The research presented in this dissertation harnesses two secondary data sources, administrative databases of patient-level healthcare data and adverse event (AE) data reported in randomized clinical trials (RCTs), to assess the relationship between intravenous immune globulin (IVIg) and the risk of clinically serious thromboembolic adverse events (TEEs). Since 2013, IVIg products have carried a boxed warning concerning TEE risk, a determination supported by numerous case reports, a large claims-based risk assessment, and laboratory evaluations of the thrombogenecity of IVIg products. Questions remain concerning the magnitude of the risk overall and across subgroups of IVIg users. Taken together, our results are compatible with the conclusion that the absolute risk of TEE following IVIg use is likely to be low overall. While these results are reassuring, a clinically meaningful elevation in risk cannot be ruled out in certain patient sub-groups, such as older adults and others with a high baseline risk of TEE. A limitation of our research is that differences in TEE risk across products could not be evaluated with sufficient statistical power.

Following rabies virus (RABV) exposure, a combination of thorough wound washing, multiple-dose vaccine administration and the local infiltration of rabies immune globulin (RIG) are essential components of modern post-exposure prophylaxis (PEP). Although modern cell-culture-based rabies vaccines are increasingly used in many countries, RIG is much less available. The prohibitive cost of polyclonal serum RIG products has prompted a search for alternatives and design of anti-RABV monoclonal antibodies (MAbs) that can be manufactured on a large scale with a consistent potency and lower production costs. Robust in vitro neutralization activity has been demonstrated for the CL184 MAb cocktail, a 1:1 protein mixture of two human anti-RABV MAbs (CR57/CR4098), against a large panel of RABV isolates. In this study, we used a hamster model to evaluate the efficacy of experimental PEP against a lethal challenge. Various doses of CL184 and commercial rabies vaccine were assessed for the ability to protect against lethal infection with representatives of four distinct bat RABV lineages of public health relevance: silver-haired bat (Ln RABV); western canyon bat (Ph RABV); big brown bat (Ef-w1 RABV) and Mexican free-tailed bat RABV (Tb RABV). 42–100% of animals survived bat RABV infection when CL184 (in combination with the vaccine) was administered. A dose-response relationship was observed with decreasing doses of CL184 resulting in increasing mortality. Importantly, CL184 was highly effective in neutralizing and clearing Ph RABV in vivo, even though CR4098 does not neutralize this virus in vitro. By comparison, 19–95% survivorship was observed if human RIG (20 IU/kg) and vaccine were used following challenge with different bat viruses. Based on our results, CL184 represents an efficacious alternative for RIG. Both large-scale and lower cost production could ensure better availability and affordability of this critical life-saving biologic in rabies enzootic countries and as such, significantly contribute to the reduction of human rabies deaths globally.

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