Elsevier

Vaccine

Volume 33, Issue 43, 26 October 2015, Pages 5794-5800
Vaccine

Defining long-term drivers of pertussis resurgence, and optimal vaccine control strategies

https://doi.org/10.1016/j.vaccine.2015.09.025Get rights and content

Abstract

Pertussis resurgence has been reported from several developed countries with long-standing immunisation programs. Among these, Australia in 2003 discontinued an 18 months (fourth) booster dose in favour of an adolescent (fifth) dose. We developed a model to evaluate determinants of resurgence in Australia and alternative vaccine strategies for mitigation.

Novel characteristics of our model included the use of seroepidemiologic data for calibration, and broad investigation of variables relevant to transmission of, and protection against, pertussis. We simulated multiple parameter combinations, retaining those consistent with observed data for subsequent use in predictive models comparing alternative vaccination schedules.

Reproducing the early control of pertussis followed by late resurgence observed in Australia required natural immunity to last decades longer than vaccine-acquired immunity, with mean duration exceeding 50 years in almost 90% of simulations. Replacement of the dose at 18 months with an adolescent dose in 2003 resulted in a 40% increase in infections in the age group 18–47 months by 2013. A six dose strategy (2, 4, 6, 18 months, 4 and 15 years) yielded a reduction in infection incidence (pre-school 43%, infants 8%) greater than any alternative strategies considered for timing of five administered doses.

Our finding that natural immunity drives long-term trends in pertussis cycles is relevant to a range of pertussis strategies and provides the necessary context in which to consider maternal vaccination. Comparatively short-lived vaccine-acquired immunity requires multiple boosters over the first two decades of life to maximise reduction in infections.

Introduction

Mass vaccination against pertussis, introduced from the 1950s, spectacularly reduced pertussis mortality and morbidity in developed countries. Following long periods of control, substantial increases in whooping cough cases in adolescents and adults were reported during the whole cell vaccine era in the 1990s [1] and more recently in children of school and pre-school age in the United States (US) [2], Australia [3] and the United Kingdom (UK), associated with severe outcomes [4]. Although diagnostic and reporting factors have played a part, a recent review by the Strategic Advisory Group of Experts of the World Health Organization concluded that Australia, the US and the UK had experienced a true resurgence [5]. Waning of acellular vaccine effectiveness has been documented following three doses in pre-school children in Australia [6] and five doses in school-aged children in the US [7], but many factors associated with resurgence are not understood [5].

Mathematical models provide a principled framework to study drivers of resurgence and consider options for reconfiguring immunisation schedules to regain pertussis control. Several models of pertussis infection and disease have considered the impact of alternative vaccination strategies on incidence [8], [9]; studied the importance of waning immunity and repeat infections to transmission [10], [11]; and determined infection, immunity and demographic characteristics consistent with observed disease patterns [12], [13]. While such models have improved our understanding of pertussis epidemiology, a consensus view on primary drivers of transmission remains elusive.

We developed an age-structured model of pertussis transmission that improves on existing models by explicitly examining uncertainty regarding biological and immunological mechanisms. We then used the model to estimate the impact of alternative immunisation strategies on pertussis control in Australia, taken as an exemplar of a developed country. We used a range of empiric Australian data to validate the model's assumptions, quantifying the characteristics of pertussis transmission and immunity consistent with key epidemiologic observations while accounting for all changes to the National Immunisation Program (NIP), (Fig. 1).

Section snippets

Model structure and assumptions

Given variations in reporting, epidemic cycles and vaccine implementation across Australian jurisdictions, we constructed an age-structured, dynamic, compartmental model of pertussis transmission for one Australian state—New South Wales (NSW). Outputs were validated against epidemiologic observations from NSW where available, and from Australia otherwise.

The model includes states of varying immunity against infection:

  • very high and high-immunity (fully protected);

  • mid-immunity (able to be

Reproducing the broad features of pertussis in Australia

We found 1623 of the 100,000 parameter combinations (1.6%) used to simulate the model produced behaviour consistent with all key epidemiologic features. Of note, only 2.4% of the 100,000 simulations produced both a large reduction in modelled incidence and a mostly seropositive adult population (Supplementary Fig. 4). Natural immunity lasting decades longer than vaccine immunity (and mostly exceeding 50 years) was needed to explain initial control followed by late resurgence (Fig. 3). Posterior

Discussion

Our model of pertussis infection and vaccination highlights the importance of long-lasting natural immunity in driving long-term trends in pertussis cycles. Resurgence of infection, associated with declining vaccine coverage or effectiveness, may enhance population protection over a period of decades. Late waning of this immunity may then reveal the underlying true effectiveness of immunisation programs. Given this context, a six-dose schedule was identified as optimal in the Australian

Funding

P Campbell was in receipt of an Australian Postgraduate Award; J McVernon receives a Career Development Fellowship from the NHMRC (CDF1061321); J McCaw receives a Future Fellowship from the ARC (FT110100250). The funders had no role in study design, analysis, manuscript preparation nor the decision to publish.

