ARTICLE

Safety, Immunogenicity, and Immune Memory

of a Novel Meningococcal (Groups A, C, Y, and
W-135) Polysaccharide Diphtheria Toxoid Conjugate
Vaccine (MCV-4) in Healthy Adolescents
Harry Keyserling, MD; Thomas Papa, MD; Katalin Koranyi, MD; Robert Ryall, PhD; Ehab Bassily, MSc;
Michael J. Bybel, BS; Kevin Sullivan, PhD; Gregory Gilmet, MD; Al Reinhardt, PhD

Objective: A meningococcal (groups A, C, Y, and
W-135) polysaccharide diphtheria toxoid conjugate
vaccine (MCV-4; Menactra; Sanofi Pasteur Inc, Swift-
water, Pa) was developed to improve the profile of cur-
rently licensed products. The objective of this study
was to compare the tolerability, immunogenicity, and
immune memory of MCV-4 with those of a quadriva-
lent polysaccharide vaccine (PSV-4; Menomune A/C/Y/
W-135; Sanofi Pasteur Inc).
Design, Setting, Participants: A randomized, double-
blind trial was performed at 11 clinical centers in the
United States. The vaccine MCV-4 or PSV-4 was admin-
istered to 881 healthy 11- to 18-year-olds. Sera were col-
lected prevaccination and 28 days postvaccination. Three-
year follow-up and booster vaccination with MCV-4 were
performed in a participant subset from each group and
a control group.
Main Outcome Measures: Proportion of partici-
pants with a 4-fold or greater increase in serum bacteri-
cidal antibody against each serogroup 28 days after ini-
tial vaccination, geometric mean serum bactericidal
antibody titers, and safety assessments.
Results: Both vaccines were well tolerated; most reac-
tions were mild. More MCV-4 recipients reported solic-
ited local reactions (68.9%) than PSV-4 recipients (30.2%).
Both MCV-4 and PSV-4 were highly immunogenic; simi-
lar proportions of participants had 4-fold or greater in-
creases in serum bactericidal antibody (range, 80.1%-
96.7%) to the 4 serogroups. Three-year follow-up showed
persistence of serum bactericidal antibody and booster
responses to MCV-4 consistent with immune memory
in participants previously vaccinated with MCV-4, but
not in those who had previously received PSV-4.
Conclusions: The vaccine MCV-4 was well tolerated and
highly immunogenic. Persistence of bactericidal activ-
ity with MCV-4, but not PSV-4, was evident 3 years af-
ter the initial immunization. Booster response was dem-
onstrated after a second vaccination with MCV-4.
Arch Pediatr Adolesc Med. 2005;159:907-913

Author Affiliations: Emory
University, Atlanta, Ga
(Drs Keyserling and Sullivan);
Sanofi Pasteur Inc, Swiftwater,
Pa (Drs Papa and Ryall,
Messrs Bassily and Bybel, and
Drs Gilmet and Reinhardt); and
Children’s Hospital, Columbus,
Ohio (Dr Koranyi).
Group Information: A list of
the members of the group
appears on page 913.
I
N S EPTEMBER 2004, THE V AC -
cines and Related Biological Prod-
ucts Advisory Committee of the
US Food and Drug Administra-
tion voted unanimously for reg-
istration of the first quadrivalent menin-
gococcal conjugate vaccine against
serogroups A, C, Y, and W-135 (MCV-4;
Menactra; Sanofi Pasteur Inc, Swiftwater,
Pa) intended for use in adolescents and
adults, which was licensed in January
2005. In the United States, approxi-
mately 97% of invasive meningococcal dis-
ease is sporadic, which underscores the
need for a vaccine prevention strategy.1-3
Adolescents are a key target group for vac-
cination against invasive meningococcal
disease because of a high incidence rate and
risk of serious untoward outcomes. Me-
ningococcal disease is the leading cause of
meningitis and sepsis in adolescents and
young adults and is associated with re-
ported mortality rates as high as 22.5%.1,4
Up to 83% of meningococcal disease re-
ported in adolescents would be poten-
tially preventable with a vaccine directed
against serogroups A, C, Y, and W-135.4
In 2000, the US Advisory Committee
on Immunization Practices recom-
mended informing college freshmen about
meningococcal disease and the benefits of
vaccination. 5 The currently available
quadrivalent meningococcal polysaccha-
ride vaccine against groups A, C, Y, and
W-135 combined (PSV-4; Menomune A/C/
Y/W-135; Sanofi Pasteur Inc) induces T-
cell–independent immune responses that
diminish over time and is not recom-
mended for routine immunization.2,5 In
contrast, T-cell–dependent antibody re-
sponses, such as those produced by mono-
valent meningococcal conjugate vac-
cines against serogroup C, are intended to
persist over a longer period of time and

