Avidity of anti-pertussis toxin antibodies is associated with symptomatic Bordetella pertussis infection in a novel controlled human infection model
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Background
The association between functional antibody responses following Bordetella pertussis infection and symptomatic disease remains unclear. We characterized the maturation of anti-pertussis toxin (PT) IgG avidity after human challenge with B. pertussis and determined its association with symptomatic infection.
Methods
Healthy adults were intranasally inoculated with live B. pertussis organisms in a controlled human infection model and monitored for development of pertussis symptoms ( NCT05136599 ). Serum samples were collected one day before inoculation and at 14, 28, 56, 180, and 365 days post-challenge. Anti-PT IgG avidity was tested using a titration of ammonium isothiocyanate (the bond-breaking agent) to quantify a wide range of antibody avidities from low to very-high. Associations between covariates and avidity were examined using linear regression models, and high-dimensional analyses were used to integrate all data.
Findings
Anti-PT IgG avidity increased in both symptomatic (n=20) and asymptomatic (n=10) participants after the challenge, reached maximum levels at day 56, and then declined through day 365. Symptomatic participants developed significantly higher levels of high- and very high-avidity anti-PT antibodies at 28, 56, 180, and 365 days post-challenge compared with those who remained asymptomatic. In multivariate analyses, symptomatic infection was associated with higher levels of high and very high avidity anti-PT IgG at day□180 and□365 after challenge. Distinct avidity profiles in symptomatic vs asymptomatic participants emerged at day□28 onwards, with the former group having higher levels of antibodies with higher avidities. However, levels of medium-high, high and very high avidity antibodies in symptomatic participants were lower at day 365 after challenge compared to their peak levels.
Interpretation
Anti-PT IgG avidity was associated with symptomatic B. pertussis infection and thus may serve as a surrogate of clinical disease outcome. These results highlight that antibody avidity provides an additional functional assay besides antibody quantitation to dissect immune responses to pertussis. Further investigation of anti-PT IgG avidity should be pursued in natural pertussis outbreaks to determine whether it might be used to differentiate symptomatic from asymptomatic infections for epidemiologic purposes.
Funding
Canadian Association for Immunization Research Evaluation and Education.
Research in context
Evidence before this study
The relationship between antibody immune responses to B. pertussis infection and clinical disease is incompletely characterized. While antibody quantification is commonly measured, functional assessments of antibody can provide additional information. Antibody avidity, reflecting the binding strength of antibodies to their antigen, may provide additional insight into antibody function.
While B. pertussis expresses several antigens, pertussis toxin (PT) is specific to B. pertussis and is a pivotal virulence factor. For this reason, it has been chosen as the target for high-resolution avidity profiling in our study characterizing antibody immune responses after controlled human challenge with B. pertussis .
Traditionally, avidity has been measured based on a comparison of antibody levels with and without the addition of a single concentration of ammonium isothiocyanate (as a bond-breaking agent), leading to an arbitrary separation into “low” and “high” avidity antibodies. However, relying on this traditional approach of using a single concentration of ammonium isothiocyanate provides more limited insight into avidity quantification and maturation. In addition, studies assessing avidity after B. pertussis infection have been limited, cross-sectional, and lacked well-defined characterization of B. pertussis exposure and clinical disease outcomes. Consequently, the potential relevance of anti-PT IgG avidity as a surrogate of pertussis clinical disease outcome remains insufficiently defined.
Added value of this study
We used sera from participants enrolled in a controlled human infection model with a well-defined exposure to a standardized B. pertussis challenge dose, frequent longitudinal sampling, and clearly defined clinical disease outcomes (symptomatic versus asymptomatic infection). We then applied a novel analytical approach that measures anti-PT IgG avidity across a wide spectrum of binding strengths. We clearly demonstrated higher anti-PT IgG avidity in symptomatic participants, compared with those who remained asymptomatic after inoculation. Anti-PT IgG avidity peaked at day 56 post-challenge, and then avidity antibodies subsequently declined through day 365 in symptomatic participants. These findings suggest that high-resolution avidity profiling provides additional detail about the immune response after asymptomatic and asymptomatic infections.
Implications of all the available evidence
Anti-PT IgG avidity emerges from our findings as a clinically relevant, functional component of the antibody response to B. pertussis infection. Avidity may contribute useful information for differentiating clinical disease outcomes and interpreting infection history. Additional studies are needed to confirm these findings after natural pertussis outbreaks and exposures.
