ACIP Evidence to Recommendations for Use of Pfizer’s Pentavalent Meningococcal Vaccine (MenACWY-TT/MenB-FHbp)

Policy Question 1: Should the pentavalent vaccine be included as an option for MenACWY/MenB vaccination in people currently recommended to receive both vaccines?

Policy Question 2: Should the pentavalent vaccine be included as an option for MenACWY/MenB vaccination in people currently recommended to receive MenACWY only?

Policy Question 3: Should the pentavalent vaccine be included as an option for MenACWY/MenB vaccination in people currently recommended to receive MenB only?

Population: All individuals aged 10 years or older currently recommended to receive MenACWY and MenB vaccines, MenACWY only, or MenB only, depending on the policy question.

Intervention: Vaccination with the pentavalent vaccine.

Comparison(s): Vaccination with a currently licensed MenACWY vaccine and a MenB vaccine, a MenACWY vaccine only, or a MenB vaccine only, depending on the policy question.

Outcome: Meningococcal disease caused by serogroups A, B, C, W, and Y (as appropriate by policy question); short-term immunity; persistent immunity; interference with other recommended vaccines administered concurrently; serious adverse events; non-serious adverse events.

Background: While rare, Neisseria meningitidis causes severe illness and death in the United States each year. Six serogroups of the pathogen are responsible for most of the invasive disease in the world (A, B, C, W, X, Y), with serogroups B and C causing most of the disease in the United States. ACIP recommends routine vaccination against serogroups A, C, W, and Y for adolescents aged 11 or 12 years with a booster dose at age 16 years. ACIP also recommends vaccination against serogroup B based on shared clinical decision making, with a preferred age of 16 through 18 years.¹

Persons considered to be at increased risk for invasive meningococcal disease should be routinely vaccinated with one or both vaccine types. These groups include people with complement component deficiency (both MenACWY and MenB recommended), functional or anatomic asplenia (both vaccines recommended), and HIV infection (MenACWY only recommended). Microbiologists who are routinely exposed to Neisseria meningitidis should receive both vaccines. Persons exposed during an outbreak of meningococcal disease should receive the vaccine covering the serogroup causing the outbreak. Persons who travel to or live in countries where the disease is hyperendemic or epidemic, college freshmen living in residence halls, and military recruits are also recommended to received MenACWY.¹

Pfizer developed a pentavalent vaccine (MenABCWY) comprised of Trumenba (MenB), which is licensed in the United States, and Nimenrix (MenACWY), which is licensed outside of the United States. The ACIP Meningococcal Vaccines Work Group assessed this pentavalent vaccine using the Evidence to Recommendation (EtR) framework and the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach.

Public Health Problem

Public Health Problem
Criteria	Work Group Judgements	Evidence	Additional Information
Is the problem of public health importance?	Policy Questions (PQ) 1, 2, and 3: Yes	Invasive meningococcal disease is a rare disease in the United States causing around 350 cases per year,² and it is a severe disease that progresses rapidly with 10–15% of infections ending in death. Additionally, around 10–20% of survivors have permanent sequelae, including brain injury, limb amputation due to necrosis of the extremities, hearing loss, and reduced kidney function.^3,4 ACIP has recognized meningococcal disease as a problem of public health importance by recommending MenACWY vaccination for all adolescents and MenB vaccination under shared clinical decision-making.¹	Recently, meningococcal disease outbreaks have been adversely affecting specific populations, including people experiencing homelessness and men who have sex with men, some of whom are also living with HIV.^5,6 Minority populations (Hispanic and Black) also have been disproportionately affected by new serogroup Y strains in the United States, including one that is resistant to ciprofloxacin and penicillin.

