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Adverse events following immunization of elderly with COVID-19 inactivated virus vaccine (CoronaVac) in Southeastern Brazil: an active surveillance study

ABSTRACT

Healthcare workers, the elderly and other vulnerable populations were the first to receive COVID-19 vaccines in public health programs. There were few vaccine safety data available on the elderly. This observational study aimed to evaluate the inactivated vaccine (CoronaVac) safety in the elderly, at the beginning of the vaccination program, in Sao Paulo city, Brazil. The elderly people that received CoronaVac at the Reference Center for Special Immunobiologicals (CRIE) or at home, administered by the Interdisciplinary Home Care Team (NADI) of the Hospital das Clinicas were invited to participate in this phase 4 observational study. The vaccination schedule included two CoronaVac doses 28 days apart. The information on solicited and unsolicited adverse events following immunization were collected by phone calls on days 4 and 8 after each vaccine dose. We enrolled 158 adults aged 65 to 101 years (mean of 84.1 years); 63.9% were females and 95.6% had chronic conditions, 21.5% had moderate or severe impairment in daily living activities; 34.2% were pre-frail and 19.6% were frail. We were able to contact 95.6% and 91.6% of the vaccinated people, after the first and second doses, respectively; 31.8% and 23.4% of the contacted participants reported some adverse events (AE) following the first and second doses, respectively. Pain at the injection site, fatigue, myalgia and headaches were the most frequent solicited AE. Most AE were mild to moderate. There were eight severe adverse events, but none of them were considered related to the vaccine. The CoronaVac was safe and well tolerated by these adults of advanced age with frailty and comorbidities.

COVID-19 vaccine; Inactivated vaccine; Safety; Adverse events; Elderly; Post-marketing product surveillance

INTRODUCTION

Brazil was intensely affected by the COVID-19 pandemic with more than 22 million cases and more than 600,000 deaths by the end of 202111. Brasil. Ministério da Saude. Painel Coronavírus. [cited 2022 Aug 12]. Available from: https://covid.saude.gov.br/
https://covid.saude.gov.br/...
,22. Castro MC, Kim S, Barberia L, Ribeiro AF, Gurzenda S, Ribeiro KB, et al. Spatiotemporal pattern of COVID-19 spread in Brazil. Science. 2021;372:821-6.. In the first semester of 2021, the SARS-CoV-2 gamma variant, initially identified in Manaus, North of Brazil, spread throughout the country, making it the global epicenter of the pandemic33. Faria NR, Mellan TA, Whittaker C, Claro IM, Candido DD, Mishra S, et al. Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus, Brazil. medRxiv. 2021 In Press.. The elderly were seriously affected. Although persons aged 80 years and more represented approximately 2% of the estimated Brazilian population in 202044. Brasil. Ministério da Saúde. DATASUS. [cited 2022 Aug 12]. Available from: https://datasus.saude.gov.br/
https://datasus.saude.gov.br/...
, deaths in this age group constituted 25 to 30% of all reported COVID-19 deaths in the first six weeks of 202155. Victora C, Castro MC, Gurzenda S, Medeiros AC, França GV, Barros PA. Estimating the early impact of vaccination against COVID-19 on deaths among elderly people in Brazil: analyses of routinely-collected data on vaccine coverage and mortality. EClinicalMedicine. 2021;38:101036..

In December 2020, the phase 3 trials’ preliminary results enabled vaccine licensing for emergency use and the introduction of the COVID-19 vaccination in several countries. In Brazil, the vaccination was initiated in late January 2021, with two vaccines: the inactivated vaccine produced by Sinovac/Instituto Butantan (CoronaVac) and the viral vector vaccine produced by Oxford University/AstraZeneca/BioManguinhos (ChAdOx1), both approved by the National Regulatory Agency (ANVISA, Agencia Nacional de Vigilancia Sanitaria). The first months of the Brazilian vaccination program largely relied on the inactivated virus vaccine (CoronaVac). In Sao Paulo state, the COVID-19 vaccination program initially targeted healthcare workers, the elderly, indigenous populations, quilombolas and institutionalized persons. The vaccination for the elderly started in February, for people aged ≥ 90 years, followed by people aged 85 to 89 years, and so on, progressively reaching the younger age groups66. São Paulo. Secretaria da Saúde. Vacinômetro. [cited 2022 Aug 12]. Available from: https://www.vacinaja.sp.gov.br/
https://www.vacinaja.sp.gov.br/...
.

