Dynamics of Naturally Acquired Antibody Against Haemophilus Influenzae Serotype 'A' and the Impact of Vaccination

Haemophilus (H.) influenzae is a human-restricted bacterial pathogen that can cause severe invasive disease. During the past two decades, the incidence of infections caused by H. influenzae serotype a (Hia) has increased in several parts of the world, particularly in Aboriginal populations of North America. Currently, there is no vaccine available to prevent Hia infection. While efforts continue to develop an anti-Hia vaccine candidate, a number of key questions must be addressed to ensure that vaccination is effective in curtailing and possibly eliminating Hia from affected populations. In this thesis, we develop mathematical models of Hia transmission and control dynamics and analyze them to address important practical questions. By simulating an in-host antibody boosting model, we predict the timelines and frequency of natural boosting of immunity in order to prevent invasive Hia disease. Using laboratory data collected in a Canadian population, this model indicates that frequent boosting of natural immunity is required to maintain anti-Hia antibodies at levels required to prevent Hia invasive disease. We also develop a stochastic in-host model of immune dynamics to evaluate the immune responses to a bivalent glycoconjugate vaccine against the two serotypes a and b of H. influenzae. In particular, we investigate the effect of such a vaccine on the generation of anti-Hia immune response in the presence of pre-existing immunity to one serotype elicited by prior vaccination or natural infection. Our results suggest that the protection conferred by a bivalent combined vaccine may be affected by the use of carrier protein previously used in H. influenzae serotype b conjugate vaccines. At the population level, we develop the first stochastic model of Hia transmission dynamics to evaluate vaccination strategies and the effect of booster doses. Our results highlight the importance of primary vaccination and timely booster doses of the individual immunity not only for infants, but also for a sizeable portion of susceptible individuals to maintain a high level of herd immunity in the population. Since age plays an important role in transmission of Hia, we also develop an age-structured model to evaluate vaccination strategies and determine the effect of age-specific vaccination coverages. We discuss the implications of our findings for population health.