Abstract
Vaccination is a proven strategy to mitigate morbidity and mortality of infectious diseases. The methodology of identifying and testing new vaccine candidates could be improved with rational design and in vitro testing prior to animal experimentation. The tularemia vaccine, Francisella tularensis live vaccine strain (LVS), does not elicit complete protection against lethal challenge with a virulent type A Francisella strain. One factor that may contribute to this poor performance is limited stimulation of antigen-presenting cells. In this study, we examined whether the interaction of genetically modified LVS strains with human antigen-presenting cells correlated with effectiveness as tularemia vaccine candidates. Human dendritic cells infected with wild-type LVS secrete low levels of proinflammatory cytokines, fail to upregulate costimulatory molecules, and activate human T cells poorly in vitro. One LVS mutant, strain 13B47, stimulated higher levels of proinflammatory cytokines from dendritic cells and macrophages and increased costimulatory molecule expression on dendritic cells compared to wild type. Additionally, 13B47-infected dendritic cells activated T cells more efficiently than LVS-infected cells. A deletion allele of the same gene in LVS displayed similar in vitro characteristics, but vaccination with this strain did not improve survival after challenge with a virulent Francisella strain. In vivo, this mutant was attenuated for growth and did not stimulate T cell responses in the lung comparable to wild type. Therefore, stimulation of antigen-presenting cells in vitro was improved by genetic modification of LVS, but did not correlate with efficacy against challenge in vivo within this model system.
Highlights
The development of vaccines is essential to combat harmful infectious diseases [1]
Human macrophages and dendritic cells (DCs) were co-cultured with live vaccine strain (LVS), and supernatants were harvested and analyzed for the proinflammatory cytokines TNF-a, IL-6, and IL-12p40
Similar to our findings with macrophages (Fig. 1A), LVS elicited little to no proinflammatory cytokines from human DCs (Fig. 1B)
Summary
Obtaining licensure after discovery of a vaccine, can take up to 20 years due to the stringent testing required to confirm the safety and efficacy of the vaccine [2]. To expedite this process, in vitro tests could be developed to define correlates of protection and identify more promising vaccine candidates. In vitro tests could be developed to define correlates of protection and identify more promising vaccine candidates These assays would be beneficial with vaccine candidates for highly pathogenic organisms, such as the bacterium Francisella tularensis, when challenge studies cannot be performed in humans because of contemporary regulations that govern clinical trials [3]. An effective vaccine would be useful to reduce the number of naturally occurring tularemia cases and to protect against a possible intentional release
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