Past, present, and future policy considerations regarding meningococcal vaccination in the United States.

INTRODUCTION: In 2005, the United States Advisory Committee on Immunization Practices (ACIP) recommended routine vaccination against invasive meningococcal disease (IMD) caused by serogroups A, C, W, and Y (MenACWY) for all 11-12-year-olds, as well as 2-10-year-olds at high risk. In 2010, a booster dose was recommended for all 16-year-olds, as well as for high-risk patients every 3-5 years. In 2015, optional (as opposed to routine) vaccination against meningococcal serogroup B (MenB) at the preferred age of 16-18 years was recommended (Category B, later changed to shared clinical decision-making). In 2023, a vaccine (MenABCWY) against the five serogroups primarily responsible for IMD in the U.S. became available. AREAS COVERED: This review summarizes the evolution of public policy that led to each milestone vaccine recommendation, reviews epidemiologic data published following the recommendations, and discusses the current state of meningococcal immunization policy. EXPERT OPINION: The use of MenABCWY has the potential to consolidate policy, improve coverage rates for the five serogroups, address disparities in vaccination coverage, and simplify vaccine delivery.

Understanding the Sequelae of Invasive Meningococcal Disease in the United States.

Invasive meningococcal disease (IMD) is an uncommon but serious and potentially fatal condition that can result in reduced life expectancy and a broad spectrum of sequelae, many of which may be lifelong and devastating for those who survive the acute disease period. In the United States of America (USA), vaccination is available against the five meningococcal serogroups (A, B, C, W, and Y), but meningococcal vaccination rates among healthy USA adolescents and individuals at high risk because of medical conditions are low, rendering them vulnerable to IMD and its sequelae. Despite the severity of the disease, the clinical impact and rates of IMD sequelae in the USA are poorly understood, as USA-specific data are limited, and the methodology of existing research is heterogenous. This commentary presents clinical experts' perspectives on IMD sequelae based on the available published evidence and direct clinical experience. Among sequelae previously identified in a global systematic literature review, 16 conditions were considered as related to IMD by the present authors. These sequelae include short- and long-term physical, neurological, and emotional consequences that impose a substantial humanistic burden on survivors and their caregivers and result in considerable healthcare and societal costs. This commentary highlights existing knowledge gaps concerning IMD sequelae, including the unclear relationship between IMD and mental health disorders, the contribution of sequelae to the disease burden, prevalence of late-onset sequelae among survivors, and timing of the development of sequelae in different age groups. Addressing these knowledge gaps can inform decisions regarding clinical management in the post-acute period and help quantify the impact of prevention through meningococcal vaccination.

Invasive meningococcal disease is uncommon but life-threatening. Those who survive may have lasting conditions, also known as sequelae, that negatively impact their health. In this commentary, expert physicians used previous publications to identify 16 sequelae of invasive meningococcal disease, many of which, including loss of limbs, blindness, and intellectual disabilities, can severely affect the lives of survivors and their caregivers. It is important to better understand how sequelae affect patients and the cost of living with these conditions for the healthcare system and society. This information would help policymakers make decisions on preventing invasive meningococcal disease with vaccination and managing its sequelae.

Meningococcal Vaccination of Adolescents in the United States: Past Successes and Future Considerations.

Invasive meningococcal disease (IMD) is a rare but serious illness, and adolescents and young adults in the United States are at increased risk. Here, we discuss US IMD history and how successful disease prevention through routine vaccination against the most common disease-causing serogroups (A, B, C, W, and Y) can inform future recommendations. Before the introduction of quadrivalent meningococcal conjugate (MenACWY) vaccines, most US cases of IMD were caused by serogroups B, C, and Y. After recommendation by the Advisory Committee on Immunization Practices for routine MenACWY vaccination of 11-12-year-olds in 2005, followed by a 2010 booster recommendation, MenCWY disease incidence declined dramatically, and vaccine coverage remains high. Two serogroup B (MenB) vaccines are licensed in the United States, but uptake is low compared with MenACWY vaccines, likely because Advisory Committee on Immunization Practices recommends MenB vaccination subject to shared clinical decision-making rather than routinely for all adolescents. The proportion of adolescent IMD caused by MenB has now increased. Pentavalent vaccines that protect against serogroups A, B, C, W, and Y may provide an optimal strategy for improving vaccination rates to ultimately reduce MenB incidence while maintaining the historically low rates of IMD caused by serogroups A, C, W, and Y.

Public health perspective of a pentavalent meningococcal vaccine combining antigens of MenACWY-CRM and 4CMenB.

