Evidence to Recommendations for Serogroup B Meningococcal Vaccine Booster Dose Recommendations in Persons at Increased Risk of Meningococcal Disease Because of Complement Deficiency, Complement Inhibitor Use, Asplenia, or Routine Exposure to Isolates of Neisseria meningitidis as a Microbiologist

Question: Should persons vaccinated with a serogroup B meningococcal (MenB) primary series who remain at increased risk for serogroup B meningococcal disease because of certain underlying conditions or occupational exposure receive a MenB booster dose?

Population: Persons aged ≥10 years who have previously completed a MenB-FHbp or MenB-4C primary series who remain at increased risk for serogroup B meningococcal disease because of persistent complement component deficiencies, complement inhibitor use, functional or anatomic asplenia, or routine exposure to isolates of Neisseria meningitidis as a microbiologist

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

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

Outcome: Short-term immunogenicity of the booster dose (critical), persistence of the immune response to the booster dose (important), serious adverse events from the 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 die 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 (https://www.cdc.gov/meningococcal/surveillance).

Despite the current low incidence of meningococcal disease in the United States, certain groups are at increased risk for serogroup B meningococcal disease, including persons with certain underlying conditions (persistent complement component deficiency, complement inhibitor (e.g., eculizumab [Soliris®]) use, and anatomic or functional asplenia), microbiologists with routine exposure to Neisseria meningitidis isolates, and persons at increased risk during a serogroup B meningococcal disease outbreak. In 2015, the Advisory Committee on Immunization Practices (ACIP) recommended that persons aged ≥10 years at increased risk for serogroup B meningococcal disease receive a MenB primary series.^1-3 Additionally, adolescents and young adults aged 16–23 years may receive a MenB series based on individual clinical decision-making (with a preferred aged of age 16–18 years).^1,2 Available evidence suggests that antibodies wane in the years following completion of the primary series. MenB booster doses may be necessary to sustain protection in persons who become or remain at increased risk for meningococcal disease.

The ACIP Meningococcal Vaccines Work Group assessed data related to potential benefits and harms of MenB booster doses in persons at increased risk for serogroup B meningococcal disease because of complement deficiency, complement inhibitor use, asplenia, or routine occupational exposure to N. meningitidis isolates. 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. Because the duration of risk and goals for a MenB booster dose during serogroup B outbreaks differs from those in persons with underlying conditions and microbiologists, GRADE and EtR were completed separately for persons at risk during an outbreak and are presented elsewhere (link). Additional background information supporting the ACIP recommendations on the use of MenB booster doses in persons at increased risk for serogroup B meningococcal disease can be found in the relevant publication of the recommendation referenced on the ACIP website (link).

Problem

Problem
Criteria	Work Group Judgments	Evidence	Additional Information
Is the problem of public health importance?	Yes	Meningococcal disease is a serious bacterial infection with high rates of morbidity and mortality. The current burden of serogroup B meningococcal disease and approximate population sizes of persons at increased risk aged ≥10 years in the United States are not well characterized due to limitations in national surveillance. The increased risk of meningococcal disease in persons with persistent complement component deficiency is estimated to be up to 10,000-fold⁴, with an approximate population size of 86,000.⁵ The increased risk in persons with complement inhibitor use (e.g., eculizumab) is estimated to be 2,000-fold⁶, with an approximate population size of 3,000.⁷ The increased risk in persons with anatomic or functional asplenia (e.g., sickle cell disease) has not be quantified but a higher case-fatality ratio compared to the national average for meningococcal disease has been observed, with an approximate population size for persons with sickle cell disease of 80,000.⁸ The increased risk in microbiologists routinely exposed to Neisseria meningitidis is estimated to be 120-fold⁹, with an approximate population size of ~100,000.¹⁰ Based on the population estimates for each group, these persons comprise less than 0.1% of the U.S. population aged at least 10 years (approximately 269,000 persons). Conclusion: Persons with certain underlying conditions or microbiologists with routine exposure to N. meningitidis isolates comprise small, targeted populations with a substantially increased risk for meningococcal disease (up to 10,000-fold). Thus, serogroup B meningococcal disease is a problem of public health importance in this population.

