COVID-19 Vaccination Induces Cross-Reactive Dengue Antibodies with Altered Isotype Profiles and In Vitro ADE

Abstract

Dengue virus is a mosquito transmitted flavivirus that cause inapparent or mild disease but can also cause severe hemorrhagic fever in humans. Cross-reactive IgG antibodies can cause under specific conditions antibody dependent enhancement (ADE) of the infection via Fc-receptor interaction. Antibodies from SARS-CoV-2 (anti-S) causing COVID-19 disease can also cross-react against the dengue envelope (anti-E). We therefore investigated the antibody profile of these cross-reactive antibodies and their ability to induce ADE. We found that the cross-reactive anti-E in COVID-19 vaccinated are dominated by IgM/A while, anti-S from vaccinated or anti-E from dengue infected patients have an IgG1 dominated antibody profile. The low-level anti-E IgG from COVID-19 vaccinated are dominated by low Fc-affinity IgG2/4 subclass. These antibodies were able to induce in vitro ADE stronger than from Dengue infected for the 1^st,2^nd dose of the vaccine or later omicron variant booster. This could partially be explained that ADE was inhibited by the complement system in dengue infected but not in COVID-19 vaccinated.

Keywords: Cross-reactive; Dengue; antibody dependent enhancement; isotype.

Figure 1:

Antibody titers for anti-SARS-CoV-2 spike (anti-S) and anti-Dengue type 2 envelope (anti-E) were measured in unvaccinated, COVID-19 vaccinated, and dengue-recovered individuals. Titers are reported in μg/ml for each isotype (IgM, IgA, total IgG [IgG1+2+3+4], and the sum of all isotypes) in sections (A-B). Titers for anti-S and anti-E are further detailed for each IgG subclass (IgG1–4) in sections (C-D). The average contribution of each isotype to anti-S and anti-E responses in the COVID-19 vaccinated group is visualized in radar plots (E-F), and for the dengue-recovered group in radar plots (G-H). Radar plots are normalized to the highest average isotype concentration. Statistical significance is denoted as *p<0.01.

Figure 2:

Concentrations of anti-E and anti-S antibodies were measured in non-vaccinated Taiwanese and pre-pandemic U.S. cohorts for the following isotypes: (A) IgM, (B) IgA, and (C-F) IgG subclasses. Statistical significance is indicated as *p<0.05 and **p<0.01., * p<0.05, ** p<0.01

Figure 3:

(A-B) Pearson correlation between anti-spike an anti-E Isotypes in COVID-19 vaccinated individuals. (C-E) Anti-E titer before (untreated) or after removal of anti-S or anti-E antibodies with magnetic beads either from COVID-19 vaccinated (3 dose) or Dengue recovered individuals. (C1-E2) the direct titer of vaccinated and Dengue recovered after anti-S and anti-E removal. Samples classified as non-cross reactive are marked as black with solid lines, partial cross-reactive blue with dashed lines and full cross-reactive as red with dotted lines. (C3-E3) Distribution of non-, partial and fully cross-reactive anti-E samples. (C4-E4) Level of cross-reactivity given as <mi>. C * p<0.05, ** p<0.01

Figure 4:

(A) Antibody dependent enhancement in THP-1 monocytes. Viral replication is measured by qPCR for Dengue RNA. Fold change is the difference to virus only treatment.(B-C) Affinity of anti-E antibodies to FcγIIa and FcγIIIa IgG receptor. Fold change is measured as ratio to the signal for IgG isotype unspecific for Dengue. (D-E) correlation of ADE, FcγIIa and FcγIIIa to anti-spike or anti-E antibody isotypes. (F-G) ADE measured by qPCR before and after removal of anti-spike or anti-E antibodies. (H-I) ADE measured in untreated versus complement inactivated sera (56⁰C) and complement inactivated versus guinea pig complement added samples in COVID-19 vaccinated (1 dose) and COVID-19 recovered individuals. * p<0.05, ** p<0.01