Ancestral Wuhan SARS-CoV-2 anti-spike CD4⁺ T cells predict protection from symptomatic omicron breakthrough infection

Neutralizing antibodies are considered the best surrogate markers of protection against a SARS-CoV-2 infection. However, the predictive value of these antibodies overlaps only slightly with other variants. In a case-control study, in pre-infected vaccinated patients, polyfunctional anti-Wuhan CD4⁺ T cell responses predicted protection against both the ancestral Wuhan strain and the distant Omicron variant, whereas CD4⁺ T cell responses to unrelated viruses (e.g., CMV, influenza) did not. Conversely, neutralizing antibodies to the Wuhan spike correlated with protection from Wuhan infection, but failed to predict breakthroughs with divergent variants such as Omicron. Confounding factors (age, sex, timing of sampling related to infection onset, number of booster doses) were accounted for to minimize bias. To explain these results, we observed very strong correlations between the anti-Wuhan CD4⁺ T cell responses and the corresponding anti-Omicron BA.1 CD4⁺ T cell response. CD4⁺ T cell responses may serve as a potential surrogate marker of protection, regardless of the variant.