Serum Bactericidal Antibody Responses of Students Immunized With a Meningococcal Serogroup B Vaccine in Response to an Outbreak on a University Campus

Summary

Two MenB-4C doses are recommended based on studies of serum bactericidal antibody using reference strains. Against 4 college outbreak strains, 53%–93% of students had protective titers at 1 month, which decreased to 31%–86% at 7 months. A booster dose may be required to increase duration of protection.

Abstract

Background

MenB-4C is a recently licensed meningococcal serogroup B vaccine. For vaccine licensure, short-term efficacy was inferred from serum bactericidal antibody (SBA) titers against 3 antigen-specific indicator strains, which are not necessarily representative of US disease-causing strains.

Methods

A total of 4923 students were immunized with MenB-4C in response to an outbreak at a university. Serum samples were obtained at 1.5–2 months from 106 students who received the recommended 2 doses and 52 unvaccinated students. Follow-up serum samples were obtained at 7 months from 42 vaccinated and 24 unvaccinated participants. SBA was measured against strains from 4 university outbreaks.

Results

At 1.5–2 months, the proportion of immunized students with protective titers ≥1:4 against an isolate from the campus outbreak was 93% (95% confidence interval [CI], 87%–97%) vs 37% (95% CI, 24%–51%) in unvaccinated students. The proportion with protective titers against strains from 3 other university outbreaks was 73% (95% CI, 62%–82%) vs 26% (95% CI, 14%–41%) in unvaccinated; 71% (95% CI, 61%–79%) vs 19% (95% CI, 10%–33%) in unvaccinated; and 53% (95% CI, 42%–64%) vs 9% (95% CI, 3%–22%) in unvaccinated (P < .0001 for each strain). At 7 months, the proportion of immunized students with titers ≥1:4 was 86% (95% CI, 71%–95%) against the isolate from the campus outbreak and 57% (95% CI, 41%–72%), 38% (95% CI, 24%–54%), and 31% (95% CI, 18%–47%), respectively, for the other 3 outbreak strains.

Conclusions

MenB-4C elicited short-term protective titers against 4 strains responsible for recent university campus outbreaks. By 7 months the prevalence of protective titers was <40% for 2 of the 4 outbreak strains. A booster dose of MenB-4C may be needed to maintain protective titers.

Neisseria meningitidis causes septicemia and meningitis. In the United States, nearly all cases are caused by encapsulated serogroup B, C, or Y strains [1]. Since 2005, there has been a steady decline in the incidence of meningococcal disease, in part from routine adolescent immunization with quadrivalent serogroup A, C, Y, and W conjugate vaccines [2]. Until 2014, however, there were no vaccines available in the United States against serogroup B strains, which account for approximately one-third of cases of disease in the United States [3], and an even greater proportion in Europe [4, 5]. Serogroup B strains also are responsible for recent meningococcal outbreaks on US college campuses [6–11].

In the United States, there are 2 US Food and Drug Administration (FDA)–approved meningococcal serogroup B vaccines that target protein antigens. One vaccine (Trumenba, Pfizer Vaccines), is called MenB-FHbp because it contains 2 Factor H binding protein (FHbp) antigens from subfamilies A and B [12]. The second vaccine (Bexsero, GlaxoSmithKline) is called MenB-4C [13] or 4CMenB [14] because it contains 4 components (antigens) that elicit serum bactericidal antibody (SBA) [15, 16]. The US Advisory Committee on Immunization Practices recommends serogroup B vaccination for all persons with certain host abnormalities (eg, complement deficiencies or hyposplenic function), or those with increased risk of exposure (eg, microbiologists, or persons exposed to outbreaks) [13]. Vaccination also should be considered for persons aged 16–23 years who wish to have short-term protection [13, 17].

For licensure of the serogroup B vaccines, efficacy was inferred from SBA responses against 3 or 4 reference strains [18, 19]. Whereas SBA titers ≥1:4 are sufficient for protection against developing meningococcal disease [20, 21], estimating strain coverage for vaccines that target protein antigens is challenging because of diversity in antigen amino acid sequence and expression [22–25]. Also, nearly all of the serologic data supporting vaccine licensure were based on peak serum antibody responses at 1 month postimmunization, with limited information on the duration of protective antibody [26].

