Preclinical identification of vaccine induced protective correlates in human leukocyte antigen expressing transgenic mice infected with Coccidioides posadasii.

Abstract

There is an emerging interest to develop human vaccines against medically-important fungal pathogens and a need for a preclinical animal model to assess vaccine efficacies and protective correlates. HLA-DR4 (DRB1∗0401 allele) transgenic mice express a human major histocompatibility complex class II (MHC II) receptor in such a way that CD4+ T-cell response is solely restricted by this human molecule. In this study HLA-DR4 transgenic mice were immunized with a live-attenuated vaccine (ΔT) and challenged by the intranasal route with 50-70 Coccidioides posadasii spores, a potentially lethal dose. The same vaccination regimen offers 100% survival for C57BL/6 mice. Conversely, ΔT-vaccinated HLA-DR4 mice displayed 3 distinct manifestations of Coccidioides infection including 40% fatal acute (FAD), 30% disseminated (DD) and 30% pulmonary disease (PD). The latter 2 groups of mice had reduced loss of body weight and survived to at least 50days postchallenge (dpc). These results suggest that ΔT vaccinated HLA-DR4 mice activated heterogeneous immunity against pulmonary Coccidioides infection. Vaccinated HLA-DR4 mice displayed early expansion of Th1 and Th17 cells and recruitment of inflammatory innate cells into Coccidioides-infected lungs during the first 9dpc. While contraction rates of Th cells and the inflammatory response during 14-35dpc significantly differed among the 3 groups of vaccinated HLA-DR4 mice. The FAD group displayed a sharply reduced Th1 and Th17 response, while overwhelmingly recruiting neutrophils into lungs during 9-14days. The FAD group approached moribund by 14dpc. In contrast, vaccinated HLA-DR4 survivors gradually contracted Th cells and inflammatory response with the greatest rate in the PD group. While vaccinated HLA-DR4 mice are susceptible to Coccidioides infection, they are useful for evaluation of vaccine efficacy and identification of immunological correlates against this mycosis.

• Authors: Brady J Hurtgen, Natalia Castro-Lopez, Maria Del Pilar Jiménez-Alzate, Garry T Cole, Chiung-Yu Hung
• Journal: Vaccine (Vaccine) Vol. 34 Issue 44 Pg. 5336-5343 (10 17 2016) ISSN: 1873-2518 [Electronic] Netherlands
• PMID: 27622300 (Publication Type: Journal Article)
• Copyright: Copyright © 2016 Elsevier Ltd. All rights reserved.

Chemical References

• Cytokines
• Fungal Vaccines
• HLA-DR4 Antigen
• Vaccines, Attenuated

Topics

• Adaptive Immunity
• Animals
• Coccidioides (immunology, isolation & purification)
• Coccidioidomycosis (immunology, microbiology, prevention & control)
• Cytokines (biosynthesis)
• Fungal Vaccines (administration & dosage, immunology)
• HLA-DR4 Antigen (genetics, immunology)
• Humans
• Immunity, Innate
• Lung (immunology, microbiology)
• Mice
• Mice, Inbred C57BL
• Mice, Transgenic
• Spores, Fungal
• Th17 Cells (immunology)
• Vaccines, Attenuated