Pertussis re-emergence in the post-vaccination era

Several countries, including US and UK, currently recommend Tdpa administration in pregnant women (Table 2) [39]. Safety data on Tdap vaccination in pregnant women are limited, however existing Tdap data from the CDC, US Food and Drug Administration and the pharmaceutical pregnancy registries do not indicate a safety signal [40]. A recent US survey based on Vaccine Adverse Event Reporting System (VAERS) data, including 2 reports of Tdap administered to pregnant women, did not identify any concerning patterns in maternal, infant, or fetal outcomes [41]. Previous studies have shown that the levels of pertussis antibodies are so low in unimmunized or incompletely immunized mothers that they will be undetectable in their infants’ blood within 2 months of age [42]. Efficient transplacental antibody transfer and significantly higher titers have been found in 1-month-old infants, born after a maternal booster vaccination, compared with siblings born before the maternal booster (Figure 2) [43, 44]. A recent report assessed paired maternal and umbilical cord sera collected from 52 women immunized with Tdap during pregnancy compared with 52 women who were not. The data indicated that newborns born to mothers who received Tdap during pregnancy had significantly higher antibody titers to diphtheria anti-toxin (p < 0.001), tetanus antitoxin (p = 0.004), PT (p < 0.001), FHA (p = .0002), PRN (p < 0.0001) and fimbriae type 2/3 (p < 0.001) when compared with newborns born to unimmunized mothers [40]. However, it is uncertain whether this increase in antibodies can be considered clinically protective because no serological correlate of protection is universally accepted for pertussis [40]. Healy et al. have recently stressed the importance of timing of maternal Tdap immunization [45]. Maternal vaccination is ineffective during early weeks of gestation because of the rapid decay of antibodies. It should be administered during the third trimester to have maternal pertussis antigen-specific IgG levels at their peak when placental transport is the most efficient as possible. This may protect the infant during the immediate postpartum period when he is more vulnerable. Moreover, immunization should be repeated in each subsequent pregnancy [40, 45].

Concern about the potential interference of maternal pertussis antibodies with infant immune response to primary DTaP vaccination has been raised [44]. It seems that the presence of circulating maternal antibodies can inhibit active pertussis-specific antibody production in the child. This blunting might reduce protection after first months of life [18, 39, 46, 47]. A 1995 study by Englund and colleagues included 2,342 infants, who were randomized to receive DTaP or DTP vaccines at 2, 4, and 6 months of age. After DTP but not DTaP, higher levels of preexisting antibody were associated with substantial (28% to 56%) reductions in the subsequent antibody response to pertussis toxin (PT). This finding suggests that the use of aP vaccines in adults, which could confer higher levels of antibody in women before pregnancy, would be unlikely to adversely affect pertussis antibody responses after DTaP among infants born to mothers with high antibody levels [48]. Currently, two clinical trials are underway in Canada and the United States to measure the response to routine active immunization in the infants whose mothers received Tdap vaccine during the third trimester of pregnancy [49, 50].

Immunization of newborns is another possible strategy that has been investigated in some recent studies with the rationale to provide protection in first months of life when infants are more vulnerable. Halasa et al. analysed the results of neonatal vaccination with DTaP vaccine in 50 infants between 2 to 14 days of age. The administration of an additional dose at birth was safe and well tolerated, but was associated with lower geometric mean antibody concentration for toxin and pertactin at 6, 7, and 18 months, for fimbrae at 6, 7, 17, and 18 months, and for FHA at 18 months and lower geometric mean antibody concentrations for diphtheria at 7 months [51].

In contrast, two other studies administering only aP at birth, without diphtheria or tetanus toxoids, followed by the DTaP series at 2, 4 and 6 months, reported an enhanced immune response against pertussis antigens at 2 and 8 months of age but lower levels of antibodies against Haemophilus infuenzae type B and hepatitis B [52, 53]. However, at least 96% of subjects achieved antibody concentrations associated with seroprotection after a booster dose of DTaP-HBV-IPV/Hib at 12 to 23 months [54]. An Australian study assessed the immunogenicity and reactogenicity of two doses of aP vaccine, one given at birth and the other one at 1 month. Data suggest that aP vaccine administered before 2 months of age induces significantly higher pertussis antibody titers by 2 months of age without interference with responses to routine active immunization [55].

