Published: December 1998

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Vaccine Adverse Reactions: Separating Fact from Speculation

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Prescriber Update 17: 20-24
December 1998

Medsafe Editorial Team

The US Institute of Medicine reviewed data on certain possible vaccine adverse reactions. The evidence established causal relationships for:

• anaphylaxis with DTP, DT/Td/T, MMR and hepatitis B vaccines;
• death from a vaccine-strain infection (largely in immunocompromised individuals and extremely rare) with measles and polio vaccines;
• poliomyelitis in a contact of the recipient with oral polio vaccine;
• DTP vaccine and protracted, inconsolable crying;
• MMR vaccine and thrombocytopenia; and
• rubella vaccine and acute arthritis.

Evidence favoured (but did not establish) a number of causal relationships.

Following a review of certain data the New Zealand Medicines Adverse Reactions Committee concluded that the biological plausibility for a causal relationship between vaccination against measles and inflammatory bowel disease (IBD) and autism was no better than tenuous, and the best epidemiological evidence did not support an association with IBD. Further, if a causal connection exists between chronic arthropathy and rubella vaccine, the incidence is very low.

The US Institute of Medicine conducted a rigorous review of data available on certain possible adverse reactions of vaccines as requested by the Federal Government.^1,2 The interdisciplinary committee conducting the review covered published and unpublished data in five categories: human experiments; animal studies; case-control studies, cohort studies and other controlled studies; case reports and case report series; and biological plausibility. The analysis was completed in September 1993. The results are presented in the table below.

After reviewing the evidence the Committee reached one of five conclusions with regard to causality for each of the adverse reactions reviewed, depending on the nature and strength of evidence. The conclusions are used in the table and are explained here:

1. No evidence bearing on a causal relationship. There was no evidence in any category bearing on the causal relationship between these events and the vaccine in question.
2. Evidence inadequate and inconclusive. Evidence relating to causality was found in one or more categories, but was not found to be adequate to determine whether causality existed.
3. Evidence against a causal relationship. On balance the available evidence was against the existence of a causal relationship.
4. Evidence favours a causal relationship. On balance the evidence supports a causal relationship.
5. Evidence establishes a causal relationship. The evidence is in support of a causal relationship, and is stronger than that found in conclusion 4.

The review committee considered that if evidence established a causal relationship between a vaccine and an event, a causal relationship also exists between a composite vaccine containing that vaccine component and that event. For example, the evidence favours a causal relationship between Guillain-Barré syndrome and DT vaccine; and hence favours such a relationship with DTP vaccine.

The review of the Institute of Medicine did not include assessment of incidence. However, while some of the non-serious reactions (such as protracted, inconsolable crying) are relatively common, all of the serious adverse reactions included in the table are very rare.

Recently the Medicines Adverse Reactions Committee (MARC) has reviewed some evidence on inflammatory bowel disease (IBD) and measles vaccine, and chronic arthropathy and rubella vaccine. The results of this review are included in the final column of the table.

In the last 12 months there have been two waves of speculation in New Zealand that there may be a causal association between measles or MMR vaccine and IBD and autism. Both waves have been generated by the same group in London. The first wave resulted from a poorly controlled case-control study which found an increased risk of IBD in those who had received measles vaccination.³ A subsequent more rigorously conducted epidemiological study found no association.⁴ The second wave of speculation was initiated by a case series of 12 children with IBD and autism.⁵ IBD was thought to have led to autism by altering absorption. The evidence was discussed in the April 1998 edition of Prescriber Update.⁶ The MARC concluded that the biological basis for a causal connection with measles vaccination is speculative, and the best epidemiological evidence suggests there is no association.

At the time of its review, the Institute of Medicine committee concluded that evidence favoured a causal relationship between chronic arthritis and rubella vaccine in women (conclusion 4). Note that this conclusion is not included in the table. Two more recent studies have been reviewed by the MARC. One of these was a prospective randomised study that found a marginally significant excess of risk of persistent joint problems in women who had received rubella vaccine.⁷ However, the background rate of chronic arthropathy in this study was higher than would have been expected. The second study, published soon after, found no evidence of chronic arthropathy being causally associated with rubella vaccination in women.⁸ The study had a case-control design and both cases and controls were selected from women who were registered with a large health maintenance programme in California. The results of a smaller study published in 1995 also failed to find an association with chronic arthropathy.⁹ The MARC concluded that, if an association does exist, the excess risk of chronic arthropathy following rubella vaccine is very small.

The following table is presented for the benefit of general practitioners or nurses counselling members of the public on the safety of vaccination.

Table: The conclusions of reviews of vaccine adverse reactions by the US Institute of Medicine and the New Zealand Medicines Adverse Reactions Committee (MARC).

