Pre-existing humoral immunity and CD4+ T cell response correlate with cross-reactivity against SARS-CoV-2 Omicron subvariants after heterologous prime-boost vaccination

Abstract

Background: Information regarding the heterologous prime-boost COVID vaccination has been fully elucidated. The study aimed to evaluate both humoral, cellular immunity and cross-reactivity against variants after heterologous vaccination.

Methods: We recruited healthcare workers previously primed with Oxford/AstraZeneca ChAdOx1-S vaccines and boosted with Moderna mRNA-1273 vaccine boost to evaluate the immunological response. Assay used: anti-spike RBD antibody, surrogate virus neutralizing antibody and interferon-γ release assay.

Results: All participants exhibited higher humoral and cellular immune response after the booster regardless of prior antibody level, but those with higher antibody level demonstrated stronger booster response, especially against omicron BA.1 and BA.2 variants. The pre-booster IFN-γ release by CD4⁺ T cells correlates with post-booster neutralizing antibody against BA.1 and BA.2 variant after adjustment with age and gender.

Conclusions: A heterologous mRNA boost is highly immunogenic. The pre-existing neutralizing antibody level and CD4⁺ T cells response correlates with post-booster neutralization reactivity against the Omicron variant.

Keywords: Adenovirus vector vaccine; COVID-19 vaccines; Heterologous prime-boost immunization; Neutralizing antibody; T cell response; mRNA vaccine.

Fig. 1

Neutralizing antibodies to wildtype SARS-CoV-2 or Delta, BA.1 and BA.2 variant before and after booster dose. The neutralizing antibodies against (A) wildtype (n = 63), (B) Delta (n = 63), (C) BA.1 (n = 63) and (D) BA.2 (n = 62) for participants in the HNT and LNT groups. The blue dots represent the HNT group, and the orange dots represent the LNT group. Lines and error bars indicate mean and standard deviation. The neutralizing antibodies for each group were measured before booster vaccination and one month after booster vaccination. *** p value <0.001, ** p value <0.01, * p value <0.05, ns indicates no significant difference (p value >0.05). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Comparison of neutralizing antibodies against wildtype and other variants of concern (VOCs). (A)The neutralizing antibodies against wildtype and Delta variant before booster dose (n = 63). (B) The neutralizing antibodies against wildtype and BA.1 variant before booster dose (n = 63). (C) The neutralizing antibodies against wildtype and BA.2 variant before booster dose (n = 63). (D) The neutralizing antibodies against wildtype and Delta variant after booster dose (n = 63). (E) The neutralizing antibodies against wildtype and BA.1 variant after booster dose (n = 63). (F) The neutralizing antibodies against wildtype and BA.2 variant after booster dose (n = 62). The blue symbols represent the HNT group, and the orange symbols represent the LNT group. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 3

The IFN-γ releasing assay (QuantiFERON ELISA) in HNT and LNT group before and after heterologous booster. The IFN-γ measured by QuantiFERON ELISA in response to Ag1 and Ag 2 in (A) all participants, (B) all participants by groups, (C) increase of INF-γ release by group. The blue symbols represent Ag1, and the orange symbols represent Ag2. Lines and error bars indicate mean and standard deviation. The increase in INF-γ means that the level of INF-γ after booster receipt reduces the level before booster, expressed by median (IQR). *** p value <0.001, ** p value <0.01, * p value <0.05, and indicates no significant difference (p value >0.05). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 4

The correlation of pre-booster cellular immunity with post-booster humoral response. The correlation of pre-booster cellular immunity by IFN-γ releasing assay (QuantiFERON ELISA) in response to Ag1 with post-booster neutralizing antibody against BA.1 (A) and BA.2 (C). The correlation of pre-booster cellular immunity by IFN-γ releasing assay (QuantiFERON ELISA) in response to Ag2 with post-booster neutralizing antibody against BA.1 (B) and BA.2 (D). r indicates the Spearman correlation coefficient, and the grey area indicates 95% confidence interval. The black line indicates fitted regression line.