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 have been associated with the development of immune
memory, reductions in carriage rates, and herd immu-
nity in the United Kingdom.2,6-8 The vaccine MCV-4 was
developed in the hope that it would have similar effects
and broader protection against 4 major meningococcal
disease-causing serogroups.9-13 This study was designed
to assess the immunogenicity and safety profile of MCV-4
compared with PSV-4 after an initial vaccination and a
3-year follow-up assessment and vaccination with MCV-4.
METHODS
STUDY DESIGN
This randomized, blinded, multicenter trial was conducted at
11 clinical sites in the United States in accordance with the prin-
ciples outlined in the Declaration of Helsinki. Local institu-
tional review boards approved the protocol and consent forms.
Written informed consent was obtained from a parent or guard-
ian and assent from each participant was obtained as required
by the institutional review board.
Eligible participants were healthy adolescents 11 to 18 years
of age. On the day of initial immunization, participants had no
recent history (within the preceding 72 hours) of acute illness
or antibiotic use, serious chronic illness, immunologic defi-
ciency, prior diagnosis of meningococcal disease, or prior me-
ningococcal vaccination. Three years after the initial vaccina-
tion, a convenience sample of participants from each vaccine
group and a meningococcal vaccine–naive group received an
open-label dose of MCV-4.
All vaccines were provided by Sanofi Pasteur Inc. Each freeze-
dried dose of PSV-4 contained 50 µg of capsular polysaccha-
ride from each serogroup (A, C, Y, and W-135) with lactose
stabilizer. Each dose was reconstituted with 0.5 mL of sterile,
pyrogen-free distilled water.
Each dose of MCV-4 contained 4 µg of capsular polysac-
charide from each serogroup (A, C, Y, and W-135) covalently
attached to a total of approximately 48 µg of diphtheria toxoid
protein. Each dose was formulated in 0.5 mL sterile, pyrogen-
free, phosphate-buffered physiological saline without preser-
vative in a prefilled syringe.
Vaccines were administered in the deltoid region; MCV-4
was administered intramuscularly and PSV-4 was adminis-
tered subcutaneously. A blinded, computer-generated random-
ized allocation schedule with a block size of 2 was provided by
the sponsor. To maintain blinding of study personnel, vacci-
nations and safety assessments were performed by different study
personnel. Booster vaccination was performed 3 years after ini-
tial vaccination with open-label MCV-4.
Participants were monitored for 30 minutes postvaccina-
tion for immediate reactions. Solicited local and systemic re-
actions were recorded on diary cards for 7 days following vac-
cination. Any serious adverse events were to be reported
throughout the trial. Safety assessments were made 28 days and
6 months after the initial vaccination and 28 days after the
booster vaccination. Sera were obtained prior to and 28 days
after each vaccination and also on day 8 after the booster vac-
cination. Assays were performed by Sanofi Pasteur Inc Global
Clinical Immunology Laboratory (Swiftwater, Pa) to deter-
mine functional serum bactericidal antibody (SBA) responses
for each serogroup.
The SBA responses were determined using 2-fold serial di-
lutions of sera incubated in sterile 96-well microtiter plates with
baby rabbit complement and serogroup-specific meningococ-
cal bacteria. An agar overlay medium was added to the serum/
complement/bacteria mixture and allowed to harden. Follow-
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ing an overnight incubation at 37°C with 5% CO2, bacteria
colonies in the wells were counted. The endpoint titer was de-
termined as the reciprocal serum dilution yielding 50% or greater
