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The pertussis enigma: reconciling epidemiology, immunology and evolution

Monday, 25th of July 2016

“We have summarized empirical evidence showing that, contrary to the prevailing view, pertussis vaccines confer long-term protection against transmission and disease, so that previously infected or vaccinated adults play a minimal role in transmission.”

Excerpts below; full text is at http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4721090/

The pertussis enigma: reconciling epidemiology, immunology and evolution

Matthieu Domenech de Cellès,¹ Felicia M. G. Magpantay,¹ Aaron A. King,^1,2,3 and Pejman Rohani^3,4,5

¹Department of Ecology and Evolutionary Biology, University of Michigan, Ann Arbor, MI 48109, USA

²Department of Mathematics, University of Michigan, Ann Arbor, MI 48109, USA

³Fogarty International Center, National Institutes of Health, Bethesda, MD 20892, USA

⁴Odum School of Ecology, University of Georgia, Athens, GA 30602, USA

⁵College of Veterinary Medicine, University of Georgia, Athens, GA 30602, USA

e-mail: ude.agu@inahor

Author information ▼ Article notes ► Copyright and License information ►

This article has been cited by other articles in PMC.

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Pertussis, a highly contagious respiratory infection, remains a public health priority despite the availability of vaccines for 70 years. Still a leading cause of mortality in developing countries, pertussis has re-emerged in several developed countries with high vaccination coverage. Resurgence of pertussis in these countries has routinely been attributed to increased awareness of the disease, imperfect vaccinal protection or high infection rates in adults. In this review, we first present 1980–2012 incidence data from 63 countries and show that pertussis resurgence is not universal. We further argue that the large geographical variation in trends probably precludes a simple explanation, such as the transition from whole-cell to acellular pertussis vaccines. Reviewing available evidence, we then propose that prevailing views on pertussis epidemiology are inconsistent with both historical and contemporary data. Indeed, we summarize epidemiological evidence showing that natural infection and vaccination both appear to provide long-term protection against transmission and disease, so that previously infected or vaccinated adults contribute little to overall transmission at a population level. Finally, we identify several promising avenues that may lead to a consistent explanation of global pertussis epidemiology and to more effective control strategies.

Keywords: pertussis, pertussis epidemiology, pertussis vaccines, pertussis resurgence, vaccine-derived immunity, infection-derived immunity

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Pertussis, or whooping cough, is a highly contagious respiratory disease, primarily caused by the bacterium Bordetella pertussis [1]. Historically, a prominent cause of mortality in young children [2], routine paediatric immunization with whole-cell pertussis (wP) vaccines brought about large (typically exceeding 90%) reductions in reported cases in most developed countries, such as the USA [3] and Canada [4]. Despite these indisputable successes, alarming statistics indicate that pertussis remains a public health challenge. According to 2008 estimates, pertussis caused 16 million cases and 195 000 deaths in children younger than 5 years old worldwide, despite a global 82% vaccine coverage [5,6]. While this burden remains overwhelmingly concentrated in developing countries, pertussis has also re-emerged in some developed countries that maintain high vaccine coverage, including the USA [3], the UK [7] and Australia [8]. Many candidate explanations have been advanced, but the causes of these resurgences remain enigmatic and contentious.

Clinically, pertussis first manifests in mild, non-specific symptoms (catarrhal phase), which progress to a cough of remarkably long duration, marked by paroxysms, inspiratory whoop and post-tussive vomiting [1,9]. Critically, the infection is most transmissible during the catarrhal phase, when it is least apparent, hampering early diagnosis, treatment and isolation of the bacterium [1]. Unlike other childhood diseases, pertussis exhibits no consistent pattern of seasonality [1,9]. The immunology of pertussis, however, remains its most obscure aspect. Despite considerable effort, no reliable serological correlates of protection have been identified, reflecting what is probably a complex immune response to the many virulence factors expressed by B. pertussis [10].

Surprisingly, while these complexities leave key questions in pertussis unanswered, a number of robust opinions are frequently expressed (illustrated in electronic supplementary material, figure S6). In particular, pertussis is resurgent universally [11,12]; whole-cell and acellular pertussis (aP) vaccines do not protect against transmission [13–15] and that waning of infection- or vaccine-derived immunity generates an endemic pool of adults, who act as a reservoir of transmission to young children [15–17]. In this review, we re-examine the evidence supporting these widespread opinions and propose that they are inconsistent with the body of evidence taken as a whole. Finally, we highlight promising ideas that may lead to a coherent picture of pertussis epidemiology.

 

. . .  

In §2, we have shown that none of the frequently cited mechanisms proposed to explain pertussis epidemiology is consistent with all available. Here, we discuss additional candidate explanations.