Benefits and Harms

Benefits and Harms
Criteria	Work Group Judgements	Evidence	Additional Information
How substantial are the desirable anticipated effects?	PQ 1: Small PQ 2: Minimal, small, and moderate PQ 3: Minimal	Among both MenACWY-naïve and MenACWY-primed participants, seroresponse* for serogroups A, C, W, and Y one month after the first trial dose of ACWY-containing vaccine was achieved as often or more often in the pentavalent group compared with the control group. Based on a composite measure, seroresponse* for serogroup B 1 month after the second dose of B-containing vaccine was achieved more often in the pentavalent group than in the control group. Among both MenACWY-naïve and MenACWY-primed participants, seroprotection for serogroups A, C, W, and Y occurred as often or more often in the pentavalent group (48 months after receipt of 2 doses MenACWY-TT/MenB-FHbp) compared with the control group (54 months after 1 dose MenACWY-CRM). Little or no difference was observed in the frequency of serogroup B strain-specific seroprotection 48 months after receipt of 2 doses of pentavalent vaccine when compared with those seen 48 months after 2 doses of MenB-FHbp + 1 dose MenACWY-CRM.	Populations at high risk, such as people living with HIV, asplenia, or complement deficiency, were not included in the clinical trials. The ability of the vaccine to prevent meningococcal disease in healthy or in high-risk subjects also was not assessed directly — immunogenicity was used as a surrogate.^7,8,9
How substantial are the undesirable anticipated effects?	PQ 1: Small PQ 2: Minimal or small PQ 3: Minimal or small	The proportion of participants who experienced serious adverse events (SAEs)^¶ was similar in the pentavalent group (0.6%) and the control group (0.5%, p = 0.7). No serious adverse events were deemed related to the vaccine by the study investigators. The pentavalent group had significantly fewer nonserious adverse events^¶¶ than did the control group (24.6% versus 32.5%, p<0.0001). The most common solicited adverse events within 7 days after receipt of either trial dose of MenACWY-TT/MenB-FHbp were injection site pain (84.4%–89.3%, mostly mild or moderate), fatigue (47.6%–52.1%; mostly mild or moderate), and headache (39.8%–46.8%; mostly mild or moderate).	Pfizer’s clinical trials did not assess interference with other vaccines, but some data on vaccine interference were available for Nimenrix and Trumenba.
Do the desirable effects outweigh the undesirable effects?	PQ 1: Favors intervention PQ 2: Favors intervention, comparison, or both PQ 3: Favors intervention or comparison	The pentavalent vaccine would increase the number of vaccines available for providers and might be particularly useful for patients looking to be vaccinated against all 5 serogroups because it would reduce the number of doses needed from 4 to 3.	None.
What is the overall certainty of this evidence for the critical outcomes?	Effectiveness of the intervention: PQ 1, 2, 3: Moderate for healthy persons and low for those at increased risk Safety of Intervention: PQ 1, 2, 3: Low for healthy persons and very low for those at increased risk	There are 2 critical outcomes with data available: short-term immunity and SAEs. The certainty of evidence for short-term immunity is moderate for healthy persons because of indirectness. hSBA titers are the established correlate of protection for serogroup C meningococcal disease; this correlation is assumed to extend to other serogroups, but direct evidence for these serogroups is limited. The certainty of evidence is low for persons at increased risk for invasive disease because the clinical trials did not evaluate these patients. The certainty of evidence for SAEs is low for healthy individuals. It was downgraded for indirectness (2 doses of MenABCWY were compared with 1 dose of MenACWY-CRM plus 2 doses of MenB-FHbp) and imprecision (the relative effect as measured by confidence intervals was wide). The certainty of evidence for those at increased risk was very low; this reflects an additional downgrade for indirectness because the clinical trials did not study this population.	None.

*Seroresponse was based on serum bactericidal assays using human complement (hSBA). For participants with a baseline hSBA titer <1:4, seroresponse is defined as a titer ≥1:16. For those with a baseline hSBA titer ≥1:4 and <1:8 (<1:16 for FHbp type A22), seroresponse is defined as a titer ≥1:32 (≥1:64 for A22). For those with a baseline hSBA titer ≥1:8 (≥1:16 for A22), seroresponse is a titer ≥4 times the baseline titer.
**Seroprotection was based on serum bactericidal antibody assays using human complement (hSBA) and defined as achieving an hSBA titer ≥1:8 for serogroups A, C, W and Y and an hSBA titer ≥1:8 for serogroup B (≥1:16 for strain A22).
^¶Serious adverse events were any undesirable experience associated with vaccination in which the patient outcome was death, was life-threatening, required or prolonged hospitalization, caused disability or permanent damage, was a congenital anomaly/birth defect, or was another serious or important medical events as defined by Pfizer.
^¶¶Nonserious adverse events included all adverse events during the vaccination phase except for serious adverse events. As defined by Pfizer, all adverse events included serious adverse events, nonserious adverse events, medically attended events (nonserious adverse events that resulted in evaluation at a medical facility), and newly diagnosed chronic medical conditions (a disease or medical condition, not previously identified, that is expected to be persistent or is otherwise long-lasting in its effects). The vaccination phase was defined as the time from the first study vaccination through 1 month after the second study vaccination.