Vaccine	1: no evidence bearing on a causal relationship*	2: evidence inadequate and inconclusive*	3: evidence against a causal relationship*	4: evidence favours a causal relationship*	5: evidence establishes a causal re-lationship*	Evidence reviewed by MARC#
DTP+	Autism	Aseptic meningitis Chronic neurological  damage§ Erythema-multiforme GBS+ Haemolytic anaemia Juvenile diabetes Learning disabilities Peripheral mononeuropathy Thrombocytopenia	Infantile spasms Hypsarrhythmia Reye’s syndrome SIDS+	Acute encephalopathy Shock and shock-like state (hypotonic, hyporesponsive episodes)ƒ	Anaphylaxis Protracted, inconsolable crying
DT/Td /T+		Residual seizure disorder (except infantile spasm) Demyelinating diseases of CNS Mononeuropathy Arthritis Erythema multiforme	Encephalopathy Infantile spasms (DT only) SIDS (DT only)	GBS† Brachial neuritis	Anaphylaxis
MMR+		Sensorineural deafness			Thrombocytopenia Anaphylaxis
Measles		Encephalopathy Subacute sclerosing panencephalitis Residual seizure disorder Optic neuritis Transverse myelitis GBS Thrombocytopenia Insulin-dependent diabetes mellitus		Anaphylaxis	Death from measles vaccine-strain viral infection†	Inflammatory bowel disease and autism (biological plausability speculative; best epidemi-ological evidence negative)‡
Mumps	Neuropathy Residual seizure disorder	Encephalopathy Aseptic meningitis Insulin-dependent diabetes mellitus Sterility Thrombocytopenia Anaphylaxis
Rubella		Radiculoneuritis and other neuropathies Thrombocytopenic purpura			Acute arthritis	Chronic arthropathy (balance of evidence negative)£
Hepatitis B		GBS Demyelinating diseases of CNS Arthritis SIDS			Anaphylaxis
OPV /IPV+	Transverse myelitis (IPV) Thrombocyto-penia (IPV) Anaphylaxis (IPV)	Transverse myelitis (OPV) GBS (IPV) SIDS		GBS (OPV)	Poliomyelitis in recipient or contact (OPV) Death from polio vaccine-strain infection†
Hib+		GBS Transverse myelitis Thrombocytopenia Anaphylaxis SIDS	Early-onset Hib disease

* See text for an explanation of the categories of conclusion. The information in these columns comes from a review by the US Institute of Medicine.
# The review by the MARC was not as comprehensive with respect to data as that of the Institute of Medicine. Hence it was not appropriate to use the same conclusions.
§ This issue was further analysed by the Institute of Medicine in Stratton KR, Howe CJ, Johnston RB (Ed) DPT vaccine and chronic nervous system dysfunction: a new analysis National Academy Press Washington, DC, 1994, using the data from the National Childhood Encephalopathy Study, United Kingdom, see Miller DL, et al. BMJ 1993;307:1171-6. The findings are mentioned in Immunisation Handbook Ministry of Health, Wellington, NZ, 1996, p.68-9.
⁺ Abbreviations: DTP (diphtheria-tetanus-pertussis vaccine), DT (diphtheria-tetanus toxoid for paediatric use), Td (adult diphtheria-tetanus toxoid), T (tetanus vaccine), MMR (measles-mumps-rubella vaccine), OPV (oral polio vaccine), IPV (inactivated polio vaccine), Hib (Haemophilus influenzae type b vaccine), GBS (Guillain-Barré syndrome) and SIDS (sudden infant death syndrome).
ƒ The Institute of Medicine concluded the evidence is inadequate or inconclusive with regard to a causal relationship between hypotonic, hyporesponsive episodes and death or permanent disability.
† Data largely from immunocompromised individuals.
‡ References 3-5.
£ References 6-8.

References

1. Howson CP, Fineberg HV. Adverse events following pertussis and rubella vaccines. JAMA 1992;267:392-6.
2. Stratton KR, Howe CJ, Johnston RB. Adverse events associated with childhood vaccines other than pertussis and rubella. JAMA 1994;271:1602-5.
3. Thompson NP, Montgomery SM, Pounder RE, Wakefield AJ. Is measles vaccination a risk factor for inflammatory bowel disease? Lancet 1995;345:1071-4.
4. Feeney M, Clegg A, Winwood P, Snook J. A case-control study of measles vaccination and inflammatory bowel disease. Lancet 1997;350:764-6.
5. Wakefield AJ, Murch SH, et al. Ileal-lymphoid-nodular hyperplasia, non-specific colitis, and pervasive developmental disorder in children. Lancet 1998;351:637-41.
6. Mansoor O. MMR vaccine, bowel disease and autism. Prescriber Update No.16, Apr 1998, p.41-2.
7. Tingle AJ, Mitchell LA, Grace M, et al. Randomised double-blind placebo-controlled study on adverse effects of rubella immunisation in seronegative women. Lancet 1997;349:1277-81.
8. Ray P, Black S, Shinefield H, et al. Risk of chronic arthropathy among women after rubella vaccination. JAMA 1997;278:551-6.
9. Slater PE, Ben-Zvi T, Fogel A, et al. Absence of an association between rubella vaccination and arthritis in underimmune postpartum women. Vaccine 1995;13:1529-32.