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 FREE

In September 2004, the Vaccines and Related Biological Products Advisory Committee of the US Food and Drug Administration voted unanimously for registration of the first quadrivalent meningococcal 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, approximately 97% of invasive meningococcal disease is sporadic, which underscores the need for a vaccine prevention strategy.^1- 3 Adolescents are a key target group for vaccination against invasive meningococcal disease because of a high incidence rate and risk of serious untoward outcomes. Meningococcal disease is the leading cause of meningitis and sepsis in adolescents and young adults and is associated with reported mortality rates as high as 22.5%.^1,4 Up to 83% of meningococcal disease reported in adolescents would be potentially preventable with a vaccine directed against serogroups A, C, Y, and W-135.⁴

In 2000, the US Advisory Committee on Immunization Practices recommended informing college freshmen about meningococcal disease and the benefits of vaccination.⁵ The currently available quadrivalent meningococcal polysaccharide 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 recommended for routine immunization.^2,5 In contrast, T-cell–dependent antibody responses, such as those produced by monovalent meningococcal conjugate vaccines against serogroup C, are intended to persist over a longer period of time andhave been associated with the development of immune memory, reductions in carriage rates, and herd immunity 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.

This randomized, blinded, multicenter trial was conducted at 11 clinical sites in the United States in accordance with the principles outlined in the Declaration of Helsinki. Local institutional review boards approved the protocol and consent forms. Written informed consent was obtained from a parent or guardian 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 deficiency, prior diagnosis of meningococcal disease, or prior meningococcal vaccination. Three years after the initial vaccination, 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 polysaccharide 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 polysaccharide 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 preservative in a prefilled syringe.

Vaccines were administered in the deltoid region; MCV-4 was administered intramuscularly and PSV-4 was administered subcutaneously. A blinded, computer-generated randomized allocation schedule with a block size of 2 was provided by the sponsor. To maintain blinding of study personnel, vaccinations and safety assessments were performed by different study personnel. Booster vaccination was performed 3 years after initial vaccination with open-label MCV-4.

Participants were monitored for 30 minutes postvaccination for immediate reactions. Solicited local and systemic reactions were recorded on diary cards for 7 days following vaccination. 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 vaccination. Assays were performed by Sanofi Pasteur Inc Global Clinical Immunology Laboratory (Swiftwater, Pa) to determine functional serum bactericidal antibody (SBA) responses for each serogroup.

The SBA responses were determined using 2-fold serial dilutions of sera incubated in sterile 96-well microtiter plates with baby rabbit complement and serogroup-specific meningococcal bacteria. An agar overlay medium was added to the serum/complement/bacteria mixture and allowed to harden. Following an overnight incubation at 37°C with 5% CO₂, bacteria colonies in the wells were counted. The endpoint titer was determined as the reciprocal serum dilution yielding 50% or greater killing of the bacteria as compared with the mean of the complement 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).

For the initial vaccination, the primary immunogenicity criterion 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, defined 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% confidence 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 provide 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. Participants who provided sera between 28 and 56 days after the initial vaccination were evaluated. Analyses were performed using SAS version 8.2 (SAS Institute, Cary, NC). We assessed safety based on the proportion of participants who experienced a severe 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 reaction was associated with vaccination.

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 between September 2000 and October 2001. The 2 groups were similar in sex distribution, age, and racial composition. A total of 425 participants from the MCV-4 group and 423 from the PSV-4 group were included in the immunogenicity analysis. Of the 33 total participants excluded from the immunogenicity analysis, 23 (10 receiving MCV-4 and 13 receiving PSV-4) did not provide sera within the prespecified visit windows, and 6 (2 receiving MCV-4 and 4 receiving PSV-4) had not met entry criteria and were enrolled in error. The distribution of participants 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 participants who received a 3-year booster dose of MCV-4, control participants, or the overall study population for the initial vaccination.

All enrollees provided a baseline blood sample, received the study vaccine, and attended the 28-day follow-up visit for safety assessment and second blood draw. Ten participants did not provide safety data at the 6-month follow-up: 4 were MCV-4 recipients (2 lost to follow-up and 2 voluntarily withdrew) and 6 were in the PSV-4 group (4 lost to follow-up and 2 voluntarily withdrew). No participant dropped out or was withdrawn from the study because of an adverse event.