OBJECTIVES: Invasive meningococcal disease (IMD) is a life-threatening disease that can rapidly progress to death or leave survivors with severe, life-long sequelae. Five meningococcal serogroups (A, B, C, W and Y) account for nearly all IMD. Meningococcal serogroup distribution fluctuates over time across the world and age groups. Here, we consider the potential public health impact of a pentavalent MenABCWY vaccine developed to help further control meningococcal disease and improve immunisation rates. RESULTS: The GSK MenABCWY vaccine combines the antigenic components of MenACWY-CRM (Menveo®) and 4CMenB (Bexsero®), building on a wide body of clinical experience and real-world evidence. Both approved vaccines have acceptable safety profiles, demonstrate immunogenicity, and are broadly used, including in national immunisation programmes in several countries. Since the advent of quadrivalent vaccines, public health in relation to IMD has improved, with a decline in the overall incidence of IMD and an increase in vaccine coverage. CONCLUSION: A pentavalent MenABCWY has the potential to provide further public health benefits through practical, broad IMD protection programmes encompassing serogroups A, B, C, W and Y, and is currently in late-stage development.

Potential public health impact of a Neisseria meningitidis A, B, C, W, and Y pentavalent vaccine in the United States.

OBJECTIVE: Globally, 5 serogroups (A, B, C, W, and Y) cause the majority of invasive meningococcal disease (IMD). Vaccines targeting these serogroups are currently part of the US adolescent immunization platform, which includes 1 + 1 dosing of a MenACWY vaccine routinely at ages 11 and 16 years and 2 doses of a MenB vaccine at age 16-23 years under shared clinical decision-making between the patient and healthcare provider. In 2018, MenACWY vaccination coverage was 86.6% for ≥1 dose and 50.8% for ≥2 doses, whereas MenB vaccination coverage was 17.2% for ≥1 dose and <50% for completion of the multidose series. A pentavalent MenABCWY vaccine could simplify immunization schedules and improve vaccination coverage. We estimated the public health impact of a pentavalent MenABCWY vaccine using a model that considers meningococcal carriage and vaccination coverage. METHODS: A population-based dynamic model estimated the 10-year reduction in IMD from implementing a MenABCWY vaccine within the existing US meningococcal immunization platform. Five vaccination schedules (4 new, 1 existing) were examined to estimate the impact of different recommendations on the overall reduction in the number of IMD cases. Sensitivity analyses were performed by varying vaccination coverage at age 16 years. RESULTS: The existing schedule and coverage of MenACWY and MenB vaccines (total 4 doses) could potentially avert 165 IMD cases over 10 years versus no vaccination. Assuming similar MenABCWY and MenACWY vaccination coverage rates at age 16 years, replacing 1 or more MenACWY and/or MenB doses with MenABCWY could avert more cases, ranging from 189 to 256. The most beneficial MenABCWY vaccine schedule was 2 doses at age 11 years and 1 dose at age 16 years. CONCLUSIONS: Replacing one or more MenACWY/MenB vaccine doses with MenABCWY could reduce IMD caused by all 5 meningococcal serogroups among the US adolescent population, while also reducing the number of injections required.

Immunogenicity and Safety of Investigational MenABCWY Vaccine and of 4CMenB and MenACWY Vaccines Administered Concomitantly or Alone: a Phase 2 Randomized Study of Adolescents and Young Adults.

This phase 2, randomized, open-label study assessed the immunogenicity and safety of an investigational meningococcal ABCWY vaccine (MenABCWY) that contains components of licensed vaccines against meningococcal serogroup B (4CMenB) and serogroups ACWY (MenACWY). A total of 500 healthy 10- to 25-year-old participants were randomly assigned to one of five study groups in a 1:1:1:1:1 ratio. Four groups received two doses 2 months apart of MenABCWY and 4CMenB plus MenACWY administered concomitantly in the same arm (4CMenB+ACWY/S group) or different arms (4CMenB+ACWY/D group) or 4CMenB administered alone. A fifth group received a single MenACWY dose. Immunogenicity was determined by serum bactericidal assay using human complement (hSBA). The study was powered to assess immunological interference against pooled serogroup B test strains. One month after the second vaccine dose, hSBA geometric mean titers (GMTs) (with 80% confidence intervals [CI]) against pooled serogroup B strains were 31.84 (80% CI, 28.18 to 35.98), 38.48 (80% CI, 34.23 to 43.26), 40.08 (80% CI, 35.44 to 45.33), and 42.38 (80% CI, 37.31 to 48.13) in the MenABCWY, 4CMenB+ACWY/S, 4CMenB+ACWY/D, and 4CMenB groups, respectively. Immune responses (GMTs and 80% CIs) were lower for PorA and NHBA serogroup B test strains in the MenABCWY group compared to the 4CMenB+ACWY/D group and 4CMenB group. Evaluation of solicited and unsolicited adverse events (AEs) identified no safety concerns for the MenABCWY vaccine. One serious AE (syncope in the 4CMenB group) was considered related to vaccination. In conclusion, there is no evidence of substantial immunological interference between 4CMenB and MenACWY vaccine components against serogroup B. The safety and tolerability profile of the investigational MenABCWY vaccine was acceptable. (This study has been registered at ClinicalTrials.gov under registration no. NCT03587207.) IMPORTANCE The bacterial species Neisseria meningitidis is a major cause of meningitis, with six meningococcal groups (serogroups) causing most cases. A licensed vaccine, MenACWY (Menveo), targets four of these meningococcal serogroups, and another vaccine, 4CMenB (Bexsero), targets serogroup B. A combined vaccine (MenABCWY) that targets all five serogroups is under development to simplify the vaccination schedule. In a previous study, the immune response to serogroup B was found to be overall higher in individuals who received 4CMenB than in those who received an investigational MenABCWY vaccine. We investigated this further by giving healthy adolescents and young adults the MenABCWY vaccine, 4CMenB plus MenACWY vaccine in the same or different arms, 4CMenB vaccine alone, or MenACWY vaccine alone. Immunogenicity results for serogroup B across study groups suggest no major interference between the MenB and MenACWY vaccine components. This supports further development of the combined MenABCWY vaccine.

