Evaluating Efficacy of Pertussis Vaccines in Children
Bordetella pertussis is the cause of the childhood illness whooping cough, or pertussis. The disease is characterized by episodes of repetitive coughing with an inspiratory “whoop,” complicated by cyanosis, a bluish discoloration of the skin, particularly common in infants, and episodes of cough-related vomiting. These episodes may last for as long as 3 weeks. In infants, the repetitive coughing may lead to respiratory fatigue and apneic episodes requiring hospitalization for respiratory support. Although often thought of as a childhood disease, cases in both adolescents and adults are being seen with greater frequency. As with many respiratory infections, mortality, which is low in the industrialized world, is highest in those under 1 year and those over 65 years old. Unlike other childhood vaccine preventable diseases, the number of cases of pertussis have increased since the 1980s. The reasons for this increase are complex.
The Pertussis Vaccine Controversy
DTP is a well-established childhood vaccine containing 3 components, diphtheria and tetanus toxoids and inactivated whole cell B. pertussis. Despite its clear effectiveness in reducing B. pertussis infections, there were concerns that the B. pertussis component of the vaccine was responsible for severe post-vaccine reactions, such as febrile seizures and encephalopathy, or non-focal disease of the brain, that occurred infrequently post-DTP vaccination.
Unlike the diphtheria and tetanus components of the vaccine, which were clearly defined and, when given to adolescents and adults, did not cause these types of reactions, the pertussis component was the entire bacterial cell, which has many different, poorly defined antigens (the molecule that elicits the immune response induced by a vaccine). During the late 1970s and early 1980s, there was significant controversy concerning the safety of the pertussis component. One large study conducted in England between 1976-1979 suggested that encephalopathy was more common following DTP vaccination, but still rare (1 in 110,000 vaccinations) with long term effects being seen in 1 in 310,000 vaccinations.
When 2 infants in Japan died in Spring of 1975 within 24 hours of receiving DTP, the Japanese government suspended the administration of DTP for 2 months. When vaccination resumed, the age at the initial dose in Japan was raised from 3 months to 2 years based on a rationale that vaccine-induced reactions might be more common in infants. Because pertussis most frequently occurs in children less than 1 year of age, the increase from 300 cases with 3 pertussis deaths in 1975, to 40,000 cases with 41 deaths in 1979, is not surprising. Not until 1989, after the 1981 introduction of an acellular, protein-based pertussis vaccine in Japan, did pertussis case numbers decrease to levels seen prior to raising the age of vaccination to 2 years.
Development of the Acellular Pertussis Vaccine
The primary rationale for developing an acellular vaccine (one that contains cellular material, but not complete cells) is that the antigenic components are defined, thus eliminating antigens that could induce non-specific inflammatory responses. Secondly, this approach allows antigens that would be highly protective against infection to be targeted. The initial acellular vaccines that were developed in Japan were either 2-component (comprised of bacterial antigens, filamentous hemagglutinin (FHA) and inactivated pertussis toxin (PT)) or 4-component (comprised of antigens, FHA, PT, fimbria and pertactin). FHA, fimbria and pertactin are important in bacterial adherence to respiratory epithelium, while PT induces very high numbers of lymphocytes in the bloodstream (a.k.a. lymphocytosis). Lymphocytosis is a characteristic of pertussis that is generally not seen with other bacterial infections, can cause pulmonary hypertension and can eventually lead to respiratory failure and death.
Antibodies that block the activity of these virulence factors prevent disease. Seven DTaP (diphtheria and tetanus toxoid, acellular pertussis) vaccines are currently approved in the U.S. for immunization series in infants starting at 2 months of age. Two are DTaP only, 2 are DTaP plus inactivated polio virus (IPV), and 1 each of DTaP-IPV plus conjugated polysaccharide H. influenzae serotype (HIB), DTaP-IPV and Hepatitis B virus (HBV) and DTaP-IPV-HIB-HBV. DTaP combined with different antigens limits the number of injections that the child needs to receive.
Effectiveness of Acellular Pertussis Vaccine
DTaP vaccines were found to be less reactogenic than DTP vaccines containing whole cell components. During the mid-1990s, DTaP replaced DTP vaccines in the U.S., but by the early 2000s, the number of U.S. cases of pertussis began to increase substantially again, reaching as high as 47,000 in 2012 (Figure 2). Cases increased primarily in those less than 1 year of age, but also spiked in elementary age students and adolescents. What caused this persistent rise in pertussis cases in the acellular vaccine era?
