Blood samples from healthy individuals have pre-existing anti-SARS-CoV-2 IgGs and IVIg may be an effective therapy for severe COVID-19

By Dr. Liji Thomas, MDReviewed by Danielle Ellis, B.Sc.Nov 14 2022

A new paper introduces evidence of effective alleviation of disease severity using intravenous immunoglobulin (IVIg). This is in the form of immunoglobulin (Ig) G antibodies directed against the coronavirus disease 2019 (COVID-19) pathogen, namely, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Introduction

SARS-CoV-2 is a beta-coronavirus that can infect humans and other vertebrates, transmitted via respiratory droplets. It is one of only six pathogenic coronaviruses (CoVs), the others being 229E, NL63, HKU1, OC43, SARS, and MERS) in humans. Only the currently circulating virus, and the latter two, are associated with potentially severe disease, however.

The other four cause common cold, which is ubiquitous and has been occurring for hundreds of years. The corollary of this observation is that humans are very likely to carry Ig antibodies against these viruses.

There is a lack of effective therapies against this virus. The current study, published in Virology Journal, examines the utility of IVIg in COVID-19. Such therapy has already come into clinical use against a host of inflammatory diseases, including allergies, autoimmune and neurological diseases, and atopy, but also in the previous outbreaks of severe acute respiratory syndrome (SARS) and Middle East respiratory syndrome (MERS).

There is an urgent need to develop effective methods to mitigate the severity of COVID-19 in about 14% of patients who would otherwise develop severe or critical disease. An earlier study demonstrated the anti-inflammatory activity of IVIg in this condition, attributed to its ability to remove complement, block immune cell receptors and directly inhibit the virus.

The researchers in this study sought to look at whether cross-reactive antibodies are present in individuals before their exposure to the infection due to the presence of epitopes common to SARS-CoV-2 and the four common cold CoVs. They examined pre-existing Ig antibodies from healthy people for reactivity to conserved peptides taken from the viral spike (S) and membrane (M) proteins of the SARS-CoV-2.

The study took place from January 11 to February 28, 2020, including a small cohort of 23 patients who had severe COVID-19. All were admitted to the intensive care unit (ICU) in the same hospital. Nearly 200 healthy volunteers were also included in the study as controls, none of whom were positive for the virus.

The scientists picked similar 25 amino acid sequences from the S, M, and envelope € proteins of SARS-CoV-2 and the four common cold CoVs. When tested for reactivity with IVIg against SARS-CoV-2, they found three conserved peptides in the C-terminal domain (CTD) of the S protein and one from the M protein.

When samples from the healthy controls were examined for seropositivity, they found that over 80% had antibodies to at least one of the three conserved SARS-CoV-2 S peptides, and almost a third were seropositive for the conserved M peptide. This exceeded the rate of T cell positivity for the virus.

Again, females were much more likely to be seropositive for one of the peptides than males, at over 80% vs. 60%, respectively. Finally, individuals over 50 were seropositive for one specific peptide, at over 90%, vs. younger people.

What are the implications?

The implications of this work include the possibility of pre-existing immunity to SARS-CoV-2 in non-infected individuals in the form of antibodies to certain epitopes of the viral proteins. The identification of four conserved peptides to which the control samples were cross-reactive lead to this conclusion. “Thus, most people who have experienced the common cold may have immune memory for coronaviruses, especially those infected with the widespread 229E and OC43 coronaviruses.”

Other studies showed that healthy prepandemic populations did not contain SARS-CoV-2-specific antibodies. However, several reasons have been suggested for this discrepancy in results, indicating assay insensitivity and the use of only neutralizing antibodies in a single cell line rather than a broader detection of binding antibodies.

Secondly, the results corroborate several earlier studies showing that high doses of IVIg in severe COVID-19 patients can improve the clinical status in terms of oxygenation and lymphocyte count, reduced inflammation, and lower mortality rates compared to those who did not receive this therapy. Yet, other studies contradict these findings, indicating the need for further research. It is especially important to confirm the direct antiviral activity of IVIg in future studies.

Interestingly, older controls were more likely to be seropositive for the virus than younger ones, though age is a high-risk factor for COVID-19 severity. Further study is required to explain this finding, though it is possible that cross-reactive antibodies may block the binding site on the target cell and thus inhibit infection.

Future studies are needed to validate these results by examination of a large cohort of healthy individuals. These results could be precision medicine tools which can accelerate the understanding and treating of COVID-19.”