killing of the bacteria as compared with the mean of the comple-
ment control wells. The lower limit of detection was a titer of
8. Samples with no detectable antibody were assigned a titer
of 4 for the calculation of geometric mean titers (GMTs).
STATISTICAL METHODS
For the initial vaccination, the primary immunogenicity crite-
rion was the proportion of participants with a 4-fold or greater
rise in SBA titer for each serogroup 28 days postvaccination. We
calculated GMTs, seroconversion rates, and the distribution and
cumulative frequency of SBA titers for each of the 4 serogroups
for both treatment groups at baseline and day 28. For GMTs, we
calculated 95% confidence intervals and P values using a t test;
we calculated 95% confidence intervals for seroconversion, de-
fined as proportion of participants with titers of less than 8 at
day 0 who achieved a 4-fold or greater rise in SBA titers on day
28. For participants receiving a booster vaccination, 95% con-
fidence intervals were calculated for the GMTs on day 0 and 28
of the initial vaccination, before booster vaccination, and 8 and
28 days after booster vaccination. The sample size was chosen
based on the minimum number of participants needed to pro-
vide 90% power to assess whether a similar proportion of the
MCV-4 and PSV-4 had a 4-fold or greater rise in SBA titer. Par-
ticipants who provided sera between 28 and 56 days after the
initial vaccination were evaluated. Analyses were performed us-
ing SAS version 8.2 (SAS Institute, Cary, NC). We assessed safety
based on the proportion of participants who experienced a se-
vere solicited reaction after initial vaccination and calculated 95%
confidence intervals. We calculated P values based on the Fisher
exact text for individual solicited reactions to determine whether
the observed proportion of participants with an individual re-
action was associated with vaccination.
RESULTS
DEMOGRAPHICS
For the initial vaccination, 881 participants (Table 1)
were randomized to the MCV-4 (N = 440) and PSV-4
(N=441) groups and underwent study procedures be-
tween September 2000 and October 2001. The 2 groups
were similar in sex distribution, age, and racial compo-
sition. A total of 425 participants from the MCV-4 group
and 423 from the PSV-4 group were included in the im-
munogenicity analysis. Of the 33 total participants ex-
cluded from the immunogenicity analysis, 23 (10 receiv-
ing MCV-4 and 13 receiving PSV-4) did not provide sera
within the prespecified visit windows, and 6 (2 receiv-
ing MCV-4 and 4 receiving PSV-4) had not met entry cri-
teria and were enrolled in error. The distribution of par-
ticipants over the course of the trial is illustrated in
Figure 1.
For the 3-year follow-up vaccination, 153 previously
vaccinated and 88 control participants underwent study
procedures between February and April 2004 (Figure 1).
There were no significant differences in demographic or
immunogenicity parameters between the cohort of par-
ticipants who received a 3-year booster dose of MCV-4,
control participants, or the overall study population for
the initial vaccination.
WWW.ARCHPEDIATRICS.COM
 Table 1. Participant Demographics, Initial Vaccination* A Safety Population 881 Participants Enrolled
and Randomized
MCV-4 PSV-4
Characteristic (N = 440) (N = 441)
MCV-4 PSV-4
Age, mean (range), y 14.3 (11-18) 14.3 (11-17)
N (%) N (%)
Sex, No. (%)
Male 236 (53.6) 250 (56.7) Enrolled and Vaccinated 440 (100) 441 (100)
Female 204 (46.4) 191 (43.3)
Race, No. (%)
Provided Local and Systemic 440 (100) 441 (100)
White 421 (95.7) 418 (94.8)
Reaction Data (Days 0-7)
Black 14 (3.2) 15 (3.4)
Hispanic 1 (0.2) 2 (0.5)
Asian 1 (0.2) 1 (0.2) Lost to Follow-up 2 (0.5) 4 (0.9)
Other 3 (0.7) 5 (1.1) Voluntary Withdrawal 2 (0.5) 2 (0.5)

