Abstract:One of the most appreciated consequences of immunosenescence is an impaired response to vaccines with advanced age. While most studies report impaired antibody responses in older adults as a correlate of vaccine efficacy, it is now widely appreciated that this may fail to identify important changes occurring in the immune system with age that may affect vaccine efficacy. The impact of immunosenescence on vaccination goes beyond the defects on antibody responses as T cell-mediated responses are reshaped during … Show more
“…The magnitude and durability of immune responses to COVID-19 vaccines remain incompletely characterized 22 , particularly among the elderly after only the first of a two-dose mRNA vaccine regime. Our observation of lower humoral responses to the BNT162b2 mRNA vaccine among residents of LTC facilities is nevertheless consistent with prior literature describing poor reactivity to vaccines in older adults that often necessitates the use of higher vaccine antigen concentrations, stronger adjuvants and additional booster shots 23-25 . To our knowledge, this is only the second study to report on the strength of humoral immunity in elderly participants following one dose of mRNA vaccine, and the first in Canada.…”
Background. Several Canadian provinces are extending the interval between COVID-19 vaccine doses to increase population vaccine coverage more rapidly. However, immunogenicity of these vaccines after one dose is incompletely characterized, particularly among the elderly, who are at greatest risk of severe COVID-19.
Methods. We assessed SARS-CoV-2 humoral responses pre-vaccine and one month following the first dose of BNT162b2 mRNA vaccine, in 12 COVID-19 seronegative residents of long-term care facilities (median age, 82 years), 18 seronegative healthcare workers (HCW; median age, 36 years) and 4 convalescent HCW. Total antibody responses to SARS-CoV-2 nucleocapsid (N) and spike protein receptor binding domain (S/RBD) were assessed using commercial immunoassays. We quantified IgG and IgM responses to S/RBD and determined the ability of antibodies to block S/RBD binding to ACE2 receptor using ELISA. Neutralizing antibody activity was also assessed using pseudovirus and live SARS-CoV-2.
Results. After one vaccine dose, binding antibodies against S/RBD were ~4-fold lower in residents compared to HCW (p<0.001). Inhibition of ACE2 binding was 3-fold lower in residents compared to HCW (p=0.01) and pseudovirus neutralizing activity was 2-fold lower (p=0.003). While six (33%) seronegative HCW neutralized live SARS-CoV-2, only one (8%) resident did (p=0.19). In contrast, convalescent HCW displayed 7- to 20-fold higher levels of binding antibodies and substantial ability to neutralize live virus after one dose.
Interpretation. Extending the interval between COVID-19 vaccine doses may pose a risk to the elderly due to lower vaccine immunogenicity in this group. We recommend that second doses not be delayed in elderly individuals.
“…The magnitude and durability of immune responses to COVID-19 vaccines remain incompletely characterized 22 , particularly among the elderly after only the first of a two-dose mRNA vaccine regime. Our observation of lower humoral responses to the BNT162b2 mRNA vaccine among residents of LTC facilities is nevertheless consistent with prior literature describing poor reactivity to vaccines in older adults that often necessitates the use of higher vaccine antigen concentrations, stronger adjuvants and additional booster shots 23-25 . To our knowledge, this is only the second study to report on the strength of humoral immunity in elderly participants following one dose of mRNA vaccine, and the first in Canada.…”
Background. Several Canadian provinces are extending the interval between COVID-19 vaccine doses to increase population vaccine coverage more rapidly. However, immunogenicity of these vaccines after one dose is incompletely characterized, particularly among the elderly, who are at greatest risk of severe COVID-19.
Methods. We assessed SARS-CoV-2 humoral responses pre-vaccine and one month following the first dose of BNT162b2 mRNA vaccine, in 12 COVID-19 seronegative residents of long-term care facilities (median age, 82 years), 18 seronegative healthcare workers (HCW; median age, 36 years) and 4 convalescent HCW. Total antibody responses to SARS-CoV-2 nucleocapsid (N) and spike protein receptor binding domain (S/RBD) were assessed using commercial immunoassays. We quantified IgG and IgM responses to S/RBD and determined the ability of antibodies to block S/RBD binding to ACE2 receptor using ELISA. Neutralizing antibody activity was also assessed using pseudovirus and live SARS-CoV-2.