The purpose of the present study was to investigate the prevalence of protective SBA titers at 1.5–2 months postimmunization in students immunized with MenB-4C in response to a serogroup B outbreak on a university campus. In addition, we obtained follow-up serum samples in a subset of participants 7 months after vaccination to determine SBA persistence. The target serogroup B strains included an isolate from the outbreak, 3 genetically diverse case isolates from other US university outbreaks, and an endemic case isolate matched with the vaccine for only 1 antigen (see below).

METHODS

Outbreak and Vaccination Campaign

Santa Clara University is located in Northern California, with 5438 undergraduate students during the 2016 academic year. Between 31 January 2016 and 2 February 2016, 2 culture-confirmed cases and 1 clinically compatible case with negative cultures occurred in undergraduate students (Figure 1) [8]. Both serogroup B isolates were from clonal complex 32 with a new sequence type, ST11910. The isolates expressed 3 MenB-4C antigens: FHbp subfamily B, neisserial adhesin A (NadA), and neisserial heparin binding antigen (NHba) (Table 1).

Figure 1.

Time course of outbreak and study. Cases 1 and 2 were culture confirmed; case 3 was suspected based on clinically compatible data and negative cultures. Polymerase chain reaction of cerebrospinal fluid was weakly positive for serogroup B meningococci at the California State Health Department Laboratory, but was repeated and considered inconclusive at the Centers for Disease Control and Prevention. Of the 79 students in the 1-dose group with serum samples, 75 were immunized during the first campaign in February (3.5 months earlier) and 4 were immunized in April (1.5 months earlier). In the analyses of the responses of the 1-dose group, only subjects immunized in the first campaign were included (see text of Methods section).

Table 1.

Meningococcal Strains Used to Test Serum Bactericidal Activity^a

Strain	Location (Year and No. of Cases)	Sequence Typeb (Clonal Complex)	Relative Strain Antigen Expressionc			OMV (PorA)
			FHbp Subfamily (Pep ID)	NadA	NHba	P1.4
CH863, college outbreak [8]	Santa Clara University, California (2016, 2 confirmed and 1 suspected case)	11910 (32)	B, ++ (510)	+	++	No
CH855, college outbreak [27]	Ohio University (2010, 13 cases)	269 (269)	B, + (15)	++	++	No
CH819, college outbreak [6, 7, 28]	Princeton University, New Jersey (2013, 9 cases)	409 (41/44)	B, + (276)	Absent	+	No
CH865, college outbreak [11]	Rutgers University, New Jersey (2016, 2 cases)	11 (11)	A, +/– (19)	Absent	+/–	No
B11, M4407 (CH258) [29]	Minnesota (1996) Endemic case isolate	6160 (41/44)	A, ++ (19)	Absent	++	No

^aAdapted from previously reported data [30].

^bSequence type and inferred clonal complexes were determined by multilocus sequence typing [46].

^cAntigen expression was measured by flow cytometry using live bacteria as previously described [31, 32] and polyclonal antiserum from mice immunized with recombinant FHbp ID 1 (subfamily B) or ID 22 (subfamily A), NHba (ID 2), or NadA (ID 8). For quantitation of antigen expression, +/– is <20%; + is 20%–80%; and ++ is >80% of expression compared to a positive control strain tested in parallel. Expression of FHbp was compared with strains H44/76 (subfamily B) or M4407 (subfamily A), depending on the subfamily of the test isolate. Expression of NadA was compared to strain 5/99 [47], and expression of NHba was compared to strain M4407. All of these strains are naturally high expressers of the respective antigen being measured [29, 48]. Absent NadA indicates no detectable binding and absence of or a truncated NadA gene. For OMV, PorA P1.4 was measured with a specific mouse monoclonal antibody and the strain variable region sequence type was inferred by gene sequencing.

