Evidence to Recommendations for Serogroup B Meningococcal Vaccine Booster Dose Recommendations in Persons at Increased Risk of Meningococcal Disease During an Outbreak

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The Evidence to Recommendations (EtR) frameworks describe information considered in moving from evidence to ACIP vaccine recommendations.

Summary

Question: Should persons vaccinated with a serogroup B meningococcal (MenB) primary series who are at increased risk for serogroup B meningococcal disease during an outbreak receive a MenB booster dose?

Population: Persons aged ≥10 years who have previously completed a MenB-FHbp or MenB-4C primary series who are at increased risk for serogroup B meningococcal disease during an outbreak of serogroup B meningococcal disease

Intervention: MenB-FHbp or MenB-4C booster dose

Comparison: No MenB-FHbp or MenB-4C booster dose

Outcome: Short-term immunogenicity of booster (critical), persistence of the immune response to the booster dose (important), serious adverse events from booster dose (critical)

Background

Meningococcal disease is a rare but severe infection that can progress rapidly. Among the 12 serogroups that cause disease, serogroups B, C, and Y are the most common in the United States. One in ten persons with meningococcal disease dies despite proper antibiotic treatment, and one in five survivors have long-term sequelae. The incidence of meningococcal disease has declined from 0.42 cases per 100,000 population in 2005 to 0.11 cases per 100,000 population in 2017. Serogroup B disease currently accounts for approximately 40% of U.S. cases.

Although incidence of meningococcal disease is low in the United States, outbreaks remain a public health concern due to the serious nature of Neisseria meningitidis infection. In 2015, the Advisory Committee on Immunization Practices (ACIP) recommended that adolescents and young adults aged 16-23 years may receive a MenB series based on individual clinical decision-making, with a preferred age of 16-18 years.12 Additionally, ACIP recommends that persons aged ≥10 years at increased risk for serogroup B meningococcal disease, including those at increased risk during a serogroup B outbreak, receive a MenB primary series.123 Available evidence suggests that antibodies wane in the years following completion of the primary series. Thus, a MenB booster dose may be necessary to sustain protection in previously vaccinated persons who become at increased risk for meningococcal disease during a serogroup B outbreak.

The ACIP Meningococcal Vaccines Work Group assessed data related to potential benefits and harms of MenB booster doses in persons at increased risk during a serogroup B meningococcal disease outbreak. A Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) was completed for each MenB vaccine (MenB-FHbp and MenB-4C) to assess the certainty of evidence for a MenB booster dose (link). Additional factors related to MenB booster vaccination were assessed as part of the Evidence to Recommendations Framework (EtR), summarized below. GRADE and EtR for other persons at increased risk of meningococcal disease (e.g., person with certain underlying medical conditions and microbiologists routinely exposed to Neisseria meningitidis isolates) were completed separately and are presented elsewhere. Additional background information supporting the ACIP recommendations on the use of MenB booster doses can be found in the relevant publication of the recommendation referenced on the ACIP website.

Problem

References in this table:45

Criteria Work Group Judgments Evidence Additional Information
Is the problem of public health importance? Yes Serogroup B meningococcal disease outbreaks are an important public health concern in the United States:
  • Prevents a serious disease with high rates of morbidity and mortality
  • Create considerable concern in affected communities
  • Require substantial public health resources

Serogroup B outbreaks are rare in the United States, but disproportionately affect college students:

  • 7% of all serogroup B cases and 30% among college students are outbreak-associated4

From 2013–2018, 11 college-based outbreaks (41 cases and 2 deaths) were reported.5

Conclusion: Serogroup B meningococcal disease outbreaks are a public health concern that have disproportionately affected college students in recent years.

College students are the primary group at increased risk for serogroup B outbreaks who may have previously received a MenB primary series as a healthy adolescent.

Benefits and Harms

References in this table:67891011121314151617

Criteria Work Group Judgments Research Evidence Additional Information
How substantial are the desirable anticipated effects? Large A MenB booster dose elicits robust short-term immunogenicity:
  • MenB-FHbp: 1 month following a booster dose administered 4 years after the completion of a primary series, ≥94% of subjects who received either a 2- or 3-dose primary series achieved a human serum bactericidal activity (hSBA) assay titer of ≥1:4 against the 4 test strains (A22, A56, B24, B44).6
  • MenB-4C: 1 month following a booster dose administered 4 or 7.5 years after the primary series, ≥93% of subjects achieved an hSBA titer of ≥1:4 across the four vaccine antigens (fHBp, NadA, PorA, NHBA).7
  • MenABCWY (as a proxy for MenB-4C, as the MenB components are the same in both vaccines): 1 month following a MenABCWY booster dose administered 2 years after a MenB-4C primary series, ≥91% of subjects achieved an hSBA titer of ≥1:5 against fHbp, NadA, NHBA, and 82% against PorA.8