Values

Values
Criteria	Work Group Judgements	Evidence	Additional Information
Does the target population feel that the desirable effects are large relative to undesirable effects?	PQ 1: Probably yes PQ 2: Probably yes PQ 3: Probably yes or don’t know	Limited data are available on values of the target population toward inclusion of the pentavalent vaccine. In 2021, vaccination coverage with at least 1 dose was 89% for MenACWY and 31% for MenB among adolescents.¹⁰ Limited data are available on vaccine uptake in other individuals recommended to receive MenACWY or MenB vaccine.	Use of combination vaccines can reduce the number of injections and is generally preferred over separate injections of equivalent component vaccines, though administering extra antigens should generally be avoided.¹¹
Is there important uncertainty about or variability in how much people value the main outcomes?	PQ 1: Probably no PQ 2: Probably yes PQ 3: Probably yes	Limited data are available on how much people value the main outcomes. Vaccination rates for MenACWY, a routine recommendation, are high among the target population.¹⁰ Vaccination rates for MenB are considerably lower, and decisions to vaccinate are based on shared clinical decision-making.	None.

Acceptability

Acceptability
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention acceptable to key stakehold-ers?	PQ 1: Probably yes or yes PQ 2: Probably yes or yes PQ 3: Don’t know	Limited data are available on the acceptance among key stakeholders of including MenABCWY as an option in the current vaccination schedule. Acceptability likely depends on the PICO question and stakeholder values. Healthcare providers are likely supportive of options that allow stocking fewer vaccines.^11,12Proponents for increasing MenB vaccination likely would be supportive of all policy options, as the pentavalent vaccine combines MenB with MenACWY. MenACWY is recommended for all adolescents, and thus pentavalent vaccine would likely increase vaccination rates against serogroup B. Patients who seek vaccination against all 5 serogroups also might be supportive due to the reduced number of doses needed (4 versus 3). However, the pentavalent vaccine may also incentivize MenB administration at age 16 years, which could result in waning immunity by the time of peak risk for some patients. Many vaccine providers prefer waiting to administer MenB until closer to the typical age of exposure to congregate settings (e.g., college, military). Work Group and ACIP members also raised concerns about increasing exposure to MenB, which is more reactogenic than MenACWY,¹ when the burden of serogroup B disease is generally low despite low vaccine coverage.	None.

Resource Use

Resource Use
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention a reasonable and efficient allocation of resources?	PQ 1: Probably yes or yes PQ 2: Probably no or no PQ 3: Probably yes or yes	Using the pentavalent vaccine to replace a single dose of MenACWY and MenB and using the pentavalent vaccine to replace the second dose of a MenB series that began with MenABCWY were societally cost saving strategies according to the CDC model. The CDC model also estimated that replacing both doses of MenACWY with the pentavalent vaccine would be incrementally costly.¹³	In the CDC and Pfizer models, the weighted cost per dose of the pentavalent vaccine (plus administration) varied by strategy according to the number of doses used. Cost per dose for single-dose strategies was $254.05 ($205–290) for the CDC model and $243.11 for the Pfizer model. Cost per dose for strategies with at least 2 doses was $217.86 ($192–250) for the CDC model and $208.48 for the Pfizer model. Cost for MenACWY was $162.61 ($128–$191) for the CDC model and $155.61 for the Pfizer model. Cost for MenB was $209.70 ($155–$250) for the CDC model and $200.67 for the Pfizer model.¹³

Equity

Equity
Criteria	Work Group Judgements	Evidence	Additional Information
What would be the impact of the intervention on health equity?	PQ 1: Probably no impact or varies PQ 2: Probably increased, varies, or don’t know PQ 3: Don’t know	Limited data are available on the impact of the pentavalent vaccine on health equity. It is not expected that the vaccine will negatively impact health equity. It could potentially reduce disparities among those who might be interested in being vaccinated against serogroup B and who might not receive clinical care that includes discussion of the MenB vaccine. Some policy options have a possible risk of clinics not stocking monovalent B vaccines, which could affect availability for outbreaks and people at increased risk who are recommended to receive three doses of MenB-FHbp (Trumenba).	Patients at high risk for invasive meningococcal disease, some of whom have social and economic challenges, were not included in the vaccine trials, so the effect of the vaccine on these populations is unknown.

Feasibility

Feasibility
Criteria	Work Group Judgements	Evidence	Additional Information
Is the intervention feasible to implement?	PQ 1, 2, 3: Probably yes or yes	Challenges with insurance coverage specific to the pentavalent vaccine are not expected. Substantial financial burdens for providers and health systems are not expected. The pentavalent vaccine would provide an additional option in the current schedule and may reduce the number of doses for some people. However, administration of the pentavalent vaccine requires reconstitution, which may lead to administration errors.¹⁴Stocking three different meningococcal vaccine types may be prohibitive for some providers, and the lack of MenB-containing vaccine interchangeability between manufacturers complicates stocking considerations.	None.

