Post-Licensure Safety of the Meningococcal Group C Conjugate Vaccine

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Dec 13, 2006 - Passive surveillance reports of adverse events following ... meningococcal serogroup C conjugate vaccine (MCCV) into its national ... so-called Yellow Card system), any suspected reaction to an MCC vaccination, whatever.
[Human Vaccines 3:2, 59-63, March/April 2007]; ©2007 Landes Bioscience

Research Paper

Post-Licensure Safety of the Meningococcal Group C Conjugate Vaccine Nick Andrews1,* Julia Stowe2,3 Elizabeth Miller2 Brent Taylor3

Abstract

3Institute of Child Health; University College London; London, UK

Previously published online as a Human Vaccines E-publication: http://www.landesbioscience.com/journals/vaccines/abstract.php?id=3878

Key words

Introduction

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vaccine safety, convulsions, ITP, purpura, meningococcal group C conjugate vaccine

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Original manuscript submitted: 12/13/06 Manuscript accepted: 01/17/06

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*Correspondence to: Nick Andrews; Statistics Unit; Health Protection Agency; Centre for Infections; London NW9 5EQ, UK; Tel.: +020.83277419; Fax: +020.83277404; Email: [email protected]

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Infections; London, UK

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1Statistics Unit; 2Immunization Department; Health Protection Agency; Centre for

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Passive surveillance reports of adverse events following meningococcal group C conjugate vaccine (MCCV) in the United Kingdom suggested a possible increased risk of convulsions and purpura��. To ����������������������������� investigate this further, ������������������������������� hospital admissions for convul� sions and purpura were obtained for the period November 1999 to September 2003 in children from the South East of England and these were linked to vaccine records for MCCV, ������ ��������������������������������������������������������������������� Diphtheria/Tetanus/Pertussis vaccine (DTP) and Measles/Mumps/Rubella vaccine (MMR). A total of 1,715 children with convulsions and 363 with purpura were successfully linked to vaccination records. The self‑controlled case‑series method was then used to investigate whether there was any epidemiological evidence of an increased risk of convulsions or purpura following vaccination. The results showed that there was no evidence of an increased relative incidence (RI) of convulsions in the two weeks following MCCV with RI estimates (95% confidence intervals) of 0.57 (0.36‑0.86), 1.03 (0.62‑1.69) and 0.81 (0.51‑1.30) for children aged < 1, 1, 2‑17 years respectively. There was also no increased relative incidence of purpura in the 4 weeks following MCCV, with an overall RI of 1.15 (0.80‑1.67). There was evidence of an increased risk of convulsions and idiopathic thrombocytopenic purpura following MMR vaccination as previously documented.

In November 1999, the United Kingdom (UK) became the first country to introduce meningococcal serogroup C conjugate vaccine (MCCV) into its national immunization programme. Infants were routinely scheduled to receive three doses at 2, 3 and 4 months with a single dose catch‑up programme for all children aged 1 to 17 years which ran from November 1999 to the end of 2000. The vaccine campaign had a large impact on group C disease with the number of cases falling from 964 in 1998/99 to only 64 in 2003/4 ‑ a 93% decline.1 Three manufacturers’ vaccines were used in the immunisation campaign, each of which had been evaluated for safety and immunogenicity in a comprehensive series of prelicensure trials in the UK.2 The safety profile in these trials had been reassuring, with no material differences between manufacturers.2,3 However, there was necessarily limited data on the occurrence of rare adverse events, particularly as MCC vaccines were licensed on the basis of immunogencity data without a large efficacy trial.2 Enhanced post‑licensure safety surveillance was therefore undertaken to identify any hitherto undetected adverse events. Health professionals were requested to report to the UK licensing authority (via the so‑called Yellow Card system), any suspected reaction to an MCC vaccination, whatever the severity. If a signal suggesting an adverse event was generated in the reports then the plan was to investigate such signals further using record linkage methods.4 Analysis of Yellow Card reports suggested that there might be an increased risk of convulsions and possibly purpura following MCCV.5 The association between these conditions and MCCV was therefore investigated using hospital episode data linked to child‑health immunisation data and analysed by the self‑controlled case series method.6 This is an established approach in the UK which has been used to investigate possible adverse vaccine events resulting in hospital admission.4 In some age groups, MCC vaccines were given concurrently with measles/mumps/rubella (MMR) or whole cell diphtheria/tetanus/pertussis (DTP) vaccines, both of which have been causally associated with convulsions, and, in the case of MMR, also with purpura.7,8,9,10 A possible effect of concomitant vaccine administration on the risk of convulsion or purpura after MCC vaccines was therefore investigated.

