Safety and Immunogenicity of the tetravalent protein-conjugated meningococcal vaccine (MCV4) in recipients of related and unrelated allogeneic stem cell transplantation (alloHCT)

Abstract

Due to the morbidity and mortality of meningococcal disease, the Advisory Committee of Immunization Practices recommended in 2007 immunization of all children 11–18 years old with a protein-conjugated meningococcal vaccine. There is limited data on the immunogenicity of this vaccine following alloHCT. Since 2007, we immunized 48 patients with MCV4. Two vaccinated patients lacking follow-up titers were excluded from analysis. Stem cells were derived from an HLA-identical sibling (n=17) or an alternative donor (n=29). The median time to vaccination was 2.34 years post alloHCT. Only 7 patients responded to all 4 serogroups and 16 responded to none. The response to serogroups A, C, Y, and W-135 was 52%, 30%, 46%, and 33%, respectively. The ability to respond to ≥2 serogroups was not affected by age, diagnosis, time to vaccination, or history of GVHD. Receipt of a T cell depleted graft was associated with a poorer response (p=0.044). Eight of 16 patients who received a second MCV4 responded to all 4 serogroups. This retrospective study suggests that response to a single MCV4 is poor following alloHCT. Administration of a two dose series as currently recommended for patients with asplenia, complement deficiency, or HIV should be evaluated in this patient population.

INTRODUCTION

It is estimated that 1.2 million cases of invasive meningococcal disease occur worldwide per year, causing 135,000 deaths annually (1–3). Each year in United States, about 1000 to 3000 cases are reported (2). Bacteremia, meningitis, and pneumonia occur in approximately 75%, 50%, and 15% of infected patients, respectively. In patients with bloodstream infections, fulminant sepsis occurs in 5 to 20% of patients. Despite rapid institution of appropriate antibiotics, 10%–14% of infected patients die. Of those who survive, up to 20% experience significant morbidity including vasculitis, suppurative arthritis, myocarditis, and permanent neurologic sequelae such as deafness (1–4).

In the United States, meningococcal disease occurs in two peaks; one in infancy, the other in adolescents and young adults (1–4). In infants, 50% of meningococcal disease is due to serogroup B which shares homology with fetal neural tissue and is poorly immunogenic (5). Although several groups are working on vaccines containing this serogroup (reviewed in 6), no currently licensed vaccine in the United States contains this antigen (3,4, 6). In individuals > 11 years of age, 75% of meningococcal disease is caused by serogroups C, Y, and W-135, each of which is included in the currently licensed meningococcal vaccines (reviewed in 3,4,6).

Prior to 2005, Menomune – A,C,Y,W-135, Sanofi Pasteur, Inc., Swiftwater, Pennsylvania) licensed in 1981 was the only meningococcal vaccine available in the United States (reviewed in 3). This pure polysaccharide vaccine although immunogenic in older children and adults, does not induce long-term memory nor an anamnestic response upon antigenic re-exposure (3). In 2005, the FDA licensed the protein conjugated meningococcal vaccine, MCV4 (Menactra™, Sanofi Pasteur, Inc, Swiftwater, Pennsylvania), which contains 4 micrograms each of meningococcal polysaccharides A, C, Y, and W-135 conjugated to approximately 48 micrograms of diphtheria toxoid protein carrier. Compared to the pure polysaccharide vaccine, the conjugated vaccine is more immunogenic in young children, elicits a T cell dependent B cell response, decreases nasal colonization, results in higher seroconversion rate, and provides more durable seroprotection (3–5).

Over the past decade, disease-free survival following hematopoietic stem cell transplantation has continued to improve resulting in an increasing number of patients entering college, the work-force, and traveling abroad (7). To date, there is one study evaluating the immunogenicity of the polysaccharide meningococcal vaccine in allogeneic transplant survivors (8), and none evaluating the immunogenicity of a quadrivalent protein conjugated meningococcal vaccine.

To determine the safety and immunogenicity of this vaccine in allogeneic HCT, this retrospective study analyzed the response and adverse side effects in 46 patients who received this vaccine at this center from 2007 to 2010. The effect of transplant type, patient age, stem-cell and donor type, use of T-cell depletion, and history of prior acute or chronic graft-versus-host disease (GVHD) on seroconversion was assessed.

