Editorial
Control of pertussis in infants: time has finally come? Expert Rev. Vaccines 14(6), 781–783 (2015)
Expert Review of Vaccines Downloaded from informahealthcare.com by Nyu Medical Center on 07/22/15 For personal use only.
Marco Aurelio P Safadi Department of Pediatrics, Division of Infectious Diseases, FCM da Santa Casa de Sao Paulo, Sao Paulo, Brazil [email protected]
Despite the success of routine immunization programs against pertussis worldwide, control of the disease in young infants has never been achieved. The greatest risk of disease, hospitalization and death occur in infants, who are too young to have received the primary pertussis immunization course. Different interventions to provide indirect protection to infants were recommended, including vaccination programs with Tdap for adolescents, adults, postpartum women and household contacts of infants, but all of them failed to effectively control the disease in infants. Based on the successful experience of maternal tetanus vaccination, and more recently influenza vaccination, maternal Tdap vaccine has been universally recommended since 2011/2012 in several countries to prevent pertussis in infants. The recent publication of data on the uptake, safety and effectiveness of these programs, as well as impact on disease rates in infants is encouraging, anticipating the possibility to at last control pertussis in this vulnerable age group.
The introduction of routine vaccination programs against pertussis (whooping cough) worldwide resulted in a substantial reduction in the incidence of disease [1]. However, despite sustained high levels of vaccine coverage, resurgence of pertussis, with increased rates reported among adolescent and adults, has been observed in different parts of the world, particularly in the last decade [2]. In all these places, a common observation was that the highest incidence rates were observed in infants, particularly in those under 3 months of age, the age group in whom the rates of hospitalizations, complications and deaths were also significantly higher. In general, > 90% of all pertussis-associated deaths occurred in infants too young to have achieved protection provided by the primary 3-dose pertussis immunization series, which starts at 2 months of age in most countries [3]. The reasons for the resurgence of pertussis are not yet fully understood and several hypotheses were raised to explain this phenomenon, including improvement in diagnostic techniques (particularly availability of routine use of polymerase chain reaction); increased
awareness among healthcare workers; genetic changes in circulating Bordetella pertussis strains and rapid waning immunity after acellular vaccines [2]. It is intriguing, however, that resurgence of pertussis has also been reported in places like South America, with limited widespread availability of the more sensitive diagnostic tools and where whole-cell pertussis vaccines are still being routinely used [4]. The importance of older children, adolescents and adults, especially household members, on disease transmission to unprotected young infants were demonstrated in several studies [5,6], motivating the recommendation of vaccination strategies targeting adolescents and adults in addition to children [7,8]. The objective of these strategies, vaccinating close contacts, in addition to directly protecting immunized persons, was to induce herd immunity, thereby reducing the burden and transmission of disease in infants. The recommendation of adolescent programs with a single tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) dose was implemented in several countries during
KEYWORDS: effectiveness . maternal immunization . pertussis . safety . vaccine
informahealthcare.com
10.1586/14760584.2015.1043274
2015 Informa UK Ltd
ISSN 1476-0584
781
Expert Review of Vaccines Downloaded from informahealthcare.com by Nyu Medical Center on 07/22/15 For personal use only.