The immaturity of the neonatal immune system and the impact of passively transferred maternal antibodies could explain the poor immune response in infants vaccinated at birth [43]. In infants DTaP vaccination may trigger CD4⁺ T-lymphocytes functionally and phenotypically dissimilar from those of older children and adults [56]. Given these controversial reports, currently, immunization with DTaP or aP vaccines is not recommended in newborns. Additional clinical trials are needed in this regard [18].

Cocooning strategy consists of providing indirect protection to infants who are too young to be immunized or protected by vaccine through immunization of their parents and other family members, caregivers and close contacts [7, 18]. Household members, particularly mothers, are the source of transmission of pertussis to infants in up to 75% of cases [57]. However, casual community contacts have been estimated to account for up to 34% of cases [58]. There are very few empirical studies examining the impact of cocooning strategy. In a US cross-sectional study including more than 500 infants, immunizing only postpartum mothers with Tdap did not reduce pertussis cases in infants ≤6 months of age [59, 60] suggesting that efforts should be directed at immunizing all household and key contacts of newborns, not just mothers. It should also be considered that a maximum response to Tdap is not achieved until 14 days after vaccination and in this gap newborns are at risk of infection [61]. Despite the paucity of data, economic and logistical difficulties, efforts to promote and effectively implement cocooning in Western countries is continuing [18]. In 2006 the Advisory Committee on Immunization Practices (ACIP) recommended routine administration of Tdap to all unvaccinated postpartum mothers and in 2011 recommendations were extended including pregnant women and all people who have or anticipate having close contact with an infant aged <12 months if they have not previously received it [39]. During the 2010 Californian epidemic the cocoon strategy was adopted together with other strategies such as adolescent and adult boosters, resulting in an incidence decline from 23.4 to 2 cases/100,000 in one year [62]. Given the majority of studies currently available are from the United States, these results may not necessarily be applicable to other settings. It is crucial that the countries where cocooning has been implemented investigate its impact on pertussis incidence to clarify its cost-effectiveness [63].

A preschool booster is usually included in the vaccination schedules of many countries (Table 2). It contributes to increase herd immunity and to reduce transmission to susceptible subjects [7]. A case–control study was conducted in California from 2006 to 2011, involving children who were vaccinated with all the five DTaP doses. The aim was to establish the risk of pertussis in relation to the time since the fifth DTaP dose. In this study protection against pertussis waned during the 5 years after the fifth dose of vaccine and the risk of disease increased by 42% each year [64]. Since the highest incidence of the disease is currently reported among adolescents, a universal booster vaccination in this age class has been proposed. In one RCT efficacy of Tdap in adolescents/adults was 92% [27], but the reported effectiveness is lower. In 499 adolescents, during a pertussis outbreak in a US school, vaccine effectiveness was only 65.5% (95% CI: 35.8-91.3%) [65]. In Australia, Tdap was administered from 2004 for 272,000 adolescents (aged 12–19 years) during a mass vaccination program. Vaccine effectiveness was evaluated by the screening method and it was 78.0%. The Australian experience supported the positive impact of a large use of Tdap to rapidly control pertussis in adolescents and suggested that a school-based catch-up program followed by immunization of school entrants might be the optimum strategy for the implementation of adolescent coverage [32, 66].

Since 2005, the ACIP has expanded the routine adolescent vaccination schedule with the administration of one Tdap dose. Therefore, from 2006 to 2009, Tdap coverage among US adolescents increased from 10.8% to 55.6% and then it reached 78.2% in 2011, but it still remains below target levels [67]. Currently, the American Academy of Pediatrics recommends that adolescents 11 to 18 years of age should receive a single booster dose of Tdap instead of tetanus and diphtheria toxoids (Td) vaccine (the preferred age is 11 to 12 years). Those who have received Td but not Tdap are encouraged to receive a single dose of Tdap with a suggested interval of at least 5 years between Td and Tdap to reduce the risk of local and systemic reactions. The primary goal is to protect immunized adolescents against pertussis. A secondary object is to reduce the reservoir of pertussis within the population and prevent indirectly pertussis cases in infants and young children, who have the highest risk of complications [20]. Although a decreasing trend of pertussis cases was observed in adolescents after the introduction of Tdap vaccination, the average incidence among infants younger than 1 year did not change [68]. In Europe only few countries have introduced booster doses for adolescents (eg, Austria, Belgium, Finland, France, Germany and some Italian regions) (Table 1) [7, 69]. Data on effectiveness of adolescent boosters in these countries are lacking [70]. Furthermore, at the Global Pertussis Initiative meeting in Paris 2010, members stressed the need of efficacious surveillance systems to evaluate the impact of dTap booster on the disease incidence in adolescents [66, 69].

