The immune reaction to SARS-CoV-2 plays a crucial role in how severe COVID-19 becomes. Recent studies have begun to shed light on the antibody responses elicited by this virus. While some of these findings are from preprint articles that haven't undergone peer review yet, they collectively enhance our understanding of the varied immune responses to SARS-CoV-2.

Grasping the nature of the antibody response is vital for assessing whether exposure leads to immunity, the duration of that immunity, and the methods to test for it. Furthermore, differences in these antibody responses could potentially influence the severity of the disease, a phenomenon known as antibody-dependent enhancement (ADE).

Rapid Emergence of IgG Antibodies

Suthar and colleagues investigated the immune response to the viral protein that binds to human cell receptors. This protein, known as the Spike (S) protein, contains a region called the receptor-binding domain (RBD) that interacts with ACE2, the receptor on human cells. This S protein is what gives coronaviruses their crown-like appearance in visual representations.

All coronaviruses possess an S protein, but the specific amino acid sequences vary among different strains. The virus most closely related to SARS-CoV-2 is SARS-CoV, sharing only 73% of its amino acid sequence in the S protein.

Additionally, these proteins undergo glycosylation, a process where sugars are added by enzymes within infected cells. The glycosylation patterns can differ among various coronaviruses, contributing to the lack of cross-immunity; thus, infection with one coronavirus does not guarantee immunity against another. Despite the differences, some components of these proteins may be similar enough to elicit cross-reactive antibodies, allowing prior exposure to a coronavirus to generate some immunity against SARS-CoV-2. Notably, there are four common coronaviruses that infect humans: HCoV-HKU1, HCoV-OC43, HCoV-NL63, and HCoV-229E.

The focus on antibodies against the S protein is due to its exposure on the virus's surface. Antibodies targeting the RBD can block the virus from entering human cells, essentially neutralizing it.

A significant aspect of the research by Suthar and colleagues was their examination of IgG antibodies, one of five types of antibodies identified by their heavy chains. The heavy and light chains of these antibodies collaborate to identify foreign proteins.

IgM antibodies are the first responders to a new pathogen, while IgG antibodies are produced upon re-exposure. By tracking IgG antibodies that target the RBD of the S protein, Suthar and his team focused on the antibodies most likely to confer immunity.

Initially, they assessed the RBD antibodies in 44 COVID-19 patients, using blood plasma samples from 12 healthy individuals collected prior to the pandemic as a control group. The researchers produced the RBD from the S protein, isolating a segment (amino acids 319 to 541) to test patient serum for binding capabilities. Their assays identified the types of antibodies present.

Among the 44 patients, 36 exhibited detectable RBD-specific IgG antibodies, with variable quantities noted across samples. Antibody levels are quantified as "titers," indicating how much a sample can be diluted before losing detectability. The IgG RBD titers among the 36 patients varied widely, from under 100 to 142,765.

Interestingly, some patients displayed higher levels of IgM antibodies targeting the RBD than IgG antibodies, while others exhibited the opposite. This observation is noteworthy, as the proportion of antibody types changes in response to viral exposure over time.

Initially, IgM antibodies are produced, followed by a switch in B cells to generating IgA or IgG antibodies. IgM and IgG circulate in the bloodstream, while IgA is primarily found in mucus. Thus, lower levels of IgA compared to IgG or IgM in blood samples are expected, as are instances of higher IgM levels than IgG.

The first antibodies to appear upon initial infection are IgM. Consequently, individuals experiencing their first SARS-CoV-2 infection within roughly two weeks of symptom onset would show high IgM levels with minimal detectable IgG.

The presence of high IgG levels alongside low IgM titers raises several possibilities: - The patients may be in the later stages of their first infection, with B cells primarily producing IgG. - The individuals could be experiencing a secondary response due to prior exposure to SARS-CoV-2, consistent with reports of asymptomatic cases testing positive. - Memory B cells from previous coronavirus infections could be generating cross-reactive IgG antibodies against SARS-CoV-2.

Given the varying symptom durations among study participants, some may have been experiencing their first SARS-CoV-2 infection while others were responding to a subsequent exposure. Patient testing occurred at different intervals, with some exhibiting RBD IgG antibodies as soon as two days after testing positive for COVID-19. Such early detection of IgG antibodies is atypical, assuming that symptom onset aligns with viral exposure.

Neutralizing Antibodies Against SARS-CoV-2

Another critical component of Suthar and colleagues' study involved assessing the patients’ antibodies for their ability to neutralize the virus. This was done by mixing diluted plasma samples with SARS-CoV-2 and infecting cultured cells with the mixture. Among the 44 patients, 40 demonstrated neutralizing antibodies in their plasma.

The quantity of neutralizing antibodies varied significantly, with some samples only able to be diluted 55 times, while others could withstand dilution up to 5,763 times.

It is important to note that not all antibodies against a virus are neutralizing; some may target viral proteins not exposed on the virus's surface, becoming visible when infected cells are attacked by the immune system. Others may bind to surface proteins but fail to block viral entry or replication in cells. Thus, simply detecting antibodies against a viral protein does not guarantee that they are neutralizing.

Predicting Neutralizing Antibodies from RBD-Specific IgG Titers

To explore whether RBD-specific IgG antibodies could reliably predict neutralizing activity, the researchers analyzed a larger cohort of 231 confirmed COVID-19 patient samples collected within 22 days of testing positive for the virus. These samples were categorized based on the time elapsed since testing positive.

The researchers examined the correlation between RBD-specific antibodies and neutralizing antibody activity across these groups. Their findings suggested that this antibody test had a negligible false positive rate and produced no false negatives, indicating its potential as a reliable means of assessing immunity to SARS-CoV-2.

This research has significant implications for timing antibody testing in individuals. It also raises the possibility that some hospitalized COVID-19 patients may not be encountering the virus for the first time; rather, they could be mounting a secondary response dominated by IgG from a previous asymptomatic infection or an infection with another coronavirus.

It is essential to highlight that this study did not evaluate whether these antibodies provide protection against subsequent exposures or mitigate disease severity. Furthermore, not all COVID-19 patients exhibited detectable antibodies; out of the 44 initially assessed, 8 lacked detectable antibodies. These individuals may have been tested before their antibody levels had risen, or their antibodies may not have recognized the S proteins, evading detection in the assay. The study in question is a preprint and has yet to undergo peer review.

Highlighted Article

13. 19. Suthar, et al., Rapid Generation of Neutralizing Antibody Responses in COVID-19 Patients. MedRxiv 2020.05.03.20084442 (8 May 2020). https://doi.org/10.1101/2020.05.03.20084442

Also of Interest

Interferon Responses Could Explain Susceptibility to Severe COVID-19 Impaired or delayed antiviral signaling could be a treatable cause of serious COVID-19.

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