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Four-component Meningococcal Serogroup B Vaccine Induces Antibodies With Bactericidal Activity Against Diverse Outbreak Strains in Adolescents

Biolchi, Alessia MSc*; Tomei, Sara MSc*; Santini, Laura MSc*; La Gaetana, Rita MSc*; Mori, Elena PhD*; Novy, Patricia PhD; Rappuoli, Rino PhD*; Bekkat-Berkani, Rafik MD; Giuliani, Marzia Monica MSc*; Pizza, Mariagrazia MSc*

Author Information
The Pediatric Infectious Disease Journal: February 2021 - Volume 40 - Issue 2 - p e66-e71
doi: 10.1097/INF.0000000000002957
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Abstract

Plain Language Summary

What is the Context?

  • Invasive meningococcal disease is a devastating infection with increased incidence in infants and adolescents and can be prevented by vaccination.
  • Meningococcal outbreaks consist of more cases of disease than expected in a given place, a particular period of time, and among specific groups of people (communities, schools, and colleges). In high-income countries, most meningitis outbreaks have been caused by serogroup B (MenB).
  • Vaccination is used to control outbreaks. In recent years, a vaccine against MenB (4CMenB) has been introduced in vaccination programs and used to control outbreaks at universities in the United States.

What is New?

  • In this study, we tested how antibodies induced by 4CMenB vaccination in adolescents from the United States and Chile perform against 14 MenB and 1 MenW invasive strains responsible for recent outbreaks in the United States, the United Kingdom, and France.
  • We found that vaccination with 4CMenB induced high-bactericidal antibody responses against the outbreak strains.

What is the Impact?

  • The 4CMenB vaccination is able to induce a functional immune response against diverse outbreak strains.
  • The immune response to 4CMenB is comparable in adolescents from different geographic areas.
  • Vaccination with 4CMenB has the potential to confer protection in an outbreak setting.

Invasive meningococcal disease (IMD) is caused by Neisseria meningitidis and predominantly affects infants, children, and adolescents.1 Five immunologically distinct Neisseria meningitidis serogroups (men) A, B, C, W, and Y are responsible for most cases of IMD. While Neisseria meningitidis serogroup B (MenB) is frequently associated with outbreaks and sporadic disease in high-income countries, including the United States and some European countries,2,3 disease caused by MenW was sporadic until the annual Islamic pilgrimage to Mecca in 2000, after which an epidemic occurred in Europe.4 MenW also emerged thereafter as a major cause of IMD worldwide.5–7

MenB causes the majority of meningitis outbreaks globally. Outer membrane vesicle-based vaccines have been successfully used to contain MenB outbreaks in Norway,8 New Zealand,9 and France.10 However, these vaccines are highly strain-specific, and their use is therefore limited to specific epidemiologic events.11 By contrast, recombinant protein vaccines elicit immune responses that are protective against a broad spectrum of MenB strains. The 4-component MenB vaccine (4CMenB, BEXSERO, GSK) contains 3 main recombinant antigens (factor H-binding protein [fHbp], Neisseria adhesin A, and Neisserial heparin-binding antigen), and the outer membrane vesicle of the New Zealand outbreak strain (NZ 98/254), which expresses Porin A (PorA) P1.4 as an immunodominant antigen.12 4CMenB has been approved for the prevention of MenB-caused IMD in individuals ≥2 months old in >40 countries worldwide.13 In recent years, 4CMenB also effectively controlled MenB outbreaks in Canada (QC)14 and at universities and college campuses across the United States.15–19 Following mass vaccination campaigns in response to university outbreaks, 2 doses of 4CMenB were shown to elicit protective bactericidal antibody responses against the outbreak strain in >66% of vaccines, and no cases of disease occurred in vaccinated individuals.17,20 The other licensed protein-based MenB vaccine (rLP2086, TRUMENBA, Pfizer Inc.) has also been shown to induce protective bactericidal antibody responses against MenB outbreak strains in ≥56% of vaccines when administered on a 3-dose schedule.21,22

The most accurate tool for evaluating the strain coverage of 4CMenB is the serum bactericidal antibody assay with human complement (hSBA), which measures the complement-mediated killing of bacteria by vaccine-induced antibodies. Since hSBA requires serum samples for each strain to be tested individually, it is not adequate to assess coverage for larger strain panels. Other tools such as the meningococcal antigen typing system, genetic meningococcal antigen typing system, and the BEXSERO antigen sequence type have been shown to underestimate 4CMenB strain coverage compared with hSBA but do not require human serum samples.12,23–26

A characterization of individual outbreak strains, along with their susceptibility to vaccine-induced serum bactericidal activity, are important to further assess vaccine efficacy. Thus, the aim of this study was to determine if antibodies elicited by 2 doses of 4CMenB in adolescents from the United States or Chile were able to induce the complement-mediated bactericidal killing of a panel of 14 MenB outbreak strains and 1 non-B (MenW) hyperendemic strain isolated in the United States, the United Kingdom, and France.