Patients and methods

A waiver of authorization to conduct this retrospective study was approved by the Memorial Sloan Kettering Cancer Center Institutional Review Board. Routine immunization of patients with MCV4 was initiated at Memorial Sloan-Kettering Cancer Center in 2007 as per the Advisory Committee Immunization Practices (ACIP) guidelines published that year. These guidelines recommended immunization of all children 11–18 years of age, splenectomized individuals of any age, individuals > 18 years of age enrolled in the military, living in a college dormitory, traveling to a high risk area, or working as a healthcare professional (9). The medical records of all patients who remained disease-free for at least 6 months after an allogeneic transplant performed at this center from 1/1/04 through 12/31/09 were reviewed for immunization against meningococcus. Dates of vaccination and pre and post vaccine titers were obtained from a prospectively maintained database and confirmed by retrospective chart review. Only patients transplanted since 2004 were included in order to limit the maximum time from HCT to vaccination to 6 years.

Antibody response

Serum IgG antibodies recognizing the four Neisseria meningitidis serogroups included in MCV4 were assessed by Focus Technologies (Cypress, CA) using a Multi-Analyte Immunodetection (MAID) procedure, based on the Luminex® flow cytometric system (10). Threshold for response against serogroups A, C, Y, and W-135 was defined as a specific IgG level of > 4, 5, 4, and 3 micrograms/ml, respectively. For patients with positive titers prior to vaccination, response was defined as a 3 -fold increase in titer. Patients who responded to all 4 serogroups were defined as having a full response. A good partial response was defined as the development of protective titers against at least two serogroups. All patients were evaluated at MSKCC before and after vaccination including assessment of acute and chronic GVHD using established criteria (11,12).

Patient and transplant characteristics

Forty-eight patients, median age at vaccination: 14.7 (range:9.6–25.4) years received an initial MCV4 between 1/1/07 and 12/31/10. Two recipients of a T cell depleted transplant derived from an unrelated (n=1) or HLA identical sibling donor (n=1) were not evaluable for response due to lack of follow-up titers. The remaining 46 patients form the basis of this study. Patient and donor characteristics are shown in Table 1. All patients received a myeloablative conditioning regimen which included hyperfractionated total body irradiation in 29 patients.

Table 1.

Patient and Transplant demographics

	Study group n=46
Sex (male/female)	27/19
Median age (range) at HCT	13.9 (6–23)
Median age (range) at vaccination	14.7 (9.6–25.4)
Diagnosis
Malignancy/bone marrow failure	40
Acute Leukemia	32
MDS/aplastic anemia	5 (3/2)
CML/myeloproliferative disorder	2 (1/1)
Ewing’ sarcoma	1
Non-malignant disease	6
Hemoglobinopathy	4
Combined immunodeficiency disease	1
Hereditary Lymphohistiocytosis	1
Median time (range) from HCT to vaccine	2.34 (0.6–5.2) years
Donor
HLA-identical sibling	17 (37%)
HLA-Mismatched related	6 (13%)
Unrelated	23 (50%)
HCT type
T cell depleted	26 (57%)
T cell depleted HLA-identical sibling	4
T cell depleted HLA-mismatched related	6
T cell depleted Unrelated	16
T-replete	20 (43%)
Unmodified HLA-identical sibling	13
Unmodified Unrelated	2
Unmodified double cord blood	5

Stem cells for the 46 patients were derived from an HLA-identical sibling, an HLA-mismatched family member, or unrelated donor in 37%, 13%, and 50% of cases, respectively. Fifty-seven percent of patients (26/46) received a T cell depleted transplant from an unrelated (n=16), HLA mismatched related (n=6) or HLA-identical sibling (n=4) donor. T cells were depleted from bone marrow by soybean agglutination followed by sheep red blood cells, n=7 (13). G-CSF mobilized peripheral blood stem cells underwent positive selection for CD34+ stem cells followed by T cell depletion by rosetting with sheep erythrocytes, n=19 (14). The remaining 20 patients received an unmodified HCT from an HLA identical sibling (n=13) or unrelated (n=7) donor. The source of the unmodified graft(s) was double cord blood (n=5), bone marrow (n =13), or peripheral blood (n=2). Six of 46 patients evaluable for response received post transplant rituximab for the prevention (n=5) or treatment of EBV-LPD (n=1).

