Quantifying how single dose Ad26.COV2.S vaccine efficacy depends on Spike sequence features

Area of Science:

• Virology
• Immunology
• Vaccinology

Background:

• Understanding SARS-CoV-2 sequence features is crucial for assessing vaccine resistance.
• The Ad26.COV2.S vaccine demonstrated 56% efficacy against moderate to severe-critical COVID-19 in the ENSEMBLE trial.
• Spike protein sequence variation influences vaccine effectiveness.

Approach:

• Analyzed SARS-CoV-2 Spike sequences from 484 vaccine and 1,067 placebo recipients in the ENSEMBLE trial.
• Evaluated vaccine efficacy (VE) against different Spike variants, including Lambda, in Latin America.
• Assessed the relationship between VE and sequence distance, physicochemical properties, antibody-epitope escape scores, and neutralization resistance.

Key Points:

• VE was significantly lower against the Lambda variant compared to reference and non-Lambda variants in Latin America.
• VE decreased significantly with increasing physicochemical-weighted Hamming distance to the vaccine strain across Spike, RBD, NTD, and S1 regions.
• VE also differed based on antibody-epitope escape scores and neutralization resistance levels.

Conclusions:

• SARS-CoV-2 sequence features, particularly Spike protein variations and distances to the vaccine strain, are critical determinants of vaccine resistance.
• The study maps the antigenic specificity of in vivo vaccine protection, highlighting reduced efficacy against variants with greater sequence divergence.
• Findings inform the development of next-generation vaccines with broader protective capacity against evolving SARS-CoV-2 strains.