Meningococcal meningitis, caused by the bacterium

, is a potentially fatal bacterial infection that is characterized by inflammation of the meninges around the brain or spinal cord, which can develop rapidly, often among previously healthy persons. Although the rate of meningococcal disease has declined in the United States since the 1990s, in 2019, there were about 375 total cases of meningococcal disease reported (incidence rate of 0.11 cases per 100,000 persons), with the highest rates being among adolescents and young adults aged 16 through 23 years (CDC, 2022b). Even with appropriate antimicrobial therapy, the overall case-fatality ratio in the United States is 15%, and 10% - 20% of survivors have long-term sequelae such as neurologic disability, limb or digit loss, or hearing loss (Mbaeyi et al, 2020).

Per Mbaeyi and colleagues (2020),

is classified into 12 serogroups according to the composition of its polysaccharide capsule. Serogroups A, B, C, W, X, and Y cause most of the disease globally.

colonizes mucosal surfaces of the nasopharynx and is transmitted through direct contact with large-droplet respiratory tract secretions from patients or asymptomatic carriers. Nasopharyngeal carriage rates are highest in adolescents and young adults, who serve as reservoirs for transmission of

. Invasive disease is an infrequent consequence of nasopharyngeal colonization.

In addition, two serogroup B meningococcal (MenB) vaccines are licensed and available in the United States:

MenB-FHbp consists of two purified recombinant lipidated FHbp antigens, one from each FHbp subfamily (A and B). MenB-4C consists of three recombinant proteins (neisserial adhesin A [NadA], factor H binding protein [FHbp] fusion protein from subfamily B, and neisserial heparin binding antigen [NhbA] fusion protein) and outer membrane vesicles (OMVs) containing outer membrane protein porin A (PorA) serosubtype P1.4. Two additional licensed meningococcal vaccines are no longer available in the United States:

In October 2016, GlaxoSmithKline (GSK) issued a letter to the customer regarding the decision to discontinue the manufacture and sale of MenHibrix® [Meningococcal Groups C and Y and Haemophilus b Tetanus Toxoid Conjugate Vaccine] in the US. This decision was made due to low demand for the vaccine and the resulting opportunity to shift GSK vaccine production capacity to other GSK vaccines with greater customer demand. MenHibrix continued to be available to order through February 2017 or until inventory levels were depleted (whichever occured first), at which point, GSK discontinued availability of the vaccine (GSK, 2016).

In February 2017, Sanofi Pasteur, the manufacturer of meningococcal polysaccharide vaccine (Menomune), announced that it is discontinuing production of the vaccine. The company expects to be able to ship orders to providers until mid-2017. The remaining lots will expire in June or in September 2017, according to Sanofi Pasteur (CDC, 2017).

Efforts are under way to reduce the global incidence of meningococcal disease and other causes of meningitis through a strategy that includes optimizing the use of current vaccines as well as developing additional vaccines, such as an expanded conjugate vaccine that includes serogroups A, C, W, Y, and X for use in sub-Saharan Africa (Mbaeyi et al, 2020).

Advisory Committee on Immunization Practices (ACIP) Recommendations

The Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP) released updated meningococcal vaccination recommendations which now include routine use of serogroup B meningococcal (MenB) vaccine series among individuals aged 10 years or older who have increased risk for serogroup B meningococcal disease, including persons with complement deficiency, use a complement inhibitor, have asplenia, or are microbiologists routinely exposed to isolates of

. In addition, ACIP recommends administration of booster doses of the MenB vaccine for persons at increased risk for serogroup B meningococcal disease (Mbaeyi et al, 2020).

Groups identified for increased risk for meningococcal disease include the following (Mbaeyi et al, 2020):

In general, ACIP recommends routine vaccination with a quadrivalent meningococcal conjugate vaccine (MenACWY) for all persons aged 11 to 18 years. ACIP also provides recommendations for the MenB vaccine for persons aged 16 to 23 years on the basis of shared clinical decision-making to provide short-term protection against most strains of serogroup B meningococcal disease. The preferred age for MenB vaccination is 16 to 18 years (Mbaeyi et al, 2020).