After the initial vaccination, 2 participants had a vasovagal episode within 30 minutes of receiving MCV-4. These events resolved spontaneously without medical intervention. No other immediate reactions were reported after the initial 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 common 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 local 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 participants in the MCV-4 group and 441 participants in the PSV-4 group after the initial vaccination. The overall frequency of systemic reactions was similar in both groups. More than half of the participants reported at least 1 solicited systemic reaction, 251 (57.2%) of 439 participants in the MCV-4 group vs 229 (51.9%) of 441 participants in the PSV-4 group (Table 3). Mild to moderate headache was the most common systemic reaction, reported 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 occurred with similar frequencies in both groups. Almost all reported solicited systemic reactions were mild to moderate in severity and resolved within 3 days of vaccination. One case of high fever, defined as an oral temperature 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 reactions.

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 fixation, acetaminophen overdose, facial baseball injury, torn meniscus, preexisting supraventricular tachycardia—was considered unrelated to the vaccine by study investigators.

At the 3-year follow-up, the safety profile, including solicited reactions, was generally similar between participants in the MCV-4, PSV-4, and control groups. No serious adverse events or new or unexpected effects were observed for any participant in any group. Among the cohort of 76 initial MCV-4 recipients revaccinated 3 years later, a second dose of MCV-4 was generally well tolerated.

The SBA GMTs for each serogroup were similar between the MCV-4 and PSV-4 groups prior to the initial vaccination. Marked increases in SBA levels were observed 28 days after the initial vaccination for both study groups (Table 4). The SBA response for serogroup A, assessed by GMTs, was significantly higher in the MCV-4 group compared with the PSV-4 group. The GMTs for the other serogroups were similar in the 2 vaccine groups.

Overall, more than 90% of participants had titers of 128 or more against all 4 serogroups after the initial vaccination (Table 4). The percentage of participants who had a 4-fold or greater rise in SBA 28 days after the initial vaccination was highest for serogroups A and W-135 for both vaccine groups. For all serogroups, the percentage of participants with a 4-fold or greater rise was similar in the MCV-4 group compared with the PSV-4 group.

Among participants with an SBA titer of less than 8 before the initial vaccination, seroconversion, defined as a 4-fold or greater rise, occurred in the vast majority of participants 28 days after vaccination for all 4 serogroups. Values for the MCV-4 group ranged from 98.2% to 100% while those observed in the PSV-4 group were from 99.3% to 100% (data not shown).

In both groups of participants evaluated 3 years after the initial vaccination, bactericidal antibody levels remained markedly higher than initial baseline values for all 4 serogroups (Table 5). Overall, the percentage of participants with SBA titers 128 or more ranged from 71% to 95% for the MCV-4 group and from 57% to 83% for the PSV-4 group (data not shown). A booster dose of MCV-4 resulted in a rise in antibody response for all 4 serogroups 8 days postvaccination. Participants who had previously received PSV-4 also had high antibody responses 8 days postvaccination; however, the booster antibody responses to the PSV-4 primed participants were not as high compared with the MCV-4 primed participants (Table 5). Both MCV-4 and PSV-4 groups had higher bactericidal antibody levels compared with baseline for all 4 serogroups at Day 28. Responses in the group of previously meningococcal vaccine–naive participants were consistent with those observed after the initial vaccination with MCV-4, showing a marked rise in SBA levels. These findings are further illustrated by the reverse cumulative distribution curves for bactericidal antibodies against the 4 serogroups on day 28 (Figure 2).

Adolescents and young adults in the United States represent a major target group for immunoprophylaxis against meningococcal disease.^4- 5 The reported incidence of invasive disease in this age group and the number of outbreaks have increased since 1991.³ The diagnosis of meningococcal disease presents challenges to the clinician because symptoms are similar to those of less serious illnesses, the symptoms have a sudden onset, and the disease 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 immunization 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 toxoid 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 immunogenicity of the vaccines within the time frame currently recommended for revaccination with PSV-4.⁵

In this study, the safety profiles of the 2 vaccines were comparable following the initial vaccination. The percentages of participants with systemic reactions were similar for both vaccines. A greater percentage of participants in the MCV-4 group reported immediate and local reactions, primarily pain, after initial vaccination compared with those in the PSV-4 group. These reactions were generally mild and resolved within 2 to 3 days. This finding was not unexpected because PSV-4 has shown excellent safety in clinical practice and the inclusion of a diphtheria toxoid carrier protein in MCV-4 had the potential to cause more local reactions, similar to observed reactions following tetanus-diphtheria vaccination. Further, the intramuscular route of MCV-4 injection might have caused increased reactogenicity relative to the subcutaneous route used for PSV-4. Participants receiving 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 receiving 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 responses elicited by the MCV-4 vaccine measured 28 days after the initial vaccination were comparable with or higher than those observed after administration of the PSV-4 vaccine. Those participants with prevaccination SBA titers of less than 8, a level considered at risk for serogroup C meningococcal disease,¹⁶ exhibited comparable seroconversion rates to both vaccines, more than 98% for all 4 serogroups. Similarly, the proportion displaying a 4-fold increase in SBA titers in the MCV-4 group was similar to that observed with the licensed comparator vaccine, PSV-4, which has proven efficacy and immunogenicity.⁵

