Real-world assessment of immunogenicity in immunocompromised individuals following SARS-CoV-2 mRNA vaccination: a one-year follow-up of the prospective clinical trial COVAXID

Abstract

Background: Immunocompromised patients have varying responses to SARS-CoV-2 mRNA vaccination. However, there is limited information available from prospective clinical trial cohorts with respect to long-term immunogenicity-related responses in these patient groups following three or four vaccine doses, and in applicable cases infection.

Methods: In a real-world setting, we assessed the long-term immunogenicity-related responses in patients with primary and secondary immunodeficiencies from the prospective open-label clinical trial COVAXID. The original clinical trial protocol included two vaccine doses given on days 0 and 21, with antibody titres measured at six different timepoints over six months. The study cohort has subsequently been followed for one year with antibody responses evaluated in relation to the third and fourth vaccine dose, and in applicable cases SARS-CoV-2 infection. In total 356/539 patients were included in the extended cohort. Blood samples were analysed for binding antibody titres and neutralisation against the Spike protein for all SARS-CoV-2 variants prevailing during the study period, including Omicron subvariants. SARS-CoV-2 infections that did not require hospital care were recorded through quarterly in-person, or phone-, interviews and assessment of IgG antibody titres against SARS-CoV-2 Nucleocapsid. The original clinical trial was registered in EudraCT (2021-000175-37) and clinicaltrials.gov (NCT04780659).

Findings: The third vaccine dose significantly increased Spike IgG titres against all the SARS-CoV-2 variants analysed in all immunocompromised patient groups. Similarly, neutralisation also increased against all variants studied, except for Omicron. Omicron-specific neutralisation, however, increased after a fourth dose as well as after three doses and infection in many of the patient subgroups. Noteworthy, however, while many patient groups mounted strong serological responses after three and four vaccine doses, comparably weak responders were found among patient subgroups with specific primary immunodeficiencies and subgroups with immunosuppressive medication.

Interpretation: The study identifies particularly affected patient groups in terms of development of long-term immunity among a larger group of immunocompromised patients. In particular, the results highlight poor vaccine-elicited neutralising responses towards Omicron subvariants in specific subgroups. The results provide additional knowledge of relevance for future vaccination strategies.

Funding: The present studies were supported by grants from the Swedish Research Council, the Knut and Alice Wallenberg Foundation, Nordstjernan AB, Region Stockholm, and Karolinska Institutet.

Keywords: COVID-19; Chronic lymphocytic leukemia; Clinical study; HIV; Haematopoietic stem cell transplantation; Primary immunodeficiency disease; SARS-CoV-2; Solid organ transplantation; mRNA vaccine.

Fig. 1

Dynamics of antibody titres of the COVAXID cohort. Epidemiology of prevailing SARS-CoV-2 subvariants in Sweden during the study period in relation to (A) number of verified SARS-CoV-2 infections (histogram) among study participants and (B) administration of third (shaded green cumulative histogram) and fourth (shaded blue cumulative histogram) mRNA vaccine doses. Below each graph, boxplots show the distribution of sample dates for each sampling timepoint. (C) Dynamics of Spike Ig RBD Ab titres (geometric mean with 95% CI) (shaded range) for each subgroup. The vertical dotted line represents the timepoint for the primary endpoint of the original clinical trial (35-day timepoint). (D) Fold change of Spike-RBD titres at each timepoint at a study group level. Values are normalized to the day 35-timepoint. Statistical tests were performed on paired Spike-RBD titres using Wilcoxon, and Bonferroni correction for multiple comparisons. (E) Seroconversion rates over time in each subgroup as defined by Spike RBD titres ≥0·8 AU/ml in the entire COVAXID cohort. Ab titres were quantified using the Roche-Elecsys platform. The star annotation (∗) indicates statistical significance at a p-value threshold of 0.05 (or ∗∗ for p < 0.01, ∗∗∗ for p < 0.001, ∗∗∗∗ for p < 0.0001). For sample sizes, please see Table 1. Whiskers for all box plots represents 1.5× IQR.

Fig. 2

Quantitative serological response in relation to number of vaccine doses and SARS-CoV-2 infection (COVID-19). (A) Box plot showing Spike Wu-Hu.1 stratified based on COVID-19 status as defined by prior positive COVID-19 test (PCR/RAT) and/or anti-nucleocapsid Ab titres >5000 AU/ml. Subgroup analysis of Spike Wu-Hu.1 Ab titres following three (B) and four (C) vaccine doses ordered by the mean Ab-titre levels in each subgroup. Only subgroups with more than five recorded samples are displayed. All Ab titres were quantified using V-PLEX Serology Panels (MSD). Statistical tests performed were Mann–Whitney with Bonferroni correction for multiple comparisons. The star annotation (∗) indicates statistical significance at a p-value threshold of 0.05 (or ∗∗ for p < 0.01, ∗∗∗ for p < 0.001, ∗∗∗∗ for p < 0.0001). For sample sizes, please see Table 1. Whiskers for all boxplots represents 1.5× IQR.

Fig. 3

Antibody titres and neutralising capacity of SARS-CoV-2 Omicron in relation to number of vaccine doses and SARS-CoV-2 infection (COVID-19). Ab titres (A) and neutralizing capacity (B) of SARS-CoV-2 variants at the 12-month timepoint (left) showing individual samples as blue connected lines, and mean value across SARS-CoV-2 variants (orange line), and correlation matrices (Pearson correlation) of Ab titres for analysed SARS-CoV-2 variants (right) with correlations between Omicron-variants and non-Omicron variants in highlighted (black rectangle) areas. (C) Box plot showing neutralisation of individual samples, grouped based on COVID-19 status as defined by prior positive COVID-19 test and/or Nucleocapsid Ab titres >5000 AU/ml. Neutralisation was quantified using V-PLEX Serology Panels with an ACE2 surrogate virus neutralisation kit (Meso Scale Diagnostics, MSD). (D–G) Neutralisation of Spike Wu-Hu.1 and Spike BA.1 following three or four vaccine doses in each patient subgroup, ordered by their respective mean neutralizing capacity. Only subgroups with more than five recorded samples are displayed. Statistical tests performed were Mann–Whitney with Bonferroni correction for multiple comparisons. The star annotation (∗) indicates statistical significance at a p-value threshold of 0.05 (or ∗∗ for p < 0.01, ∗∗∗ for p < 0.001, ∗∗∗∗ for p < 0.0001). For sample sizes, please see Table 1. Whiskers for all boxplots represents 1.5× IQR.

Fig. 4

Prospective risk for SARS-CoV-2 infection and COVID-19 severity in relation to antibody titres. (A) Ab titres at 3-, 6-, and 9-months in patients without a prior history of COVID-19 (and Nucleocapsid Ab titres <5000 AU/ml) in relation to later development of COVID-19. Statistical test performed were Mann–Whitney U test. Correlation between Wu-Hu.1 (B) or BA.1 (C) reactive Ab titres at different sampling timepoints and future COVID-19 severity. Statistical tests performed were Spearman correlation. For sample sizes, please see Table 1. Whiskers for all boxplots represents 1.5× IQR.