Abbreviations: MCV-4, quadrivalent meningococcal conjugate vaccine

against groups A, C, Y, and W-135; PSV-4, quadrivalent meningococcal Completed 6-Month Safety 436 (99.1) 435 (98.6)
polysaccharide vaccine against groups A, C, Y, and W-135. Follow-up
*No significant between-group differences were observed.

B Immunogenicity Population 881 Participants Enrolled

and Randomized
SAFETY AND REACTIONS

All enrollees provided a baseline blood sample, received MCV-4 PSV-4

N (%) N (%)
the study vaccine, and attended the 28-day follow-up visit
for safety assessment and second blood draw. Ten par- Enrolled and Vaccinated 440 (100) 441 (100)

ticipants did not provide safety data at the 6-month follow-

up: 4 were MCV-4 recipients (2 lost to follow-up and Did Not Meet an Entry Criterion 2 (0.5) 4 (0.9)
2 voluntarily withdrew) and 6 were in the PSV-4 group Visit Outside of Time Window 10 (2.3) 13 (2.9)
(4 lost to follow-up and 2 voluntarily withdrew). No par- Other Reason 3 (0.7) 1 (0.2)
ticipant dropped out or was withdrawn from the study
because of an adverse event. Per Protocol Immunogenicity 425 (96.6) 423 (95.9)
After the initial vaccination, 2 participants had a va- Data at Day 28
sovagal episode within 30 minutes of receiving MCV-4.
Vaccine-Naive
These events resolved spontaneously without medical in- Group Added
tervention. No other immediate reactions were re-
Convenience Sample for 76 77 88
ported after the initial vaccination. 3-Year Booster Vaccination
After the initial vaccination, local reaction data were
available for 438 participants in the MCV-4 group and
440 in the PSV-4 group. Local reactions were more com- Immunogenicity Data Reported 76 77 88

mon in MCV-4 recipients (Table 2). The majority of

these reactions were mild (73%) or moderate (26%) in
severity and of limited duration (median, 2 days). All lo-
cal reactions in the PSV-4 group were either mild (88%)
or moderate (12%). The most frequent local reaction in
both groups was pain at the injection site, 302 (68.9%)
of 438 participants vs 133 (30.2%) of 441 participants
in the MCV-4 and PSV-4 groups, respectively. All local
reactions resolved without sequelae.
Systemic reaction data were available for 439 partici-
pants in the MCV-4 group and 441 participants in the
PSV-4 group after the initial vaccination. The overall fre-
quency of systemic reactions was similar in both groups.
More than half of the participants reported at least 1 so-
licited systemic reaction, 251 (57.2%) of 439 partici-
pants in the MCV-4 group vs 229 (51.9%) of 441 par-
ticipants in the PSV-4 group (Table 3). Mild to moderate
headache was the most common systemic reaction, re-
ported in 197 (44.9%) of 439 participants in the MCV-4
group and 174 (39.5%) of 441 participants in the PSV-4
group. Fatigue, anorexia, and diarrhea were the next most
commonly reported solicited systemic reactions and oc-
curred with similar frequencies in both groups. Almost
Figure 1. Participant flow.
all reported solicited systemic reactions were mild to mod-
erate in severity and resolved within 3 days of vaccina-
tion. One case of high fever, defined as an oral tempera-
ture of 40°C or higher, occurred on day 7 after MCV-4
vaccination and lasted for 1 day. A similar percentage of
participants in the MCV-4 group (17/439; 3.9%) and the
PSV-4 group (18/441, 4.1%) had severe systemic reac-
tions.
SERIOUS ADVERSE EVENTS
Six participants, 5 in the MCV-4 group and 1 in the PSV-4
group, experienced 7 serious adverse events within 189
days after the initial vaccination. Each of these events—
dehydration and pyelonephritis, bilateral testicular fixa-
tion, acetaminophen overdose, facial baseball injury, torn
meniscus, preexisting supraventricular tachycardia—
was considered unrelated to the vaccine by study inves-
tigators.

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 Table 2. Solicited Local Reactions in the 2 Study Groups Table 3. Solicited Systemic Reactions in the 2 Study Groups
After Initial Vaccination* After Initial Vaccination*