Benefits and Harms

Benefits and Harms
Criteria	Work Group Judgments	Research Evidence	Additional Information
How substantial are the desirable anticipated effects?	Varies	No data are available on immunogenicity and antibody persistence of a MenB booster dose in persons with underlying conditions, though there may be differences in the immune response within this group: Immunogenicity of a MenB-4C primary series in children and adolescents with asplenia was similar to healthy persons, but was lower in persons with complement deficiencies (including eculizumab recipients).¹¹ Meningococcal primary or booster vaccination may confer little to no protection in persons taking eculizumab.^12-13 In healthy persons, 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).¹⁴ 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).¹⁵ 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.¹⁶ In healthy persons, persistence of the immune response to a MenB booster dose is likely longer than that observed for the primary series: 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.¹⁴ MenB-4C: No data available; however, modeled data presented by the manufacturer suggests persistence for several years.¹⁷ 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.¹⁶ No data are available on vaccine effectiveness or duration of protection of MenB vaccines in adolescents or adults with certain underlying conditions. Conclusion: Although data in healthy persons demonstrates robust immunogenicity to a MenB booster dose, no data are available in persons with certain underlying conditions. However, data from the primary series suggest that those with complement deficiencies have reduced immune responses to MenB vaccination compared to healthy persons; vaccination may have little-to-no effect in those taking a complement inhibitor. Because of this, the magnitude of desirable effects varies among the target population.	No consistent evidence to-date that MenB vaccines reduce or prevent serogroup B meningococcal carriage; therefore, herd immunity is unlikely particularly in the context of vaccination of this very small population at increased risk for meningococcal disease.
How substantial are the undesirable anticipated effects?	Minimal	No safety data for booster dose administration in persons with certain underlying conditions are available. However, among children and adolescents with complement deficiency, eculizumab use, or asplenia who received a MenB-4C primary series, rates of local and systemic reactions were generally similar to those observed in healthy controls.¹² Clinical trials for MenB boosters in healthy persons 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.^18-19 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.^20-23 Conclusion: Although safety of MenB booster doses has not been assessed in persons with certain underlying medical conditions, persons with these conditions who received a MenB-4C primary series had a similar safety profile as healthy controls. Because of the acceptable safety profile of MenB primary and booster vaccination in healthy persons and no anticipated differences in safety among persons with certain underlying conditions, the undesirable effects of MenB booster vaccination are anticipated to be minimal.	All studies were small, and rare serious adverse events may not be detected. All studies related to MenB booster doses were conducted in healthy persons. No studies were conducted in persons who received multiple booster doses.
Do the desirable effects outweigh the undesirable effects?	Favors intervention	MenB booster dose in persons at increased risk of meningococcal disease due to certain underlying conditions or occupational exposure is favored as an intervention due to: Substantially increased risk of meningococcal disease and associated morbidity and mortality in this small group of individuals. Robust short-term immunogenicity and immune persistence for likely at least 2–3 years based on available observed and modelled data. Acceptable safety profile with no serious adverse events reported in study arms assessed through GRADE. 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 analyses were 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 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. See link to the associated GRADE tables for additional details. Conclusion: Overall certainty of evidence for effectiveness and safety of MenB booster doses in this population is very low.	Full grading of recommendations, assessment, development, and evaluation (GRADE) for use of 4vHPV and 9vHPV in males have been available since these ACIP recommendations were made in 2011 and 2015, respectively.

Values

Values
Criteria	Work Group Judgments	Research Evidence
Does the target population feel that the desirable effects are large relative to undesirable effects?	Uncertain	No data are available on values of the target population towards either primary or booster MenB vaccination. Conclusions: As there are no available data, it is uncertain whether the target population feels that the desirable effects are large relative to undesirable effects.
Is there important uncertainty about or variability in how much people value the main outcomes?	Important uncertainty or variability	No data are available on values of the target population towards either primary or booster MenB vaccination. Conclusions: As there are no available data, there is important uncertainty in how much people in the target population value MenB vaccination.

