Pertussis is a highly infectious respiratory disease, and even though vaccination has been globally implemented since the 1940s, we are far from elimination, and even still suffering from many outbreaks throughout the world.
1. Vaccination with whole cell Pertussis (wP) vaccine, a success: The establishment of the Expanded Program on Immunization (EPI) in 1974 significantly improved pertussis vaccination coverage. By the early 1980s, widespread vaccination efforts led to a dramatic reduction in the morbidity and mortality associated with the disease.
2. Safety Concerns, discontinuation of wP vaccine, and resurgence of Pertussis. In the 1980s, as the risks of pertussis markedly declined, public attention shifted from the dangers of the disease to concerns over vaccine side effects. Doubts regarding the safety of wP vaccines led to decreased public acceptance, and in some countries, their use was completely discontinued. For example, in the United Kingdom and the United States, media coverage, including reports in newspapers and television programs, heightened fears about vaccine safety, contributing to declining vaccination rates. The reactogenicity of wP vaccines was extensively studied. The pertussis component—specifically the lipooligosaccharide—was identified as the primary factor responsible for vaccine-associated toxicity. Reported adverse reactions ranged from local effects such as redness, swelling, and pain at the injection site to systemic effects including fever (ranging from mild to high), persistent crying, irritability, and, in rare cases, seizures and encephalopathy.
3. Debunking the Myth: Encephalopathy and Seizures Associated with the Whole-Cell Pertussis Vaccine: In 1994, Jale G. et al. conducted a population-based case-control study involving 424 confirmed cases of neurological illness identified through statewide active surveillance over a 12-month period. The study population consisted of 218,000 children aged 1 to 24 months living in Washington and Oregon, who received an estimated 368,000 DTP immunizations. The odds ratios (OR) for specific neurological diagnoses within seven days of vaccination varied, but all confidence intervals (CI) included 1, indicating no significant association. Furthermore, no elevated risk of nonfebrile seizures was observed. In 2001, Barlow W.E. et al. assessed the relative risks (RR) of febrile and nonfebrile seizures among 679,942 children after receiving 340,386 DTP vaccinations. The study found no increased risk of nonfebrile seizures following pertussis vaccination. Additionally, children who experienced febrile seizures after vaccination were not at higher risk of subsequent seizures or neurodevelopmental disabilities compared to children with febrile seizures unrelated to vaccination. At least three additional studies reported similar findings, providing no evidence of a link between WP vaccination and seizures or encephalopathy. However, variations in vaccine manufacturing processes may contribute to higher reactogenicity in some WP vaccines.
4. Concerns with acellular Pertussis (aP) vaccines:
a. Reduced duration of immunity compared to wP vaccines. Numerous studies indicate that immune protection against pertussis lasts between 10 and 20 years following natural infection and up to 12 years after whole-cell pertussis (wP) vaccination. In contrast, immunity from acellular pertussis (aP) vaccines typically wanes within 3 to 5 years, increasing susceptibility among school-aged children and necessitating booster doses at younger ages. Furthermore, cohort-based efficacy studies conducted in several European countries and Senegal, involving infants and toddlers who received three- or four-dose pertussis vaccine series, demonstrated that immunity waned more rapidly following aP vaccination compared to wP vaccination.
b. Reduced mucosal immunity compared to wP vaccines. Warfel, Merkel, et al. analyzed T-cell phenotypes in infant baboons before and after challenge infection with Bordetella pertussis and following wP or aP vaccination. As expected, Bordetella pertussis infection induced a predominantly TH17 immune response. Similarly, wP vaccination elicited a primarily TH17 response, accompanied by a lesser TH1 response, resulting in the production of both IgG and IgA antibodies. In contrast, baboons vaccinated with aP exhibited only TH2 responses, characterized mainly by IgE antibody production, which is unlikely to provide effective mucosal protection.
c. Reduced nasopharyngeal carriage and indirect (herd) immunity compared to wP vaccines. For both wP and aP vaccines, studies assessing nasopharyngeal (NP) carriage or colonization reduction were not conducted during late-phase 3 clinical trials or phase 4 cohort studies. Consequently, the impact of vaccination on indirect (herd) immunity remained unclear until recently. Research conducted in baboons by Warfel et al. demonstrated that wP vaccines, but not aP vaccines, reduce nasopharyngeal colonization, thereby contributing to indirect immunity. Supporting this finding in humans, a 2003 longitudinal study conducted in Senegal observed secondary attack rates among vaccine failures. The results showed that wP vaccination reduced secondary infections by 86%, compared to only 6% among individuals vaccinated with aP.