Results. After one vaccine dose, binding antibodies against S/RBD were ~4-fold lower in residents compared to HCW (p<0.001). Inhibition of ACE2 binding was 3-fold lower in residents compared to HCW (p=0.01) and pseudovirus neutralizing activity was 2-fold lower (p=0.003). While six (33%) seronegative HCW neutralized live SARS-CoV-2, only one (8%) resident did (p=0.19). In contrast, convalescent HCW displayed 7- to 20-fold higher levels of binding antibodies and substantial ability to neutralize live virus after one dose.
Interpretation. Extending the interval between COVID-19 vaccine doses may pose a risk to the elderly due to lower vaccine immunogenicity in this group. We recommend that second doses not be delayed in elderly individuals.
“…Ageing is often associated with a state of low grade inflammation, termed 'inflammaging' (47)(48)(49). However, in this study we observed no age-related difference in inflammatory gene signatures in HA-specific CD4 + T cells at day 0, which suggests the cTfh cell response was negatively impacted by inflammation post vaccination, rather than preexisting inflammation having affected resting memory T cell function prior to vaccination.…”
Antibody production following vaccination can provide protective immunity to subsequent infection from pathogens such as influenza. However, circumstances where antibody formation is impaired after vaccination, such as in older people, require us to better understand the cellular and molecular mechanisms that underpin successful vaccination in order to improve vaccine design for at risk groups. Here, by studying the breadth of anti-hemagglutinin (HA) IgG, serum cytokines, and B and T cell responses by flow cytometry before and after influenza vaccination, we show that formation of circulating T follicular helper cells (cTfh) cells are the best predictor of high titre antibody responses. Using MHC class II tetramers we demonstrate that HA-specific cTfh cells can derived from pre-existing memory CD4+ T cells and have a diverse TCR repertoire. In older people, the differentiation of HA-specific cells into cTfh cells was impaired. This age-dependent defect in cTfh cell formation was not due to a contraction of the TCR repertoire, but rather was linked with an increased inflammatory gene signature in cTfh cells. Together this suggests that strategies that temporarily dampen inflammation at the time of vaccination may be a viable strategy to boost optimal antibody generation upon immunisation of older people.
“…2 ), their long-term use needs to be carefully balanced with regard to susceptibility to infectious disease and potential other side effects. Further research is also needed to explain the paradox why reducing systemic low-grade inflammation may boost vaccine responses while the prevailing view in vaccinology is that adjuvants improve vaccine responses by promoting local inflammation [ 126 ]. Fig.…”
Section: Conclusion and Future Perspectivesmentioning
The microbiome plays a fundamental role in the maturation, function, and regulation of the host-immune system from birth to old age. In return, the immune system has co-evolved a mutualistic relationship with trillions of beneficial microbes residing our bodies while mounting efficient responses to fight invading pathogens. As we age, both the immune system and the gut microbiome undergo significant changes in composition and function that correlate with increased susceptibility to infectious diseases and reduced vaccination responses. Emerging studies suggest that targeting age-related dysbiosis can improve health- and lifespan, in part through reducing systemic low-grade inflammation and immunosenescence—two hallmarks of the aging process. However—a cause and effect relationship of age-related dysbiosis and associated functional declines in immune cell functioning have yet to be demonstrated in clinical settings. This review aims to (i) give an overview on hallmarks of the aging immune system and gut microbiome, (ii) discuss the impact of age-related changes in the gut commensal community structure (introduced as microb-aging) on host-immune fitness and health, and (iii) summarize prebiotic- and probiotic clinical intervention trials aiming to reinforce age-related declines in immune cell functioning through microbiome modulation or rejuvenation.
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