Reports from Europe and the United States highlight the growing burden of pertussis in adult population [7]. Since 2005, the ACIP has recommended a Tdap vaccine booster dose for those adults aged 19 through 64 years who have not yet received a dose or have received their last dose of Td ≥10 years earlier and they have not previously received Tdap [71, 72]. Despite these recommendations, Tdap coverage remained low in the US adults. In 2008 only 5.9% of adults received a dose of Tdap and coverage among adults with infant contact was estimated to be 5% [9].

In October 2010, ACIP recommended that unimmunized adults aged ≥ 65 years shall be vaccinated with Tdap if in close contact with an infant, and that other adults aged ≥ 65 years may receive Tdap. In February 2012, ACIP recommended Tdap vaccination for all adults aged ≥ 65 years [72]. Universal adult vaccination is an important strategy to build up herd immunity and eradicate pertussis infection [73]. In a randomized, multicenter, double-blind, controlled trial called APERT (Acellular Pertussis Vaccine Trial), 2781 healthy subjects between the ages of 15 and 65 years were recruited and received a single dose of either an acellular pertussis vaccine or a hepatitis A vaccine (control). It was estimated that a single dose if Tdap gave a protective efficacy of 92% among adolescents and adults [27]. A cost-benefit analysis showed that decennial adult booster vaccination, although more expensive than adolescent boosting, could prevent 0.9-4.7 million adult cases of pertussis and save $1.3-6.4 billion in the US every 10 years [74].

In the past decade, the confusing recommendations about Tdap immunization and the lack of precise guidelines resulted in underuse of the vaccine [75]. A universal decennial Tdap booster program should be implemented starting in preadolescents and continuing throughout adulthood, including persons aged ≥65 years. The Consensus on Pertussis Booster Vaccination in Europe group proposes the administration of a single dose of Tdap instead of dT in adults aged 18 years or older who have received the preceding dT dose for more than 10 years. Epidemiological studies are needed to define the appropriate interval of time between the two boosters [7]. Until now only a French study has assessed this problem. It concluted that Tdap-IPV (inactivated poliovirus) may be administered to adults as little as one month after Td-IPV without exacerbating post-vaccination side-effects [76]. Although Tdap booster dose 10 years later the initial booster has been proven to be equally immunogenic and well tolerated [77], there is currently paucity of data regarding the incidence of local reactions after repeated immunizations in adults. Some authors advocated the production of a monovalent acellular vaccine without diphtheria and tetanus toxoids which could allow more frequent boosters in adults [78].

Health-care workers are at a higher risk of infection than the general population and, in turn, may be a substantial source for susceptible individuals. As an example, in one single-center study, 17 pertussis cases were identified, which exposed 355 unprotected health-care workers [79]. Pertussis among health-care personnel has been reported to be 1.7 times higher than among the general population [72]. In 2006, the Health-care Infection Control Practises Advisory Committee supported the recommendations of ACIP for the use of Tdap in health-care providers. It was proposed that health-care personnel who work in hospital or ambulatory care settings and have direct contact with patients should receive a single dose of Tdap as soon as feasible if they have not previously received Tdap; an interval as short as 2 years from the last dose of Td was recommended. The aim was to protect health-care workers against pertussis and to reduce transmission to patients. Priority had to be given to those ones in frequent contact with pregnant women, infants, children or immune compromised patients [71]. However, in 2008 Tdap vaccination coverage was only 15.9% among the United States health-care workers [9].

In some European countries (eg, France and Belgium), Tdap boosters for health-care workers are recommended (Table 2) [7]. In 2007, the French National Institute for Health Surveillance analysed data about nosocomial infections and community clusters of pertussis in France, reported between 2000 and 2005. Almost half of the 67 reports analysed were coming from hospitals and health-care workers were usually the first to be affected [80, 81]. Studies are needed to evaluate the effectiveness of Tdap immunization in preventing pertussis in health-care providers and in their contacts, and to establish the duration of protection [71].