Rewilding immunology: response profiles and side effects of immunization in natural VS. Controlled genetic backgrounds

The National Institute of Allergy and Infectious Diseases awarded Auburn University $439,335 on July 15, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to conduct comparative immunological research using wild-derived and laboratory mice as vaccine development models.

The project addresses the poor translation of nanoparticle vaccine formulations from preclinical mouse studies to human clinical trials, where only approximately 10 percent of treatments succeed. Auburn researchers will compare baseline and vaccine-induced immune responses across inbred laboratory mice, wild-derived house mice, and published data on wild mice and humans to determine whether wild-derived mice produce immune response profiles closer to human outcomes than conventionally used laboratory strains. The work evaluates both the magnitude and diversity of immune responses across genetically variable populations, recognizing that laboratory mice maintained in specific pathogen-free facilities exhibit substantially lower and less variable immune responses than wild mice or humans.

The project runs through June 30, 2029, with work performed at Auburn University in Auburn, Alabama. This is a Project Grant, the standard assistance type for research support under the program.

Abstract

The lab mouse has been used almost exclusively as the model for developing and testing nanoparticle (NP) formulations for DNA/mrna vaccine delivery. The problem: only about 10% of NP treatments and vaccinations are successful in clinical trials. Nanomedicine, immunological, and vaccine development studies commonly rely on inbred mice kept in specific pathogen-free facilities. As a result, the magnitude and individual variation in the responses of lab mice to immune challenges is low. Humans display immune responses that are higher in magnitude and highly variable due to genetic variation among individuals and exposure to diverse microbial environments. This difference between lab mice and humans contributes to poor translation of mouse to human outcomes. The solution: the use of an immunologically robust and genetically variable model would allow researchers to evaluate how a diverse population responds to their product before clinical trials. Studies comparing the baseline and vaccine-induced immune responses of inbred lab and wild house mice have consistently shown that the immune responses of lab mice are substantially lower than those of wild mice. Further, the range and diversity of immune responses observed in wild house mice mimic humans more closely than inbred lab mice. While wild house mice can be challenging to collect, and they carry pathogens that can alter immunological responses and put animals in other studies at risk, wild-derived mice could serve as a valuable supplement to lab mice for NP vaccine research. Our approach: by comparing wild-derived house mice, and lab mice, we will determine if the baseline and stimulated immune responses of wild-derived house mice are similar to published data on wild mice and humans, and greater than lab mice. Further, we will evaluate the responses of the same populations of mice to an mrna vaccine that includes a model mrna carried by a well-characterize lipid nanoparticle and a novel nanoparticle to determine if the wild-derives mouse has an immunological memory that is greater than lab mice. Undergraduate student involvement: we estimate that 48 undergraduates will be involved in this project, 24 research assistants who will receive credit to monitor the live mice and help with vaccinations and tissue collection, and four undergraduates will be awarded full-time summer positions each year to participate in lab work. Finally, 20 undergraduates from t. Schwartz's functional genomics class (20 u) will complete the transcriptomics analysis.