Table 2

Included studies implemented near real-time vaccine safety monitoring methods (sequential analysis)

Study, Country	Data sources and period	Study design	Study subject	Vaccine studied	Adverse events studied	Analysis approach and signal detection method	Main finding
Yih, 2009 USA64	VSD (from August 2005 to May 2008)	Prospective active surveillance with observed vs expected analysis	10–64 years of age	Tdap (new vaccine)	Encephalopathy-encephalitis-meningitis, paralytic syndromes, seizures, cranial nerve disorders (including Belly's palsy) and GBS.	Weekly sequential analysis, PMaxSPRT Supplementary analysis: end of surveillance analysis, temporal clustering and logistic regression analysis	No increased risks were identified for any of the outcomes over the course of 145 weeks surveillance
Klein, 2010 USA43	VSD (from January 2006 to October 2008)	Prospective active surveillance with observed vs expected analysis	Children age 12–23 months	MMRV	Seizures and fever	Weekly sequential analysis, PMaxSPRT Supplementary analysis: temporal clustering analysis, Poisson, logistic and case-centred regression analyses	Signal for seizure during days 7–10 was identified and confirmed, IRR=1.98 (1.43–2.73)
Huang, 2010 Taiwan34	(2009/2010 season)	Prospective active surveillance with SCRI and observed vs expected analysis	≥6 months old age	H1N1 vaccine (LAMV and MIV)	Neurological, allergic and haematological AEs.	Weekly sequential analysis, BMaxSPRT and PMaxSPRT	No increased risks were identified for any of the outcomes over the course of 22 weeks follow-up
Belongia, 2010 USA22	VSD (May 2006 to May 2008)	Prospective active surveillance with observed vs expected analysis	Infant aged 4–48 weeks	Penta-Valente rota virus (new vaccine)	Intussusception and other (seizures, meningitis/encephalitis, myocarditis, Gram negative sepsis, gastrointestinal bleeding and Kawasaki syndrome)	Weekly sequential analysis, PMaxSPRT End of surveillance period analysis Single non-sequential analysis for gastrointestinal bleeding and Kawasaki syndrome	No increased risks were identified for any of the outcomes over the course of 164 weeks surveillance
Lee, 2011 USA47	VSD (November 2009 to April 2010)	Prospective active surveillance with SCRI and observed vs expected analysis	≥6 months old age	H1N1 and seasonal influenza vaccine	11 potential neurological, allergic and cardiac AEs.	Weekly sequential analysis, BMaxSPRT and PMaxSPRT Supplementary analysis: Temporal cluster analysis and Case-centred logistic regression	Signal was observed for Bell’s palsy at week 20, but not confirmed after further analysis
Gee, 2011 USA29	VSD (August 2006 to October 2009)	observed vs expected and Cohort with concurrent comparison	9–26-year-old female	Quadrivalent human papillomavirus vaccine (HPV4)	GBS), stroke, venous thromboembolism (VTE), appendicitis, seizures, syncope, allergic reactions, and anaphylaxis	Weekly sequential analysis, PMaxSPR and exact sequential analysis Supplementary analysis: Temporal cluster analysis and Case-centred and logistic regression analysis	Excess risk for appendicitis was identified but not confirmed
Tse, 2012 USA57	VSD (August 2010 to February 2011)	observed vs expected analysis and SCRI designs	Children ages 6–59 months	TIV	Febrile seizures in the 0–1 days following first dose TIV	Weekly analysis, both BMaxSPRT and PMaxSPRT	Excess risk for seizures identified and confirmed, IRR=2.4 (1.3–4.7)
Wise, 2012 USA62	Emerging Infections Programme (EIP) (October 2009 to May 2010)	Retrospective active surveillance with SCRI design	All individuals who received the vaccine	Influenza A (H1N1) monovalent vaccines	GBS during the 42 days following vaccination	Weekly sequential analysis, PMaxSPRT Sensitivity analysis Temporal cluster analysis	Excess risk for GBS was identified, not confirmed
Tseng, 2013 USA60	VSD (from April 2010 to January 2012)	Observed vs expected analysis	1 month to 2 years	PCV13 Vaccine	Febrile seizures, encephalopathy, urticaria and angioneurotic oedema, asthma, anaphylaxis, thrombocytopenia, Kawasaki disease	Group sequential analysis (12 repeated tests were performed)	Excess risks for encephalopathy and Kawasaki disease identified but not confirmed
Nelson, 2013 USA49	VSD (September 2008 to January 2011)	Prospective active surveillance with observed vs expected analysis	children aged 6 weeks to 2 years	DTaP-IPV-Hib (combination)	MAF, seizure, meningitis/encephalitis/myelitis, series no anaphylactic allergic reaction; not formally tested—anaphylaxis, GBS, invasive Hib disease, all hospitalisation	Group sequential testing, Poisson MaxSPRT (11 repeated tests were conducted) Sub group end-study-analysis	No increased risks were identified
Weintraub, 2014 USA61	VSD (April 2008 to March 2013)	Retrospective active surveillance with observed vs expected analysis	Infants ages of 4 and 34 weeks	Monovalent Rotavirus vaccine	Intussusception within 7 days following vaccination	Weekly sequential analysis, PMaxSPRT Temporal cluster analysis Exact logistic regression	Increased risk identified and confirmed, IRR=9.4 (1.4–103.8)
Kawai, 2014 USA39	VSD (September 2012 to February 2013)	Retrospective active surveillance with SCRI and observed vs expected analysis	6 months to 17 years and 2–49 years	TIV, LAIV (first-dose vaccine)	Seizures, GBS, encephalitis and anaphylaxis	Weekly sequential analysis, BMaxSPRT and PMaxSPRT End of surveillance Logistic regression	No increased risks for any of the outcomes were identified
Daley, 2014 USA24	VSD (January 2009 to September 2012)	Prospective active surveillance Observed vs expected analysis	4– 6 years old	DTaP-IPV combination	Meningitis/encephalitis, seizures, stroke, GBS, Stevens–Johnson syndrome and anaphylaxis	Weekly sequential analysis, PMaxSPRT and conditional MaxSPRT Posthoc analysis	No increased risks for any of the outcomes were identified
Li, 2016 USA48	VSD (June 2013 to April 2015)	Retrospective active surveillance with SCRI and observed vs expected analysis	≥6 months old age	First dose of IIV3, IIV4 and LAIV4)	Acute disseminated encephalomyelitis, anaphylaxis, Bell’s palsy, encephalitis, GBS, febrile seizures and transverse myelitis	Weekly sequential analysis using both BMaxSPRT and PMaxSPRT End of surveillance analysis after all the data have been collected	Excess risks for febrile seizure were identified and confirmed after vaccination of—IIV3: IRR=5.25 (1.57–1.75) and IIV4: IRR=12.3 (2.5–58.9)

BMaxSPRT, binomial-based maximised sequential probability; CMaxSPRT, conditional maximised sequential probability; GBS, Guillain-Barré syndrome; IIV3, trivalent inactivated influenza vaccine; IIV4, quadrivalent inactivated influenza vaccine; IRR, incidence rate ratio; LAIV, live attenuated influenza vaccine; LAMIV, live attenuated monovalent influenza vaccine; MIV, monovalent influenza vaccine; MMRV, measles, mumps, rubella and varicella vaccine; PCV13, 13-valent pneumococcal vaccine; PMaxSPRT, Poisson-based maximised sequential probability test; TIV, trivalent influenza vaccine; VSD, vaccine safety data-link.