Predictive factors of a viral neutralizing humoral response after a third dose of COVID-19 mRNA vaccine

Abstract

Kidney transplant recipients (KTRs) have reduced ability to mount adequate antibody response after two doses of the COVID-19 mRNA vaccine. French health authorities have allowed a third booster dose (D3) for KTRs, but their response is heterogeneous and tools able to discriminate the responders are lacking. Anti-RBD IgG titers (chemiluminescence immunoassay), spike-specific cellular responses (IFN-γ-releasing assay, IGRA), and in vitro serum neutralization of the virus (the best available correlate of protection), were evaluated 7-14 days after the second dose (D2) of BNT162b2 vaccine in 93 KTRs. Among the 73 KTRs, whose serum did not neutralize SARS-CoV-2 in vitro after D2, 14 (19%) acquired this capacity after D3, and were considered as "responders." Exploratory univariate analysis identified short time from transplantation and high maintenance immunosuppression as detrimental factors for the response to D3. In addition, any of the presence of anti-RBD IgGs and/or positive IGRA after D2 was predictive of response to D3. By contrast, none of the KTRs with both a negative serology and IGRA responded to D3. In summary, routinely available bioassays performed after D2 allow identifying KTRs that will respond to a booster D3. These results pave the way for the personalization of vaccination strategy in KTRs.

Keywords: COVID-19; SARS-CoV-2; mRNA-vaccine; renal transplantation.

FIGURE 1

Flow chart of the study. D2, second dose of BNT162b2 vaccine; D3, third dose of BNT162b2 vaccine

FIGURE 2

Spike-specific humoral and cellular responses after the second dose of BNT162b2 vaccine. Spike-specific humoral and cellular responses were measured 7–14 days after the D2 in kidney transplant recipients naïve for the SARS-CoV-2 (white circles) or with a previous history of COVID-19 (black circles). (A) Histogram showing the titers of anti-receptor binding domain (RBD) IgG before vaccination and after D2 of vaccine. Dashed line represents the limit of positivity of the assay. Wilcoxon test; ***p < .001; ****p < .0001. (B) Histogram showing the viral neutralization capacity of the serum in in vitro functional assay after D2. Mann-Whitney U test. Pie charts represent the proportion of patients with viral neutralization capacity. Fisher test; ****p < .0001; VNT, viral neutralization titer. (C) The relationship between the anti RBD IgG titers and viral neutralization capacity was plotted. A linear regression was performed for patients with anti-RBD IgG titer above 1000 BAU/ml. R²: Pearson’s coefficient. (D) Histogram showing the concentration of interferon gamma (IFN-γ) measured in IGRA (Quantiferon SARS-CoV-2) after D2. Dashed line represents the limit of positivity of the assay. IU, international units

FIGURE 3

Tolerability of the third dose of BNT162b2 vaccine. The proportion of kidney transplant recipients that developed local or systemic adverse events after the second and after the third dose of vaccine are plotted

FIGURE 4

Spike-specific humoral and cellular responses after the third dose of BNT162b2 vaccine. Humoral and cellular responses were measured 7–14 days after the third dose of vaccine in kidney transplant recipients without viral neutralization capacity after D2. (A) Histogram showing the individual evolution of anti-receptor binding domain (RBD) IgG tiers (in binding antibody units, B.A.U.) after D2 and D3. Dashed line represents the limit of positivity of the test. Wilcoxon test; ****p < .0001. (B) Histogram showing the viral neutralization capacity of the serum in in vitro functional assay after D3. VNT, viral neutralization titer. (C) Histogram showing the evolution of the concentration of interferon gamma (IFN-γ) in IGRA (Quantiferon SARS-CoV-2) between D2 and D3. Dashed line represents the limit of positivity of the test. IU, international units. (D, E) Histogram showing the viral neutralization capacity after D3 according to the absence (neg) or the presence (pos) of anti-RBD IgG (D) or IFN-γ in IGRA (E) after D2. Mann-Whitney U test. Pie charts represent the proportion of patients with viral neutralization capacity after D3. Fisher test. VNT, viral neutralization titer; *p < .05; **p < .01; ***p < .001. (F). Histogram showing the proportion of patients with viral neutralization capacity after D3 according to the presence (+) or the absence (−) of anti-RBD IgG and or positive IGRA after D2