Adverse events following immunisation with BCG vaccination: baseline data to inform monitoring in Australia following introduction of new unregistered BCG vaccine

This report examines Australian rates and reaction types of adverse events following immunisation (AEFI) with BCG vaccine between 2009 and 2014 in children aged less than 7 years, to provide baseline data and inform future monitoring following the introduction of an unregistered vaccine from early 2016. It highlights the need for improved recording of both administered BCG vaccine doses and the reporting of BCG vaccine-related AEFI in order to facilitate close monitoring of BCG vaccine safety.

Page last updated: 24 December 2016

Alexandra J Hendry, Aditi Dey, Frank H Beard, Gulam Khandaker, Richard Hill, Kristine K Macartney

Abstract

In recent years there has been a global shortage of bacille Calmette-Guérin (BCG) vaccine and, from September 2012, unregistered vaccines have needed to be used in Australia (a Danish product initially until the end of 2015, and a Polish product used in some jurisdictions from early 2016). We examined rates and types of adverse events following immunisation (AEFI) with BCG vaccine reported to the Therapeutic Goods Administration between 2009 and 2014 in children aged less than 7 years. Reporting rates of AEFI with BCG vaccine increased from 87 per 100,000 doses (registered Sanofi Pasteur product) in 2009 to 201 per 100,000 doses (unregistered Danish Statens Serum Institute product) in 2014, with Victoria having the highest rate each year. Substantial variation between jurisdictions exists, suggesting differential reporting of BCG vaccine doses administered and/or BCG vaccine-related AEFI. The most commonly reported reactions were abscess (31%), injection site reaction (27%) and lymphadenopathy/lymphadenitis (17%). This study provides baseline data on BCG vaccine safety to inform surveillance. Given the current use of unregistered vaccines in the context of vaccine supply issues, improved recording of both administered BCG vaccine doses and the reporting of BCG vaccine-related AEFI are required to facilitate close monitoring of vaccine safety. Commun Dis Intell 2016;40(4):E470–E474.

Keywords: adverse events; bacille Calmette-Guérin; vaccination

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Introduction

In Australia, bacille Calmette-Guérin (BCG) vaccine programs to protect against tuberculosis (TB) are funded by state and territory governments, rather than under the National Immunisation Program (NIP). Given the low incidence of TB in Australia, current Australian guidelines recommend BCG vaccination for groups of people who are at an increased risk of TB, in particular children aged less than 5 years who will be travelling to or living for an extended period of time in countries with a high prevalence of TB (annual TB incidence of 40 per 100,000 or more), and Aboriginal and Torres Strait Islander neonates in high-incidence communities (currently implemented in Queensland, the Northern Territory and northern South Australia only).1,2

BCG vaccine has been in use since 1921.3 As a result of repeated passage under different conditions in different laboratories, BCG vaccine strains have diverged genetically.4 The Sanofi Pasteur BCG vaccine is the only product registered for use in Australia but has been unavailable since a recall was issued in June 2012 due to a possible breach in the sterility of the product following a flood at the manufacturing plant.5 As of September 2012, an alternative unregistered vaccine (BCG Denmark-Serum Statins Institute (SSI)) was supplied under provisions of Section 19A of the Therapeutic Goods Act 1989, which allows for importation and supply of products that are registered in the specified countries under Section 19A(3) of the Therapeutic Goods Act 1989.6 However, this product has also been unavailable in Australia since 1 January 2016 and a critical shortage of BCG vaccine has been reported globally since 2013.7,8 From early 2016, another alternative unregistered Polish BCG vaccine (BCG-10) has been supplied in some jurisdictions in Australia. Whilst BCG-10 has been manufactured and registered for use in Poland since 19559 and is also available (but not registered) in some other European countries,7 Poland is not one of the Section 19A(3) specified countries. As such, it is only able to be supplied via the ‘Authorised Prescriber Scheme’ or Special Access Scheme.6

BCG vaccine is considered safe, however, it is one of the more reactogenic vaccines currently available and reactogenicity may differ between BCG vaccine strains.10 Currently there are no available longitudinal national data on adverse events following immunisation (AEFI) with BCG vaccine in Australia. To provide baseline data and inform monitoring following introduction of BCG-10 vaccine, or other unregistered vaccines, we examined rates and reaction types of BCG vaccine-related AEFI between 2009 and 2014 in children aged less than 7 years, by jurisdiction and vaccine type.