Three years following primary vaccination, adolescents previously vaccinated with MCV-4 had higher SBA GMTs compared with those who had been vaccinated with PSV-4. A higher proportion of participants in the MCV-4 primed group had SBA titers 128 or greater against serogroups A, C, Y, and W-135 compared with the PSV-4 primed group. Rapid and robust booster SBA responses to a second dose of MCV-4 were observed in MCV-4 primed participants as illustrated by the reverse cumulative distribution curves. Responses to the MCV-4 booster dose among the PSV-4 primed group were less pronounced but nonetheless consistent with levels associated with protection against serogroup C meningococcal disease. The pattern of response observed in the PSV-4 primed group was similar to that observed with monovalent C conjugate vaccination of persons previously vaccinated with meningococcal polysaccharide vaccines.¹⁷ The finding that titers at day 8 were significantly higher than those seen at day 28 in all groups is unique compared with other trials of conjugate vaccines.¹⁸ We speculate that such a rise may be due to early onset of high-avidity IgG antibodies. This is consistent with other studies that have shown that booster responses are characterized by the presence of high-avidity IgG antibodies.

Immunogenicity findings in the current report are consistent with those observed for the serogroup C meningococcal conjugate vaccines, all of which induce robust immune responses in this age group.⁶ The efficacy of these vaccines against serogroup C meningococcal disease after 4 years was 96% in 15- to 17-year olds in the United Kingdom and 96.8% in 2- to 20-year-olds in Quebec.^19- 20 The introduction of a universal vaccination program in the United Kingdom resulted in a meningococcal serogroup C carriage reduction of 66% in 15- to 17-year-olds and herd immunity as evidenced by a 67% reduction of disease incidence among unvaccinated infants, children, and adolescents.^7- 8,21 Further experience is needed to determine whether the immunological properties observed with serogroup C meningococcal conjugate vaccines will be observed with MCV-4 and the important disease-causing serogroups A, Y, and W-135.

In summary, results from this study of more than 800 adolescents show that levels of protective serum bactericidal antibodies to meningococcal serogroups A, C, Y, and W-135 28 days after vaccination with MCV-4 were comparable with or higher than those observed after vaccination with PSV-4. Importantly, MCV-4 demonstrated the expected attributes of a conjugate vaccine, including protective antibody persistence, priming and booster responses, and a lack of hyporesponsiveness following repeat vaccination. Taken together, these findings 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

Correspondence: Harry L. Keyserling, MD, Emory University School of Medicine, 2015 Uppergate Dr, NE, Atlanta, GA 30322 (hkeyser@emory.edu).

Financial Disclosure: Dr Keyserling has received honoraria from Sanofi Pasteur Inc, Swiftwater, Pa, as a speaker.

Previous Presentations: Information about the initial immunization was presented in part at the 43rd Interscience Conference on Antimicrobial Agents and Chemotherapy; September 17, 2003; Chicago, Ill; the 4th Pediatric Infectious Disease Society Conference; October 12, 2003; Rancho Bernardo, Calif; and the 6th Canadian Immunization Conference; December 6, 2004; Montreal, Quebec. A presentation of partial data from the 3-year follow-up was made at the Pediatric Academic Societies Meeting; May 15, 2005; Washington, DC.

Accepted for Publication: July 28, 2005.

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.

Meningococcal Vaccine Study Group Institutions and Investigators: Center for Pediatric Research, Norfolk, Va, Douglas K. Mitchell, MD; Emory University School of Medicine, Atlanta, Ga, Harry L. Keyserling, MD; Children’s Hospital, Columbus, Ohio, Katalin Koranyi, MD; Pennridge Pediatric 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 Medicine, Winston-Salem, NC, Charles Woods, MD; Children’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.

Role of the Sponsor: Sanofi Pasteur Inc was actively involved in the conception and design of the study, monitoring, evaluation and analysis of the data, manuscript writing, review, and authorization for manuscript submission.

Acknowledgment: Keith Veitch, PhD, and Lisa DeTora, PhD, of Sanofi Pasteur Inc provided guidance for the writing 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.