IgG3 Antibody Response to COVID-19 Vaccination in a Patient With a Large Heavy Chain Deletion

Abstract

Vaccinations for pathogenic organisms have been utilized for decades in both the protection and diagnosis of immunodeficiency patients. Some of these immunodeficient patients may not create an adequate response to vaccination, although some who have significant aberrancies in their immune system may surprisingly create antibodies to immunizations. We present a patient with a large Ig heavy chain deletion (severe deficiency of serum IgG1, IgG2, IgG4, and IgA1) that showed a considerable response (presumably through IgG3) after the Pfizer BioNTech COVID-19 vaccination. This finding in this unique immunodeficient patient warrants further research into alternate antibody response pathways against COVID-19.

Introduction

Multiple immunologic and genetic variables are at the forefront of a host's response to vaccinations. ¹ There have been many technological innovations to evaluate a host's response to vaccination, one of which is through direct antibody titer detection. ² A protective antibody titer is generated by a series of interactions between the vaccine delivery and immunological support. ¹ The production of antibodies is vital in the adaptive immune system for fighting off recurring infections. The inability to isotype switch or the complete absence of B Cells can both cause an antibody insufficiency. A deletion of portions or the entire Ig heavy chain is another cause of the failure of an Ig antibody response as this segment is crucial in antibody production. ¹ A deficiency of this immune pathway could disrupt antibody response to the vaccination. ³ Alternate pathways may be theorized in the context of a severe immunodeficiency phenotype that has surprisingly created an immune response to a pandemic organism. We present a patient with a large immunoglobulin heavy (IgH) constant region deletion of Cγ1, Cα1, ΨCγ, Cγ2, and Cγ4 (Figure 1) with deficient serum levels of IgG1, IgG2, IgG4, and IgA1, who preferentially created antibodies to COVID-19 vaccine through IgG3.

Figure 1.

Map of the human Ig heavy chain locus in germline configuration. The box demonstrates the large deletion found in the described patient.

Case Presentation

We present a 66-year-old male with a known history of a large IgH chain deletion diagnosed 15 years prior to presentation. ¹ The diagnosis was preceded by a concern for primary immunodeficiency and lab studies revealing low serum levels of IgG1, IgG2, and IgG4 (Figure 1). The patient reported having recurrent upper and lower respiratory tract infections since childhood. Although recurrent, the infections were never life-threatening nor did they require hospitalization. The patient's serum immunoglobulin studies revealed deficient serum levels of IgG1, IgG2, and IgG4, while IgG3 levels were significantly elevated at the time of diagnosis (Table 1). ¹ The status of the Ig heavy chain genes was previously examined by means of Southern blotting of genomic DNA isolated from EBV-transformed B cells. ¹

Table 1.

Serum Immunoglobulin Levels Demonstrating Lack of IgG1, IgG2, IgG4, and IgA1 in Described Patient.

Ig isotype	Patient	Control
IgG (mg/dL)	437	625-1319
IgA (mg/dL)	317	72-321
IgM (mg/dL)	216	44-247
IgE (mg/dL)	158	5-79
IgG1 (mg/dL)	<1	271-1010
IgG2 (mg/dL)	<1	104-570
IgG3 (mg/dL)	522	14-133
IgG4 (mg/dL)	<1	4-71
IgA1 (mg/dL)	1.2	57-321
IgA2 (mg/dL)	650	5-82

He was vaccinated with tetanus toxoid and polyvalent pneumococcal vaccine (Pneumovax) in which he had a poor antibody response. ¹ Further evaluation noted that despite the poor response to pneumovax, the patient's protective response leading to his good health was due to IgG3 antibodies against anti-PspA family 1, anti-PsaA, and anti-pneumolysin. These are three pneumococcal virulence proteins that have been found to be protective in mice models ¹ and are now seen as protective in this patient. These results can be found in the original description of the case. ¹ Due to the lack of severe infections, this patient has never received any long-term treatment other than medications for acute infections. The most recent serology and Ig isotype studies of this patient in August of 2021 were similar to the initial studies at diagnosis with decreased IgG, IgG1, IgG2, IgG4, and IgA1 levels, followed by the presence of tetanus antibodies. ¹ The patient was later recommended to receive the COVID-19 vaccination series. Five months after completing the second dose of BioNTech 162b2 mRNA COVID-19 vaccine, the patient's qualitative serum studies showed reactivity to SARS-CoV-2 spike total antibody titers. His response to this vaccine was most likely the result of IgG3 production to the coronavirus spike protein.

Discussion

The body's ability to produce antibodies to a wide spectrum of antigens is promoted by germline variance, resulting from high gene duplication and point mutations. These genes are, therefore, susceptible to a high frequency of insertion and deletion events possibly leading to a large Ig heavy chain deficiency. ⁴ Large Ig heavy chain deficiencies are very rare in the population and have been seen as an incidental finding. ¹ Part of this finding is due to their lack of serious infections. ¹ The significance of this patient's response with known IgH chain deletion shows that there may be alternative methods of protective antibody production in patients with deficient IgG1, IgG2, IgG4, and IgA1 levels, largely through IgG3 production. His response to the COVID-19 vaccine shows a potential benefit of vaccination in these rare large heavy chain deletions.

We describe the antibody response to the COVID vaccinations in a patient with a large deletion of the constant heavy chain of immunoglobulin. The deletion only allows for an IgG3 response although an IgA2 response should have occurred as well. The subsequent anti-COVID antibody determination after vaccination was specific for IgG/IgM and not IgA. The authors assumed that since the measurement was after the second vaccine dose, the response would have been IgG3. Unfortunately, at the time of the patient's presentation, an anti-COVID antibody of the IgA isotype was not available commercially nor was it available in a laboratory in the United States. Shipping of biological products overseas was not possible during the pandemic.

The point of the manuscript was to show that an antibody response to the COVID vaccine was possible in a patient with a rare heavy chain gene deletion that would only allow an IgG3 response. Although an IgA response would have been interesting those capabilities at the time were not available.

Declarations