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Methods

De-identified information on BCG vaccine-related AEFI that were reported to the Therapeutic Goods Administration and entered into the Adverse Drug Reactions System (ADRS) database were extracted from a dataset released to the National Centre for Immunisation Research and Surveillance in March 2015. AEFI data where BCG vaccine was recorded as suspected of involvement were included in the analysis for children vaccinated at less than 7 years of age between 1 January 2009 and 31 December 2014.

The number of BCG vaccine doses administered was obtained from the Australian Childhood Immunisation Register (ACIR). AEFI reporting rates per 100,000 doses and 95% confidence intervals were calculated and analysed by jurisdiction and age group. Adverse reaction types were also examined. Using the date of vaccination, we determined the number of BCG vaccine doses that had been administered for each vaccine product (Sanofi Pasteur or Denmark-SSI) and the number and reporting rate of AEFI related to each of these products.

All data analyses were performed using SAS software version 9.4 (SAS Institute Inc. Cary, NC, USE) and Excel 2010 (Microsoft, Redmond, PA, USA).

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Results

Table 1 shows the number of BCG vaccine doses recorded on the ACIR between 2009 and 2014, by jurisdiction. Queensland is recorded as administering the highest number of doses each year. The ADRS database for the period 1 January 2009 to 31 December 2014 included a total of 110 AEFI reports related to BCG vaccination in children aged less than 7 years. Fifty-eight per cent of BCG AEFI reports were for males, and 68% were for children aged less than 1 year. The rate of reported BCG-related AEFI in children aged less than 7 years varied substantially between Australian states and territories, with Victoria having the highest rate each year (Table 1).

Figure 1: Adverse events following immunisation with bacille Calmette-Guérin vaccine in children aged less than 7 years, Australia, 2009 to 2014, by year of vaccination

bar and line chart. text description follows.

Source: Australian Childhood Immunisation Register and the Australian Adverse Drug Reactions System database.

Text version of Figure 1 (TXT 1 KB)

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The rate of reported BCG vaccine-related AEFI increased nationally from 87 per 100,000 doses in 2009 to 201 per 100,000 doses in 2014 (Figure 1).

Figure 2: Number of bacille Calmette-Guérin vaccine doses recorded as administered and adverse events following immunisation reporting rate per 100,000 doses in children aged less than 7 years, Australia, 2009 to 2014, by age at vaccination

bar and line chart. text description follows.

Source: Australian Childhood Immunisation Register and the Australian Adverse Drug Reactions System database.

Text version of Figure 2 (TXT 1 KB)

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Table 1: Number of bacille Calmette-Guérin vaccine doses recorded as administered and adverse events following immunisation reporting rate per 100,000 doses in children aged less than 7 years, Australia, 2009 to 2014, by state or territory and year
State or territory 2009 2010 2011 2012 2013 2014
Doses AEFI rate / 100,000 doses 95% CI Doses AEFI rate / 100,000 doses 95% CI Doses AEFI rate / 100,000 doses 95% CI Doses AEFI rate / 100,000 doses 95% CI Doses AEFI rate / 100,000 doses 95% CI Doses AEFI rate / 100,000 doses 95% CI
Source: Australian Childhood Immunisation Register and Australian Adverse Drug Reactions System database.
ACT 202 0 0–1826 181 0 0–2038 166 0 0–2222 145 0 0–2544 86 1,163 29–6479 55 0 0–6707
NSW 2,033 0 0–181 2,111 0 0–175 1,866 0 0–198 1,674 0 0–220 1,180 85 2–472 716 0 0–515
NT 1,125 267 55–779 1,018 98 3–547 1,098 182 22–658 969 103 3–575 780 128 3–714 615 0 0–600
Qld 5,782 0 0–64 6,516 15 1–86 6,025 0 0–61 5,206 19 1–107 6,007 67 18–170 4,264 0 0–87
SA 466 0 0–792 423 0 0–872 358 0 0–1030 276 0 0–1337 183 0 0–2016 87 0 0–4240
Tas. 51 0 0–7233 52 0 0–7094 46 0 0–8019 40 0 0–9222 28 0 0–13175 10 0 0–36889
Vic. 2,693 334 153–634 2,845 457 243–781 2,804 678 408–1058 2,228 763 445–1222 2,359 678 388–1101 2,496 681 397–1090
WA 1,389 0 0–266 1,094 183 22–660 853 0 0–432 607 165 4–918 440 0 0–838 233 0 0–1583
Aus. 13,741 87 45–153 14,240 119 70–191 13,216 159 98–243 11,145 180 110–277 11,063 208 132–312 8,476 201 117–321

