Conclusion
Myocardial infarction (MI) has been associated with natural influenza infection, and stroke has been associated with natural varicella infection, albeit both very rarely. Thus, influenza vaccine prevents MI and varicella vaccine prevents stroke by protecting against natural infection. Vaccines currently routinely recommended to the general population in the U.S.* have not been shown to cause myocardial infarction or stroke. Influenza vaccine has been associated with a reduced risk of stroke.
Epidemiological Evidence
The 2012 report by the Institute of Medicine (IOM), now called the National Academy of Medicine (NAM), described one study with sufficient validity and precision that reported a decreased risk of both MI and stroke within the first month after influenza vaccine 1. The report also described one study assessing stroke and varicella vaccine (Varivax®) 2, but this study did not provide convincing evidence due to a lack of validity and precision 3.
Since the 2012 IOM report, a matched case-control study of 78,706 persons found that receipt of seasonal influenza vaccine within the previous year was significantly associated with lower odds of MI (adjusted odds ratio: 0.81; 95% confidence interval: 0.77-0.85) and receipt of pneumococcal vaccine was not associated with a change in odds of MI in adults 4. Another matched case-control study of 94,022 persons found that receipt of seasonal influenza vaccine within-season was significantly associated with lower odds of stroke (aOR: 0.76; 95% CI: 0.72-0.80) and receipt of pneumococcal vaccine was not associated with a change in odds of stroke 5. A self-controlled case-series study of 17,853 persons found a reduction in incidence of stroke after receipt of influenza vaccine 6. In all three of these studies, early seasonal influenza vaccination (before mid-November) was much more beneficial than later seasonal influenza vaccination.
A 2017 meta-analysis also concluded that influenza vaccine was associated with a reduced risk of stroke (OR: 0.82; 95% CI: 0.75-0.91) 7.
A 2011 self-controlled case series found a decreased incidence of MI up to 60 days after seasonal influenza vaccination, ranging from a 32% reduction within the first 14 days (incidence rate ratio: 0.68; 95% CI: 0.60-0.78) to a 18% reduction within 29-59 days (IRR: 0.82; 95% CI: 0.75-0.90) 8.
A 2013 case-control study of 559 Australian patients also found decreased odds of MI after influenza vaccination (aOR: 0.55; 95% CI 0.35-0.85) 9. Pooled data from several studies examining adults with recent ischemic stroke found no association between influenza vaccination and MI or stroke 10.
Two case-control studies, one population-based cohort study, and one propensity score-matched retrospective cohort study of Taiwanese patients at least 65 years of age found decreased odds of cardiovascular events such as MI and stroke after influenza vaccination 11-14.
A 2019 Danish national population-based cohort study found influenza vaccination decreased the risk of stroke (and had no association with MI) among patients at least 65 years of age discharged from intensive care units 15.
A 2021 self-controlled case series using data from Norwegian national registers found a decreased risk of cardiovascular events such as MI and stroke following influenza vaccination, especially among higher-risk individuals (i.e., those using anti-diabetic, anti-obesity, anti-thrombotic, pulmonary, or cardiovascular medications) 16.
A 2021 randomized, double-blind, placebo-controlled, multicenter trial found that influenza vaccination shortly after an MI decreased the risk of a subsequent MI or cardiovascular mortality within the next year 17.
A 2014 review and meta-analysis suggested that among patients with coronary artery disease, influenza vaccination may lead to a decrease in incidence, morbidity, and mortality from MI (pooled relative risk: 0.39; 95% CI: 0.20-0.77) 18.
A 2015 Cochrane review determined that influenza vaccination may reduce cardiovascular mortality and combined cardiovascular events among patients with cardiovascular disease, although not enough evidence was available to establish whether influenza vaccination prevented primary cardiovascular disease 19.
A 2019 systematic review and meta-analysis of self-controlled case series studies found a decreased risk of MI in the four weeks after influenza vaccination (IRR: 0.84; 95%CI: 0.78-0.91) 20.
A 2021 systematic review and meta-analysis of studies among patients with cardiovascular disease found influenza vaccination associated with a lower risk of cardiovascular mortality and major cardiovascular events 21.
A 2021 systematic review determined influenza vaccination decreased risk of cardiovascular mortality and cardiovascular events such as MI 22.
Prospective cohorts of older adults found that receipt of pneumococcal polysaccharide vaccine was either not associated with MI or stroke 23,24 or associated with a decreased risk of acute coronary syndrome events in general 25,26. A prospective cohort of 27,204 Spanish individuals initially found a decreased risk of stroke in individuals receiving 23-valent pneumococcal polysaccharide vaccine (PPV) 27; however, this association was later refuted by the authors 28. This study did show that influenza vaccine was associated with reduced risk of death from stroke 29, and that pneumococcal vaccine was not associated with MI 30.
