Pandemic Influenza A H1N1 Vaccination and Subsequent Risk of Type 1 Diabetes in Norway

To the Editor:

Given the association between the 2009 pandemic influenza A H1N1 vaccination and narcolepsy,¹ it is of interest to study other human leukocyte antigen (HLA)–associated autoimmune diseases such as type 1 diabetes. While an analysis from Stockholm did not show any association with type 1 diabetes (hazard ratio [HR] = 1.0; 95% CI = 0.7, 1.5),² a Swedish nationwide analysis showed an increased incidence of type 1 diabetes (HR = 1.23; 95% CI = 1.00, 1.51 in 10- to 19-year-olds; HR = 1.13, 95% CI = 1.00, 1.29 in all <30 years of age),³ which has raised concerns that warrant further study.⁴ Because type 1 diabetes develops over several months or years,⁵ a longer follow-up is important. During the 2009–2010 influenza pandemic in Norway, the whole population was offered an AS03-adjuvanted influenza A(H1N1)pdm09 vaccine (Pandemrix) free of charge or with a small administration fee.⁶ Using nationwide data from Norway, we investigated whether Pandemrix vaccination in 2009–2010 was associated with increased risk of subsequent type 1 diabetes from 2009 to 2014.

We included all residents in the Norwegian National Registry ages 30 years and younger per 1 October 2009. Dates of vaccination were obtained from the Norwegian Immunization Register, in which Pandemrix registration was mandatory. We identified newly onset type 1 diabetes during the period 1 October 2009 to 30 June 2014 from combining information on antidiabetic drugs dispensed from pharmacies in Norway from the Norwegian Prescription Database, specialist care diagnosis, from the Norwegian Patient Registry and primary care diagnoses from the reimbursement database (eFigure 1; https://links.lww.com/EDE/B264). These nationwide databases are independently reported and mandatory with a high level of completeness.

Information from the different sources was linked using the personal identification number assigned to all residents in Norway. Further details of the Norwegian health registries and the pandemic are given elsewhere.⁶

Type 1 diabetes was defined as registration of at least one type 1 diabetes diagnosis in primary or specialist health care combined with continuation with insulin for at least 6 months and no use of oral antidiabetic drugs within 12 months after diagnosis. To avoid any prevalent cases of diabetes at baseline, individuals who had a diagnosis of diabetes or use of any glucose-lowering medication between 2004 and 1 October 2009 were excluded. Immigrants were included only if they immigrated to Norway more than 1 year before 1 October 2009, to ensure that immigrants with prevalent diabetes did not appear as incident cases. We used Cox regression with time-dependent exposures to estimate hazard ratios (aHRs) adjusted for age, sex, place of birth, and highest level of education (in 2013) for the individual or his/her parents. The study was approved by the Regional Committee for Medical and Health Research Ethics and the Norwegian Data Protection Authority.

Of the 1,825,117 individuals in the study 40% were vaccinated with Pandemrix and 2098 were diagnosed with type 1 diabetes (incidence rate 26.5/100,000 person-years). Risk of type 1 diabetes was not increased after vaccination (aHR = 0.97; 95% CI = 0.89, 1.07), consistently throughout the follow-up period and after restricting the age group to <15 years (1,301 cases; aHR = 0.99; 95% CI = 0.88, 1.11; Figure).

FIGURE: Association between Pandemrix and subsequent risk of type 1 diabetes. A, Cumulative hazard function for development of type 1 diabetes before 30 years of age, adjusted for year of birth, sex, education, and place of birth (cumulative hazard can be interpreted approximately as a probability). B, Adjusted hazard ratios (aHR) and unadjusted hazard ratios (uHR) for type 1 diabetes by pandemic influenza A vaccination in predefined subgroups. The cumulative hazard can be interpreted as a probability. The difference between unadjusted and adjusted HR was owing to confounding by age (see eAppendix; https://links.lww.com/EDE/B264 for details).

We found no evidence of an association between vaccination with Pandemrix and risk of developing type 1 diabetes in this large, registry-based study. The study strengths include the combination of several high-quality registers and a large sample size. As in any nonrandomized study, we cannot exclude unmeasured confounding. Our results are not consistent with the suggestion of increased risk observed in Sweden after 2 years postvaccination follow-up until 2011.³ Among possible explanations for the inconsistency may be chance finding attributable multiple testing in the Swedish study, or residual confounding by age or year of birth in the Swedish study (see eAppendix; https://links.lww.com/EDE/B264 for details). We conclude that pandemic influenza A H1N1 vaccination with Pandemrix was not associated with increased risk of type 1 diabetes within 4 years of follow-up.

Paz L. D. Ruiz

Norwegian Institute of Public Health

Oslo, Norway

Department of Endocrinology, Morbid Obesity and Preventive Medicine

Oslo University Hospital

Oslo, Norway

Faculty of Medicine

University of Oslo

Oslo, Norway

Lars C. Stene

Norwegian Institute of Public Health

Oslo, Norway

Hanne L. Gulseth

Norwegian Institute of Public Health

Oslo, Norway

Department of Endocrinology, Morbid Obesity and Preventive Medicine

Oslo University Hospital

Oslo, Norway

German Tapia

Lill Trogstad

Inger J. Bakken

Siri E. Håberg

Norwegian Institute of Public Health

Oslo, Norway