Pertussis in England and Wales: an investigation of transmission dynamics and control by mass vaccination

The epidemiology of pertussis and its prospects for control by mass vaccination in England and Wales are investigated by analyses of longitudinal records on incidence and vaccine uptake, and horizontal data on age-stratified case reports. Mathematical models of the transmission dynamics of the infection that incorporate loss of natural and vaccine-induced immunity plus variable vaccine efficacy are developed, and their predictions compared with observed trends. Analyses of case reports reveal that the individual force of infection is age dependent, with peak transmission in the 5- to 10-year-old age class. A model incorporating this age dependency, along with partial vaccine efficacy and loss of vaccine-induced immunity, generates predicted patterns that best mirror observed trends since mass vaccination was inaugurated in 1957 in England and Wales. Model projections accurately mirror the failure of mass vaccination to increase the inter-epidemic period of the infection (three years) over that pertaining before control. The analysis suggests that this is due to the impact of partial vaccine efficacy. Projected trends do not accurately reflect the low levels of pertussis incidence reported between epidemics in the periods of high vaccine uptake. This is thought to arise from a combination of factors, including loss of natural and vaccine induced immunity, biases in case reporting (where reporting efficiency is positively associated with the incidence of pertussis), and seasonal variations in transmission. Model predictions suggest that the vaccination of 88% of each birth cohort before the age of 1 year will eliminate bacterial transmission, provided the vaccine confers lifelong protection against infection. If vaccine-induced immunity is significantly less than lifelong (or if vaccination fails to protect all its recipients) repeated cohort immunization is predicted to be necessary to eliminate transmission. Future research needs are discussed, and emphasis is placed on the need for more refined data on vaccine efficacy, the duration of natural and vaccine-induced immunity and the incidence of clinical pertussis and subclinical infections (perhaps by the development of reliable serological tests). Future mathematical models will need especially to incorporate seasonality in transmission.     

Impact of vaccination and birth rate on the epidemiology of pertussis: a comparative study in 64 countries

Bordetella pertussis infection remains an important public health problem worldwide despite decades of routine vaccination. A key indicator of the impact of vaccination programmes is the inter-epidemic period, which is expected to increase with vaccine uptake if there is significant herd immunity. Based on empirical data from 64 countries across the five continents over the past 30–70 years, we document the observed relationship between the average inter-epidemic period, birth rate and vaccine coverage. We then use a mathematical model to explore the range of scenarios for duration of immunity and transmission resulting from repeat infections that are consistent with empirical evidence. Estimates of pertussis periodicity ranged between 2 and 4.6 years, with a strong association with susceptible recruitment rate, defined as birth rate × (1 − vaccine coverage). Periodicity increased by 1.27 years on average after the introduction of national vaccination programmes (95% CI: 1.13, 1.41 years), indicative of increased herd immunity. Mathematical models suggest that the observed patterns of pertussis periodicity are equally consistent with loss of immunity that is not as rapid as currently thought, or with negligible transmission generated by repeat infections. We conclude that both vaccine coverage and birth rate drive pertussis periodicity globally and that vaccination induces strong herd immunity effects. A better understanding of the role of repeat infections in pertussis transmission is critical to refine existing control strategies.     

The benefits of using diverse animal models for studying pertussis

Pertussis, a respiratory disease caused by infection with Bordetella pertussis, represents one of the most devastating diseases in infants and young children worldwide. Significant research efforts over the last five decades have led to the introduction of two types of vaccines, which are now available worldwide and which have significantly reduced the global incidence of pertussis. The use of animal models and, in particular, the mouse model has benefited in the development of these vaccines tremendously. However, open questions regarding the duration of immunity, the type of immune response needed for protection and the role of mucosal and innate immunity in disease protection still remain. Here, we review the various animal models available currently and their benefits for studying this important disease.     

Simulations of pertussis epidemiology in the United States: effects of adult booster vaccinations

An expanded pertussis (whooping cough) vaccination program which includes adult boosters every 10 yr is studied using computer simulations of two models. These age-structured pertussis transmission models include waning of both infection-acquired and vaccine-induced immunity, and vaccination of children corresponding to the vaccination coverage since 1940. Adult vaccinations cause a larger boost in the immunity level in the second model than in the first model. In the simulations the addition of adult pertussis booster vaccinations every 10 yr is beneficial in reducing adult incidence, but causes only modest reductions in the incidence in infants and young children. These simulations suggest that a careful cost effectiveness analysis is needed before implementation of an adult pertussis vaccination program.     

