Pertussis — A Disease and Vaccine for All Ages
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《新英格兰医药杂志》
There is increasing evidence and awareness that pertussis is not just a disease of children. Although most severe disease and almost all mortality occur in young infants, the overall disease burden is increasingly shifting to adolescents and adults.1 There have been large outbreaks of pertussis among adolescents who had both classic pertussis symptoms and prolonged illness with cough.2 Pertussis is less well characterized in adults than in adolescents but has been associated with up to 20 percent of prolonged illness with cough. Studies have suggested that the clinical severity of pertussis in adults increases with age.3
This change in epidemiologic profile is due in large part to waning vaccine-induced immunity. The resurgence of pertussis during the past 20 years followed 50 years of increasing pertussis control. With widespread use of pertussis vaccine, rates of pertussis decreased by more than 90 percent in North America and Europe. With the change from whole-cell pertussis vaccines to the less reactogenic acellular pertussis vaccines in the 1990s, excellent pertussis control has been achieved in the immunized age groups. In North America, where children routinely receive five doses of pertussis-containing vaccine at 2 months, 4 months, 6 months, and 18 months and between the ages of 4 and 6 years, an increasing number of cases of pertussis are being reported in preadolescents and adolescents between the ages of 10 and 19 years.1 Contrary to long-held dogma, immunity after natural pertussis infection is also not lifelong, which means there is a large pool of susceptible adolescents and adults.
To meet the need for better control of pertussis, acellular pertussis vaccines have been developed for use in adolescents and adults. Two adult formulations of acellular pertussis vaccines combined with an adult formulation of diphtheria and tetanus toxoids (dTap) are licensed in North America and Europe (Boostrix, GlaxoSmithKline; and Adacel, Sanofi Pasteur). With these vaccines, there is no incremental increase in vaccine-associated adverse events from adding the acellular pertussis antigens to the diphtheria and tetanus toxoids. In addition, the vaccines are highly immunogenic after a single dose in adolescents and adults.4 Although no specific serologic correlate of protection has been established for pertussis, protection after the infant series has been associated with higher levels of antibody against pertussis toxoid, pertactin, and fimbriae.5,6 After a single dose of dTap vaccine, adolescents and adults have levels of antibody against all component antigens that are three to five times the levels in infants after their three-dose primary series (which results in approximately 85 percent efficacy).7,8 Therefore, it was assumed that dTap vaccines would be similarly effective.
The study by Ward et al.9 in this issue of the Journal is the first (and will probably be the only) study to measure this hypothesis directly. In a randomized, controlled, double-blind study funded by the National Institute of Allergy and Infectious Diseases at its Vaccine Evaluation Units, the efficacy of an adult formulation of acellular pertussis vaccine was compared with that of the hepatitis A vaccine (as the control) in more than 2700 adolescents and adults. With the use of carefully constructed case definitions, intense active surveillance, and state-of-the-art, meticulously validated laboratory assays (culture, polymerase chain reaction, and serologic analysis), investigators found 10 cases of laboratory-confirmed pertussis during the two-year follow-up period; nine cases were in control subjects, and one case was in a pertussis vaccine recipient, resulting in an adjusted efficacy of 92 percent (95 percent confidence interval, 32 to 99 percent). Although the confidence intervals are wide as a result of the small number of cases detected, the point estimate of efficacy is consistent with that found for acellular pertussis vaccines in young children.7,8
The importance of this complex and well-organized clinical trial should not be diminished, but its most important contribution may well be in the evaluation of the controls. With close follow-up of illnesses with cough, Ward et al. documented 1284 such illnesses in the control group, of which 9 were caused by Bordetella pertussis. This yields a rate of 370 cases of pertussis per 100,000 person-years, a rate similar to that found in the only other population-based study of pertussis in adults.10 Although pertussis accounts for only 0.7 percent of illness with cough that lasts more than 5 days and 5.7 percent of illness with cough that lasts more than 56 days, the incidence translates into approximately 1 million vaccine-preventable illnesses with cough in adults in the United States each year. Although pertussis was identified as a cough that lasted more than 5 days, the mean duration of these illnesses was 24 days (and longer in those with documented pertussis), suggesting a substantial amount of vaccine-preventable morbidity. What is not clear is whether the estimate is a low, high, or median estimate of the incidence of pertussis in adults. In children, pertussis is a cyclic disease with peaks occurring every three to five years. Pertussis in adults is thought to be endemic; however, it is not known whether there are cyclic increases in incidence. It can be speculated that the incidence of pertussis in adults that was found by Ward et al. is a minimum estimate since pertussis was not being reported at high rates in children during the study.