MCV-4 PSV-4 MCV-4 PSV-4

(N = 438), (N = 441), (N = 439), (N = 441),
Reaction Severity No. (%) No. (%) Reaction Severity No. (%) No. (%)
Any reaction Mild 230 (52.5) 135 (30.6) Any reaction Mild 145 (33.0) 150 (34.0)
Moderate 82 (18.7) 18 (4.1) Moderate 89 (20.3) 61 (13.8)
Severe 5 (1.1) 0 Severe 17 (3.9) 18 (4.1)
Pain Mild 228 (52.1) 116 (26.3) Headache Mild 120 (27.3) 126 (28.6)
Moderate 73 (16.7) 17 (3.9) Moderate 70 (15.9) 40 (9.1)
Severe† 1 (0.2) 0 Severe† 7 (1.6) 8 (1.8)
Induration Mild 73 (16.7) 32 (7.3) Fatigue Mild 86 (19.6) 79 (17.9)
Moderate 13 (3.0) 2 (0.5) Moderate 33 (7.5) 22 (5.0)
Severe† 3 (0.7) 0 Severe† 5 (1.1) 3 (0.7)
Swelling Mild 49 (11.2) 21 (4.8) Diarrhea Mild 42 (9.6) 52 (11.8)
Moderate 11 (2.5) 3 (0.7) Moderate 6 (1.4) 9 (2.0)
Severe† 3 (0.7) 0 Severe† 0 1 (0.2)
Redness Mild 45 (10.3) 27 (6.1) Anorexia Mild 40 (9.1) 39 (8.8)
Moderate 7 (1.6) 1 (0.2) Moderate 10 (2.3) 12 (2.7)
Severe† 1 (0.2) 0 Severe† 4 (0.9) 3 (0.7)
Fever‡ Mild 12 (2.7) 10 (2.3)
Abbreviations: MCV-4, quadrivalent meningococcal conjugate vaccine Moderate 2 (0.5) 1 (0.2)
against groups A, C, Y, and W-135; PSV-4, quadrivalent meningococcal ⱖ40°C 1 (0.2) 0
polysaccharide vaccine against groups A, C, Y, and W-135. Vomiting Mild 7 (1.6) 2 (0.5)
*For all individual local reactions, a significantly greater percentage of Moderate 2 (0.5) 6 (1.4)
participants in the MCV-4 group had mild and moderate events compared Severe† 1 (0.2) 1 (0.2)
with the PSV-4 group (P⬍.001 for pain, induration, and swelling; P⬍.006
Rash Any 7 (1.6) 7 (1.6)
for redness).
†Severe pain is defined as disabling, unable to move arm; all other severe
reactions indicated were more than 2 inches in diameter. Abbreviations: MCV-4, quadrivalent meningococcal conjugate vaccine
against groups A, C, Y, and W-135; PSV-4, quadrivalent meningococcal
polysaccharide vaccine against groups A, C, Y, and W-135.
*The proportion of participants with moderate headache was significantly
higher in the MCV-4 group compared with the PSV-4 group (P = .02). No
At the 3-year follow-up, the safety profile, including other significant between-group differences were observed.
solicited reactions, was generally similar between †Severe symptoms were defined as follows: headache and fatigue,
participants in the MCV-4, PSV-4, and control groups. disabling requiring bed rest; anorexia, missing 3 or more meals; vomiting,
3 or more episodes; diarrhea, 5 or more episodes.
No serious adverse events or new or unexpected effects ‡Temperature measurement was not performed for 1 PSV-4 recipient,
were observed for any participant in any group. Among N = 440.
the cohort of 76 initial MCV-4 recipients revaccinated 3
years later, a second dose of MCV-4 was generally well
tolerated.
to 100% while those observed in the PSV-4 group were
IMMUNOGENICITY from 99.3% to 100% (data not shown).
In both groups of participants evaluated 3 years after
The SBA GMTs for each serogroup were similar be- the initial vaccination, bactericidal antibody levels re-
tween the MCV-4 and PSV-4 groups prior to the initial mained markedly higher than initial baseline values for
vaccination. Marked increases in SBA levels were ob- all 4 serogroups (Table 5). Overall, the percentage of
served 28 days after the initial vaccination for both study participants with SBA titers 128 or more ranged from 71%
groups (Table 4). The SBA response for serogroup A, to 95% for the MCV-4 group and from 57% to 83% for
assessed by GMTs, was significantly higher in the MCV-4 the PSV-4 group (data not shown). A booster dose of
group compared with the PSV-4 group. The GMTs for MCV-4 resulted in a rise in antibody response for all 4
the other serogroups were similar in the 2 vaccine groups. serogroups 8 days postvaccination. Participants who had
Overall, more than 90% of participants had titers of previously received PSV-4 also had high antibody re-
128 or more against all 4 serogroups after the initial vac- sponses 8 days postvaccination; however, the booster an-
cination (Table 4). The percentage of participants who tibody responses to the PSV-4 primed participants were
had a 4-fold or greater rise in SBA 28 days after the ini- not as high compared with the MCV-4 primed partici-
tial vaccination was highest for serogroups A and W-135 pants (Table 5). Both MCV-4 and PSV-4 groups had higher
for both vaccine groups. For all serogroups, the percent- bactericidal antibody levels compared with baseline for
age of participants with a 4-fold or greater rise was simi- all 4 serogroups at Day 28. Responses in the group of pre-
lar in the MCV-4 group compared with the PSV-4 group. viously meningococcal vaccine–naive participants were
Among participants with an SBA titer of less than 8 consistent with those observed after the initial vaccina-
before the initial vaccination, seroconversion, defined as tion with MCV-4, showing a marked rise in SBA levels.
a 4-fold or greater rise, occurred in the vast majority of These findings are further illustrated by the reverse cu-
participants 28 days after vaccination for all 4 sero- mulative distribution curves for bactericidal antibodies
groups. Values for the MCV-4 group ranged from 98.2% against the 4 serogroups on day 28 (Figure 2).

