Elsevier

Vaccine

Volume 37, Issue 2, 7 January 2019, Pages 280-288
Vaccine

Use of different combination diphtheria-tetanus-acellular pertussis vaccines does not increase risk of 30-day infant mortality. A population-based linkage cohort study using administrative data from the Australian Childhood Immunisation Register and the National Death Index.

https://doi.org/10.1016/j.vaccine.2018.11.025Get rights and content

Abstract

Objective

To determine whether differences in combination DTaP vaccine types at 2, 4 and 6 months of age were associated with mortality (all-cause or non-specific), within 30 days of vaccination.

Design

Observational nationwide cohort study.

Setting

Linked population data from the Australian Childhood Immunisation Register and National Death Index.

Participants

Australian infants administered a combination trivalent, quadrivalent or hexavalent DTaP vaccine (DTaP types) between January 1999 and December 2010 at 2, 4 and 6 months as part of the primary vaccination series. The study population included 2.9, 2.6, & 2.3 million children in the 2, 4 and 6 month vaccine cohorts, respectively.

Main outcome measures

Infants were evaluated for the primary outcome of all-cause mortality within 30 days. A secondary outcome was non-specific mortality (unknown cause of death) within 30 days of vaccination. Non-specific mortality was defined as underlying or other cause of death codes, R95 ‘Sudden infant death syndrome’, R96 ‘Other sudden death, cause unknown’, R98 ‘Unattended death’, R99 ‘Other ill-defined and unspecified cause of mortality’ or where no cause of death was recorded.

Results

The rate of 30 day all-cause mortality was low and declined from 127.4 to 59.3 deaths per 100,000 person-years between 2 and 6 month cohorts. When compared with trivalent DTaP vaccines, no elevated risk in all-cause or non-specific mortality was seen with any quadrivalent or hexavalent DTaP vaccines, for any cohort.

Conclusion

Use of routine DTaP combination vaccines with differing disease antigens administered during the first six months of life is not associated with infant mortality.

Introduction

Combination vaccines incorporating multiple vaccine-preventable disease (VPD) antigens in the same injection, have led to increased compliance in child vaccination schedules and improved vaccination coverage [1], [2]. Some public uncertainty remains however, about inclusion of additional VPD antigens in combination vaccines and their effect on infant immune systems. Some parents may refuse to vaccinate their children or express hesitancy in accepting multivalent vaccines due to concerns increased VPD antigens may overload child immune systems [3], [4], [5], [6].

An area of further debate discussed in the research literature, has been the effect of combination vaccines on morbidity and death in conditions other than the target diseases of the vaccine – described as non-specific vaccine effects [7], [8]. One explanation postulated for these observed effects is that the disease-specific vaccine components either augment or diminish the innate immune response to other pathogens resulting in increased or decreased morbidity and mortality effects [9].

A 2016 systematic review investigating effects of vaccination on childhood mortality concluded receipt of diphtheria-tetanus-pertussis (DTP) vaccines may be associated with increased all-cause mortality, and recommended further assessment of DTP immunisation on mortality [10]. The findings however, related to studies conducted in low-income countries (predominately, West Africa and Southern Asia) with known higher child mortality compared to high-income nations [11]. Furthermore, the combination DTP vaccines described in these studies were restricted to three VPD antigen (trivalent) whole-cell DTP vaccines. Whole-cell DTP vaccines are recognised as having higher rates of systemic adverse reactions compared with the diphtheria-tetanus-acellular pertussis (DTaP) vaccines administered in most high-income nations [12], [13], [14]. Contemporary immunisation schedules also recommend use of combination DTaP vaccines containing additional VPD antigens (Hepatitis B, Haemophilus influenzae type b (Hib) and inactivated poliomyelitis (IVP)) as well as DTP, providing combined protection for up to six diseases. If non-specific effects were to contribute to all-cause mortality then increased mortality risk may be evident with administration of additional VPD antigens. The progression in current vaccine practice from whole-cell trivalent DTP vaccines to multivalent acellular DTP vaccines protecting against three to six diseases, raises the question of whether combination DTaP vaccines both individually or collectively, have non-specific effects and affect post-vaccination mortality.

Australia has varied its selection of combination DTaP-containing vaccines in the infant-based schedule both over time and between jurisdictions. The changing usage of different DTaP vaccines provides a natural experiment for studying the effect of combination DTaP vaccines on post-vaccination infant mortality. We sought to assess this using a linked population dataset comprising immunisation exposure data from the Australian Childhood Immunisation Register (ACIR) and mortality from the National Death Index (NDI). Our primary objective was to determine whether combination DTaP vaccines protecting against a differing number of diseases administered at 2, 4 and 6 months of age were associated with post-vaccination all-cause mortality within 30 days of vaccination. A secondary objective examined whether non-specific mortality within 30 days post-vaccination, differed across combination DTaP vaccines.