In response to the outbreak, public health officials and the Student Health Services held mass immunization clinics and administered the first doses of MenB-4C to 4923 students between 4 and 8 February 2016. Six to 8 weeks later, second doses (and some first doses) were administered to 3741 students (Figure 1) [8]. No further cases were identified during 1 year of follow-up.

Study Design

We obtained serum samples from undergraduate students 1.5–2 months after the second MenB-4C campaign. Students were eligible if they had no significant underlying diseases or treatments expected to impair immune responses, had a written record of vaccination, and provided written informed consent. The protocol and consent form were approved by the institutional review boards of Santa Clara University, the California Department of Public Health, and UCSF Benioff Children’s Hospital Oakland. Of the 247 students who enlisted (Supplementary Figure 1), 8 failed eligibility criteria or were unable to provide a blood sample. For the remaining 239 students, blood was collected in coded red-top tubes. Serum was separated and stored frozen at –80°C. Two students were subsequently excluded because vaccination status could not be confirmed in 1 student, and the second enrolled twice, leaving 237 eligible subjects: 106 two-dose recipients, 79 one-dose recipients, and 52 unvaccinated students. In the 1-dose group, 75 subjects had been immunized during the first vaccination campaign, 3.5 months earlier, and 4 subjects had been immunized 1.5 months earlier during the second campaign. To maintain homogenous groups with respect to follow-up time after immunization, data from the 4 subjects immunized during the second campaign were not included in the final analyses, leaving 75 participants in the 1-dose group. At 7 months, we also obtained follow-up serum samples from 42 of the 106 students given 2 doses and 24 of the 52 unvaccinated students.

The sizes for each of the groups for the first serum sample approximated those projected in the original protocol (80 students each in the 1- or 2-dose groups, and 40 unvaccinated), which had an 80% power to detect an average 1.75-fold change in antibody in the vaccinated groups compared to unvaccinated (at a type I error rate of 5%).

The mean age of the 3 groups ranged from 20.2 to 20.4 years (Table 2). The mean body mass index (BMI) value ranged from 24.0 to 24.6. The recommended MenB-4C immunization schedule is 2 doses separated by 1–2 months. Our main serologic comparisons were between students given 2 doses and unvaccinated students. Among these groups, the percentage of immunized students who were male was 42% vs 50% in unvaccinated students (P = .39). The percentage of immunized students who lived in campus residence halls was 64% vs 40% for unvaccinated students (P = .006). For the 1-dose group, the percentage of immunized subjects who were male was 67% (P = .032 compared to unvaccinated), and the percentage of immunized students who lived on campus was 51% (P = .28 compared to unvaccinated).

Table 2.

Description of Demographic Characteristics of Student Groups by Number of Vaccine Doses

Characteristic	No. of Doses of Vaccine			P Value
	2	1	0	2 vs 0 Doses	1 vs 0 Doses
No. of subjects	106	75	52
Age, y, mean (range)	20.3 (18–24)	20.2 (18–25)	20.4 (18–23)	.81a	.46a
BMI, mean ± SD	24.0 ± 4.3	24.0 ± 4.5	24.6 ± 4.2	.49a	.63a
Male sex, No. (%)	44 (42)	50 (67)	26 (50)	.39b	.03b
First-year student, No. (%)	21 (20)	21 (28)	15 (29)	.23b	1.00b
On-campus residencec, No. (%)	68 (64)	38 (51)	21 (40)	.006b	.28b

Abbreviations: BMI, body mass index; SD, standard deviation.

^aTwo-way comparisons by t test.

^bTwo-way comparison by Fisher exact test.

^cFor off-campus residence, we included 1%–3% in each group residing in fraternity or sorority houses that were located off campus.