MenACWY Vaccine ACIP Recommendations

MenACWY primary vaccinations are licensed as a single dose in persons aged 2 to 55 years for MenACWY-D and MenACWY-CRM or 2 years and older for MenACWY-TT. Two-dose primary series is considered off-label.

ACIP provides the following recommendations for MenACWY booster vaccination:

For microbiologists who remain at risk for exposure to isolates of

:

Single dose at 5 yrs after primary vaccination and every 5 yrs thereafter

If person previously vaccinated and identified as being at increased risk during an outbreak:

For persons who travel to countries where meningococcal disease is hyperendemic or epidemic and person remains at increased risk:

MenACWY vaccines are licensed in the United States only for a single booster dose for persons aged 15 to 55 years for MenACWY-D and MenACWY-CRM or aged 15 years or older for MenACWY-TT. Booster doses administered outside of these ages or administration of greater than 1 booster dose are considered off-label (Mbaeyi et al, 2020).

MenACWY vaccines are interchangeable; however, the same vaccine product is recommended but not required for all doses. MenACWY vaccines can be administered simultaneously with other vaccines indicated for this age group, but at a different anatomic site, if feasible. MenACWY-TT, which is conjugated to tetanus toxoid, is only licensed for the prevention of meningococcal disease. Thus, use of this vaccine does not replace doses or affect the dosing intervals of routinely recommended tetanus toxoid–containing vaccines in any age group (Mbaeyi et al, 2020).

MenB Vaccine ACIP Recommendations

ACIP recommends routine vaccination of persons aged 10 years or older at increased risk for meningococcal disease (dosing schedule varies by vaccine brand; boosters should be administered at 1 year after primary series completion, then every 2 - 3 years thereafter). Note that MenB vaccines are licensed in the United States only for persons aged 10 to 25 years. Vaccination of persons aged 26 years and older is considered off-label. Furthermore, administration of booster doses is considered off-label.

MenB vaccine may be considered for persons with the following risks for meningococcal disease:

MenB vaccination is not routinely recommended for all adolescents. Instead, ACIP recommends a 2-dose MenB series for persons aged 16 to 23 years on the basis of shared clinical decision-making, which refers to an individually based vaccine recommendation informed by a decision-making process between the health care provider and the patient or parent/guardian. The preferred age for MenB vaccination is 16 to 18 years. Booster doses are not recommended unless the person becomes at increased risk for meningococcal disease (Mbaeyi et al, 2020).

For adolescents who are not otherwise at increased risk for meningococcal disease (e.g., due to complement deficiency or asplenia), a 2-dose series of MenB vaccine should be administered as follows: 2 doses of MenB-FHbp administered at 0 and 6 months or 2 doses of MenB-4C administered at 0 and greater than or equal to 1 month. If the second dose of MenB-FHbp is administered earlier than 6 months after the first dose, a third dose should be administered at least 4 months after the second dose. Either of the MenB vaccines can be used when indicated. ACIP does not state a product preference. However, MenB vaccines are not interchangeable, and the same vaccine product must be used for all doses. If one MenB dose was received but the vaccine product is unknown, the series must be restarted with either product to ensure completion of a 2-dose series using the same product. If 2 doses were administered using different MenB products, one product should be selected for administration of an additional dose at an appropriate interval to ensure valid completion of a MenB series; the dose from the product not selected for series completion should be considered invalid. For situations in which a MenB dose or doses must be repeated, a minimum interval of 4 weeks should be used between any 2 doses. MenB vaccines can be administered simultaneously with other vaccines indicated for this age group, but at a different anatomic site, if feasible (Mbaeyi et al, 2020).

ACIP recommends booster doses for previously vaccinated persons who become or remain at increased risk. For persons 10 years of age or older with persistent complement deficiencies (including patients using a complement inhibitor), anatomic and functional asplenia (including sickle cell disease), or are microbiologists routinely exposed to isolates of

, ACIP recommends single booster dose at 1 yr after completion of primary vaccination and every 2–3 yrs thereafter. If person was previously vaccinated and identified as being at increased risk during an outbreak, ACIP recommends a single booster dose if greater than or equal to 1 yr after MenB primary series completion (≥6 mos interval might also be considered by public health professionals) (Mbaeyi et al, 2020).

As a reminder, MenB vaccines are licensed in the United States only for persons aged 10 to 25 years. Vaccination of persons aged 26 years and older is considered off-label. Furthermore, administration of booster doses is also considered off-label.

