During and after bioprocessing a vaccine, many things can go wrong, and it’s not easy to see the problem. So, scientists at California-based NanoImaging Services use transmission electron microscopy (TEM) to analyze vaccines—and a wide range of other nanoparticles, most commonly sized anywhere from five to 400 nanometers.

As Mandy Janssen, PhD, group leader for the company’s characterization scientists, explains, “We analyze tiny amounts of sample vaccine across the entire spectrum, from discovery through manufacturing, and know that actually seeing the sample tells you many different things at once.”

Mandy Janssen, PhD

She describes a list of what TEM analysis can reveal in a vaccine, including particle size, the aggregation stage, concentration, contamination, proper protein folding, and much more. In addition to analyzing vaccines with TEM during development, this technology can be used even after a vaccine reaches the market. “If a vaccine’s efficacy goes down, how do you rapidly pinpoint what happened?” Janssen asks. TEM can be used to answer such questions.

Most biomanufacturers use indirect methodologies

Most bioprocessors use indirect methods to test vaccines. For example, PCR could measure the levels of nucleic acids in a vaccine, but it doesn’t tell a bioprocessor anything about the integrity of vaccine particles or whether the measured amount of nucleic acids is inside or outside the lipid nanoparticle. Consequently, bioprocessors often outsource that work to Janssen and her colleagues. “Electron microscopy in general is an expensive technique that requires a lot of expertise—both to run the microscopes and interpret the data,” according to Janssen.

One bioprocessor came to NanoImaging Services with a mysterious problem in one batch of vaccine that the manufacturer could not pinpoint. In TEM images, Janssen could see odd structures, which she describes as particles shaped like “very small tater tots.” They weren’t in other batches.

By taking images at each phase of production, she and her team tracked down the problem to culture media used in the bioprocessing. Without the ability to visualize the vaccine at nanoscale, it would have been much harder to isolate the problem and fix it.

When it comes to vaccines and TEM, one might say that a picture is worth a thousand experiments.