Abstract
Older individuals are at higher risk of SARS-CoV-2 infection and severe outcomes, but the underlying mechanisms are incompletely understood. In addition, how age modulates SARS-CoV-2 re-infection and vaccine breakthrough infections remain largely unexplored. Here, we investigated age-associated SARS-CoV-2 pathogenesis, immune responses, and the occurrence of re-infection and vaccine breakthrough infection utilizing a wild-type C57BL/6N mouse model. We demonstrated that interferon and adaptive antibody response upon SARS-CoV-2 challenge are significantly impaired in aged mice compared to young mice, which results in more effective virus replications and severe disease manifestations in the respiratory tract. Aged mice also showed increased susceptibility to re-infection due to insufficient immune protection acquired during the primary infection. Importantly, two-dose COVID-19 mRNA vaccination conferred limited adaptive immune response among the aged mice, making them susceptible to SARS-CoV-2 infection. Collectively, our findings call for tailored and optimized treatments and prevention strategies against SARS-CoV-2 among older individuals.
Keywords:
Age; COVID-19; SARS-CoV-2; immune breakthrough; re-infection; vaccination.
MeSH terms
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Age Factors*
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Aging / immunology
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Animals
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Antibodies, Viral / immunology
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COVID-19 / immunology*
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COVID-19 / pathology
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COVID-19 / prevention & control
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COVID-19 / virology
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COVID-19 Vaccines / administration & dosage
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COVID-19 Vaccines / immunology*
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Disease Models, Animal
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Disease Susceptibility
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Female
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Humans
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Immunity
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Mice
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Mice, Inbred C57BL
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Respiratory System / immunology
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Respiratory System / virology
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SARS-CoV-2 / genetics
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SARS-CoV-2 / immunology*
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SARS-CoV-2 / physiology
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Vaccination
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Virus Replication
Substances
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Antibodies, Viral
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COVID-19 Vaccines
Supplementary concepts
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COVID-19 breakthrough infections
Grants and funding
This work was partly supported by funding from the Health and Medical Research Fund [CID-HKU1-5, COVID1903010-14, and 20190652], the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region; the General Research Fund [17118621] of Research Grants Council, The Government of the Hong Kong Special Administrative Region; Health@InnoHK, Innovation and Technology Commission , the Government of the Hong Kong Special Administrative Region; National Natural Science Foundation of China Excellent Young Scientists Fund (Hong Kong and Macau) [32122001]; University of Hong Kong Li Ka Shing Faculty of Medicine Enhanced New Staff Start-up Fund; National Program on Key Research Project of China [grant number 2020YFA0707500 and 2020YFA0707504], the Consultancy Service for Enhancing Laboratory Surveillance of Emerging Infectious Diseases and Research Capability on Antimicrobial Resistance for the Department of Health of the Hong Kong Special Administrative Region Government, and Sanming Project of Medicine in Shenzhen, China [No. SZSM201911014]; the High Level-Hospital Program, Health Commission of Guangdong Province, China; and the research project of Hainan Academician Innovation Platform [YSPTZX202004]; and the donations of May Tam Mak Mei Yin, Richard Yu and Carol Yu, the Shaw Foundation Hong Kong, Michael Seak-Kan Tong, Lee Wan Keung Charity Foundation Limited, Hui Ming, Hui Hoy and Chow Sin Lan Charity Fund Limited, Chan Yin Chuen Memorial Charitable Foundation, Marina Man-Wai Lee, the Hong Kong Hainan Commercial Association South China Microbiology Research Fund, the Jessie & George Ho Charitable Foundation, Perfect Shape Medical Limited, Kai Chong Tong, Foo Oi Foundation Limited, Tse Kam Ming Laurence, Betty Hing-Chu Lee, Ping Cham So, and Lo Ying Shek Chi Wai Foundation. The funding sources had no role in the study design, data collection, analysis, interpretation, or writing of the report.