R&D on today’s coronavirus vaccines started in 2013

The coronavirus vaccines made by Moderna, Pfizer–BioNTech, and Johnson & Johnson each deliver genetic information that codes for a stabilized form of the spike protein, the protrusions on the virus through which SARS-CoV-2 infects human cells. Depending on the vaccine, the messenger RNA (mRNA) or DNA instructs cells to produce copies of slightly altered versions of the spike, which stimulates the immune system to develop the antibodies to deactivate the viral spike, preventing infection. A vaccine by CureVac, now in clinical trials, includes the same mRNA coding, whereas the Novavax vaccine, which could be authorized in May, contains recombinant versions of the stabilized spike itself.

The research that led to those vaccines dates to 2013, when scientists at NIH’s Vaccine Research Center were hunting for a vaccine to prevent respiratory syncytial virus (RSV), which can cause serious disease in infants and older adults. Jason McLellan, now associate professor of molecular biosciences at the University of Texas at Austin, and collaborators were targeting the RSV fusion (F) protein, which is ancestrally related to the SARS-CoV-2 spike protein.

The team knew that the F protein existed in two conformations, corresponding to before and after fusing to the human cell. Although human antibodies to the virus were known to act against the pre-fusion form, the researchers were unable to obtain stable pre-fusion F proteins in isolation because the molecules immediately refolded into the post-fusion state. Using a beamline at Argonne National Laboratory’s Advanced Photon Source (APS), “we were able to get the crystal structure of post-fusion F,” says McLellan. “That was a helpful reagent allowing us to characterize different antibodies, and we were eventually able to find pre-fusion-specific antibodies.”

After purifying and crystallizing the protein–antibody complex, McLellan and his team obtained its structure at APS. “I was able to eventually determine the structure of pre-fusion F [pictured here in green, pink, and multicolor] bound to a human monoclonal antibody [red and white] that was extremely potent,” says McLellan. The researchers then slightly altered the protein’s chemical structure to prevent it from refolding. “Ultimately we created a molecule stabilized in the pre-fusion form that we could express and purify in the absence of those antibodies, and we had in our hands pre-fusion F. We crystallized that and solved the structure at APS.”

A similar process was used to develop stabilized pre-fusion versions of the spike proteins of coronaviruses that cause severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and in 2020, SARS-CoV-2. Because the spike of SARS-CoV-2 can’t be crystallized, its structure was resolved using cryoelectron microscopy.

The RSV vaccine, which entered phase 3 clinical trials late last year, has followed the more typical 7- to 10-year timeline for vaccine development. The SARS-CoV-2 vaccines were developed and approved in about as many months.