The development and deployment of mRNA vaccines during the COVID-19 pandemic was a landmark achievement in modern medicine and ushered in a new age of vaccine innovation. The vaccines strongly elicited both neutralizing and non-neutralizing antibody responses against the viral Spike protein, but these waned over time. Self-amplifying mRNA (sa-mRNA) vaccines such as ARCT-154 can prolong antigen production and durability of humoral immune response post-immunization and can thus be administered at a lower dose. How this translates into the overall humoral architecture compared to that shaped by conventional mRNA vaccinations is unclear.
We analyzed serum antibody responses from a Phase III trial comparing humoral responses elicited by ARCT-154 and mRNA BNT162B2 by systems serology. All participants had received three doses of mRNA COVID-19 vaccines and were randomized to receive a booster dose of ARCT-154 or BNT162B2. Primary outcomes were to quantify waning responses against ancestral SARS-CoV-2 Spike and a panel of antigenically drifted SARS-CoV-2 variant Spikes.
We identified that the sa-mRNA vaccine ARCT-154 elicited a unique antibody response compared to BNT162B2 defined by a sustained, activating profile to the vaccine-encoded Spike protein and a broad spectrum of drifted Spikes. Notably, potently activating FcgRIIIA-binding antibodies showed a sustained stimulation in the ARCT-154-treatment arm, and this translated to enhanced antibody-dependent natural killer cell activation (ADNKA) to both target WT Spike and the antigenically drifted BA.5 Spike, which was the predominant form of SARS-CoV-2 during the observation period.
Recipients of the sa-mRNA booster showed a temporally sustained humoral activation and an overall antibody architecture that favored pro-activating phenotypes. Our results support a model whereby prolonged antigen expression and presentation moves immune profiles towards activating phenotypes with broad antigenic coverage.
Bill and Melinda Gates Foundation INV-080712
Vaccines and Immunotherapy (VAC)
Kate S. Levine, Ross Blanc, Qixin Wang et al.· Journal of Immunology· 0 citations
Using systems serology, it is possible to create an assay that quantifies a human receptor’s binding levels to a virus receptor binding protein in the presence of neutralizing antibodies. For example, human influenza A virus predominantly binds to alpha 2’6-linked sialic acids, while avian influenza A prefers alpha 2’3-linked sialic acids. Modeling this binding in the presence of neutralizing antibodies using a systems serology approach would allow us to quantify neutralization breadth and capacity at a throughput and scale not previously known.
Using four parameter or Michaelis-Menton fitted models, we can quantify the complete binding and complete inhibition of binding for virus receptor binding proteins and human receptor pairs at the multiplex level. From this, percent inhibition can be quantified, and a systems-predicted neutralizing antibody (SNAb) titer can be calculated. This titer was compared against existing neutralization assays and readouts for validation. This was done using serum and lavage samples from vaccinated/boosted non-human primates.
Neutralizing antibody levels, whether they were measured by microneutralization assay, hemagglutinin inhibition assay, or SNAb were tightly correlated, and showed dependence on route of vaccination. The SNAb assay could successfully multiplex hemagglutinin molecules to quantify the predicted neutralization of twelve analytes simultaneously. The SNAb assay was performance-validated and did not show an overcounting or undercounting of neutralizing antibody titers.
Neutralizing antibody levels can be quantified in an efficient way using a systems-based approach. This allows for the multiplexing of readouts in a high-throughput assay. The assay itself is built on four-parameter or Michaelis-Menton binding modeling, which does not bias the titer compared to other commonly used methods.
National Institutes of Health Grant CA260476, PO1AI165072, and U19AI135995, and National Institutes of Health Contract 75N93021C00029
Technological Innovations in Immunology (TECH)
Lindsay R. McManus, Qixin Wang, Kate S. Levine et al.· Journal of Immunology· 0 citations
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