The inactivated virus vaccine produced by Sinovac, China, was evaluated in phase 3 trials in several countries, including China, Brazil, Chile77. Bueno SM, Abarca K, González PA, Gálvez NM, Soto JA, Duarte LF, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine in a subgroup of healthy adults in Chile. Clin Infect Dis. 2021 In Press. and Turkey88. Tanriover MD, Doğanay HL, Akova M, Güner HR, Azap A, Akhan S, et al. Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey. Lancet. 2021;398:213-22.. In Brazil, the CoronaVac phase 3 trial involved 12,396 healthcare workers aged 18 years or older (only 5.1% were aged ≥60 years). The most frequent adverse reactions were pain at the injection site, headaches and fatigue99. Instituto Butantan, CoronaVac. [cited 2022 Aug 12]. Available from: https://vacinacovid.butantan.gov.br/
https://vacinacovid.butantan.gov.br/...
. A phase 1 and 2 study in China1010. Wu Z, Hu Y, Xu M, Chen Z, Yang W, Jiang Z, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2021;21:803-12. evaluated 348 people aged ≥ 60 years, who received different doses of CoronaVac. In this study, the vaccine was well tolerated and all adverse events were mild to moderate, as well as found in the younger population. Data on specific populations, including the elderly, especially those with comorbidities are scarce which means that phase 4 studies are required to evaluate the vaccine’s safety, immunogenicity and effectiveness in those groups. This observational study aimed to evaluate the adverse events following the inactivated virus vaccine (CoronaVac) in the elderly, through active surveillance, in Sao Paulo city.

MATERIALS AND METHODS

This observational retrospective cohort study was conducted at the Reference Center for Special Immunobiologicals (CRIE, Centro de Referencia para Imunobiologicos Especiais) of the Hospital das Clinicas (HC), a tertiary/quaternary care hospital attached to the University of Sao Paulo Medical School (FMUSP, Faculdade de Medicina da Universidade de Sao Paulo), in Sao Paulo city, from February to April 2021. Data were collected in active surveillance of adverse events following the immunization (AEFI). The CoronaVac was administered in a 2-dose schedule, with a 28-day interval between doses, following the recommendations of the National Immunization Program.

A convenience sample was adopted. The elderly people (EP) who searched for or were referred to CRIE to receive the COVID-19 vaccine were asked for authorization for follow-up calls in order to evaluate the adverse events temporally associated with vaccination. Persons who were vaccinated at home by the HC Interdisciplinary Home Care team (NADI, Nucleo de Assistencia Domiciliar) were also invited to participate. The vaccinated participants were advised to return or make contact with the CRIE staff in case of AEFI.

The following data were collected: age, gender, skin color, comorbidities, functionality (using the Katz Index of Independence in Activities of Daily Living – Katz IADL) and frailty (through the Study of Osteoporotic Fractures – SOF).

The Katz IADL is an instrument to assess functional status as a measurement of the ability to perform activities of daily living independently. The Katz IADL evaluates the performance in the six functions of bathing, dressing, using the toilet, transferring, continence, and feeding, resulting in three classifications: independent, moderate impairment, and severe impairment1111. Rubenstein LZ, Wieland D, English P, Josephson K, Sayre JA, Abrass IB. The Sepulveda VA Geriatric Evaluation Unit: data on four-year outcomes and predictors of improved patient outcomes. J Am Geriatr Soc. 1984;32:503-12.

12. Lino VT, Pereira SR, Camacho LA, Ribeiro Filho ST, Buksman S. Adaptação transcultural da Escala de Independência em Atividades da Vida Diária (Escala de Katz). Cad Saude Publica. 2008;24:103-12
-1313. Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged. The index of adl: a standardized measure of biological and psychosocial function. JAMA. 1963;185:914-9.. The Frailty Syndrome is a clinical entity that describes the presence of multisystemic impairment and increasing vulnerability in older adults and can predict adverse health outcomes in this population, such as falls, fractures, severe adverse drug reactions, disabilities and death1414. Ensrud KE, Ewing SK, Taylor BC, Fink HA, Cawthon PM, Stone KL, et al. Comparison of 2 frailty indexes for prediction of falls, disability, fractures, and death in older women. Arch Intern Med. 2008;168:382-9.. The SOF is a simple instrument that provides an operational definition of frailty and determines 3 classifications: frail, prefrail and robust.

