An Immunologic Model for Rapid Vaccine Assessment — A Clinical Trial in a Test Tube

Abstract

While the duration and size of human clinical trials may be difficult to reduce, there are several parameters in pre-clinical vaccine development that may be possible to further optimise. By increasing the accuracy of the models used for pre-clinical vaccine testing, it should be possible to increase the probability that any particular vaccine candidate will be successful in human trials. In addition, an improved model will allow the collection of increasingly more-informative data in pre-clinical tests, thus aiding the rational design and formulation of candidates entered into clinical evaluation. An acceleration and increase in sophistication of pre-clinical vaccine development will thus require the advent of more physiologically-accurate models of the human immune system, coupled with substantial advances in the mechanistic understanding of vaccine efficacy, achieved by using this model. We believe the best viable option available is to use human cells and/or tissues in a functional in vitro model of human physiology. Not only will this more accurately model human diseases, it will also eliminate any ethical, moral and scientific issues involved with use of live humans and animals. An in vitro model, termed “MIMIC” (Modular IMmune In vitro Construct), was designed and developed to reflect the human immune system in a well-based format. The MIMIC® System is a laboratory-based methodology that replicates the human immune system response. It is highly automated, and can be used to simulate a clinical trial for a diverse population, without putting human subjects at risk. The MIMIC System uses the circulating immune cells of individual donors to recapitulate each individual human immune response by maintaining the autonomy of the donor. Thus, an in vitro test system has been created that is functionally equivalent to the donor's own immune system and is designed to respond in a similar manner to the in vivo response.

Development of Newborn and Infant Vaccines

“…Accordingly, for preclinical evaluation of pediatric vaccine components, including adjuvants, in vitro work using human neonatal and infant primary cells in media containing the relevant composition of human humoral components (such as autologous plasma) will be important for modeling the distinct immune responses of neonatal and infant monocytes, APCs, and lymphocytes (67). Related approaches have been recently described in adult settings (68). Results from such in vitro studies should inform the selection of appropriate preclinical animal models, to see whether the adjuvants identified in vitro are bioactive in neonates of the test species.…”

Adjuvant-induced Human Monocyte Secretome Profiles Reveal Adjuvant- and Age-specific Protein Signatures

“…For example, TLR8As such as the imidazoquinoline R848 (TLR7/8A), can induce adult-like Th cytokine induction and co-stimulatory molecule expression in neonatal leukocytes suggesting they may be promising candidate neonatal vaccine adjuvants (18, 24–26). For novel adjuvants, a practical approach to characterize adjuvant-induced responses employs in vitro human cell systems that model the immune response (21, 26–28), and may inform subsequent adjuvant selection for in vivo studies.…”

Biomaterial Strategies for Immunomodulation

“…These constructs have shown the ability to support antibody responses to licensed vaccines and physiologically relevant alterations in cytokine production in response to immunosuppressive drugs (146). Higbee et al (148) developed a modular in vitro system termed MIMIC (Modular Immune In vitro Construct) with separate in vitro scaffolds representing peripheral tissues and LNs, and that aimed to predict the responses of cultured human leukocytes to vaccine administration or other biologicals. The lymphoid tissue module of this system was able to predict antibody responses measured in the blood of immunized individuals following tetanus vaccination.…”