MATERIALS AND METHODS

In previous multicenter studies (NCT02212457 and NCT00661713), adolescents 10–18 and 11–17 years of age, respectively, received 2 doses of 4CMenB 2 months apart. In the present study, individual sera were collected at prevaccination and 1 month after the second 4CMenB dose from a subset of 20 participants from the United States (enrolled in clinical trial NCT02212457) and tested by hSBA against a meningococcal strain panel. The 20 participants were selected based on the availability of a serum volume sufficient to perform the bactericidal testing of all 15 strains.

The full panel consisted of MenB strains that were provided by reference laboratories as representative of outbreaks occurring from 2001 to 2017 in different countries and regions (Table 1). Of the 11 MenB strains from the United States, 8 caused university outbreaks from March 2013 to November 2017 and were provided by the US Centers for Disease Control and Prevention,19 1 caused a prolonged university outbreak in Ohio between January 2008 and November 2010,27 and 2 caused outbreaks in Oregon in 2001 and 2005. These last 2 strains have almost the same genetic profile as the 1 responsible for the epidemic ongoing in Oregon since the mid-1990s.28 The strain from France caused an outbreak of IMDs from 2003 to 2010 in the region around the city of Dieppe, in Normandy.29 The 2 MenB strains from the United Kingdom had a genetic profile similar to those that caused a cluster of meningococcal disease in 2011 in the towns of Maryport and Workington in the Allerdale borough of West Cumbria, England.30

TABLE 1. - Full Meningococcal Outbreak Strain Panel Used for hSBA Testing in the Present Study
Country State University Year of outbreak Serogroup Strain alias Clonal complex Sequence type PorA VR1 PorA VR2 NadA fHbp NHBA
United States Oregon Oregon State 2016–2017 B M41050 CC32 32 7 16-20 yes* 1.1 5
United States Wisconsin Wisconsin-Madison 2016 B M40973 CC32 11,556 7 16 yes* 1.1 3
United States Oregon Unnamed 2015 B M29401 CC32 32 7 16-20 yes* 1.1 5
United States California Santa Barbara 2013 B M27703 CC32 32 7 16-20 yes* 1.1 5
United States Oregon N/A 2005 B M14181 CC32 1364 7 16 yes 1.1 5
United States Oregon N/A 2001 B M09992 CC32 32 7 16 yes 1.1 5
France N/A N/A 2003 B LNP20404 CC32 800 7 16 yes 1.1 28
United Kingdom N/A N/A 2011 B M11 0240079 CC41-44 41 7-2 4 no 1.4 2
United States New Jersey Princeton 2013–2014 B M26312 CC41-44 409 5-1 2-2 no 1.512 2
United States California Santa Clara 2016 B M39090 CC32 11,910 18-1 30 yes* 1.510 29
United States Ohio Unnamed 2008–2010 B M21317 CC269 269 22 9 no 1.15 21
United Kingdom NA NA 2008 B M08 0240745 CC269 269 19-1 15-11 no 1.15 21
United States Pennsylvania Penn 2009 B M18680 CC269 283 19-1 15-11 no 3.143 21
United States New Jersey Rutgers 2016 B M39535 CC11 11 5-1 10-1 truncated 2.19 20
United Kingdom NA NA 2011 W M11 240798 CC11 11 5 2 yes 2.22 29
*indicates the presence of NadA peptide 1 (for strains for which the nadA gene was fully sequenced).
Exact matches for 1 of the 4-component meningococcal serogroup B recombinant vaccine (4CMenB) antigens are bolded. 4CMenB contains fhbp variant 1.1, NHBA peptide 2, NadA peptide 3, and PorA P1.4 serosubtype.
CC indicates clonal complex; hSBA, serum bactericidal antibody assay with human complement; fHbp, factor H-binding protein; NA, not applicable; NadA, Neisseria adhesin A; NHBA, Neisserial heparin-binding antigen; PorA, Porin A; VR, variable region.

