Health

Nucleocapsid-based vaccines may prevent SARS-CoV-2 dissemination to distal organs

A team of scientists from the University of Illinois and Northwestern University, Chicago, USA, has recently investigated and compared the efficacy of spike-based and nucleocapsid-based coronavirus disease 2019 (COVID-19) vaccines in mice infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Their findings reveal that nucleocapsid-based vaccines are effective in preventing SARS-CoV-2 infection in distal organs, such as the brain. The study is currently available on the bioRxiv* preprint server.

Background

As of April 27, 2021, globally, there have been 146 million cases of confirmed COVID-19, including 3.1 million deaths, registered to the World Health Organization (WHO). To tackle the rapid viral spread and its devastating impact on the global economic and healthcare structures, several prophylactic vaccines have been made at record speed, in addition to repurposing and developing therapeutic interventions. According to the WHO record, so far, about 933 million doses of COVID-19 vaccines have been administered globally.

Because of robust immunogenicity, the spike glycoprotein of SARS-CoV-2 is considered to be the most potent target for developing COVID-19 vaccines. Many vaccines containing spike protein as an antigen are currently rolling out globally and showing good efficacy in preventing symptomatic and asymptomatic infections and mortality. These vaccines are particularly effective in inducing robust neutralizing antibody response, which in turn is necessary to prevent the progression of SARS-CoV-2 infection at the proximal site of challenge, such as the respiratory system. However, it is still not known whether these vaccines can prevent viral dissemination to the distal organs, such as the brain.

In the current study, scientists have investigated the efficacy of nucleocapsid-based, spike-based, and a combination of nucleocapsid-based and spike-based vaccines in preventing viral dissemination in SARS-CoV-2-infected mice.

Study design

The study was conducted on mice expressing human angiotensin-converting enzyme 2 (ACE2) receptor in the epithelial cells. The mice were intramuscularly injected with adenovirus-based vaccines containing SARS-CoV-2 spike protein, nucleocapsid protein, or both.

After 3 weeks of immunization, peripheral blood mononuclear cells were collected from the mice to detect spike- and nucleocapsid-specific CD8+ T cells. In addition, serum samples were collected to estimate SARS-CoV-2 specific binding antibody titers.  

Afterward, the immunized mice were infected with SARS-CoV-2, and the viral load was estimated at the proximal (lungs) and distal (brain) infection sites.

Important observations

Regarding vaccine immunogenicity, the findings revealed that both spike-based and nucleocapsid-based vaccines are capable of inducing CD8+ T cell response and SARS-CoV-2 specific antibody response in mice.

To determine the vaccine efficacy, acute viral loads were estimated in the lung and brain tissues of vaccinated mice 72 hours after the intranasal challenge with SARS-CoV-2. As experimental controls, viral loads were also detected in the tissues of unvaccinated but SARS-CoV-2-infected mice.

The findings revealed that the viral load increased significantly in the lungs of unvaccinated mice, followed by viral dissemination to the brain. Interestingly, spike-based vaccines showed significantly higher antiviral protection in the lungs than nucleocapsid-based vaccines. However, no synergistic protection was observed in the lungs of mice immunized with both spike-based and nucleocapsid-based vaccines. These observations indicate that spike-based vaccines provide the highest level of protection against viral entry and propagation in the respiratory tract.

Regarding protection against viral dissemination, the findings revealed that mice immunized with spike-based or nucleocapsid-based vaccines have lower viral loads in the brain tissues compared to that in unvaccinated mice. However, a significant reduction in brain viral load was observed in mice immunized with both spike-based and nucleocapsid-based vaccines. These observations indicate that nucleocapsid-based immunity might be essential for preventing viral propagation to distal organs, such as the brain.

Study significance

The study findings reveal that apart from spike protein, other structural proteins of SARS-CoV-2, including the nucleocapsid protein, can be potentially targeted as a vaccine antigen. While spike-specific immunity is indispensable for preventing viral entry or neutralizing the virus at an early stage of infection, nucleocapsid-specific immunity might play a vital role in preventing further propagation of the infection.

Previous studies have shown that antibody-mediated immune responses ensure virus neutralization in the proximal infection site. However, once the infection is established, T cell-mediated immune responses act as a second line of defense to prevent viral dissemination to distal sites. Thus, nucleocapsid-induced T cell responses and spike-induced antibody responses may synergistically improve the overall efficacy of COVID-19 vaccines.

*Important Notice

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.

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