Editorial
Safadi
the last decade, resulting in decrease of the incidence rates of disease among the age group targeted for the vaccination. However, no significant impact on disease rates was observed in other unvaccinated age groups. Retrospective analysis of nationally reported pertussis cases in the USA showed that indirect effects of adolescent Tdap vaccination were not observed among infants [9]. The modest coverage achieved among adolescents, the limitations of the Tdap vaccine to protect against pertussis infection and also the limited role that adolescents play in the transmission of disease to infants are probably the main reasons for the results observed. A ‘cocooning’ strategy of vaccinating postpartum women and adolescents and adults who have close contact with infants, including healthcare workers, was also recommended to prevent transmission to this vulnerable group. This strategy also proved to be of limited impact in the real-world setting. The major challenge for the ‘cocoon’ strategy is to achieve broad vaccination coverage among all potential close contacts of the newborn infant. Immunization with Tdap vaccine only of postpartum mothers, in a cross-sectional study performed in the USA, was demonstrated to be insufficient to reduce pertussis illness in infants £6 months of age [10]. The persisted high rates of disease in infants in the USA, with increasing reports of pertussis-related deaths, despite the implementation of the strategies previously discussed led to the 2011 Advisory Committee on Immunization Practices recommendation to vaccinate previously Tdap unimmunized pregnant women, and then in 2012 all pregnant women during every pregnancy, regardless of prior Tdap immunization history [11]. In 2012, the Department of Health in the UK recommended that all pregnant women should be offered pertussis vaccination in the third trimester of each pregnancy [12]. Following these recommendations, Belgium, New Zealand, Argentina, Brazil, Colombia, Costa Rica, Mexico, Panama, Uruguay, Israel, among other countries, also started to recommend Tdap during pregnancy. The aim of these programs is to protect infants from birth, through transplacental passive transfer of maternal antibodies. This strategy has the added benefit of protecting the mother against disease, potentially reducing household transmission and preventing infant infection. Based on pertussis antibody kinetics studies performed in healthy adults, the recommendations are to vaccinate women between 28 and 38 weeks gestation in order to optimize antibody transfer and protection at birth [13–15]. In these studies, a peak in the immune response was observed 2 weeks after the vaccination, with rapid antibody decay thereafter. Studies on the persistence of anti-pertussis antibodies in women who received a dose of Tdap within 2 years before pregnancy showed that the concentration of maternal antibodies was unlikely to be sufficient to provide protection to infants. Even women vaccinated at the first or second trimester had low levels of maternal antibodies at birth [13]. These results emphasize the need to recommend a Tdap dose in each pregnancy. An area of controversy is the potential concern that the presence of high levels of maternal antibodies could interfere with 782
the infant’s responses to active immunization. It has been shown that higher levels of pre-existing pertussis antibodies were associated with significant reductions in the subsequent antibody response to pertussis toxin in infants receiving diptheria, tetanus toxoids and pertussis (DTP), but not diptheria, tetanus toxoids and acellular pertussis (DTaP). It was also demonstrated that slight reductions in pertussis antibody levels following the primary 3-dose DTaP immunization series were observed in studies performed in infants born to women vaccinated with Tdap during pregnancy [15,16]. However, the clinical relevance, if any, of these modest decreased immune responses observed after the primary series is not clear yet and, more importantly, did not persist following the booster dose of DTaP. Despite the theoretical basis to assume that high levels of antibodies at birth will likely confer protection against pertussis or at least modify disease severity in the young infant, it is important to acknowledge that the effectiveness of this intervention and the serological correlate of protective anti-pertussis antibodies in newborns in the prevention of infant disease had not been established before the implementation of these programs. The early results from studies evaluating the safety of pertussis vaccines during the third trimester of pregnancy are reassuring, showing no evidence of an increased risk of adverse events among these women or their infants [16–18]. In the UK, 2 years after the start of the program, pertussis vaccine coverage in pregnant women reached 62.6%. A significant reduction in disease rates has been observed in infants under 6 months of age who are targeted by the maternal pertussis vaccination program. After the introduction of the pregnancy program in the UK, 10 deaths had been reported in young infants with confirmed pertussis, of which 9 infants were born to mothers who had not been vaccinated against pertussis. An overall decline in pertussis cases reported in infants under 3 months of age was observed in England since the pregnancy immunization program started in October 2012 [18]. Furthermore, the results of the first two studies evaluating the effectiveness of the maternal vaccination program, using different methods, provided robust evidence that this program was highly effective to prevent disease in young infants [19,20]. The first one, an observational study performed in England using the screening method, found a vaccine effectiveness of 90% (95% CI: 82–95%) when the analysis was restricted to cases in infants younger than 2 months of age [19]. The second study, a case–control study performed in England and Wales, found consistent results, with a vaccine effectiveness of 93% (95% CI: 81–97%) for the prevention of disease in infants aged
Control of pertussis in infants: time has finally come? Expert Rev. Vaccines 14(6), 781–783 (2015)
Expert Review of Vaccines Downloaded from informahealthcare.com by Nyu Medical Center on 07/22/15 For personal use only.
