The relationship between mucosal immunity, nasopharyngeal carriage, asymptomatic transmission and the resurgence of Bordetella pertussis

Abstract

The incidence of whooping cough in the US has been rising slowly since the 1970s, but the pace of this has accelerated sharply since acellular pertussis vaccines replaced the earlier whole cell vaccines in the late 1990s. A similar trend occurred in many other countries, including the UK, Canada, Australia, Ireland, and Spain, following the switch to acellular vaccines. The key question is why. Two leading theories (short duration of protective immunologic persistence and evolutionary shifts in the pathogen to evade the vaccine) explain some but not all of these shifts, suggesting that other factors may also be important. In this synthesis, we argue that sterilizing mucosal immunity that blocks or abbreviates the duration of nasopharyngeal carriage of Bordetella pertussis and impedes person-to-person transmission (including between asymptomatically infected individuals) is a critical factor in this dynamic. Moreover, we argue that the ability to induce such mucosal immunity is fundamentally what distinguishes whole cell and acellular pertussis vaccines and may be pivotal to understanding much of the resurgence of this disease in many countries that adopted acellular vaccines. Additionally, we offer the hypothesis that observed herd effects generated by acellular vaccines may reflect a modification of disease presentation leading to reduced potential for transmission by those already infected, as opposed to inducing resistance to infection among those who have been exposed.

Keywords: acellular pertussis vaccine; bordetella pertussis; whooping cough.

Figure 1.. Trends in US pertussis incidence, 1940–2012.

This figure depicts the annual per-capita incidence of pertussis infections in the US over the past seven decades, with the timing of the introduction of whole cell (wP) and acellular (aP) vaccines noted in annotations. The inset at the top right expands the details and readjusts the scale relevant to the period of rising incidence. As can be seen, pertussis rates were slowly rising since the 1970s but accelerated sharply following the transition to aP vaccines in 1996. The data are truncated as of 2010, but the rise of pertussis incidence has continued since that time.

Figure 2.. Changes in pertussis incidence relative to the introduction of acellular pertussis vaccines in the US, UK, Australia, and Ireland.

Depicted are incidence data over time from the US, Australia, the United Kingdom (including Northern Ireland), and the Republic of Ireland. In each case, the introduction of acellular (aP) pertussis vaccines preceded an abrupt increase in disease incidence rates following a delay of 5–10 years. The declining incidence seen for the UK and Republic of Ireland from the early 1990s is likely explained by a reduction in whole cell pertussis vaccine uptake that occurred in the 1980s following several highly publicized adverse events that were attributed to pertussis vaccines.

Figure 3.. Pertussis incidence in the United Kingdom, by age group, 1998–2015.

This figure presents data from the United Kingdom of pertussis incidence disaggregated by age categories over a 17-year period. The introduction of enhanced pertussis diagnostics and of the transition from whole cell to acellular (aP) pertussis vaccines are noted in annotations. To note, the scale representing incidence differs by age category (≥6 months versus <6 months of age). While there is year to year fluctuation in the incidence of pertussis, during the period 2011–2013, incidence rates spike. This abrupt increase cannot be easily explained as an artefact of enhanced diagnostics that were being phased in since 2006. A more parsimonious explanation is that this represents a nationwide epidemic of pertussis occurring after some delay from the transition to aP vaccines in 2005. PCR, polymerase chain reaction.

Figure 4.. A natural experiment exploring the effect of infant exposure to acellular or whole cell pertussis vaccines and age-specific incidence of pertussis

These data from the Kaiser Permanente health maintenance organization in Northern California reflect a natural experiment centered on the transition from whole cell to acellular pertussis vaccines in the US in the 1990s. These data were all collected over a narrow time window, and so the incidence by age should be understood in relation to what vaccine these individuals had received as infants. Those above the age of 15 could have received only whole cell pertussis vaccines, those under the age of 11 could have received only acellular pertussis vaccines, and those aged in between could have received a blended schedule of both vaccines, reflecting the transition period. The blue line depicts pertussis incidence as a function of age; the red line represents the proportion of each age stratum that received the acellular vaccine (100% of those vaccinated below the age of 11; ~0% of those aged 15 years and older). We make several observations: First, there is a decline in incidence from birth through the first year of life. This is likely explained by the induction of immunity through infant vaccination. Pertussis incidence then increases steadily through age 10. In light of what has been learned, this most likely reflects waning of acellular pertussis vaccine-induced immunity with time. Second, rather than continuing to rise with age, the incidence instead plummets above the age of 11 years, falling essentially to zero in those 15 years and older. It is remarkable to observe that receipt of any whole cell pertussis vaccines during infancy continues to exert such durable protection, to the extent that the 15 years and older birth cohort remain almost completely protected even decades out. This strongly argues that the immunologic effects resulting from whole cell and acellular pertussis vaccines are quite distinct. DTaP, diphtheria, tetanus, and acellular pertussis.

Figure 5.. Effect of infection-blocking versus disease-preventing vaccines on the inter-epidemic cycle lengths of a hypothetical respiratory disease.

These cartoons depict the effect on inter-epidemic cycle lengths by vaccines with different immunological effects in terms of whether they prevent infections (regardless of symptoms) as well as clinical disease (by definition symptomatic) or that only prevent clinical disease. At a population level, immunity waxes and wanes over time. With increased infection rates, the population acquires immunity and disease incidence subsequently falls. Over time, population immunity wanes (for example, because of the introduction of non-immune infants born into the population), leading to a resurgence of disease. The inter-epidemic cycle length is the average time between peaks in this cycle. The amplitude of each peak reflects the number of observed symptomatic cases in the population. •  Panel A depicts the base case absent any vaccination. For pertussis absent vaccination, the inter-epidemic cycle length has been estimated at between 3 and 5 years. •  Panel B depicts the effect of a vaccine that prevents infections and clinical disease. By blocking infections, the pace of spread through the population is slowed, leading to an extension of the inter-epidemic cycle length as well as a decline in amplitude of peaks due to prevention of clinical disease. •  Panel C depicts a vaccine that fails to block infection but effectively prevents clinical disease. This vaccine only reduces the amplitude of peaks but has no impact on period length, since transmission is not affected.