The follow-up phone calls were made by healthcare workers and medical students, who made at least three contact attempts for each participant, on days 4 and 8 after both the first and second vaccine doses. If we were not able to talk to the vaccinated participants or his/her caregiver on the scheduled day, we kept trying for 3 to 5 days (at least three attempts). A standardized AEFI form was applied, which was answered by the vaccinated people or, in case of disability, by their caregivers. The solicited local adverse events were pain, erythema, swelling, induration and pruritus at the injection site. Solicited systemic adverse events were fever, chills, fatigue, headaches, myalgia, arthralgia, nausea, vomiting, diarrhea, anorexia and pruritus. The solicited adverse events were based on the most common expected adverse reactions listed in the CoronaVac package insert. The unsolicited adverse events were any other events reported by the vaccinated participants. The data on AEFI intensity, dates of onset and end, medications used and healthcare assistance needed were also collected. We used FDA’s toxicity grading scale to classify AEFI intensity1515. United State. Food and Drug Administration. Toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials: guidance for industry. [cited 2022 Aug 12]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-preventive-vaccine-clinical
https://www.fda.gov/regulatory-informati...
. Accordingly, local and systemic events were classified in: mild (grade 1: does not interfere with daily activity), moderate (grade 2: interferes with activity), severe (grade 3: prevents daily activity or requires outpatient treatment) and potentially life-threatening (grade 4: requires emergency room visit for more than 12 h or hospitalization). We used the WHO-Uppsala Monitoring Centre System for causality assessment1616. Uppsala Monitoring Centre. The use of the WHO-UMC system for standardised case causality assessment. [cited 2022 Aug 12]. Available from: https://who-umc.org/media/164200/who-umc-causality-assessment_new-logo.pdf
https://who-umc.org/media/164200/who-umc...
, which takes into account expected adverse events, time between vaccination and symptom onset, and the possibility of another cause for the event.

A descriptive analysis was conducted with measures of central tendency for continuous variables and estimation of frequencies for categorical variables. Data were summarized in tables.

This retrospective report was approved by the Research Ethics Committee of the Department of Infectious and Parasitic Diseases (001/22).

RESULTS

From February 8th to March 3rd, 2021, 158 elderly people who received the first dose of the COVID-19 inactivated virus vaccine (CoronaVac) agreed to be contacted by phone for AEFI assessment; 126 of them were vaccinated at CRIE-HC and 32 persons received the vaccine at home, administered by the NADI-HC team. Their demographic characteristics, underlying diseases and functional status are presented in Table 1. Their ages ranged from 65 to 101 years old, with a median of 83 years. And 74.7% of participants were aged ≥80 years. Most participants (95.6%) had at least one underlying disease; the most frequent morbidity was arterial hypertension (60.1% of participants), followed by heart disease (32.9%), dyslipidemia (25.3%) and diabetes (22.8%).

Table 1
Characteristics of 158 elderly participants included in the active surveillance of adverse events following the COVID-19 inactivated vaccine (CoronaVac). Sao Paulo, February to April 2021.

The Katz IADL showed that 7.6% and 13.9% of participants had, respectively, moderate and severe impairment in activities of daily living. The SOF showed that 34.2% of participants were pre-frail and 19.6% were frail (Table 1).

Of the 158 vaccinated people, 151 participants (95.6%) were successfully contacted at least once for the AEFI assessment after the first vaccine dose and 48 (31.8%) of the contacted vaccinated participants reported at least one AEFI; 154 (97.5%) subjects received the second vaccine dose within the follow-up period (up to April 8th, 2021), of whom 141 (91.6%) were successfully contacted at least once for the AEFI assessment after the second vaccine dose and 33 (23.4%) of the latter reported at least one AEFI (Table 2). The numbers of AEFI ranged from one to six (mean of 1.8) per person after the first vaccine dose and from one to five (mean of 2.2) per person after the second vaccine dose.

Table 2
Numbers of reported adverse events (AE) following the COVID-19 inactivated vaccine (CoronaVac) in the elderly and proportions of events per contacted participants, according to dose. Sao Paulo, 2021.

Table 2 presents the reported solicited local and systemic AEFI, as well as the unsolicited adverse events according to the vaccine dose. The most common solicited adverse event after the first vaccine dose was pain at the injection site (13 reports, 8.7% of contacted participants), followed by fatigue (9, 6%) and headaches, diarrhea and pruritus (6, 4% each). After the second dose, the most common solicited adverse event was myalgia (10 reports, 7.2%), followed by fatigue (8, 5.8%), anorexia (7, 5%), and headaches and nausea (6, 4.3% each).

