Public health consequences

Although pertussis can cause morbidity and mortality across all age groups, infants are at greatest risk for severe disease, especially during the first months of life. Despite the implementation of effective vaccination programmes, pertussis remains a significant global health problem and protecting those at highest risk is a priority. Numerous public health strategies, including cocooning, maternal vaccination during pregnancy, targeted vaccination of healthcare personnel, and post-exposure antibiotic prophylaxis, have been used to control the burden of pertussis with varying degrees of success. While maternal immunization during pregnancy has been demonstrated to be highly effective at preventing disease among infants during the first months of life, no single strategy alone is sufficient to control pertussis across age groups. In the setting of a resurgence in disease, a combination of approaches is needed to minimize the burden of disease, especially among those at highest risk for severe morbidity and mortality.

The immunology of Bordetella pertussis infection and vaccination

Bordetella pertussis causes whooping cough (pertussis), a severe and sometimes fatal respiratory infectious disease, especially in young infants. Pertussis can be prevented in infants and children by immunization with either whole-cell pertussis (wP) or acellular pertussis (aP) vaccines; however, its incidence is increasing in many countries despite high vaccine coverage. This resurgence in populations immunized with aP vaccines has been attributed to (1) genetic changes in circulating strains of B. pertussis resulting from vaccine-driven immune selection, (2) waning protective immunity due to poor induction of immunological memory, or (3) a failure of aP vaccines to induce the appropriate arm(s) of the cellular immune responses required to prevent infection. Studies in a baboon model have suggested that previous infection prevents reinfection as well as disease, whereas aP vaccines fail to prevent nasal colonization and transmission of B. pertussis. Studies in the mouse model have demonstrated that immunization with wP vaccines induces Th1 and Th17 responses, whereas aP vaccines promote Th2-skewed responses and high antibody titres. Thus, while aP vaccine-induced antibodies may prevent pertussis, they may not prevent nasal colonization or transmission. Emerging data have suggested that replacing alum with novel adjuvants based on pathogen-associated molecular patterns has the capacity to switch the responses induced with aP vaccines to the more protective Th1/Th17 responses and may also enhance immunological memory. It is likely that third-generation pertussis vaccines will be based on live attenuated bacteria or aP formulations with novel adjuvants, which prevent nasal and lung infection and induce sustained immunity through induction of memory T cells.

Introduction to pertussis transmission and epidemiological dynamics

Resolving the long-term, population-level consequences of changes in pertussis epidemiology, arising from bacterial evolution, shifts in vaccine-induced immunity, or changes in surveillance, are key challenges for devising effective control strategies. This chapter reviews some of the key features of pertussis epidemiology, together with the underlying epidemiological principles that set the context for their interpretation. These include the relationship between the age distribution of cases and pertussis transmission potential, the impact of vaccine uptake on incidence, periodicity and age incidence, as well as spatially explicit recurrent pertussis epidemics and associated extinction frequency. This review highlights some of the predictable and consistent aspects of pertussis epidemiology (e.g. the systematic increase in the inter-epidemic period with the introduction of whole-cell vaccines) and a number of important heterogeneities, including variations in contemporary patterns of incidence and geographic spread.

Epilogue

“Today it is possible to predict one thing for this book with confidence. It will reveal controversy over the causative organism(s) of the disease, the diagnosis of infection, the relative importance of possible virulence factors, the suitability of animal models, therapeutic procedures, and the composition and administration of vaccines....

Contrasting ecological and evolutionary signatures of whooping cough epidemiological dynamics

The enigmatic global pattern of whooping cough incidence presents a unique set of challenges for controlling the disease and uncovering the mechanisms underlying its epidemiological dynamics. In countries experiencing an increase in cases, five hypotheses have been proposed to explain the resurgence: (1) there has been an increase in Bordetella pertussis reporting rates, (2) waning of protective immunity from vaccination or natural infection over time, (3) evolution of B. pertussis to escape protective immunity, (4) vaccines that fail to induce sterilizing (mucosal) immunity to B. pertussis, and (5) asymptomatic transmission from individuals vaccinated with the currently used acellular B. pertussis vaccines. Each of these five hypotheses can leave contrasting signatures in both epidemiological and genomic data; however, these hypotheses must also be evaluated against data from locations that are either not experiencing a resurgence or are witnessing a declining incidence. This chapter discusses how to—and whether it is possible to—disentangle the various mechanisms proposed for whooping cough’s resurgence. It identifies a pathological lack of data sufficient for testing hypotheses and demonstrates how detailed, high-resolution data (in geography, time, and age) are required to distinguish even the most basic models. The chapter further discusses how approaches linking genomic and epidemiological data, (i.e. phylodynamic models) may prove beneficial. The results suggest that while evidence exists for each of the five proposed hypotheses, it is unlikely that any single mechanism can account for the global pattern of whooping cough incidence and that determining the relative importance of each mechanism remains uniquely challenging.

