Insights on COVID-19 vaccine, mAb development from spike protein structure

How COVID-19 spike cryo-EM structure could guide vaccine, mAb development

A UT Austin and NIH Vaccine Research Center team has uncovered the structure of the COVID-19 spike protein, which mediates viral entry into cells via membrane fusion. The findings, published in a Science paper Wednesday, could guide vaccine and mAb development for the new coronavirus.

To generate the spike protein's structure, the researchers introduced mutations that locked it into a conformation that binds host cells. Next, the University of Texas at Austin team plans to identify neutralizing antibodies against the novel coronavirus using conformation-stabilized spike.

The analyses also lend support to the design of mRNA-1273, a COVID-19 vaccine that NIH is developing in collaboration with Moderna Inc. (NASDAQ:MRNA). The candidate delivers mRNA encoding the spike protein, and is one of at least 38 vaccine programs in development for COVID-19 (see "WHO Mapping Out COVID-19 Vaccines").

Furthermore, the structure could help identify which vaccines and treatments targeting the SARS spike protein could be effective against COVID-19.

At least three groups -- Vir Biotechnology Inc. (NASDAQ:VIR), Sanofi (Euronext:SAN; NASDAQ:SNY) and Texas Children’s Hospital Center for Vaccine Development at Baylor College of Medicine -- are evaluating whether mAbs or vaccines that emerged from SARS R&D can be deployed against the novel coronavirus (see "Antibodies Advancing").

Encouraging protection

Anthony Fauci, director of NIH's National Institute of Allergy and Infectious Diseases (NIAID) -- which houses the VRC -- previously told BioCentury one of his priorities is to capitalize on cryo-electron microscopy (cryo-EM) and other advances in structural biology techniques to guide the design of vaccines that induce broadly neutralizing antibodies (bNAbs) (see "Vax to the Future").

In the new study, the UT Austin and VRC team used cryo-EM to unveil the structure of the extracellular portion of COVID-19 spike, which forms trimers that bind ACE2 on host cells. Upon ACE2 engagement, the spike changes from a prefusion to a postfusion conformation as part of the cell entry process.

Antibodies binding the prefusion structure are more likely to be neutralizing antibodies; the cryo-EM study uncovered the prefusion conformation.

The information could enable scientists to predict how changes to the spike protein sequence may alter the ability of antibodies to neutralize the virus, and to design small molecules that prevent the spike from mediating viral fusion.

The mutations promoting the prefusion spike conformation have been incorporated into Moderna's COVID-19 vaccine candidate.

The team introduced two proline substitution mutations into the spike protein sequence to stabilize the trimer's prefusion conformation.

Kizzmekia Corbett, scientific lead of the coronavirus team at VRC, told BioCentury the team previously used this method to uncover the prefusion structure of the Middle East respiratory syndrome coronavirus (MERS-CoV) spike. Preliminary data showed that a MERS spike protein with stabilization mutations more potently elicited neutralizing antibodies than the wild-type MERS spike.

The strategy also works for the spike protein of other coronaviruses, said Corbett.

She added that the mutations promoting the prefusion spike conformation have been incorporated into Moderna's COVID-19 vaccine candidate mRNA-1273, which is ready to enter Phase I testing (see "Moderna Raises $500M, Readies Coronavirus Vaccine").

Spike differences limit repurposing

Corbett told BioCentury the high-resolution structure enables visualization of how COVID-19's spike structure differs from the spikes of other coronaviruses.

The paper depicted the similarities and differences between the structures of the SARS-CoV and COVID-19 spike proteins. In vitro assays showed that prefusion COVID-19 spike binds ACE2 10-20 times more strongly than the SARS-CoV spike protein. “The spike protein, in its prefusion conformation, doesn’t bind to several of the published SARS-specific monoclonal antibodies," added Corbett.

Those SARS-specific mAbs bound the spike's receptor binding domain, she said.

The observation means that some SARS mAbs targeting the spike may not be applicable to COVID-19. However, SARS mAbs against spike epitopes that are structurally conserved between SARS and COVID-19 could see cross-reactivity between the two coronaviruses.

The implications extend to vaccines targeting SARS-CoV that researchers hope to repurpose for COVID-19.

The UT Austin scientists plan to use the COVID-19 prefusion-stabilized trimers to isolate neutralizing antibodies from patients who recovered from COVID-19. The neutralizing antibodies could be administered to prevent disease or treat newly infected individuals.

The U.S. government has a handful of other partnerships focused on COVID-19. For example, HHS's Biomedical Advanced Research and Development Authority (BARDA) has collaborations with Sanofi and the Janssen unit of Johnson & Johnson (NYSE:JNJ); both pharmas are developing vaccines targeting the spike protein (see "Sanofi Enters Vaccine Race").

Sanofi declined to say whether its vaccine candidates will include a mechanism promoting adoption of the spike protein's prefusion structure. A J&J spokesperson told BioCentury the company is exploring "multiple approaches, which target all or some parts of the protein" but didn't say whether the vaccine would be designed around the prefusion conformation.

Further analysis of the coronavirus crisis can be found at The COVID-19 content is free to all who visit the site.


ACE2 - Angiotensin-converting enzyme 2

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