Characterization of natural bactericidal antibody against Haemophilus influenzae type a in Canadian First Nations: A Canadian Immunization Research Network (CIRN) Clinical Trials Network (CTN) study

Abstract

During the last two decades, Haemophilus influenzae serotype a (Hia) emerged as an important cause of invasive disease in Canadian First Nations and Inuit, and Alaskan Native populations, with the highest rates reported in young children. Immunocompetent adults, in contrast to children, do not typically develop invasive Hia disease. To clarify factors responsible for an increased burden of invasive Hia disease in certain population groups we studied serum bactericidal activity (SBA) against Hia and quantified IgG and IgM specific to Hia capsular polysaccharide in healthy adult members of two First Nations communities: 1) with reported cases of invasive Hia disease (Northern Ontario, NO), and 2) without reported cases (Southern Ontario, SO), in comparison to non-First Nations living in proximity to the NO First Nations community, and non-First Nations elderly non-frail Canadians from across the country (total of 110 First Nations and 76 non-First Nations). To elucidate the specificity of bactericidal antibodies, sera were absorbed with various Hia antigens. Naturally acquired SBA against Hia was detected at higher rates in First Nations (NO, 80%; SO, 96%) than non-First Nations elderly Canadians (64%); the SBA titres in First Nations were higher than in non-First Nations elderly Canadians (P<0.001) and NO non-First Nations adults (P>0.05). Among First Nations, SBA was mediated predominantly by IgM, and by both antibodies specific to Hia capsular polysaccharide and lipooligosaccharide. Conclusions: The SBA against Hia is frequently present in sera of First Nations adults regardless of the burden of Hia disease observed in their community; it may represent part of the natural antibody repertoire, which is potentially formed in this population under the influence of certain epigenetic factors. Although the nature of these antibodies deserves further studies to understand their origin, the data suggest that they may represent important protective mechanism against invasive Hia disease.

Invasive and Non-invasive Clinical Haemophilus influenzae Type A Isolates Activate Differentiated HL-60 Cells In Vitro

“…By contrast, in the case of non-invasive Hia 14-61, bacterial survival did not depend on serum dilutions in the absence of dHL-60 cells, suggesting the role of the alternative complement pathway. This is consistent with previous findings that Hia 11-139 was more sensitive to the complement-dependent SBA than 14-61 [ 25 ]. In the presence of neutrophil-like cells, opsonophagocytosis of Hia 14-61 may depend on the engagement of complement receptors.…”

“…The killing of Hia 11-139 relied on opsonization by antibodies and complement, suggesting that invasive strains require classical complement activation for killing. This supports previous observations that opsonization with capsular and non-capsular antibodies was necessary to kill invasive Hi strains [ 13 , 25 ]. By contrast, in the case of non-invasive Hia 14-61, bacterial survival did not depend on serum dilutions in the absence of dHL-60 cells, suggesting the role of the alternative complement pathway.…”

“…Hia 13-240 (ST-4) contain an IS 1016-bexA partial deletion and are associated with severe disease and high case-fatality rate [ 12 , 15 ]. The origin of naturally acquired specific antibodies against Hia is undetermined, and the sensitivity of individual clinical isolates to their bactericidal effect varies [ 25 ]. As ST-4 Hi do not circulate in our area, the pooled human serum from this region may lack protective antibodies against Hia 13-240.…”

“…As ST-4 Hi do not circulate in our area, the pooled human serum from this region may lack protective antibodies against Hia 13-240. Although Nix et al found similar sensitivity of Hia 11-139 (ST-23) and 13-240 (ST-4) in the serum bactericidal assay (SBA) [ 25 ], lack of serum sensitivity of Hia 13-240 in OPA may be attributed to undefined virulence factors. Unexpectedly, Hia 13-240 experienced significantly higher killing than 11-139 when dHL-60 cells were removed.…”

Naturally acquired antibodies against 7 Streptococcus pneumoniae serotypes in Indigenous and non-Indigenous adults

“…Ethnicity was determined based on self-declaration. Serum samples from both Indigenous communities, Kenora, and a part of the Thunder Bay samples were collected during January—November 2015, as we previously described [ 25 ]. The remaining Thunder Bay samples were collected between November 2016 and November 2017.…”