Modeling the public health impact of different meningococcal vaccination strategies with 4CMenB and MenACWY versus the current toddler MenACWY National Immunization Program in Chile.

Invasive meningococcal disease (IMD) is an uncommon yet unpredictable, severe, and life-threatening disease with the highest burden in young children. In Chile, most IMD is caused by meningococcal serogroup B (MenB) and W (MenW) infection. In response to a MenW outbreak in 2012, a toddler vaccination program was implemented using quadrivalent meningococcal conjugate vaccine against serogroups A, C, W and Y (MenACWY). The vaccine program, however, does not protect infants or other unvaccinated age groups and does not protect against MenB IMD. Since 2017, MenB IMD cases are becoming increasingly prevalent. Using a dynamic transmission model adapted for Chile, this analysis assessed the public health impact (reduction in IMD cases, long-term sequelae, deaths, and quality-adjusted life-years) of six alternative vaccination strategies using MenACWY and/or the four-component MenB (4CMenB) vaccine in infants, toddlers, and/or adolescents compared to the National Immunization Program (NIP) implemented in 2014. Strategies that added infant 4CMenB to MenACWY in toddlers or adolescents would prevent more IMD than the current NIP, observed within the first 5 years of the program. Replacing the NIP by an adolescent MenACWY strategy would prevent more IMD in the longer term, once herd immunity is established to protect unvaccinated infants or older age groups. The strategy that maximized reduction of IMD cases and associated sequelae in all age groups with immediate plus long-term benefits included infant 4CMenB and MenACWY in both toddlers and adolescents. This analysis can help policymakers determine the best strategy to control IMD in Chile and improve public health. A set of audio slides linked to this manuscript can be found at https://doi.org/10.6084/m9.figshare.16837543.

Plain Language Summary (PLS)What is the context?Invasive meningococcal disease (IMD) is a severe, sometimes fatal, unpredictable disease with highest rates in infants, young children, and adolescents. It is caused by different serogroups of Neisseria meningitidis bacteria. Most cases in Chile are due to meningococcal serogroups B (MenB) and W (MenW). Following a MenW IMD outbreak in 2012, vaccination was introduced, leading to the current National Immunization Program (NIP) in toddlers with quadrivalent meningococcal conjugate vaccine (MenACWY) (protecting against IMD caused by MenA, C, W, and Y).What is new?A disease model to predict the impact of vaccination strategies in the Chilean population compared six alternative strategies, using the multi-component MenB (4CMenB) vaccine for infants (protecting against MenB, with potential cross-protection against MenW and Y IMD) and/or the MenACWY vaccine for toddlers and/or adolescents.What is the impact?Results, compared to the NIP, show that: Strategy 1 (a program targeting only infants with 4CMenB) would reduce more MenB cases but fewer MenA, C, W and Y cases resulting in a lower reduction of total IMD cases in the long term; Strategy 3 (a program targeting only adolescents with MenACWY) would have a similar effect to the NIP in the short term but a far greater IMD reduction in the long term (as vaccinating this age group eventually reduces transmission to other age groups, reducing their risk of disease); all the other strategies targeted more than one age group, further reducing numbers of IMD cases compared with the NIP. The greatest benefits were seen with infant 4CMenB vaccination combined with toddler and adolescent MenACWY vaccination. Results can help policymakers determine the best IMD strategy to maximize the benefits of available meningococcal vaccines.

Del genoma de un patógeno a una vacuna efectiva: la vacuna de cuatro componentes frente a los meningococos del serogrupo B / From a pathogen's genome to an effective vaccine: the four-component meningococcal serogroup B vaccine

