Neurology -- Correspondence for Hernán et al., 63 (5) 838-842

Correspondence published:

Recombinant hepatitis B vaccine and the risk of multiple sclerosis: A prospective study: C Raina MacIntyre, Heath Kelly, Damien Jolley, Helmut Butzkueven, Daniel Salmon, Neal Halsey, Lawrence H Moulton (11 November 2004)

Recombinant hepatitis B vaccine and the risk of multiple sclerosis: A prospective study: Frank DeStefano, Eric S. Weintraub and Robert T. Chen (11 November 2004)

Reply to DeStefano and MacIntyre: Miguel A Hernán, Susan S. Jick (11 November 2004)

Recombinant hepatitis B vaccine and the risk of multiple sclerosis: A prospective study 11 November 2004

C Raina MacIntyre,
National Centre for Immunisation Research, Australia
NCIRS, Children's Hospital at Westmead and University of Sydney, Westmead, 2145, NSW, Australia,
Heath Kelly, Damien Jolley, Helmut Butzkueven, Daniel Salmon, Neal Halsey, Lawrence H Moulton
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Re: Recombinant hepatitis B vaccine and the risk of multiple sclerosis: A prospective study

RainaM{at}chw.edu.au C Raina MacIntyre, et al.

Hernan et al [1] report an association between hepatitis B vaccine (HBV) and multiple sclerosis (MS) in a study mislabelled as “prospective”. Although the source data were recorded prospectively, this is a retrospective nested case control study. This introduces potential biases, such as ascertainment of HBV status when vaccinations were recorded in the notes but not in the computerized database.
The UK HBV program is targeted at people at high risk of infection. [2] However, uptake of HBV is sub-optimal in these groups [3,4], so that vaccinated individuals are those at highest risk. This means that HBV status was highly likely to be confounded by risk factors such as intravenous drug use (IVDU) and sexual practice, neither of which were adjusted for by Hernan. [1]
IVDU is associated with immune-mediated diseases, which may include MS. [5] The sub-analysis excluding the 2% of subjects with “risk factors” was inadequate, as it excluded only people whose records indicated a history of occupational risk, alcoholism, drug abuse or chronic renal failure. Most of this information on these and other critical variables was not in the database or medical records. The inclusion of influenza and tetanus vaccinations does not rule out bias, which could operate selectively for exposure to HB vaccination.
Only 163 of the 438 eligible cases were included in the study, creating the potential for bias in ascertaining cases, and in selectively determining onset and severity of symptoms for vaccinated cases. The principal analysis was based on only 11 vaccinated patients with MS. [1] This may explain an association between HBV and MS when analyzed by date of symptom onset, but not by date of diagnosis. The diagnosis was made in the past, independently of the study investigators, while the investigators determined date of symptom onset. Data for cases came from both the database and notes, whereas data on controls were obtained only from the database.
Upper respiratory tract infections exacerbate or trigger MS within a few weeks, so why would HBV trigger MS three years after vaccination? HBV is a subunit of the HB virus, which is not one of the many viruses previously implicated in MS. Using the Bradford Hill criteria for causation, the criteria of biological plausibility, consistency, coherence and dose–response are not met. The temporal association reported in this study requires one to assume a long lead-time, and is perhaps the strongest single argument in favor of a spurious association. The large body of negative evidence and the significant methodological weaknesses of the study indicate no need for change in vaccination policy.
References
1. Hernan MA, Jick SS, Olek MJ, Jick H. Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study. Neurology 2004; 63:838-42.
2. Goldberg D, McMenamin J. The United Kingdom’s hepatitis B vaccination strategy – where now? Communicable Disease and Public Health 1998; 1:79-83.
3. Opaneye AA. Bashford J. Audit of hepatitis B immunization at the genitourinary medicine department in Middlesbrough, UK.International Journal of STD & AIDS. 13:268-70, 2002 Apr.
4. Dunn J, Shukla R, Neal K. Survey of neonatal hepatitis B vaccination in Leicestershire. Communicable Disease & Public Health 1999;2:218-9
5. Brosseau L, Philippe P, Methot G, Duquette P, Haraoui B. Drug abuse as a risk factor of multiple sclerosis: case-control analysis and a study of heterogeneity. Neuroepidemiology 1993; 12:6-14.

Recombinant hepatitis B vaccine and the risk of multiple sclerosis: A prospective study 11 November 2004

Frank DeStefano,
Centers for Disease Control and Prevention
MS E61, 1600 Clifton Rd., Atlanta, GA 30333,
Eric S. Weintraub and Robert T. Chen
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Re: Recombinant hepatitis B vaccine and the risk of multiple sclerosis: A prospective study

fxd1{at}cdc.gov Frank DeStefano, et al.