Marco Aurelio P Safadi Department of Pediatrics, Division of Infectious Diseases, FCM da Santa Casa de Sao Paulo, Sao Paulo, Brazil [email protected]
Despite the success of routine immunization programs against pertussis worldwide, control of the disease in young infants has never been achieved. The greatest risk of disease, hospitalization and death occur in infants, who are too young to have received the primary pertussis immunization course. Different interventions to provide indirect protection to infants were recommended, including vaccination programs with Tdap for adolescents, adults, postpartum women and household contacts of infants, but all of them failed to effectively control the disease in infants. Based on the successful experience of maternal tetanus vaccination, and more recently influenza vaccination, maternal Tdap vaccine has been universally recommended since 2011/2012 in several countries to prevent pertussis in infants. The recent publication of data on the uptake, safety and effectiveness of these programs, as well as impact on disease rates in infants is encouraging, anticipating the possibility to at last control pertussis in this vulnerable age group.
The introduction of routine vaccination programs against pertussis (whooping cough) worldwide resulted in a substantial reduction in the incidence of disease [1]. However, despite sustained high levels of vaccine coverage, resurgence of pertussis, with increased rates reported among adolescent and adults, has been observed in different parts of the world, particularly in the last decade [2]. In all these places, a common observation was that the highest incidence rates were observed in infants, particularly in those under 3 months of age, the age group in whom the rates of hospitalizations, complications and deaths were also significantly higher. In general, > 90% of all pertussis-associated deaths occurred in infants too young to have achieved protection provided by the primary 3-dose pertussis immunization series, which starts at 2 months of age in most countries [3]. The reasons for the resurgence of pertussis are not yet fully understood and several hypotheses were raised to explain this phenomenon, including improvement in diagnostic techniques (particularly availability of routine use of polymerase chain reaction); increased
awareness among healthcare workers; genetic changes in circulating Bordetella pertussis strains and rapid waning immunity after acellular vaccines [2]. It is intriguing, however, that resurgence of pertussis has also been reported in places like South America, with limited widespread availability of the more sensitive diagnostic tools and where whole-cell pertussis vaccines are still being routinely used [4]. The importance of older children, adolescents and adults, especially household members, on disease transmission to unprotected young infants were demonstrated in several studies [5,6], motivating the recommendation of vaccination strategies targeting adolescents and adults in addition to children [7,8]. The objective of these strategies, vaccinating close contacts, in addition to directly protecting immunized persons, was to induce herd immunity, thereby reducing the burden and transmission of disease in infants. The recommendation of adolescent programs with a single tetanus toxoid, reduced diphtheria toxoid and acellular pertussis (Tdap) dose was implemented in several countries during
KEYWORDS: effectiveness . maternal immunization . pertussis . safety . vaccine
informahealthcare.com
10.1586/14760584.2015.1043274
2015 Informa UK Ltd
ISSN 1476-0584
781
Expert Review of Vaccines Downloaded from informahealthcare.com by Nyu Medical Center on 07/22/15 For personal use only.