Neisseria meningitidis Strains

The serogroup B outbreak strains included a case isolate from the Santa Clara University outbreak, and 1 case isolate each from 3 previously described outbreaks at Ohio University [27], Princeton University [6, 28] and Rutgers University [11]. In studies of serum antibody persistence we included a fifth serogroup B strain, designated M4407, which is an endemic case isolate used in previous studies to measure anti-NHba SBA responses to MenB-4C [29, 30]. Based on multilocus sequence typing, the 5 isolates were from 4 distinct hypervirulent genetic lineages (Table 1). None of the strains expressed PorA VR2 P1.4, which is present in the vaccine OMV component. Based on flow cytometric studies [31, 32], the isolates from Ohio, Princeton, and Santa Clara universities were predicted to be susceptible to anti-MenB-4C antibodies (ie, expression of 2 or 3 antigens that matched the vaccine; Table 1), whereas the Rutgers University isolate was predicted to be resistant (absent or low expression of all 4 MenB-4C antigens).

Serum Bactericidal Assays

The assay was performed as described previously [31, 33]. Test sera were heated for 30 minutes at 56°C to inactivate endogenous complement and immunoglobulin G–depleted human serum was used as a source of exogenous complement [34]. We graphed the percentage survival of colony-forming units/mL after 60 minutes’ incubation at 37°C for each serum dilution tested. The titer was determined by the 50% intercept. For serum sample 1, we tested all 237 available sera against the Santa Clara and Ohio University strains. Because of limited human complement, for the Princeton and Rutgers University isolates we tested a subset of 88 of the 106 samples post–dose 2, 45 of the 75 post–dose 1, and 43 of the 52 sera from unvaccinated students.

Statistical Analyses

The proportions of students with SBA titers of ≥1:4 (presumed to confer protection) and ≥1:16 (a more robust response) were computed along with exact 95% confidence intervals using Prism version 7.00 software (GraphPad, La Jolla, California). The possible effects of different risk factors on protective antibody titers ≥1:4 at 1.5–2 months in students immunized with the recommended 2 doses were determined by logistic regression analyses using Stata softare version 13. The variables considered were age, BMI measured at time of enrollment, sex, academic year, and on-campus residency. Among the paired samples, the significance of differences in the respective proportions of vaccinated students with protective titers at 1.5–2 and 7 months postvaccination was computed by exact McNemar test. All statistical tests were 2-tailed; P values ≤.05 were considered statistically significant.

RESULTS

Serum Bactericidal Antibody Responses to 1 Dose

Because adolescents receiving a multidose vaccine often fail to return for subsequent doses [35], it was of interest to compare SBA titers ≥1:4 in students given 1 dose compared to unvaccinated students. For the 1-dose group, the serum samples were obtained 3.5 months postimmunization (Figure 1). Against the Santa Clara University strain, 57% (95% confidence interval [CI], 45%–69%) had titers ≥1:4 vs 37% (95% CI, 24%–51%) in unvaccinated students (P = .03; Supplementary Figure 2). Against the other 3 university outbreak strains, the proportion of immunized students with titers ≥1:4 was approximately 1.5- to 2-fold higher than in unvaccinated students, but the respective differences were not significant: Princeton University, 42% (95% CI, 28%–57%) vs 26% (95% CI, 14%–41%) (P = .12); Ohio University, 32% (95% CI, 22%–44%) vs 19% (95% CI, 10%–33%) (P = .15); and Rutgers University, 20% (95% CI, 10%–35%) vs 9% (95% CI, 3%–22%) (P = .23). For the Princeton and Rutgers University isolates, we analyzed a subset of sera from 45 of the 75 subjects in the 1-dose group, which limited the statistical power to detect a significantly higher prevalence of protective SBA titers, if present.

