Meningococcal Antigen Typing System (MATS)-Based Neisseria meningitidis Serogroup B Coverage Prediction for the MenB-4C Vaccine in the United States

Abstract

is the most common cause of bacterial meningitis in children and young adults worldwide. A 4-component vaccine against serogroup B (MenB) disease (MenB-4C [Bexsero]; GSK) combining factor H binding protein (fHBP), neisserial heparin binding protein (NHBA), neisserial adhesin A (NadA), and PorA-containing outer membrane vesicles was recently approved for use in the United States and other countries worldwide. Because the public health impact of MenB-4C in the United States is unclear, we used the meningococcal antigen typing system (MATS) to assess the strain coverage in a panel of strains representative of serogroup B (NmB) disease in the United States. MATS data correlate with killing in the human complement serum bactericidal assay (hSBA) and predict the susceptibility of NmB strains to killing in the hSBA, the accepted correlate of protection for MenB-4C vaccine. A panel of 442 NmB United States clinical isolates (collected in 2000 to 2008) whose data were down weighted with respect to the Oregon outbreak was selected from the Active Bacterial Core Surveillance (ABCs; CDC, Atlanta, GA) laboratory. MATS results examined to determine strain coverage were linked to multilocus sequence typing and antigen sequence data. MATS predicted that 91% (95% confidence interval [CI], 72% to 96%) of the NmB strains causing disease in the United States would be covered by the MenB-4C vaccine, with the estimated coverage ranging from 88% to 97% by year with no detectable temporal trend. More than half of the covered strains could be targeted by two or more antigens. NHBA conferred coverage to 83% (CI, 45% to 93%) of the strains, followed by factor H-binding protein (fHbp), which conferred coverage to 53% (CI, 46% to 57%); PorA, which conferred coverage to 5.9%; and NadA, which conferred coverage to 2.5% (CI, 1.1% to 5.2%). Two major clonal complexes (CC32 and CC41/44) had 99% strain coverage. The most frequent MATS phenotypes (39%) were fHbp and NHBA double positives. MATS predicts over 90% MenB-4C strain coverage in the United States, and the prediction is stable in time and consistent among bacterial genotypes. The meningococcal antigen typing system (MATS) is an enzyme-linked immunosorbent assay (ELISA)-based system that assesses the levels of expression and immune reactivity of the three recombinant MenB-4C antigens and, in conjunction with PorA variable 2 (VR2) sequencing, provides an estimate of the susceptibility of NmB isolates to killing by MenB-4C-induced antibodies. MATS assays or similar antigen phenotype analyses assume importance under conditions in which analyses of vaccine coverage predictions are not feasible with existing strategies, including large efficacy trials or functional antibody screening of an exhaustive strain panel. MATS screening of a panel of NmB U.S. isolates ( = 442) predicts high MenB-4C vaccine coverage in the United States.

Potential benefits of using a multicomponent vaccine for prevention of serogroup B meningococcal disease

“…A MATS analysis of 442 diseasecausing MenB isolates collected in the USA predicted that 91% of strains would be covered by 4CMenB, with coverage varying little year-to-year. NHBA was found to cover the most strains (83%), followed by fHbp (53%), PorA (5.9%), and NadA (2.5%) (Rajam et al, 2017). As expected, the 4CMenB fHbp component contributed strongly to the coverage of strains expressing fHbp variant 1, but provided almost no coverage of strains expressing fHbp variants 2 and 3 (approximately 40% of the panel).…”

“…Notably, among the 442 USA MenB mentioned previously, 42% were simultaneously covered by two vaccine antigens, and 6% were covered by three antigens (Rajam et al, 2017). In a recent study, the evaluation of monoclonal antibodies elicited by 4CMenB vaccination showed that they were cross-reactive against different antigen variants and recognized multiple epitopes on each of the antigens.…”

“…As expected, the 4CMenB fHbp component contributed strongly to the coverage of strains expressing fHbp variant 1, but provided almost no coverage of strains expressing fHbp variants 2 and 3 (approximately 40% of the panel). Importantly, 83% of these strains were estimated to be covered by non-fHbp components of 4CMenB (Rajam et al, 2017).…”

“…MATS-based estimates of 4CMenB coverage range from 68% to 89% in European countries and from 66% to 91% in Australia, Canada, Brazil, and the USA (Abad et al, 2016;Medini et al, 2015;Parikh et al, 2017;Rajam et al, 2017;Simoes et al, 2017;Tzanakaki et al, 2014;Vogel et al, 2013;Wasko et al, 2016), with an overall estimated coverage of 81% calculated for a sample size of 3912 invasive MenB strains, collected from 17 different countries (Muzzi et al, 2019). Antibodies induced by the NHBA and fHbp components of 4CMenB have been consistently observed to make the highest contribution to coverage.…”

A review of the immunogenicity, safety and current recommendations for the meningococcal serogroup B vaccine, MenB‐FHbp

“…MenB‐FHbp contains two FHbp variants, one each from subfamilies A and B, and is sufficient to provide broad coverage against the diversity of disease‐causing MenB strains; >99% of 650 US strains surveyed by the CDC contain FHbp , and >91% of invasive MenB strains express FHbp at sufficient levels to be susceptible to bactericidal antibodies elicited by the vaccine . MenB‐4C is composed of four protein antigens present in variable percentages of 442 US strains surveyed by the CDC: recombinant FHbp subfamily B fusion protein (53% of strains); recombinant neisserial heparin‐binding antigen fusion protein (NHBA; 83% of strains); recombinant neisserial adhesin A protein (NadA; 2.5% of strains); and outer membrane vesicles containing PorA (5.9% of strains) . Licensure of meningococcal vaccines, including MenB vaccines, has relied on the use of serum bactericidal assays (SBAs) as a surrogate measure of vaccine efficacy .…”