Serogroups A, C, W, and Y Meningococcal Vaccines
MenACWY-D was first licensed in the United States in 2005. Clinical trials have demonstrated immunogenicity of MenACWY-D among persons aged 9 months–55 years, although antibody waning is observed during the 3–5 years after primary vaccination (67,80–104). Booster vaccination elicits a robust immune response, and data in adolescents demonstrate persistence for at least 4 years after a booster dose (105,106). Clinical trials have demonstrated an acceptable safety profile, with injection site pain and erythema as the most common local reactions; irritability and drowsiness are the most common systemic adverse events among infants and children, and myalgia, headache, and fatigue are the most common systemic adverse events among adolescents and adults (67,80,81,85,87–90,92–96,98–103). Most adverse events are mild to moderate and resolve within 3 days. Early postlicensure surveillance raised the concern of a potential risk for Guillain-Barré syndrome (GBS), but subsequent evaluations have not identified an increased risk for GBS after MenACWY-D vaccination (107–110). No other vaccine safety concerns have been identified in postlicensure surveillance (111–114).
Infants and Children
In clinical trials among infants who received MenACWY-D as a 2-dose series at ages 9 and 12 months, 89%–96% achieved an hSBA titer ≥1:8 against serogroup A, ≥98% against serogroup C, 81%–92% against serogroup W, and 95%–97% against serogroup Y 1 month after completion of the series (80,98). Administration of MenACWY-D simultaneously with routine vaccines did not result in reduced immune responses to meningococcal serogroups A, C, W, or Y or measles, mumps, rubella, or varicella antigens; however, when MenACWY-D was administered simultaneously with seven-valent pneumococcal conjugate vaccine (PCV7) (Prevnar), noninferiority criteria were not met for three of seven pneumococcal serotypes (98). By 3 years after primary series completion, substantial MenACWY-D waning occurred, with 13%–46% of recipients having an hSBA titer ≥1:8 across serogroups, although this proportion increased to ≥98% 1 month after a single booster dose (80).
Among toddlers receiving a 2-dose primary series at ages 12 and 15 months, 85% achieved an hSBA titer ≥1:8 against serogroup A and ≥96% against serogroups C, W, and Y at 1 month after the primary series (80). In another study in which MenACWY-D was administered at ages 12 and 18 months, ≥96% achieved rSBA titers ≥1:8 for all serogroups (95). In this study, administration of MenACWY-D simultaneously with routine vaccines did not result in reduced immune responses to meningococcal serogroups A, C, W, or Y or tetanus, diphtheria, pertussis, poliovirus, or H. influenzae type b antigens.
Among children aged 2–10 years, the rate of seroresponse (defined as a greater than fourfold rise in hSBA or a titer ≥1:8 among persons with baseline titers <4) was highest for serogroup A (80%) and lower for serogroups C, W, and Y (42%–57%) at 1 month after a single dose (88). Studies using rSBA demonstrated a higher proportion of seroresponse across serogroups (≥86%) using different thresholds (either a greater than fourfold rise in titers among persons with baseline titers <1:8 or a titer ≥1:8) (91,93,96,104). Among children aged 4–6 years, administration of MenACWY-D simultaneously with routine vaccines did not result in reduced immune response to meningococcal serogroups A, C, or W or diphtheria, tetanus, or poliovirus antigens; however, the noninferiority criteria were not met for serogroup Y and one pertussis antigen (anti-fimbriae) (67). Because no clinical correlates of protection are available for pertussis antigens, the clinical significance of this finding is unknown. When MenACWY-D was administered 30 days after diphtheria and tetanus toxoids and acellular pertussis (DTaP) vaccine (DAPTACEL), significantly lower geometric mean titers (GMTs) were observed for all meningococcal serogroups (67). Among children aged 4–6 years vaccinated previously at age 2–3 years, the proportions maintaining an rSBA titer ≥1:128 were 75%, 52%, 61%, and 90% for serogroups A, C, W, and Y, respectively (97).
Adolescents and Adults
Among adolescents and adults aged 10–55 years, 64%–71% achieved an hSBA titer ≥1:8 against serogroup A, 72%–99% against serogroup C, 64%–90% against serogroup W, and 39%–82% against serogroup Y at 1 month after vaccination with a single dose (81,87,89,99). In studies assessing immunogenicity using rSBA, ≥80% and ≥88% achieved seroprotection across serogroups when the thresholds of ≥1:128 and ≥1:8 were used, respectively (85,90,92,102,104). Administration of MenACWY-D simultaneously with routine vaccines did not result in reduced immune responses to meningococcal serogroups A, C, W, or Y or tetanus, diphtheria, pertussis, human papillomavirus (HPV), MenB-FHbp, or typhoid antigens (67,94,100–103).