A Change in Vaccine Efficacy and Duration of Protection Explains Recent Rises in Pertussis Incidence in the United States

Over the past ten years the incidence of pertussis in the United States (U.S.) has risen steadily, with 2012 seeing the highest case number since 1955. There has also been a shift over the same time period in the age group reporting the largest number of cases (aside from infants), from adolescents to 7–11 year olds. We use epidemiological modelling and a large case incidence dataset to explain the upsurge. We investigate several hypotheses for the upsurge in pertussis cases by fitting a suite of dynamic epidemiological models to incidence data from the National Notifiable Disease Surveillance System (NNDSS) between 1990–2009, as well as incidence data from a variety of sources from 1950–1989. We find that: the best-fitting model is one in which vaccine efficacy and duration of protection of the acellular pertussis (aP) vaccine is lower than that of the whole-cell (wP) vaccine, (efficacy of the first three doses 80% [95% CI: 78%, 82%] versus 90% [95% CI: 87%, 94%]), increasing the rate at which disease is reported to NNDSS is not sufficient to explain the upsurge and 3) 2010–2012 disease incidence is predicted well. In this study, we use all available U.S. surveillance data to: 1) fit a set of mathematical models and determine which best explains these data and 2) determine the epidemiological and vaccine-related parameter values of this model. We find evidence of a difference in efficacy and duration of protection between the two vaccine types, wP and aP (aP efficacy and duration lower than wP). Future refinement of the model presented here will allow for an exploration of alternative vaccination strategies such as different age-spacings, further booster doses, and cocooning.     

Waning immunity and sub-clinical infection in an epidemic model: implications for pertussis in The Netherlands

In The Netherlands, an epidemic outbreak of pertussis took place in 1996-1997. Understanding of the causes of the epidemic is hampered by the fact that many cases of infection with Bordetella pertussis go by unnoticed, and by the fact that immunity against infection does not last lifelong. Motivated by these observations, we develop and analyze an age-structured epidemic model that takes these factors into account. A distinction is made between infection in immunologically naive individuals, and infection in individuals whose immune system has been primed before by infection or vaccination. While the former often lead to severe symptoms and thus are more often diagnosed and notified, the latter are largely sub-clinical. The main questions are: (1) to what extent do sub-clinical infections contribute to the circulation of B. pertussis; and (2) what might be the causes for the recent epidemic? To answer these questions, we first present a new method to estimate the force of infection from notification data. The method is applied to the 1988-1995 case notification data from The Netherlands. Estimates of the force of infection vary greatly, depending on the rate at which immunity is lost, and on the fraction of sub-clinical infections. For the 1988-1995 period, our analysis indicates that if immunity is lost at a small rate and if a majority of infections is sub-clinical, the contribution of infection in adults to the transmission process cannot be neglected. Our results furthermore indicate that a decrease in the duration of protection after vaccination due to a change in the pathogen is the most likely factor to account for the 1996-1997 epidemic.     

Impact of vaccination on the infectious diseases epidemiology: example of pertussis

Several vaccines are now routinely used since fifty years in different developed countries. Their principal impact has been to decrease morbidity and mortality of the infectious diseases they are targeting. One disease, smallpox, is eradicated, poliomyelitis will be soon, diphteria is controlled in several countries but pertussis is still endemic although an efficacious vaccine was used. Why? Pertussis is an example of an infection for which the immunity of the population has changed after the introduction of generalized vaccination with killed whole cell pertussis vaccines, from a natural immunity due to infection to different types of vaccine-induced immunity. These different types of immunity have changed the protection against infection, disease and transmission. The impact of the generalized vaccination in a human population has been an important change in the epidemiology of the disease. In fact, a child-to-child transmission observed before the introduction of vaccination is now replaced by an adolescent-adult to infant transmission. The major consequence is an increase in the mortality and morbidity in non vaccinated infants mostly contaminated by their parents. Researches undertaken on the agent of the disease, the bacterium, Bordetella pertussis, conducted to the development of subunits vaccines, efficacious and better tolerated by infants than whole-cell vaccines. Many developed countries decided to change vaccines but also to add vaccine boosters for adolescents and adults in order to stop the transmission of the disease to infants. However, even after 15 years of studies in many countries, pertussis is still underestimated in adults and generalized adult vaccination remains difficult. The new goal now is to give information to medical students and health care workers in general in order to increase adolescent and adult's vaccination coverage.     