Serum Bactericidal Antibody Responses to 2 Doses

Among 2-dose recipients, the prevalence of protective SBA titers ≥1:4 at 1.5–2 months post–dose 2 was 93% (95% CI, 87%–97%) against the Santa Clara University isolate, and 73% (95% CI, 62%–82%), 71% (95% CI, 61%–79%), and 53% (95% CI, 42%–64%), for the Princeton, Ohio, and Rutgers University strains, respectively (Figure 2A). For each strain, the percentage of students given 2 doses with titers ≥1:4 was significantly higher than in unvaccinated students (P < .0001). Figure 2B depicts the reverse cumulative distribution of titers at 1.5–2 months against each of the outbreak strains. The lowest dilution tested was 1:4. For the Santa Clara University strain, the prevalence of titers ≥1:16 (the minimum required by the FDA for a 4-fold titer increase after vaccination; Bexsero US package insert, Table 1, https://gsksource.com/pharma/content/dam/GlaxoSmithKline/US/en/Prescribing_Information/Bexsero/pdf/BEXSERO.PDF) was 62% (95% CI, 52%–71%) compared with 12% (95% CI, 4%–23%) for unvaccinated students (P < .0001). The proportion of 2-dose recipients with titers ≥1:16 also was significantly higher than in unvaccinated students for the Princeton University (26% vs 7%) and Ohio University (10% vs 0%) strains (P ≤ .017), but not for the Rutgers University strain (3% vs 0%; P = .55). The reciprocal geometric mean titers (GMTs) were >3-fold higher for the Santa Clara University strain (24.3) than for the other 3 outbreak strains (4.2–8; Figure 2B).

Figure 2.

Prevalence of serum bactericidal antibody (SBA) titers 1.5–2 months after 2 doses of vaccine. A, Proportion of students with SBA titers ≥1:4 (presumed to be protective) measured against college outbreak strains from Santa Clara, Princeton, and Ohio Universities (each with 2 or 3 antigens in MenB-4C) and Rutgers University (no MenB-4C antigens). Dashed line, 70%. B, Reverse cumulative distribution of serum bactericidal titers. The Santa Clara University and Ohio University outbreak isolates were tested with sera from all 106 subjects who received 2 doses of vaccine and all 52 unvaccinated controls. The Princeton and Rutgers University isolates were tested against a subset of sera (n = 88 of 106 given 2 doses; and 43 of the 52 unvaccinated). Error bars, 95% confidence intervals (CIs). Numbers in parentheses represent 1 / geometric mean titer. For all 4 strains, the percentage of vaccinated students with protective titers ≥1:4 was higher than in unvaccinated students (P < .001).

By logistic regression analyses after adjusting for age, BMI, sex, being a first-year student, or living in residence halls on campus, there remained a strong vaccine effect on protective titers (odds ratios [OR], 228 [95% CI, 30.2–1718], 8.28 [95% CI, 3.4–20.2], 26.7 [95% CI, 7.54–87.3], and 14.2 [95% CI, 4.26–47.4] for the Santa Clara, Princeton, Ohio, and Rutgers isolates, respectively, Supplementary Table 1; P < .001 for each strain). However, depending on the strain, several factors such as living on campus, sex, or being a first-year student independently affected the ORs differently for having a protective titer in vaccinated and unvaccinated students. In subsequent analyses of only students with 2 doses of vaccine, none of the above variables significantly affected the OR for having a protective SBA titer at 1.5–2 months after vaccination (Supplementary Table 2).

Persistence of Serum Bactericidal Antibody 7 Months After Vaccination

We obtained paired serum samples at 7 months from 42 of the 106 students given 2 doses and 24 of the 52 unvaccinated students (Supplementary Figure 1). At 1.5–2 months, the respective percentages of students with protective SBA titers against each strain were similar for the subset and entire sample set (compare Figure 2A, entire sample set, with Figure 3A, subset). At 7 months, 86% (95% CI, 71%–95%) of 2-dose recipients had protective titers ≥1:4 against the Santa Clara University strain, compared with 12.5% (95% CI, 3%–32%) of unvaccinated students sampled at the same time point (Figure 3B). The corresponding proportions of 2-dose recipients at 7 months with protective titers was 57% (95% CI, 41%–72%) for the Princeton University strain; 38% (95% CI, 24%–54%) for the Ohio University strain; and 31% (95% CI, 18%–47%) for the Rutgers University strain. The proportion of vaccinated students with protective titers at 7 months was lower than at 1.5–2 months for 3 of the 4 outbreak strains (exact McNemar test P < .03). The only exception was the Santa Clara University isolate (P = .125). The respective reciprocal GMTs in vaccinated students also declined between 1.5–2 months and 7 months (Supplementary Table 3). Despite the decline in protective titers, the proportion of 2-dose vaccinated students with protective titers at 7 months was higher than in unvaccinated students for all 4 outbreak strains (Figure 3B; P ≤ .019). Interestingly, at 1.5–2 months, unvaccinated students were more likely to have protective titers against the Santa Clara University strain than at 7 months (37.5% vs 12.5%; P = .03). A higher prevalence of protective titers at 1.5–2 months than at 7 months was not present for the other outbreak strains (P > .5). Conceivably, the outbreak strain may have circulated among the students and elicited transient strain-specific increases in SBA.