A retrospective observational study of adults hospitalized in the US found combined PPV and influenza vaccination was associated with a reduced risk of cardiac arrest and mortality among those admitted with MI or stroke 31. A 2020 systematic review and meta-analysis found PPV was associated with a reduced risk of cardiovascular events (RR: 0.91; 95% CI: 0.84-0.99) and MI (RR: 0.88; 95% CI: 0.79-0.98) 32.
A study in 193,083 adults at least 50 years of age found no association between herpes zoster vaccine and MI using both case-centered and self-controlled case series analyses 33. A population-based cohort study including 1.6 million Medicare beneficiaries receiving herpes zoster vaccine and 1.6 million propensity score-matched unvaccinated beneficiaries found that vaccination was associated with lower incidence of stroke 34. A self-controlled case series among Australians 70-79 years old found a decreased risk of stroke (relative incidence: 0.58; 95% CI: 0.44-0.78) and no change in the risk of MI in the 42 days after herpes zoster vaccination versus control periods 35. Herpes zoster vaccine was not associated with an increased risk of stroke or cardiovascular events in numerous other safety studies 36.
Two large Vaccine Safety Datalink studies found no association between stroke and receipt of quadrivalent HPV vaccine (Gardasil®) in females age 9 to 26 37 or receipt of the DTaP-IPV combination vaccine (Kinrix®) in children age 4 to 6 38, respectively. A review of quadrivalent HPV vaccine safety data published between 2006 and 2015 found no increase in incidence of stroke compared to background rates 39.
A 2020 self-controlled risk interval analysis of Taiwanese children using nationwide data found no increased risk of ischemic stroke after varicella vaccination 40. A 2015 international case-control study concluded that routine vaccinations in childhood appear to be protective against stroke 41.
Analyses of safety surveillance data from the Vaccine Safety Datalink found no significant associations between mRNA COVID-19 vaccines and 23 serious health outcomes (including acute myocardial infarction and stroke) 42. A self-controlled case series using national English data found an increased risk of hemorrhagic stroke 15-21 days after vaccination with Comirnaty, the Pfizer-BioNTech COVID-19 vaccine (IRR: 1.38; 95% CI: 1.12-1.71) 43. Another self-controlled case series analysis using national English data found an increased risk of ischemic stroke 15-21 days after vaccination with Comirnaty (IRR: 1.12; 95%CI: 1.04-1.20) 44. A self-controlled case series analysis using national French data found no increased risk of MI or stroke among persons at least 75 years old within 14 days of vaccination with Comirnaty 45.
Proposed Biological Mechanism
Potential mechanisms for MI include viral infection and alterations in the coagulation cascade 3. MI has been associated with natural influenza infection, albeit very rarely 20,46. Potential mechanisms for stroke include direct viral infection, viral reactivation, and alterations in the coagulation cascade 3. Stroke has been associated with natural varicella infection, at an incidence of about 1 in 15,000 cases 47.
The IOM concluded that the only mechanistic evidence for an association between MI and live attenuated influenza vaccine or between stroke and varicella vaccine was knowledge about the natural infections. The IOM also concluded that there was no mechanistic evidence for an association between stroke and influenza vaccine or between MI and inactivated influenza vaccine, as the publications reviewed provided little evidence beyond a temporal association 3.
* These conclusions do not necessarily consider vaccines recommended only for special populations in the United States such as Yellow Fever vaccine (international travelers) or Smallpox vaccine (military personnel), or vaccines no longer recommended to the public such as the Janssen (J&J) COVID-19 vaccine.
References
1. Smeeth L, Thomas SL, Hall AJ, Hubbard R, Farrington P, Vallance P. Risk of myocardial infarction and stroke after acute infection or vaccination. The New England journal of medicine 2004; 351(25): 2611-8.
2. Donahue JG, Kieke BA, Yih WK, Berger NR, McCauley JS, Baggs J, Zangwill KM, Baxter R, Eriksen EM, Glanz JM, Hambidge SJ, Klein NP, Lewis EM, Marcy SM, Naleway AL, Nordin JD, Ray P, Belongia EA. Varicella vaccination and ischemic stroke in children: is there an association? Pediatrics 2009; 123(2): e228-34.