There were 37 unsolicited AEFI, 18 after the first vaccine dose and 19 after the second dose (Table 2). Drowsiness was the most frequent unsolicited AE (6 reports, 3 after each dose), followed by stroke (5 events, two after the first dose and three after the second dose). Seven people presented eight severe adverse events (two deaths, four hospitalizations and two Emergency Room visits), five after the first vaccine dose and three after the second dose (Table 2). None of these severe AEFIs were considered related to the vaccine. A detailed description of the severe AEFI is presented in Supplementary Material S1.

There were two COVID-19 cases among those vaccinated, one case diagnosed 25 days after the first vaccine dose and another diagnosed two days after the second vaccine dose. They did not require hospitalization.

Most solicited local AE were mild and did not interfere with daily activities (80.95% of local AE after the first dose and 5/6 AE after the second dose). The systemic solicited AE were mild (63.8% and 62.2% of systemic AE after the first and second dose, respectively) or moderate / had little interference in daily activities (27.6% and 31.1% of systemic AE after the first and second dose, respectively). Few solicited systemic adverse events (8.5% and 6.7% AE after the first and second dose, respectively) were intense, preventing daily activities (Table 3).

Table 3
Intensity of solicited adverse events (AE) following the COVID-19 inactivated vaccine (CoronaVac) in the elderly, according to dose. Sao Paulo, 2021.

Most of the solicited AE started soon after or in the first days following the vaccination (local AE, 0-6 days, mean=1.4; systemic AE, 0-7, mean=1.9 days) and the last few days (local AE, 1-5 days, mean=1.9; systemic AE, 1-9 days, mean=2.4) (Table 4).

Table 4
Interval from elderly vaccination with the COVID-19 inactivated vaccine (CoronaVac) to adverse events (AE) and duration of AE, according to event and dose. Sao Paulo, 2021.

DISCUSSION

This study evaluated the safety of CoronaVac, an inactivated SARS-COV-2 vaccine, in adults of advanced age (mean age of 83 years); 53.8% were pre-frail or frail; 21.5% had moderate to severe impairment in ADL; and most of them (95.6%) had a chronic condition. We were able to make contact with most of the vaccinated participants, and 31.8% and 23.4% of participants reported at least one adverse reaction following the first and second vaccine doses, respectively. Most common adverse events reported, such as pain at injection site, fatigue, headaches, diarrhea, pruritus and myalgia, were expected and are listed in the vaccine package insert. Most adverse reactions were mild to moderate. There were eight serious adverse events, but none of them were considered related to the vaccine. The severe AE occurred mainly in frail or pre-frail individuals of advanced age (>80 years), with comorbidities, who were at high risk of negative health outcomes independent of the vaccination1717. Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet. 2013;381:752-62.

Few studies evaluated CoronaVac safety in the elderly, particularly in those very old and with comorbidities. In China, phase 1 and 2 clinical trials evaluated CoronaVac safety in healthy adults aged ≥ 60 years1010. Wu Z, Hu Y, Xu M, Chen Z, Yang W, Jiang Z, et al. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine (CoronaVac) in healthy adults aged 60 years and older: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2021;21:803-12.. It is important to emphasize that their population was healthier and younger (mean age = 65.8 and 66.6 years, respectively, in phase 1 and phase 2 trials) than those included in our study. They reported lower adverse reaction rates (21% or 84/421 participants reported at least one adverse reaction) as compared to our study (31.8% and 23.4% of those vaccinated reported adverse reactions after the first and second doses, respectively). Pain at the injection site was the most common local solicited adverse reaction in both studies. In the Chinese study, fever (3%) was the most frequent systemic reaction whereas fatigue, myalgia and headaches were more common in our study.

The CoronaVac phase 3 trial in Brazil included 632 persons aged ≥ 60 years (316 in the vaccine group)1818. World Health Organization. Background document on the inactivated vaccine SinovacCoronaVac against COVID-19: background document to the WHO interim recommendations for use of the inactivated COVID-19 vaccine, CoronaVac, developed by Sinovac. [cited 2022 Aug 12]. Available from: https://www.who.int/publications/i/item/WHO-2019-nCoV-vaccines-SAGE_recommendation-Sinovac-CoronaVac-background-2021.1
https://www.who.int/publications/i/item/...
. Considering only the vaccinated group, 24.7% of participants reported any solicited local adverse reaction after the first dose and 31.7% after the second dose, both higher than in our study (13.9% and 4%, respectively). The Brazilian trial reported lower solicited systemic adverse reactions (24% of the vaccinated participants with any systemic AE after the first dose and 25.6% after the second one) as compared to our study (31.8% and 34.8%, respectively, Table 2). In both studies, most adverse reactions were mild to moderate.