Acellular Pertussis vaccine implementation related to the increased number of Pertussis cases in developed countries. The licensure of aP was first started in 1991 as 4th and 5th doses only, followed by recommendation for all five doses in childhood by 1996-1997, as DTaP. Accordingly, a rise in Pertussis cases rose significantly in 2005, and was markedly increased by 2010. Similar trends occurred also in Australia, the Republic of Ireland, and England/Wales, with reemergence of Pertussis cases between 3 to 6 years of aP vaccine introduction (see Figure 1).
FIGURE 1
Trends of Pertussis incidence in the US, Australia, England/Wales, and the Republic of Ireland. 1992 – 2012
Taken from Gil GJ, et al,28.
Proposed guidelines for Pertussis vaccination in infants and toddlers:
a. Countries using only WP vaccines. The World Health Organization (WHO) recommends a 3-dose primary series, with the first dose administered as early as 6 weeks of age; subsequent doses should be given 4–8 weeks apart, at age 10–14 weeks and 14–18 weeks. The last dose of the recommended primary series should ideally be completed by 6 months of age with either wP or aP vaccines.
b. Countries with mixed aP and wP vaccines schedules. No accepted serological correlate of protection after vaccination with either wP- or aP-containing vaccines has been established, although various parameters have been suggested, hence, interchangeability between wP and aP vaccines is difficult to assess in a non-large clinical trial. Nonetheless, few studies have addressed this issue, as an example, a novel liquid hexavalent DTwP-containing vaccine (EasySix, Panacea Biotec®) was compared with Pentavac® + inactivated poliovirus (IPV) in a small study of around 300 infants in India, and it was reported that the immunogenicity would be similar. The lack of robust data resulted in a general recommendation from the WHO not to interchange wP or aP vaccines from different manufacturers during the primary series,45, though this recommendation is not universally followed.
c. Countries only using aP vaccines. Most developed countries use solely aP vaccines for primary immunization in infants. Returning to wP vaccines is not feasible since it would most likely carry out significant criticism by the media, and, particularly, antivaccination groups. Both the Pertussis Global Initiative and the WHO strongly recommend high vaccination coverages and enhancing surveillance.
d. Vaccination in adolescents, adults, and during pregnancy. Indeed, aP vaccines are currently the only option for these populations, and we strongly advocate for their use to enhance overall protection, as demonstrated by numerous studies. Specifically, for pregnant women, preventing pertussis in both the mother and the infant is crucial for ensuring optimal health outcomes.
Next steps:
a. Improve coverage.
b. Better surveillance.
c. New vaccine platforms: Recently, results from a phase 2/3 randomized-controlled clinical trial evaluating a monovalent pertussis vaccine containing recombinant, genetically inactivated pertussis toxin (aPgen®), either alone or as DTaPgen®, were published. These were compared to a chemically detoxified comparator vaccine (DTaPchem®). Three years post-vaccination, seroconversion rates for PT-neutralizing antibodies were 65.0% (95% CI 44.1–85.9) for aPgen® recipients and 55.0% (95% CI 33.2–76.8) for DTaPgen® recipients. Based on these results, the genetically detoxified aPgen® and DTaPgen® vaccines are expected to provide longer-lasting protection than chemically inactivated DTaP vaccines, although larger clinical trials are needed to confirm these findings. Mucosal (nasal) vaccines represent the ideal approach to immunization, as delivering immunogens via the natural route of infection could potentially induce stronger mucosal immunity and reduce nasopharyngeal colonization compared to intramuscular vaccines. This could result in better indirect (herd) immunity and a greater overall impact. Nasal vaccines are currently under development, with several animal studies completed and some human clinical trials in early stages. Examples of these platforms include live attenuated vaccines, aP vaccines with adjuvants, and nasal wP vaccines with outer membrane vesicle pertussis vaccines. We must await the results of phase 3 clinical trials to assess their efficacy.
Conclusions:
Despite being a vaccine-preventable disease, pertussis remains far from eradication in many regions worldwide. In a landscape where both whole-cell and acellular pertussis vaccines are in use, adherence to established vaccination guidelines is crucial to optimizing protection and safety for all populations. While prioritizing the immunization of young infants is essential, it is equally important to strongly recommend vaccination for adolescents and adults.
Guidelines from reputable organizations like the Global Pertussis Alliance and the World Health Organization emphasize the need to strengthen surveillance systems and pharmacovigilance efforts. Additionally, investing resources in the clinical development of novel and improved vaccines is key to addressing the evolving challenges of pertussis.
Ongoing medical education on pertussis and its vaccines, along with raising societal awareness about this potentially deadly disease, is of utmost importance. Such collective efforts are essential to maintaining a global, comprehensive approach to the prevention and control of pertussis.
