Pneumococcal Vaccine — Direct and Indirect ("Herd") Effects
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《新英格兰医药杂志》
A nationwide vaccination program may have direct or indirect health effects that may be anticipated or unanticipated; although these effects are, of course, intended to be beneficial, some potentially adverse ones may occur. The full range of such effects are well illustrated in the important study of the impact of widespread administration of the protein-conjugate pneumococcal vaccine PCV-7 (Prevnar, Wyeth) from the Active Bacterial Core Surveillance of the Centers for Disease Control and Prevention, reported by Kyaw et al. in this issue of the Journal.1
The most obvious direct effect of widespread vaccination of infants with protein-conjugated capsular polysaccharides from the seven most commonly isolated pneumococcal serotypes, PCV-7, is the remarkable reduction in infection due to vaccine strains in vaccine recipients. This was the anticipated, desired effect in developing the vaccine (Table 1). In studies involving 38,000 children in the Kaiser Permanente health care system, the administration of PCV-7 nearly eliminated meningitis and bacteremic pneumonia due to vaccine serotypes.2 Not surprisingly, a lesser impact was observed for diseases in which the cause was less specifically determined. Thus, when a causative diagnosis of pneumococcal otitis media was determined on the basis of culture of middle-ear fluid, the vaccine was protective in about two thirds of vaccinated subjects,6 but the overall reduction in acute otitis media was less than 10 percent.2
Table 1. Varying Effects of Conjugate Pneumococcal Vaccine.
A second major direct effect of PCV-7, which was not specifically anticipated, has been a reduction in nasopharyngeal carriage of vaccine strains.4 Strains targeted by the vaccine were those that had been most commonly isolated in young children; they were also strains that had been most consistently exposed to the pressure of antibiotic overuse and, therefore, the most likely to be resistant to antibiotics. Thus, a third, unanticipated, direct effect of PCV-7 has been to reduce carriage of antibiotic-resistant serotypes in vaccine recipients.4
As substantial as these direct effects have been, they may be matched in importance by indirect effects. In a closed environment, such as a day-care center, the rate of colonization by vaccine serotypes is inversely proportional to the number of attendees who have been vaccinated, up to a certain threshold. Once a certain proportion of the children have received PCV-7 to block transmission, pneumococci will not spread successfully throughout the center. Epidemiologists use the term "herd effect" to describe the benefit that unvaccinated subjects receive from those who have been vaccinated. However, no one knows what percentage of children need to be vaccinated in order to create the threshold. Similar beneficial effects may be observed in other closed environments, such as families,7 as well as in society at large.
A major principle of contagion of respiratory pathogens is that, within a family setting, adults are likely to acquire the given infection from children.8 Reduction of colonization in vaccinated children implies a reduced likelihood that potentially infective pneumococci will spread to adult members of their families. And, extending the example of herd effect even further, unvaccinated children whose risk of nasopharyngeal colonization is reduced because many of their playmates have been vaccinated are similarly less likely to bring home common infecting pneumococcal types.
These points provide a context for the findings of Kyaw et al. Since PCV-7 was introduced in 2000, the rate of invasive pneumococcal disease due to vaccine serotypes in children younger than five years of age has declined by 94 percent.9 Since less than 75 percent of children have been vaccinated, some of this decline reflects an indirect or herd effect. Among adults, invasive pneumococcal disease has also decreased by more than 50 percent; some of this decline might be due to the increase in the use of traditional pneumococcal polysaccharide or influenza vaccines, or both, but most of the decrease seems to be attributable to the use of PCV-7 in children, further indicating a herd effect. Since vaccine types were those that were most likely to be resistant to antibiotics, implementation of a widespread vaccination program has greatly decreased the incidence of disease caused by antibiotic-resistant pneumococci in children and, through reduced transmission, in adults.