Persistence of the immune response to MenB booster doses is sufficient to provide protection to persons at short-term increased risk of exposure during an outbreak:

  • MenB-FHbp: 12 months following booster administration, 62–82% of subjects who received a 2-dose primary series and 73–93% who received a 3-dose series achieved an hSBA titer of ≥1:4 against the four test strains. By 26 months, 59–67% of subjects who received a 2-dose series and 71–90% who received a 3-dose series remained seroprotected.6
  • MenB-4C: No data available; however modeled data presented by the manufacturer suggests persistence for several years.9
  • MenABCWY: 12 months following booster administration, the proportion of subjects with an hSBA titer of ≥1:5 was 100% against NadA, 82% against fHbp and NHBA, and 45% against PorA.8

Limited data are available on vaccine effectiveness or duration of protection of MenB vaccines in adolescents or adults:

  • Primary vaccination: In the four years following mass MenB-4C vaccination of persons aged <20 years to control increased incidence of serogroup B disease in a region of Canada, vaccine effectiveness was 79% (95% CI: -231 to 99%).10
  • Booster vaccination: no data available

Conclusion: MenB booster doses elicit a robust immune response; persistence appears to exceed that of a primary series (likely 2–3 years). No data on effectiveness of a MenB booster doses are available. However, based on the limited data available on the primary series, booster vaccinations are expected to be effective for the short-term protection against serogroup B disease during an outbreak.

No consistent evidence todate that MenB vaccines reduce or prevent serogroup B meningococcal carriage; therefore, herd immunity is unlikely.
How substantial are the undesirable anticipated effects? Minimal Clinical trials for MenB boosters demonstrated an acceptable safety profile:
  • Rates of local or systemic reactions were generally similar to those observed following MenB-FHbp or MenB-4C primary series doses.11-12
  • No serious adverse events were reported following a MenB booster dose in the study arms assessed through the GRADE analysis.

Although clinical trials assessing safety of MenB booster doses are limited due to the small size of study population, clinical trials and post-marketing safety surveillance including over 69,000 healthy adolescents and adults have demonstrated the safety of a MenB-FHbp and MenB-4C primary series. 13-17

  • Among U.S. university students vaccinated during outbreaks, local and systemic reactions consistent with those reported during clinical trials, with no new safety concerns identified.

Conclusion: Given the acceptable safety profile observed during clinical trials and observational studies for MenB booster doses, as well as that observed during clinical trials and post-marketing safety surveillance of the primary series, undesirable effects of MenB boosters are likely to be minimal.

All studies related to safety of MenB booster doses had a small number of enrolled subjects; rare adverse events may not have been detected.
Do the desirable effects outweigh the undesirable effects? Favors intervention MenB booster dose in persons at increased risk of meningococcal disease during an outbreak is favored as an intervention due to:
  • Serious risk of death and disability due to meningococcal disease in otherwise healthy persons.
  • Robust short-term immunogenicity and immune persistence for likely at least 2–3 years based on available observed modelled data (sufficient for protection during a short-term period of increased exposure).
  • Acceptable safety profile, with no serious adverse events reported in study arms assessed in the GRADE analysis.

Conclusion: The desirable effects of a MenB booster dose in this population outweighs the undesirable effects.

What is the overall certainty of this evidence for the critical outcomes? Certainty of the evidence on effectiveness is Level 4 (Very low)

Certainty of the evidence on safety is Level 4 (Very low)

GRADE analysis was completed for each MenB vaccine to assess certainty of evidence.

MenB-FHbp:

  • Overall evidence type was 4 for short-term immunogenicity, persistence of the immune response, and serious adverse events.
  • The initial evidence types were downgraded because of risk of bias, indirectness and issues related to imprecision.
  • The overall certainty of evidence was very low.

MenB-4C:

  • Overall evidence types ranged from 3–4 for short-term immunogenicity, persistence of the immune response, and serious adverse events.
  • The initial evidence types were downgraded because of risk of bias, indirectness and issues related to imprecision.
  • The overall certainty of evidence was low.

See link to the associated GRADE tables for additional details.

Conclusion: Overall certainty of evidence for effectiveness and safety of MenB booster doses in persons at increased risk during a serogroup B outbreak is very low.

Values

References in this table:51516

Criteria Work Group Judgments Research Evidence Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects? Yes All 11 universities that experienced serogroup B outbreaks during 2013–2018 implemented MenB primary series vaccination5, reflecting in part the target population’s value of the intervention.
  • Students at two universities received MenB vaccination prior to U.S. licensure of the vaccine, indicating that the target population likely felt the desirable effects were large relative to undesirable effects, or, because the vaccine was not yet licensed, uncertain effects.

Conclusion: Widespread implementation of MenB primary vaccination during university-based serogroup B outbreaks in the United States indicates that the target population values the intervention.