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 Table 4. Serum Bactericidal Antibody Activity: Initial Vaccination (per Protocol Population)

MCV-4 PSV-4 MCV-4 PSV-4

(N = 425) (N = 423) (N = 425) (N = 423)

Day 0 GMTs Day 28 GMTs Day 0 GMTs Day 28 GMTs Participants Participants
(95% (95% (95% (95% With ⱖ4-Fold Participants With ⱖ4-Fold Participants
Confidence Confidence Confidence Confidence Increase From With Titer Increase From With Titer
Serogroup Interval) Interval) Interval) Interval) Baseline, % ⱖ128, % Baseline, % ⱖ128, %
A 106 (87.6-129) 5483 (4920-6111) 88.7 (73.1-108) 3246 (2910-3620)* 92.7 99.8 92.4 100
C 33.7 (27.5-41.3) 1924 (1662-2228) 37.4 (30.4-46.0) 1639 (1406-1911) 91.7 98.9 88.7 98.5
Y 103 (87.8-121) 1322 (1162-1505) 112 (96.0-130) 1228 (1088-1386) 81.8 99.6 80.1 99.3
W-135 20.7 (17.7-24.2) 1407 (1232-1607) 23.9 (20.4-28.0) 1545 (1384-1725) 96.7 98.7 95.3 98.9

Abbreviations: GMTs, geometric mean titers; MCV-4, quadrivalent meningococcal conjugate vaccine against groups A, C, Y, and W-135; PSV-4, quadrivalent
meningococcal polysaccharide vaccine against groups A, C, Y, and W-135.
*P⬍.001 for MCV-4 vs PSV-4 at day 28.

Table 5. MCV-4 Booster 3 Years After Initial Vaccination: Convenience Sample From MCV-4 and PSV-4 Groups
With Vaccine-Naive Comparison

Geometric Mean Serum Bactericidal Antibody Titers (95% Confidence Intervals)

Day 0 Day 8 Day 28

MCV-4 PSV-4 Naive MCV-4 PSV-4 Naive MCV-4 PSV-4 Naive

Serogroup (n = 76) (n = 77) (n = 88) (n = 76) (n = 77) (n = 88) (n = 76) (n = 77) (n = 88)
A 1082 171 84 9393 4406 12 936 4326 3270 6399
(785-1491) (101-289) (48-146) (7613-11 590) (3286-5908) (10 007-16 722) (3475-5386) (2460-4348) (5069-8078)
C 211 109 43 18 113 1196 7453 8192 665 2955
(121-370) (59-203) (26-70) (14 296-22 949) (737-1939) (5340-10 402) (6317-10 624) (410-1078) (2045-4269)
Y 592 380 211 12 808 2896 7053 5846 2327 4366
(377-931) (251-577) (138-323) (9227-17 778) (2046-4100) (5072-9810) (4200-8137) (1690-3203) (3117-6114)
W-135 447 120 22 9566 1921 5657 4612 1577 2954
(305-654) (77-189) (15-32) (7244-12 633) (1450-2545) (4269-7498) (3523-6037) (1217-2044) (2314-3773)

Abbreviations: MCV-4, quadrivalent meningococcal conjugate vaccine against groups A, C, Y, and W-135; PSV-4, quadrivalent meningococcal polysaccharide
vaccine against groups A, C, Y, and W-135.

