Testing the capacity of humanized immune system mice to induce a protective antibody response against the Lyme...

Mus musculus has been a key animal model whereby important discoveries on bacterial pathogenesis of the Lyme disease (LD) pathogen, Borreliella burgdorferi (Bb), were made. In the United States alone, LD affects the lives of about half a million new patients each year, making it the most prevalent tick-borne illness. To date, however, there is no LD vaccine for humans on the market, and therefore, much research effort has focused on identifying protective Bb vaccine candidates. Because murine and human immune responses to Bb significantly differ, we evaluated humanized mice to improve the translatability of preclinical Lyme vaccine studies. Specifically, we assessed two humanized mouse models, UCB-HSC NSG and huNOG-EXL SA, for their capacity to induce protective anti-Bb antibodies. For that, we utilized an antibody-susceptible Bb (∆VlsE), which is effectively cleared by acquired anti-Bb antibodies of immunocompetent mice; and outer surface protein A (OspA), a surface Bb antigen that proved efficacious not only as part of licensed canine vaccines but also as part of a human LD vaccine that was transiently available to the public in the past. The data demonstrated that the tested models could not clear the ∆VlsE infection. Likewise, OspA-vaccinated humanized mouse immune system failed to prevent wild-type challenge. Given that no better alternative preclinical model has been developed, we hope that the inherent translatability limitations of standard LD mouse models will continue to be favorably accepted. Although our results do not encourage the use of the tested humanized models for preclinical LD vaccine efficacy testing, their utility remains valuable for mechanistic studies.

In this study, we assessed the ability of mice with humanized immune systems to develop protective antibodies against the bacterial agent of Lyme disease (LD), Borreliella burgdorferi. In contrast to an intact mouse immune system of classical LD models, the humanized immune system could not prevent vaccinated mice from being infected with LD spirochetes. The findings demonstrate that two tested humanized models cannot be used for preclinically testing LD vaccine candidates. Given the results, we hope that the animal-to-human translatability limitations of existing LD mouse models will be more favorably taken as there is no better alternative preclinical model developed.