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Long-Term Protection Against Symptomatic Omicron Infections Requires Balanced Immunity Against Spike Epitopes After

Heiko Pfister1, Carsten Uhlig1, Zsuzsanna Mayer1

  • 1Munich Biomarker Research Center, Institute of Laboratory Medicine, TUM University Hospital German Heart Center, Lazarettstr. 36, 80636 Munich, Germany.

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Summary

Long-term protection against Omicron requires balanced immunity to conserved and non-conserved SARS-CoV-2 Spike epitopes. Future vaccines should target a broad spectrum for sustained protection against variants.

Keywords:
OmicronSARS-CoV-2adaptive immunityantibodiescellular immune responsemRNA vaccinepredictive markersvaccinationviral infection

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Area of Science:

  • Immunology
  • Virology
  • Vaccinology

Background:

  • Limited studies differentiate immunity against conserved and non-conserved SARS-CoV-2 Spike epitopes for long-term protection.
  • Existing research insufficiently guides pan-variant vaccine development.
  • This study investigates immunity against Spike protein and Omicron breakthrough infections.

Purpose of the Study:

  • To evaluate the correlation between neutralizing antibody and cellular immunity levels against SARS-CoV-2 Spike protein and symptomatic Omicron breakthrough infections.
  • To assess the role of immunity targeting conserved and non-conserved epitopes in protection.

Main Methods:

  • Observational cohort study of 107 subjects.
  • Analysis of neutralizing antibody levels against SARS-CoV-2 (sub)variants 6 months post-vaccination and post-booster using a multiplex surrogate virus neutralization assay.
  • Assessment of cellular immunity via cytokine mRNA expression after peptide pool stimulation in whole blood samples.

Main Results:

  • Neutralizing antibody titers reliably predicted protection before booster but diminished post-booster due to antibody repertoire remodeling.
  • Balanced immune response to conserved and non-conserved Spike epitopes enhanced Omicron vaccine effectiveness.
  • Neutralizing antibodies against mutated epitopes protected against symptomatic infection, while cellular immunity targeting conserved epitopes was most effective.

Conclusions:

  • Optimal long-term protection against Omicron necessitates balanced immunity to both conserved and non-conserved SARS-CoV-2 Spike epitopes.
  • Waning humoral immunity and limited cross-neutralizing antibodies against non-conserved epitopes pose challenges for long-term protection.
  • Future pan-SARS-CoV-2 vaccines targeting a broad epitope spectrum, including conserved and non-conserved epitopes, may offer more effective long-term protection than those focusing solely on conserved epitopes.