In a recent medRxiv* preprint paper, researchers from Mount Sinai in New York showed that all three major immunoglobulin isotypes (IgM, IgG, and IgA) produced by our immune cells were capable of mediating neutralization of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, neutralization titers correlated much better with binding levels of IgM and IgA1 than IgG.
The unfaltering coronavirus disease (COVID-19) pandemic, caused by SARS-CoV-2, is currently rampant in many countries, infecting millions of people and causing hundreds of thousands of fatal outcomes. Therefore, effective therapeutic and preventive options are desperately needed.
We know that cell entry of the virus depends on the receptor-binding domain (RBD) of the spike protein. Albeit previous studies identified anti-spike and anti-RBD antibodies as vital for protection and convalescent plasma as a promising therapeutic option, little is known about the exact immunoglobulin isotypes that can successfully block viral entry.
In the case of SARS-CoV-1 (i.e., a causative agent of the original SARS outbreak), high titers of mucosal IgA in the lungs were linked to reduced pathology upon viral challenge in animal models. It is not known whether the same is valid for SARS-CoV-2, and there is scarce data regarding the contribution of IgM to neutralize and protect against viruses in general.
Consequently, this new scientific endeavor by researchers from Mount Sinai in New York decided to appraise in detail spike- and RBD-specific Ig isotypes in sera/plasma from two individuals acutely infected with COVID-19 and 29 convalescent ones.
Evaluating neutralization properties
In this study, citrated plasma specimens of convalescent COVID-19 individuals destined for transfusion to acutely infected individuals were obtained from the Division of Transfusion Medicine of the Department of Pathology, Molecular and Cell-Based Medicine at the Icahn School of Medicine at Mount Sinai.
The SARS-CoV-2 antigens, prepared as a soluble recombinant trimerized form of the spike protein and a recombinant RBD protein, were coupled with uniquely labeled fluorochromes and ran in the Luminex binding antibody assay.
The SARS-CoV-2 pseudovirus, known as COV2pp, was used to ascertain the neutralization propensity of tested samples. In short, human embryonic kidney 293 cells transformed with a large T antigen were transfected to overexpress SARS-CoV-2 glycoproteins.
Neutralizing activity gradient
This study has demonstrated that spike and RBD-specific IgM, IgG1, and IgA1 antibody fractions were present in plasma or serum of all (or almost all) analyzed COVID-19 convalescent study subjects. Furthermore, they were also detected at exceptionally early stages of the infection (i.e., 7-8 days after disease onset).
The correlation of neutralizing activity was strongest with IgM antibodies, followed by IgA1 antibody isotypes; conversely, no correlation has been observed with IgG1 or other IgG isotypes.
"The lack of correlation between IgG1 binding titers and neutralization activities may be explained by the fact that the dominant IgG1 responses may target sites not critical for blocking virus entry", explain study authors.
But although these correlations can be considered important, direct testing of neutralizing activities of different isotypes revealed that neutralizing activity was displayed most potently by IgM and IgG, and less strongly by IgA antibodies.
Protective potential of immunoglobulins
This study unveiled the first evidence that purified plasma IgG, IgM, and IgA antibodies may indeed contribute to SARS-CoV-2 neutralization. Accordingly, such findings carry significant implications for using hyperimmune globulin for therapeutic or prophylactic purposes.
"These data indicate the protective potential of all three major immunoglobulin isotypes and suggest that induction of each of these isotypes by vaccination may offer optimal protection against infection", say study authors in their medRxiv study.
Furthermore, the results point towards the conclusion that measuring total immunoglobulin levels, rather than just IgG, would give us a much better outcome for establishing a diagnosis in the early stages of the disease.
All of this has important implications for future expansion of our diagnostic and therapeutic armamentarium against COVID-19. Hence, further studies should replicate these findings, but also include specific clinical data that has not been available for the subjects included in this study.
medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.