Pregnancy and Lactation ACIP Recommendations

Pregnant and lactating women should receive MenACWY vaccine if indicated. Because limited data are available for MenB vaccination during pregnancy, vaccination with MenB should be deferred unless the woman is at increased risk and, after consultation with her health care provider, the benefits of vaccination are considered to outweigh the potential risks.

Altered Immunocompetence

Persons with functional or anatomic asplenia (including sickle cell disease) and persistent complement component deficiency (including persons taking eculizumab [Soliris]) are at increased risk for meningococcal disease and should receive both MenACWY and MenB vaccines.

A hematopoietic cell transplant (HCT) results in immunosuppression because of the hematopoietic ablative therapy administered before the transplant, drugs used to prevent or treat graft-versus-host disease, and, in some cases, from the underlying disease process necessitating transplantation. HCT recipients of all ages are at increased risk for certain vaccine-preventable diseases, including diseases caused by encapsulated bacteria (i.e., pneumococcal, meningococcal, and Hib infections). As a result, HCT recipients who received vaccines prior to their HCT should be revaccinated routinely after HCT, regardless of the source of the transplanted stem cells. Vaccination or revaccination doses of pneumococcal vaccines, DTaP vaccine, Hib vaccine, hepatitis A vaccine, hepatitis B vaccine, meningococcal vaccines, IPV, inactivated influenza vaccines, and human papillomavirus (HPV) vaccines (for individuals aged 9-26 years) are recommended after HCT (CDC, 2022c).

Certain immunosuppressive medications are administered to prevent solid organ transplant rejection (CDC, 2022c).

Meningococcal Conjugate (MenACWY) Vaccines

U.S. Food and Drug Administration (FDA)-Approved Indications

Menactra is supplied as a 0.5 mL dose for intramuscular injection. The primary vaccination schedule, per the label, include children 9 through 23 months of age: two doses, three months apart; and a single dose for individuals 2 through 55 years of age.

Booster vaccination is labeled as a single dose for individuals 15 through 55 years of age at continued risk for meningococcal disease, if at least 4 years have elapsed since the prior dose.

Persons previously diagnosed with Guillain-Barré syndrome (GBS) may be at increased risk of GBS following receipt of Menactra. The decision to give Menactra should take into account the potential benefits and risks. Common (≥10%) solicited adverse events in infants and toddlers 9 and 12 months of age were injection site tenderness, erythema, and swelling; irritability, abnormal crying, drowsiness, appetite loss, vomiting, and fever. Common (≥10%) solicited adverse events in individuals 2 through 55 years of age who received a single dose were injection site pain, redness, induration, and swelling; anorexia and diarrhea. Other common solicited adverse events were irritability and drowsiness (2-10 years of age), headache, fatigue, malaise, and arthralgia (11-55 years of age). Safety and effectiveness of Menactra have not been established in children younger than 9 months of age, pregnant women, nursing mothers, and adults older than 55 years of age (Sanofi Pasteur, 2018).

Menveo is available as a solution for intramuscular injection supplied as a lyophilized MenA conjugate vaccine component to be reconstituted with the accompanying MenCYW-135 liquid conjugate vaccine component. A single dose after reconstitution is 0.5 mL. The primary vaccination schedule, pre the label, include the following:

Booster vaccination is labeled as a single dose to be administered to individuals aged 15 through 55 years who are at continued risk for meningococcal disease if at least 4 years have elapsed since a prior dose of a meningococcal (serogroups A, C, Y, W-135) conjugate vaccine.