An interim analysis of CoronaVac in healthy adults, in Chile, included 37 volunteers aged ≥60 years (25 in the vaccine group), with a mean age of 64 years77. Bueno SM, Abarca K, González PA, Gálvez NM, Soto JA, Duarte LF, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine in a subgroup of healthy adults in Chile. Clin Infect Dis. 2021 In Press.. Considering only the vaccine group, pain at the injection site was the most frequent solicited local reaction (55.6%). Headaches were the most frequent systemic reaction (37.5%), followed by fatigue (25%)77. Bueno SM, Abarca K, González PA, Gálvez NM, Soto JA, Duarte LF, et al. Safety and immunogenicity of an inactivated SARS-CoV-2 vaccine in a subgroup of healthy adults in Chile. Clin Infect Dis. 2021 In Press.. Both frequencies were higher than the ones found in our study, even though the sample size of the Chilean study was very small, which may have biased the results.

The comparison of adverse events following immunization with distinct vaccine platforms, in different countries, is very difficult, but local reactions were less common after CoronaVac, in our study, than reported for BNT162b2 and ChAdOx1 in phase 4 studies. A phase 4 active surveillance study of the BNT162b2 vaccine in people aged ≥ 75 years, in South Korea, used methods similar to ours (phone calls 7 days after each vaccine dose to assess adverse events)1919. Choi YY, Kim MK, Kwon HC, Kim GH. Safety monitoring after the BNT162b2 COVID-19 vaccine among adults aged 75 years or older. J Korean Med Sci. 2021;36:e318.. Local reactions were reported by 50.3% of 638vaccinated participants after the first dose and 45.2% of 560 vaccinated participants after the second dose. Systemic reactions were reported by 15.2% and 26% of participants, after the first and second dose, respectively. Pain at the injection site, muscle pain, fatigue, chills and fever were the most frequently reported adverse reactions1919. Choi YY, Kim MK, Kwon HC, Kim GH. Safety monitoring after the BNT162b2 COVID-19 vaccine among adults aged 75 years or older. J Korean Med Sci. 2021;36:e318.. A large phase 4 observational study in the UK assessed BNT162b2 and ChAdOx1 safety through self-report2020. Menni C, Klaser K, May A, Polidori L, Capdevila J, Louca P, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis. 2021;21:939-49.. Systemic adverse events were reported by 13.5% and 22% of recipients of BNT162b2, after the first and second doses, respectively, and by 33.7% of persons after the first ChAdOx1 dose (none of the participants had received the second ChAdOx1 dose at the time of study analysis). Headaches and fatigue were the most frequent systemic AE after both vaccines. Local adverse events were reported by 71.9% and 68.5% of vaccinated participants after the first and second dose of BNT162b2, respectively, and by 58.7% after the first dose of ChAdOx1. Tenderness and pain at the injection site were the most frequent local AE for both vaccines2020. Menni C, Klaser K, May A, Polidori L, Capdevila J, Louca P, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis. 2021;21:939-49..

A strength of our research is the active surveillance of adverse events after immunization by follow-up phone calls after each dose. This makes it possible to capture mild and moderate events, which are not usually reported in passive surveillance systems. Limitations of our study include the small sample size and the lack of a control unvaccinated group. However, this is the first research to evaluate CoronaVac in adults of advanced age, with frailty and comorbidities in a real-world study, and we were able to contact the vast majority of participants.

CONCLUSION

Our results are similar to those found in other studies involving the inactivated COVID-19 vaccines among the elderly. Most reported adverse events were mild to moderate as expected, suggesting that the COVID-19 inactivated virus vaccine (CoronaVac) is safe in very old adults, even with multiple comorbidities. Other pharmacovigilance studies with larger samples are needed to determine the real frequency of AEFI and if there are prognostic factors for AEFI in the elderly.