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The large majority of BCG doses were recorded as administered to children aged less than 3 months, with the rate of reported BCG vaccine-related AEFI in this age group relatively low at 56 per 100,000 doses (Figure 2).

The 110 BCG vaccine-related AEFI reports involved 150 reaction types recorded in the ADRS database. The most commonly reported reactions were abscess (31%), injection site reaction (27%) and lymphadenopathy/ lymphadenitis (17%).

The number of BCG vaccine-related AEFI reports from the Sanofi Pasteur product and the Denmark-SSI product were 63 (57%) and 47 (43%) respectively. Table 2 displays the number of BCG vaccine-related AEFI reports and the reporting rate per 100,000 doses by vaccine product.

Table 2: Bacille Calmette-Guérin vaccine-related adverse event following immunisation number and reporting rate per 100,000 doses in children aged less than 7 years, Australia, 2009 to 2014, by vaccine product and year
Year of BCG vaccination Sanofi Pasteur product Denmark-Serum Statins Institute product
Number of AEFI AEFI rate per 100,000 doses (95% CI) Number of AEFI AEFI rate per 100,000 doses (95% CI)
– Denotes bacille Calmette-Guérin (BCG) vaccine product not in use.

AEFI Adverse event following immunisation.

Source: Australian Childhood Immunisation Register and Australian Adverse Drug Reactions System database.

2009 12 87 (45 –153)
2010 17 119 (70–191)
2011 21 159 (98–243)
2012 13 191 (102–327) 7 161 (65–332)
2013 23 208 (132–312)
2014 17 201 (117–321)

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Discussion

The rate of reported BCG vaccine-related AEFI in children aged less than 7 years appears to have been increasing in Australia since 2009. Consistent with previously published Australian and international data, we found that 58% of BCG AEFI reports were for male children,11,12 and that the rate of reported AEFI generally increased with increasing age at time of BCG vaccination.11,13 The most frequently reported BCG-related AEFI in children under the age of 7 years were localised abscesses, injection site reactions and lymphadenopathy, consistent with other published data from Australia and overseas.9,11–14

Our data shows substantial variation between jurisdictions in the reporting of BCG doses administered and BCG-related AEFI. However, this could be influenced by differential reporting of vaccination and/or AEFI. As BCG vaccination is not funded under the NIP and there are no incentives for immunisation providers to report BCG vaccination to the ACIR, it is likely that there is under-reporting of BCG vaccine dose administration. Under-reporting of AEFI is also acknowledged to be a major limitation of all passive AEFI surveillance systems including those used in Australia, due to the reliance on voluntary reporting by immunisation providers, other health professionals and consumers.15 As such the calculation of AEFI rates in our study is limited by potential inaccuracies in both numerator and denominator data. There has also been a general increase in reporting of AEFI related to other vaccines in children over our study period.16 Our finding that Victoria consistently had the highest BCG vaccine-related AEFI reporting rate could be in part due to the establishment of an enhanced passive surveillance system in 2007, which was shown to significantly improve AEFI reporting rates in its first 3 years of operation.17