Vaccine-driven selection and the changing molecular epidemiology of Bordetella pertussis

Pertussis remains one of the least controlled vaccine-preventable diseases despite high vaccine coverage in many countries. There are ongoing debates about the causes of its resurgence. Major changes have occurred in the Bordetella pertussis population since the introduction of vaccination. Currently circulating strains in Australia and many other developed countries are grouped in single nucleotide polymorphism (SNP) cluster I (also known as ptxP3 strains). The emergence and expansion of SNP cluster I has been associated with two major genetic changes in B. pertussis: a change in its pertussis toxin promoter (to ptxP3) which leads to increased pertussis toxin production and the change of the acellular vaccine pertactin gene allele to prn2. More recently, strains that lack pertactin have emerged independently in different lineages. The resurgence of pertussis in highly vaccinated populations can be, at least in part, explained by genetic changes that increase the fitness of circulating B. pertussis strains.

Role of vaccine schedules

Over the past 60 years, pertussis vaccines have been implemented in national immunization programme schedules at a variety of ages. All countries administer the vaccine as an infant primary series, but the number and exact timing of these doses differ, as do the number and timing of booster doses. In consequence, short-term direct protection of age-appropriately immunized children varies by schedule. This variability influences vaccine impact on the burden of disease, because the risk of severe morbidity and mortality is greatest in early life and decreases thereafter. In addition, vaccine-derived immunity wanes over time, meaning that longer intervals between doses are predicted to increase the risk of breakthrough infections throughout childhood and adolescence, fuelling ongoing transmission and cyclic epidemics. The duration of protection following vaccination is substantially shorter than following infection, although absolute estimates vary widely across populations and studies.

Pertussis immunity and the epidemiological impact of adult transmission

An understanding of the consequences of infection and vaccination on host immunity sets the stage for interpreting pertussis epidemiology. Yet, with no known serological marker of protection, such an understanding is currently not possible. This chapter interrogates longitudinal age-stratified pertussis incidence reports from Sweden and Massachusetts, United States, with the aim of quantifying the impact of infection and immunization on protective immunity. The analysis of data from Sweden during the vaccination hiatus period (1986–1996) indicates that adults contribute little to transmission. This may either be because infection-derived immunity is very long-lasting, or that individuals whose immunity has waned are subsequently less susceptible. The analysis of data from Massachusetts (1990–2005) identifies the primary mechanism of vaccine failure—for both whole-cell and acellular pertussis vaccines—to be waning. However, the average duration of immunity is identified as many decades, though the model predicts substantial individual variability in this trait. Finally, the chapter demonstrates the estimates to be consistent with those obtained from popular measures of vaccine effectiveness, though the interpretation of these findings is quite different.

Evolutionary epidemiology theory of vaccination

The aim of vaccination is to prevent or limit the risk of pathogen infections for individual hosts but large vaccination coverage often has dramatic epidemiological consequences at the scale of the whole host population. This massive perturbation of the ecology and transmission of the pathogen can also have important evolutionary effects. In particular, vaccine-driven evolution may lead to the spread of new pathogen variants that may erode the benefits of vaccination. This chapter presents a theoretical framework for modelling the short- and long-term epidemiological and evolutionary consequences of vaccination. This framework can be used to make quantitative predictions about the speed of such evolutionary processes. This work helps identify the relevant phenotypic traits that need to be measured in specific parasite populations in order to evaluate the potential evolutionary consequences of vaccination. In particular, this may help in the debate regarding the involvement of evolution in the re-emergence of pertussis in spite of the high coverage of vaccination.

The human immune responses to pertussis and pertussis vaccines

Two types of pertussis vaccines are currently available: the first-generation, whole-cell (wP) and more recent, acellular (aP) vaccines. The aP vaccine has replaced the wP vaccine in most industrialized countries, based on an improved safety profile and comparable efficacy of the former compared to the latter. As both vaccines, as well as prior infection, protect well against whooping cough disease, albeit by different mechanisms, the human immune responses to natural infection and vaccination have been extensively studied over the last decades. Shortly after the discovery of the causative agent Bordetella pertussis, both agglutinating antibodies and complement-binding antibodies have been identified in the serum of convalescent patients. However, how much they contribute to protection against disease or infection is still not known. Nevertheless, passive transfer of convalescent serum can significantly attenuate the disease and placental transfer of maternal antibodies induced by vaccination during pregnancy has recently been shown to provide strong protection against severe disease in the offspring. Natural infection and wP vaccination have both been shown to induce a strong Th-1-oriented T-cell response, whereas administration of aP vaccine shifts the response to a Th-2 profile, which may be a reason for the fast waning of immunity upon aP vaccination, compared to wP vaccination and natural infection. None of the current vaccines induce sterilizing immunity and limit circulation of B. pertussis. Therefore, new vaccines are needed that protect both against disease and infection. One such candidate, live attenuated BPZE1, designed to prevent B. pertussis infection, is currently in clinical development.