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Abbreviations

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Acknowledgements

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MCCV meningococcal group C conjugate vaccine DTP Diphtheria/Tetanus/Pertussis vaccine MMR Measles/Mumps/Rubella vaccine ITP idiopathic thrombocytopenic purpura UK United Kingdom ICD International Classification of Disease

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We would like to acknowledge the hospital medical-record staff who provided case-notes for validation. J.S. was funded by the Research and Development Directorate of the United Kingdom Department of Health, grant reference number 1216520.

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Table 1

Number of convulsions occurring in the study period and vaccine doses given during the study period by age group



Infants 28 to 365 days

Toddlers Age 1 yr Children Age 2‑17 yrs

Nov. 1st 1999 to Sept. 30th 2003

Nov. 1st 1999 to April 30th 2001

Nov.1st 1999 to April 30th 2001

Number of individuals

585

342

788

Convulsions

651

367

862

Febrile convulsions (R560)

338

326

500

Other/unspecified convulsions (R568)

313

41

363

MCCV doses

1 : 91

342

788



2 : 80



3 : 414 N/A

197

150

DTP doses or DT/Td

0 : 28

N/A

89



1 : 60

Study Period

MMR doses



2 : 67



3 : 430

Patients and Methods Study Period. Hospital admissions with purpura or convulsions during the period November 1st 1999 to April 30th 2001 were identified for children aged 1‑17 years vaccinated in the catch‑up programme and admissions from November 1st 1999 to September 30th 2003 for those aged 28 to 365 days who were vaccinated in the ongoing infant programme. Case Selection and Linkage to Vaccine Records. Hospital episode data from the London and South East region of England were used to obtain admissions with International Classification of Disease (ICD10) codes for convulsions (R560, R568) or purpura (D69) in any diagnostic field. Where children had more than one episode recorded, a gap of more than ten days was required between episodes for them to be regarded as separate. Excluding episodes within ten days ensured that children who were transferred between hospitals or who had a cluster of convulsions due to a single cause were not counted more than once. The selected hospital episodes were linked using NHS number, or sex, date of birth and post‑code to child‑health databases containing information on vaccination (RICHS, National, TotalCare and Cambridge) from the same region. Children were only included if they matched and had at least one dose of MCCV recorded. Information on MMR, DTP, DT and Td vaccine doses was also obtained. Children were considered in three age groups for analysis: those aged under one (infants), those aged one year (toddlers) and those aged two years or more (children). In infants the vaccines considered were MCCV (up to 3 doses) and, for convulsions DTP (up to three doses). In toddlers the vaccines considered were MCCV and MMR (dose 1) and in children MCCV, MMR (dose 2) and, for convulsions, DT and Td as well. Children were not included if they had vaccine doses recorded outside the expected age range, for example MMR under 12 months, because such data are likely to reflect incorrect recording of vaccination dates. For the purpura analyses, toddlers and children were combined due to the small number of toddlers. ‘Purpura’ was considered overall (D69) as well as in three sub‑groups: allergic purpura (D690), idiopathic thrombocytopenic purpura (ITP) (D693) and ‘others’ comprising the remaining D69 codes. 60