Persistence studies conducted among adolescents and adults demonstrated antibody waning after primary vaccination; however, serogroup-specific degree of waning varied between the studies. In one study, antibody waning was observed for all serogroups, particularly serogroup A, by 22 months postvaccination and titers remained stable thereafter at 3 and 5 years postvaccination; 21%–34% of recipients achieved an hSBA titer ≥1:8 for serogroup A, 58%–62% for serogroup C, 71%–74% for serogroup W, and 53%–54% for serogroup Y between 22 months and 5 years postvaccination (83,84,86). In another study, antibody waning was observed by 4–6 years postvaccination but was more marked for serogroups C and Y (44% and 39% achieved an hSBA titer ≥1:8, respectively) compared with serogroups A and W (65% and 69%, respectively) (105). In a separate study, serogroup A waning was most pronounced, although for the other serogroups the proportion of recipients with hSBA titers ≥1:8 was higher than that observed in previously mentioned studies and was stable at 1, 3, and 5 years postvaccination with 32%–44% seroprotected against serogroup A, 73%–81% against serogroup C, 76%–85% against serogroup W, and 87%–91% against serogroup Y (82). Thus, although antibody waning after primary vaccination of adolescents and adults was observed across studies, time points assessed and patterns of waning by serogroup were not consistent. In a study of adolescents who received a booster dose of MenACWY-D, ≥99% achieved hSBA titers ≥1:8 against all serogroups at 1 month postvaccination; this proportion remained ≥90% 4 years later (105,106).
Among infants vaccinated at ages 9 and 12 months and toddlers vaccinated at ages 12 months and 15 or 18 months, the most commonly reported local reactions after either of the doses were injection site pain (35%–59%) and erythema (23%–43%) (80,95,98). The most commonly reported systemic adverse events were irritability (49%–72%) and drowsiness (27%–44%); fever was reported in 11%–50% of recipients. Adverse events among infants were similar when MenACWY-D was administered alone or simultaneously with other vaccines (98). After receipt of a booster dose 3 years after vaccination as an infant, rates of local and systemic adverse events were similar to those observed for the primary series (115). Similar adverse events were observed among children aged 2–10 years after a single dose, although typically at a slightly lower rate; injection site pain (32%–48%), induration (11%–22%), and erythema (10%–30%) were the most commonly reported local reactions, and drowsiness (9%–26%), irritability (7%–35%), and fever (2%–11%) were the most common systemic adverse events (67,88,93,96).
Among adolescents and adults aged 11–55 years who received a single dose, injection site pain (31%–69%) was the most common local reaction, followed by induration (9%–20%), erythema (3%–20%), and swelling (1%–14%) (81,85,87,89,90,92,99,102). Myalgia (15%–26%), headache (11%–45%), fatigue or malaise (10%–28%), and diarrhea or other gastrointestinal symptoms (11%–17%) were the most commonly reported systemic adverse events; fever was observed in <8%. Similar types and rates of adverse events were observed after a booster dose administered 4 years later (105). In general, MenACWY-D administered simultaneously with HPV vaccine, tetanus and reduced diphtheria toxoids and acellular pertussis vaccine (Tdap), MenB-FHbp, or typhoid vaccines was well tolerated, although rates of some adverse events (e.g., headache and fatigue) were slightly higher with simultaneous administration compared with MenACWY-D administered alone (67,94,100–103). Across age groups, whether MenACWY-D was administered alone or simultaneously with other vaccines, adverse events were mild to moderate and typically resolved within 3 days.
Postlicensure Safety Monitoring
After licensure of the vaccine in 2005, several cases of GBS after MenACWY-D vaccination were reported to VAERS (116). ACIP reviewed the available data and determined that the benefits of meningococcal vaccination outweighed the small potential increased risk for GBS (107). By 2010, two retrospective evaluations had been conducted in which no GBS cases were observed in the 6 weeks after 2.3 million doses of MenACWY-D were administered (108,110). The excess risk for GBS after vaccination, if it exists, is estimated to be <0.66 cases per 1 million adolescents vaccinated (110). In 2010, ACIP voted to remove the precaution for persons with a history of GBS from the ACIP recommendations, although it continues to be listed as a precaution in the package insert (16,67). Evaluations of VSD data through 2014 and VAERS data through 2016 have since been conducted, identifying no new GBS-related concerns (CDC, unpublished data, 2020).
