Complete protection against severe acute respiratory syndrome coronavirus-mediated lethal respiratory disease in aged
Craig Fett1, Marta L DeDiego, Jose A Regla-Nava
1Department of Microbiology, University of Iowa, Iowa City, Iowa, USA.
Abstract:
Zoonotic coronaviruses, including the one that caused severe acute respiratory syndrome (SARS), cause significant morbidity and mortality in humans. No specific therapy for any human coronavirus is available, making vaccine development critical for protection against these viruses. We previously showed that recombinant SARS coronavirus (SARS-CoV) (Urbani strain based) lacking envelope (E) protein expression (rU-ΔE) provided good but not perfect protection in young mice against challenge with virulent mouse-adapted SARS-CoV (MA15). To improve vaccine efficacy, we developed a second set of E-deleted vaccine candidates on an MA15 background (rMA15-ΔE). rMA15-ΔE is safe, causing no disease in 6-week-, 12-month-, or 18-month-old BALB/c mice. Immunization with this virus completely protected mice of three ages from lethal disease and effected more-rapid virus clearance. Compared to rU-ΔE, rMA15-ΔE immunization resulted in significantly greater neutralizing antibody and SARS-CoV-specific CD4 and CD8 T cell responses. After challenge, inflammatory cell infiltration, edema, and lung destruction were decreased in the lungs of rMA15-ΔE-immunized mice compared to those in rU-ΔE-immunized 12-month-old mice. Collectively, these results show that immunization with a species-adapted attenuated coronavirus lacking E protein expression is safe and provides optimal immunogenicity and long-term protection against challenge with lethal virus. This approach will be generally useful for development of vaccines protective against human coronaviruses as well as against coronaviruses that cause disease in domestic and companion animals.
Insights
Developing an E protein-deleted SARS-CoV vaccine candidate (rMA15-ΔE) in mice proved safe and highly effective. This improved vaccine offers complete protection against lethal SARS-CoV challenge and enhances immune responses.
Area of Science:
- Virology
- Immunology
- Vaccinology
Background:
- Zoonotic coronaviruses, like SARS-CoV, pose significant public health threats due to high morbidity and mortality.
- The absence of specific therapies for human coronaviruses underscores the urgent need for effective vaccine development.
- Previous SARS-CoV vaccine candidates showed partial protection, necessitating further improvements in efficacy.
Purpose of the Study:
- To develop and evaluate a novel, highly attenuated SARS-CoV vaccine candidate with enhanced immunogenicity and protective capacity.
- To assess the safety and efficacy of an E protein-deleted SARS-CoV vaccine (rMA15-ΔE) across different age groups in mice.
Main Methods:
- Generation of a recombinant, E protein-deleted SARS-CoV (rMA15-ΔE) on a mouse-adapted virulent strain background.
- Safety assessment in BALB/c mice of varying ages (6 weeks, 12 months, 18 months) post-immunization.
- Evaluation of protective efficacy against lethal SARS-CoV challenge, including viral clearance, immune responses (neutralizing antibodies, T cells), and lung pathology.
Main Results:
- The rMA15-ΔE vaccine was found to be safe and caused no disease in mice across all tested age groups.
- Immunization with rMA15-ΔE conferred complete protection against lethal SARS-CoV challenge and accelerated viral clearance.
- rMA15-ΔE immunization induced significantly stronger neutralizing antibody and SARS-CoV-specific CD4/CD8 T cell responses compared to a previous vaccine candidate.
- Histopathological analysis revealed reduced lung inflammation and damage in rMA15-ΔE-immunized mice post-challenge.
Conclusions:
- Immunization with a species-adapted, attenuated coronavirus lacking E protein expression is a safe and effective strategy.
- The rMA15-ΔE vaccine candidate demonstrates optimal immunogenicity and provides long-term protection against lethal SARS-CoV challenge.
- This approach holds promise for developing broadly protective vaccines against human and animal coronaviruses.
