This Preclinical Model has a Fully Human Immune System for Vaccine Development

In the field of vaccine development, preclinical models support researchers in determining the immunosafety and efficacy of their compounds. In the same field, animal models are also used to develop a variety of antibodies. 

However, species that are traditionally used, such as conventional mice and rabbits, do not elicit a fully human immune response unless they are modified using genetic engineering or phage display techniques.

These techniques are often time-consuming and costly. Hence, there is a need within the biotech and pharma industry for animal models that allow researchers to directly assess the human immune response and develop fully human antibodies. 

Addressing the need for a fully human immune response in preclinical models

Sebastien Tabruyn, Chief Scientific Officer, TransCure bioServices

Sebastien Tabruyn, Chief Scientific Officer at TransCure bioServices

A team of researchers at the contract research organization (CRO) TransCure bioServices set out to address this need. The team has developed an Advanced Human Immune System Mouse Model with a functional human immune system. Unlike other transgenic animal models, it elicits a full humoral and cellular immune response. 

“Our preclinical in vivo model reconstitutes a fully functional human immune system,” says Sebastien Tabruyn, Chief Scientific Officer at TransCure bioServices. “It contains all of the cells found in the human immune system, including B cells, which are essential for antibody production; macrophages that not only protect the body against pathogens but are also responsible for presenting antigens to T and B cells; and dendritic cells, which are also antigen-presenting cells.”

With the help of these antigen-presenting cells (APCs), cross-presentation occurs – a process in which APCs react to, process, and present antigens to cytotoxic T cells. In the case of vaccine development, for example in cancer vaccinations, cross-presentation between APCs and T cells is also needed to create cell-mediated immunity. 

Immunization in the Advanced Human Immune System Mouse Model 

mouse model, fully human immune system, preclinical model

Preparation of hu-mouse models, which elicit a fully human immune response

TransCure bioServices’ preclinical models help biotech companies in two areas of vaccine development and immunization. Either, customers want to develop a specific human antibody against a known target, or they may want to use full human immune system mouse models to predict the efficacy of their compound before it enters clinical trials. 

The team prepares the preclinical mouse models with a series of immunizations. “First, we use a cocktail of human cytokines as a boost for the generation and propagation of APCs and for priming the cellular immune response,” Tabruyn explains. “Then, the boost is followed by a series of immunization rounds with the antigen, which can be injected as a recombinant protein but also as a cell extract or plasmid.”

As a result of the immunization rounds, immunoglobulin isotopic class switching occurs. This means that B cells start producing a different kind of antibody, switching from the production of isotype IgM to isotype IgG. Furthermore, immunization results in an increase in antibody production. 

Here’s how even weak antigens can elicit an immune response

KLH immunization, antibody production, immunoglobulins

Specific anti-KLH IgG’s in 50% of the Hu-NOG mouse model (left) and increased % of CD4+ memory following KLH immunization (right)

Using Keyhole limpet hemocyanin (KLH) as a strong antigen, TransCure’s team has developed an IgG production model for the successful assessment of immune-modulators. “In this model, even weak antigens will elicit an immune response,” says Tabruyn. “Our preclinical model’s immune system can respond to a wide variety of antigens thanks to their large repertoire of antibodies.”

KLH immunization, antibody production, immunoglobulins, TransCure bioServices

Modulation of anti-KLH IgG responses after KLH immunization

Following KLH immunization, the team at TransCure observed a steady increase of CD4+ T cell memory. By week nine after immunization, CD4+ memory increased by  40%, showing the immune system’s heightened capability to recognize antigens. 

Analyzing the outcome of immunization and efficacy of compounds in preclinical models

“To analyze the outcome of antibody production, we isolate the B cells from the spleen and present the customer with a library of B cells. Moreover, using ELISA, cytometric bead array (CBA), flow cytometry or enzyme-linked immune absorbent spot (ELISpot), we can analyze the blood to determine the total amount and specific type of human immunoglobulins and the activation status of B and T cells.” 

Other customers of TransCure bioServices want to test the efficacy of their vaccines on the human immune system. For example, by observing the effect of immunomodulators to see whether they boost or block the immune system. The team at TransCure bioServices uses flow cytometry to check the activation of T cells and B cells, as well as using a readout of antibodies from peripheral blood. 

With their Advanced Human Immune System Mouse ModelTM, the TransCure bioServices team has developed a preclinical model that allows the production of a variety of fully human antibodies, as well as efficacy testing for their customer’s vaccine compounds. 

Are you in the preclinical stage of vaccine development and in need of the right preclinical models to fully recapitulate the human immune system response for antibody production or preclinical profiling? Get in touch with the team at TransCure bioServices or check out their website for more information!

Images via TransCure bioServices. Header image via David Crockett/Shutterstock.com

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