Menveo carries the following warnings and precautions:

Common solicited adverse reactions (≥10%) among children initiatingvaccination at 2 months of age and receiving the 4-dose series weretenderness (24% to 41%) and erythema at injection site (11% to 15%),irritability (42% to 57%), sleepiness (29% to 50%), persistent crying(21% to 41%), change in eating habits (17% to 23%), vomiting (5% to11%), and diarrhea (8% to 16%).Common solicited adverse reactions (≥10%) among children initiatingvaccination at 7 months through 23 months of age and receiving the 2-dose series were tenderness (10% to 16%) and erythema at injection site(12% to 15%), irritability (27% to 40%), sleepiness (17% to 29%),persistent crying (12-21%), change in eating habits (12% to 20%), anddiarrhea (10% to 16%).Common solicited adverse reactions (≥10%) among children aged 2through 10 years who received MENVEO were injection site pain (31%),erythema (23%), irritability (18%), induration (16%), sleepiness (14%), malaise (12%), and headache (11%). Common solicited adverse reactions (≥10%) among adolescents and adults who received a single dose of Menveo were pain at the injection site (41%), headache (30%), myalgia (18%), malaise (16%), and nausea (10%). Similar rates of solicited adverse reactions were observed following a single booster dose (GSK, 2020).

MenQuadfi is available as a soution for injection in 0.5 mL single-dose vials for intramuscular injection. The primary vaccination, per the label, include administration of a single dose for individuals 2 years of age and older. Per the label, a booster vaccination is administered as a single dose to individuals 15 years of age and older who are at continued risk for meningococcal disease if at least 4 years have elapsed since a prior dose of meningococcal (groups A, C, W, Y) conjugate vaccine.

The most commonly reported adverse reactions (≥10%) following a primary dose were as follows:

Serogroup B Meningococcal (MenB) Vaccines

U.S. Food and Drug Administration (FDA)-Approved Indications

The FDA granted accelerated approval of Bexsero (meningococcal group B Vaccine [recombinant, adsorbed]) for active immunization to prevent invasive meningococcal disease caused by serogroup B in adolescents and young adults from 10 years through 25 years of age (Novartis, 2015). As part of the accelerated approval process, the manufacturer will complete its ongoing studies to confirm the effectiveness of Bexsero against diverse serogroup B strains.

In phase II and phase III studies, Bexsero demonstrated a protective immune response in adolescents and young adults after two doses. Approval of Bexsero is based on demonstration of immune response, as measured by serum bactericidal activity against three serogroup B strains representative of prevalent strains in the United States. The effectiveness of Bexsero against diverse serogroup B strains has not been confirmed (Novartis, 2015).

Three studies evaluating Bexsero’s effectiveness were conducted in Canada, Australia, Chile, and the United Kingdom in approximately 2,600 adolescents and young adults (FDA, 2015). Among study participants who received two doses of Bexsero, after vaccination, 62 to 88 percent had antibodies in their blood that killed three different

serogroup B strains in tests carried out in a laboratory, compared with 0 to 23 percent before vaccination. These three strains are representative of strains that cause serogroup B meningococcal disease in the U.S.

The tolerability profile of Bexsero was also demonstrated as part of a CDC-sponsored clinical trial conducted in approximately 15,000 individuals at Princeton University and the University of California, Santa Barbara (UCSB) during meningitis B outbreaks on these college campuses (Novartis, 2015). The safety data from the CDC clinical trial are consistent with results observed in previous studies.

Bexsero is supplied as a suspension for intramuscular injection in 0.5 mL single-dose prefilled syringes, which is labed to be administered as 2 doses (0.5 mL each) at least 1 month apart. The label for Bexsero cautions that the tip caps of the prefilled syringes contain natural rubber latex which may cause allergic reactions. The most common solicited adverse reactions observed in clinical trials were pain at the injection site (≥83%), myalgia (≥48%), erythema (≥45%), fatigue (≥35%), headache (≥33%), induration (≥28%), nausea (≥18%), and arthralgia (≥13%) (GSK, 2022).

Trumenba was approved by the FDA via the accelerated approval regulatory pathway was annouced October 2014 by the U.S. Food and Drug Administration (FDA). Trumemba is licensed in the United States to prevent invasive meningococcal disease caused by Neisseria meningotidis serogroup B in individuals 10 to 25 years of age (FDA, 2014).

The FDA announced that three randomized studies that were conducted in the United states and Europe in approximately 2,800 adolescents showed that after vaccination, 82 percent had antibodies against four different serogroup B strains compared with less than 1 percent before vaccination (FDA, 2014). The effectiveness of Trumenba against diverse serogroup B strains has not been confirmed (Pfizer, 2015).

