Predicting protection against tuberculosis from BCG using the guinea pig model

Abstract

Guinea pigs, while having been used as a model animal for tuberculosis infections for over a century, modern literature about their response to the commonly used BCG vaccination is limited. In this study, we investigated whether immune responses to the BCG vaccine are variable and if these differences could predict protection after exposure to Mycobacterium tuberculosis. Using the guinea pig model, the only rodent species that reliably develops delayed-type hypersensitivity responses similar to humans, we evaluated inflammation in response to BCG vaccination, tuberculin skin test (TST) response, and capacity for antigen-specific secretion of IFN-γ by ELISpot in response to M. bovis purified protein derivative (PPD). We hypothesized that the degree of inflammation incited by BCG vaccination would correlate with TST size and frequency of antigen-specific IFN-γ production. Most of the animals developed an inflammatory response to TST within 24-72 hours, indicating a Th1 response was developed post-vaccination. However, 4 out of 18 individuals lacked an inflammatory response that lasted over 24 hours. To confirm this, IFN-γ production was assessed in PBMCs isolated from BCG-vaccinated and unvaccinated guinea pigs, finding little correspondence between IFN-γ production and increased skin inflammation. We hypothesized that IFN-γ secretion would be highest in guinea pigs with the largest TST response. The results of this study demonstrate the development of a delayed-type hypersensitivity response to BCG vaccination, albeit inconsistent in its systemic effects. Collectively, our results a highly differential response to BCG vaccination. If vaccination confers variable protection against M. tuberculosis infection, this variable vaccine response may offer insight into correlates of immune protection.