Balance of consequences

Policy Question 1: A majority of work group members thought desirable consequences probably or clearly outweigh undesirable consequences in most settings.

Policy Question 2: A majority of work group members thought undesirable consequences probably or clearly outweigh desirable consequences in most settings.

Policy Question 3: The work group members did not reach a majority consensus and were evenly split between three positions: desirable consequences probably outweigh undesirable consequences in most settings, the balance between desirable and undesirable consequences is closely balanced or uncertain, and undesirable consequences probably outweigh desirable consequences in most settings.

Policy options for ACIP consideration

Pfizer’s MenABCWY vaccine may be used when both MenACWY and MenB are indicated at the same visit.* If MenABCWY is administered in this way, a second dose of MenABCWY may be administered 6 months later to complete the series.

*1) Healthy individuals aged 16–23 years (routine schedule) when shared clinical decision-making favors administration of MenB vaccination and 2) individuals aged 10 years and older at increased risk of meningococcal disease (e.g., due to persistent complement deficiencies, complement inhibitor use, or functional or anatomic asplenia) due for both vaccines.

Final deliberation and decision by the ACIP

Pfizer’s MenABCWY vaccine may be used when both MenACWY and MenB are indicated at the same visit.*

References

Mbaeyi SA, Bozio CH, Duffy J, et al. Meningococcal vaccination: recommendations of the Advisory Committee on Immunization Practices, United States, 2020. MMWR Recomm Rep 2020;69(No. RR-9):1–41.
Centers for Disease Control and Prevention. Meningococcal disease surveillance. https://www.cdc.gov/meningococcal/surveillance/index.html.
Pace D, Pollard AJ. Meningococcal disease: clinical presentation and sequelae. Vaccine 2012;30(Suppl 2):B3–9.
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Rudmann KC, Brown NE, Rubis AB, et al. Invasive meningococcal disease among people experiencing homelessness—United States, 2016–2019. J Infect Dis. 2022 Oct 7;226(Suppl 3):S322-S326.
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A Trial to Describe the Immunogenicity and Safety of 2 Doses of Bivalent rLP2086 (Trumenba) and a Pentavalent Meningococcal Vaccine in Healthy Subjects >=10 to <26 Years of Age (NCT03135834). https://classic.clinicaltrials.gov/ct2/show/NCT03135834.
MenABCWY Noninferiority Study in Healthy Participants ≥10 to <26 Years of Age (NCT04440163). https://classic.clinicaltrials.gov/ct2/show/NCT04440163.
A Trial to Describe the Safety and Immunogenicity of MenABCWY When Administered on 2 Schedules (NCT04440176). https://classic.clinicaltrials.gov/ct2/show/NCT04440176.
Pingali C, Yankey D, Elam-Evans LD, Markowitz LE, Valier MR, Fredua B, et al. National vaccination coverage among adolescents aged 13–17 Years — National Immunization Survey-Teen, United States, 2021. MMWR 2022;71(35):1101–08.
Centers for Disease Control and Prevention. Timing and Spacing of Immunobiologics: General Best Practice Guidelines for Immunization. ACIP Timing and Spacing Guidelines for Immunization | CDC.
Hall E, Odafe S, Madden J, Schillie S. Qualitative Conceptual Content Analysis of COVID-19 Vaccine Administration Error Inquiries. Vaccines. 2023; 11(2):254.
Ortega-Sanchez I. Economics of Potential Pentavalent Meningococcal Conjugate Vaccine (MenABCWY) versus the Current MenACWY and MenB Vaccines for US Adolescents. A Summary Report Comparing Models from: Pfizer and CDC. Advisory Committee on Immunization Practices. Advisory Committee on Immunization Practices October 25, 2023 Meeting. Atlanta, GA: US Department of Health and Human Services, CDC; 2023. https://www.cdc.gov/vaccines/acip/meetings/downloads/slides-2023-10-25-26/03-Meningococcal-Ortega-Sanchez-508.pdf
Su JR, Miller ER, Duffy J, et al. Notes from the Field: Administration Error Involving a Meningococcal Conjugate Vaccine―United States, March 1, 2010 –September 2, 2015. MMWR Weekly. 2016;65(6):161–162.

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