The safety of Trumenba was assessed in approximately 4,500 patients who received the vaccine in studies conducted in the United States, Europe, and Australia, in which the most commonly reported side effects were pain and swelling at the injection site, headache, diarrhea, muscle pain, joint pain, fatigue and chills (FDA, 2014). Individuals with weakened immune systems may have a reduced immune response (Pfizer, 2015).

Trumenba is also supplied as a suspension for intramuscular injection in 0.5 mL single-dose prefilled syringe. However, Trumenba is labeled to be administered as a two-dose or three-dose schedule. For two-dose schedule, Trumenba dose (0.5 mL) is labeled to be administered at 0 and 6 months. Per the label, if the second dose is administered earlier than 6 months after the first dose, a third dose should be administered at least 4 months after the second dose. The three-dose schedule, per the labeled recommendation, includes administration of 0.5 mL at 0, 1-2, and 6 months. Syncope (fainting) can occur in association with administration of injectable vaccines, including Trumenba. Procedures should be in place to avoid injury from fainting. The most common solicited adverse reactions in adolescents and young adults were pain at the injection site (≥85%), fatigue (≥60%), headache (≥55%), and muscle pain (≥35%) (Pfizer, 2021).

Beeslaar and colleagues (2018) stated that invasive meningococcal disease (IMD) caused by

is a potentially devastating condition that can result in death and is associated with serious long-term sequelae in survivors. Vaccination is the preferred preventative strategy. Quadri-valent polysaccharide-based vaccines that protect against infection caused by meningococcal serogroups A, C, W, and Y are not effective against meningococcal serogroup B (MenB), which was responsible for approximately 60 % and 35 % of confirmed IMD cases in the European Union (EU) and the U.S. in 2016, respectively. A recombinant protein MenB vaccine (MenB-FHbp [bivalent rLP2086; Trumenba®]) has been approved for protection against MenB infection in persons 10 to 25 years of age in the U.S. and Canada and for individuals greater than or equal to 10 years of age in the EU and Australia. In these regions, MenB-FHbp is approved as a 2- or 3-dose primary vaccination schedule. These investigators reviewed the current evidence supporting administration of MenB-FHbp as a 2-dose primary vaccination schedule. They also reviewed different contexts in which a 2- or 3-dose primary vaccination schedule might be preferred (e.g., routine prospective vaccination versus outbreak control).

Use of Saliva Testing of Antibody Levels Against Meningococcal Serogroups for Monitoring Meningococcal Vaccine Responses

van Ravenhorst and associates (2018) noted that meningococcal infection starts with colonization of the upper respiratory tract. Mucosal immunity is important for protection against acquisition and subsequent meningococcal carriage. In this study, these researchers evaluated salivary antibody levels against meningococcal serogroup A (MenA), W (MenW) and Y (MenY) after vaccination with a quadri-valent MenACWY conjugated vaccine. They also compared salivary meningococcal serogroup C (MenC) antibody levels after monovalent MenC and quadri-valent MenACWY conjugated vaccination. Healthy participants, who had received MenC conjugate vaccine between 14 months and 3 years of age, received a (booster) MenC or MenACWY vaccination at age 10 to 15 years. MenA-, MenC-, MenW- and MenY-polysaccharide (PS) specific IgG and IgA levels in saliva and serum and PS specific secretory component levels in saliva were measured using the fluorescent-bead-based multiplex immunoassay. MenACYW vaccination increased salivary PS-specific IgA (2-fold) and IgG levels(greater than 10-fold) for MenA, MenY, and MenW. After 1 year, salivary IgA levels had returned to baseline levels. Both vaccines induced an increase in salivary MenC-PS specific IgA (greater than 3-fold) and IgG (greater than 100-fold), with higher levels after MenC as compared to MenACWY vaccination. The antibody decay rate of MenC in saliva between 1 month and 1 year was similar for both vaccines. The overall correlation between serum and saliva IgA levels was low (R = 0.39, R = 0.58, R = 0.31, and R = 0.36 for MenA, MenC, MenW and MenY, respectively). Serogroup-PS specific IgG levels between serum and saliva correlated better (R ranged from 0.51 to 0.88). The authors concluded that both primary and booster parenteral meningococcal conjugate vaccination induced antibody levels in saliva for all targeted sero-groups. These investigators stated that salivary samples might be an interesting screening tool to measure vaccine responses after both primary and booster vaccination, especially in geographical areas where blood collection is challenging. They noted that while a minimal threshold needs yet to be assessed, IgG antibodies in saliva samples could potentially serve as surrogate of protection.