3. Institute of Medicine. In: Stratton K, Ford A, Rusch E, Clayton EW, eds. Adverse Effects of Vaccines: Evidence and Causality. Washington (DC): National Academies Press (US); 2012.
4. Siriwardena AN, Gwini SM, Coupland CA. Influenza vaccination, pneumococcal vaccination and risk of acute myocardial infarction: matched case-control study. CMAJ 2010; 182(15): 1617-23.
5. Siriwardena AN, Asghar Z, Coupland CC. Influenza and pneumococcal vaccination and risk of stroke or transient ischaemic attack-matched case control study. Vaccine 2014; 32(12): 1354-61.
6. Asghar Z, Coupland C, Siriwardena N. Influenza vaccination and risk of stroke: Self-controlled case-series study. Vaccine 2015; 33(41): 5458-63.
7. Lee KR, Bae JH, Hwang IC, Kim KK, Suh HS, Ko KD. Effect of Influenza Vaccination on Risk of Stroke: A Systematic Review and Meta-Analysis. Neuroepidemiology 2017; 48(3-4): 103-10.
8. Gwini SM, Coupland CA, Siriwardena AN. The effect of influenza vaccination on risk of acute myocardial infarction: self-controlled case-series study. Vaccine 2011; 29(6): 1145-9.
9. Macintyre CR, Heywood AE, Kovoor P, Ridda I, Seale H, Tan T, Gao Z, Katelaris AL, Siu HW, Lo V, Lindley R, Dwyer DE. Ischaemic heart disease, influenza and influenza vaccination: a prospective case control study. Heart 2013; 99(24): 1843-8.
10. Lavallee PC, Labreuche J, Fox KM, Lavados P, Mattle H, Steg PG, Amarenco P. Influenza vaccination and cardiovascular risk in patients with recent TIA and stroke. Neurology 2014; 82(21): 1905-13.
11. Lin HC, Chiu HF, Ho SC, Yang CY. Association of influenza vaccination and reduced risk of stroke hospitalization among the elderly: a population-based case-control study. International journal of environmental research and public health 2014; 11(4): 3639-49.
12. Chiang MH, Wu HH, Shih CJ, Chen YT, Kuo SC, Chen TL. Association between influenza vaccination and reduced risks of major adverse cardiovascular events in elderly patients. American heart journal 2017; 193: 1-7.
13. Hsu SY, Chen FL, Liaw YP, Huang JY, Nfor ON, Chao DY. A Matched Influenza Vaccine Strain Was Effective in Reducing the Risk of Acute Myocardial Infarction in Elderly Persons: A Population-Based Study. Medicine 2016; 95(10): e2869.
14. Wu HH, Chang YY, Kuo SC, Chen YT. Influenza vaccination and secondary prevention of cardiovascular disease among Taiwanese elders-A propensity score-matched follow-up study. PloS one 2019; 14(7): e0219172.
15. Christiansen CF, Thomsen RW, Schmidt M, Pedersen L, Sørensen HT. Influenza vaccination and 1-year risk of myocardial infarction, stroke, heart failure, pneumonia, and mortality among intensive care unit survivors aged 65 years or older: a nationwide population-based cohort study. Intensive care medicine 2019; 45(7): 957-67.
16. Sen A, Bakken IJ, Govatsmark RES, Varmdal T, Bønaa KH, Mukamal KJ, Håberg SE, Janszky I. Influenza vaccination and risk for cardiovascular events: a nationwide self-controlled case series study. BMC cardiovascular disorders 2021; 21(1): 31.
17. Fröbert O, Götberg M, Erlinge D, Akhtar Z, Christiansen EH, MacIntyre CR, Oldroyd KG, Motovska Z, Erglis A, Moer R, Hlinomaz O, Jakobsen L, Engstrøm T, Jensen LO, Fallesen CO, Jensen SE, Angerås O, Calais F, Kåregren A, Lauermann J, Mokhtari A, Nilsson J, Persson J, Stalby P, Islam A, Rahman A, Malik F, Choudhury S, Collier T, Pocock SJ, Pernow J. Influenza Vaccination After Myocardial Infarction: A Randomized, Double-Blind, Placebo-Controlled, Multicenter Trial. Circulation 2021; 144(18): 1476-84.
18. Hebsur S, Vakil E, Oetgen WJ, Kumar PN, Lazarous DF. Influenza and coronary artery disease: exploring a clinical association with myocardial infarction and analyzing the utility of vaccination in prevention of myocardial infarction. Reviews in cardiovascular medicine 2014; 15(2): 168-75.
