Age-associated SARS-CoV-2 breakthrough infection and changes in immune response in a mouse model

Chen, Yanxia; Li, Can; Liu, Feifei; Ye, Zhanhong; Song, Wenchen; Lee, Andrew Chak-Yiu; Shuai, Huiping; Lu, Lu; To, Kelvin Kai-Wang; Chan, Jasper Fuk‐Woo; Zhang, Anna Jinxia; Chu, Hin; Yuen, Kwok‐Yung

doi:10.1080/22221751.2022.2026741

Cited by 42 publications

(34 citation statements)

References 44 publications

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“…Indeed, vaccinated aged mice elicited lower level of immune responses compared to vaccinated young mice, which were found to be due to a low frequency of IgG- and IFN- γ -secreting cells in vaccinated aged mice [33]. These results were parallel to previous findings that older individuals have lower immune responses to approved COVID-19 vaccine than younger individuals [10, 12, 33, 34]. Specially, lower serum IgG levels of SARS-CoV-2 in elderly peoples were from a lower proportion of peripheral spike-specific memory B cells [12].…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 S1 Subunit Booster Vaccination Elicits Robust Humoral Immune Responses in Aged Mice

Kim

Khan

Ferrari

et al. 2022

Preprint

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Currently approved COVID-19 vaccines prevent symptomatic infection, hospitalization, and death of the disease. However, the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants raises concerns of reduced vaccine effectiveness and increased risk of infection. Repeated homologous booster in elderly individuals and immunocompromised patients is considered to solve severe form of disease caused by new SARS-CoV-2 variants but cannot protect completely against breakthrough infection. In our previous study we assessed the immunogenicity of an adenovirus-based vaccine expressing SARS-CoV-2-S1 (Ad5.S1) in mice, resulting in that a single immunization with Ad5.S1, via subcutaneously injection or intranasal delivery, induced robust humoral and cellular immune responses. As a follow up study, here we showed that vaccinated mice had high titers of anti-S1 antibodies at one year after vaccination compared to PBS immunized mice. Furthermore, one booster dose of non-adjuvanted recombinant S1Beta (rS1Beta) subunit vaccine was effective in stimulating strong long-lived S1-specific immune responses and inducing significantly high neutralizing antibodies against the Wuhan, Beta, and Delta strain with 3.6- to 19.5-fold change increases. Importantly, the booster dose elicits cross-reactive antibody responses resulting in ACE2 binding inhibition against spike of SARS-CoV-2 variants (Wuhan, Alpha, Beta, Gamma, Delta, Zeta, Kappa, New York, India) as early as two-week post-boost injection, persisting over 28 weeks after a booster vaccination. Interestingly, levels of neutralizing antibodies were correlated with not only level of S1-binding IgG but also level of ACE2 inhibition in the before- and after-booster serum samples. Our findings show that S1 recombinant protein subunit vaccine candidate as a booster has potential to offer cross-neutralization against broad variants, and has important implications for vaccine control of new emerging breakthrough SARS-CoV-2 variants in elderly individuals primed with adenovirus-based vaccine like AZD1222 and Ad26.COV2.S.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 S1 Subunit Booster Vaccination Elicits Robust Humoral Immune Responses in Aged Mice

Kim

Khan

Ferrari

et al. 2022

Preprint

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“…Although wild-type C57BL/6 mice model is reported as not being a viable in vivo model for the SARS-CoV-2 infection, many studies have shown that common laboratory mice are susceptible to SARS-CoV-2 infection as well [38,39]. Chen Y and coworkers have recently shown the age-associated SARS-CoV-2 pathogenesis, immune responses, occurrence of re-infection and vaccine breakthrough infection using a wild-type C57BL/6 mouse model [40]. Different SARS-CoV-2 variants of concern are being reported to infect the respiratory tract and induce inflammatory response in wild-type laboratory mice [41].…”

Section: Discussionmentioning

confidence: 99%

Intranasal Coronavirus SARS-CoV-2 Immunization with Lipid Adjuvants Provides Systemic and Mucosal Immune Response against SARS-CoV-2 S1 Spike and Nucleocapsid Protein

et al. 2022

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In this preclinical two-dose mucosal immunization study, using a combination of S1 spike and nucleocapsid proteins with cationic (N3)/or anionic (L3) lipids were investigated using an intranasal delivery route. The study showed that nasal administration of low amounts of antigens/adjuvants induced a primary and secondary immune response in systemic IgG, mIL-5, and IFN-gamma secreting T lymphocytes, as well as humoral IgA in nasal and intestinal mucosal compartments. It is believed that recipients will benefit from receiving a combination of viral antigens in promoting a border immune response against present and evolving contagious viruses. Lipid adjuvants demonstrated an enhanced response in the vaccine effect. This was seen in the significant immunogenicity effect when using the cationic lipid N3. Unlike L3, which showed a recognizable effect when administrated at a slightly higher concentration. Moreover, the findings of the study proved the efficiency of an intranasally mucosal immunization strategy, which can be less painful and more effective in enhancing the respiratory tract immunity against respiratory infectious diseases.