(a) Bordetella pertussis populations evolve

The adaptation of B. pertussis to vaccination has been proposed as an explanation of recent epidemiological trends [69]. Indeed, many studies identified temporal variations in B. pertussis populations as a possible consequence of vaccine immune escape [70]. Serotyping—based on agglutination assays using antisera against antigens 1, 2 and 3—provided the first such evidence. In the UK, several studies documented a shift in the relative abundance of serotypes after the start of routine wP vaccination, from a predominance of serotypes containing antigen 2 (serotypes Fim2 and Fim2,3) in the 1940s to Fim3 in the 1960s [71]. Similar observations in other countries [72], particularly in Sweden during three consecutive periods with wP vaccination, no vaccination and aP vaccination [73], provided evidence of vaccine-driven evolution to serotype Fim3, hypothesized to be less antigenic and therefore at a selective advantage in vaccinated children [74].

Using newer molecular typing methods, many studies have also documented shifts in allele frequencies of major B. pertussis antigens following inception of vaccination [69]. A prominent example is the resurgence of pertussis in the Netherlands, which coincided with the emergence and subsequent spread of a novel allele of the pertussis toxin promoter, suggested to improve fitness by increasing pertussis toxin production and severity of infections [75]. In the USA, where similar epidemiological trends have been observed since the 1980s, pertussis resurgence was associated with a mutation in the gene coding for fimbrial proteins, although the functional role of that mutation remains unclear [76].

Based on the above observations, it has been proposed that vaccination has resulted in selection of more virulent strains that are more efficiently transmitted by previously primed hosts [69]. To assess the weight of evidence in support of this hypothesis, several key questions will need to be answered, with important implications for the design and the use of current and future vaccines [77]. For example, why have novel, beneficial variants not spread more broadly across the globe? What is the impact, if any, of these novel variants on vaccine effectiveness [73]? More importantly, a tentative test of this hypothesis will require a comprehensive description of variations in B. pertussis populations, notably in countries, such as Australia [78], where resurgence has not coincided with the timing of strain changes.

Answering the above-mentioned questions will require highly resolved, geographically distributed gene sequences from bacterial isolates. The phylodynamic analysis of such sequences would permit the identification of associations between transmission and genetic markers for virulence and antigenicity. Furthermore, such an analysis would permit the quantification of gene flow between geographical regions. Additionally, animal challenge experiments can be invaluable in quantifying the relative transmissibility ofB. pertussis variants.

(b) Circulation of congeners is increasing

In addition to B. pertussis, the main aetiological agent of pertussis—other bacterial species from the genusBordetella—can infect humans and may play a role in the epidemiology of pertussis-like illness [9]. Among these, B. parapertussis has been shown to cause symptoms very similar to those caused by B. pertussis, though shorter-lived [79,80]. Moreover, because they express two closely related surface proteins, filamentous haemagglutinin and pertactin, the two species induce quantitatively similar antibody response against these two antigens [79]. Although estimates of B. parapertussis incidence rates are low [80], experimental evidence suggests that aP fails to confer cross-protection and can even facilitate infection by this species [81]. This suggests, therefore, that a role for B. parapertussis in highly vaccinated populations should not be disregarded.

Another Bordetella species, B. holmesii, has recently attracted attention [82]. Although its epidemiology remains largely unstudied, the bacterium is known to cause invasive disease as well as pertussis-like respiratory infections, mostly in adolescents and adults [82]. Remarkably, current PCR-based methods do not discriminate between B. holmesii and B. pertussis, and several studies have identified B. holmesii in a substantial proportion of individuals clinically diagnosed with pertussis. For example, in a 2010 pertussis outbreak in Ohio, B. holmesii accounted for 43% of cases in the 11–18 age group and 30% of cases overall [83]. In addition, B. holmesii was retrospectively identified in 20% of samples from patients with suspected pertussis in a study in France [84]. These findings raise the possibility of frequent misdiagnosis of pertussis, with considerable implications for the estimation of vaccine efficacy [85]. While the pathogenicity and prevalence of B. pertussis congeners need to be established, their role will be important to consider in future studies. To properly quantify the contribution of B. pertussis congeners to reported incidence, there is a need for more sensitive diagnostic tools capable of distinguishing between differentBordetella species, in addition to more frequent bacterial isolation from suspected cases. Finally, animal challenge experiments aimed at determining heterospecific cross-immunity will be invaluable.

