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      Age and frailty in COVID-19 vaccine development

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      Lancet (London, England)
      Elsevier Ltd.

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          Abstract

          Older adults, particularly those who are frail or living in long-term care facilities, have been disproportionately affected by the COVID-19 pandemic. 1 Vaccines that are safe and effective in this population have been eagerly anticipated. In The Lancet, Maheshi Ramasamy and colleagues present results of the safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine in older adults (those older than 55 years). 2 Their results are part of a larger single-blind, randomised, controlled, phase 2/3 trial of the ChAdOx1 nCoV-19 vaccine (which is a replication-defective chimpanzee adenovirus-vector vaccine) with a MenACWY meningococcal vaccine comparison group. The study design was complex, with participants randomly assigned using block randomisation to one of ten different groups, and older adults were only enrolled after initial determination of safety in the youngest age group (aged 18–55 years). Participants in the two older age groups (aged 56–69 and ≥70 years) were further randomly assigned to receive either one dose (day 0) or two doses (day 0 and a boost dose on day 28) of vaccine. The ChAdOx1 nCoV-19 groups were also sequentially recruited to receive either a low dose or (after demonstration of safety) a standard dose of the vaccine. In this immunogenicity subgroup of the larger study, 560 healthy adults were included, distributed among the three age groups (160 participants aged 18–55 years, of whom 100 received the COVID-19 vaccine; 160 aged 56–69 years, of whom 120 received the COVID-19 vaccine, and 240 aged ≥70 years, of whom 200 received the COVID-19 vaccine). 280 (51%) of 552 analysed participants were female and the median age in the 18–55 years group was 43·0 years (IQR 33·6–48·0), in the 56–69 years group was 60·0 years (57·5–63·0), and in the 70 years and older group was 73·0 years (71·0–76·0). For 7 days after each dose, participants completed diary cards for solicited local and systemic adverse events. Serious adverse events were recorded and will be monitored for 1 year. Severity of reactions and adverse events was graded as mild, moderate, or severe, depending on their effect on daily activities. Immune responses were measured using assays of anti-spike protein IgG and neutralising antibody titres for humoral immunity and IFN-γ enzyme-linked immunospot (ELISpot) for cell-mediated immunity. In this Article, the authors focus on safety and immunogenicity in older adults; reporting on efficacy outcomes is pending. They found that both local and systemic reactions were more common with ChAdOx1 nCoV-19 than with MenACWY, but decreased with increasing age. For example, in those who received the ChAdOx1 nCoV-19 two standard-dose regimen, 43 (88%) of 49 participants aged 18–55 years, 22 (73%) of 30 aged 56–69 years, and 30 (61%) of 49 aged 70 years and older reported at least one local reaction (most commonly injection-site pain and tenderness) and 42 (86%) of 49 participants in the 18–55 years group, 23 (77%) of 30 in the 56–69 years group, and 32 (65%) of 49 in the 70 years and older group reported at least one systemic reaction (most commonly fatigue, headache, feverishness, and myalgias; these were graded as severe in seven [5%] of 128 participants after the prime dose and one [1%] of 127 participants after the boost dose). 13 participants had serious adverse events during the study period, none of which were judged to be due to study vaccine. The decrease in local and systemic reactions with increasing age might be explained by the anti-inflammatory response to low-grade chronic inflammation, and suppression of acute inflammatory processes. 