In addition to assessing risk for GBS, data from VAERS and VSD have been evaluated to assess for other potential postvaccination adverse events. In a comprehensive review of VAERS reports received from 2005 through June 2016, during which approximately 70 million MenACWY-D doses were distributed, no new safety concerns were identified (CDC, unpublished data, 2020). A total of 13,075 adverse events related to MenACWY-D were reported, of which 846 (6.5%) were serious. Reports predominantly related to adolescents aged 11–18 years simultaneously vaccinated with MenACWY-D and other vaccines. The most commonly reported events were injection site erythema, fever, and headache, consistent with findings from clinical trials.
An analysis of VSD during 2005–2014, when 1.4 million doses, including 245,000 booster doses, were administered, was conducted to evaluate prespecified outcomes (CDC, unpublished data, 2020). Although rates of syncope and medically attended fever increased after MenACWY-D vaccination, no new safety concerns were identified. Furthermore, tree-temporal scan data mining through VSD of primary doses administered to 1.2 million adolescents aged 11–18 years during the same period identified no new or unexpected adverse events within 42 days after MenACWY-D administration (114). Several smaller studies, including VSD- and manufacturer-sponsored studies conducted during 2005–2014, similarly did not identify any additional safety concerns for MenACWY-D among infants, children, adolescents, or adults (111–113).
MenACWY-CRM was first licensed in the United States in 2010. MenACWY-CRM has been demonstrated to be immunogenic among persons aged 2 months–55 years (88,89,99,117–130). Antibody waning occurs by 3–5 years after primary vaccination, and booster vaccination elicits a robust immune response (83,84,131–133). No consistent or clinically relevant concerns about MenACWY-CRM administered simultaneously with other vaccines have been identified (134–136). Clinical trials have demonstrated an acceptable safety profile, with injection site pain and erythema as the most common local reactions (88,118–124,126,127,129,137). Irritability and sleepiness were the most commonly reported systemic adverse events among infants and toddlers. Among children, irritability, myalgia, headache, and sleepiness were the most commonly reported systemic adverse events, whereas myalgia, headache, and fatigue were the most commonly reported systemic adverse events among adolescents and adults. Most adverse events were mild to moderate and resolved within 3 days. One study observed an increased risk for Bell’s palsy among adolescents after MenACWY-CRM vaccination, although this was based on a small number of cases and the importance of this finding is uncertain (138). No additional safety concerns have been identified in postlicensure surveillance, although administration errors appear more common than with other vaccines, predominantly because of the need to reconstitute the vaccine using lyophilized and liquid components (139,140).
Infants and Children
Among infants vaccinated at ages 2, 4, and 6 months with MenACWY-CRM and routine vaccines, 76%–89% achieved an hSBA titer ≥1:8 for serogroup A and ≥94% for serogroups C, W, and Y 1 month after the third dose (119,124,128,130,141). Antibody titers waned by age 12 months, particularly for serogroup A. Following the fourth dose in the infant series at age 12–17 months, the proportions of infants with an hSBA titer ≥1:8 were 89%–96% for serogroup A and ≥95% for serogroups C, W, and Y. Administration of MenACWY-CRM simultaneously with routine vaccines did not result in reduced immune responses to meningococcal serogroups A, C, W, or Y or diphtheria, tetanus, hepatitis B, poliovirus, measles, mumps, rubella, varicella, H. influenzae type b, or most pneumococcal antigens (136). For the few pneumococcal serotypes for which noninferiority criteria were not met, results were not consistent across studies and age of administration (136). Noninferiority was not consistently met for pertussis antigens across studies when MenACWY-CRM was administered with routine vaccines; however, the clinical relevance is unclear because of the lack of clinical correlates of protection for pertussis antigens. By age 2 years, or 1 year after completion of a 4-dose MenACWY-CRM series, 88%–89% achieved an hSBA titer ≥1:8 for serogroups W and Y, 61% for serogroup C, and 39% for serogroup A (141). By age 40 months, most children still had an hSBA titer ≥1:8 for serogroups W and Y (76% and 67%, respectively), although this proportion was only 34% for serogroup C and 10% for serogroup A. By age 60 months, similar but slightly lower proportions were observed; following a single booster dose, ≥96% of recipients achieved hSBA titers ≥1:8 across all serogroups.