Hernan et al found a puzzling increased risk of multiple sclerosis (MS) within three years of a hepatitis B vaccination. [1] No previous epidemiological study has found a significantly increased risk and a review by the U.S. Institute of Medicine determined that the evidence favors rejection of a causal association between hepatitis B vaccine and MS. [2]
We conducted one of the studies that did not find an increased risk. [3]. Differences between our study, which was conducted in three large U.S. health maintenance organizations, and the GPRD study included: we evaluated optic neuritis as well as MS; we included information from personal interviews in addition to medical record data; and we evaluated different time intervals. To determine if these differences could account for the different findings, we reanalyzed our data using similar methods as the GPRD study. [4]
In the re-analysis, we included only MS cases (according to the International Panel criteria), assessed relative risks by single years after vaccination, and further restricted the analysis to documented data. When we restricted to medical records data, we identified 119 eligible MS cases, of which only three had been vaccinated. The odds ratios (ORs) were 0.4 (95% confidence interval, 0.1 – 1.5) for ever versus never vaccinated, and 1.4 (0.1 - 23.6) for 0-1 year and 0.8 (0.1 - 8.9) for > 5 years after vaccination; in the intervening years ORs could not be estimated due to lack of vaccinated cases or controls. When we supplemented the medical record data with information from the standardized personal interviews, we were able to include 276 cases of MS in the analysis; the OR for ever versus never vaccinated was 0.8 (0.4 – 1.4). According to timing of vaccination, the ORs were 0.7 (0.3 - 2.0), 0.7 (0.2 - 2.5), and 0.6 (0.1 - 3.1), respectively, for 0-1, 1-2, and 2-3 years after vaccination. The main concern with the analysis that included interview data is possible preferential recall of vaccinations by the cases. That all the OR point estimates were <1.0 argues against this possibility.
We found no increased risk of MS overall or at any time during the first three years after hepatitis B vaccination. Restricting the analysis to data from medical records did not alter this conclusion.
References
1. Hernan MA, Jick SS, Olek MJ, Jick H. Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study. Neurology 2004;63:838-842.
2. Institute of Medicine. Hepatitis B vaccine and demyelinating neurological disorders. In: Stratton K, Almario DA, McCormick MC, eds. Immunization safety review. Washington, DC: The National Academies Press, 2002.
3. DeStefano F, Verstraeten T, Jackson LA, et al. Vaccinations and risk of central nervous system demyelinating diseases in adults. Arch Neurol 2003;60:504–509.
4. DeStefano F, Weintraub ES, Chen RT. Detemining risk of multiple sclerosis after hepatitis B vaccine: Time since vaccination and source of data. Pharmacoepidemiol Drug Safety 2004;13:S143.

Reply to DeStefano and MacIntyre 11 November 2004

Miguel A Hernán,
Harvard School of Public Health
677 Huntington Avenue, Boston, MA 02115,
Susan S. Jick
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Re: Reply to DeStefano and MacIntyre

miguel_hernan{at}post.harvard.edu Miguel A Hernán, et al.

We welcome the reanalysis by DeStefano et al which not only constitutes a methodologic improvement, but also allows for a more direct comparison with our estimates. Unfortunately, the stricter criteria used in the reanalysis resulted in period-specific estimates with confidence intervals too wide to draw firm conclusions. This sample size problem would have only been aggravated had the authors mimicked our eligibility criteria more closely by restricting their cohort to individuals who were members of the health maintenance organizations for at least, say, three years before the start of follow-up (see below).
MacIntyre et al do not consider ours to be a prospective study. We believe this is a semantic disagreement. In our study, the exposure information was collected before first symptoms of MS. This key feature of fully prospective investigations prevents recall bias. Whether the investigators made the decision to conduct this study in 1990 or in 2000 is irrelevant: the information was collected in the same way and would not change because of the timing of the decision. The hypothesis that intravenous drug use and sexual practices are important risk factors for MS needs to be tested given its potential consequences for MS research.
MacIntyre et al are concerned about our exclusion of cases who had MS before the start of follow-up. To understand the rationale for this exclusion, it is helpful to consider two cohorts with different eligibility criteria: (a) all individuals without MS at start of follow- up; (b) individuals without MS at start of follow-up who had at least three years of computerized information. An individual’s follow-up starts at her first computer record in cohort (a), and three years after her first computer record in cohort (b). All individuals in (b) had the opportunity to have their exposure recorded during the three-year period prior to the start of follow-up, thus reducing bias from between-subject differences in exposure misclassification. Of the 438 MS cases, 282 in (a) and 163 in (b) occurred after the start of follow-up; the odds ratios estimated from case-control studies nested in these cohorts were 2.7 for (a) and 3.1 for (b).1 As a further clarification, our exposure information came from the computerized records only. Paper medical records were used to confirm the cases’ diagnosis and to determine their date of first symptoms.
Finally, MacIntyre et al’s questions about the time between HB vaccination and MS onset are crucial. Future research efforts should be directed towards answering them.
1. Hernán MA, Jick SS, Olek MJ, Jick H. Recombinant hepatitis B vaccine and the risk of multiple sclerosis: a prospective study. Neurology 2004; 63:838- 42.