Evaluating Current Vaccine Strategies for Tdap

Reemergence of pertussis continues despite high immunization rates.

Bordetella pertussis is a human-specific pathogen associated with severe coughing spells, known as whooping cough—a tenacious respiratory illness that has evaded elimination by vaccine.

Reemergence of pertussis continues despite high immunization rates due to the pathogen’s virulence, incomplete protection, waning immunity, and strain polymorphism. Pertussis remains a challenge globally, as population-based surveillance estimates from the World Health Organization (WHO) show 16 million cases and 200,000 deaths from pertussis annually.1-4

The first known appearance of the disease occurred in 1414 with an epidemic to follow in 1578. However, isolation of B. pertussis was not successful until 1906 with the development of Bordet-Gengou medium widely used today.4

In response, the innovation of pertussis whole-cell (Pw) vaccines emerged, composed of 3 predominate pertussis toxins (PT) serotypes and combined collectively as diphtheria-pertussis-tetanus (DTP) for widespread immunization programs in 1947. Immunization efforts saw a dramatic decline in the incidence of pertussis in the United States with that trend reflected globally.2,5,6

Pw vaccines in infants and toddlers produced a broad immune response to some, but not all, circulating PT isolates, allowing genetic diversity of B. pertussis to express immunomodulating factors, by only affecting vaccine strains, and leaving virulent isolates. In addition, reactogenic manifestations of the inflammatory response and links to neurologic complications (pertussis encephalitis) in infants raised concerns about vaccination. Continual outbreaks despite vaccine-induced immunity prompted changes in the prevention of clinical disease with development of pertussis acellular (Pa) vaccines.3-5

Pa vaccines introduced in the 1990s were not only used in infants and toddlers, but adults and adolescents as well. These vaccines targeted bacterial virulence while increasing vaccine coverage to reduce infection transmission. Pa vaccines contain up to 5 purified PT subunits targeting circulating isolates, and interrupting transmission with adhesins pertactin (Prn), filamentous hemagglutinin (FHA), and 2 fimbrial proteins.2,5,6

Cyclic outbreaks have not ceased with the switch from Pw to Pa vaccines, which suggests resurgence is multifactorial. B. pertussis has adapted to circulating isolates through deletion or inactivation of insertion sequence elements in PT, promoting conformational change and aiding in the escape of vaccine antigens.

Functional domains in Prn and FHA necessary for host attachment have diversified to express strains distinct from vaccine strains, damaging the respiratory tract and leading to evasion of host defenses. Increased fitness has resulted in the ability of B. pertussis to escape the raised antibody response of vaccine efforts and contributes to waning immunity with humoral and cellular response.2,3,5,6

Epidemiological data comparing the immune responses of children primed with Pa vs Pw up to 10 years suggest a limited duration of protection against pertussis. Prior to age 6, Pa primed booster vaccines achieved higher IgG levels for PT specific antibodies.

Boosters administered after 9 years, resulted in lower humoral B-cell and T-helper 1 (Th1) cells. Memory B-cells failed to reach significance and returned to pre-booster levels after a year.

T-helper ratios of Th1/Th2 resulted in lower antigens in the Pa primed group. Diminishing Th1 effects in the immune response crucial for bacterial clearance, long-term immunity, and waning protection with Pa primed boosters suggest the need for the development of a more Th1-dominated primary vaccination series.3

The Acellular Pertussis Vaccine Efficacy Trial (APERT) ascertained serological data for prevention using IgG antibodies to pertussis-specific unique toxin and decay rate. Serological data in the unimmunized control group showed antibodies increased over an 11-month period, representing nonimmunized adults who are asymptomic.

Pertussis antibodies ranged from 0.4%-2.7%, with 20% to 46% of those having a prolonged cough illness, indicating approximately 5 cases of asymptomatic pertussis for every clinical case and validating the need for Pa boosters to confer protection.7

Control of pertussis remains problematic with neither vaccination nor infection inducing long-lived immunity. Recent efforts have focused on the potential of adults and adolescents in the spread of infection and reducing transmission risk. Older persons with waning immunity serve as reservoirs for transmission, often affecting infants with incomplete immunization who have not received the 2 or more doses needed to confer protection.2,7

Microbiological eradication with antibiotics reduces transmission and use is recommended by the CDC, although antibiotic treatment does not improve clinical symptoms. Current vaccine recommendations set forth by the Advisory Committee on Immunization Practices recommends cocooning and vaccination strategies that protect infants and other vulnerable individuals from disease. These steps all contribute to a decline in B. pertussis infection.

References

1. Kline JM, Lewis WD, Smith EA, Tracy LR, Moerschel SK. Pertussis: a reemerging infection. Am Fam Physician. 2013;88(8):507-514.

2. Wood N, McIntyre P. Pertussis: review of epidemiology, diagnosis, management, and prevention. Paediatr Respir Rev. 2008;9(3):201-212.

3. van der Lee S, Hendrikx LH, Sanders EAM, Berbers GAM, Buisman AM. Whole-Cell or Acellular Pertussis Primary Immunizations in Infancy Determines Adolescent Cellular Immune Profiles. Front Immunol. 2018; 9:51.

4. Tan T, Trindade E, Skowronski D. Epidemiology of pertussis. Pediatr Infect Dis J. 2005;24(5 Suppl):S10-S18.

5. Guiso N. Bordetella pertussis and pertussis vaccines. Clin Infect Dis. 2009;49(10):1565-1569.

6. Etskovitz H, Anastasio N, Green E, May M. Role of Evolutionary Selection Acting on Vaccine Antigens in the Re-Emergence of Bordetella PertussisDiseases. 2019;7(2):35.

7. Acellular Pertussis Vaccine Trial (APERT). Clin Infect Dis. 2006;43(2):151-157.