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“…Though several of these studies examined the effects of infection in C57BL6 mice [7,3,[10][11][12] these were limited to single sex or age cohorts or employed strains of SARS-CoV-2 that were too virulent for elucidating immune mechanisms of recovery by genetic screens. Compared to the few studies in C57BL/6 mice, the most comprehensive early studies with mouse-adapted strains characterized infection in Balb/c mice [7,3,11,13] which do not permit the vast number of genetic screens that are possible with transgenic and gene knockout lines on the C57BL/6 background. Important to our future goals of genetically dissecting key immune pathways for disease recovery of knockout mouse strains on the C57BL/6 background, the immune responses and disease severity observed in Balb/c and C57BL/6 mice are different.…”

Section: Discussionmentioning

confidence: 99%

“…As the pandemic progressed, several groups reported on mouse-adapted strains of SARS-CoV-2 that acutely infected mice and produced disease re ecting what was seen in humans at that time [6-8, 14, 3, 9-13]. Though several of these studies examined the effects of infection in C57BL6 mice [7,3,[10][11][12] these were limited to single sex or age cohorts or employed strains of SARS-CoV-2 that were too virulent for elucidating immune mechanisms of recovery by genetic screens. Compared to the few studies in C57BL/6 mice, the most comprehensive early studies with mouse-adapted strains characterized infection in Balb/c mice [7,3,11,13] which do not permit the vast number of genetic screens that are possible with transgenic and gene knockout lines on the C57BL/6 background.…”

Section: Discussionmentioning

confidence: 99%

A C57BL/6 Mouse model of SARS-CoV-2 infection recapitulates age- and sex-based differences in human COVID-19 disease and recovery

Davis

Voss

Turnbull

et al. 2022

Preprint

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We present a comprehensive analysis of SARS-CoV-2 infection and recovery in wild type C57BL/6 mice, demonstrating that this is an ideal model of infection and recovery that accurately phenocopies acute human disease arising from the ancestral SARS-CoV-2. Disease severity and infection kinetics are age- and sex-dependent, as has been reported for humans, with older mice and males in particular exhibiting decreased viral clearance and increased mortality. We identified key parallels with human pathology, including intense virus positivity in bronchial epithelial cells, wide-spread alveolar involvement, recruitment of immune cells to the infected lungs, and acute bronchial epithelial cell death. Moreover, older animals experienced increased virus persistence, delayed dispersal of immune cells into lung parenchyma, and morphologic evidence of tissue damage and inflammation. Parallel analysis of SCID mice revealed that the adaptive immune response was not required for recovery from COVID disease symptoms nor early phase clearance of virus but was required for efficient clearance of virus at later stages of infection. Finally, transcriptional analyses indicated that induction and duration of key innate immune gene programs may explain differences in age-dependent disease severity. Importantly, these data demonstrate that SARS-CoV-2-mediated disease in C57BL/6 mice accurately phenocopies human disease across ages and establishes a platform for future therapeutic and genetic screens for not just SARS-CoV-2 but also novel coronaviruses that have yet to emerge.

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Age-associated SARS-CoV-2 breakthrough infection and changes in immune response in a mouse model

Cited by 42 publications

References 44 publications

SARS-CoV-2 S1 Subunit Booster Vaccination Elicits Robust Humoral Immune Responses in Aged Mice

SARS-CoV-2 S1 Subunit Booster Vaccination Elicits Robust Humoral Immune Responses in Aged Mice

Intranasal Coronavirus SARS-CoV-2 Immunization with Lipid Adjuvants Provides Systemic and Mucosal Immune Response against SARS-CoV-2 S1 Spike and Nucleocapsid Protein

A C57BL/6 Mouse model of SARS-CoV-2 infection recapitulates age- and sex-based differences in human COVID-19 disease and recovery

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