Immunogenicity and safety of different schedules of the meningococcal ABCWY vaccine, with assessment of long-term antibody persistence and booster responses - results from two phase 2b randomized trials in adolescents.

The meningococcal serogroup B (MenB) protein vaccine, 4CMenB, combined with MenA, MenC, MenW and MenY polysaccharide-protein conjugates for a pentavalent MenABCWY vaccine, can potentially protect against most causative agents of invasive meningococcal disease worldwide. Two phase 2b, randomized, multicenter studies were conducted (NCT02212457, NCT02946385) to assess the immunogenicity and safety of the MenABCWY vaccine as well as antibody persistence and response to a booster dose 2 years after the last vaccination, compared to 4CMenB vaccination. Participants (10 - 18 years), randomized (3:3:2:2:2:2), received the 4-component 4CMenB vaccine according to a 0-2 month (M) schedule or MenABCWY according to a 0-2, 0-6, 0-2-6, 0-1, or 0-11 M schedule. All participants received 5 injections (at M0, M1, M2, M6 and M12) with either the study vaccines or placebo/hepatitis A vaccine. Follow-on participants (4CMenB-0-2, MenABCWY-0-2, MenABCWY-0-6 and MenABCWY-0-2-6 groups) received one dose of either 4CMenB (4CMenB-0-2 group) or MenABCWY and newly enrolled, age-matched, meningococcal vaccine-naïve adolescents (randomized 1:1) received 2 doses (0-2 M) of either 4CMenB or MenABCWY. MenABCWY vaccination was immunogenic against MenB test strains. Non-inferiority for all 4 components of the 4CMenB vaccine could not be demonstrated for the 0-2 M schedule. Antibodies persisted up to 2 years post-MenABCWY vaccination and a booster dose induced an anamnestic response as higher titers were observed in follow-on participants compared to the first-dose response in vaccine-naïve participants. MenABCWY had a clinically-acceptable safety profile, not different from that of 4CMenB.

Breadth of coverage against a panel of 110 invasive disease isolates, immunogenicity and safety for 2 and 3 doses of an investigational MenABCWY vaccine in US adolescents - Results from a randomized, controlled, observer-blind phase II study.

BACKGROUND: Neisseria meningitidis serogroups A, B, C, W and Y cause most meningococcal disease worldwide. An investigational MenABCWY vaccine combining serogroup B antigens and a meningococcal ACWY CRM197-glycoconjugate vaccine (MenACWY-CRM) could provide protection against all 5 serogroups. Complement mediated bactericidal activity induced by MenABCWY was tested against a panel of 110 randomly-selected serogroup B strains causing invasive disease in the US to evaluate the vaccine's breadth of coverage (BoC). METHODS: We conducted this observer-blind study (NCT02140762) and its extension (NCT02285777) in 8 centers in the US. Adolescents aged 10-18 years were randomized (1:1) to receive either 3 MenABCWY doses (MenABCWY group), on a 0, 2, 6-month (M) schedule or a single MenACWY-CRM dose at M2 and placebo at 0,6-M (Control group). MenABCWY BoC was calculated as (1 - relative risk) × 100 (relative risk = ratio between the percentage of samples seronegative at 1:4 dilution against the selected strains in the MenABCWY vs Control group). BoC was determined at 1 M and 4 M after 2 and 3 doses, using an endogenous complement serum bactericidal assay. Immunogenicity and safety were assessed. RESULTS: 301 and 189 adolescents were vaccinated in the parent and extension study, respectively. At 1 M post-vaccination, the BoC of MenABCWY across the 110 serogroup B strains was 67% (95%CI: 65-69) after 2 doses and 71% (95%CI: 69-73) after 3 doses. BoC decreased to 44% (95%CI: 41-47) and 51% (95%CI: 48-55) at 4 M after 2 and 3 MenABCWY doses, respectively. Robust immune responses to antigen-specific test strains for each serogroup were observed at all timepoints in the MenABCWY group. No reactogenicity or safety concerns arose during the study. CONCLUSION: Two or 3 doses of MenABCWY showed similar BoC against the panel of invasive US serogroup B isolates and comparable immunogenicity against the antigen-specific test strains, with no safety concerns identified.