3 Immunogenicity was robust and similar across age groups, as long as a boost dose was provided. Anti-spike protein IgG responses at 28 days after the boost dose were similar among the three age groups (in the standard-dose groups: 18–55 years, median 20 713 arbitrary units [AU]/per mL [IQR 13 898–33 550], n=39; 56–69 years, 16 170 AU/mL [10 233–40 353], n=26; ≥70 years, 17 561 AU/mL [9705–3 7796], n=47; p=0·68), and 208 (>99%) of 209 participants in the boost dose groups had neutralising antibodies by day 14 after the last vaccination. In IFN-γ ELISpot assays enumerating antigen-specific T cells done for those in the prime-boost standard-dose group, T-cell responses peaked at 14 days after a single standard dose and did not increase significantly after a boost dose (18–55 years, median 1187 spot forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841–2428], n=24; 56–69 years, 797 SFCs [383–1817], n=29; and ≥70 years 977 SFCs [458–1914], n=48; p=0·46). The authors state that these results based on IFN-γ ELISpot will be followed up with a more detailed analysis of other measures of cell-mediated immunity. The strengths of the study include a large sample with a wide age range, and a robust trial design. The inclusion of measures of cell-mediated immunity is important given the limitations of relying solely on antibody titres in older adults.4, 5 The main study limitations were its single-blind design, the inclusion of few participants older than 80 years, and exclusion of people with substantial underlying chronic illnesses and frailty. Overall, Ramasamy and colleagues summarise that the ChAdOx1 nCoV-19 vaccine is better tolerated in older adults than younger adults and has similar immunogenicity across all age groups after a boost dose; both conclusions are well supported by their results. How might the results be applied to the true target populations for COVID-19 vaccines? The current UK Joint Committee on Vaccination and Immunisation top priority groups are: older adults living in care homes and care home workers, all those aged 80 years and older, and health-care and social-care workers, and all those aged 75 years and older. 6 Frailty is common to each, and gives a more holistic understanding than comorbidities alone of susceptibility to adverse outcomes. 7 The concept of immunosenescence (waning of immune responses) is important for understanding vaccine responses in older adults. There is increasing evidence that immunosenescence is not universally or evenly experienced with biological ageing but is part of what contributes to the variability in susceptibility that is seen with frailty and an increasing burden of health conditions.5, 8 So the story is more complex than simply older age brings immunosenescence. Frailty is increasingly understood to affect older adults' responses to vaccines for infections such as influenza, shingles, and pneumococcus.9, 10, 11 Even when a measure of frailty has not been included in a study upfront, generation of a robust frailty measure using data already collected is possible.10, 12 A plan for how to consider frailty in COVID-19 vaccine development is important. Involving geriatricians could bring a key lens to assist with planning these ongoing studies focusing on older adults and interpreting the results. Consideration of the dosing would be important. In this study, the low-dose regimen appeared to be as good or at least nearly as good as the standard-dose regimen, which could be useful for antigen and dose sparing as production ramps up. However, frail older adults might benefit from a higher dose of vaccine and we would not be able to assess this effect unless frailty was specifically queried in immunogenicity studies. It is encouraging that more studies in older adult populations are underway and will hopefully bring opportunities to implement nuanced analyses of how underlying health status and frailty affect vaccine safety, reactogenicity, immunogenicity, and efficacy in older adults in real-world settings. Older adults (across the full spectrum of frailty) and those who care about them are eagerly awaiting this progress towards safe and effective COVID-19 vaccines. © 2020 Norberto Duarte/Getty Images 2020 Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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          Most cited references11

