
MenACWY-CRM and Routine Vaccines (Group 1)	Hib	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.
MenACWY-CRM and Routine Vaccines (Group 2)	Hib	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.
MenACWY-CRM and Routine Vaccines (Group 3)	PCV	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.

Primary Outcome Measures

Name	Time	Method
Summary of Memory B Cells Per 2 x 105 LOC by Serogroup A, C, W-135 and Y	1 month after primary vaccination and immediately before third dose at 12 months of age	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.

Secondary Outcome Measures

Name	Time	Method
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	1 month after primary vaccination and 1 month after third 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.
Memory B Cells 1 Month After Primary Vaccination and Rise From Pre-third Dose to 1 Month After Third Dose of MenACWY-CRM Vaccination	1 month after primary and pre-third and 1 month after third 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.
Memory B Cells 1 Month After Primary Vaccination and 1 Week After Third Vaccination by Serogroup A, C, W-135 and Y	One month after primary vaccination and 1 week after third vaccination	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.
Percentage of Subjects Who Reported Solicited Systemic Reactions After MenACWY-CRM and Routine Infants Primary Vaccinations	7 days post vaccination at 2, 3, and 4 months of age	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).
CRM197 Specific Memory B Cells 1 Month After Primary Vaccination and at 12 Months of Age and One Month After MenACWY-CRM Third Vaccination	5 months (B cells), 12 months and 13 months (B cells and IgG) of age	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.
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	Before and one month after booster vaccination	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.
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	Before and one month after booster vaccination	hSBA GMTs were measured before and one month after MenACWY-CRM booster vaccination at 12 months of age.
Serogroup A, C, W-135 and Y Specific hSBA Titers After MenACWY-CRM Primary Vaccination	Day 0, 7, 14, 30, 49, 90,120 after MenACWY-CRM vaccination at month 4	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.
Percentage of Subjects Who Reported Injection Site Local Reactions After Each MenACWY-CRM and Routine Infant Vaccinations.	7 days post each MenACWY-CRM and routine infant vaccination	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.
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	One month after 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.
Serogroup A, C, W-135 and Y Specific Memory B Cells and Plasma B Cells After MenACWY-CRM Primary Vaccination	Day 0, 7, 14, 49, 90, and 120 after MenACWY-CRM vaccination at month 4	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.
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	Day 1 (IgG) and one month after primary vaccination (B cells)	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.
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	1 month post primary vaccination (B cells) and 12 months (hSBA titers and IgG)	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.
Percentage of Subjects Who Reported Solicited Systemic Reactions After MenACWY-CRM and PCV Vaccination at 12 Months of Age	7 days post 12 months vaccination	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.
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	Before and one month after booster vaccination	Serogroup A, C, W-135 and Y specific IgG concentrations were measured before and one month after MenACWY-CRM booster vaccination by ELISA.
Serogroup A, C, W-135 and Y Specific IgG Concentrations After MenACWY-CRM Primary Vaccination	Day 0, 7, 14, 30, 49, 90,120 after MenACWY-CRM vaccination at month 4	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.
Memory B Cells by Serogroup A, C, W-135 and Y	1 month after primary vaccination and immediately before third dose	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.
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	1 month post primary vaccination (B cells) and 12 months (hSBA titers and IgG)	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.
Percentage of Subjects Who Reported Injection Site Local Reactions After MenACWY-CRM and PCV Vaccinations at 12 Months of Age	7 days post 12 month vaccination	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.