An unwanted effect of vaccination has been the emergence of what are called "replacement strains." If pneumococci of vaccine serotypes occupy an ecologic niche in the nasopharynx, and if potential colonization by some of these pneumococci is reduced, then others might appear to take their place. For me, this was not an intuitive leap. I thought that there was such complexity of nasopharyngeal flora and so much potential for other streptococci to occupy an ecologic niche that there was no reason to assume other encapsulated pneumococci would rise to the occasion. Clearly, I was wrong. Whereas disease due to the chief infecting serotypes has shown a tremendous decline, there has been a substantial increase in nonvaccine serotypes such as 11, 15, and 19A. In the case of type 11, the increase began from a tiny denominator, and the impact is still minor, but types 15 and 19A have become more prominent; what is even more worrisome is that these strains also carry antibiotic resistance.1,5 This problem is compounded by the fact that, through genetic transformation, pneumococci can switch capsules. For poorly understood reasons, certain strains, such as original types 6B, 9V, and 23F, have a special capacity for worldwide spread. If these strains acquire genes for nonvaccine capsules, new types may emerge that can both escape containment by vaccine and spread throughout the world. Thus, the prognosis for a lasting suppression of pneumococcal disease is guarded.
There are many ramifications of the observations on antibiotic-resistant pneumococci. If pneumococci return to their earlier, pristine, antibiotic-susceptible state, the medical profession can be more at ease regarding the choice of empirical therapy for respiratory infections, such as the recommendation for a macrolide as empirical therapy for pneumonia in outpatients, given the decline in the proportion of macrolide-resistant pneumococci in the community. In this context, it is worth noting that the 2005 Swedish guidelines continue to recommend oral penicillin for outpatient treatment of pneumonia10; in nearly all instances, conventional doses of penicillins overcome the observed in vitro resistance.11
The herd effect, although important from an epidemiologic perspective, is much less strongly protective than is the direct effect of vaccination. I regularly receive calls from parents who, having delayed vaccinating their children because of widely prevalent but erroneous concepts about the adverse effects of vaccination, are now concerned because an active case of infection has surfaced and their child has been exposed. These parents may have been counting on the benefits of the herd effect. Unfortunately, once there is a direct exposure, the herd effect is no longer applicable. Our task, as physicians, is to ensure that our colleagues and patients understand the complex individual and societal benefits of vaccinations, in order to optimize adherence to vaccination recommendations.
Supported in part by funding from the Department of Veterans Affairs Merit Review program.
Source Information
From the Medical Care Line (Infectious Disease Section), Michael E. DeBakey Veterans Affairs Medical Center, and the Departments of Medicine and Molecular Virology and Microbiology, Baylor College of Medicine — both in Houston.
References
Kyaw MH, Lynfield R, Schaffner W, et al. Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae. N Engl J Med 2006;354:1455-1463.
Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-195.
Dagan R, Givon-Lavi N, Zamir O, et al. Reduction of nasopharyngeal carriage of Streptococcus pneumoniae after administration of a 9-valent pneumococcal conjugate vaccine to toddlers attending day care centers. J Infect Dis 2002;185:927-936.
Dagan R, Givon-Lavi N, Zamir O, Fraser D. Effect of a nonavalent conjugate vaccine on carriage of antibiotic-resistant Streptococcus pneumoniae in day-care centers. Pediatr Infect Dis J 2003;22:532-540.
Huang SS, Platt R, Rifas-Shiman SL, Pelton SI, Goldmann D, Finkelstein JA. Post-PCV7 changes in colonizing pneumococcal serotypes in 16 Massachusetts communities, 2001 and 2004. Pediatrics 2005;116:e408-e413.
Eskola J, Kilpi T, Palmu A, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001;344:403-409.
Givon-Lavi N, Fraser D, Dagan R. Vaccination of day-care center attendees reduces carriage of Streptococcus pneumoniae among their younger siblings. Pediatr Infect Dis J 2003;22:524-532.