In order to increase the number of purpura cases in those aged 0, 1 and 2 years of age immunisation data was sought from case‑notes in a subset of those cases which did not match to a community‑system MCCV record. These cases also formed part of the validation exercise. Risk Periods. For convulsions the risk period of interest for MCCV was two weeks following vaccination—split into 0 to 3, 4 to 7 and 8 to 14 days. For DTP the main period of interest was 3 days after the third dose. For DT and Td no risk of convulsions has been documented but, to allow for a possible effect, risk periods of 0 to 3, 4 to 7 and 8 to 14 days were chosen. For MMR the risk periods of interest were 6 to 11 and 15 to 35 days post vaccination based on earlier studies with this vaccine in the UK.7,10 For purpura the risk period of interest for MCCV was 0 to 27 days post vaccination based on Yellow‑Card reports and the fact that MCCV is an inactivated vaccine. For MMR a previous study suggested that the greatest risk was 14‑27 days post vaccination for ITP with a lower risk in the two weeks before and after this.8 For this study we just considered the whole 0‑42 day period. Statistical Methods. The self‑controlled case‑series method was used for the analysis with age adjusted for in one‑month periods for infants and toddlers and in six‑month periods in children from age two to five, then one‑year periods.6 For convulsions a pre-vaccination low risk period of seven days was removed from the background by treating it as a separate ‘risk’ period to allow for possible delays in vaccination following a convulsion. For purpura a fourteen‑day prevaccination period was used, except for doses 2 and 3 of MCCV in infants, because for many children this period overlaps with the post dose 1 and 2 risk periods. Relative incidence estimates are reported with 95% confidence intervals for each age group. For convulsions in infants, an additional analysis was performed in which DTP risk periods of 0 to 3, 4 to 7 and 8 to 14 days were used after all three doses. For purpura the data were also stratified according to type of purpura (allergic, ITP and other). Validation. Validation of purpura diagnosis was performed using case‑note review in children aged 0, 1 and 2 years. The validation process included 38 cases who were matched to immunisation data by record linkage and 95 who did not match.

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Table 2

Number of purpura episodes occurring in the study period and vaccine doses given during the study period by age group

Infants 28 to 365 days Study Period

1st

Toddlers Age 1 yr Children Age 2‑17 yrs

Nov. 1999 to Sept. 30th 2003

Nov. 1st 1999 to April 30th 2001

Nov. 1st 1999 to April 30th 2001

56

40

267

tion of relative incidence and loss of study power, it does not affect estimates of attributable risk.

Results

Convulsions. A total of 1880 convulsions in 1715 individuals were matched Purpura to an MCCV record after removal of (D69) 59 41 321 those episodes within ten days of a previous episode and those with erroAllergic purpura neous vaccination dates. The breakdown (D690) 11 11 187 of these convulsions by age group and ITP ICD coding is shown in (Table 1). (D693) 9 15 84 In infants, 414/585 (71%) had three Other purpura �������� 39 15 50 vaccine doses during the study period; (D691/2/4/5/6/7/8/9)��� the remaining infants, who had one or MCCV doses 1: 13 40 267 two doses, may have received further 2: 10 doses outside the study period or had only been scheduled to receive 2 doses 3: 33 in the infant catch‑up. Similarly the MMR doses N/A 30 41 proportion of children who had MMR, DT and Td was small because most had Table 3 Relative incidence of convulsions following Meningococcal received these vaccines outside the study period. group C Vaccine, DTP, DT/Td and MMR Vaccines There was no evidence of a significantly increased risk of convulsions in any risk period for any age group Age Group Vaccine Risk Period RI (95% CI) [N] following MCCV (Table 3). For infants the risk was Infants Meningococcal ‑7 to ‑1 0.39 (0.19‑0.81) [12] significantly below 1 with a relative incidence for the Group C 0 to 3 0.60 (0.27‑1.31) [11] 0 to 14 day period of 0.57 and 95% CI 0.36 to 0.86. 4 to 7 0.65 (0.34‑1.24) [13] There was no evidence of an increased risk following 8 to 14 0.52 (0.30‑0.91) [20] DTP vaccination or DT/Td although confidence inter 0 to 14 0.57 (0.36‑ 0.86) [44] vals were wide. For MMR there was an increased risk in DTP (dose 3) ‑7 to ‑1 1.46 (0.51‑4.24) [5] the 6 to 11 day period in toddlers with a RI of 2.07 and 0 to 3 1.04 (0.28‑3.91) [3] 95% CI 1.00‑4.27. Toddlers Meningococcal ‑7 to ‑1 0.86 (0.32‑2.31) [4] Purpura. A total of 368 purpura episodes in 310 indi Group C 0 to 3 1.13 (0.47‑2.74) [5] viduals were matched to an MCCV record after removal 4 to 7 0.91 (0.36‑2.29) [5] of episodes within ten days of a previous episode. In 8 to 14 1.03 (0.52‑2.06) [10] addition, a further 53 episodes in 53 individuals were 0 to 14 1.03 (0.62‑1.69) [20] added following case‑note review, giving a total of 421 MMR ‑7 to ‑1 0 [0] episodes in 363 individuals. The breakdown of these 6 to 11 2.07 (1.00‑4.27) [10] 15 to 35 0.65 (0.36‑1.19) [12] episodes by age group and type of purpura is shown in (Table 2). The distribution of purpura cases by type of Children Meningococcal ‑7 to ‑1 0.31 (0.10‑0.96) [3] Group C 0 to 3 0.49 (0.16‑1.54) [3] purpura varied greatly by age, with “other” purpura most 4 to 7 0.68 (0.25‑1.81) [4] common in infants and allergic purpura most common 8 to 14 1.08 (0.59‑1.96) [11] in children. Because of the small number of purpura 0 to 14 0.81 (0.51‑1.30) [18] cases in toddlers combined with the fewer vaccine doses DT/Td ‑7 to ‑1 0 [0] at this age, the toddler cases were combined with older 0 to 3 2.87 (0.70‑11.75) [1] children for analysis. The number of MMR doses given 4 to 7 1.13 (0.14‑8.94) [1] was small because most children were not of the recom 8 to 14 0.60 (0.07‑4.80) [1] mended age for MMR during the study period. 0 to 14 1.33 (0.44‑4.00) [3] There was no evidence of a significantly increased MMR ‑7 to ‑1 0 [0] relative incidence of purpura in the 4 weeks following 6 to 11 1.74 (0.49‑6.14) [3] MCCV in either age group (Table 4). There was also 15 to 35 1.39 (0.71‑2.74) [9] no increased relative incidence when the analysis was 95% Confidence intervals are give in brackets ( ) and the number of hospital admissions in each period are given in square stratified by type of purpura. The overall estimate of the brackets [ ] relative incidence of purpura in the 4 weeks following MCCV when combining all age groups was 1.15 with We did not consider it necessary to validate convulsions because 95% CI 0.80‑1.67. An increased relative incidence of 6.91 with 95% previous publications have demonstrated an increased relative inci- CI 1.81‑26.4 was identified for ITP following MMR. dence following vaccination without validation of the specificity of Purpura Validation. A total of 133 case notes were reviewed of the ICD coding.7 Although lack of specificity leads to underestima- which 32 were in infants, 55 in toddlers and 46 in children aged Number of individuals