Acceptability

Acceptability
Criteria	Work Group Judgments	Research Evidence	Additional Information
Is the intervention acceptable to key stakeholders?	Probably yes	No data are available on the acceptance of MenB booster vaccination in the target population among key stakeholders. In a survey of providers, the majority reported recommending a MenB primary series for children aged ≥10 years at increased risk for serogroup B meningococcal disease: Pediatricians: 81% Family physicians: 56%²⁴ No data on acceptance of MenB primary vaccination among adults at increased risk for meningococcal disease or among other provider types are available. Acceptance may be higher among providers for pediatric and adolescent populations. Conclusion: The majority of pediatricians and family physicians recommend MenB primary vaccination for children at increased risk, which may reflect the level of acceptance among other providers and for MenB booster vaccination as well.	Lack of universal recommendation for MenB vaccine by providers and disparity by provider type (pediatricians vs. family physicians) may also reflect level of awareness or feasibility of MenB primary series vaccination.

Resource Use

Resource Use
Criteria	Work Group Judgments	Research Evidence	Additional Information
Is the intervention a reasonable and efficient allocation of resources?	Uncertain	No published cost-effective analyses on vaccination with a MenB primary series or booster dose are available in this population. Conclusions: Given the lack of data, it is uncertain whether MenB booster vaccination in this population is a reasonable and efficient allocation of resources.

Feasibility

Feasibility
Criteria	Judgments	Research Evidence	Additional Information
Is the intervention feasible to implement?	Uncertain	Among persons aged ≥10 years with complement deficiency, complement inhibitor use, anatomic asplenia, and sickle cell disease coverage with ≥1 MenB dose is low (based on claims data from October 2014-July 2018) (CDC unpublished data): 9% compared with 22% for a serogroups A, C, W, Y meningococcal conjugate vaccine. MenB coverage varies by age: Coverage highest in those aged 10-15 years (24%) and 16-23 years (29%). Coverage low in adults aged ≥24 years (1%). Low MenB primary series coverage in persons with certain underlying conditions, particularly among adults, may indicate feasibility challenges for booster doses: Potential need for repeated booster doses may not be easily integrated into providers’ practices Ability to adequately stock MenB vaccine, particularly since MenB vaccines are not interchangeable Financial barriers to vaccination (e.g., high vaccine cost, insurance concerns) Conclusion: Low MenB primary series coverage among persons at increased risk for meningococcal disease with certain underlying conditions, particularly adults, is likely multifactorial but may include feasibility concerns (in addition to factors related to awareness of the recommendations, values, and acceptance of the intervention). These factors will also likely affect MenB booster implementation as well.	Low MenB primary series coverage, lack of universal MenB recommendation by providers, and disparity in recommendations by provider type may also reflect the level of awareness of MenB vaccine recommendations, values of the target population towards MenB vaccination, and acceptance of the vaccine by providers.

Balance of Consequences

Desirable consequences probably 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 because of functional or anatomic asplenia, persistent complement component deficiency, complement inhibitor use, or routine exposure to isolates of Neisseria meningitidis as a microbiologist, a MenB booster dose is recommended if it has been at least 1 year since completion of a MenB primary series. For persons who remain at increased risk, booster doses should be administered every 2-3 years thereafter, for as long as risk remains.

Final deliberation and decision by the ACIP

Final ACIP recommendation

ACIP recommends the intervention

ACIP considerations

Additional safety and effectiveness data on MenB booster doses, particularly repeated 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.

References

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Preliminary estimate projected from 2017 claims data (MarketScan and Medicaid)
Based on estimated 100,000 persons with sickle cell disease (CDC data), minus the ~20,000 children aged <10 years with disease (estimated 1,800-2,000 children identified with sickle cell disease annually through newborn screening, with 95% survival to age 18 years).
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