Statistical analysis

Frequency distributions of characteristics of patients who responded to the meningococcal vaccine and the study cohort were summarized. Logistic regression was used to identify clinical variables associated with a good partial vaccine response (response to at least 2 serotypes). The variables consisted of: age, sex, T-cell depletion, matched related transplant (vs. other), time to first vaccination, and history of GVHD. Univariate analysis was performed. In order to assess for potential confounding effects, predictors with a univariate P-value of <0.25 were incorporated into a multivariate model. All analyses were performed using Stata version 10 [StataCorp. 2007. Statistical Software: Release 10.0. College Station, TX: Stata Corporation].

Results

Prior to immunization, two patients had protective titers against serogroup A. These were the only two patients who were seropositive for any serogroup prior to vaccination.

The median time to initiate vaccination was 2.34 years (range: 0.6–5.2) years post HCT. The median time to vaccination was 2.0 (range 0.6–5.0) years in recipients of a T cell depleted HCT and 2.6 years (range 0.8–5.2) in recipients of a T cell replete graft (p=0.36). In the 6 patients who received post HCT rituximab, the median time from HCT to vaccination was 2.4 years. The median time from the last dose of rituximab to initial MCV4 was 25 (range: 0.2–37.2) months, with 5 of 6 patients receiving their first vaccine >20 months post rituximab treatment.

The median time to measure antibody levels following the initial MCV4 vaccine was 113 days. Sixteen patients failed to respond to any serogroup following immunization, including all 6 patients who received post HCT rituximab. Of the remaining 30 patients, response to 1, 2, 3, or 4 serogroups was observed in 8, 7, 8, and 7 patients, respectively. The threshold for response against serogroups A, C, Y, and W-135 was reached in 56%, 31%, 45%, and 36% of patients, respectively. Logistic regression analysis demonstrated that the ability to respond to at least 2 serogroups was not significantly affected by age at HCT, sex, time from transplant, or underlying diagnosis. Only receipt of a T cell depleted HCT was associated with a trend to poorer response to ≥ 2 serogroups (p=0.044) (Table 2). With respect to response to an individual serogroup, response to serogroup C was significantly poorer in patients who received a T cell depleted transplant and/or or stem cells derived from an unrelated or HLA-mismatched (alternative) donor (Table 3). In our analysis, no significant univariate predictors were detected for serogroups A, Y, and W-135, and results from multivariate analysis of overall response and serogroup C were similar to univariate but with decreased statistical power (data not shown).

Table 2.

Response to ≥2 MCV4 serogroups

Characteristic	univariate OR	95% CI	p-value
Age>10 years at HCT	0.72	0.21 – 2.48	0.604
Male sex (vs. female)	1.03	0.32 – 3.34	0.958
T-cell depletion	0.29	0.08 – 0.97	0.044
HLA-identical sibling (vs. alternative donor)	3.00	0.86 – 10.43	0.084
Time from HCT to MCV4
0.5 to 1 year	1.00	-	-
1 to 2 years	0.77	0.09 – 6.98	0.822
>2 years	1.00	0.12 – 8.21	1.000
Hx of chronic GVHD	1.77	0.47 – 6.72	0.399

Table 3.

Logistic regression: Serogroup C Response

Characteristic	univariate OR	95% CI	p-value
Age>10 years at HCT	1.13	0.28 – 4.48	0.867
Male sex (vs. female)	0.76	0.21 – 2.77	0.675
T-cell depletion	0.22	0.06 – 0.89	0.033
HLA-identical sibling (vs. alternative donor)	7.03	1.70 – 29.14	0.007
Time from HCT to MCV4
0.5 to 1 year	1.00	-	-
1 to 2 years	0.43	0.03 – 6.41	0.539
>2 years	1.88	0.17 – 20.61	0.607
Hx of chronic GVHD	1.39	0.34 – 5.76	0.651

Note: No significant univarate predictors were detected for serogroups A, Y, and W (data not shown)

To date, 16 patients have received a second MCV4 following a T cell depleted (n=9) or T-replete HCT (n=7). The second vaccine was administered at a median of 8.9 (range 1.6–28.4) months following the first vaccine due to complete lack of response (n=8) or response to only 1 (n=5) or 2 (n=3) serogroups. Stem cells for the 16 patients were derived from an HLA-identical sibling (n=4), HLA mismatched related (n=3), or an unrelated volunteer donor (n=9). Following a second MCV4, 8 of 16 patients responded to each of the 4 serogroups, 5 patients responded to 3 serogroups, and 1 patient responded to 2 serogroups. The only two patients who failed to respond to any serogroup following a second MCV4 received rituximab 21.6 and 28.8 months following their last dose of rituximab. The threshold for response against serogroups A, C, Y, and W-135 was reached in 81% (13/16), 63% (10/16), 88% (14/16), and 69% (11/16) of patients following their second MCV4, respectively. Figure 1 demonstrates the geometric mean titer following one (n=46) or two immunizations with MCV4 (n=16).

