A re-assessment of 4CMenB vaccine effectiveness against serogroup B invasive meningococcal disease in England based on an incidence model

Background The four-component serogroup B meningococcal 4CMenB vaccine (Bexsero, GSK) has been routinely given to all infants in the United Kingdom at 2, 4 and 12 months of age since September 2015. After 3 years, Public Health England (PHE) reported a 75% [95% confidence interval 64%; 81%] reduction in the incidence of serogroup B invasive meningococcal disease (IMD) in age groups eligible to be fully vaccinated. In contrast, vaccine effectiveness (VE) evaluated in the same immunization program applying the screening method was not statistically significant. We re-analyzed the data using an incidence model. Methods Aggregate data—stratified by age, year and doses received—were provided by PHE: serogroup B IMD case counts for the entire population of England (years 2011–2018) and 4CMenB vaccine uptake in infants. We combined uptake with national population estimates to obtain counts of vaccinated and unvaccinated person-time by age and time. We re-estimated VE comparing incidence rates in vaccinated and non-vaccinated subjects using a Bayesian Poisson model for case counts with person-time data as an offset. The model was adjusted for age, time and number of doses received. Results The incidence model showed that cases decreased until 2013–2014, followed by an increasing trend that continued in the non-vaccinated population during the immunization program. VE in fully vaccinated subjects (three doses) was 80.1% [95% Bayesian credible interval (BCI): 70.3%; 86.7%]. After a single dose, VE was 33.5% [12.4%; 49.7%]95%BCI and after two doses, 78.7% [71.5%; 84.5%]95%BCI. We estimated that vaccination averted 312 cases [252; 368]95%BCI between 2015 and 2018. VE was in line with the previously reported incidence reduction. Conclusions Our estimates of VE had higher precision than previous estimates based on the screening method, which were statistically not significant, and in line with the 75% incidence reduction previously reported by PHE. When disease incidence is low and vaccine uptake is high, the screening method applied to cases exclusively from the population eligible for vaccination may not be precise enough and may produce misleading point-estimates. Precise and accurate VE estimates are fundamental to inform public health decision making. VE assessment can be enhanced using models that leverage data on subjects not eligible for vaccination.

02. Beyond B Antigen Coverage: The Potential of the 4CMenB Vaccine for Cross-protection Against Pathogenic Neisseria Infections

Background Two human pathogenic Neisseria species exist: N. meningitidis (Nm) and N. gonorrhoeae (Ng). Although causing disparate clinical syndromes, invasive meningococcal disease (IMD) and gonorrhea, they are genetically similar and share key protein antigens. The 4CMenB vaccine, licensed against meningococcal B disease, comprises 4 antigenic components (factor H binding protein (fHbp), variant 1.1, subfamily B; Neisseria heparin binding antigen (NHBA) peptide 2; Neisserial adhesin A (NadA) variant 3; and Porin A (PorA) P1.4), and potentially protects against non-B invasive meningococcal and gonococcal strains. In this review, we summarize the similarities between these antigens and those in Nm serogroups A, C, W, X and Y and Ng. Methods Published data in humans were analyzed to conduct a narrative literature review of the potential extent of meningococcal vaccine-induced protection against non-B meningococcal strains and Ng. Techniques applied to indirectly measure this effect are based on genotype-phenotype modelling, strain coverage, bactericidal killing and direct impact on disease reduction. Results Data were identified from countries in America, Europe, Africa and Oceania. The genes encoding for fHbp and NHBA are also present in strains belonging to the five non-B serogroups, while NadA is present in several strains of serogroups C, W and Y, and PorA P1.4 mainly in serogroup W. At the genome level, Ng and Nm share up to 90% homology. Most of the outer membrane vesicle antigens, like PilQ, Omp85 (BamA), NspA, MtrE, MetQ, LbpA, PorB, FetA, OpcA and NHBA, are highly conserved in Ng. In addition, a synergistic effect might enhance immunogenicity against non-B serogroups as shown against serogroup B. Conclusion 4CMenB components are present and conserved in several Ng and Nm strains. Recent results demonstrate that 4CMenB reduces MenW disease incidence in infants and might generate cross-protection against other non-B serogroups. In addition, 4CMenB has been proven to be effective in reducing gonococcal infections in adolescents. Research on future genomic and proteomic characterizations of IMD and gonorrhea strains will provide information on the molecular basis of the underlying broad strain coverage, while informing decisions regarding prevention and immunization programmes. Disclosures Yara Ruiz Garcia, MSc, PhD, GSK group of companies (Employee) Woo-Yun Sohn, MD, GSK group of companies (Employee, Shareholder) Mariagrazia Pizza, Biological Sciences, PhD, GSK group of companies (Employee, Shareholder) Rafik Bekkat-Berkani, M.D, GSK group of companies (Employee, Shareholder)