The MenW strain belonged to the sequence type 11 complex (CC11), which caused an increase in invasive MenW disease across all age groups since 2009 in the United Kingdom.31

A subset of 4 strains, against which 45%–100% of the US adolescent serum samples showed bactericidal killing and which were representative of high, medium, and low seroresponse rates, was also tested by hSBA using sera from 23 adolescents who received 2 4CMenB doses 2 months apart in a clinical trial conducted in Chile (NCT00661713).32

The method used for hSBA was adapted from the literature.33 Briefly, bacteria were subcultured overnight on chocolate agar plates at 37°C with 5% CO2, resuspended in liquid Mueller Hinton Medium, and grown until an optical density of 0.24–0.25 at 600 nm was achieved (corresponding to a concentration of 109 colony forming units [CFUs] per milliliter). Serum bactericidal titers were determined as the last dilution that resulted in at least a 50% reduction in CFUs relative to the number of CFUs present at the beginning of the bactericidal reaction (ie, 50% of T0). Human plasma from volunteer donors was used as complement source for an isolate if, when added to the assay at a final concentration of 50%, it did not reduce the number of CFUs of that isolate compared with the start of the bactericidal reaction. The final hSBA mixture had a complement-preserved human plasma content of 25%.

Bactericidal activity was determined for each strain by evaluating the number and percentage of adolescents with an hSBA titer of ≥1:4, which indicates a generally accepted surrogate of protection,34,35 or ≥1:8.

RESULTS

Outbreak Strain Collection

Eleven outbreak strains from the United States, 3 from the United Kingdom, and 1 from France, isolated between 2001 and 2017, were characterized by multilocus sequence typing and by sequencing the genes that encode the 4CMenB antigens. Fourteen of the outbreak strains belonged to serogroup B and 1 to serogroup W. The strains were genetically diverse, belonged to different clonal complexes, and carried different antigenic variants of peptides (Table 1).

Analysis of the Bactericidal Response

We evaluated the ability of 4CMenB to induce antibodies with bactericidal activity against diverse outbreak strains. Sera from vaccinated adolescents from the United States were tested against the full outbreak strain panel using hSBA. At 1 month after the second 4CMenB dose, antibodies from 65% (95% confidence interval [CI]: 41–85) to 100% [95% CI: 83–100] of the US adolescents were able to kill 12 of 15 evaluated strains, as shown by the percentages of adolescents with hSBA titers of ≥1:4 (Fig. 1A). The remaining 3 strains (M080240745 [United Kingdom], M18680 [Penn University, Philadelphia, PA], and M39535 [Rutgers University, New Brunswick, NJ]) were killed by 45% (95% CI: 23–69), 25% (95% CI: 9–49), and 15% (95% CI: 3–38) of US adolescent sera, respectively (Fig. 1A). Interestingly, 95% (95% CI: 75–100) of the US adolescents developed protective bactericidal titers (≥1:4) against the hyperendemic MenW outbreak strain (M11 240798, United Kingdom), further supporting the additional benefit of 4CMenB vaccination against nonserogroup B strains. Percentages of US adolescents with prevaccination hSBA titers of ≥1:4 ranged between 5% (95% CI: 0–25) and 35% (95% CI: 15–59) for US strains and 5% (95% CI: 0–25) and 15% (95% CI: 3–38) for strains from Europe (15% [95% CI: 3–38] for the M11 240798 hyperendemic MenW strain from the United Kingdom) (Fig. 1A). The majority of strains were killed with high-bactericidal titers, resulting in nonsignificant changes when results were expressed as percentages of US adolescents with hSBA titers of ≥1:8 (Fig. 1B).

FIGURE 1.
FIGURE 1.:
Bactericidal activity of adolescent sera from the United States, measured as percentage of adolescents with hSBA titers of (A) ≥1:4 or (B) ≥1:8.Error bars represent 95% confidence intervals. *Lujan et al20 evaluated serum bactericidal antibody responses of students immunized with the 4CMenB vaccine in response to an outbreak on a university campus. The gray rectangle on the x-axis denotes the hyperendemic serogroup W strain (M11 240798); all other strains belong to serogroup B. 4CMenB indicates the 4-component meningococcal serogroup B recombinant vaccine; hSBA, serum bactericidal antibody assay with human complement; N, number of adolescents with sera collected at pre-vaccination and 1 month after the second 4CMenB vaccine dose; UK, United Kingdom; US, United States (CA, California; NJ, New Jersey; OH, Ohio; OR, Oregon; PA, Pennsylvania; WI, Wisconsin).

