Artificial Lymphoid Organs Could Help Predict Efficacy of Booster Vaccines

Researchers at the Institut Pasteur in France have developed artificial "lymphoid organ-chips" that recreate much of the human immune system's response to booster vaccines. The technology, described in an article published September 6 in the Journal of Experimental Medicine, could potentially be used to evaluate the likely effectiveness of new protein and mRNA-based booster vaccines for COVID-19 and other infectious diseases.

The rapid mutation and evolution of SARS-CoV-2 and other viruses means that booster vaccines must be developed equally rapidly to provide protection from emerging viral strains. The effectiveness of updated vaccines can be hard to predict, however. The recent bivalent mRNA COVID vaccine, for example, turned out to be no more effective than the original monovalent vaccine against the emerging omicron variant that it was designed to combat.

One reason for this unpredictability is that the laboratory animals used to test new vaccines have slightly different immune systems than humans. Another reason is that humans can vary greatly in their response to a vaccine--depending, in part, on their individual history of infection and vaccination.

"The COVID-19 pandemic has emphasized the need for preclinical systems that enable a rapid evaluation of immune responses elicited by candidate booster vaccines, particularly within specific cohorts of high-risk individuals," says Lisa Chakrabarti, a group leader within the Virus and Immunity Unit at the Institut Pasteur.

The immune system's response to a vaccine is coordinated in secondary lymphoid organs, such as the lymph nodes and spleen, where various types of immune cell gather and interact with each other to spur the development of specific antibody-producing B cells. Chakrabarti's team, led by postdoctoral researcher Raphaël Jeger-Madiot, created an artificial version of these organs by embedding small samples of human blood cells in 3D collagen matrices on tiny microfluidic chips. These lymphoid organ-chips can then be exposed to viral proteins and RNAs used in vaccines.

"The continuous perfusion of microfluidic chips with antigen and nutrients greatly facilitates the growth and activation of immune cells," explains Samy Gobaa, who leads the Pasteur Microfluidics platform and collaborated on the study.

When the researchers exposed the lymphoid organ-chips to the SARS-CoV-2 spike protein, B cells and T cells within the blood samples became active and clustered together, just as they do in real lymphoid organs. The B cells then matured and began to produce antibodies capable of neutralizing the SARS-CoV-2 virus.

The presence of multiple other immune cell types in the human blood samples allowed the lymphoid organ-chips to respond to mRNA-based COVID vaccines as well. Similar to the real world results, the bivalent vaccine was, in general, no more effective at inducing omicron-neutralizing antibodies than the monovalent vaccine.

By comparing lymphoid organ-chips created with blood samples from different donors, however, Chakrabarti and colleagues were able to observe a variety of different responses. Chips created from some donors responded equally well to either type of mRNA booster, while chips created from other donors showed a stronger response for either the monovalent or bivalent vaccine.

"This illustrates the diversity of immunological histories in the population, and the resulting individual variability in vaccine responses," says Jeger-Madiot.

"In the face of such variability, the lymphoid organ-chip could provide a useful preclinical system to evaluate the capacity of candidate vaccines to induce neutralizing antibodies against current SARS-CoV-2 variants in diverse human populations. This should be an asset in the face of a rapidly evolving SARS-CoV-2 pandemic," adds Chakrabarti.