The simplest explanation is that the acellular vaccine is not as protective as the whole cell vaccine. There is some evidence that the immune response wanes more quickly with acellular compared to whole cell vaccines. As a result, an additional dose of acellular pertussis vaccine is recommended at the age of 11-12 years.
Factors Contributing to Decreased Vaccine Efficacy
Additional factors may further contribute to the significant rise in pertussis cases in the acellular vaccine era. First, replacement of culture with polymerase chain reaction (PCR) as the primary diagnostic tool increased sensitivity of organism detection during this time.
Secondly, non-medical exemptions for childhood vaccinations have increased over the last 2 decades and are presently available in 47 states. In most states, these exemptions are based on religious beliefs, but in 17 states they can also be based on philosophical or moral beliefs. The easier it is to get non-medical exemptions, the greater the number of unvaccinated children will be, increasing the likelihood of pertussis outbreaks in schools and communities. School age students can bring this highly contagious organism home and infect non-boosted parents and unvaccinated siblings, especially infants. They may also spread it to vaccinated children who have waning immunity and are at increased risk for infection.
A third reason for increasing pertussis cases is the emergence of pertactin-deficient B. pertussis strains. Up to 85% of B. pertussis isolates in the U.S. are pertactin-deficient. The reason this is important is that antibody response to pertactin is more durable than antibody responses to those of both PT and fimbrae. Although antibody response is equally durable to pertactin and FHA, it is speculated that pertactin antibodies are superior at blocking colonization when compared to FHA antibodies. As a result, when a vaccinated individuals becomes infected, they may remain asymptomatic (due to FHA and a lesser degree PT and fimbrae antibodies) and still transmit pertussis.
Tdap, first approved by the FDA in 2005, is a vaccine with reduced concentrations of both diphtheria toxoid and pertussis antigens. The CDC recommends that pertussis boosters be given at 11-12 years of age, for all pregnant women and at 10-year intervals for all other adults. Concerns about minor vaccine reactions such as sore arms with a DTaP in adults was the rationale for reducing these antigen concentrations. Safety data indicates that Tdap is safe and is not associated with neurologic or pregnancy complications. Immunity is similar to DTaP. Tdap pertussis efficacy wanes significantly after 4 years. This waning immunity, coupled with under vaccination and vaccine refusal, is associated with school and community outbreaks.
Tdap in Pregnancy
Between 2000-2017, 84% of fatal pertussis cases were seen in infants less than 2 months of age. The CDC, along with professional societies for obstetricians, mid-wives, family medicine practitioners and pediatricians, recommended that all pregnant women receive Tdap between 27-36 weeks of gestation. The rationale for Tdap vaccination during pregnancy was pertussis antibodies from the newly vaccinated mother could be transferred transplacentally to the infant in utero. These antibodies would protect the infant during their period of greatest risk of pertussis hospitalization and death until they begin pertussis vaccination at 2 months.
Infants of vaccinated mothers have higher level of antibodies to pertussis antigens than those of non-vaccinated mothers. However, conclusive evidence of the efficacy of preventing pertussis in the infants of vaccinated mothers is not yet available.
A recent survey shows that only 51% of pregnant women were vaccinated with Tdap during pregnancy. Part of the reason for this poor vaccination uptake is only 66% of pregnant women were offered Tdap vaccination by their provider. The CDC and professional societies' recommendation for pertussis vaccination during pregnancy needs to be followed more widely to reduce the pertussis risk in newborns.
Will an mRNA Vaccine Solve the Pertussis Vaccine Shortcoming?
The fact that pertussis vaccines are less effective when compared to other childhood vaccines such as polio, tetanus, diphtheria, S. pneumoniae, H. influenzae type B, measles, mumps and rubella, is both troubling and complex. One potential solution might be to use mRNA vaccine technology, which has proved to be effective against SAR-CoV-2, to attempt to develop a more effective pertussis vaccine platform. Unfortunately, vaccines against both pathogens share a similar shortcoming, waning immunity. It is clear that a greater understanding of the immune response generated by the acellular pertussis vaccine is needed to address the shortcomings of the currently used vaccines.