Epidemiological and immunological criteria of the effectiveness of immunization with adsorbed DPT vaccine by the old and new schedules

The study revealed that the immunization of children with adsorbed DPT vaccine from the age of 3-4 months, as compared with the immunization of children from the age of 5-6 months, did not lead to an essential increase in the coverage of children with immunization at the period under study (1970-1983) and did not affect the total level of pertussis morbidity, as well as the proportion of children aged up to 1 year in the total number of pertussis cases. Children immunized at an early age produced antibodies in titers, equivalent to the titers in older children, but their immunity against pertussis, in contrast to their immunity against diphtheria and tetanus, was retained for a shorter period. The injection of adsorbed DPT vaccine at the age of 3-4 months was accompanied by a poorly pronounced increase in the content of IgG, the predominant synthesis of IgM and the suppression of the synthesis of IgA. The shift of the start of vaccination to the age of 3-4 months has probably some immunological grounds for diphtheria and tetanus, but it is premature with respect to pertussis.     

Pertussis Circulation Has Increased T-Cell Immunity during Childhood More than a Second Acellular Booster Vaccination in Dutch Children 9 Years of Age

Here we report the first evaluation of T-cell responses upon a second acellular pertussis booster vaccination in Dutch children at 9 years of age, 5 years after a preschool booster vaccination. Blood samples of children 9 years of age were studied longitudinally until 1 year after the second aP booster and compared with those after the first aP booster in children 4 and 6 years of age from a cross-sectional study. After stimulation with pertussis-vaccine antigens, Th1, Th2 and Th17 cytokine responses were measured and effector memory cells (CCR7-CD45RA-) were characterized by 8-colour FACS analysis. The second aP booster vaccination at pre-adolescent age in wP primed individuals did increase pertussis-specific Th1 and Th2 cytokine responses. Noticeably, almost all T-cell responses had increased with age and were already high before the booster vaccination at 9 years of age. The enhancement of T-cell immunity during the 5 year following the booster at 4 years of age is probably caused by natural boosting due to the a high circulation of pertussis. However, the incidence of pertussis is high in adolescents and adults who have only received the Dutch wP vaccine during infancy and no booster at 4 years of age. Therefore, an aP booster vaccination at adolescence or later in these populations might improve long-term immunity against pertussis and reduce the transmission to the vulnerable newborns. TRIAL REGISTRATION: Controlled-Trials.com ISRCTN64117538.     

Dynamics of acquired immunity boosted by exposure to infection

A mathematical model is presented to describe the dynamics of immunity which can be boosted by reexposure to infection. Immunity is assumed to last until a specified interval of time elapses without an exposure. This assumption is incorporated into a compartmental model as a differential-delay equation. When the model is applied to malaria epidemiology, the prevalence of disease among adults is greatest at intermediate rates of infection. Observed age-prevalence curves have shapes similar to those of the predicted curves. Immunity in an individual is formulated in terms of a stochastic process, and an expression for the average duration of immunity is obtained. The average duration of immunity increases with the rate of exposure, but the presence of mortality (or other kinds of removal) shortens the average duration observed, in analogy with the theoryof competing risks.     

Seroprevalence of Antibodies to Pertussis Toxin among Different Age Groups in Thailand after 37 Years of Universal Whole-Cell Pertussis Vaccination

Despite the high coverage of prophylactic vaccine against Bordetella pertussis infection in many countries for more than three decades, pertussis remains a common vaccine-preventable disease. Infections have been detected more commonly in countries using acellular pertussis vaccine in their Expanded Program of Immunization. Thailand implemented a routine infant immunization program with whole-cell pertussis vaccine in 1977, and since 1992, the national vaccine policy has offered a five-dose whole-cell pertussis vaccine for children given at the ages of 2, 4, 6, 18, and 48 months. This study aimed to investigate the seroprevalence of antibodies to pertussis toxin among healthy people across all ages to determine the level of whole-cell vaccine-induced immunity in the population, and to identify which age group should be targeted for a booster dose. The lowest seronegative rate and highest geometric mean concentrations were found in the 0–10 years age group, corresponding to their recent pertussis vaccination. The proportion of people with undetectable IgG level was prominent, starting after 11 years of age onwards. Now that a reduced-dose pertussis vaccine with fewer adverse effects is available, a booster dose during adolescence should be considered in order to reduce the incidence of pertussis disease. Further studies exploring how long the reduced-dose pertussis vaccine can provide protective immunity against pertussis disease when administered to adults and adolescents should also be performed.     

Whooping cough morbidity and inoculation status

The analysis of pertussis morbidity and the state of immunity to pertussis has made it possible to evaluate the existing epidemiological situation as unfavorable. The restraining influence of specific prophylaxis on the epidemic process of pertussis becomes weaker due to the growing number of nonimmunized children; for this reason, the maximum morbidity rate in pertussis is observed among children under 5 years of age, as it was at the period before the introduction of mass immunization against pertussis. To prevent further possible increase in the intensity of the epidemic process of pertussis and in the severity of the clinical course of the disease, the number of children under 3 years of age, not immunized against pertussis, must be reduced by limiting the number of children exempted from immunization on medical grounds and by increasing the proportion of children immunized from the age of 3 months.     