After a 2-dose series among older infants and toddlers at either ages 7–9 months and 12 months or 12 and 15 months, the proportions who achieved an hSBA titer ≥1:8 1 month after the second dose were 88%–97% for serogroup A and ≥96% for serogroups C, W, and Y (125,130). Administration of MenACWY-CRM simultaneously with routine vaccines did not result in reduced immune responses to meningococcal serogroups A, C, W, or Y or measles, mumps, rubella, or varicella antigens (136). Among children who received the 2-dose primary series at ages 12–13 and 15 months, serogroup-specific antibody waning patterns similar to those among infants also were observed; however, the proportion of recipients with an hSBA titer ≥1:8 was higher at age 40 months (85%, 79%, 55%, and 31% for serogroups W, Y, C, and A, respectively) among this group (131). Similar results were observed by age 60 months; after a single booster, all subjects achieved hSBA titers ≥1:8 for all serogroups (131).
Among children who received a single dose at age 2–10 years, the proportions who achieved hSBA titers ≥1:8 (≥1:4 in one study) were 72%–89% for serogroup A, 68%–94% for serogroup C, 90%–96% for serogroup W, and 65%–91% for serogroup Y (88,118,120,121,123,126). No data are available on MenACWY-CRM administered simultaneously with routine vaccines among this age group. Twelve months after the primary dose, the proportion with seroprotective titers declined, particularly for serogroups A and C (118,123). Five years after a primary dose administered at age 2–10 years, 14%–22% of recipients remained seroprotected against serogroup A, 32%–56% against serogroup C, 74%–80% against serogroup W, and 48%–53% against serogroup Y; these proportions were lower among those vaccinated at age 2–5 years compared with age 6–10 years. One month after a single booster dose, all recipients achieved hSBA titers ≥1:8 for all serogroups (132).
Adolescents and Adults
One month after a single MenACWY-CRM dose among adolescents and adults aged 11–75 years, 66%–92% of recipients achieved an hSBA titer ≥1:8 for serogroup A, 79%–98% for serogroup C, 84%–99% for serogroup W, and 79%–96% for serogroup Y (89,99,117,120–122,126,127,129). In one study that reported immunogenicity separately for adults aged ≥55 years, those aged 56–65 years had results similar to those aged 19–55 years (129). Administration of MenACWY-CRM simultaneously with other vaccines did not result in reduced immune responses to meningococcal serogroups A, C, W, or Y or tetanus, diphtheria, HPV, hepatitis A, hepatitis B, typhoid, yellow fever, Japanese encephalitis, or rabies antigens (117,135,142–146). After simultaneous administration of MenACWY-CRM and MenB-4C, a robust immune response to meningococcal serogroups A, C, W, and Y and to select meningococcal serogroup B strains was observed, although the majority of persons had high prevaccine hSBA titers across serogroups (134). Noninferiority criteria were not met for two pertussis antigens (i.e., pertussis toxoid and pertactin) when MenACWY-CRM and Tdap were administered simultaneously, although the clinical relevance of this is unclear (135).
By 12–22 months postvaccination, substantial antibody waning was observed for serogroup A, though the majority of recipients remained seroprotected for serogroups C, W, and Y (86,122). After this initial decline, hSBA titers remained relatively stable at 3 and 5 years postvaccination, with 28%–32% of recipients having an hSBA titer ≥1:8 against serogroup A, 59%–76% against serogroup C, 72%–82% against serogroup W, and 64%–76% against serogroup Y (83,133). One month after a single MenACWY-CRM booster dose administered at 3–6 years after the primary dose, ≥94% of subjects achieved an hSBA titer ≥1:8 across all serogroups. Booster vaccination elicited a robust immune response whether MenACWY-CRM or MenACWY-D was used for the primary dose (83,147). By 2 years after the booster dose, the proportion of recipients with an hSBA titer ≥1:8 decreased to 79% for serogroup A but remained at ≥95% for serogroups C, W, and Y (84).
Among infants and toddlers vaccinated with a MenACWY-CRM series (4-dose and 2-dose series, respectively) administered with routine vaccines, injection site pain (19%–39%) and erythema (12%–22%) were the most common local reactions after the third or fourth infant doses and second toddler dose (119,124,137,141). Irritability (36%–50%), sleepiness (22%–31%), and decreased appetite (15%–20%) were the most common systemic adverse events; fever was reported in 5%–9% of recipients. Reactogenicity among infants and toddlers vaccinated with a 4- or 2-dose series, respectively, did not increase with subsequent MenACWY-CRM doses. Among children aged 2–10 years vaccinated with a single dose, injection site pain (<40%) and erythema (<32%) were the most commonly reported local reactions (88,118,120,121,123,126). Irritability was reported in 7%–26%, myalgia in <29%, headache in <21%, and fatigue in <21%. Adverse events were similar whether vaccination was administered at ages 2–5 or 6–10 years. Adverse events were similar after a booster dose administered 5 years after primary vaccination (132).
