A new study published in the journal iScience reported that nanoparticles (NPs) co-expressing spike proteins from different sarbecoviruses improved the breadth of neutralizing responses.
The coronavirus disease 2019 (COVID-19) vaccines are based on the spike protein of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Wuhan-Hu-1 strain. Mutant variants of SARS-CoV-2 are less susceptible to immune responses induced by these vaccines. Therefore, sequence diversity vaccines may increase protection against novel SARS-CoV-2 variants.
Previously, the authors described a two-component NP vaccine (I53-50) that induces neutralizing antibodies (nAbs) against SARS-CoV-2 in animal models. I53-50 NP contains the 20-trimer component (I53-50A, component A) and the 12-pentamer component (I53-50B, component B). The two components combine into icosahedral particles.
Study and findings
In this study, the researchers used the I53-50 platform to co-image various spike proteins and evaluate immune responses. First, they fused the N-terminus of component A to the C-terminus of the spike protein of the Beta variant via a glycine-serine linker. Then, after purification, the spike-A fusion protein was mixed with an equimolar amount of component B for coupling.
Mosaic NPs (which display different spike proteins together) were produced by mixing equimolar amounts of the appropriate spike-A fusion proteins (ancestral strain and Beta variant) before adding component B. Negative blot electron microscopy confirmed the aggregation of NPs. Biolayer interferometry (BLI)-based analysis revealed strong binding to ancestral spike NPs by specific monoclonal antibodies (mAbs).
Similarly, Beta-specific mAbs showed strong binding to NPs displaying Beta spike protein. Some ancestral spike-specific mAbs (those that do not bind to Beta spike) and another mAb with reduced potency for Beta spike exhibited interbinding to mosaic NPs. Next, the authors inoculated rabbits with ancestral spike NPs, Beta spike NPs, an ancestral cocktail, and Beta spike NPs or mosaic NPs at weeks 0 and 4 and bleed from them at weeks 0, 4, and 6. they got it.
A pseudovirus neutralization assay was performed to evaluate the neutralization of relevant SARS-CoV-2 variants (VOCs), SARS-CoV-1 and animal CoVs (pangolin GD, WIV1 and SHC014). The ancestral spike NPs induced the strongest nAbs against the ancestral strain, but weaker against variants, with significantly lower titers against Beta and Omicron variants.
Neutralizing titers of Beta spike, cocktail and mosaic NPs against ancestral strain, Alpha and Delta variants were similar but several fold improved against Beta, Gamma and Omicron variants relative to ancestral spike NPs. All vaccinated animals elicited significant neutralizing responses to SARS-CoV-1 and animal CoVs.
Next, the researchers created NPs showing the increase in SARS-CoV-1 and mosaic NPs showing the increases from SARS-CoV-1 and SARS-CoV-2 together. As before, the BLI-based assay confirmed the formation of mosaic NPs. Next, the researchers evaluated the immunogenicity of cocktail and mosaic NPs of SARS-CoV-1 and SARS-CoV-2 spikes in rabbits and mice.
BALB/c mice and rabbits were vaccinated with cocktail or mosaic NPs at weeks 0, 4, and 12, and blood was drawn at week 0 and two post inoculation. The authors reanalyzed data from previous studies using SARS-CoV-2 soluble spike antigen and NPs to vaccinate rabbits and mice using the same dosing regimen. SARS-CoV-2 spike NPs caused three times greater neutralization in mice than other immunogens, but this was not statistically significant.
Vaccination with the soluble SARS-CoV-2 spike induced the strongest neutralizing responses against ancestral SARS-CoV-2 in rabbits. The nAb responses induced by the mosaic NPs and the cocktail were lower than those elicited by the soluble spike antigen. However, nAb titers were significantly stronger against SARS-CoV-1 with cocktail and mosaic NPs than with SARS-CoV-2 soluble spike antigens or NPs.
All immunogens induced nAbs against animal CoV SHC014. Cocktail and mosaic NPs induced the most robust nAb responses to SHC014. Cocktail and mosaic NPs showed neutralization against pangolin GD CoV to similar levels with SARS-CoV-2 spike NPs. Finally, serum samples from vaccinated rabbits were tested for neutralization against SARS-CoV-2 VOCs.
Cocktail and mosaic NPs elicited SARS-CoV-2 soluble spike antigen against the ancestral strain and VOCs, and nAb titers approximately two to three times lower than those induced by NPs. Neutralizing potency against SARS-CoV-2 VOCs increased after the third vaccination (at week 12), with titers 2 to 18 times higher in those vaccinated with soluble antigens or spike NPs.
The authors noted that vaccination with the ancestral spike protein induced the weakest nAb responses against SARS-CoV-2 Omicron. Surprisingly, nAb responses against the Omicron variant were most enhanced at the third vaccination. To summarize, the results showed that spike proteins from different SARS-CoV-2 variants and SARS-CoV-1 could be imaged together on the I53-50 NP platform for broad neutralization responses. Moreover, mosaic NPs that induce pan-sarbecovirus immunity may be protective against future variants.
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