Pertussis: acellular, whole-cell, new vaccines, what to choose?

KEYWORDS:

• Pertussis
• whole-cell vaccines
• acellular vaccines
• live vaccines
• maternal vaccination

Pertussis or whooping cough, caused by Bordetella pertussis, is a severe respiratory disease that can be fatal in young infants. Two types of vaccines are available and widely used, first-generation whole-cell vaccines (wPV) and more recent acellular vaccines (aPV). Nevertheless, pertussis is still not under control, and its incidence is rising in several countries that have switched from wPV to aPV. Both protect against disease, but none of them prevents infection, as shown in a recently developed baboon model. Yet, asymptomatic B. pertussis transmission may be the single most important cause for the resurgence of pertussis. Vaccines that prevent infection in addition to disease are needed to ultimately control whooping cough. Although one such vaccine is in clinical development, it will still take years before it can be used. Meanwhile, recent evidence shows that aPV is effective for vaccination during pregnancy to protect the newborns against severe and deadly pertussis.

Pertussis or whooping cough, caused by Bordetella pertussis, is a severe respiratory childhood disease that can be fatal, especially in very young infants. However, it also represents a significant disease burden in older children, adolescents, and adults [1]. Efficacious vaccines against pertussis are available since the middle of the last century, and global vaccination coverage for the three primary vaccine doses has now reached >85% [2]. Nevertheless, the disease is still not under control and is today the most prevalent vaccine-preventable childhood disease. The World Health Organization (WHO) records close to 200,000 pertussis-related deaths and more than 16 million yearly pertussis cases globally [3]. However, before the implementation of mass vaccination the reported incidence of the disease in countries like the U.S. was as high as 150 cases per 100,000 population, which was likely a vast underestimation [4]. Since the 1950s, the incidence and the numbers of pertussis-linked deaths have declined dramatically to reach a nadir in the late 1970s in several countries, illustrating the effectiveness of mass vaccination against pertussis. However, more recently, the numbers of cases and associated deaths have again increased in several industrialized countries, illustrating, in turn, the shortcomings of current vaccination strategies.

Two types of pertussis vaccines are currently available, the first-generation whole-cell vaccines (wPV) and the more recent acellular vaccines (aPV), composed of one to five purified antigens. All available pertussis vaccines are combined with tetanus and diphtheria toxoids and many also with hepatitis B, inactivated polio, and Haemophilus influenza B polysaccharide [5]. The efficacy of wPV has been demonstrated to be >90% after three administrations, although the efficacy of some wPV was as low as 30–50% [6].

The more defined aPV have been developed in the 1980, subsequent to local and systemic adverse events that have been associated with wPV, but also because of the difficulties in lot consistency. All contain inactivated pertussis toxin, most of them contain also filamentous haemagglutinin, many contain pertactin in addition and some contain also fimbriae. They have a clearly improved safety profile over wPV [5], and their short-term efficacy after three administrations was estimated to be 67–70% and even 84% for vaccines containing three or five B. pertussis components. However, when compared in these short-term studies to well-performing wPV, the efficacy of aPV was slightly lower. Because of their improved safety profile and similar efficacy, most industrialized countries have replaced wPV with aPV. Nevertheless, wPV are still the most used vaccine globally, mostly because of the high cost of aPV, difficult to afford in resource-poor countries.

In recent years, it has become apparent that immunity induced by aPV wanes substantially faster than that induced by wPV [7], which led the Strategic Advisory Group of Experts on Immunization at the WHO (WHO/SAGE) to recommend that countries considering a switch from wPV to aPV should await further guidance [8]. However, increases in pertussis incidence have also been observed in countries in which wPV continue to be used. Thus waning immunity induced by aPV is not the only reason for the resurgence of pertussis. A study based on mathematical modeling concluded that asymptomatic transmission is the most parsimonious explanation of the current resurgence of B. pertussis [9]. Results coming from a recently developed baboon model suggest that aPV does not prevent transmission of B. pertussis, even though it protects against disease, and that neither aPV, nor wPV prevents infection by virulent B. pertussis, although, wPV-vaccinated animals appeared to clear the infection faster than aPV-vaccinated baboons [10]. Nevertheless, the total bacterial burden was lower in the vaccinated compared to the naïve animals, suggesting that both vaccines may have some, albeit limited impact on infection.