Compared with data generated in an independent study by Lujan et al,20 similar percentages of US adolescents had protective bactericidal titers (ie, ≥1:4) against the M26312 (Princeton University, Princeton, NJ) and M21317 (unnamed university, Ohio) strains, while different percentages were reported for the M39090 (Santa Clara University, Santa Clara, CA) and M39535 (Rutgers University) strains, for which the prevalence of protective bactericidal titers was 93% (95% CI: 87–97) and 53% (95% CI: 42–64), compared with 65% (95% CI: 41–85) and 15% [95% CI: 3–38] in US adolescents in the present study (Fig. 1A). This discrepancy suggests that our study may be underestimating the full potential of the protection induced by 4CMenB vaccination.

Bactericidal Activity of Sera From United States and Chilean Adolescents Against Outbreak Strains

A subset of strains was also tested with sera derived from a clinical study conducted in Chilean adolescents. A comparison with adolescents from the United States is shown in Fig. 2. The point estimates for the percentages of adolescents from Chile with bactericidal titers of ≥1:4 were similar to those for adolescents from the United States, with the exception of strain M39090 (Santa Clara University, Santa Clara, CA), for which the percentage of Chilean adolescents with hSBA titers of ≥1:4 was similar to that reported by Lujan et al20 (Fig. 2). In particular, the prevalence of hSBA titers of ≥1:4 in Chilean and US adolescents was 100% (95% CI: 85–100) and 100% (95% CI: 83–100) for strain M27703 (Santa Barbara University, Santa Barbara, CA), 74% (95% CI: 52–90) and 80% (95% CI: 56–94) for strain M26312 (Princeton University, Princeton, NJ), and 52% (95% CI: 31–73) and 45% (95% CI: 23–68) for strain M08 0240745 (United Kingdom), respectively. The most pronounced difference was observed for the M39090 (Santa Clara University) strain, for which the prevalence of hSBA titers ≥1:4 was 91% (95% CI: 72–99) for Chilean and 65% (95% CI: 41–85) for US adolescents (Fig. 2).

FIGURE 2.
FIGURE 2.:
Bactericidal activity of adolescent sera from the US or Chile, measured as the percentage of adolescents with an hSBA titer of ≥1:4. *Lujan et al20 evaluated serum bactericidal antibody responses of students immunized with the 4CMenB vaccine in response to an outbreak on a university campus. Error bars represent 95% confidence intervals. 4CMenB indicates the four-component meningococcal serogroup B recombinant vaccine; hSBA, serum bactericidal antibody assay with human complement; N, number of adolescents with sera collected 1 month after the second 4CMenB vaccine dose; UK, United Kingdom; US, United States (CA, California; NJ, New Jersey).

DISCUSSION

The present study demonstrates that 2 doses of 4CMenB administered to adolescents elicited bactericidal activity against a panel of 14 MenB outbreak strains and 1 hyperendemic MenW strain. These results confirm that 4CMenB vaccination effectively induces a functional immune response against genetically diverse MenB strains.

The assay used to evaluate bactericidal activity in our study—hSBA—exhibits a degree of variability across studies. When comparing our results to those published by Lujan et al,20 the M39535 (Rutgers University) outbreak strain, which in our study appeared to be the least susceptible to killing, showed a much higher susceptibility (53% vs. 15% in the present study). This was also true for the M39090 (Santa Clara University, Santa Clara, CA) outbreak strain (93% vs. 65% in the present study). The prevalence of protective bactericidal titers was similar for all other common strains. These differences—likely owing to the different sensitivities of the bactericidal assays for some strains—suggest that our data and surrogate of protection assays in general, could be underestimating the actual strain coverage of 4CMenB.

At Princeton University in New Jersey (2013–2014), students were vaccinated with 2 doses of 4CMenB,17,18 and hSBA titers of ≥1:4 were detected against the outbreak strain in 66% of students after the second dose.17 Consequently, hSBA findings suggest that 4CMenB did not elicit bactericidal activity against the outbreak strain in the remaining 34% of students. Nonetheless, considering that no cases of MenB disease occurred after vaccination, these data further support the notion that in vitro bactericidal activity is an underestimate of protective immunity. This is in agreement with the initial findings of Goldschneider et al,36,37 who concluded that while a positive hSBA result indicates protection against meningococcal disease, a negative hSBA result is not an indication of susceptibility.