Whilst our study cannot draw any conclusions about the different reactogenicity of the Sanofi product and the Denmark SSI product, due to the limitations discussed above, reactogenicity is reported to differ between BCG vaccine strains.10 The Polish BCG-10 vaccine that has been used in some jurisdictions in Australia in 2016 and is not included in this study, is derived from yet another BCG strain, BCG-Moreau. Although a low (0.2%–0.6%) frequency of BCG-AEFI has been reported from passive surveillance in Poland, understanding of its vaccine safety profile is based on this single study, and should be prospectively monitored using baseline data on other strains from Australia.9

Conclusion

As the use of unregistered BCG vaccines is likely to be needed for the foreseeable future in Australia, close monitoring of vaccine safety will be important. Our study provides baseline AEFI data against which to monitor the introduction of new, and particularly unregistered BCG vaccines, in Australia. However, improving data quality in relation to both the recording of administered BCG vaccine doses and the reporting of BCG vaccine-related AEFI will be essential to facilitate this monitoring.

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Author details

Alexandra J Hendry1

Aditi Dey1,2

Frank H Beard1,2

Gulam Khandaker1,2

Richard Hill3

Kristine K Macartney1,2

  1. National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, The Children’s Hospital at Westmead, New South Wales
  2. Discipline of Paediatrics and Child Health, University of Sydney, New South Wales
  3. Adverse Event Monitoring and Vaccine Safety, Pharmacovigilance and Special Access Branch, Therapeutic Goods Administration, Canberra, Australian Capital Territory

Corresponding author: Dr Alexandra Hendry, Research Officer, Coverage and Surveillance, National Centre for Immunisation Research and Surveillance of Vaccine Preventable Diseases, The Children’s Hospital at Westmead, Locked Bag 4001, Westmead NSW 2145. Telephone: +61 2 9845 1423. Email: alexandra.hendry@health.nsw.gov.au

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References

  1. Australian Technical Advisory Group on Immunisation. The Australian Immunisation Handbook. 10th edn. Canberra: Australian Government Department of Health and Ageing; 2013.
  2. National Tuberculosis Advisory Committee. The BCG vaccine: information and recommendations for use in Australia: National Tuberculosis Advisory Committee Update October 2012. Commun Dis Intell 2013;37(1):E65–E72.
  3. Wittes R. Immunology of bacille Calmette-Guérin and related topics. Clin Infect Dis 2000;31 Suppl 3:S59–S63.
  4. Ritz N, Hanekom WA, Robins-Browne R, Britton WJ, Curtis N. Influence of BCG vaccine strain on the immune response and protection against tuberculosis. FEMS Microbiol Rev 2008;32(5):821–841.
  5. Therapeutic Goods Administration. Tuberculosis vaccine: urgent medicine recall. 2012. Accessed on 10 April 2016. Available from: http://www.tga.gov.au/safety/recalls-medicine-tuberculosis-bcg-vaccine-120620.htm#.UqZVM6wf6OQ
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  13. Turnbull FM, McIntyre PB, Achat HM, Wang H, Stapledon R, Gold M, et al. National study of adverse reactions after vaccination with bacille Calmette-Guérin. Clin Infect Dis 2002;34(4):447–453.
  14. World Health Organization. Information Sheet. Observed rate of vaccine reactions bacille Calmette-Guérin (BCG) vaccine. 2012. Accessed on 9 February 2016. Available from: http://www.who.int/vaccine_safety/initiative/tools/BCG_Vaccine_rates_information_sheet.pdf?ua=1
  15. Isaacs D, Lawrence G, Boyd I, Ronaldson K, McEwen J. Reporting of adverse events following immunization in Australia. J Paediatr Child Health 2005;41(4):163–166.
  16. Mahajan D, Dey A, Cook J, Harvey B, Menzies R, Macartney K. Surveillance of adverse events following immunisation in Australia annual report, 2013. Commun Dis Intell 2015;39(3):E369–E386.
  17. Clothier HJ, Crawford NW, Kempe A, Buttery JP. Surveillance of adverse events following immunisation: the model of SAEFVIC, Victoria. Commun Dis Intell 2011;35(4):294–298.

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