This impact may not be sufficient to control the circulation of B. pertussis but can, instead, lead to the generation of vaccine escape mutants, which have indeed been observed in several countries where aPV is in use. As an example, strains not producing pertactin are rapidly expanding [11]. Multiple molecular mechanisms have been identified to lead to the absence pertactin, strongly suggesting selective pressure. There is no apparent major difference in the pathogenesis of whooping cough when children were infected with pertactin-deficient strains compared to pertactin-producing strains, indicating that pertactin is neither required for infection by B. pertussis, nor for the development of the disease.

In contrast to vaccination with aPV or wPV, prior infection with B. pertussis is able to induce sterilizing immunity in baboons [10]. Since B. pertussis is a strictly mucosal pathogen, it is likely that mucosal immunity induced by the infection may contribute to protection, although the protective role of mucosal immunity has so far attracted little attention. Furthermore, several studies have shown that infection-induced immunity is longer lived than vaccine-induced immunity [12], although probably not life-long and re-infections have been reported to occur. However, second attacks are very rare and usually much milder than the first attacks [13]. Therefore, a vaccination approach that mimics infection without causing disease may be a potential solution to ultimately control pertussis. A vaccine that may achieve this goal is currently under clinical development. It is based on a live attenuated B. pertussis strain, named BPZE1, in which three different toxins have been genetically removed, strongly reduced, or inactivated [14]. This strain, reviewed in [15], has been documented to be safe in pre-clinical models and genetically stable over at least one year of continuous passaging in vitro and in vivo in mice. It induces strong protection against challenge infection after a single intranasal administration, which lasted at least for up to one year, whereas protection conferred by aPV started to wane already after 6 months. BPZE1 has now successfully completed a Phase I clinical trial and was shown to be safe in young male volunteers for doses up to 10⁷ colony-forming units in 100 µl/nostril [16]. This trial also showed that BPZE1 can transiently colonize the human naso-pharynx and induce B. pertussis-specific antibody responses in all colonized individuals. The study subjects were followed up for 6 months, at which time the antibody titers to all antigens tested were at least as high as at 1 month after vaccination. However, not all subjects were colonized, even at the highest dose tested, and colonization by BPZE1 was found to be essential for the induction of immune responses. One possible reason of the lack of colonization in some individuals may have been their prior exposure to wild-type B. pertussis, which might have prevented vaccine take. Consistent with this hypothesis, the non-colonized individuals had pre-existing antibody titers, especially to pertactin, that were significantly higher than the colonized individuals. A new clinical trial is currently under way to test this hypothesis and to assess whether increased doses and/or volumes may overcome the effect of pre-existing antibodies or prior exposure to wild-type B. pertussis.

As promising as this type of vaccine may be, it will still take several years before it can be made available. Meanwhile, a more optimal use of the current vaccines should be made. An apparently effective way of limiting severe and deadly pertussis at the very young age is maternal immunization with aPV between 28 and 38 weeks of gestation. The effectiveness of this approach against laboratory-confirmed pertussis in infants less than 2 months of age was shown during the recent pertussis outbreak in the U.K. to be over 90% [17]. These data support recommendations now made in several countries for pertussis vaccination during pregnancy. However, several issues remain to be fully addressed, such as the impact of maternal immunization on the immune responses to the primary vaccination of the infants. Some studies describe blunting of primary antibody responses to B. pertussis antigens by maternal vaccination [18], whereas in other studies only minimal blunting, if any, was detected [19]. In the absence of clear correlates of protection against pertussis, the clinical relevance of this blunting effect remains to be determined. However, recent mouse challenge studies have shown reciprocal interference of maternal and primary vaccination, which was reflected in the functionality of vaccine-induced antibodies [20].

In conclusion, in order to ultimately control pertussis, novel vaccines are needed that not only protect against disease but also prevent infection and thereby asymptomatic transmission. One such vaccine is currently in clinical development, but it will take several years before it can reach the market. Cocoon vaccination with current vaccines, especially with aPV, has not been very effective, as it relies on herd immunity, which is not sufficiently well induced by aPV. In contrast, maternal immunization with aPV has proven safe and effective in limiting severe and deadly pertussis in young infants. However, aPV does not prevent infection, and aPV-induced immunity wanes unexpectedly faster than wPV-induced immunity. Therefore, it is currently recommended for those countries in which wPV is still in use, not to switch to aPV. On the other hand, the use of wPV for maternal vaccination may raise important safety issues. Thus, before new vaccines can be made available, there is room for a more optimal use of current vaccines, which will, however, not be sufficient to ultimately control pertussis.

Financial and competing interests disclosure

C Locht declares to be an inventor on patents related to the live attenuated pertussis vaccine and is a consultant of ILiAD Biotechnology. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.