Humoral immunity against SARS-CoV-2 variants including omicron in solid organ transplant recipients after three doses of a COVID-19 mRNA vaccine

Abstract

Objectives: Solid organ transplant recipients (SOTR) receiving post-transplant immunosuppression show increased COVID-19-related mortality. It is unclear whether an additional dose of COVID-19 vaccines can overcome the reduced immune responsiveness against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants.

Methods: We analysed humoral immune responses against SARS-CoV-2 and its variants in 53 SOTR receiving SARS-CoV-2 vaccination.

Results: Following the initial vaccination series, 60.3% of SOTR showed no measurable neutralisation and only 18.9% demonstrated neutralising activity of > 90%. More intensive immunosuppression, antimetabolites in particular, negatively impacted antiviral immunity. While absolute IgG levels were lower in SOTR than controls, antibody titres against microbial recall antigens were higher. By contrast, SOTR showed reduced vaccine-induced IgG/IgA antibody titres against SARS-CoV-2 and its delta variants and fewer linear B-cell epitopes, indicating reduced B-cell diversity. Importantly, a third vaccine dose led to an increase in anti-SARS-CoV-2 antibody titres and neutralising activity across alpha, beta and delta variants and to the induction of anti-SARS-CoV-2 CD4⁺ T cells in a subgroup of patients analysed. By contrast, we observed significantly lower antibody titres after the third dose with the omicron variant compared to the ancestral SARS-CoV-2 and the improvement in neutralising activity was much less pronounced than for all the other variants.

Conclusion: Only a small subgroup of solid organ transplant recipients is able to generate functional antibodies after an initial vaccine series; however, an additional vaccine dose resulted in dramatically improved antibody responses against all SARS-CoV-2 variants except omicron where antibody responses and neutralising activity remained suboptimal.

Keywords: COVID‐19; SARS‐CoV‐2; antibody responses; omicron variant; solid organ transplant; vaccine.

Figure 1

Neutralising activity in the peripheral blood of SOT recipients after two doses of a COVID‐19 mRNA vaccine. Neutralising activity of vaccine‐induced anti‐RBD antibodies in the peripheral blood of SOT recipients (N = 53) and healthy controls (N = 5; blue bars) after the second dose of the vaccine was measured as the degree of inhibition of RBD‐ACE2 interactions. Green, orange and red bars indicate different degrees of inhibition as indicated in the legend.

Figure 2

Absolute concentrations of immunoglobulins in the peripheral blood of SOT recipients. Absolute levels of IgG, IgM and IgA antibodies in our study subjects were measured after the second dose of the vaccine using a commercially available ELISA. Concentrations of total IgG, IgM and IgA are shown in ng mL^–1 for healthy vaccinated controls and the three different groups of vaccinated SOT patients (Good Responders [GR], Reduced Responders [RR] and Non‐Responders [NR]) according to the degree of viral neutralisation after the second dose of the vaccine. Bars indicate means + SD. Differences between groups were analysed for statistical significance (*P < 0.05, **P < 0.01) using the Mann–Whitney U‐test.

Figure 3

Titres of antibodies against different microbial antigens in the peripheral blood of SOT recipients. Titres of IgG antibodies against full‐length recombinant Influenza A nucleoprotein (Flu), tetanus toxoid (TT), cytomegalovirus (CMV), Epstein–Barr virus (EBV) and herpes simplex virus type 1 (HSV) were measured in an ELISA. Antibody titres are shown for healthy vaccinated controls and the three different groups of vaccinated SOT patients (Good Responders [GR], Reduced Responders [RR] and Non‐Responders [NR]) according to the degree of viral neutralisation after the second dose of the vaccine. Bars indicate means + SD. Differences between groups were analysed for statistical significance (*P < 0.05, **P < 0.01) using the Mann–Whitney U‐test.

Figure 4

Titres and neutralising activity anti‐SARS‐CoV‐2 antibodies in SOT recipients after two doses of a COVID‐19 mRNA vaccine. Titres of (a) IgG and (b) IgA antibodies against different full‐length recombinant SARS‐CoV‐2 proteins and their delta variants were measured in an ELISA after two doses of a COVID‐19 mRNA vaccine. Antibody titres are shown for healthy vaccinated controls and the three different groups of vaccinated SOT patients (Good Responders [GR], Reduced Responders [RR] and Non‐Responders [NR]) according to the degree of viral neutralisation after the second dose of the vaccine. Correlation between anti‐RBD IgG antibody titres and (c) neutralising activity in the same sample and (d) time from SOT at the time of the first dose of the vaccine. (e) Impact of steroid or antimetabolite intake on anti‐RBD IgG antibody titres after two doses of the vaccine. Bars indicate means + SD. Differences between groups were analysed for statistical significance (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001) using the Mann–Whitney U‐test.

Figure 5

Peptide epitopes within the S1 protein targeted by vaccine‐induced antibodies. Plasma samples from five COVID‐19 patients, five vaccinated healthy controls after two doses of the vaccine, the same controls before receiving the first dose of the vaccine, five non‐vaccinated healthy controls and five SOT recipients with known anti‐SARS‐CoV‐2 reactivity after the second dose of the vaccine were analysed for immunodominant peptide epitopes. Peptide pools of 5 20mer peptides each overlapping by 10aa were used in an ELISA. Grey bars indicate background levels. RBD and RBM regions within the S1 protein are highlighted in yellow and orange, respectively.

Figure 6

Effect of a third dose of an mRNA vaccine on anti‐SARS‐CoV‐2 antibodies and neutralising activity. (a) Titres of IgG antibodies against different full‐length recombinant SARS‐CoV‐2 proteins and their delta variants were measured in 32 SOT recipients using an ELISA before and after a third ‘booster’ dose of a COVID‐19 mRNA vaccine. (b, d) Neutralising activity before and after a third ‘booster’ dose of a COVID‐19 mRNA vaccine in the peripheral blood of the same SOT recipients. Green, orange and red areas indicate different degrees of inhibition (green, > 90%; orange, 30–89%; red, < 30%). (c) Titres of post‐booster IgG antibodies against the original anti‐SARS‐CoV‐2 RBD and S1 proteins vs. their omicron variants. Bars indicate median levels. Differences between groups were analysed for statistical significance (*P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001) using the Mann–Whitney U‐test.