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Table 4

Relative incidence (RI) of Purpura following Meningococcal group C Vaccine and MMR Vaccine

Age Group

Vaccine

All purpura

Allergic Purpura

ITP

Other Purpura

Risk Period ��������������������������������������������������������������� RI (95% CI) [N] RI (95% CI) [N] RI (95% CI) [N] RI (95% CI) [N]

Infants �������������� Meningococcal ‑14 ������� to ‑1 ������������������������������������������������������������������ (dose 1) 0.38 (0.05‑2.81) [1] 0 [0] 0 [0] 0.60 (0.07‑4.88) [1] Group C 0 to 27 1.34 (0.66‑2.71) [17] 0.88 (0.11‑6.70) [2] 1.81 (0.31‑10.77) [4] 1.23 (0.52‑2.94) [11] Todders Meningococcal ‑14 to ‑1 and children Group C 0 to 27

0.78 (0.37‑1.67) [7] 0.96 (0.60‑1.52) [21]

1.04 (0.42‑2.55) [5] 1.12 (0.61‑2.06) [12]

0.40 (0.05‑2.89) [1] 0.97 (0.41‑2.33) [6]

0.66 (0.09‑4.88) [1] 0.78 (0.23‑2.66) [3]



MMR ‑14 to ‑1



(dose 1 or 2)

0 to 41

0 [0]

0 [0]

0 [0]

0 [0]

2.06 (1.08‑3.91) [14]

1.76 (0.69‑4.50) [6]

6.91 (1.81‑26.4) [6]

0.99 (0.16‑6.04) [2]

95% Confidence intervals are give in brackets ( ) and the number of hospital admissions in each period are given in square brackets [ ]

Table 5

Case note review of 133 Purpura cases aged under 28 days to 35 months

ICD Code ICD Description D690

Allergic purpura

D691

Qualitative platelet defects

Number Reviewed 46

Final Reviewed Diagnosis Henoch SP (43), Meningococcal septicaemia, Mild pneumonia, Bee sting

2

ITP, Genetic bleeding disorder

D692 Other non- thrombocytopenic purpura 17

HSP (6), Post viral rash (4), Purpuric rash unspecified (3), Cough induced purpura (2), ITP, Toxic shock syndrome

D693

Idiopathic thrombocytopenia purpura

ITP (38), Post viral rash, Seborrhoeic dermatitis

D694

Other primary thrombocytopenia

D695

Secondary thombocytopenia ����������������������������� 1 Myeloproliferative disorder