Acellular pertussis vaccines are increasingly being used worldwide to control pertussis in adolescents and, to some extent, adults.11 In Canada, all provinces and territories have substituted dTap for the adult formulation of tetanus–diphtheria toxoids (Td) in adolescents, mostly administered in government-funded, school-based programs. In France and Germany, dTap is given to adolescents between the ages of 11 and 13 years and between 14 and 16 years, respectively, after a three-dose infant series and a fourth dose in the second year of life (with no preschool dose). In Australia, the fourth dose of the pediatric formulation that was given to infants at 18 months in their five-dose preschool series was replaced by a dose of dTap in mid-adolescence. In the United States, where two dTap formulations were recently licensed by the Food and Drug Administration,12,13 provisional recommendations that were just released by the Advisory Committee on Immunization Practices suggest a dose of dTap in place of the Td vaccine at the preadolescent visit.14 Widespread use of dTap among adolescents will likely occur, resulting in control of pertussis in this population.
It is less clear how dTap will be used in adults. Although studied in adolescents and adults, the dTap vaccine containing the acellular pertussis formulation studied by Ward et al. was licensed in the United States only for adolescents between the ages of 10 and 18 years. However, the other dTap vaccine was licensed for use in both adolescents and adults between the ages of 11 and 64 years. Of note, there is no acellular pertussis vaccine for adolescents and adults, such as the one used in the study by Ward et al., that is not combined with diphtheria and tetanus toxoids. This fact could complicate the use of the vaccine since a minimum interval of five years between doses of tetanus-containing vaccines is recommended. A recent study evaluating intervals that were shorter than the typical 10-year interval recommended for a previous vaccine containing diphtheria and tetanus toxoids did not find substantially increased rates of injection-site reaction.15 The Advisory Committee on Immunization Practices suggests that the use of dTap vaccine with shorter intervals be considered in settings with an increased risk of pertussis.14
How should acellular pertussis vaccines be used in adolescents and adults? On the basis of the safety, the immunogenicity, and the now-demonstrated efficacy of these vaccines and the demonstrated burden of pertussis in adolescents and adults, dTap vaccines should be widely used in place of the Td vaccine. All adolescents should receive a dose of dTap, and consideration should be given to the use of dTap for any adult for whom Td vaccine is being considered. However, there are still gaps in our knowledge that need to be filled through continued research. The true burden of pertussis will be identified only if the diagnosis of pertussis is considered by health care providers caring for adults with prolonged illness with cough. The availability of better tools for the laboratory diagnosis of pertussis is essential to facilitate a better understanding of the epidemiology of the disease. The burden of pertussis in the elderly is not well defined, and the safety and immunogenicity of dTap vaccine in the elderly need to be determined. Finally, study is needed of the use of dTap vaccine during pregnancy and the effect of its use (and widespread use in other adults) on the epidemiology of pertussis in infants who are too young to have completed immunization.
Dr. Halperin reports having received consulting and advisory fees from GlaxoSmithKline and Sanofi Pasteur and grant support from Sanofi Pasteur and has contracts with GlaxoSmithKline and Sanofi Pasteur.
Source Information
From the Departments of Pediatrics and Microbiology and Immunology, Dalhousie University and the IWK Health Centre, Halifax, N.S., Canada.
References
Guris D, Strebel PM, Bardenheier B, et al. Changing epidemiology of pertussis in the United States: increasing reported incidence among adolescents and adults, 1990-1996. Clin Infect Dis 1999;28:1230-1237.
Skowronski DM, De Serres G, MacDonald D, et al. The changing age and seasonal profile of pertussis in Canada. J Infect Dis 2002;185:1448-1453.
De Serres G, Shadmani R, Duval B, et al. Morbidity of pertussis in adolescents and adults. J Infect Dis 2000;182:174-179.
