Immune responses and reactogenicity after ChAdOx1 in individuals with past SARS-CoV-2 infection and those without

Dear Editor:

We have read the article by E. Sansone, et al.¹ with great interest. The authors found the significant protective effect of BNT162b2 vaccination against SARS-CoV-2 infection and symptom development after SARS-CoV-2 infection among healthcare workers (HCWs). However, individuals with past natural infection with SARS-CoV-2 and those without may have different immune responses to COVID-19 vaccination. Some studies have quickly compared the immune responses to the mRNA-based vaccines between individuals with past infection with SARS-CoV-2 and those without[2], [3], [4], [5]; but their kinetics in the adenovirus-vector-based vaccines remain unknown. In this study, we evaluated the immunogenicity and reactogenicity of the first dose of the adenovirus-vector-based ChAdOx1 nCoV-19 vaccine in HCWs with or without past infection with SARS-CoV-2.

This study enrolled HCWs who received the 1st dose of ChAdOx1 vaccine between March 5 and March 26, 2021, at Asan Medical Center, a 2700-bed tertiary care teaching hospital in Seoul, South Korea. The study was reviewed and approved by the Institutional Review Board of Asan Medical Center (IRB No. 2021-0170). Adverse reactions were evaluated through self-reported questionnaires (Supplementary material). SARS-CoV-2-S1 specific IgG antibody, neutralizing antibody, and T cell responses were measured by ELISA, microneutralization assay by using SARS-CoV-2 (βCoV/Korea/KCDC/2020 NCCP43326), and ELISPOT assay using SARS-CoV-2 spike-overlapping peptides (Miltenyi Biotec, Bergisch Gladbach, Germany), respectively.

A total of 38 HCWs were enrolled in this study. Of them, 11 (29%) had past infection with SARS-CoV-2 confirmed by real-time reverse transcriptase-polymerase chain reaction with nasopharyngeal samples, and the rest of the participants (n = 27; 71%) were infection-naïve. The baseline characteristics of the participants are shown in Supplemental Table 1. There was no significant difference in the age and sex distribution between those with past infection and infection-naïve individuals (P = 0.52 and P = 0.48, respectively).

The baseline SARS-CoV-2-S1 specific IgG titers were positive in all participants with past infection and negative in all infection-naïve participants. The mean values of SARS-CoV-2-specific IgG antibody titer of participants with past infection were significantly higher than those of infection-naïve participants at baseline (8.29 vs. 0.12) and at week 1 (74.98 vs. 0.14), week 2 (61.73 vs. 1.88), and week 3 (46.34 vs. 5.56) after vaccination (all P < 0.0001) (Fig. 1 A). The neutralizing antibody titer was significantly higher in the past infection group compared with the infection-naïve group at week 1 and week 3 as well (mean ± SEM, 4644 ± 1416 vs. 7.2 ± 3.6 and 6108 ± 1255 vs. 144.6 ± 24.1, respectively, both P < 0.0001) (Fig. 1B). IFN-gamma-producing T cell responses were higher in the past infection group at baseline and 1 week after vaccination (P = 0.04 and 0.02, respectively), but were comparable at 2 (P = 0.53) and 3 weeks (P = 0.81) after vaccination (Fig. 1C).

Fig. 1.

Detailed kinetics of immune responses and reactogenicity after a single dose of ChAdOx1 nCoV-19 vaccine in infection-naïve individuals and those with past SARS-CoV-2 infection (A) Humoral immune response measured by SARS-CoV-2 S1-specific IgG antibodies. (B) Neutralizing antibody measured by microneutralization assay. (C) Cell-mediated immune response measured by IFN-gamma-producing T cells from isolated PBMCs. Error bars denote the standard error of the mean values. Mann–Whitney U test was used for the statistical analysis between past infection and infection-naive.

Reactogenicity in terms of adverse reactions during the 7-day reporting period after vaccination was analyzed in the two groups. Local and systemic reactogenicity was similar between individuals with past SARS-CoV-2 infection and those without (Fig. 2 ). The severities of adverse events in the two groups according to each symptom after vaccination are shown in Supplemental Table 2 and Supplemental Figs. 1 and 2.

Fig. 2.

Reactogenicity during the 7-day period after the 1st dose of the ChAdOx1 nCoV-19 vaccine in infection-naïve individuals and those with past infection with SARS-CoV-2. Horizontal bars denote the mean values. Error bars denote the standard error of the mean values. Mann–Whitney U test was used for the statistical analysis between past infection and infection-naive.

Consistent with the previous studies on the immunogenicity of the BNT162b2 vaccine between those with past infection with SARS-CoV-2 and those without[2], [3], [4], we found that the immunogenicity of the ChAdOx1 nCoV-19 vaccine was stronger and more rapid in those with past infection compared with those without. Our study has two unique findings. First, our detailed kinetic data on the immunogenicity of the ChAdOx1 nCoV-19 vaccine revealed that the antibody response peaked at 1 week after vaccination in individuals with past infection, while the antibody response gradually increased until 3 weeks after vaccination in infection-naïve individuals. Moreover, whereas the SARS-CoV-2-specific T cell responses were higher in the past infection group at baseline and 1 week after vaccination but were comparable at 2 and 3 weeks after vaccination. In contrast, a previous study on the BNT162b2 vaccine showed that the SARS-CoV-2-specific T cell responses at 21–25 days after vaccination were higher in individuals with past infection than in infection-naïve individuals.³ Such difference in the kinetics of T cell response and antibody responses after different types of COVID-19 vaccines provides further insight into the immune response after COVID-19 vaccination according to the history of past natural infection with SARS-CoV-2. For example, the rapid increase of virus-specific T cell response by vaccination in the past infection group likely reflects the presence of memory T cells induced by previous natural infection with SARS-CoV-2. However, in contrast to the wide range of viral epitope stimulation by natural SARS-CoV-2 infection, the ChAdOx1 vaccine only provides spike-derived epitopes; therefore, it may not be able to fully boost the pre-existing virus-specific memory T cells. Moreover, the strong pre-existing T cell response may restrict the efficient supply of antigens, thus resulting in a curtailed expansion of memory T cells. Second, whereas the antibody responses were significantly higher in the past infection group, the reactogenicity after ChAdOx1 vaccine was similar between individuals with past SARS-CoV-2 infection and those without. These findings are in contrast with a previous study on mRNA-based COVID-19 vaccines in which the frequency of systemic reactions was higher in those with previous natural infection than in those without.⁴ The stronger immediate reactogenicity in the young population after the ChAdOx1 vaccine than after the BNT162b2 vaccine⁶ might partially explain the differences between our data and those from mRNA-based vaccines. Alternatively, the unknown immunologic mechanism that is associated with less adverse reactions after the second dose of the ChAdOx1 vaccine than those after its first dose⁶ might explain our observation.

In conclusion, those with past SARS-CoV-2 infection had similar reactogenicity and stronger antibody responses compared with infection-naïve individuals after receiving the ChAdOx1 vaccine. T cell responses were not significantly different between the two groups after 2 weeks after vaccination.