Pertussis Resurgence: Perspectives From the Working Group Meeting on Pertussis on the Causes, Possible Paths Forward, and Gaps in Our Knowledge

The incidence of reported pertussis has steadily increased in the United States since the 1980s, with a striking increase observed since 2005 [1]. Provisional case counts in the United States for 2012 exceed 41 000, with 14 deaths among infants [2]. This resurgence in pertussis that has been seen in the United States and other countries [3] has caused considerable concern. On 6 March 2013, 64 experts in the field of pertussis vaccinology, from academia, government agencies, and pharmaceutical companies, met during the Working Group Meeting on Pertussis that was held in Bethesda, Maryland. This workshop offered a unique opportunity for experts to discuss possible causes of the resurgence in pertussis, the possible paths forward, and the remaining gaps in our knowledge. To take advantage of this collection of experts, 3 discussion sessions were held during the workshop to discuss (1) potential root cause(s) of the problem, (2) what interim solutions may exist, and (3) how the problem might be solved in the long term. At the end of the workshop, the experts agreed that use of the currently available vaccines is an important strategy but that longer-term solutions are necessary to more effectively control pertussis. No clear consensus was reached as to a single root cause of the problem nor did a clear long-term solution emerge. However, the group began to define gaps in knowledge, discussed hypotheses that could be tested, and suggested priorities for research and development. The workshop participants thought that while the primary goal of the pertussis immunization program should be protection of infants, who are most vulnerable to pertussis-associated mortality and severe morbidity, we should not be limited to that goal. Broader goals, including prevention of morbidity and mortality in all age groups, as well as prevention of Bordetella pertussis infection and transmission, should be targeted. Identification of the root cause of the resurgence in pertussis is the first step in designing a vaccine and vaccination program that would best meet these goals. A number of possible causes were suggested and considered by participants of the workshop, including (1) short-lived adaptive immunity following immunization, (2) suboptimal balance of immune response (eg, skewed too much towards a T-helper 2 [Th2] response), (3) need for additional vaccine antigens for optimal protection, 4) insufficient quantity or incorrect balance of antigens, 5) antigen mismatch with circulating strains, 5) lack of vaccine protection against transmission, 6) suboptimal schedule or population coverage, 7) differential effectiveness of the vaccines in current use, and 8) increased awareness, better diagnostic tests, and/or more-complete reporting. The working group participants discussed the data showing a short duration of protection following administration of acellular pertussis vaccines, suggesting that waning vaccine immunity may be a contributing factor to the observed increase in pertussis incidence [4–7]. Participants expressed concern that induction of a suboptimal type of T-cell response by acellular pertussis vaccines may contribute to shorter-lived immunity. Data from both human and animal studies suggest that whole-cell and acellular pertussis vaccines direct the immune response differently. Whole-cell vaccines favor a T-helper 1 (Th1) response, whereas acellular pertussis vaccines skew the response more toward a Th2 or mixed Th1/Th2 response [8–10]. Natural infection, which is believed to provide long-lasting protection, primes primarily Th1 cells [11]. Recently, Ross et al [12] reported that, in a mouse model, T-helper 17 (Th17) responses were also seen after natural infection, vaccination with a whole cell reference preparation, and vaccination with an aluminum-adjuvanted acellular pertussis vaccine. In that study, protection by the whole-cell preparation was found to be mediated largely via a Th1 response, with the Th17 response contributing some protection. The acellular pertussis vaccine induced Th2 and Th17 responses, with only a weak Th1 response. The Th17 response was found to be important in mediating protection afforded by the acellular pertussis vaccine, but the Th2 response appeared to be dispensable in that model. The workshop participants thought that additional research is needed to better understand the type of immune responses that yield optimal, long-lasting protection and the mechanisms responsible for this protection. The workshop participants also discussed antigenic variation due to emergence of variant vaccine-antigen alleles as a possible contributor to pertussis reemergence. A number of articles have documented circulating allelic variants that differ from those of the vaccine strain [13, 14]. In most cases, the differences between the alleles are single-nucleotide polymorphisms. Others have questioned strain variation as being a major cause of the recent increase in pertussis incidence, since allelic variation would not account for the age-related trends observed in surveillance data [4, 5]. A study evaluating historical pertussis strains in the United States indicated that divergence of circulating strains away from those used for vaccine production had been occurring long before the transition to acellular vaccines [15]. Recently, emergence of pertactin-deficient strains has been noted in several countries that are using acellular pertussis vaccines [16–19]. What effect, if any, the loss of production of pertactin might have on the protection afforded by pertactin-containing acellular pertussis vaccines against these strains is not yet known. Increased awareness or improved diagnosis and reporting of pertussis were also mentioned at the workshop as possible contributors to the observed increase in pertussis cases. However, others have cautioned that we would not expect to see the age-related trends that are occurring if these factors were the sole cause of the increase in disease [4]. While no clear-cut explanation for the resurgence of pertussis has emerged, the question arises as to what might be done in the short term to help mitigate this resurgence until a longer-term permanent solution can be put into place. New vaccines are unlikely to be available within the short term (eg, less than 3–5 years); thus, the focus of the working group was on optimizing the use of currently available acellular pertussis vaccines. The working group felt that particular focus should be put on interim solutions that would help protect neonates, the most vulnerable population. Certain efforts in this regard have already begun. In October 2012, the Advisory Committee for Immunization Practices recommended the use of combined tetanus, diphtheria, and acellular pertussis (adolescent and adult formulation; Tdap) vaccine during the third trimester of every pregnancy, with the goal of providing protection to infants from pertussis until they are old enough to be vaccinated [2]. Recently, immunization of pregnant