19. Clar C, Oseni Z, Flowers N, Keshtkar-Jahromi M, Rees K. Influenza vaccines for preventing cardiovascular disease. The Cochrane database of systematic reviews 2015; (5): Cd005050.
20. Caldeira D, Rodrigues B, David C, Costa J, Pinto FJ, Ferreira JJ. The association of influenza infection and vaccine with myocardial infarction: systematic review and meta-analysis of self-controlled case series. Expert review of vaccines 2019; 18(11): 1211-7.
21. Yedlapati SH, Khan SU, Talluri S, Lone AN, Khan MZ, Khan MS, Navar AM, Gulati M, Johnson H, Baum S, Michos ED. Effects of Influenza Vaccine on Mortality and Cardiovascular Outcomes in Patients With Cardiovascular Disease: A Systematic Review and Meta-Analysis. Journal of the American Heart Association 2021; 10(6): e019636.
22. Pérez-Rubio A, San Román JA, Eiros Bouza JM. The impact of influenza vaccination on cardiovascular disease. Medicina clinica 2021; 157(1): 22-32.
23. Tseng HF, Slezak JM, Quinn VP, Sy LS, Van den Eeden SK, Jacobsen SJ. Pneumococcal vaccination and risk of acute myocardial infarction and stroke in men. Jama 2010; 303(17): 1699-706.
24. Hedlund J, Christenson B, Lundbergh P, Ortqvist A. Effects of a large-scale intervention with influenza and 23-valent pneumococcal vaccines in elderly people: a 1-year follow-up. Vaccine 2003; 21(25-26): 3906-11.
25. Eurich DT, Johnstone JJ, Minhas-Sandhu JK, Marrie TJ, Majumdar SR. Pneumococcal vaccination and risk of acute coronary syndromes in patients with pneumonia: population-based cohort study. Heart 2012; 98(14): 1072-7.
26. Vlachopoulos CV, Terentes-Printzios DG, Aznaouridis KA, Pietri PG, Stefanadis CI. Association between pneumococcal vaccination and cardiovascular outcomes: a systematic review and meta-analysis of cohort studies. European journal of preventive cardiology 2015; 22(9): 1185-99.
27. Vila-Corcoles A, Ochoa-Gondar O, Rodriguez-Blanco T, Gutierrez-Perez A, Vila-Rovira A, Gomez F, Raga X, de Diego C, Satue E, Salsench E. Clinical effectiveness of pneumococcal vaccination against acute myocardial infarction and stroke in people over 60 years: the CAPAMIS study, one-year follow-up. BMC Public Health 2012; 12: 222.
28. Vila-Corcoles A, Ochoa-Gondar O, Rodriguez-Blanco T, de Diego C, Satue E. Ineffectiveness of pneumococcal vaccination in cardiovascular prevention: the CAPAMIS study. JAMA Intern Med 2013; 173(20): 1918-20.
29. Vila-Corcoles A, Ochoa-Gondar O, Rodriguez-Blanco T, de Diego-Cabanes C, Satue-Gracia E, Vila-Rovira A, Torrente Fraga C. Evaluating clinical effectiveness of pneumococcal vaccination in preventing stroke: the CAPAMIS Study, 3-year follow-up. J Stroke Cerebrovasc Dis 2014; 23(6): 1577-84.
30. Ochoa-Gondar O, Vila-Corcoles A, Rodriguez-Blanco T, de Diego-Cabanes C, Hospital-Guardiola I, Jariod-Pamies M. Evaluating the clinical effectiveness of pneumococcal vaccination in preventing myocardial infarction: The CAPAMIS study, three-year follow-up. Vaccine 2014; 32(2): 252-7.
31. Ma J, Mena M, Mandania RA, Ghosh A, Dodoo C, Dwivedi AK, Mukherjee D. Associations between Combined Influenza and Pneumococcal Pneumonia Vaccination and Cardiovascular Outcomes. Cardiology 2021; 146(6): 772-80.
32. Marra F, Zhang A, Gillman E, Bessai K, Parhar K, Vadlamudi NK. The protective effect of pneumococcal vaccination on cardiovascular disease in adults: A systematic review and meta-analysis. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases 2020; 99: 204-13.
33. Tseng HF, Liu A, Sy L, Marcy SM, Fireman B, Weintraub E, Baggs J, Weinmann S, Baxter R, Nordin J, Daley MF, Jackson L, Jacobsen SJ. Safety of zoster vaccine in adults from a large managed-care cohort: a Vaccine Safety Datalink study. J Intern Med 2012; 271(5): 510-20.