Is there important uncertainty about or variability in how much people value the main outcomes? Possibly important uncertainty or variability Wide range in coverage of ≥1 MenB dose (14–98%)5 in 11 universities that implemented MenB primary vaccination during outbreaks of serogroup B meningococcal disease, regardless of university size, time since licensure of the vaccine, or number of cases in the outbreak, potentially indicates important uncertainty and/or variability in values of the target population.

Conclusion: Given variable rates of MenB vaccine uptake during college outbreaks, there may be important uncertainty and/or variability in how much people value the main outcomes.

Additional factors unrelated to values (e.g., logistical/financial concerns, differences in student population15,16) may also have contributed to this range in MenB  coverage.

Acceptability

References in this table:1217181920

Criteria Work Group Judgments Research Evidence
Is the intervention acceptable to key stakeholders? Yes Following the availability of MenB vaccines in the United States, all universities that experienced serogroup B outbreaks implemented primary series vaccination as part of outbreak response, demonstrating acceptability of the intervention to:
  • University leadership and health providers5
  • Local and state health departments
  • College students12, 17
  • Parents of students18-20

Conclusion: MenB vaccination is acceptable to a wide variety of stakeholders.

Resource Use

References in this table:182122

Criteria Work Group Judgments Research Evidence Additional Information
Is the intervention a reasonable and efficient allocation of resources? Yes No cost-effectiveness analyses of a MenB booster dose during serogroup B outbreaks have been conducted. However, the strategy of mass vaccination of a MenB primary series for outbreak response is estimated to be more cost-effective than universal vaccination of all students at college entry.21

Experience demonstrates that MenB primary series mass vaccination during outbreaks requires substantial resources.18,22

  • At one large university with approximately 20,000 undergraduate students, the total costs of vaccination were $1.7 million dollars (projected: $7.7 million for 100% primary series coverage).18

The high costs incurred by universities may reflect the belief that vaccination with a MenB primary series in response to a serogroup B outbreak were a reasonable and efficient allocation of resources.

  • Since the booster among persons previously vaccinated with a primary series would require fewer doses than the primary series, MenB booster doses are also anticipated to be reasonable and efficient use of resources.

Conclusion: MenB booster vaccination is a reasonable and efficient allocation of resources given the serious nature of meningococcal disease infections and lack of more resource-efficient yet effective options to control serogroup B outbreaks.

Feasibility

References in this table:18192324

Criteria Judgments Research Evidence Additional Information
Is the intervention feasible to implement? Yes Serogroup B meningococcal disease outbreaks require intensive coordination, significant human resources, and action among multiple stakeholders to efficiently respond within a short time. 18,19,23,24

Low coverage of ≥1 MenB dose during some university-based serogroup B outbreaks may indicate feasibility concerns (e.g., programmatic, financial).18,24

As MenB vaccine products are not interchangeable, potential barriers to implementation include determining:

  • Whether a MenB primary series was completed
  • Which vaccine was used for the primary series
  • Date of last dose of primary series
  • Availability of both MenB vaccine products

Despite challenging circumstances, universities have demonstrated the feasibility of conducting mass vaccination campaigns for the MenB primary series during outbreaks.

  • Thus, administration of a MenB booster dose is anticipated to be feasible as well.

Conclusion: Although programmatic challenges to MenB booster doses are anticipated, the intervention is expected to be feasible based on successful implementation of MenB primary series campaigns during university outbreaks.

A simplified HPV vaccine schedule is expected to be easier to explain and remember.

Balance of Consequences

Desirable consequences clearly outweigh undesirable consequences in most settings.

Is there sufficient information to move forward with a recommendation? Yes

Policy option for ACIP consideration

ACIP recommends the intervention

Recommendation

For persons at increased risk for serogroup B meningococcal disease during an outbreak, a one-time MenB booster dose is recommended if it has been at least 1 year since completion of a MenB primary series. A booster dose interval of ≥6 months may be considered by public health officials depending on the specific outbreak, vaccination strategy, and projected duration of elevated risk.

Additional considerations (optional)

Booster vaccination is only indicated for persons at increased risk for meningococcal disease during an outbreak, not for adolescents who previously received a MenB primary series as part of shared clinical decision-making and who are not at increased risk.

Additional guidance related to the programmatic implementation of MenB booster doses in persons at increased risk during a serogroup B outbreak will be addressed in revisions to CDC's Guidance for the Evaluation and Public Health Management of Suspected Outbreaks of Meningococcal Disease.

Final ACIP recommendation

ACIP recommends the intervention

ACIP considerations

Additional safety and effectiveness data on MenB booster doses will be necessary for the ongoing evaluation of this recommendation by ACIP.

This Evidence to Recommendation table is based on the GRADE Evidence to Decision framework developed through the DECIDE project. See further information. Framework last updated 19 June 2019.

View the complete list of EtR Frameworks‎‎‎

List of Evidence to Recommendations Framework Tables
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Content Source:
National Center for Immunization and Respiratory Diseases (NCIRD)
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