COMMENT centages of participants with systemic reactions were simi-

Adolescents and young adults in the United States repre-
sent a major target group for immunoprophylaxis against
meningococcal disease.4,5 The reported incidence of in-
vasive disease in this age group and the number of out-
breaks have increased since 1991.3 The diagnosis of me-
ningococcal disease presents challenges to the clinician
because symptoms are similar to those of less serious ill-
nesses, the symptoms have a sudden onset, and the dis-
ease may rapidly progress to permanent disability or
death.3,13,14 Public concern is further heightened when cases
occur in school or college settings, resulting in mass im-
munization efforts as part of outbreak control.5
The study described here was undertaken to evaluate
the immunogenicity and safety of a novel meningococcal
(groups A, C, Y, and W-135) polysaccharide diphtheria tox-
oid conjugate vaccine, MCV-4, vs those of PSV-4 in more
than 800 participants. A 3-year follow-up was performed
in a convenience sample of participants to evaluate the im-
munogenicity of the vaccines within the time frame cur-
rently recommended for revaccination with PSV-4.5
In this study, the safety profiles of the 2 vaccines were
comparable following the initial vaccination. The per-
lar for both vaccines. A greater percentage of partici-
pants in the MCV-4 group reported immediate and local
reactions, primarily pain, after initial vaccination com-
pared with those in the PSV-4 group. These reactions were
generally mild and resolved within 2 to 3 days. This find-
ing was not unexpected because PSV-4 has shown ex-
cellent safety in clinical practice and the inclusion of a
diphtheria toxoid carrier protein in MCV-4 had the po-
tential to cause more local reactions, similar to ob-
served reactions following tetanus-diphtheria vaccina-
tion. Further, the intramuscular route of MCV-4 injection
might have caused increased reactogenicity relative to the
subcutaneous route used for PSV-4. Participants receiv-
ing a second dose of MCV-4 reported a similar level of
local and systemic reactions compared with those who
received a dose of MCV-4 3 years after an initial dose of
PSV-4. Overall, safety findings among participants re-
ceiving MCV-4 were consistent with those observed in
earlier trials in infants, toddlers, and adults.9-12
Immunogenicity was evaluated using a standardized
functional antibody assay, SBA with baby rabbit serum as
a complement source, as recommended by the World Health
Organization (Geneva, Switzerland).15 The SBA re-

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 A Serogroup A B Serogroup C

100 100
90 90
Subjects Achieving Titer, %

80 80
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
8

16

32

64

24

48

96

92

36

16

32

64

24

48

96

92

36
12

25

51

38

76

53

12

25

51

38

76

53
10

20

40

81

55

10

20

40

81

55
16

32

65

16

32

65
>6

>6
C Serogroup Y D Serogroup W-135

100 100
90 90
Subjects Achieving Titer, %

80 80
70 70
60 60
50 50
40 40
30 30
20 20
10 10
0 0
8

16

32

64

24

48

96

92

36

16

32

64

24

48

96

92

36
12

25

51

38

76

53

12

25

51

38

76

53
10

20

40

81

55

10

20

40

81

55
16

32

65

16

32

65
>6

>6
SBA Antibody Titer SBA Antibody Titer

Figure 2. Reverse cumulative distribution curves for meningococcal (groups A, C, Y, W-135) polysaccharide diphtheria toxoid conjugate vaccine (MCV-4) booster
3 years after initial vaccination. Open circles indicate vaccine-naive subjects; triangles, quadrivalent polysaccharide vaccine (PSV-4) recipients; filled circles,
MCV-4 recipients; dotted lines, prebooster levels; solid lines, 28 days postvaccination; SBA, serum bactericidal antibody.

sponses elicited by the MCV-4 vaccine measured 28 days late that such a rise may be due to early onset of high-avidity
after the initial vaccination were comparable with or higher IgG antibodies. This is consistent with other studies that
than those observed after administration of the PSV-4 vac- have shown that booster responses are characterized by the
cine. Those participants with prevaccination SBA titers of presence of high-avidity IgG antibodies.
less than 8, a level considered at risk for serogroup C me- Immunogenicity findings in the current report are con-
ningococcal disease,16 exhibited comparable seroconver- sistent with those observed for the serogroup C menin-
sion rates to both vaccines, more than 98% for all 4 sero- gococcal conjugate vaccines, all of which induce robust
groups. Similarly, the proportion displaying a 4-fold increase immune responses in this age group.6 The efficacy of these
in SBA titers in the MCV-4 group was similar to that ob- vaccines against serogroup C meningococcal disease after
served with the licensed comparator vaccine, PSV-4, which 4 years was 96% in 15- to 17-year olds in the United King-
has proven efficacy and immunogenicity.5 dom and 96.8% in 2- to 20-year-olds in Quebec.19,20 The in-
Three years following primary vaccination, adolescents troduction of a universal vaccination program in the United
previously vaccinated with MCV-4 had higher SBA GMTs Kingdom resulted in a meningococcal serogroup C carriage
compared with those who had been vaccinated with PSV- reduction of 66% in 15- to 17-year-olds and herd immunity
4. A higher proportion of participants in the MCV-4 primed as evidenced by a 67% reduction of disease incidence among
group had SBA titers 128 or greater against serogroups A, unvaccinated infants, children, and adolescents.7,8,21 Further
C, Y, and W-135 compared with the PSV-4 primed group. experience is needed to determine whether the immunologi-
Rapid and robust booster SBA responses to a second dose cal properties observed with serogroup C meningococcal
of MCV-4 were observed in MCV-4 primed participants as conjugate vaccines will be observed with MCV-4 and the im-
illustrated by the reverse cumulative distribution curves. portant disease-causing serogroups A, Y, and W-135.
Responses to the MCV-4 booster dose among the PSV-4 In summary, results from this study of more than 800
primed group were less pronounced but nonetheless con- adolescents show that levels of protective serum bacte-
sistent with levels associated with protection against sero- ricidal antibodies to meningococcal serogroups A, C, Y,
group C meningococcal disease. The pattern of response and W-135 28 days after vaccination with MCV-4 were
observed in the PSV-4 primed group was similar to that ob- comparable with or higher than those observed after vac-
served with monovalent C conjugate vaccination of persons cination with PSV-4. Importantly, MCV-4 demon-
previously vaccinated with meningococcal polysaccharide strated the expected attributes of a conjugate vaccine, in-
vaccines.17 The finding that titers at day 8 were significantly cluding protective antibody persistence, priming and
higher than those seen at day 28 in all groups is unique com- booster responses, and a lack of hyporesponsiveness fol-
pared with other trials of conjugate vaccines.18 We specu- lowing repeat vaccination. Taken together, these find-

