Antigenic imprinting of sarbecovirus

By Dr. Liji Thomas, MDOct 19 2020

The COVID-19 pandemic continues to cause economic and physical suffering worldwide, fueling the drive to bring out a vaccine that will allow control of the virus. A recent study published on the preprint server bioRxiv* in October 2020 shows that the design of a vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) must consider the prior history of exposure to coronaviruses since these affect the antibody response to the virus.

olorized scanning electron micrograph of an apoptotic cell (red) infected with SARS-COV-2 virus particles (yellow), isolated from a patient sample. Image captured at the NIAID Integrated Research Facility (IRF) in Fort Detrick, Maryland. Credit: NIAID

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources

History of Prior Immune Exposure Impacts Current Response

Previous studies have shown that in the case of influenza, a given vaccine has varying efficacy depending on the subject – whether the flu vaccine has been given previously or a history of natural flu infection. In both these scenarios, the common factor is exposure to the influenza virus, either the same or another strain.

The explanation is that prior exposure to the same or closely related antigens results in the awakening of immunological memory on a subsequent challenge by a similar antigen. The first exposure primed innate and adaptive immune elements to clear the antigen and activate clones of long-lasting memory cells that retain its memory. This then modulates the response to the second exposure - a phenomenon is called antigenic imprinting.

Similar results have been reported with the dengue virus and HIV. The fact that several zoonotic sarbecoviruses have the potential to cause future outbreaks, as well as the broadly reported prediction that SARS-CoV-2 may become a seasonal human coronavirus, lends urgency to the task of understanding and characterizing this phenomenon.

Testing Different Immunization Scenarios

The current study uses a mouse model, in which two strains of Sarbecovirus with different antigens were used for immunization in succession - SARS-CoV and SARS-CoV-2. They administered two such intraperitoneal immunizations, along with the Addavax adjuvant, to enhance immunogenicity.

Four patterns were used:

• Homologous prime-boost SARS-CoV immunization
• Heterologous SARS-CoV-prime, 68 SARS-CoV-2-boost
• Homologous SARS-CoV-2 prime-boost
• Heterologous SARS-CoV-2-prime, SARS-CoV-boost

The antibody titers and types were assessed on day 14 following the booster dose. As expected, the booster dose produced a higher antibody response, both binding and neutralizing in type, compared to the homologous priming dose. This demonstrates the role of induced immunological memory following the prime dose, which resulted in virus-neutralizing antibody generation after the booster was given.

Repeat Exposure to Same Virus Most Effective

One constant observation, regardless of the specific protocol, was that cross-reactive antibodies against the viral receptor-binding domain (RBD) were elicited in all four scenarios. However, the researchers also noted that homologous prime-dose regimens produced much stronger neutralizing antibody responses after the second dose was administered in all cases. Thus, following either SARS-CoV or SARS-CoV-2 prime, a boost of SARS-CoV or SARS-CoV-2 respectively resulted in the most robust response.

With only one round of immunization, a detectable neutralizing response was induced to either strain. However, the boost strain failed to produce such a response in the heterologous regimens.

The authors illustrate this, “While one round of SARS-CoV immunization was sufficient to elicit a detectable SARS-CoV neutralization response, a SARS-CoV neutralization response was undetectable when SARS-CoV was used as a heterologous boost after priming with SARS-CoV-2.”

Non-Neutralizing Response to Related Strains

The host receptor for both viruses is the angiotensin-converting enzyme 2 (ACE2). Typically, neutralizing activity is a function of the antibody's ability to compete with ACE2 for virus binding. Thus, the researchers performed plasma binding assays using the RBD and the RBD/ACE2 in the complex. They expected that in samples containing antibodies with a higher capacity to compete with ACE2 for binding the RBD, the reduction in binding to RBD/ACE2 complex should be higher than for the RBD alone.

Testing showed that for SARS-CoV RBD binding, the plasma from the mice that had received a priming dose of SARS-CoV showed greater ACE2 competition than from mice that were primed with SARS-CoV-2. Binding to SARS-CoV-2 RBD showed the same pattern, with mouse plasma from animals that were primed with SARS-CoV-2 showing a stronger Ace2 competition than those that were primed with SARS-CoV.

Implications

The researchers concluded, “These results indicate that the heterologous boost predominantly induces antibodies to conserved regions outside of the ACE2-binding site that has minimum neutralizing activity. One such example is CR3022, which has a strong cross-reactive binding activity to a conserved epitope on RBD, but has weak neutralization activity to SARS-CoV and undetectable neutralization activity to SARS-CoV-2.”

The study points to the importance of antigenic imprinting in modifying the antibody response to Sarbecovirus. The antibody response following immunization may be ineffective or lower than expected with a history of prior immune exposure to a Sarbecovirus strain that has different antigens or shows antigenic drift. This should be taken note of by investigators exploring vaccine design.

This news article was a review of a preliminary scientific report that had not undergone peer-review at the time of publication. Since its initial publication, the scientific report has now been peer reviewed and accepted for publication in a Scientific Journal. Links to the preliminary and peer-reviewed reports are available in the Sources section at the bottom of this article. View Sources