3. Difficulties with vaccine reformulation

While adults and adolescents normally only experience mild symptoms from a pertussis infection, they are the usual source of infection for neonates, and adoptive maternal immunity does not appear to prevent pertussis in neonates. In a study that compared the specific immune response in mothers of neonates diagnosed with pertussis and mothers of control children [28], preexisting pertussis-specific antibodies were insufficient for protection suggesting that memory B cells play a major role in the adult defense, which is not transferred to neonates. To provide newborns with protection, a new approach would be required, but to change the vaccine given to infants in the first 2 years of life is a discouraging proposition. It would involve a large data set for safety evaluation. Also, the pertussis vaccine is often combined into a multivalent formula with components against other pathogens. Any change directed at improving effectiveness against pertussis would require a recertification process that would impact a wide spectrum of vaccines currently on the market.

4. Protecting versus vaccination during pregnancy

critical role in the potential transmission of pertussis to a newborn.

both Switzerland and the UK [64].

of age [66].

Since the resurgence of pertussis infection, several studies have shown that the main source of infections in newborns and infants involved close-contact persons, mostly family members [53, 54]. In the first attempt to reduce the incidence of pertussis infections, indirect protection for the reduction of transmission rates was favored, the so-called cocooning strategy. In response, some countries adapted their national immunization guidelines [53–55]. Another study focused on the influence of vaccination rates among siblings and vaccination rates among mothers showed that the provided protection rates are comparable [56, 57]. In contrast, a recent study on the effect of cocooning infants younger than 6 months of age did not detect any reduction in pertussis cases [57]. Besides that, it is not yet clear and has created some controversy if cocoon strategies are cost-effective or even prevent infections [38, 58]. Even in the absence of definitive proof, it is still advisable for recent mothers to know their immunization status as well as those of all potentially close-contact individuals, all of whom can play a

Preventive and Protective Properties of Pertussis Vaccines: Current Situation and Future Challenges

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Another means to reduce the rate of pertussis transmission to neonates and young infants is the practice of providing pertussis vaccinations during pregnancy. This has become an important strategy in many countries in the absence of vaccines licensed for use before the age of 6 weeks and unknown effectiveness of cocooning strategies [53, 59–61]. The observation of the transplacental transfer of maternal anti-pertussis antibodies to the fetus led health authorities to first recommend the use of pertussis vaccinations during pregnancy in 2011 [62–64]. In the USA, a maternal vaccination was first recommended after gestational week 20 that was later shifted to a window between weeks 27 and 36 [65]. This recommendation has been adopted by

Early studies showed that vaccination with Tdap vaccines during gestational week 27–30 + 6 was associated with the highest levels of IgG in umbilical cord blood when compared to vaccination beyond gestational week 31 [59], according to one of the most potent virulence factors of pertussis PTx. A recent study supports these data by showing that the maternal vaccination with Tdap early in the second trimester significantly increased neonatal antibodies at birth in comparison with neonates born from mothers vaccinated in the third trimester [61]. All in all, the antenatal vaccination campaign in the UK achieved a vaccine coverage of 60% with >90% effectiveness [66, 67]. A UK study conducted after initiating maternal vaccinations identified a large reduction in the number of confirmed cases of pertussis infection reported as the cause for a hospital admission that was especially notable for infants younger than 3 months

From this campaign, the question arose as to whether a vaccination early in pregnancy might adversely affect the immune response in an infant to vaccinations after birth. Some studies showed that antibody concentrations at birth did not interfere with the immune response to further immunizations after birth [68]. However, it is known that maternally derived antibodies can interfere with the immune response in an infant vaccinated with the same vaccine [68],

More importantly, it would be unethical to conduct formal efficacy studies for new vaccines/ formulations that included a non-vaccinated control group. Considering the epidemiological and serological studies that show a rapid decline in immunity after the recommended aPV boosters at ages 4–6 and 10–12 years [13, 15, 16, 18], an intensive focus is being given on the booster vaccines given to preschool-age children and adolescents. However, even for a new booster vaccine, the regulatory pathway is unclear. A classical efficacy study would have to compare a new vaccine with a currently accepted one to show non-inferiority or superiority. Such studies would be expensive and require a long evaluation period considering that the current vaccines are effective for the first couple of years after administration.

Ideally, licensing authorities could present new approaches to evaluate the efficacy of a new vaccine. Alternatives include a greater reliance on the use of protection data obtained from animal studies [52]. The newly developed baboon model could provide in-depth serological data on the levels and duration of antibody titers, which can be verified in smaller human challenge studies using circulating strains of B. pertussis. Safety profiles could also be generated from fewer participants if modifications simply involve an update in the components with newer inactivation methods, such as genetic modifications. However, the greatest obstacle is most likely to recruit manufacturers to participate in the development of a new pertussis vaccine or booster. After the tremendous effort and expenditure invested to launch the aPVs along with shifting priorities to new pathogens, major manufacturers are resistant to shouldering multiple and simultaneous clinical development programs [52]. Physicians and government health agencies will be critical to creating a new demand. Assistance from academia and science funding agencies could assist vaccine development by conducting basic research on the pathogenesis and immunology of pertussis along with preliminary clinical trials [52]. All of this implies an enormous effort, but a new pertussis vaccine is needed. It is unethical to continue to allow a vaccine-preventable disease to be incompletely controlled, especially one that prejudices the very young people and disproportionately in less developed countries.