(c) The nature of vaccine failure matters

Quantification of not only the probability of vaccine failure, but also the manner in which a vaccine fails, may prove critical in understanding pertussis epidemiology. Although pertussis immunity is complex [10], two simplified models of vaccine failure help clarify the issues by capturing opposite extremes [86]. A leaky vaccine confers equal, though incomplete, protection to all vaccinated individuals, by reducing the probability of infection at each exposure. By contrast, an all-or-nothing vaccine confers complete protection to a fraction of vaccinated individuals, but no protection to the others [86]. In addition, under both these models, vaccinal immunity can wane [53,87,88]. These alternative models lead to different interpretations of age-specific vaccine efficacy estimates from longitudinal studies [50,53,86], and to different predicted effectiveness of booster vaccination strategies [89].

Interestingly, these different models of vaccine failure leave distinct signatures in epidemiological dynamics. In particular, theory indicates that leakiness can give rise to a reinfection threshold [90] separating a high-transmission regime—characterized by frequent, immunity-boosting reinfections, infrequent waning and severe infections concentrated in children—from a low-transmission regime marked by infrequent reinfections, waning immunity and high prevalence of severe infections in older age groups. Intriguingly, this pattern results in an overall increase in severe infections as a result of reduced transmission and was proposed as an explanation for recent epidemiological shifts in pertussis [90]. Nevertheless, because previous studies could not discriminate between the different modes of vaccine failure [53,88], key assumptions underlying this hypothesis remain unsupported by data. Recent analysis of models has revealed distinct epidemiological signatures for these different modes [55], suggesting that statistical inference on longitudinal incidence data may identify the mode of vaccine failure. Ideally, this question can be answered with longer-term vaccine trial designs [87]. Comparative epidemiological dynamics in the decades following changes in the vaccine regimen has the potential to resolve this issue.

(d) The honeymoon is over

For any infectious disease, transmission results from interactions between susceptible and infected individuals of a population. Because such interactions are inherently nonlinear, seemingly straightforward interventions can have unanticipated consequences. In particular, immediately following the roll-out of a vaccination programme, it is possible to observe a honeymoon period, during which incidence is very low. This phenomenon arises via the combined effects of vaccination in newborns and initially high herd immunity from previously infected older individuals. As susceptibles slowly accumulate owing to incomplete immunization and herd immunity gradually dissipates through natural deaths of immune individuals, the honeymoon period eventually ends, leading to a rise in prevalence especially among older individuals who escaped both infection and vaccination. This effect, predicted by models [91] and documented for measles [92], has recently been shown to be consistent with pertussis resurgence in England and Wales [7]. Specifically, using an age-structured transmission model and assuming slowly waning vaccinal immunity, Riolo et al. interpreted the recent resurgence of pertussis in England and Wales as the inevitable consequence of a spillover of susceptible individuals into older age groups over decades of incomplete coverage with an imperfect vaccine [7]. Although the generality of this phenomenon is unknown, it demonstrates that recent epidemiological trends need not necessarily reflect recent changes in epidemiology or biology, but rather the slow-to-manifest effects of long-standing practice.

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We have summarized empirical evidence showing that, contrary to the prevailing view, pertussis vaccines confer long-term protection against transmission and disease, so that previously infected or vaccinated adults play a minimal role in transmission. While this may appear at odds with the results of particular studies, we submit that the totality of the evidence is fully consistent with this conclusion. In general, because of the substantial heterogeneity among individuals, great care is needed in the extrapolation of clinical evidence to the population level, and vice versa.

We have highlighted several promising ideas that may explain the perplexing features of pertussis. Most of these ideas have implications that can be tested by integrating models with relevant data. While at present insufficient information is available on B. pertussis congeners, the growing interest in B. holmesii may soon yield enough data to inform a detailed transmission model, which would take into account the selective advantage imposed by widespread vaccination against B. pertussis. Similarly, estimation of key parameters from longitudinal incidence data, using modern inference techniques [93], will help elucidate the mechanisms of vaccinal immunity conferred by wP and aP vaccines. Pinpointing the vaccine impact will also be critical for the design of immunization strategies to protect newborns, such as cocooning or maternal immunization [94]. Finally, applying the concept of a honeymoon period to countries with resurging pertussis might help focus efforts on those characteristics of pertussis epidemiology most in need of further explanation.

In their 1951 review, Gordon & Hood [2, p. 334] noted that the epidemiological behavior of whooping cough should be easy to predict; but whooping cough does not always behave according to expectation. More than 60 years after this statement, our understanding of pertussis epidemiology remains far from perfect. Indeed, our analysis indicates considerable variability in trends across countries. These findings emphasize the complexity of pertussis population biology, arising from the dynamic interplay between country-specific vaccination practices, regional variations in sociodemographic factors and in the genetic make-up of the aetiological agents, and heterogeneities among individuals in transmission and disease. Nevertheless, the considerable burden owing to pertussis makes it worthwhile to reconsider long-held beliefs in the light of all available evidence.