34. Yang Q, Chang A, Tong X, Merritt R. Herpes Zoster Vaccine Live and Risk of Stroke Among Medicare Beneficiaries: A Population-Based Cohort Study. Stroke 2021; 52(5): 1712-21.
35. Totterdell J, Phillips A, Glover C, Chidwick K, Marsh J, Snelling T, Macartney K. Safety of live attenuated herpes zoster vaccine in adults 70-79 years: A self-controlled case series analysis using primary care data from Australia’s MedicineInsight program. Vaccine 2020; 38(23): 3968-79.
36. Keating GM. Shingles (herpes zoster) vaccine (zostavax((R))): a review of its use in the prevention of herpes zoster and postherpetic neuralgia in adults aged >/=50 years. Drugs 2013; 73(11): 1227-44.
37. Gee J, Naleway A, Shui I, Baggs J, Yin R, Li R, Kulldorff M, Lewis E, Fireman B, Daley MF, Klein NP, Weintraub ES. Monitoring the safety of quadrivalent human papillomavirus vaccine: findings from the Vaccine Safety Datalink. Vaccine 2011; 29(46): 8279-84.
38. Daley MF, Yih WK, Glanz JM, Hambidge SJ, Narwaney KJ, Yin R, Li L, Nelson JC, Nordin JD, Klein NP, Jacobsen SJ, Weintraub E. Safety of diphtheria, tetanus, acellular pertussis and inactivated poliovirus (DTaP-IPV) vaccine. Vaccine 2014; 32(25): 3019-24.
39. Vichnin M, Bonanni P, Klein NP, Garland SM, Block SL, Kjaer SK, Sings HL, Perez G, Haupt RM, Saah AJ, Lievano F, Velicer C, Drury R, Kuter BJ. An Overview of Quadrivalent Human Papillomavirus Vaccine Safety: 2006 to 2015. The Pediatric infectious disease journal 2015; 34(9): 983-91.
40. Liu CH, Yeh YC, Huang WT, Chie WC, Chan KA. Assessment of pre-specified adverse events following varicella vaccine: A population-based self-controlled risk interval study. Vaccine 2020; 38(11): 2495-502.
41. Fullerton HJ, Hills NK, Elkind MS, Dowling MM, Wintermark M, Glaser CA, Tan M, Rivkin MJ, Titomanlio L, Barkovich AJ, deVeber GA. Infection, vaccination, and childhood arterial ischemic stroke: Results of the VIPS study. Neurology 2015; 85(17): 1459-66.
42. Klein NP, Lewis N, Goddard K, Fireman B, Zerbo O, Hanson KE, Donahue JG, Kharbanda EO, Naleway A, Nelson JC, Xu S, Yih WK, Glanz JM, Williams JTB, Hambidge SJ, Lewin BJ, Shimabukuro TT, DeStefano F, Weintraub ES. Surveillance for Adverse Events After COVID-19 mRNA Vaccination. Jama 2021; 326(14): 1390-9.
43. Patone M, Handunnetthi L, Saatci D, Pan J, Katikireddi SV, Razvi S, Hunt D, Mei XW, Dixon S, Zaccardi F, Khunti K, Watkinson P, Coupland CAC, Doidge J, Harrison DA, Ravanan R, Sheikh A, Robertson C, Hippisley-Cox J. Neurological complications after first dose of COVID-19 vaccines and SARS-CoV-2 infection. Nature medicine 2021; 27(12): 2144-53.
44. Hippisley-Cox J, Patone M, Mei XW, Saatci D, Dixon S, Khunti K, Zaccardi F, Watkinson P, Shankar-Hari M, Doidge J, Harrison DA, Griffin SJ, Sheikh A, Coupland CAC. Risk of thrombocytopenia and thromboembolism after covid-19 vaccination and SARS-CoV-2 positive testing: self-controlled case series study. BMJ (Clinical research ed) 2021; 374: n1931.
45. Jabagi MJ, Botton J, Bertrand M, Weill A, Farrington P, Zureik M, Dray-Spira R. Myocardial Infarction, Stroke, and Pulmonary Embolism After BNT162b2 mRNA COVID-19 Vaccine in People Aged 75 Years or Older. Jama 2022; 327(1): 80-2.
46. Estabragh ZR, Mamas MA. The cardiovascular manifestations of influenza: a systematic review. Int J Cardiol 2013; 167(6): 2397-403.
47. Nagel MA, Mahalingam R, Cohrs RJ, Gilden D. Virus vasculopathy and stroke: an under-recognized cause and treatment target. Infect Disord Drug Targets 2010; 10(2): 105-11.
