Serologic assays in patients reveal the magnitude and kinetics of the humoral immune response, identifying different viral proteins that are specifically targeted; this enriches our current understanding of the host response to viruses.
The coronavirus disease-19 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is spreading rapidly, with many unknown immune reactions varying in differently-affected clusters of people.
In a recent bioRxiv* preprint paper, Jenna J. Guthmiller et al., focus on the acute infection of SARS-CoV-2 and observe that the humoral immunity is distinctive with the infection stage and viral antigens. The cohorts of the study included acutely infected patients and those recovering from the illness. The humoral immunity in patients generates a range of antibodies against many structural (spike glycoproteins, membrane glycoproteins, envelope, and nucleocapsid (N) proteins) and non-structural viral proteins. The magnitude and severity of this humoral immune response to SARS-CoV-2 are not completely clear to date.
Transmission electron micrograph of SARS-CoV-2 virus particles, isolated from a patient. Image captured and color-enhanced at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID
To address this critical knowledge gap that would help better understand the infection process, the researchers focused on the antibody response against viral proteins, the memory B cell response, and the binding affinity between the wild type and mutant strain of the virus.
Out of the 8 SARS-CoV-2 antigen-proteins tested in this study, antibodies were present against at least one or more. Everyone had a mounting response to the spike and N protein of the virus. A specific response towards spike was predominant in recovering patients. However, in the case of acute infection, it is found that the anti-N protein antibody response was dominant. The N protein encapsulates the SARS-CoV-2 genomic RNA, which ranges from 26-32 kB in size – being the largest known RNA virus. The excess presence of N proteins compared to the spike trimers may be the reason for the immunodominance during the peak severity of the infection. It is also found that the convalescent patients with higher antibody response against multiple antigens tended to have a more severe infection. Increased severity of infection is linked to increased antibody titers.
Patients who have high antibody response against multiple SARS-CoV-2 antigens tend to have a more severe infection. Interestingly, the high antibody response mounted a larger memory B cell response against the spike protein, but not the nucleocapsid protein.
The virus carrying a mutation in the spike proteins became the dominant circulating strain globally in early April. In this study, researchers also showed that the mutation acquired by this virus (D614G) is not a major antigenic site because there was no difference found in the immune response to both the wild type and mutant strains, especially in the acute-patients cohort. This raises a question as to how the recent mutation helps the virus invade host cells successfully. Again, in the case of the convalescent cohort, a large response against the variant was observed though they were likely infected with the wild type strain. This could potentially be due to the increased stability of the variant; this throws important information about the SARS-CoV-2 mutants for our research and therapeutic trials. This imperative finding in this study points to the strong positive correlation between variant strains, indicating that the antibodies against the WT strain are likely protecting against the new variant.
To further explore the humoral response, antibodies were reacted with other pandemic threat coronaviruses; it showed a correlation between SARS-CoV-1 and SARS-CoV-2, but not MERS-CoV, indicating that closely related coronaviruses with conserved epitopes cross-reacted to trigger a large antibody response.
The CD4 T cells, critical for driving antibody responses by mediating germinal center selection of antigen-specific B cells, demonstrate an increased response in patients with severe infection. This could be leading to the spread-out antibody response observed in this study. People who lost their lives to this infection had no germinal centers for antigen-specific B cells and no CD4 T follicular helper cells.
The significance of the findings
The rapid spread of this infection across worldwide calls for a detailed understanding of the host-virus interaction and the immune responses, for development towards accelerated progress of vaccines.
This study defines the specificities of the humoral response in patients severely affected with SARS-CoV-2 and those recovering from it. It is important to assess the role played by the specific antibody responses for a successful vaccine. All the people in the study were found to have antibodies; the immunodominant epitopes of the viral antigens are identified, and a larger magnitude of circulating antibody and MBC response are linked with the severity of the infection. Also, an increased viral antigen binding with different viral antigens is observed here.
Overall, a robust antibody response in patients initiated a good response against the antigens. This study expands our limited understanding of the humoral immune response in SARS-CoV-2 infection by drawing attention to the specific antigens, their kinetics, and their relation to the magnitude of the response and infection. This also helps us in planning to prevent future pandemics caused by such viruses.
bioRxiv 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.
- SARS-CoV-2 infection severity is linked to superior humoral immunity against the spike, Jenna J. Guthmiller, Olivia Stovicek, Jiaolong Wang, Siriruk Changrob, Lei Li, Peter Halfmann, Nai-Ying Zheng, Henry Utset, Christopher T. Stamper, Haley L. Dugan, William D. Miller, Min Huang, Ya-Nan Dai, Christopher A. Nelson, Paige D. Hall, Maud Jansen, Kumaran Shanmugarajah, Jessica S. Donington, Florian Krammer, Daved Fremont, Andrzej Joachimiak, Yoshihiro Kawaoka, Vera Tesic, Maria Lucia Madariaga, Patrick C Wilson; bioRxiv 2020.09.12.294066; doi: https://doi.org/10.1101/2020.09.12.294066.