Figure 3.

Persistence of protective serum bactericidal antibody (SBA) titers 7 months after 2 doses of vaccine. Serum samples were obtained at 7 months from 42 of the 106 students given 2 doses and 24 of the 52 unvaccinated students. SBA titers were measured against the 4 college outbreak strains and an endemic case isolate, M4407, which expressed only 1 vaccine antigen (NHba) (see Methods). A, Prevalence of serum titers ≥1:4 at 1.5–2 months post–dose 2. B, Prevalence at 7 months post–dose 2. Black bars, vaccinated students. White bars, unvaccinated. Error bars indicate 95% confidence interval (CI). Horizontal line designates 70% with titers ≥1:4.

SBA titers also were tested in paired sera from 1.5–2 and 7 months against a fifth serogroup B test isolate known as M4407, which expresses NHba with 100% amino acid sequence identity to the vaccine antigen and is mismatched for the other 3 antigens in MenB-4C that elicit SBA (Table 1). At 1.5–2 months, the prevalence of titers ≥1:4 in subjects given 2 doses of vaccine was 76% (95% CI, 60%–88%), which by 7 months had declined to 52% (95% CI, 36%–68%; P = .002). In unvaccinated subjects, the prevalence of SBA titers ≥1:4 was 50% (95% CI, 29%–71%) at both time points. Thus, there was a high background of naturally acquired SBA against this strain in unvaccinated students, and the SBA responses to vaccination over background antibody were transient.

DISCUSSION

From 2013 to 2017, at least 37 cases of confirmed invasive meningococcal serogroup B disease, including 5 deaths, occurred among students on 14 US college campuses (http://www.nmaus.org/wp-content/uploads/2017/01/College-Cases-Map.pdf). Social factors such as on-campus residence, exposure to tobacco smoke, bar patronage, and intimate kissing make college campuses particularly vulnerable to spread of meningococci [7, 36–41]. The predominance of serogroup B strains in college students can be explained by routine vaccination of teenagers with quadrivalent meningococcal A, C, Y, and W conjugate vaccines, whereas serogroup B vaccination, which was first approved by the FDA in November 2014 [7, 42], has not yet been widely implemented in the United States [17].

In the present study, we measured SBA titers after a campus-wide MenB-4C vaccination campaign done in response to a serogroup B outbreak. Three of the 4 university outbreak strains were predicted to be susceptible based on moderate to high expression of 2 or 3 vaccine antigens (Table 1). The fourth outbreak strain from Rutgers University was predicted to be resistant based on absent or mismatched antigens contained in MenB-4C [11]. A fifth endemic case isolate was predicted to be susceptible to anti-NHba bactericidal activity (Table 1).

Our most important finding was that the majority of students who received the recommended 2 MenB-4C doses had protective titers ≥1:4 at 1.5–2 months against all 5 strains. The highest proportion was for the Santa Clara University isolate (93%). The lowest was for the Rutgers University isolate (53%), which was mismatched for all 4 MenB-4C antigens. The proportion for the Princeton outbreak strain, 72%, is similar to the 66% prevalence of protective SBA titers reported by Basta et al for students immunized at Princeton University in response to an outbreak on that campus [6]. The reciprocal GMTs in the 2 studies also were similar (8 for Santa Clara University students [Figure 2B] and 7.6 for Princeton University students).