It has been hypothesized that the bactericidal activity of sera derived from Chilean adolescents immunized with 4CMenB could be an overestimate of protection and antibody persistence since bactericidal activity has only been evaluated against indicator strains with antigens that were exactly matched to vaccine antigens.20 Using sera collected from Chilean adolescents, the present study evaluated the bactericidal activity elicited by 4CMenB against hypervirulent MenB strains that caused outbreaks in Europe and the US between 2008 and 2016. Our results clearly show that the immune response elicited in Chilean adolescents is comparable to the immune response elicited in US adolescents for 3 of the 4 evaluated strains. In addition, the 91% response observed in Chilean adolescents for the fourth strain (M39090, Santa Clara University) was higher than the 65% observed in US adolescents in the present study and similar to the 93% reported by Lujan et al20 in adolescents from the United States. These data clearly show the ability of 4CMenB to induce bactericidal antibodies in Chilean adolescents against genetically diverse strains that were mismatched for the vaccine antigens, and that 2 doses of 4CMenB induce antibodies with cross-protective ability, independent of geographic region.

Bactericidal activity elicited by the other licensed MenB vaccine—rLP2086—was also evaluated against a number of outbreak strains. However, a direct comparison between the response induced by the 2 vaccines—rLP2086 and 4CMenB—cannot be made, as the strains evaluated were not identical. It is noteworthy that in a study by Taha et al,21 3 doses of rLP2086 elicited bactericidal activity (hSBA titers of ≥1:4) in 87% of adolescents with 11–19 years of age against the LNP27899 strain (CC32, fHbp B24, 1.1, and PorA 7/16), while in our study, 2 doses of 4CMenB elicited bactericidal activity in 95% of US adolescents against the LNP20404 (France) strain, which belongs to the same CC and has identical fHbp variant and PorA VR1/VR2 regions to the LNP27899 strain. A study by Harris et al22 included an evaluation of bactericidal activity induced by rLP2086 against 4 strains that were derived from 2 recent US outbreaks. Of these, PMB4478 and PMB4479 belonged to the same clonal complex and had the same fHbp variant as strains M41050, M29401, M14181, M09992 (Oregon, United States), and M27703 (Santa Barbara University) from our study, while PMB5021 and PMB5025 belonged to the same clonal complex and had a similar fHbp sequence to strain M26312 (Princeton University) from the present study. For the respective outbreak strains in the study by Harris et al,22 the percentages of adolescents with bactericidal activity (hSBA titers of ≥1:8) were 44%–78% after 2 doses and 78%–100% after 3 doses of rLP2086, and were 80%–100% in the present study after 2 doses of 4CMenB. Although it is possible that different strains behave differently in the bactericidal assays, these data suggest that similar coverage of these outbreak strains could be obtained with 3 doses of rLP2086 or 2 doses of 4CMenB.

The main limitation of our study is its relatively small sample size, which also results in broad confidence intervals for the point estimates. In addition, the results of the present study are descriptive, and no formal statistical comparisons were made. However, the main strength of our study is that bactericidal activity elicited by 4CMenB in US adolescents was evaluated against a comprehensive strain panel of 14 MenB outbreak strains and 1 hyperendemic MenW strain.

In conclusion, this study demonstrates that 2 doses of 4CMenB administered to adolescents 2 months apart elicited bactericidal activity against a strain panel consisting of MenB outbreak strains and a hyperendemic MenW strain, which were isolated in the United States, the United Kingdom, and France. For a subset of 4 strains, the prevalence of protective titers in Chilean adolescents was at least as high as in US adolescents. Overall, our data suggest that 2 doses of the 4CMenB vaccine offer protection against meningococcal disease resulting from genetically diverse strains, independent of the target population’s geographic region.

ACKNOWLEDGMENTS

The authors thank the Centers for Disease Control and Prevention for providing the strains from the United States, and Dr. Muhamed-Kheir Taha and Dr. Ray Borrow for providing the strains from France and the United Kingdom. The authors also thank the Modis and Business & Decision Life Sciences platforms for editorial assistance, article coordination, and writing support, on behalf of GSK. Alpár Pöllnitz (Modis) provided medical writing support. Adrian Kremer (Modis) and Bruno Dumont (Business & Decision Life Sciences) coordinated article development and editorial support.

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Keywords:

4CMenB; outbreak strains; Neisseria meningitidis serogroup B; Neisseria meningitidis serogroup W; human complement serum bactericidal antibody assay

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