Discussion
SARS-CoV-2 infection, CLL, immunocompromising disorders, CVID, subvariants, infection, XLA
CLL, VIRUS, SARS-COV-2 INFECTION, DISEASE, CVID, INFECTION, BONE INFECTION, IMMUNODEFICIENCY DISORDERS
Longitudinal clinical studies addressing immunity in large groups of immunocompromised patients in a real-world setting, taking vaccination as well as infection into consideration, are scarce. Such studies serve the purpose of addressing the dynamics (temporal) of antibody binding titres as well as neutralizing titres in a comparative fashion among different immunocompromised patient groups and subgroups. Here, we report one-year results from such a study, based on a study cohort derived from the original open-label, prospective, clinical trial COVAXID. The results reveal that most of the immunocompromised patient subgroups who responded poorly following the initial two doses of the BNT162b2 mRNA vaccine develop significant binding antibody titres against both the Wu-Hu.1 ancestral strain and Omicron variants following subsequent booster vaccine doses, and in applicable cases SARS-CoV-2 infection. However, while several of the study groups developed neutralizing antibody responses towards the ancestral strain, markedly lower responses were observed towards Omicron subvariants. Notably, Omicron-specific neutralisation increased after a fourth dose as well as after three doses and one infection in many of the patient groups.In terms of long-term antibody responses to SARS-CoV-2 mRNA vaccination, our data grossly identifies three classes of immunocompromised patients broadly defined by their serological response patterns; 1) strong responders, e.g., patients having undergone HSCT and PLWH, 2) poor responders, e.g., patients having undergone SOT and treated with MMF, patients with CVID, and patients with CLL treated with ibrutinib, and 3) non-responders, e.g., patients with XLA. The “strong responders” showed responses equivalent to healthy controls over time. Although patients having undergone HSCT are still recommended to follow certain health-related precautions, we did not observe a compromised long-term antibody response following repeated vaccinations. The latter, most likely due to their reconstituted immune system over time. The “poor responders” comprise of a diverse group of patients. Many of the poorest responders were patients undergoing concurrent immunosuppressive treatment during vaccination. Some of these patient groups may benefit from repeated and/or more frequent vaccinations. The “non-responders” are incapable of responding with antibody responses due do their underlying disease. Importantly, some of these patients have been shown to generate strong T-cell mediated response following vaccination.Notably, study participants included in the present real-world study were subject to necessary clinical interventions due to their specific medical conditions. The latter has included therapeutic interventions with immunoglobulin replacement therapy (IGRT), affecting antibody titres in some patient groups (A strength of the present study is that data were analysed from a well-defined patient cohort based on the original clinical trial COVAXID, with set inclusion and exclusion criteria as well as independent study monitoring of data, all of which contributed to data quality. Another strength of the study is that patient groups were followed from a timepoint when they were SARS-CoV-2- and vaccination-naïve through the emergence of updated national vaccination schedule regimens and in parallel risk for exposure to multiple new SARS-CoV-2 variants, all of which together provided the possibility for a complete and comprehensive longitudinal serological assessment of the study cohort in a real-world setting. The number and frequency of study participant samplings, as well as the ability to directly compare results across subgroups and corresponding different immunodeficiency disorders, provided additional strength to the study. With respect to limitations, as mentioned the individual patients had access to the third and fourth vaccine doses based on priority as recommended by the Public Health Agency of Sweden, i.e., not as part of a pre-defined clinical schedule. Furthermore, while most patients received the mRNA BNT162b2 (Pfizer/BioNTech) vaccine, some received the mRNA1273 (Moderna) vaccine for their third and/or fourth doses (In conclusion, the present results provide a detailed comparative assessment of immunogenicity in several groups of immunocompromised patients following the third and fourth doses of mRNA vaccine as well as the result of SARS-CoV-2 infection in a real-world setting. The overall results should be generalizable to similar patient groups at other sites, in part since they mimic findings from other studies published. Proactive measures with continuously repeated vaccinations in vulnerable patient groups, despite seroconversion and significant antibody titres against the presently dominant virus strain, may still be beneficial as it could provide a degree of cross-reactivity in case of substantial mutations in future SARS-CoV-2 variants. Additionally, individuals with immunocompromising disorders might benefit from updated vaccines that target Omicron new subvariants and possible future new emerging SARS-CoV-2 variants-of-concerns. Taken together, the present data add additional information serving to improve the management of immunocompromised patients, many of which represent risk groups for severe COVID-19.