Anti-SARS-CoV-2 antibody dynamics after primary vaccination with two-dose inactivated whole-virus vaccine, heterologous mRNA-1273 vaccine booster, and Omicron breakthrough infection in Indonesian health care workers

Abstract

Background: Data on the dynamics and persistence of humoral immunity against SARS-CoV-2 after primary vaccination with two-dose inactivated vaccine (CoronaVac) are limited. This study evaluated the sequential effects of prior infection, heterologous boosting with mRNA-1273 (Moderna), and the occurrence of Omicron vaccine-breakthrough infection (VBI) thereafter.

Methods: We evaluated anti-spike IgG (Abbott) and neutralising (cPASS/GenScript) antibody (nAb) titers up to one year after mRNA-1273 boost in two-dose-CoronaVac-primed Indonesian healthcare workers (August 2021-August 2022). We used linear mixed modeling to estimate the rate of change in antibody levels, and logistic regression to examine associations between antibody levels and VBI.

Results: Of 138 participants, 52 (37.7%) had a prior infection and 78 (56.5%) received an mRNA-1273 booster. After two-dose CoronaVac, antibody titers had significantly declined within 180 days, irrespective of prior infection. After mRNA-1273 booster, anti-spike IgG (1.47% decline/day) and Omicron B.1.1.529/BA.2 nAbs declined between day 28-90, and IgG titers plateaued between day 90-360. During the BA.1/BA.2 wave (February-March 2022), 34.6% (27/78) of individuals experienced a VBI (median 181 days after mRNA-1273), although none developed severe illness. VBI was associated with low pre-VBI anti-spike IgG and B.1.1.529/BA.2 nAbs, which were restored post-VBI.

Conclusions: mRNA-1273 booster after two-dose CoronaVac did not prevent BA.1/BA.2 VBI. Periodic vaccine boosters may be warranted against emerging SARS-CoV-2 variants.

Keywords: COVID-19; CoronaVac; Humoral immunity; SARS-CoV-2; mRNA-1273.

Fig. 1

Antibody responses against SARS-CoV-2 variants in CV-CV and CV-CV-mRNA vaccinees The figure shows data separately for the CV-CV vaccinees (blues dots) and the CV-CV-mRNA vaccinees (red dots). Serum anti-spike IgG titers (A) and neutralizing antibodies (nAbs) against SARS CoV-2 wild-type (B), Delta (C), Omicron B.1.1.529 (D) and BA.2 (E) were measured: i) Pre-vaccination (Day 0), i.e. before the first dose in CV-CV vaccinees (n=60) and before third dose in CV-CV-mRNA vaccinees (n=42) ii) Post-vaccination day 28 (CV-CV n=41 and CV-CV-mRNA n=40), day 90 (CV-CV n=41 and CV-CV-mRNA n=40), day 180 (CV-CV n=9 and CV-CV-mRNA n=40), and day 360 (CV-CV-mRNA n=43). Dashed line represents the seropositivity of IgG titer [≥7.1 BAU/mL = 0.85 log10 BAU/mL] and cut-off value for presence of neutralizing antibodies [signal inhibition >30%]. P-values were derived from Kruskal-Wallis H followed by Dunn’s post-hoc tests, adjusted by Benjamini-Hochberg method for multiple comparisons. *, p<0.05; **, p<0.01; ***, p<0.001 Abbreviations: BAU, binding antibody units; CV, CoronaVac; mRNA, mRNA-1273 (Moderna)

Fig. 2

Antibody responses against SARS-CoV-2 in CV-CV-mRNA vaccinees before, during and after Omicron breakthrough infection, compared to those who never experienced breakthrough infection Figure shows anti-S IgG titers (A) and neutralizing antibodies (nAbs) against wild-type (B), Delta (C), Omicron B.1.1.529 (D) and Omicron BA.2 (E) in participants who experienced an Omicron  BA.1/BA.2 vaccine breakthrough infection (VBI; red dots, n=27) and those who did not (noVBI;blue dots, n=56). VBI (red dots) were those who had a PCR-confirmed infection at least 14 days after the third dose (CV-CV-mRNA vaccinees). The median time of VBI occurrence was 181 days (IQR170-202) since the third mRNA vaccine dose. NoVBI participants (blue dots) were those who had never experienced a VBI during or prior the Omicron wave (February-March 2022). Pre-VBI antibody levels represent the most recent measurement prior to VBI occurrence (median 55 days [IQR33-88] before VBI). Post-VBI antibody level represents the most recent measurement after VBI occurrence (median 101 days [IQR39-175] after VBI). P-values were derived from Kruskal-Wallis H followed by Dunn’s post-hoc tests, adjusted by Benjamini-Hochberg method for multiple comparisons. *, p<0.05; **, p<0.01; ***, p<0.001 Abbreviations: BAU, binding antibody units; CV, CoronaVac; mRNA, mRNA-1273 (Moderna)

Fig. 3

Dynamic changes in anti-spike IgG titers after second (CV) and third (mRNA-1273) vaccine dose Figure shows dynamic changes in anti-spike IgG titers between: (A) CV-CV and CV-CV-mRNA vaccinees after the latest vaccine dose on day 28 (n=41 and n=40), day 90 (n=41 and n=40), day 180 (n=9 and n=40), and day 360 (n=0 and n=41); (B) CV-CV vaccinees with (PI) and without (noPI) prior SARS-CoV-2 infection after the latest vaccine dose on day 28 (n=27 and n=14), day 90 (n=24 and n=17), and day 180 (n=5 and n=4); (C) CV-CV-mRNA vaccinees with (PI) and without (noPI) prior SARS-CoV-2 infection after the latest vaccine dose on day 28 (n=0 and n=40), day 90 (n=0 and n=40), day 180 (n=2 and n=38), and day 360 (n=9 and n=34); (D) CV-CV-mRNA vaccinees with VBI (n=27) and without VBI (noVBI) (n=56). The slopes were modelled with piecewise linear mixed models with each individual’s peak antibody level as a random effect, introducing knots at day 28, 90, and 180 after last vaccination. The black dots in panels (A, C and D) indicate the time of VBI occurrence. The estimated antibody values for each time point and the slopes between timepoints can be found in Table S6 Abbreviations: PI, prior infection; VBI, Omicron vaccine breakthrough infection