Among adolescents and adults aged 11–75 years who received a single MenACWY-CRM dose, injection site pain occurred in 8%–54%, erythema in <39%, and induration in <24%. Commonly reported systemic adverse events include headache (8%–41%), myalgia (<43%), and fatigue (3%–23%) (99,120–122,126,127,129,148). When MenACWY-CRM was administered simultaneously with HPV and Tdap vaccines, headache, malaise, myalgia, and arthralgia occurred more often than when MenACWY-CRM was administered alone (117). In addition, adverse events after a booster dose administered 4–6 years after primary vaccination were similar to those among persons receiving a first dose. Across age groups, whether MenACWY-CRM was administered alone or simultaneously with other vaccines, adverse events were mild to moderate and typically resolved within 3 days.
Postlicensure Safety Monitoring
In a manufacturer-sponsored cohort study of approximately 49,000 vaccinated adolescents aged 11–21 years with a self-controlled case series analysis, a statistically significant increased risk for Bell’s palsy during the 84 days after vaccination was observed when MenACWY-CRM was administered simultaneously with other vaccines but not when MenACWY-CRM was administered alone (138). However, this finding was based on only eight patients, most of whom received simultaneous vaccine administration, and several were noted to have had conditions or infections that might precede Bell’s palsy. Thus, the importance of this finding remains uncertain. No other safety signals were observed among the other predefined events of interest in this evaluation (138). No increased risk for Bell’s palsy or any other new safety concerns were observed in smaller studies conducted in the same health system among children aged 2 months–10 years (140,149).
A comprehensive review of VAERS reports from 2010 through 2015, during which 8.2 million MenACWY-CRM doses were distributed, was conducted with no new safety concerns identified (139). A total of 2,614 reports about MenACWY-CRM were received, primarily related to adolescents aged 11–18 years in whom MenACWY-CRM was administered simultaneously with other vaccines. Reported adverse events were consistent with the findings from prelicensure studies. The reporting rate of GBS or Bell’s palsy was proportionate to the rate reported for other vaccines. However, administration errors were reported more commonly for MenACWY-CRM, predominantly because of administration of only one component (most commonly the liquid component) rather than reconstituting the vaccine by mixing the liquid and lyophilized components together before administration.
MenACWY-TT was first licensed in the United States in 2020 for the prevention of meningococcal disease caused by serogroups A, C, W, and Y in persons aged ≥2 years (68). As a result, relatively limited data on MenACWY-TT safety and immunogenicity are available compared with other licensed meningococcal conjugate vaccines. MenACWY-TT has been administered to nearly 5,000 persons aged ≥2 years to date through clinical trials, with demonstrated immunogenicity in this age group and elicitation of a boost response among adolescents vaccinated with MenACWY-TT who previously received MenACWY-D or MenACWY-CRM (68,150–155). No clinically relevant concerns about MenACWY-TT administered simultaneously with HPV or Tdap vaccines among adolescents have been identified (151). Clinical trials have demonstrated an acceptable safety profile, with injection site pain as the most common local adverse event, and myalgia, headache, and malaise as the most commonly reported systemic adverse events across age groups (68,150–155). Most adverse events were mild to moderate (68,150–155).
Infants and Children
Because MenACWY-TT is currently only licensed for persons aged ≥2 years in the United States, immunogenicity and safety data for children aged <2 years are not presented in this report. Among children who received a single dose at age 2–9 years, the proportions who achieved hSBA titers ≥1:8 1 month after vaccination were 86% for serogroup A, 98% for serogroup C, 95% for serogroup W, and 99% for serogroup Y (155). MenACWY-TT seroresponse rates were demonstrated to be noninferior to those observed for MenACWY-CRM (155). No data are available on MenACWY-TT administered simultaneously with routine vaccines or on persistence of the immune response to MenACWY-TT among this age group; data will be reviewed as they become available to inform vaccine recommendations.
