To synthesize evidence on the incidence of COVID-19 vaccine-related adverse events across countries by income level.
Design
Systematic review and meta-analysis of randomized trials.
Setting
Studies published 2020-2025, retrieved from EMBASE, PubMed/MEDLINE, and Scopus.
Sample
Eleven trials with 7841 participants; seven from high-income and four from upper-middle-income countries.
Measures
Incidence per 100 vaccinated. Countries by income: low (≤$1145), lower-middle ($1146-4515), upper-middle ($4516-14,005), high (>$14,005). Inter-reviewer agreement assessed by kappa (0.684). Risk of bias evaluated with Cochrane RoB 2.
Analysis
Mantel-Haenszel random-effects models estimated relative risks (RR) with 95% confidence intervals. Heterogeneity assessed by I2. Subgroup analyses by income and dose.
Results
AEFI incidence was consistently higher in high-income vs upper-middle-income countries, especially after dose 2. Injection-site pain (68.1 vs 26.3 per 100), headache (45.7 vs 14.1), myalgia (42.5 vs 9.2), and fatigue (33.8 vs 11.4) were most common. Meta-analyses showed higher pooled RR in high-income settings: any AEFI after dose 1, RR = 1.83 (95% CI: 1.39-2.42); local, RR = 3.15; systemic, RR = 2.05. After dose 2, overall RR reached 2.94; local, 4.37; systemic, 2.48. All subgroup differences were significant.
Conclusion
Higher-income countries showed a greater incidence of mostly mild adverse events, particularly after the second dose. mRNA vaccines had the highest rates. Findings reveal income-based disparities and inform equitable post-vaccination monitoring.
WHO. Coronavirus disease (COVID-19). World Health Organization2023; 1.
2.
YuanPAiPLiuY, et al.Safety, tolerability, and immunogenicity of COVID-19 vaccines: a systematic review and meta-analysis. SSRN Electron J. Epub ahead of print 2020. doi:10.2139/ssrn.3746259
3.
MeoSABukhariIAAkramJMeoASKlonoffDC. COVID-19 vaccines: Comparison of biological, pharmacological characteristics and adverse effects of pfizer/BioNTech and moderna vaccines. Eur Rev Med Pharmacol Sci. 2021;25:1663-1679.
4.
KhatatbehINAbu-AlfoulMN. The determinants of the hidden economy in developed and developing countries. Appl Econ Lett. Epub ahead of print 2023. doi:10.1080/13504851.2023.2208331
5.
ChenJZhangSXYinA, et al.Mental health symptoms during the COVID-19 pandemic in developing countries: a systematic review and meta-analysis. J Glob Health;12. Epub ahead of print 2022. doi:10.7189/JOGH.12.05011
6.
OshinubiKRachdiMDemongeotJ. Modeling of COVID-19 pandemic vis-à-vis some socio-economic factors. Front Appl Math Stat. 2022;7:1-25.
7.
SheikhABPalSJavedNShekharR. COVID-19 vaccination in developing nations: challenges and opportunities for innovation. Infect Dis Rep. 2021;13:429-436.
8.
SinghAKhillanRMishraYKhuranaS. The safety profile of COVID-19 vaccinations in the United States. Am J Infect Control. 2022;50:15-19.
9.
OkaforLKhalidUGamaLEM. Do the size of the tourism sector and level of digitalization affect COVID-19 economic policy response? Evidence from developed and developing countries. Curr Issues Tour. 2022;1:1368-3500.
10.
LevinATOwusu-BoaiteyNPughS, et al.Assessing the burden of COVID-19 in developing countries: systematic review, meta-analysis and public policy implications. BMJ Glob Heal. 2022;7:1-17.
11.
QuinzaniMAD. O avanço da pobreza E da desigualdade social como efeitos da crise da COVID-19 E O estado de bem-estar social. Rev UFRR. 2020;2:41-48.
12.
SallesMBHermontLMFariaRPQe S. Relação da faixa de idh dos países com a população vacinada contra COVID-19. Rev Multidiscip em Saúde. 2021;2:13.
13.
Cata-PretaBde OWehrmeisterFCSantosTMBarrosAJDVictoraCG. Patterns in wealth-related inequalities in 86 Low- and middle-income countries: global evidence on the emergence of vaccine hesitancy. Am J Prev Med. 2021;60:S24-S33.
14.
MoosaIAKhatatbehIN. Robust and fragile determinants of the severity of COVID-19 in developing and developed countries: a comparative analysis. J Bus Socio-economic Dev. 2024;4:308-325.
15.
DhamantiISuwantikaAAAdliaAYamaniLNYakubF. Adverse reactions of COVID-19 vaccines: a scoping review of observational studies. Int J Gen Med. 2023;16:609-618.
16.