Figure 1.

Geometric mean concentration (GMC, micrograms/ml) and 95% confidence levels antibodies against meningococcal serogroups A, C, Y, and W-135 before and after immunization with MCV4.

Figure demonstrates the geometric mean concentrations and the 95% confidence levels of meningococcal antibodies against serogroups A, C, Y, and W-135 in patients who received one immunization (top, n=46) or after two immunizations (bottom, n=16).

*95% confidence interval for serogroup A=5.9–83 ug/ml

Discussion

Meningococcal disease is a rapidly progressive often devastating infection despite prompt diagnosis and treatment (1–3). In 2005, the ACIP recommended a single dose of MCV4 in children 11–12 years of age, vaccination of children entering high school if not previously vaccinated, and those entering college or considered at high risk for meningococcal disease (3). In 2007, the ACIP revised its recommendation to include routine immunization of all children 11–18 years of age with MCV4 at the earliest opportunity as well as immunization of individuals 19–55 years at increased risk of meningococcal disease (14). This latter group includes military recruits, travelers to endemic areas such as sub-Saharan Africa, patients with functional or anatomic asplenia, and those with congenital or acquired complement deficiency (1–4,14). Although >80% of otherwise healthy adolescents develop a ≥4 fold rise in titer to each of the 4 vaccine serogroups when measured 4 weeks after immunization (3), there is limited data on the duration of protection in healthy individuals. A recent study (15) evaluated the duration of protection in healthy adolescents following a single Menactra™ (MCV4) versus Menveo™ (MenACWY-CRM; Novartis), a conjugated quadrivalent meningococcal vaccine licensed in the United States in 2010 (16). This study demonstrated that although the initial response was comparable in recipients of either vaccine, a higher proportion of individuals had protective human serum bacterial antibody levels >1:8, when evaluated 22 months following MenACWY-CRM. Due to concerns regarding loss of protection, current ACIP recommend initial vaccination of all children at 11–12 years of age, with a booster at 15–16 years of age (17).

Currently, there is limited data on how best to protect allogeneic transplant recipients against meningococcal disease. Parkkali et al. evaluated the response of 44 adult recipients of an HLA matched sibling bone marrow to a pure polysaccharide meningococcal vaccine containing serogroups A and C. Patients were vaccinated either early or later post HCT at 8 (n=22) or 22 (n=20) months, respectively. Antibody titers measured by EIA one month following immunization demonstrated a 2-fold or greater increase in titers against serogroup A in 52% and 74% of patients and against serogroup C in 76% and 89% of individuals vaccinated early or late, respectively. Despite the initial good response, antibody titers decreased by 50% when measured 6 months post immunization.

Our study is the first to evaluate response to MCV4 following alloHCT. It demonstrates a poor response following one vaccine in this patient population. Fifty-two percent of patients had either no response (n=16) or response to only one antigen (n=8), generally type A, an uncommon cause of disease in the United States, although common in Sub-Sahara Africa and the Middle East. Response to serogroup C, a common cause of meningococcal disease world-wide, was particularly poor. The limited immunogenicity of MCV4 in our study occurred despite a median time to immunization of 2.34 years post HCT suggesting a lack of appropriate T and B cell populations necessary for response at the time of immunization. Following a booster vaccine, response was significantly better, with 13 of 16 patients responding to at least 3 serogroups.

Current post transplant vaccine guidelines do not recommend routine measurement of pre and post vaccine titers. Nevertheless for transplant survivors entering college, the military, or traveling to countries where Neisseria meningitis is prevalent or endemic, our study suggests that documentation of response would be prudent. This is particularly true in recipients of post transplant rituximab who despite recovery of B cells, did not respond to this vaccine, despite vaccination > 1.5 years following this therapy. This study suggests that alloHCT recipients would benefit by a two dose primary series administered 2 months apart as recommended by the ACIP in 2010 in patients with asplenia, HIV, or complement deficiency (17). Larger prospective studies comparing response and duration of response of the two conjugated meningococcal vaccines are warranted in allogeneic and autologous transplant survivors.