Adolescents and Adults
One month after a single MenACWY-TT dose among adolescents and adults aged 10–55 years, the proportions who achieved hSBA titers ≥1:8 were 94%–96% for serogroup A, 94%–99% for serogroup C, 95%–99% for serogroup W, and 97%–99% for serogroup Y (151,154). Among adults aged ≥56 years, these proportions were 89%–94%, 75%–90%, 77%–80%, and 81%–92% for serogroups A, C, W, and Y, respectively (152,153). Across these age groups, MenACWY-TT seroresponse rates were noninferior to those of the comparator meningococcal vaccines (68,151,153). MenACWY-TT administered simultaneously with HPV and Tdap vaccines in adolescents did not result in reduced immune responses to meningococcal serogroups or tetanus, diphtheria, or HPV antigens (151). Noninferiority criteria were not met for three pertussis antigens when MenACWY-TT and Tdap were administered simultaneously, although the clinical relevance of this is unclear. No data are available on persistence of the immune response to MenACWY-TT. When available, data will be reviewed to inform booster dose recommendations for persons primed with MenACWY-TT. Among adolescents and adults aged ≥15 years primed with MenACWY-D or MenACWY-CRM 4–10 years previously, >99% achieved an hSBA titer ≥1:8 across all serogroups at 1 month after booster vaccination with MenACWY-TT (150).
Among children aged 2–9 years vaccinated with a single MenACWY-TT dose, injection site pain occurred in 39%, erythema in 23%, and swelling in 14%; systemic adverse events included malaise in 21%, myalgia in 20%, headache in 13%, and fever in 2% within 7 days of vaccine administration (68). Among adolescents and adults aged 10–55 years, the most common local adverse event was injection site pain (35%–45%); erythema and swelling occurred in 5% and 4%–5%, respectively (68,151). Systemic adverse events included myalgia (27%–36%), headache (27%–30%), and malaise (19%–26%); fever occurred in 1% (68,151). Rates of local and systemic adverse events were typically similar in adults aged ≥56 years compared with other age groups: injection site pain (26%–31%), erythema (5%–12%), swelling (5%–8%), myalgia (22%–35%), headache (19%–24%), malaise (15%–22%), and fever (2%). When MenACWY-TT was administered simultaneously with HPV and Tdap vaccines in adolescents, rates of local and systemic adverse events were typically similar to those when MenACWY-TT was administered alone, although myalgia occurred more frequently (151). In addition, adverse events after a MenACWY-TT booster dose administered 4–10 years after primary vaccination with either MenACWY-D or MenACWY-CRM were similar to those among persons receiving a first MenACWY-TT dose (150). Across age groups, whether MenACWY-TT was administered alone or simultaneously with other vaccines, adverse events were mild to moderate (68,150–155).
Postlicensure Safety Monitoring
Given the recent licensure of MenACWY-TT, no postlicensure data were available at the time of publication of this report. Data from VAERS and VSD will be monitored as part of postlicensure safety monitoring. (See Reporting of Vaccine Adverse Events for information on how to report MenACWY-TT adverse events to VAERS.)
MenACWY Vaccine Immunogenicity and Safety in Persons with Underlying Medical Conditions
Complement-mediated bactericidal activity is important for protection against meningococcal disease; opsonophagocytic killing elicited by meningococcal antibodies is another defense against infection and is the presumed primary mechanism for vaccine-induced protection against meningococcal disease among persons with complement deficiency (35,156). No data about immunogenicity of U.S.-licensed MenACWY vaccines (MenACWY-D, MenACWY-CRM, or MenACWY-TT) are available for persons with complement deficiency. Antibody titers after vaccination with MPSV4, a vaccine that is no longer available in the United States, are similar among persons with late complement deficiency compared with healthy persons and the antibodies produced are capable of eliciting opsonophagocytosis; however, antibody titers might wane more rapidly among persons with complement deficiency and higher antibody levels might be needed for opsonophagocytosis to function (35,157–160). Data are lacking to establish the efficacy of meningococcal conjugate vaccines among persons with complement deficiency. Thus, persons with complement deficiency are at increased risk for meningococcal disease even if they develop antibodies postvaccination (66–68).
Limited data are available about efficacy of meningococcal vaccines among persons taking complement inhibitors. However, some studies suggest that opsonophagocytic killing of meningococci in the presence of eculizumab in sera from persons vaccinated with MenACWY either does not occur or is insufficient to prevent meningococcal proliferation (161). In addition, reports of meningococcal disease despite recent vaccination among persons taking eculizumab indicate that meningococcal vaccines do not provide complete protection among persons taking complement inhibitors, even if antibodies develop after vaccination (42,66–68,161).