LiXOstropoletsAMakadiaR, et al.Characterising the background incidence rates of adverse events of special interest for covid-19 vaccines in eight countries: multinational network cohort study. BMJ;373. Epub ahead of print 2021. doi:10.1136/bmj.n1435
17.
SakaiY. The vaccination Kuznets curve: do vaccination rates rise and fall with income?J Health Econ. 2018;57:195-205.
18.
WilsonKDucharmeRHawkenS. Association between socioeconomic status and adverse events following immunization at 2, 4, 6 and 12 months. Hum Vaccin Immunother. 2013;9:1153-1157.
19.
Lanza-LeónPCantarero-PrietoDPascual-SáezM. Exploring trends and determinants of basic childhood vaccination coverage: empirical evidence over 41 years. PLoS One. 2024;19:e0300404.
20.
DuanYShiJWangZZhouSJinYZhengZJ. Disparities in COVID-19 vaccination among low-middle-and high-income countries: the mediating role of vaccination policy. Vaccines. 2021;9:905.
21.
PageMJMcKenzieJEBossuytPM, et al.The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ;372. Epub ahead of print 2021. doi:10.1136/bmj.n71
22.
MethleyAMCampbellSChew-GrahamCMcNallyRCheraghi-SohiS. PICO, PICOS and SPIDER: a comparison study of specificity and sensitivity in three search tools for qualitative systematic reviews. BMC Health Serv Res. 2014;14:579.
ZhuF-CGuanX-HLiY-H, et al.Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: a randomised, double-blind, placebocontrolled, phase 2 trial. Lancet. 2020;396:479-488.
25.
SadoffJLe GarsMShukarevG, et al.Interim results of a phase 1-2a trial of Ad26.COV2.S Covid-19 vaccine. N Engl J Med. 2021;384:1824-1835.
26.
ZhangYZengGPanH, et al.Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial. Lancet Infect Dis. 2021;21:181-192.
27.
ChuLMcpheeRHuangW, et al.A preliminary report of a randomized controlled phase 2 trial of the safety and immunogenicity of mRNA-1273 SARS-CoV-2 vaccine. Vaccine. 2021;39:2791-2799.
28.
MasudaTMurakamiKSugiuraKSakuiSPhilip SchuringRMoriM. A phase 1/2 randomised placebo-controlled study of the COVID-19 vaccine mRNA-1273 in healthy Japanese adults: an interim report. Vaccine. 2022;40:2044-2052.
29.
MadhiSAMoodleyDHanleyS, et al.Immunogenicity and safety of a SARS-CoV-2 recombinant spike protein nanoparticle vaccine in people living with and without HIV-1 infection: a randomised, controlled, phase 2A/2B trial. Lancet HIV. 2022;9:e309-e322.
30.
MasudaTMurakamiKSugiuraKSakuiSSchuringRPMoriM. Safety and immunogenicity of NVX-CoV2373 (TAK-019) vaccine in healthy Japanese adults: interim report of a phase I/II randomized controlled trial. Vaccine. 2022;40:3380-3388.
31.
AsanoMOkadaHItohY, et al.Immunogenicity and safety of AZD1222 (ChAdOx1 nCoV-19) against SARS-CoV-2 in Japan: a double-blind, randomized controlled phase 1/2 trial. Int J Infect Dis. 2022;114:165-174.
32.
FolegattiPMEwerKJAleyPK, et al.Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial. Lancet. 2020;396:467-478.
33.
WalshEEFrenckRWFalseyAR, et al.Safety and immunogenicity of two RNA-based Covid-19 vaccine candidates. N Engl J Med. 2020;383:2439-2450.
34.
LiJHuiAZhangX, et al.Safety and immunogenicity of the SARS-CoV-2 BNT162b1 mRNA vaccine in younger and older Chinese adults: a randomized, placebo-controlled, double-blind phase 1 study. Nat Med. 2021;27:1062-1070.
35.
BadenLREl SahlyHMEssinkB, et al.Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N Engl J Med. 2021;384:403-416.
36.
SmithKHegazyKCaiMRMcKnightIRousculpMDAlvesK. Safety of the NVX-CoV2373 COVID-19 vaccine in randomized placebo-controlled clinical trials. Vaccine. 2023;41:3930-3936.
37.
DunkleLMKotloffKLGayCL, et al.Efficacy and safety of NVX-CoV2373 in adults in the United States and Mexico. N Engl J Med. 2022;386:531-543.
38.
Ministério da Saúde (Brasil). Calendário Nacional de Vacinação.
39.
ChenMYuanYZhouY, et al.Safety of SARS-CoV-2 vaccines: a systematic review and meta-analysis of randomized controlled trials. Infect Dis Poverty. 2021;10:1-12.
40.
KouhpayehHAnsariH. Adverse events following COVID-19 vaccination: a systematic review and meta-analysis. Int Immunopharmacol;109: Epub ahead of print 2022. doi:10.1016/j.intimp.2022.108906
41.
