When COVID-19 made it stateside a little over a year ago, it really put the novel in novel coronavirus. Although researchers have been studying coronaviruses for decades, SARS-CoV-2 was truly new. Thankfully, scientists figured out pretty quickly that the spike protein played an important role in infection and transmission—and, subsequently, treatment.
All three vaccines currently approved for use in the United States—Pfizer/BioNTech, Moderna and J&J—exploit the spike protein, which the virus uses to bind to and enter human cells. But, since its introduction in late 2019, the original coronavirus has mutated. That being said, it seems the spike protein is still important—if not more so now.
Bing Chen, a researcher at Boston Children's Hospital, and his team found that the D614G mutation present in all three coronavirus variants from the UK, South Africa and Brazil makes the spike more stable as compared with the original SARS-CoV-2 virus. As a result, more functional spikes are available to bind to human cells' ACE2 receptors, making the virus more infectious.
Researchers now think the “original” coronavirus did not spread as quickly as the variants due to faulty spike proteins. At first, the spike proteins would bind to the ACE2 receptor to infect, but then they would suddenly change shape, folding in on themselves. This premature shape change sometimes caused the spike proteins to fall apart—before the virus could bind to cells. This, in turn, slowed virus infection, but also made it harder for the human immune system to induce a strong neutralizing antibody response.
Chen and his team used cryo-electron microscopy to get an atomic level look at the mutant spike protein. They discovered that the D614G mutation stabilizes the spike protein by blocking the premature shape change. Ironically, the mutation actually makes the spike proteins bind more weakly to the ACE receptor, but the fact that the spikes are less apt to fall apart prematurely makes the virus more infectious overall.
"[Let’s] say the original virus has 100 spikes," Chen explains. "Because of the shape instability, you may have just 50 percent of them functional. In the G614 variants, you may have 90 percent that are functional, so even though they don't bind as well, the chances are greater that you will have infection."
While the currently approved vaccines have shown some success against the variants, Chen proposes that any new or redesigned vaccines incorporate the code for the mutant spike protein.
Pfizer and Moderna are already working on booster shots and next-generation COVID-19 vaccines. Pfizer and BioNTech are considering a clinical study to evaluate a variant-specific vaccine with a modified mRNA sequence. This study would use a new construct of the Pfizer/BioNTech vaccine based on the B.1.351 lineage, first identified in South Africa. Pfizer has said a study like this would allow the companies to “update” the current vaccine quickly if the need arises.
Additionally, the pharmaceutical companies are also evaluating the effect of a third dose of their currently approved BNT162b2 on immunity against COVID-19 caused by variants. The study will use 144 participants from the Phase 1 who agree to receive a 30 µg booster of the current vaccine 6 to 12 months after receiving their initial two-dose regimen. They will be assessed at the time they receive the third dose, then one week and one month after. The companies will then study the ability of the sera from these participants to neutralize SARS-CoV-2 strains of interest.
Meanwhile, Moderna has dosed its first participants with a modified COVID-19 vaccine—mRNA-1273.351. This vaccine encodes for the prefusion stabilized spike protein of the SARS-CoV-2 variant B.1.351 (South Africa). mRNA-1273.211 combines mRNA-1273—Moderna’s currently authorized vaccine—and mRNA-1273.351 in a single vaccine, intended to elicit a broad immune response as both a primary vaccine and when administered as a booster. The Phase 2 trial will enroll 60 participants previously vaccinated with mRNA-1273 to receive a single booster dose of either: 20 µg of variant-specific candidate mRNA-1273.351; 50 µg of mRNA-1273.351; or 50 µg of multivalent booster candidate mRNA-1273.211.
On Monday, the biopharma company also began dosing participants in a Phase 1 trial of mRNA-1283, its next generation COVID-19 vaccine candidate. mRNA-1283 encodes for the portions of the SARS-CoV-2 spike protein critical for neutralization, specifically the receptor binding domain (RBD) and n-terminal domain (NTD). The study will evaluate three dose levels—10, 30 and 100 µg—given to healthy adults as a two-dose series 28 days apart, as well as a 100 µg dose given to adults in a single shot. The results will be compared with a two-dose series of 100 µg of mRNA-1273, the currently approved vaccine and dose level. mRNA-1283 will also be evaluated for use as a booster dose for previously vaccinated or seropositive individuals, as well as a primary vaccine for seronegative individuals.
Photo: This model shows the structure of the spike protein in its closed configuration, in its original D614 form (left) and its mutant form (G614). In the mutant spike protein, the 630 loop (in red) stabilizes the spike, preventing it from flipping open prematurely and rendering SARS-CoV-2 more infectious. Credit: Bing Chen, Boston Children's Hospital