40 1

Post viral rash

D696 ����������������������������������������������������� Thrombocytopenia unspecified 23 Post viral rash (4), ��������������������������������� Myeloproliferative disorder (3), ����������������� Septicaemia (4), Genetic bleeding disorder (3), Toxic shock syndrome (3), Rash associated with cardiac surgery (3), Rhesus disease of new born, Near‑miss cot death, Pneumonia D699

Haemorrhagic condition unspecified

3

ITP (2), Purpuric rash

Cases in italics were deemed not to be purpura

two or more. MCCV dates were found for 62 of the 95 cases who had not matched to an MCCV vaccination date; however 9 of these doses were given outside the study period or valid age‑range. This left an additional 53 cases for inclusion in the analysis and a total of 91 validated cases included in the analysis. The results of the validation are given in (Table 5) according to the ICD diagnosis. Overall only 5/133 (4%) of cases were not purpura. Most cases were correctly assigned to the specific purpura ICD codes. Of the 5 cases incorrectly coded, 3 were among those included in the study. These cases were not removed because case‑note review was only performed on a subset.

Discussion In this large self‑controlled case‑series study no evidence was found of an increased risk of either purpura or convulsions following MCCV in children aged 0 to 18 years. This study was conducted to investigate a potential safety signal generated from suspected reactions to the newly introduced MCCV reported to the licensing authority for medicines by health professionals. In the case of purpura, there may have been concern among some health professionals that the meningococcal vaccine might cause a purpuric rash since this is a typical feature of meningococcal disease. However, since the vaccine only contains capsular polysaccharide from the meningococcus it cannot mimic disease symptoms which in the case of purpura arise from endothelial disruption caused by the septicaemia. For 62

convulsions, most of the Yellow Card cases occurred on the day of vaccination and in some instances may have been faints; cases who had received MCCV concomitantly with MMR tended to have onset of convulsions 9‑10 days after.5 Case note review was only conducted on a subset of the purpura cases included in the study. However, there is unlikely to be bias due to lack of specificity as validation of the discharge diagnosis showed high specificity with 30 of the 32 cases coded as ITP confirmed, and 43 of the 46 cases coded as allergic purpura having a diagnosis of Henoch‑Schönlein purpura (HSP) in the notes. HSP is an acute vasculitis of unknown aetiology and has been reported after a number of vaccines. It has been suggested that antigen stimulation results in the production of IgA but a causal relationship with vaccination has not been established. Our study found no evidence of an increased risk in the 4 weeks after MCCV, with an overall relative incidence of 1.15, 95% CI 0.80‑1.67. No other serious adverse reactions have been associated with the MCCV vaccine to date, although one study did report an increased risk of relapse of nephrotic syndrome.11 A later study found no such association.12 In the US, 5 cases of Guillain Barre syndrome have been reported in temporal association with a quadrivalent ACYW135 conjugate vaccine which is used routinely in adolescents and high risk individuals.13 There have also been 5 Yellow‑Card reports in the UK of Guillain Barre syndrome following MCCV. This is not more than expected due to chance association (UK Department of Health, unpublished data, 2005).

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The only associations found in this study were the known slight increased risks of convulsions and ITP following MMR vaccination. Unlike one previous study, ref 7, no increased risk was seen for convulsions following the third DTP dose, although the 95% confidence interval was fairly wide. The previous study, which spanned a period when the infant schedule changed from 3/5/10 months to 2/3/4 months, showed that the convulsions attributable to DTP were largely confined to third doses given after 6 months of age. Since there is good compliance with the recommended 2/3/4 month schedule in the UK such that most children receive their third dose on time, see ref 15, the failure to find an increased risk of convulsion after the third dose of DTP in this study is consistent with the earlier findings of Farrington.7 The reduction in risk of convulsions is probably explained by the lower incidence of post‑vaccination fever after the third dose of whole cell DTP vaccine when given at 4 months rather than 10 months and the convulsions being a direct consequence of the fever.14 The MCCV vaccine has contributed to a large decrease in cases of sero‑group C disease in the UK and elsewhere and has been shown to have high short‑term effectiveness.16 Protection may not last in the long term and has been shown to wane rapidly in children vaccinated as infants.17 A booster dose is now recommended by the licensing authority for those vaccinated in infancy. In the UK this will be given early in the second year of life with a new combined MCCV/Hib vaccine. The UK will be the first country to use the combined MCCV/Hib vaccine and, although the safety of these two vaccines when given individually or, in the case of Hib when combined with DTP, is established, the hospital‑based record linkage system described here will be used to investigate any possible safety signals that may arise from Yellow‑Cards or others sources.