PulendranBArunachalamPO’HaganDT. Emerging concepts in the science of vaccine adjuvants. Nat Rev Drug Discov. 2021;20:454-475.
42.
DucDADinhVTHaiVH, et al.Safety and immunogenicity of an egg-based inactivated Newcastle disease virus vaccine expressing SARS-CoV-2 spike: interim results of a randomized, placebo-controlled, phase 1/2 trial in Vietnam. Vaccine. 2022;40:3621-3632.
43.
PitisuttithumPLuviraVLawpoolsriS, et al.Safety and immunogenicity of an inactivated recombinant Newcastle disease virus vaccine expressing SARS-CoV-2 spike: interim results of a randomised, placebo-controlled, phase 1 trial. eClinicalMedicine;45. Epub ahead of print 2022. doi:10.1016/j.eclinm.2022.101323
44.
RawRKReesJKellyCAWroeCChadwickDR. Prior COVID-19 infection is associated with increased adverse events (AEs) after the first, but not the second, dose of the BNT162b2/Pfizer vaccine. Vaccine. 2022;40:418-423.
45.
WiYMKimSHPeckKR. Early adverse events between mrna and adenovirus-vectored covid-19 vaccines in healthcare workers. Vaccines. 2021;9:1-7.
46.
AndradeMLUeharaL. Adverse effects after vaccination against sars-cov-2 ( covid-19 ) in down syndrome adults efeito adverso pós-vacinação contra a covid-19 em adultos com introduction in December 2019, a new coronavirus, SARS-CoV-2, was identified after a reported outbre. 2023;2:1-9.
47.
IdowuAOOmosunYOIgietsemeJU, et al.The COVID-19 pandemic in Sub-Saharan Africa: the significance of presumed immune sufficiency. Afr J Lab Med. 1964;12. Epub ahead of print 30 January 2023. doi:10.4102/ajlm.v12i1
48.
GuJLiuQZhangJ, et al.COVID-19 and trained immunity: the inflammatory burden of long covid. Front Immunol;14. Epub ahead of print 28 November 2023. doi:10.3389/fimmu.2023.1294959
49.
OmolekeSABamideleMde KievLC. Barriers to optimal AEFI surveillance and documentation in Nigeria: findings from a qualitative survey. PLOS Glob Public Heal. 2023;3:e0001658.
50.
MenangOKuemmerleAMaigetterKBurriC. Strategies and interventions to strengthen pharmacovigilance systems in low-income and middle-income countries: a scoping review. BMJ Open. 2023;13:e071079.
51.
RadwanM. Disclosing adverse events in healthcare: understanding the gap between knowledge and practice in developing countries. Glob J Qual Saf Healthc. 2022;5:82-83.
52.
Adedeji-AdenolaHNlootoM. Direct reporting of adverse drug reactions by healthcare consumers in Africa: a narrative review. Int J Clin Pharm. 2020;43:11-24.
53.
AubelJChibandaD. The neglect of culture in global health research and practice. BMJ Glob Heal;7. Epub ahead of print 2022. doi:10.1136/bmjgh-2022-009914
54.
AngelRThoitsP. The impact of culture on the cognitive structure of illness. Cult Med Psychiatry. 1987;11:465-494.
55.
KudhailKThompsonJMathewsVMorrisonBHemmingK. Randomized controlled trials in patients with COVID-19: a systematic review and critical appraisal. Int J Infect Dis. 2022;122:72-80.
56.
GiduduJFShaumADodooA, et al.Barriers to healthcare workers reporting adverse events following immunization in four regions of Ghana. Vaccine. 2020;38:1009-1014.
57.
AmdanyHBKoechBB. Best practice implementation on reporting of coronavirus disease 2019 vaccine adverse events following immunization in Uasin Gishu County, Kenya. JBI Evid Implement. 2023;21:146-155.
58.
BraithwaiteJHerkesJLudlowK, et al.Association between organisational and workplace cultures, and patient outcomes: systematic review. BMJOpen;7. Epub ahead of print2017. doi:10.1136/bmjopen-2017-017708
59.
SeverP. Nocebo affects after COVID-19 vaccination. Lancet Reg Health Eur. 2022;12:100273.
60.
AmanzioMMitsikostasDDGiovannelliFBartoliMCiprianiGEBrownWA. Adverse events of active and placebo groups in SARS-CoV-2 vaccine randomized trials: a systematic review. Lancet Reg Health Eur. 2022;12:100253.
61.
CashmanPMacartneyKKhandakerGKingCGoldMDurrheimDN. Participant-centred active surveillance of adverse events following immunisation: a narrative review. Int Health. 2017;9:164-176.
62.
WHO coronavirus (COVID-19) dashboard.
63.
LeiJBalakrishnanMRGiduduJFZuberPLF. Use of a new global indicator for vaccine safety surveillance and trends in adverse events following immunization reporting 2000-2015. Vaccine. 2018;36:1577-1582.
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