Editorial
Safadi
the last decade, resulting in decrease of the incidence rates of disease among the age group targeted for the vaccination. However, no significant impact on disease rates was observed in other unvaccinated age groups. Retrospective analysis of nationally reported pertussis cases in the USA showed that indirect effects of adolescent Tdap vaccination were not observed among infants [9]. The modest coverage achieved among adolescents, the limitations of the Tdap vaccine to protect against pertussis infection and also the limited role that adolescents play in the transmission of disease to infants are probably the main reasons for the results observed. A ‘cocooning’ strategy of vaccinating postpartum women and adolescents and adults who have close contact with infants, including healthcare workers, was also recommended to prevent transmission to this vulnerable group. This strategy also proved to be of limited impact in the real-world setting. The major challenge for the ‘cocoon’ strategy is to achieve broad vaccination coverage among all potential close contacts of the newborn infant. Immunization with Tdap vaccine only of postpartum mothers, in a cross-sectional study performed in the USA, was demonstrated to be insufficient to reduce pertussis illness in infants £6 months of age [10]. The persisted high rates of disease in infants in the USA, with increasing reports of pertussis-related deaths, despite the implementation of the strategies previously discussed led to the 2011 Advisory Committee on Immunization Practices recommendation to vaccinate previously Tdap unimmunized pregnant women, and then in 2012 all pregnant women during every pregnancy, regardless of prior Tdap immunization history [11]. In 2012, the Department of Health in the UK recommended that all pregnant women should be offered pertussis vaccination in the third trimester of each pregnancy [12]. Following these recommendations, Belgium, New Zealand, Argentina, Brazil, Colombia, Costa Rica, Mexico, Panama, Uruguay, Israel, among other countries, also started to recommend Tdap during pregnancy. The aim of these programs is to protect infants from birth, through transplacental passive transfer of maternal antibodies. This strategy has the added benefit of protecting the mother against disease, potentially reducing household transmission and preventing infant infection. Based on pertussis antibody kinetics studies performed in healthy adults, the recommendations are to vaccinate women between 28 and 38 weeks gestation in order to optimize antibody transfer and protection at birth [13–15]. In these studies, a peak in the immune response was observed 2 weeks after the vaccination, with rapid antibody decay thereafter. Studies on the persistence of anti-pertussis antibodies in women who received a dose of Tdap within 2 years before pregnancy showed that the concentration of maternal antibodies was unlikely to be sufficient to provide protection to infants. Even women vaccinated at the first or second trimester had low levels of maternal antibodies at birth [13]. These results emphasize the need to recommend a Tdap dose in each pregnancy. An area of controversy is the potential concern that the presence of high levels of maternal antibodies could interfere with 782
the infant’s responses to active immunization. It has been shown that higher levels of pre-existing pertussis antibodies were associated with significant reductions in the subsequent antibody response to pertussis toxin in infants receiving diptheria, tetanus toxoids and pertussis (DTP), but not diptheria, tetanus toxoids and acellular pertussis (DTaP). It was also demonstrated that slight reductions in pertussis antibody levels following the primary 3-dose DTaP immunization series were observed in studies performed in infants born to women vaccinated with Tdap during pregnancy [15,16]. However, the clinical relevance, if any, of these modest decreased immune responses observed after the primary series is not clear yet and, more importantly, did not persist following the booster dose of DTaP. Despite the theoretical basis to assume that high levels of antibodies at birth will likely confer protection against pertussis or at least modify disease severity in the young infant, it is important to acknowledge that the effectiveness of this intervention and the serological correlate of protective anti-pertussis antibodies in newborns in the prevention of infant disease had not been established before the implementation of these programs. The early results from studies evaluating the safety of pertussis vaccines during the third trimester of pregnancy are reassuring, showing no evidence of an increased risk of adverse events among these women or their infants [16–18]. In the UK, 2 years after the start of the program, pertussis vaccine coverage in pregnant women reached 62.6%. A significant reduction in disease rates has been observed in infants under 6 months of age who are targeted by the maternal pertussis vaccination program. After the introduction of the pregnancy program in the UK, 10 deaths had been reported in young infants with confirmed pertussis, of which 9 infants were born to mothers who had not been vaccinated against pertussis. An overall decline in pertussis cases reported in infants under 3 months of age was observed in England since the pregnancy immunization program started in October 2012 [18]. Furthermore, the results of the first two studies evaluating the effectiveness of the maternal vaccination program, using different methods, provided robust evidence that this program was highly effective to prevent disease in young infants [19,20]. The first one, an observational study performed in England using the screening method, found a vaccine effectiveness of 90% (95% CI: 82–95%) when the analysis was restricted to cases in infants younger than 2 months of age [19]. The second study, a case–control study performed in England and Wales, found consistent results, with a vaccine effectiveness of 93% (95% CI: 81–97%) for the prevention of disease in infants aged