Conflict of interest statement

P. McIntyre reports membership of the Australian Technical Advisory Group on Immunisation (ATAGI), including membership of ATAGI's pertussis working group, of which he was chair prior to 2014. J. McVernon has received support from Novartis Vaccines, GlaxoSmithKline, CSL, Sanofi and Pfizer outside the submitted work; and reports membership of the Australian Technical Advisory Group on Immunisation (ATAGI) since 2012, including membership of ATAGI's pertussis working group, of which she was made

Acknowledgments

We thank Dr Nic Geard, Melbourne School of Population and Global Health for provision of data as detailed in the Supplementary material.

References (39)

  • H.E. Quinn et al.

    Duration of protection after first dose of acellular pertussis vaccine in infants

    Pediatrics

    (2014)
  • N.P. Klein et al.

    Waning protection after fifth dose of acellular pertussis vaccine in children

    N Engl J Med

    (2012)
  • J.S. Lavine et al.

    Natural immune boosting in pertussis dynamics and the potential for long-term vaccine failure

    Proc Natl Acad Sci USA

    (2011)
  • H.J. Wearing et al.

    Estimating the duration of pertussis immunity using epidemiological signatures

    PLoS Pathog

    (2009)
  • P. Rohani et al.

    Contact network structure explains the changing epidemiology of pertussis

    Science

    (2010)
  • A.M. Wendelboe et al.

    Duration of immunity against pertussis after natural infection or vaccination

    Pediatr Infect Dis J

    (2005)
  • F.G.A. Versteegh et al.

    Pertussis: a concise historical review including diagnosis, incidence, clinical manifestations and the role of treatment and vaccination in management

    Rev Med Microbiol

    (2005)
  • K.M. Edwards et al.

    Immune responses to pertussis vaccines and disease

    J Infect Dis

    (2014)
  • M.D. McKay et al.

    Comparison of three methods for selecting values of input variables in the analysis of output from a computer code

    Technometrics

    (1979)
  • Cited by (27)

    • Effect of change in vaccine schedule on pertussis epidemiology in France: a modelling and serological study

      2022, The Lancet Infectious Diseases
      Citation Excerpt :

      These variations could be partly explained by the introduction in 1998 of the booster in children aged 11–13 years, and the booster introduced in 2013 in children aged 6 years. The effect of recent changes in vaccine schedules, mainly by the introduction of boosters, was apparent in the reduction of pertussis incidence in children in several countries such as England, Wales, and Australia.26,27 Pertussis epidemiology should therefore be considered in the context of such changes, together with vaccine coverage trends, enhanced awareness and improved diagnosis methods, and the emergence of vaccine-escaping strains.

    • Modeling the waning and boosting of immunity from infection or vaccination

      2020, Journal of Theoretical Biology
      Citation Excerpt :

      The model is applicable to many diseases, including that caused by B. pertussis, which we examine as a proof-of-principle application. Several age-structured models of pertussis transmission dynamics have been proposed (e.g., Hethcote (1997, 1999); Campbell et al. (2015)). The authors of these and many subsequent articles use multiple epidemiological classes to account for recovered and vaccinated individuals with different levels of immunity and infected individuals experiencing more or less severe symptoms.

    • Emergence of pertactin-deficient pertussis strains in Australia can be explained by models of vaccine escape

      2020, Epidemics
      Citation Excerpt :

      We then examined the ability of the model to explain existing epidemic dynamics, using a maximum likelihood approach to compare the model with epidemiological and genetic data. The model was able to closely match the two sets of data, with estimated durations of natural and vaccine derived immunity of comparable lengths to those found in other recent epidemiological modelling papers for pertussis (Restif and Grenfell, 2007; Gambhir et al., 2015a; Campbell et al., 2015). The estimated basic reproduction number for the PRN− (vaccine escape) strain for a disease-free equilibrium that comprises an unvaccinated, wholly susceptible population was ∼1/2 of the wild type strain (5.37 vs 10) assumed to be in circulation prior to April 2009.

    • Core pertussis transmission groups in England and Wales: A tale of two eras

      2018, Vaccine
      Citation Excerpt :

      In recent years, England and Wales has witnessed an alarming rise in whooping cough incidence. Trying to understand the underlying mechanisms responsible for the resurgence is only a part of the puzzle [35]. Successful countermeasures will require pinpointing the optimal age groups to be targeted.

    View all citing articles on Scopus
    View full text