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          Frailty in elderly people

          Frailty is the most problematic expression of population ageing. It is a state of vulnerability to poor resolution of homoeostasis after a stressor event and is a consequence of cumulative decline in many physiological systems during a lifetime. This cumulative decline depletes homoeostatic reserves until minor stressor events trigger disproportionate changes in health status. In landmark studies, investigators have developed valid models of frailty and these models have allowed epidemiological investigations that show the association between frailty and adverse health outcomes. We need to develop more efficient methods to detect frailty and measure its severity in routine clinical practice, especially methods that are useful for primary care. Such progress would greatly inform the appropriate selection of elderly people for invasive procedures or drug treatments and would be the basis for a shift in the care of frail elderly people towards more appropriate goal-directed care. Copyright © 2013 Elsevier Ltd. All rights reserved.
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            Safety and immunogenicity of ChAdOx1 nCoV-19 vaccine administered in a prime-boost regimen in young and old adults (COV002): a single-blind, randomised, controlled, phase 2/3 trial

            Background Older adults (aged ≥70 years) are at increased risk of severe disease and death if they develop COVID-19 and are therefore a priority for immunisation should an efficacious vaccine be developed. Immunogenicity of vaccines is often worse in older adults as a result of immunosenescence. We have reported the immunogenicity of a novel chimpanzee adenovirus-vectored vaccine, ChAdOx1 nCoV-19, in young adults, and now describe the safety and immunogenicity of this vaccine in a wider range of participants, including adults aged 70 years and older. Methods In this report of the phase 2 component of a single-blind, randomised, controlled, phase 2/3 trial (COV002), healthy adults aged 18 years and older were enrolled at two UK clinical research facilities, in an age-escalation manner, into 18–55 years, 56–69 years, and 70 years and older immunogenicity subgroups. Participants were eligible if they did not have severe or uncontrolled medical comorbidities or a high frailty score (if aged ≥65 years). First, participants were recruited to a low-dose cohort, and within each age group, participants were randomly assigned to receive either intramuscular ChAdOx1 nCoV-19 (2·2 × 1010 virus particles) or a control vaccine, MenACWY, using block randomisation and stratified by age and dose group and study site, using the following ratios: in the 18–55 years group, 1:1 to either two doses of ChAdOx1 nCoV-19 or two doses of MenACWY; in the 56–69 years group, 3:1:3:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY; and in the 70 years and older, 5:1:5:1 to one dose of ChAdOx1 nCoV-19, one dose of MenACWY, two doses of ChAdOx1 nCoV-19, or two doses of MenACWY. Prime-booster regimens were given 28 days apart. Participants were then recruited to the standard-dose cohort (3·5–6·5 × 1010 virus particles of ChAdOx1 nCoV-19) and the same randomisation procedures were followed, except the 18–55 years group was assigned in a 5:1 ratio to two doses of ChAdOx1 nCoV-19 or two doses of MenACWY. Participants and investigators, but not staff administering the vaccine, were masked to vaccine allocation. The specific objectives of this report were to assess the safety and humoral and cellular immunogenicity of a single-dose and two-dose schedule in adults older than 55 years. Humoral responses at baseline and after each vaccination until 1 year after the booster were assessed using an in-house standardised ELISA, a multiplex immunoassay, and a live severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) microneutralisation assay (MNA80). Cellular responses were assessed using an ex-vivo IFN-γ enzyme-linked immunospot assay. The coprimary outcomes of the trial were efficacy, as measured by the number of cases of symptomatic, virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were by group allocation in participants who received the vaccine. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. This study is ongoing and is registered with ClinicalTrials.gov, NCT04400838, and ISRCTN, 15281137. Findings Between May 30 and Aug 8, 2020, 560 participants were enrolled: 160 aged 18–55 years (100 assigned to ChAdOx1 nCoV-19, 60 assigned to MenACWY), 160 aged 56–69 years (120 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY), and 240 aged 70 years and older (200 assigned to ChAdOx1 nCoV-19: 40 assigned to MenACWY). Seven participants did not receive the boost dose of their assigned two-dose regimen, one participant received the incorrect vaccine, and three were excluded from immunogenicity analyses due to incorrectly labelled samples. 280 (50%) of 552 analysable participants were female. Local and systemic reactions were more common in participants given ChAdOx1 nCoV-19 than in those given the control vaccine, and similar in nature to those previously reported (injection-site pain, feeling feverish, muscle ache, headache), but were less common in older adults (aged ≥56 years) than younger adults. In those receiving two standard doses of ChAdOx1 nCoV-19, after the prime vaccination local reactions were reported in 43 (88%) of 49 participants in the 18–55 years group, 22 (73%) of 30 in the 56–69 years group, and 30 (61%) of 49 in the 70 years and older group, and systemic reactions in 42 (86%) participants in the 18–55 years group, 23 (77%) in the 56–69 years group, and 32 (65%) in the 70 years and older group. As of Oct 26, 2020, 13 serious adverse events occurred during the study period, none of which were considered to be related to either study vaccine. In participants who received two doses of vaccine, median anti-spike SARS-CoV-2 IgG responses 28 days after the boost dose were similar across the three age cohorts (standard-dose groups: 18–55 years, 20 713 arbitrary units [AU]/mL [IQR 13 898–33 550], n=39; 56–69 years, 16 170 AU/mL [10 233–40 353], n=26; and ≥70 years 17 561 AU/mL [9705–37 796], n=47; p=0·68). Neutralising antibody titres after a boost dose were similar across all age groups (median MNA80 at day 42 in the standard-dose groups: 18–55 years, 193 [IQR 113–238], n=39; 56–69 years, 144 [119–347], n=20; and ≥70 years, 161 [73–323], n=47; p=0·40). By 14 days after the boost dose, 208 (>99%) of 209 boosted participants had neutralising antibody responses. T-cell responses peaked at day 14 after a single standard dose of ChAdOx1 nCoV-19 (18–55 years: median 1187 spot-forming cells [SFCs] per million peripheral blood mononuclear cells [IQR 841–2428], n=24; 56–69 years: 797 SFCs [383–1817], n=29; and ≥70 years: 977 SFCs [458–1914], n=48). Interpretation ChAdOx1 nCoV-19 appears to be better tolerated in older adults than in younger adults and has similar immunogenicity across all age groups after a boost dose. Further assessment of the efficacy of this vaccine is warranted in all age groups and individuals with comorbidities. Funding UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midlands NIHR Clinical Research Network, and AstraZeneca.
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              Inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans.

