Immunological Response to SARS-CoV-2 in Primary Immunodeficiency

Primary immunodeficiencies (PIDs) encompass a heterogeneous group of genetic disorders characterised by impaired development or function of key components of the immune system. The response to SARS-CoV-2 in individuals with PID reflects this diversity, ranging from absent or weak antibody production to variable T cell reactivity. B cell defects, such as X-linked agammaglobulinaemia, typically lead to negligible neutralising antibody titres against the viral spike protein, whereas disorders affecting T cell maturation may compromise antiviral cytotoxicity and helper functions. Despite these deficits, some patients demonstrate compensatory innate or residual adaptive responses, including natural killer cell activity and non-canonical B cell pathways. Vaccination strategies with mRNA-based or viral vector platforms elicit divergent outcomes: certain PID subgroups mount binding antibody responses but fail to generate high-affinity memory B cells, while others exhibit robust T cell–mediated immunity in the absence of seroconversion. Passive immunotherapy, including immunoglobulin replacement and convalescent plasma, has provided proof of principle for antibody-mediated protection, even when neutralisation in vitro appears limited. Understanding the interplay between humoral and cellular immunity in PID is essential to tailor vaccination schedules, optimise prophylactic antibody use and guide emerging antiviral treatments, with the ultimate goal of reducing morbidity and mortality in this vulnerable population.

Research from Nature Portfolio

Recent clinical investigation in a patient with X-linked agammaglobulinaemia demonstrated that antiviral therapy can substitute for absent humoral immunity to achieve viral clearance. In this case report, treatment with a nucleotide analogue was temporally associated with resolution of persistent pneumonitis and cessation of viral shedding, despite the patient’s inability to mount a specific antibody response. The study provided in vivo evidence of direct antiviral efficacy and highlighted the complementary role of T cells and innate mechanisms in controlling infection when B cell–derived antibodies are absent. This work underlines the potential for targeted antivirals to fill critical gaps in immune defence among individuals lacking functional B cells.

Immunological Response to SARS-CoV-2 in Primary Immunodeficiency publication trend

The graph below shows the total number of articles in immunological response to sars-cov-2 in primary immunodeficiency across all publications each year (not limited to Nature Index journals).

Technical terms

Primary immunodeficiency (PID): A genetic disorder leading to defective development or function of components of the innate or adaptive immune system.

Neutralising antibody: An antibody that binds a virus and prevents its entry into host cells, thereby blocking infection.

Memory B cell: A long-lived B lymphocyte that has been primed by antigen exposure and can rapidly produce high-affinity antibodies upon re-encounter.

Passive immunity: Protection conferred by the transfer of preformed antibodies, such as immunoglobulin replacement or convalescent plasma, rather than by eliciting an endogenous immune response.

Fc effector function: Mechanisms by which the Fc region of an antibody recruits immune cells (for example, via Fcγ receptors) to destroy pathogens or infected cells.

References

1. 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. EBioMedicine (2023).
2. Immunoglobulin replacement products confer in vivo protection against SARS-CoV-2 XBB.1.5 Omicron variant despite poor neutralizing activity. JCI Insight (2024).
3. Immune Responses 6 Months After mRNA-1273 COVID-19 Vaccination and the Effect of a Third Vaccination in Patients with Inborn Errors of Immunity. Journal of Clinical Immunology (2023).
4. Treatment of COVID-19 with remdesivir in the absence of humoral immunity: a case report. Nature Communications (2020).