REFERENCES

  • 1
    Brasil. Ministério da Saude. Painel Coronavírus. [cited 2022 Aug 12]. Available from: https://covid.saude.gov.br/
    » https://covid.saude.gov.br/
  • 2
    Castro MC, Kim S, Barberia L, Ribeiro AF, Gurzenda S, Ribeiro KB, et al. Spatiotemporal pattern of COVID-19 spread in Brazil. Science. 2021;372:821-6.
  • 3
    Faria NR, Mellan TA, Whittaker C, Claro IM, Candido DD, Mishra S, et al. Genomics and epidemiology of a novel SARS-CoV-2 lineage in Manaus, Brazil. medRxiv. 2021 In Press.
  • 4
    Brasil. Ministério da Saúde. DATASUS. [cited 2022 Aug 12]. Available from: https://datasus.saude.gov.br/
    » https://datasus.saude.gov.br/
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    Victora C, Castro MC, Gurzenda S, Medeiros AC, França GV, Barros PA. Estimating the early impact of vaccination against COVID-19 on deaths among elderly people in Brazil: analyses of routinely-collected data on vaccine coverage and mortality. EClinicalMedicine. 2021;38:101036.
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  • 8
    Tanriover MD, Doğanay HL, Akova M, Güner HR, Azap A, Akhan S, et al. Efficacy and safety of an inactivated whole-virion SARS-CoV-2 vaccine (CoronaVac): interim results of a double-blind, randomised, placebo-controlled, phase 3 trial in Turkey. Lancet. 2021;398:213-22.
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  • 11
    Rubenstein LZ, Wieland D, English P, Josephson K, Sayre JA, Abrass IB. The Sepulveda VA Geriatric Evaluation Unit: data on four-year outcomes and predictors of improved patient outcomes. J Am Geriatr Soc. 1984;32:503-12.
  • 12
    Lino VT, Pereira SR, Camacho LA, Ribeiro Filho ST, Buksman S. Adaptação transcultural da Escala de Independência em Atividades da Vida Diária (Escala de Katz). Cad Saude Publica. 2008;24:103-12
  • 13
    Katz S, Ford AB, Moskowitz RW, Jackson BA, Jaffe MW. Studies of illness in the aged. The index of adl: a standardized measure of biological and psychosocial function. JAMA. 1963;185:914-9.
  • 14
    Ensrud KE, Ewing SK, Taylor BC, Fink HA, Cawthon PM, Stone KL, et al. Comparison of 2 frailty indexes for prediction of falls, disability, fractures, and death in older women. Arch Intern Med. 2008;168:382-9.
  • 15
    United State. Food and Drug Administration. Toxicity grading scale for healthy adult and adolescent volunteers enrolled in preventive vaccine clinical trials: guidance for industry. [cited 2022 Aug 12]. Available from: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-preventive-vaccine-clinical
    » https://www.fda.gov/regulatory-information/search-fda-guidance-documents/toxicity-grading-scale-healthy-adult-and-adolescent-volunteers-enrolled-preventive-vaccine-clinical
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    Clegg A, Young J, Iliffe S, Rikkert MO, Rockwood K. Frailty in elderly people. Lancet. 2013;381:752-62
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    World Health Organization. Background document on the inactivated vaccine SinovacCoronaVac against COVID-19: background document to the WHO interim recommendations for use of the inactivated COVID-19 vaccine, CoronaVac, developed by Sinovac. [cited 2022 Aug 12]. Available from: https://www.who.int/publications/i/item/WHO-2019-nCoV-vaccines-SAGE_recommendation-Sinovac-CoronaVac-background-2021.1
    » https://www.who.int/publications/i/item/WHO-2019-nCoV-vaccines-SAGE_recommendation-Sinovac-CoronaVac-background-2021.1
  • 19
    Choi YY, Kim MK, Kwon HC, Kim GH. Safety monitoring after the BNT162b2 COVID-19 vaccine among adults aged 75 years or older. J Korean Med Sci. 2021;36:e318.
  • 20
    Menni C, Klaser K, May A, Polidori L, Capdevila J, Louca P, et al. Vaccine side-effects and SARS-CoV-2 infection after vaccination in users of the COVID Symptom Study app in the UK: a prospective observational study. Lancet Infect Dis. 2021;21:939-49.

Publication Dates

  • Publication in this collection
    03 Oct 2022
  • Date of issue
    2022

History

  • Received
    15 Mar 2022
  • Accepted
    12 July 2022
Instituto de Medicina Tropical de São Paulo Av. Dr. Enéas de Carvalho Aguiar, 470, 05403-000 - São Paulo - SP - Brazil, Tel. +55 11 3061-7005 - São Paulo - SP - Brazil
E-mail: revimtsp@usp.br