Halperin SA, Smith B, Russell M, et al. An adult formulation of a five-component acellular pertussis vaccine combined with diphtheria and tetanus toxoids is safe and immunogenic in adolescents and adults. Vaccine 2000;18:1312-1319.
Storsaeter J, Hallander HO, Gustafsson L, Olin P. Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine 1998;16:1907-1916.
Cherry JD, Gornbein J, Heininger U, Stehr K. A search for serologic correlates of immunity to Bordetella pertussis cough illnesses. Vaccine 1998;16:1901-1906.
Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996;334:349-355.
Greco D, Salmaso S, Mastrantonio P, et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. N Engl J Med 1996;334:341-348.
Ward JI, Cherry JD, Chang S-J, et al. Efficacy of an acellular pertussis vaccine among adolescents and adults. N Engl J Med 2005;353:1555-1563.
Strebel P, Nordin J, Edwards K, et al. Population-based incidence of pertussis among adolescents and adults, Minnesota, 1995-1996. J Infect Dis 2001;183:1353-1359.
Halperin SA. Canadian experience with implementation of an acellular pertussis vaccine booster-dose program in adolescents: implications for the United States. Pediatr Infect Dis J 2005;24:Suppl:S141-S146.
Food and Drug Administration. Product approval information — licensing action (Boostrix). (Accessed September 22, 2005, at http://www.fda.gov/cber/products/tdapgla050305.htm.)
Product approval information — licensing action (Adacel). (Accessed September 22, 2005, at http://www.fda.gov/cber/products/tdapave061005.htm.)
National Immunization Program, Centers for Disease Control and Prevention. Advisory Committee on Immunization Practice (ACIP) votes to recommend routine use of combined tetanus, diphtheria and pertussis (Tdap) vaccines for adolescents. (Accessed September 22, 2005, at http://www.cdc.gov/nip/vaccine/tdap/tdap_acip_recs.pdf.)
Halperin SA, Sweet L, Baxendale D, et al. Assessment of the reactogenicity of Tdap in children and adolescents 7-19 years of age by interval since prior tetanus and diphtheria toxoids containing vaccine. In: Program and abstracts of the Eighth Annual Conference on Vacccine Research, Baltimore, May 9–11, 2005:64. abstract.(Scott A. Halperin, M.D.)
This change in epidemiologic profile is due in large part to waning vaccine-induced immunity. The resurgence of pertussis during the past 20 years followed 50 years of increasing pertussis control. With widespread use of pertussis vaccine, rates of pertussis decreased by more than 90 percent in North America and Europe. With the change from whole-cell pertussis vaccines to the less reactogenic acellular pertussis vaccines in the 1990s, excellent pertussis control has been achieved in the immunized age groups. In North America, where children routinely receive five doses of pertussis-containing vaccine at 2 months, 4 months, 6 months, and 18 months and between the ages of 4 and 6 years, an increasing number of cases of pertussis are being reported in preadolescents and adolescents between the ages of 10 and 19 years.1 Contrary to long-held dogma, immunity after natural pertussis infection is also not lifelong, which means there is a large pool of susceptible adolescents and adults.
To meet the need for better control of pertussis, acellular pertussis vaccines have been developed for use in adolescents and adults. Two adult formulations of acellular pertussis vaccines combined with an adult formulation of diphtheria and tetanus toxoids (dTap) are licensed in North America and Europe (Boostrix, GlaxoSmithKline; and Adacel, Sanofi Pasteur). With these vaccines, there is no incremental increase in vaccine-associated adverse events from adding the acellular pertussis antigens to the diphtheria and tetanus toxoids. In addition, the vaccines are highly immunogenic after a single dose in adolescents and adults.4 Although no specific serologic correlate of protection has been established for pertussis, protection after the infant series has been associated with higher levels of antibody against pertussis toxoid, pertactin, and fimbriae.5,6 After a single dose of dTap vaccine, adolescents and adults have levels of antibody against all component antigens that are three to five times the levels in infants after their three-dose primary series (which results in approximately 85 percent efficacy).7,8 Therefore, it was assumed that dTap vaccines would be similarly effective.