Diagnosis and management of pertussis

PERTUSSIS IS INCREASING IN FREQUENCY among children too young to be vaccinated and among adolescents and adults. This increase is due mainly to waning immunity among vaccinated individuals, who become susceptible during adolescence and adulthood and maintain the circulation of Bordetella pertussis. Infants are at highest risk of severe illness requiring hospital admission, complications and death. The clinical presentation in adolescents, adults and vaccinated individuals may be atypical, with paroxysmal cough of short duration or simply a persistent cough. Culture and polymerase chain reaction may be used to identify B. pertussis infection, but their sensitivity is high only in the early phase of the disease. Serologic tests are not standardized for the diagnosis of pertussis, and their clinical application is limited. Erythromycin is still considered in some countries to be the “gold standard” for therapy and prophylaxis; however, azithromycin and clarithromycin seem equally efficacious and are associated with fewer side effects.The increase worldwide in vaccination coverage against pertussis has substantially reduced the morbidity and mortality associated with this disease. However, because of variability in age-specific vaccine coverage rates and waning immunity, the epidemiologic pattern of pertussis in developed countries has radically changed. Managing pertussis in a setting with high rates of vaccination uptake requires knowledge of the clinical picture of pertussis according to the vaccination status and age of the patient, the most sensitive and timely laboratory tests for diagnosis, and the safest and most efficacious methods of treatment and prophylaxis. In this article we review recent findings and issues in the diagnosis, treatment and prophylaxis of pertussis. (An outline of our strategy for the literature search is available in Appendix 1.)     

Humoral imunity to pertussis in children with diabetes of type 1

To determine the state of humoral immunity to pertussis in children with insulin-dependent diabetes, IgG antibodies to pertussis toxin (PT) were determined in blood serum samples by means of EIA. In a group of children aged up to 6 years the highest percentage (100%) received the complete course of vaccination against pertussis with Russian adsorbed DPT vaccine, containing whole-cell pertussis monovaccine, while in a group over 6 years the complete vaccination course (3 vaccinations and 1 revaccination) had 53.4% of children. Pertussis morbidity was considerably higher in nonvaccinated subjects than in children with 4-fold vaccination (p < 0.001). The coefficient of association (Q) was 0.84. Children of all age groups were found to have low and average titers of antibodies to PT. The regressive analysis showed a decrease in antibodies in persons completely immunized against pertussis by the age of 6 years old. The presence of antibodies in nonimmunized persons showed that cases of pertussis or carrier state took place among the population. High titers of antibodies, indicative of recent cases of pertussis, were registered in all age groups, but high titers of antibodies were registered mostly in the group of children over 13 years old (p < 0.05), which confirmed an increase in pertussis morbidity in adolescents. Thus, vaccination against pertussis effectively protected children with diabetes of type 1, aged up to 6 years. For more prolonged protection the vaccination and revaccination of children aged over 4 years old is necessary.     

Seasonality and comparative dynamics of six childhood infections in pre-vaccination Copenhagen

Seasonal variation in infection transmission is a key determinant of epidemic dynamics of acute infections. For measles, the best-understood strongly immunizing directly transmitted childhood infection, the perception is that term-time forcing is the main driver of seasonality in developed countries. The degree to which this holds true across other acute immunizing childhood infections is not clear. Here, we identify seasonal transmission patterns using a unique long-term dataset with weekly incidence of six infections including measles. Data on age–incidence allow us to quantify the mean age of infection. Results indicate correspondence between dips in transmission and school holidays for some infections, but there are puzzling discrepancies, despite close correspondence between average age of infection and age of schooling. Theoretical predictions of the relationship between amplitude of seasonality and basic reproductive rate of infections that should result from term-time forcing are also not upheld. We conclude that where yearly trajectories of susceptible numbers are perturbed, e.g. via waning of immunity, seasonality is unlikely to be entirely driven by term-time forcing. For the three bacterial infections, pertussis, scarlet fever and diphtheria, there is additionally a strong increase in transmission during the late summer before the end of school vacations.     

Surveillance of pertussis in the CSSR. IV. Immunological surveys of antibodies to pertussis and parapertussis in the Bohemian regions and in Slovakia in 1958 - 1971.