15. Andrews N, Miller E, Grant A, Stowe J, Osborne V, Taylor B. Thiomersal exposure in infants and developmental disorders: A retrospective cohort study in the United Kingdom does not support a causal association. Pediatrics 2004; 114:584‑591. 16. Cano R, Larrauri A, Mateo S, Alcalá B, Salcedo C, Vázquez JA. Impact of the meningococcal C conjugate vaccine in Spain: An epidemiological and microbiological decision. Eurosurveillance 2004; 9:11‑15. 17. Trotter CL, Andrews NJ, Kaczmarski EB, Miller E, Ramsay ME. Effectiveness of meningococcal C conjugate vaccine 4 years after introduction. The Lancet 2006; 364:365‑67.

References 1. Gray SJ, Trotter CL, Ramsay ME, et al. Epidemiology of meningococcal disease in England and Wales 1993/4 to 2003/04; contribution and experiences of the Meningococcal Reference Unit. J Med Microbiol 2006; 55:887‑896. 2. Miller E, Salisbury D, Ramsay M. Planning, registration, and the implementation of an immunisation campaign against meningococcal serogroup C disease in the UK: A success story. Vaccine 2002; 20:S58‑S67. 3. Southern J, Gelb D, Andrews N, Waight PA, Morris R, Cartwright K, Miller E. Reactogenicity of meningococcal C conjugate vaccines when administered at the same time as, or a month prior to or after, tetanus and diphtheria booster vaccinations. Human Vaccines����������������� 2006; 2:237‑242. 4. Miller E, Waight P, Farrington P. Safety assessment post‑licensure. Dev Biol Stand 1998; 95:235‑436. 5. Report of the committee on safety of medicines expert working group on meningococcal group C conjugate vaccines. 21st May 2002. Web reference: www.mhra.gov.uk/home/ groups/pl‑p/documents/websiteresources/con2022528.pdf, (Accessed January 15th 2007). 6. Farrington CP. Relative incidence estimation from case series for vaccine safety evaluation. Biometrics 1995; 51:228‑235. 7. Farrington P, Pugh S, Colville A, Flower A, Nash J, Morgan‑Capner P, Rush M, Miller E. A new method for active surveillance of adverse events from diphtheria/tetanus/pertussis and measles/mumps rubella vaccine. Lancet 1995; 345:567‑69. 8. Miller E, Waight P, Farrington CP, Andrews N, Stowe J, Taylor B. Idiopathic thrombocytopenic purpura and MMR vaccine. Arch Dis Child 2001; 84:227‑229. 9. Vestergaard M, Hviid A, Madsen KM, Wohlfahrt J, Thorsen P, Schendel D, Melbye M, Olsen J. MMR vaccination and febrile seizures: Evaluation of susceptible subgroups and long‑term prognosis. JAMA 2004; 292:351‑357. 10. Miller E, Andrews N, Stowe J, Grant A, Waight P, Taylor B. The risk of convulsions and aseptic meningitis following MMR vaccination in the UK. American Journal of Epidemiology, (In Press). 11. Abeyagunawardena AS, Goldblatt D, Andrews N, Trompeter RS. Risk of relapse after meningococcal C conjugate vaccine in nephrotic syndrome. The Lancet 2003; 362:449‑50. 12. Taylor B, Andrews N, Stowe J, Hamidi‑Manesh L, Miller E.������������������������������ No increased risk of relapse after meningococcal C conjugate vaccine in childhood nephrotic syndrome. Archives of Disease in Childhood, (In Press). 13. CDC. Guillain‑barre syndrome among recipients of menactra meningococcal conjugate vaccine ‑ United states, june‑july 2005. MMWR 2005; 54, (Oct 2005). 14. Miller E, Ashworth LAE, Redhead K, Thornton C, Waight PA, Coleman T. Effect of schedule on reactogenicity and antibody persistence of acellular and whole‑cell pertussis vaccines: Value of laboratory tests as predictors of clinical performance. Vaccine 1997; 15:51‑60.

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