The study by Ward et al.9 in this issue of the Journal is the first (and will probably be the only) study to measure this hypothesis directly. In a randomized, controlled, double-blind study funded by the National Institute of Allergy and Infectious Diseases at its Vaccine Evaluation Units, the efficacy of an adult formulation of acellular pertussis vaccine was compared with that of the hepatitis A vaccine (as the control) in more than 2700 adolescents and adults. With the use of carefully constructed case definitions, intense active surveillance, and state-of-the-art, meticulously validated laboratory assays (culture, polymerase chain reaction, and serologic analysis), investigators found 10 cases of laboratory-confirmed pertussis during the two-year follow-up period; nine cases were in control subjects, and one case was in a pertussis vaccine recipient, resulting in an adjusted efficacy of 92 percent (95 percent confidence interval, 32 to 99 percent). Although the confidence intervals are wide as a result of the small number of cases detected, the point estimate of efficacy is consistent with that found for acellular pertussis vaccines in young children.7,8
The importance of this complex and well-organized clinical trial should not be diminished, but its most important contribution may well be in the evaluation of the controls. With close follow-up of illnesses with cough, Ward et al. documented 1284 such illnesses in the control group, of which 9 were caused by Bordetella pertussis. This yields a rate of 370 cases of pertussis per 100,000 person-years, a rate similar to that found in the only other population-based study of pertussis in adults.10 Although pertussis accounts for only 0.7 percent of illness with cough that lasts more than 5 days and 5.7 percent of illness with cough that lasts more than 56 days, the incidence translates into approximately 1 million vaccine-preventable illnesses with cough in adults in the United States each year. Although pertussis was identified as a cough that lasted more than 5 days, the mean duration of these illnesses was 24 days (and longer in those with documented pertussis), suggesting a substantial amount of vaccine-preventable morbidity. What is not clear is whether the estimate is a low, high, or median estimate of the incidence of pertussis in adults. In children, pertussis is a cyclic disease with peaks occurring every three to five years. Pertussis in adults is thought to be endemic; however, it is not known whether there are cyclic increases in incidence. It can be speculated that the incidence of pertussis in adults that was found by Ward et al. is a minimum estimate since pertussis was not being reported at high rates in children during the study.
Acellular pertussis vaccines are increasingly being used worldwide to control pertussis in adolescents and, to some extent, adults.11 In Canada, all provinces and territories have substituted dTap for the adult formulation of tetanus–diphtheria toxoids (Td) in adolescents, mostly administered in government-funded, school-based programs. In France and Germany, dTap is given to adolescents between the ages of 11 and 13 years and between 14 and 16 years, respectively, after a three-dose infant series and a fourth dose in the second year of life (with no preschool dose). In Australia, the fourth dose of the pediatric formulation that was given to infants at 18 months in their five-dose preschool series was replaced by a dose of dTap in mid-adolescence. In the United States, where two dTap formulations were recently licensed by the Food and Drug Administration,12,13 provisional recommendations that were just released by the Advisory Committee on Immunization Practices suggest a dose of dTap in place of the Td vaccine at the preadolescent visit.14 Widespread use of dTap among adolescents will likely occur, resulting in control of pertussis in this population.
It is less clear how dTap will be used in adults. Although studied in adolescents and adults, the dTap vaccine containing the acellular pertussis formulation studied by Ward et al. was licensed in the United States only for adolescents between the ages of 10 and 18 years. However, the other dTap vaccine was licensed for use in both adolescents and adults between the ages of 11 and 64 years. Of note, there is no acellular pertussis vaccine for adolescents and adults, such as the one used in the study by Ward et al., that is not combined with diphtheria and tetanus toxoids. This fact could complicate the use of the vaccine since a minimum interval of five years between doses of tetanus-containing vaccines is recommended. A recent study evaluating intervals that were shorter than the typical 10-year interval recommended for a previous vaccine containing diphtheria and tetanus toxoids did not find substantially increased rates of injection-site reaction.15 The Advisory Committee on Immunization Practices suggests that the use of dTap vaccine with shorter intervals be considered in settings with an increased risk of pertussis.14
How should acellular pertussis vaccines be used in adolescents and adults? On the basis of the safety, the immunogenicity, and the now-demonstrated efficacy of these vaccines and the demonstrated burden of pertussis in adolescents and adults, dTap vaccines should be widely used in place of the Td vaccine. All adolescents should receive a dose of dTap, and consideration should be given to the use of dTap for any adult for whom Td vaccine is being considered. However, there are still gaps in our knowledge that need to be filled through continued research. The true burden of pertussis will be identified only if the diagnosis of pertussis is considered by health care providers caring for adults with prolonged illness with cough. The availability of better tools for the laboratory diagnosis of pertussis is essential to facilitate a better understanding of the epidemiology of the disease. The burden of pertussis in the elderly is not well defined, and the safety and immunogenicity of dTap vaccine in the elderly need to be determined. Finally, study is needed of the use of dTap vaccine during pregnancy and the effect of its use (and widespread use in other adults) on the epidemiology of pertussis in infants who are too young to have completed immunization.