La enfermedad meningocócica invasiva (EMI), causada por la bacteria Neisseria meningitidis, supone una mortalidad y morbilidad significativas. La incidencia de la enfermedad alcanza el máximo entre lactantes <1 año y niños pequeños en todo el mundo. En Europa, el serogrupo B de N. meningitidis es responsable de más del 50 % de todos los casos de EMI, mientras que en Latinoamérica la mayoría de los casos de EMI se deben a los serogrupos B o C. El desarrollo de una vacuna efectiva frente al serogrupo B ha supuesto un reto para los investigadores a lo largo de más de medio siglo. Los polisacáridos capsulares del serogrupo B no eran antígenos vacunales apropiados, y el éxito de las vacunas de vesículas de la membrana externa (OMV) se limitaba a las cepas bacterianas homólogas. La vacunología inversa permitió desarrollar una vacuna meningocócica de 4 componentes que incluía tres antígenos novedosos y las OMVs (4CMenB). Cada componente de la vacuna posee una diana distinta. La vacuna 4CMenB ha sido autorizada basándose en datos de inmunogenicidad y seguridad, debido a que la baja incidencia de la enfermedad impide la realización de estudios de eficacia clínica. El análisis de anticuerpos bactericidas en suero con complemento humano (hSBA) mide los anticuerpos funcionales del suero de los sujetos vacunados (es decir, la inmunogenicidad vacunal) y constituye un correlato de protección aceptado. La cobertura de cepas vacunales se ha evaluado tanto mediante el análisis de la hSBA, como mediante otro método más conservador denominado Sistema de Tipificación de Antígenos Meningocócicos (MATS). Desde 2013, se han recogido datos de efectividad en vida real de 4CMenB. La vacuna resultó efectiva en el control de brotes de Norteamérica y los datos recientes de introducción de la vacuna en el programa nacional de vacunación de lactantes del Reino Unido, han revelado una efectividad vacunal del 82,9 % tras las dos primeras dosis, junto a un perfil de seguridad aceptable

Invasive meningococcal disease (IMD), caused by the bacterium Neisseria meningitidis, entails significant mortality and morbidity. Disease incidence is highest in infants <1 year and young children globally. In Europe, N. meningitidis serogroup B is responsible for over 50% of overall IMD cases, whereas the majority of IMD cases in Latin America is caused either by serogroup B or C. The development of an effective vaccine against serogroup B has challenged the researchers for over half a century. Serogroup B capsular polysaccharide was an inappropriate vaccine antigen, and the success of outer membrane vesicle (OMV) vaccines was restricted to homologous bacterial strains. Reverse vaccinology led to the development of a 4-component meningococcal vaccine including three novel antigens, and OMVs (4CMenB). Each vaccine component has a different target.4CMenB has been authorised based on its immunogenicity and safety data because the low disease incidence precluded formal clinical efficacy studies. Human serum bactericidal antibody (hSBA) assay tests functional antibodies in the serum of vaccinated individuals (i. e. the vaccine immunogenicity), and is the accepted correlate of protection. Vaccine strain coverage has been assessed both through hSBA assays and a more conservative method named Meningococcal Antigen Typing System (MATS). Effectiveness data of 4CMenB have been collected in the field since 2013. The vaccine proved effective in outbreak control in North America, and recent data from the introduction of the vaccine in the United Kingdom infant national immunisation programme reveal a vaccine effectiveness of 82.9% for the first two doses, with an acceptable safety profile

Immunogenicity and safety of investigational vaccine formulations against meningococcal serogroups A, B, C, W, and Y in healthy adolescents.

This phase 2 study assessed the immunogenicity, safety, and reactogenicity of investigational formulations of meningococcal ABCWY vaccines, consisting of recombinant proteins (rMenB) and outer membrane vesicle (OMV) components of a licensed serogroup B vaccine, combined with components of a licensed quadrivalent meningococcal glycoconjugate vaccine (MenACWY-CRM). A total of 495 healthy adolescents were randomized to 6 groups to receive 2 doses (Months 0, 2) of one of 4 formulations of rMenB antigens, with or without OMV, combined with MenACWY-CRM, or 2 doses of rMenB alone or one dose of MenACWY-CRM then a placebo. Immunogenicity was assessed by serum bactericidal assay with human complement (hSBA) against serogroups ACWY and serogroup B test strains; solicited reactions and any adverse events (AEs) were assessed. Two MenABCWY vaccinations elicited robust ACWY immune responses, with higher seroresponse rates than one dose of MenACWY-CRM. Bactericidal antibody responses against the rMenB antigens and OMV components were highest in subjects who received 2 doses of OMV-containing MenABCWY formulations, with ≥68% of subjects achieving hSBA titers ≥5 against each of the serogroup B test strains. After the first dose, solicited local reaction rates were higher in the MenABCWY or rMenB groups than the MenACWY-CRM group, but similar across groups after the second dose, consisting mainly of transient injection site pain. Fever (≥38.0°C) was rare and there were no vaccine-related serious AEs. In conclusion, investigational MenABCWY formulations containing OMV components elicited highly immunogenic responses against meningococcal serogroups ACWY, as well as serogroup B test strains, with an acceptable safety profile. [NCT01210885].