Vaccines are arguably one of the most important medical innovations in human history. When it comes to which diseases have successfully been targeted with vaccines, however, the playing field is far from equal. Some diseases—like measles or tetanus—have been nearly eradicated due to the widespread use of vaccines that haven’t changed much since they were first created. Other notorious diseases—I’m looking at you, SARS-CoV-2—have been successfully targeted by vaccines which must continuously be updated to keep up with newer, craftier viral variants. Still other deadly diseases—like HIV—lack effective vaccines despite decades of tireless effort by scientists worldwide. What gives?
While it’s certainly true that the difficulty of producing a vaccine against a given pathogen is often determined by the specific biological features of that pathogen, it also pays to consider how vaccines are created and tested. Generally speaking, vaccines can be divided into three broad categories: those that contain weakened or inactivated—but intact—pathogens (live-attenuated vaccines like the measles vaccine fall into this category), those that contain nucleic acids instructing cells to make specific proteins from a pathogen (mRNA vaccines for SARS-CoV-2), and those that contain one or more individual proteins from a pathogen (protein subunit vaccines like the hepatitis-B vaccine). While mRNA vaccines are quickly gaining traction due primarily to their ease of production, protein subunit vaccines are still the go-to for many applications, including HIV.
The proteins that go into subunit vaccines are usually produced by mammalian cells genetically engineered to express them—this engineering can either take the shape of stable transfection, where the vaccine protein is integrated into the genomes of the cells, or transient transfection, in which the protein sequence is inserted into cells by means of a plasmid and does not integrate into their genomes. While stable transfection is the gold standard for subunit production because it leads to a more consistent and reproducible protein product (an important consideration for vaccines that may be administered to millions of patients), it can take up to a year to successfully generate stably-transfected cells for a given protein product. If you put yourself in the shoes of an eager HIV researcher with a new idea for a protein subunit HIV vaccine, the fact that it can take a year to produce your new vaccine (only after which it can start to be tested in animal models, then phase I, then phase II, and—if you’re lucky—phase III clinical trials), it’s easy to see how the vaccine design process is sluggish at best. Protein production via transient transfection has the potential to save valuable time in the vaccine development process—but is there a difference in safety between vaccine proteins produced between stable and transient transfections?
Drs. Lawrence Corey and James Kublin, two Fred Hutch researchers at the forefront of vaccine research, tackle this question in a recent publication in the Journal of Infectious Diseases. Working as part of a larger group of scientists (the HIV Vaccine Trials Network or HVTN 123 Study Team), they report the results of a phase I clinical trial testing a specific protein subunit vaccine against HIV consisting of a viral envelope protein called gp120. As part of the study, they produced this gp120 subunit vaccine via transient or stable transfection and recruited a cohort of thirty patients, half of whom received the transient variant and half the stable one. Each patient received three doses of each vaccine over six months, and their reactions were carefully monitored, both in the clinic and in self-reported journals.
Reassuringly, the team found that every measure of safety was statistically identical between the two vaccines. Further, when they quantified the extent to which the patients produced antibodies which either bound or neutralized the gp120 antigen, they found that both vaccines led to nearly identical patient antibody profiles after the last vaccine dose.
What do these results mean? Importantly, as a phase I trial, this study stopped short of testing for any differences in efficacy between the two vaccines (that would require a phase II or III clinical trial), and transient transfections are not without some technical hurdles of their own (no such thing as free lunch!). But by showing that subunit vaccines produced via transient transfection are just as safe to use in humans as their stably-transfected counterparts, this study opens the door for researchers to investigate transient transfection as a viable option to make vaccine trails more nimble and efficient. By shaving months off of the vaccine production pipeline, transient transfection could give researchers time to test more vaccine candidates and iterate based on what they learn from each trial, significantly speeding up vaccine development efforts and adding to the growing arsenal of tools in vaccine developers’ hands. And in a world where hundreds of thousands of people die each year from HIV-related causes alone, those months matter.
The spotlighted work was funded by the National Institutes of Health.
Fred Hutch/University of Washington/Seattle Children’s Cancer Consortium members Drs. James Kublin and Lawrence Corey contributed to this study.
Wilson, G. J., Church, L. W. P., Kelley, C. F., Robinson, S. T., Lu, Y., Furch, B. D., Fong, Y., Paez, C. A., Yacovone, M., Jacobsen, T., Maughan, M., Martik, D., Heptinstall, J. R., Zhang, L., Montefiori, D. C., Tomaras, G. D., Kublin, J. G., & Corey, L. (2024). HVTN 123: A Phase 1, Randomized Trial Comparing Safety and Immunogenicity of CH505TF gp120 Produced by Stably and Transiently Transfected Cell Lines. The Journal of Infectious Diseases, jiae558.
Science Spotlight writer David Sokolov is a graduate student in the Sullivan Lab at the Fred Hutch. He studies how cancer cells modify their metabolism to facilitate rapid proliferation and accommodate tumor-driving mitochondrial defects. He's originally from the east coast and has bachelors' and masters' degrees from West Virginia University. Outside of the lab, you'll find him enjoying the outdoors, playing music, or raising composting worms in his front yard.
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