Dr. Halperin reports having received consulting and advisory fees from GlaxoSmithKline and Sanofi Pasteur and grant support from Sanofi Pasteur and has contracts with GlaxoSmithKline and Sanofi Pasteur.
Source Information
From the Departments of Pediatrics and Microbiology and Immunology, Dalhousie University and the IWK Health Centre, Halifax, N.S., Canada.
References
Guris D, Strebel PM, Bardenheier B, et al. Changing epidemiology of pertussis in the United States: increasing reported incidence among adolescents and adults, 1990-1996. Clin Infect Dis 1999;28:1230-1237.
Skowronski DM, De Serres G, MacDonald D, et al. The changing age and seasonal profile of pertussis in Canada. J Infect Dis 2002;185:1448-1453.
De Serres G, Shadmani R, Duval B, et al. Morbidity of pertussis in adolescents and adults. J Infect Dis 2000;182:174-179.
Halperin SA, Smith B, Russell M, et al. An adult formulation of a five-component acellular pertussis vaccine combined with diphtheria and tetanus toxoids is safe and immunogenic in adolescents and adults. Vaccine 2000;18:1312-1319.
Storsaeter J, Hallander HO, Gustafsson L, Olin P. Levels of anti-pertussis antibodies related to protection after household exposure to Bordetella pertussis. Vaccine 1998;16:1907-1916.
Cherry JD, Gornbein J, Heininger U, Stehr K. A search for serologic correlates of immunity to Bordetella pertussis cough illnesses. Vaccine 1998;16:1901-1906.
Gustafsson L, Hallander HO, Olin P, Reizenstein E, Storsaeter J. A controlled trial of a two-component acellular, a five-component acellular, and a whole-cell pertussis vaccine. N Engl J Med 1996;334:349-355.
Greco D, Salmaso S, Mastrantonio P, et al. A controlled trial of two acellular vaccines and one whole-cell vaccine against pertussis. N Engl J Med 1996;334:341-348.
Ward JI, Cherry JD, Chang S-J, et al. Efficacy of an acellular pertussis vaccine among adolescents and adults. N Engl J Med 2005;353:1555-1563.
Strebel P, Nordin J, Edwards K, et al. Population-based incidence of pertussis among adolescents and adults, Minnesota, 1995-1996. J Infect Dis 2001;183:1353-1359.
Halperin SA. Canadian experience with implementation of an acellular pertussis vaccine booster-dose program in adolescents: implications for the United States. Pediatr Infect Dis J 2005;24:Suppl:S141-S146.
Food and Drug Administration. Product approval information — licensing action (Boostrix). (Accessed September 22, 2005, at http://www.fda.gov/cber/products/tdapgla050305.htm.)
Product approval information — licensing action (Adacel). (Accessed September 22, 2005, at http://www.fda.gov/cber/products/tdapave061005.htm.)
National Immunization Program, Centers for Disease Control and Prevention. Advisory Committee on Immunization Practice (ACIP) votes to recommend routine use of combined tetanus, diphtheria and pertussis (Tdap) vaccines for adolescents. (Accessed September 22, 2005, at http://www.cdc.gov/nip/vaccine/tdap/tdap_acip_recs.pdf.)
Halperin SA, Sweet L, Baxendale D, et al. Assessment of the reactogenicity of Tdap in children and adolescents 7-19 years of age by interval since prior tetanus and diphtheria toxoids containing vaccine. In: Program and abstracts of the Eighth Annual Conference on Vacccine Research, Baltimore, May 9–11, 2005:64. abstract.(Scott A. Halperin, M.D.)