Section snippets

Setting, study design, data sources & data linkage

In Australia, routine vaccinations administered to children and adolescents are funded by the Australian Government as part of the National Immunisation Program (NIP). Since 1996, all childhood vaccines recommended in the NIP Schedule are recorded on ACIR, with records maintained until a child reaches seven years of age [15]. Recorded on ACIR are child demographic details, Aboriginality and immunisation history (date, vaccine brand name, dose and batch number of vaccine administered), together

Cohort description

Characteristics of the 2-, 4- and 6-month DTaP-containing cohorts are presented in Table 1. Around 35% of individuals in each age cohort used hexavalent DTaP-HepB-IPV-Hib vaccines, with 30% and 25% administered trivalent DTaP and quadrivalent DTaP-HepB vaccines, respectively (Table 1). Ten per cent of the cohort used quadrivalent DTaP-IPV vaccines. Use of combination DTaP vaccines by year are presented in Appendix Table 3. Between 1999 and 2004, two DTaP vaccines were used in the study cohort:

Principal findings

In this large vaccinated cohort, the absolute number of deaths in children following DTaP vaccination was low. No statistically significant difference in 30-day all-cause mortality risk was observed across different combination DTaP vaccines in the 2, 4 and 6-month cohorts, however, mortality rates for DTaP vaccine types varied. For example, in the 2-month cohort, all-cause mortality rates for the quadrivalent DTaP-HepB and DTaP-IVP vaccines were higher than for trivalent DTaP vaccines, while

Conclusion

In this large cohort of Australian children, there is no evidence to support exposure to different multivalent DTaP vaccines is associated with mortality. No increased mortality risk was observed with different types of combination DTaP vaccines administered in the first 6-months of life.

Acknowledgements

We acknowledge the support of the Vaccine Assessment Using Linked Data (VALiD) Working Group throughout the VALiD project. The members are (from), University of Adelaide, SA : Michael S Gold, Annette J Braunack-Mayer, Philip Ryan, Katherine M Duszynski, Jesia G Berry, Vicki Xafis, Jillian Carlson and Bernadette Richards. New South Wales Ministry of Health, NSW: Lee K Taylor. Royal Children's Hospital, Vic: Jim P Buttery. University of Melbourne, Vic: Cecily J Freemantle. Monash University, Vic:

Contributors

All authors attest they meet the ICMJE criteria for authorship. All authors contributed to study design and interpretation of data. KMD and MSG acquired the data. KMD undertook the statistical analysis, supported by NLP. All authors contributed to the interpretation of results. KMD wrote the first draft of the paper with all authors reviewing drafts and revising it critically for important intellectual content. All authors have approved the final manuscript. KMD is guarantor, with full data

Funding

This project work was supported by an Australian Research Council (ARC) Linkage Project Grant LP0882394. Michael Gold, Philip Ryan, John McNeil, Jane Freemantle, Colin Thomson, Elizabeth Roughead, Lee Taylor and Jim Buttery are Chief Investigators on this grant. Lee Taylor, David Filby, Jim Buttery and Elizabeth Elliot are Partner Investigators affiliated with organisations who provided financial and/or in-kind support for this work as part of the Vaccine Assessment Using Linked Data project.

Competing interests

All authors have completed the ICMJE uniform disclosure form at www.icmje.org/coi_disclosure.pdf and declare: KMD & MSG had grant support for the submitted work from the Australian Research Council and partner organisation support from the South Australian Department of Health & Ageing, NSW Ministry of Health, SAEFVic and APSU for undertaking the research. MSG is also the principal investigator and grant recipient of a non-related NHMRC Partnership Project which involves multiple partners

Ethics approval

Ethical approval was granted by the University of Adelaide Human Research Ethics Committee (H-148-2008), the Commonwealth Department of Health and Ageing Ethics Committee (Project 2/2009) and the AIHW Ethics Committee (EC2010-3-35).

References (36)

  • S. Black et al.

    Importance of background rates of disease in assessment of vaccine safety during mass immunisation with pandemic H1N1 influenza vaccines

    Lancet

    (2009)
  • G.S. Marshall et al.

    Use of combination vaccines is associated with improved coverage rates

    Pediatr Infect Dis J

    (2007)
  • K. Maman et al.

    The value of childhood combination vaccines: from beliefs to evidence

    Human Vac Immunotherap

    (2015)
  • B. Bardenheier et al.

    Are parental vaccine safety concerns associated with receipt of measles-mumps-rubella, diphtheria and tetanus toxoids with acellular pertussis, or hepatitis B vaccines by children?

    Arch Pediatr Adolesc Med

    (2004)
  • J. Gellatly et al.

    Predicting parents’ decisions on MMR immunisation: a mixed method investigation

    Fam Pract

    (2005)
  • P. Aaby et al.

    The introduction of diphtheria-tetanus-pertussis vaccine and child mortality in rural Guinea-Bissau: an observational study

    Int J Epidemiol

    (2004)
  • P. Aaby et al.

    Nonspecific effects of neonatal and infant vaccination: public-health, immunological and conceptual challenges

    Nat Immunol

    (2014)
  • J.P. Higgins et al.

    Association of BCG, DTP, and measles containing vaccines with childhood mortality: systematic review

    BMJ

    (2016)
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