van Ravenhorst and colleagues (2019) stated that mucosal antibodies against capsular polysaccharides offer protection against acquisition and carriage of encapsulated bacteria like

serogroup C. Measurements of salivary antibodies as replacement for blood testing has important (cost-effective) advantages, especially in studies that evaluate the impact of large-scale vaccination or in populations in which blood sampling is difficult. These researchers estimated a threshold for meningococcal IgG salivary antibody levels to discriminate between unprotected and protected vaccinated individuals. MenA-, MenC-, MenW- and MenY- PS specific IgG levels in serum and saliva from participants in a meningococcal vaccination study were measured using the fluorescent-bead-based multiplex immunoassay. Functional antibody titers in serum against the 4 serogroups were measured with serum bactericidal assay using rabbit complement (rSBA). A threshold for salivary IgG was determined by analysis of receiver operating characteristic (ROC) curves using a serum rSBA titer of greater than or equal to 128 as correlate of protection. The area under the curve (AUC) was calculated to quantify the accuracy of the salivary test and was considered adequate when greater than or equal to 0.80. The optimal cut-off was considered adequate when salivary IgG cut-off levels provided specificity of greater than or equal to 90 %. True positive rate (sensitivity), positive predictive value (PPV), and negative predictive value (NPV) were calculated to explore the possible use of salivary antibody levels as a surrogate of protection. The best ROC curve (AUC of 0.95) was obtained for MenC, with an estimated minimum threshold of MenC-PS specific salivary IgG greater than or equal to 3.54 ng/ml as surrogate of protection. An adequate AUC (greater than 0.80) was also observed for MenW and MenY with an estimated minimal threshold of 2.00 and 1.82 ng/ml, respectively. When applying these thresholds, all (100 %) samples collected 1 month and 1 year after the (booster) meningococcal vaccination, that were defined as protective in the saliva test for MenC, MenW and MenY, corresponded with concomitant serum rSBA titer greater than or equal to 128 for the respective meningococcal serogroups. The authors concluded that the saliva test offered an alternative screening tool to monitor protective vaccine responses up to 1 year after meningococcal vaccination against MenC, MenW and MenY. These researchers stated that future, large, longitudinal vaccination studies evaluating also clinical protection against IMD or carriage acquisition are needed to validate the currently proposed threshold in saliva.

The authors stated that a drawback of this study was that only samples of children aged 10 to 15 years were used here to identify the salivary thresholds. Thus, these salivary thresholds as surrogate of protection have to be validated in other large meningococcal vaccine trials, preferably studies that include participants with a wide age range. furthermore, samples were collected only up to 1 year after vaccination. Whether saliva samples could be used as a surrogate of protection in the long-term after vaccination has to be examined as well.

Scope of Policy

This Clinical Policy Bulletin addresses meningococcal vaccines.

Medical Necessity

Aetna considers meningococcal vaccines, meningococcal conjugate (MenACWY) vaccine (e.g., Menactra, Menveo, and MenQuadfi) and serogroup B meningococcal (MenB) vaccine (Bexsero and Trumenba), a medically necessary preventive service according to the recommendations of the Centers for Disease Control and Prevention's (CDC) Advisory Committee on Immunization Practices (ACIP).

Aetna considers CDC ACIP's recommendations for the meningococcal vaccine medically necessary for the following indications:

College freshmen living in residence halls do not require a booster unless person becomes at increased risk due to another indication.

Dosing schedule varies by vaccine brand; for persons who remain at increased risk for

serogroup B meningococcal disease, a single dose booster is considered medically necessary 1 year after primary series completion, then every 2 to 3 years thereafter.

ACIP does not provide a recommendation for MenB vaccine for the following risk groups: persons with HIV infection, persons who travel to countries where meningococcal (

) disease is hyperendemic or epidemic, college freshmen living in residence halls, or military recruits.

*

: Some plans exclude coverage of immunizations for travel or work. Please check benefit plan descriptions for details.

Experimental and Investigational

The following procedures/indications are considered experimental and investigational because the effectiveness of these approaches has not been established:

Notes