Although no data are available for U.S.-licensed MenACWY vaccines (MenACWY-D, MenACWY-CRM, or MenACWY-TT), adults with anatomic asplenia had a reduced immunologic response compared with healthy persons after 1 dose of a serogroup C meningococcal conjugate vaccine; after a second dose, most persons achieved seroprotection (162–164). Among children and adolescents vaccinated with a conjugate MenACWY-TT vaccine licensed outside the United States, similar immune responses were observed in children with functional or anatomic asplenia compared with healthy controls after each of 2 doses (165). However, antibodies appear to wane rapidly after serogroup C meningococcal conjugate vaccination among children with functional asplenia due to sickle cell disease, particularly among those who received primary vaccination at age <2 years (166).
Among adolescents with HIV infection, immunogenicity to MenACWY-D is reduced compared with adolescents without HIV infection. By 4 weeks postvaccination with a single dose, 52%–73% of HIV-infected adolescents had a greater than fourfold increase in rSBA across the meningococcal serogroups. Lower CD4 percentage, higher viral load, and a more advanced clinical stage were inversely associated with seroprotection against serogroup C (167). By 72 weeks subsequent to a second dose, a significantly greater proportion of adolescents with a CD4 percentage ≥15% had seroprotective rSBA titers, although this proportion was lesser for serogroup C than other serogroups, compared with those with a CD4 percentage of <15%, among whom seroprotection rates for all serogroups was reduced (168). Among children aged 2–10 years with HIV infection and a CD4 percentage ≥25%, antibody titers against serogroup C waned substantially by 72 weeks after vaccination (169). Similar trends were observed subsequent to vaccination of HIV-infected children and adolescents with serogroup C meningococcal conjugate vaccine (170–173).
Although data are limited, vaccination of persons with asplenia or HIV infection appears to be safe and well tolerated, with similar types of adverse events as reported among healthy controls or during clinical trials (165,167,169,171). Among HIV-infected children and adolescents vaccinated with MenACWY-D, rates of adverse events typically were lower than those reported during clinical trials of healthy children and adolescents, although these lower adverse event rates were not consistently observed among those vaccinated with a serogroup C meningococcal conjugate vaccine (80,167,169–171). Among children with asplenia who received a conjugate MenACWY-TT vaccine licensed outside the United States, an acceptable safety profile was observed among all age groups, although higher rates of adverse events were reported compared with healthy controls; however, the small study size limits the interpretation of this finding (165,170,171).
MenACWY Vaccines in Pregnant Women
Adverse outcomes (e.g., spontaneous abortion or birth defects) are risks for all pregnancies, occurring in approximately 15%–20% and 3%, respectively, of clinically recognized pregnancies in the United States (174,175). Although evidence is limited, rates of these outcomes after MenACWY vaccination during pregnancy are consistent with the estimated background rates, and no additional concerning maternal or neonatal safety patterns have been identified (66,67,112,139,176,177).
No controlled trials have been conducted to specifically assess the safety of meningococcal vaccination among pregnant women and birth outcomes of vaccinated women. However, among approximately 2,000 pregnant Malian women vaccinated during the third trimester with MenACWY-D as a control group in an influenza vaccine trial, rates of local and systemic adverse events were lower than those observed during MenACWY-D clinical trials of adolescents and adults and serious obstetric and nonobstetric adverse events were rare, with similar rates between MenACWY-D and influenza vaccination groups (176). In the MenACWY-D vaccinated group, 98% of pregnancies resulted in live births, and among infants, 0.3% had low birthweight and 0.2% had a congenital malformation; no differences in these outcomes were observed among women who received influenza vaccine.
Among approximately 5,000 adolescent or adult females enrolled in MenACWY clinical trials, pregnancy was reported in 43 women during the 6 months postvaccination (37 who received MenACWY-CRM and six who received MenACWY-D) (66,67). Of these, seven (19%) MenACWY-CRM recipients reported spontaneous abortion (estimated dates of conception were 5 days before vaccination for one woman, 6–17 weeks postvaccination for five women, and 6 months postvaccination for one woman). Congenital anomaly (hydrocephalus) was reported in the infant of one MenACWY-D recipient with an estimated conception date 15 weeks after vaccination.
Although data are limited, no concerning safety signals have been identified through postlicensure surveillance. In reviews of VAERS, 127 pregnancy-associated reports were identified during the periods evaluated: 113 for MenACWY-D (2005–2011) and 14 for MenACWY-CRM (2010–2015); the differences in number of reports by vaccine type probably reflect differences in numbers of doses administered during these periods (139,177). The majority of vaccine administrations occurred during the first trimester. Among the 113 pregnant women who received MenACWY-D, spontaneous abortion was reported in 17% and congenital anomaly was reported in <1% of VAERS reports (177). Following MenACWY-CRM vaccination in pregnancy, only three VAERS reports had information on birth outcome, with no adverse events reported (139). Among patients in a large health care organization, one spontaneous abortion was identified among 18 MenACWY-D exposures during pregnancy with known outcome (112).