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 ings provide the scientific basis for the recent Advisory
Committee on Immunization Practices working group
recommendation for universal vaccination of 11- to 12-
year-olds, adolescents entering high school, and college
freshmen planning to live in dormitories with MCV-4
as a public health strategy to reduce the adolescent and
young adult meningococcal disease burden in the
United States.22
Accepted for Publication: July 28, 2005.
Correspondence: Harry L. Keyserling, MD, Emory Uni-
versity School of Medicine, 2015 Uppergate Dr, NE, At-
lanta, GA 30322 (hkeyser@emory.edu).
Meningococcal Vaccine Study Group Institutions and In-
vestigators: Center for Pediatric Research, Norfolk, Va,
Douglas K. Mitchell, MD; Emory University School of Medi-
cine, Atlanta, Ga, Harry L. Keyserling, MD; Children’s Hos-
pital, Columbus, Ohio, Katalin Koranyi, MD; Pennridge Pe-
diatric Associates, Sellersville, Pa, Erik F. Lamberth, MD;
Holston Medical Group, Kingsport, Tenn, Joseph A. Ley,
MD; Woburn Pediatric Associates, Woburn, Mass, Joseph
P. Leader, MD; Wake Forest University School of Medi-
cine, Winston-Salem, NC, Charles Woods, MD; Chil-
dren’s Hospital Medical Center of Akron, Akron, Ohio,
Blaise Congeni, MD; Pediatrics and Adolescent Medicine
PA, Marietta, Ga, Wilson P. Andrews, Jr, MD; North Shore
University Hospital Division of General Pediatrics, Great
Neck, NY, Stephen Barone, MD; Albany Medical Center,
Department of Pediatrics, Albany, NY, Martha Lepow, MD.
Financial Disclosure: Dr Keyserling has received hono-
raria from Sanofi Pasteur Inc, Swiftwater, Pa, as a speaker.
Funding/Support: This study was funded by a grant from
Sanofi Pasteur Inc. Drs Papa and Ryall, Messrs Bassily and
Bybel, and Drs Gilmet and Reinhardt are employees of
Sanofi Pasteur Inc. Dr Sullivan received grant support to
conduct the statistical analysis. Drs Keyserling and
Koranyi received grant support to conduct the clinical
trial.
Role of the Sponsor: Sanofi Pasteur Inc was actively in-
volved in the conception and design of the study, moni-
toring, evaluation and analysis of the data, manuscript
writing, review, and authorization for manuscript sub-
mission.
Previous Presentations: Information about the initial
immunization was presented in part at the 43rd Inter-
science Conference on Antimicrobial Agents and Che-
motherapy; September 17, 2003; Chicago, Ill; the 4th Pe-
diatric Infectious Disease Society Conference; October
12, 2003; Rancho Bernardo, Calif; and the 6th Canadian
Immunization Conference; December 6, 2004; Mon-
treal, Quebec. A presentation of partial data from the
3-year follow-up was made at the Pediatric Academic So-
cieties Meeting; May 15, 2005; Washington, DC.
Acknowledgment:KeithVeitch,PhD,andLisaDeTora,PhD,
of Sanofi Pasteur Inc provided guidance for the writing
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process and scientific presentation of the data and prepared
drafts of the manuscript. Tom Le Duc, BS, oversaw the in-
house conduct of the clinical trials at Sanofi Pasteur Inc.
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