By 7 months post–dose 2, 86% of students in the present study maintained protective SBA titers against the Santa Clara University strain. However, the proportion of protected students had declined to 57% for the Princeton University strain and 31% and 38% for the Rutgers University and Ohio University isolates, respectively. The proportion of protected vaccinated individuals against the endemic case isolate, M4407, had returned to baseline 52% vs 50% in unvaccinated students. In previous studies, persistence of SBA was measured 18–24 months after MenB-4C immunization of adolescents in Chile [26]. For subjects immunized with 2 or 3 doses, the proportions ranged from 75% to 93% against 3 antigen-specific indicator strains compared with 25% to 50% in unvaccinated adolescents. The Chilean study, however, likely overestimated duration of protection against prevalent disease-causing strains as the indicator strains are exact matches of the vaccine antigens and/or are highly susceptible to anti-MenB-4C antibody, and no diverse strains were tested.

Several limitations of the present study are worth noting. First, the study was not a randomized trial, and the vaccinated and unvaccinated groups were not entirely comparable (eg, a higher percentage of students given 2 doses lived in campus housing than unvaccinated students). However, in multivariate analyses after controlling for the different variables, vaccination increased the odds of having a protective titer for all 4 outbreak strains (P < .001). For the 7-month follow-up, the number of fully vaccinated and unvaccinated students with serum samples was smaller than at 1.5–2 months post–dose 2, which resulted in wider confidence intervals for the prevalence of protective titers at 7 months. However, the results clearly underscored significant decreases in serologic protection at 7 months, compared to 1.5–2 months, for all of the strains tested except from Santa Clara University.

MenB-4C was licensed by the FDA for a 2-dose schedule (0 and 1–2 months) using an accelerated approval mechanism that required demonstration of safety and SBA responses against 3 antigen-specific indicator strains. In the present study, we tested 4 genetically diverse serogroup B strains responsible for university outbreaks, and a fifth endemic case isolate. The results supported a clear benefit of vaccination at 1.5–2 months after 2 doses of vaccine. However, the decline in protective SBA titers by 7 months against 4 of the 5 test strains raises concerns that protection may be short-lived, and that a third dose of MenB-4C may be needed at 6 months to maintain immunity. Note, however, that although SBA titers ≥1:4 confer protection [20, 21], titers <1:4 do not necessarily imply susceptibility to disease as meningococci can be killed at lower dilutions of serum, or by opsonophagocytosis [43, 44]. Postmarketing studies therefore are needed to determine the ability of vaccination to decrease the incidence of disease, such as recently was reported in infants in the United Kingdom immunized with MenB-4C, who appear to have high rates of short-term protection [45].

Supplementary Data

Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.

Notes

Acknowledgments. Drs Jennifer Kyle and Kathleen Harriman (California Department of Health) and Dr George Han and Linda Martinez (Santa Clara Department of Public Health) provided expert advice on management of the outbreak and design of the serologic study. Peggie Robinson, RN, Balakrishnan Ramdoss, Kathy Matsche, Jill Maggio, Maria Eugenia Arraya, and Susan Garcia (Santa Clara University Student Health Services) provided expert technical assistance. Drs Elizabeth Partridge (UCSF Benioff Children’s Hospital) and Dr Shrimati Datta (California Department of Health) helped enroll students and obtain blood samples. We are grateful for the logistical help provided by the American Red Cross of Santa Clara County, and the many students who volunteered for the study. We thank the Meningitis Laboratory, the Meningitis and Vaccine Preventable Diseases Branch, Centers for Disease Control and Prevention (CDC), for providing the isolates and determining multilocus sequence typing and genetic characterization on PorA, FHbp, NadA, and NHba vaccine variants.

Financial support. This work was supported in part by the CDC (Epidemiology and Laboratory Capacity for Infectious Diseases cooperative agreement number 6 NU50CK000410-03 to D. M. G. and J. R.), and by research grants from the National Institute of Allergy and Infectious Diseases, National Institutes of Health (grant numbers R01 AI046464 and R01 AI114701 to D. M. G.). The laboratory work was performed in a facility funded by the Research Facilities Improvement Program grant from the National Center for Research Resources, National Institutes of Health (grant number C06 RR016226).

Potential conflicts of interest. All authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.