A comparison of the results of repeated immunological surveys with the notification of morbidity and mortality to pertussis and parapertussis revealed direct dependence and simultaneously confirmed the effectiveness of Czechoslovak vaccine. Immunological surveys should be continued in spite of the fact that morbidity of pertussis is low at present, because immunological surveys may lead to timely detection of shortcomings in the quality of vaccination and vaccine. The results after 14 years of systematic vaccination and revaccination and consequent follow-up to the state of immunity in the population and of other factors in the pertussis surveillance programme rank among the other achievements of epidemiology and hygiene in Czechoslovak health services. Contemporary immunological surveys show that the state of immunity in Czechoslovak child population is such as to exclude the occurrence of pertussis in epidemics in the nearest future. The situation is different in parapertussis where epidemic incidence is still possible and where epidemics regularly occur in children of prae-school age.     

Adult Vaccination Strategies for the Control of Pertussis in the United States: An Economic Evaluation Including the Dynamic Population Effects

Background

Prior economic evaluations of adult and adolescent vaccination strategies against pertussis have reached disparate conclusions. Using static approaches only, previous studies failed to analytically include the indirect benefits derived from herd immunity as well as the impact of vaccination on the evolution of disease incidence over time.

Methods

We assessed the impact of different pertussis vaccination strategies using a dynamic compartmental model able to consider pertussis transmission. We then combined the results with economic data to estimate the relative cost-effectiveness of pertussis immunization strategies for adolescents and adults in the US. The analysis compares combinations of programs targeting adolescents, parents of newborns (i.e. cocoon strategy), or adults of various ages.

Results

In the absence of adolescent or adult vaccination, pertussis incidence among adults is predicted to more than double in 20 years. Implementing an adult program in addition to childhood and adolescent vaccination either based on 1) a cocoon strategy and a single booster dose or 2) a decennial routine vaccination would maintain a low level of pertussis incidence in the long run for all age groups (respectively 30 and 20 cases per 100,000 person years). These strategies would also result in significant reductions of pertussis costs (between −77% and −80% including additional vaccination costs). The cocoon strategy complemented by a single booster dose is the most cost-effective one, whereas the decennial adult vaccination is slightly more effective in the long run.

Conclusions

By providing a high level of disease control, the implementation of an adult vaccination program against pertussis appears to be highly cost-effective and often cost-saving.     

A new animal model of Bordetella pertussis infection and immunity

Bordetella pertussis is a strictly human pathogen. Experimental infection of other animals can occur with large inoculating doses; rat, mice and primate models have been used to study pathogenesis and immunity. Recently, it was shown that newborn piglets are susceptible to B. pertussis. Lung pathophysiology of infected piglets was similar to that of human infants that develop bronchopneumonia. Piglets and infants are anatomically similar and maternal antibodies are transferred and secreted by a similar mechanism. This model could be valuable for studying the roles of passively and actively acquired immunity against B. pertussis.     

Computational Characterization of Transient Strain-Transcending Immunity against Influenza A

The enigmatic observation that the rapidly evolving influenza A (H3N2) virus exhibits, at any given time, a limited standing genetic diversity has been an impetus for much research. One of the first generative computational models to successfully recapitulate this pattern of consistently constrained diversity posits the existence of a strong and short-lived strain-transcending immunity. Building on that model, we explored a much broader set of scenarios (parameterizations) of a transient strain-transcending immunity, ran long-term simulations of each such scenario, and assessed its plausibility with respect to a set of known or estimated influenza empirical measures. We evaluated simulated outcomes using a variety of measures, both epidemiological (annual attack rate, epidemic duration, reproductive number, and peak weekly incidence), and evolutionary (pairwise antigenic diversity, fixation rate, most recent common ancestor, and kappa, which quantifies the potential for antigenic evolution). Taking cumulative support from all these measures, we show which parameterizations of strain-transcending immunity are plausible with respect to the set of empirically derived target values. We conclude that strain-transcending immunity which is milder and longer lasting than previously suggested is more congruent with the observed short- and long-term behavior of influenza.     

The Bordetella type III secretion system: its application to vaccine development

B. pertussis is a causative agent of whooping cough (pertussis) in humans. Despite wide-scale vaccination in many countries, there is serious concern about pertussis as a re-emerging disease. Re-emergence of pertussis may be explained by several factors: the short duration of protection by the currently available acellular pertussis vaccine, an increase in asymptomatic adult carriers and expansion of strains with certain antigenic variations which are not covered by currently available vaccines. To develop safer and more efficacious vaccines which confer more prolonged protection, researchers are focusing on identification and characterization of new virulence factors. One candidate for protective antigens is the type III secretion system and its secreted proteins.