              A large part of the aging phenotype, including immunosenescence, is explained by an imbalance between inflammatory and anti-inflammatory networks, which results in the low grade chronic pro-inflammatory status we proposed to call inflammaging. Within this perspective, healthy aging and longevity are likely the result not only of a lower propensity to mount inflammatory responses but also of efficient anti-inflammatory networks, which in normal aging fail to fully neutralize the inflammatory processes consequent to the lifelong antigenic burden and exposure to damaging agents. Such a global imbalance can be a major driving force for frailty and common age-related pathologies, and should be addressed and studied within an evolutionary-based systems biology perspective. Evidence in favor of this conceptualization largely derives from studies in humans. We thus propose that inflammaging can be flanked by anti-inflammaging as major determinants not only of immunosenescence but eventually of global aging and longevity.
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                Author and article information

                Journal
                Lancet
                Lancet
                Lancet (London, England)
                Elsevier Ltd.
                0140-6736
                1474-547X
                19 November 2020
                19 November 2020
                Affiliations
                [a ]Department of Medicine (Geriatrics) and Canadian Center for Vaccinology, Dalhousie University, Halifax, B3H 2E1, NS, Canada
                [b ]Health Sciences North Research Institute, Sudbury, ON, Canada
                Article
                S0140-6736(20)32481-8
                10.1016/S0140-6736(20)32481-8
                7674981
                33220853
                a9cd3f04-6811-460c-b027-cfed93892895
                © 2020 Elsevier Ltd. All rights reserved.

                Since January 2020 Elsevier has created a COVID-19 resource centre with free information in English and Mandarin on the novel coronavirus COVID-19. The COVID-19 resource centre is hosted on Elsevier Connect, the company's public news and information website. Elsevier hereby grants permission to make all its COVID-19-related research that is available on the COVID-19 resource centre - including this research content - immediately available in PubMed Central and other publicly funded repositories, such as the WHO COVID database with rights for unrestricted research re-use and analyses in any form or by any means with acknowledgement of the original source. These permissions are granted for free by Elsevier for as long as the COVID-19 resource centre remains active.

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