No abstract

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 three 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 and obtained more precise VE estimates. 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 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 (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 has 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, that were not statistically significant. When disease incidence is low and vaccine uptake is high, the screening method applied to cases exclusively from the population eligible to vaccination may not be enough precise and produce misleading point-estimates. Precise and accurate VE estimates are fundamental for informing public health decision making. VE assessment can be enhanced using models that leverage data on subjects not eligible for vaccination.

Invasive meningococcal disease (IMD) has a low and unpredictable incidence, presenting challenges for real-world evaluations of meningococcal vaccines. Traditionally, meningococcal vaccine impact is evaluated by predicting counterfactuals from pre-immunization IMD incidences, possibly controlling for IMD in unvaccinated age groups, but the selection of controls can influence results. We retrospectively applied a synthetic control (SC) method, previously used for pneumococcal disease, to two infant immunization programs against serogroups B and C IMD in England and Brazil. Time series of infectious/non-infectious diseases in infants and IMD cases in older unvaccinated age groups were used as candidate controls, automatically combined in a SC through Bayesian variable selection. SC closely predicted IMD in absence of vaccination, adjusting for non-trivial changes in IMD incidence. Vaccine impact estimates were in line with previous assessments. IMD cases in unvaccinated age groups were the most frequent SC-selected controls. Similar results were obtained when excluding IMD from control sets and using other diseases only, particularly respiratory diseases and measles. Using non-IMD controls may be important where there are herd immunity effects. SC is a robust and flexible method that addresses uncertainty introduced when equally plausible controls exhibit different post-immunization behaviors, allowing objective between-countries comparisons of IMD programs.

Meningococcal antigen typing system (MATS) -the golden standard in many reference labs worldwide-for rapid, reproducible and accurate (conservative nonetheless) prediction of Bexsero strain

Neisseria meningitidis serogroup B (NmB) is a major cause of invasive meningococcal disease (IMD). Predicting the effectiveness of vaccines against NmB is difficult because NmB is an uncommon disease and because antigens targeted by meningococcal serogroup B (MenB) vaccines have highly variable genetic features and expression levels. Therefore, a large number of NmB isolates from different regions would need to be tested to comprehensively assess vaccine effectiveness. We examined a panel of 110 isolates obtained from NmB IMD cases in the United States and compared the genetic features of this panel with those of panels from different countries around the world. We found the 110-isolate panel included the most common clonal complexes and genetic variants of MenB vaccine antigens that exist in the global collections of invasive NmB isolates. This confirms the value of the NmB 110-isolate panel in understanding the effectiveness of MenB vaccines in clinical trials worldwide.