Looking beyond meningococcal B with the 4CMenB vaccine: the Neisseria effect

Infections with Neisseria meningitidis and Neisseria gonorrhoeae have different clinical manifestations, but the bacteria share up to 80–90% genome sequence identity. The recombinant meningococcal serogroup B (MenB) vaccine 4CMenB consists of four antigenic components that can be present in non-B meningococcal and gonococcal strains. This comprehensive review summarizes scientific evidence on the genotypic and phenotypic similarities between vaccine antigens and their homologs expressed by non-B meningococcal and gonococcal strains. It also includes immune responses of 4CMenB-vaccinated individuals and effectiveness and impact of 4CMenB against these strains. Varying degrees of strain coverage were estimated depending on the non-B meningococcal serogroup and antigenic repertoire. 4CMenB elicits immune responses against non-B meningococcal serogroups and N. gonorrhoeae. Real-world evidence showed risk reductions of 69% for meningococcal serogroup W clonal complex 11 disease and 40% for gonorrhea after 4CMenB immunization. In conclusion, functional antibody activity and real-world evidence indicate that 4CMenB has the potential to provide some protection beyond MenB disease.

‘B Part of It’ School Leaver study: a repeat cross-sectional study to assess the impact of increasing coverage with meningococcal B (4CMenB) vaccine on carriage of Neisseria meningitidis

Background Recombinant protein-based vaccines targeting serogroup B meningococci protect against invasive disease, but impacts on carriage are uncertain. This study assessed carriage prevalence of disease-associated meningococci from 2018-2020, as the proportion of vaccinated adolescents increased following introduction of a school-based 4CMenB immunisation program. Methods Eligible participants who completed high school (age 17-25) in South Australia in the previous year had an oropharyngeal swab taken and completed a risk factor questionnaire. Disease-associated meningococci (genogroups A, B, C, W, X, Y) were detected by meningococcal and genogroup-specific polymerase chain reaction. Results The final analysis included 4104 participants in 2018, 2690 in 2019, and 1338 in 2020. The proportion vaccinated with 4CMenB increased from 43% in 2018, to 78% in 2019, and 76% in 2020. Carriage prevalence of disease-associated meningococci in 2018 was 225/4104 (5.5%). There was little difference between the carriage prevalence in 2019 (134/2690, 5.0%, adjusted odds ratio [aOR] 0.82, 95% CI 0.64-1.05) and 2020 (68/1338, 5.1% aOR 0.82, 95% CI 0.57-1.17) compared to 2018. Conclusions Increased 4CMenB uptake in adolescents was not associated with a decline in carriage of disease-associated meningococci. 4CMenB immunisation programs should focus on direct (individual) protection for groups at greatest risk of disease.

Meningococcal Vaccines: A Technological Revolution

The sneaky meningococcus is a bacterium that can cause terrible disease. Development of an effective vaccine has been extremely difficult. Meningococcal vaccines developed in the 1990s are based on the bacterial capsule, a shield that protects the bacteria and that is used to instruct our body to combat this terrible disease. These vaccines work against four types of meningococcus: A, C, W, and Y. However, they do not work against meningococcus B. Scientists had to invent a completely new way to make vaccines, reading the bacterial DNA to search for new protective components. With this new approach, named reverse vaccinology, three new bacterial components were discovered: NadA, NHBA, and fHbp. When combined with a fourth component (PorA), they form the 4CMenB vaccine. This vaccine has reduced meningococcal disease in infants by 75% in the UK. Today, 4CMenB protects children all around the world.

Effectiveness of meningococcal vaccines at reducing invasive meningococcal disease and pharyngeal Neisseria meningitidis carriage: A systematic review and meta-analysis

Background Invasive meningococcal disease (IMD), caused by Neisseria meningitidis, leads to significant morbidity and mortality worldwide. This review aimed to establish the effectiveness of meningococcal vaccines at preventing IMD and N. meningitidis pharyngeal carriage. Methods A search within PubMed, Embase, Scopus, and unpublished studies up to 1st February 2020 was conducted. Results After removal of duplicates, 8565 were screened and 28 studies included. Protection was provided by meningococcal C vaccines for group C IMD (odds ratio (OR) 0·13 [95% CI, 0·07-0·23]), outer membrane vesicle (OMV) vaccines against group B IMD (OR 0·35 [0·25-0·48]), and meningococcal ACWY (MenACWY) vaccines against group ACWY IMD (OR 0·31 [0·20-0·49]). A single time series analysis found a reduction following an infant 4CMenB program (incidence rate ratio, 0·25 [0·19-0·36]). Multivalent MenACWY vaccines did not reduce carriage (relative risk [RR] 0·88 [0·66-1·18]), unlike monovalent A (RR 0·73 [0·61-0·85]), and C vaccines (RR 0·50 [0·26-0·97]). 4CMenB vaccine had no effect on group B carriage (RR 1·12 [0·90-1·40]). There was also no reduction in group B carriage following MenB-FHbp vaccination (RR 0.98 [0.53-1.79]). Conclusions Meningococcal conjugate C, ACWY, and OMV vaccines are effective at reducing IMD. A small number of studies demonstrate that monovalent C and A conjugate vaccines reduce pharyngeal N. meningitidis carriage. There is no evidence of carriage reduction for multivalent MenACWY, OMV, or recombinant meningococcal B vaccines, which has implications for immunisation strategies. Registration PROSPERO CRD42018082085