Manufacturers of MenACWY vaccines maintain registries that monitor pregnancy outcomes of women exposed to MenACWY during pregnancy. Among 87 pregnant women exposed to MenACWY-D during 2005–2016 from 30 days before or at any time during pregnancy who had known pregnancy outcome and who were enrolled in the registry before outcome being known, spontaneous abortion was reported in 7% and major congenital anomalies in 2% (67). Among 82 pregnant women exposed to MenACWY-CRM during 2014–2017 from 28 days before or at any time during pregnancy who had known outcome, spontaneous abortion was reported in 12% and congenital anomaly in 4% (GlaxoSmithKline, unpublished data, 2019). No information is available from the MenACWY-TT pregnancy registry because of the recent licensure of the vaccine.
Effectiveness of MenACWY Vaccines
Overall vaccine effectiveness of a single dose of MenACWY-D against meningococcal disease caused by serogroups A, C, W, or Y among adolescents in the United States is estimated at 69% (95% confidence interval [CI]: 51%–80%) in the 8 years after vaccination: 77% (95% CI: 57%–88%) against serogroup C and 51% (95% CI: 1%–76%) against serogroup Y (178). Effectiveness was 79% (95% CI: 49%–91%) in the first year but decreased to 69% (95% CI: 44%–83%) 1 to <3 years postvaccination and 61% (95% CI: 25%–79%) 3 to <8 years postvaccination. No data are available on the effectiveness of MenACWY-CRM or MenACWY-TT.
Vaccination and Meningococcal Disease Incidence
Measuring the association between adolescent MenACWY vaccination on rates of meningococcal disease has been challenging because of the low and decreasing incidence of meningococcal disease among all age groups. However, from MenACWY introduction through 2017, adolescents experienced the greatest percentage decreases (>90%) in meningococcal disease incidence due to serogroups C, W, or Y combined compared with other age groups (179). In the setting of 85% coverage with at least 1 dose of MenACWY-D or MenACWY-CRM among U.S. adolescents aged 13–17 years and 44% coverage with at least 2 doses among adolescents aged 17 years by 2017, a twofold to threefold increase in the rate of decline in incidence was observed during the postvaccination period compared with the prevaccination period among adolescents, suggesting that vaccination with MenACWY-D or MenACWY-CRM is associated with reductions in disease rates in adolescents (179,180). No data are available for MenACWY-TT.
Vaccination and Oropharyngeal Carriage
Although vaccination with a serogroup C meningococcal conjugate vaccine in Europe and a serogroup A meningococcal conjugate vaccine in sub-Saharan Africa has been associated with reductions in oropharyngeal carriage of these N. meningitidis serogroups and resulted in herd immunity in the population (181–183), data are limited for MenACWY vaccines. In the United States, carriage prevalence of meningococcal serogroups C, W, or Y combined among college students in the setting of high MenACWY vaccination coverage is now extremely low (<1%); however, no direct evidence exists that this low prevalence is a result of vaccination (184–186). In a small observational study of Polish military recruits, those vaccinated with a MenACWY vaccine 1–3 years earlier had lower rates of meningococcal carriage compared with unvaccinated recruits (187). In a randomized controlled trial of United Kingdom university students, those who received MenACWY-CRM had significantly lower carriage prevalence than controls for serogroup Y (39% carriage reduction) and serogroups C, W, and Y combined (36% carriage reduction) at 2 months postvaccination, although no differences in carriage acquisition rates were observed (188). In contrast, in a study conducted in a different United Kingdom university population vaccinated with MenACWY-CRM in response to rapid expansion of a serogroup W clone in England, serogroup W carriage of this clone increased despite relatively high vaccination coverage (189). However, because carriage acquisition among university students is known to rapidly increase at the beginning of the academic year (190), the majority of serogroup W transmissions might have occurred simultaneously with vaccination activities (i.e., during September).
Cost-Effectiveness of MenACWY Vaccines
Cost-effectiveness of MenACWY vaccines in the United States was last assessed in 2010 using Monte Carlo simulation (191). In this evaluation, cost per quality-adjusted life year (QALY) of vaccinating at ages 11 and 16 years was similar to vaccinating at either age 11 or 15 years ($212,000–$256,000), although the estimated number of cases and deaths averted among the vaccinated cohort was substantially higher with a 2-dose strategy (184 and 22, respectively) compared with a single-dose strategy (94–115 and 11–14, respectively) (16).