women was also recommended in the United Kingdom and other countries. Indirect evidence for possible effectiveness of this approach comes from historical data [20]. Those data show that, in the prevaccine era, pertussis deaths in the first month of life were about one-third of those of the second and third months of life but that, in the vaccine era, no significant difference in mortality has been seen in the first and second months of life. This change in epidemiology suggested that, as a consequence of vaccination, reduced levels of circulating strains might result in less efficient natural boosting of maternal anti–B. pertussis antibodies. Follow-up studies and evaluation of available epidemiologic data will be needed to determine whether the recommendation for Tdap vaccination of pregnant women helps to prevent pertussis among infants. A second option discussed by the working group was neonatal immunization. Studies of neonatal immunization by use of pertussis vaccines have been conducted, which differed in study design [21]. Early responses to the pertussis antigens have been observed in neonates primed with acellular pertussis vaccines [22, 23]. However, in one study lower pertussis antibody levels were observed after completion of the primary series [24], and in some studies lower responses to antigens given concomitantly were observed after the primary series [22, 24]. Members of the working group voiced the opinion that additional studies are needed to determine whether this approach holds promise, to determine whether the vaccine has a good safety profile in this age group, and to ascertain that such a practice does not misdirect the immune system in an unintended way. Moreover, this approach would likely require development of an acellular-pertussis-only vaccine that lacks the diphtheria and tetanus components of the combined diphtheria, tetanus, and acellular pertussis (pediatric formulation) vaccine. Other interim solutions include additional doses of acellular pertussis vaccines or an earlier dose of Tdap. Some members of the working group voiced the concern that additional doses or a change in schedule might have unintended consequences on disease epidemiology (eg, changing the age of susceptibility without changing the total incidence). In addition, the safety of additional doses would need to be considered and might require development of an acellular-pertussis-only vaccine to avoid adverse events that might be associated with repeated immunization with the diphtheria and tetanus components of Tdap. Others raised the question of which immune response—antibody levels, functional antibody levels, or T-cell responses—would be the most meaningful measure of the effectiveness of the vaccine if changes to the dosing schedule were studied. Finally, many raised questions about the relatively modest impact that would be expected for additional doses given the short duration of protection associated with current acellular pertussis vaccines. While some interim solutions might exist, the general consensus was that longer-term solutions are needed for a fundamental change in pertussis epidemiology. Optimally, a vaccine would offer long-term protection against both disease and transmission, but questions remain regarding how to attain such protection. Would addition of new antigens to the vaccine or live attenuated vaccines provide better protection? Some potential candidates for new antigens, such as an inactive form of adenylate cyclase toxin, were mentioned and discussed. If new antigens are to be considered, we should understand when and where during the course of infection the antigens are expressed, as well as the role that they play in disease. Several in the working group cautioned that we will need good evidence that the antigen is critical for the infectious process and survival of the organism in the host. The group emphasized that directing the immune system to the optimal combination of cellular immune responses is important. In this regard, novel adjuvants might be studied to determine whether they direct the immune response in a way that provides better protection. A deeper knowledge of the immunology of protection against pertussis is needed to move forward in the most productive manner. Elucidation of a correlate of protection would be important. We also need to better understand the effect that single-nucleotide polymorphisms have on the ability of the vaccine to protect against circulating strains. Moreover, we need to examine vaccine effectiveness against strains lacking one of the vaccine antigens, such as the pertactin-negative strains that have recently been discovered. The group discussed the availability of new tools that should help determine the underlying factor(s) causing the pertussis resurgence and stressed that additional research is needed. The novel baboon model of pertussis developed by Tod Merkel and his colleagues at the Food and Drug Administration may be a powerful way to study immune mechanisms [25]. Advances in sequencing techniques will facilitate analysis of circulating disease strains. Additional animal and epidemiology studies could be conducted to help assess the role, if any, that allelic variation has in the resurgence of the disease. Additional work needs to be done to discover immunological correlates of protection. Although acellular vaccines exhibit fewer adverse reactions than the whole-cell pertussis vaccines that were used from the 1950s to the 1990s, and although they provide good protection in the first few years after vaccination [5], the duration of protection is shorter than had been expected. The working group stressed that further research is needed to fully elucidate the cause(s) of this waning of protection before the best pathway forward can be determined. Additional data on pertussis epidemiology, pathogenesis, and host response to disease and vaccination are needed to best design the most effective vaccine and vaccination program. Collaborative approaches and the availability of data, specimen, and strain repositories would be expected to expedite research needed to provide insight into how best to proceed. Approaches such as systems biology and genomics might provide a more holistic picture of both disease and protective immune responses. The working group concluded that achieving a long-term solution that effectively controls pertussis will not be easy and will require significant effort on the part of researchers in the field, along with government and industry support. Disclaimer. The opinions and conclusions expressed in this article are those of individuals attending the Working Group Meeting on Pertussis that was held on 6 March 2013 in Bethesda, Maryland, and should not be construed to represent the views, determinations or policies of the Food and Drug Administration or the Centers for Disease Control and Prevention. Financial support. This work was supported by the Food and Drug and Administration and Centers for Disease Control and Prevention. Potential conflicts of interest. All authors: No reported conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.