CVR - Coronavirus Vaccines R&D Roadmap

Milestone
2.6.c

Vaccine efficacy predictions

In progress
High priority

Identify CoPs for predicting the efficacy of coronavirus vaccines based on key immune responses correlating with specific clinical end points, and that are applicable across diverse viral variants.

Progress Highlights

See CVR Scholar Hub page: Potential Immune Correlates of Protection for Coronavirus Vaccines

Neutralizing antibodies (nAb; shown to block spike protein function) as primary CoPs
Correlation with vaccine efficacy

Multiple studies show that nAb titers are strongly predictive of vaccine efficacy against symptomatic and severe COVID-19 across different vaccine platforms.

Variant-escape from nAbs

Recent studies have shown that multiple Omicron and Delta subvariants exhibit immune escape, reducing the effectiveness of ancestral-strain nAbs on a variant by variant basis.

Thresholds of protection from the COVE trial

Study: Zhang 2024

  • mRNA-1273, Moderna; Omicron CoPs from third dose of ancestral vaccine
  • 251 AU/mL nAb titer at exposure → 50% vaccine efficacy (VE).
  • 891 AU/mL nAb titer at exposure → 74% VE.
  • A 10-fold increase in nAbs was associated with a 72% lower risk of symptomatic Omicron infection.
Binding antibodies (do not necessarily block spike protein function) as secondary CoPs

Spike-specific IgG and IgA bAb responses correlate with vaccine protection, particularly in older adults and immunocompromised individuals.

Zhang 2024 found that, in the COVE trial, post-booster bAb levels were inversely associated with Omicron infection risk. A 10-fold increase in bAbs was associated with an 84% lower risk of symptomatic Omicron infection in naive subjects

Vikström 2023 found that IgG levels predict survival in elderly nursing home residents, suggesting bAbs may be more relevant for severe disease protection in high-risk populations.

Several studies define nAb and bAb thresholds required for different levels of vaccine efficacy.

Hybrid immunity enhances predictive value of nAbs and bAbs.

Martín Pérez 2024 found that vaccine CoP thresholds should be adjusted based on infection history.

T-cell responses as emerging CoPs (not yet standardized)

While nAbs and bAbs correlate strongly with protection against symptomatic infection, T-cell immunity is essential for long-term protection against severe disease.

Rahmani 2024 found that robust T-cell immunity leads to lower hospitalization and mortality rates.

T-cell immunity can remain effective across variants, even when nAbs lose neutralization ability due to immune escape mutations, likely due to T-cell recognition of conserved epitopes.

Martín Pérez 2024 found that hybrid immunity generates stronger and broader T-cell responses.

Sun 2024 show that T-cell responses to conserved regions of the spike protein correlate with reduced severity of disease, even in cases of breakthrough infections.

Higher levels of antigen-specific IFNγ-secreting CD4+ T cells are associated with stronger vaccine response.

Wagstaffe 2024 found that early mucosal CD8+ T-cell responses are associated with viral control.

Eser 2023 found that nucleocapsid-specific CD4 and CD8 T cells may serve as CoPs.

Mucosal immunity markers as potential CoPs for sterilizing immunity

Studies show that higher nasal IgA levels correlate with lower variant breakthrough infection rates, even when systemic IgG or nAbs are low.

Early mucosal interferon-stimulated gene (e.g., OAS2, OAS3, IFIT1, ISG15, ISG20, IFITM1, USP18) activation and chemokine responses (e.g., CXCL10 and CXCL11) correlate with SARS-CoV-2 control.