Musher DM. How contagious are common respiratory infections? N Engl J Med 2003;348:1256-1266.
Direct and indirect effects of routine vaccination of children with 7-valent conjugate vaccine on incidence of invasive pneumococcal disease -- United States, 1998-2003. MMWR Morb Mortal Wkly Rep 2005;54:893-897.
Hedlund J, Stralin K, Ortqvist A, Holmberg H. Swedish guidelines for the management of community-acquired pneumonia in immunocompetent adults. Scand J Infect Dis 2005;37:791-805.
Musher DM, Bartlett JG, Doern GV. A fresh look at the definition of susceptibility of Streptococcus pneumoniae to beta-lactam antibiotics. Arch Intern Med 2001;161:2538-2544.(Daniel M. Musher, M.D.)
The most obvious direct effect of widespread vaccination of infants with protein-conjugated capsular polysaccharides from the seven most commonly isolated pneumococcal serotypes, PCV-7, is the remarkable reduction in infection due to vaccine strains in vaccine recipients. This was the anticipated, desired effect in developing the vaccine (Table 1). In studies involving 38,000 children in the Kaiser Permanente health care system, the administration of PCV-7 nearly eliminated meningitis and bacteremic pneumonia due to vaccine serotypes.2 Not surprisingly, a lesser impact was observed for diseases in which the cause was less specifically determined. Thus, when a causative diagnosis of pneumococcal otitis media was determined on the basis of culture of middle-ear fluid, the vaccine was protective in about two thirds of vaccinated subjects,6 but the overall reduction in acute otitis media was less than 10 percent.2
Table 1. Varying Effects of Conjugate Pneumococcal Vaccine.
A second major direct effect of PCV-7, which was not specifically anticipated, has been a reduction in nasopharyngeal carriage of vaccine strains.4 Strains targeted by the vaccine were those that had been most commonly isolated in young children; they were also strains that had been most consistently exposed to the pressure of antibiotic overuse and, therefore, the most likely to be resistant to antibiotics. Thus, a third, unanticipated, direct effect of PCV-7 has been to reduce carriage of antibiotic-resistant serotypes in vaccine recipients.4
As substantial as these direct effects have been, they may be matched in importance by indirect effects. In a closed environment, such as a day-care center, the rate of colonization by vaccine serotypes is inversely proportional to the number of attendees who have been vaccinated, up to a certain threshold. Once a certain proportion of the children have received PCV-7 to block transmission, pneumococci will not spread successfully throughout the center. Epidemiologists use the term "herd effect" to describe the benefit that unvaccinated subjects receive from those who have been vaccinated. However, no one knows what percentage of children need to be vaccinated in order to create the threshold. Similar beneficial effects may be observed in other closed environments, such as families,7 as well as in society at large.
A major principle of contagion of respiratory pathogens is that, within a family setting, adults are likely to acquire the given infection from children.8 Reduction of colonization in vaccinated children implies a reduced likelihood that potentially infective pneumococci will spread to adult members of their families. And, extending the example of herd effect even further, unvaccinated children whose risk of nasopharyngeal colonization is reduced because many of their playmates have been vaccinated are similarly less likely to bring home common infecting pneumococcal types.
These points provide a context for the findings of Kyaw et al. Since PCV-7 was introduced in 2000, the rate of invasive pneumococcal disease due to vaccine serotypes in children younger than five years of age has declined by 94 percent.9 Since less than 75 percent of children have been vaccinated, some of this decline reflects an indirect or herd effect. Among adults, invasive pneumococcal disease has also decreased by more than 50 percent; some of this decline might be due to the increase in the use of traditional pneumococcal polysaccharide or influenza vaccines, or both, but most of the decrease seems to be attributable to the use of PCV-7 in children, further indicating a herd effect. Since vaccine types were those that were most likely to be resistant to antibiotics, implementation of a widespread vaccination program has greatly decreased the incidence of disease caused by antibiotic-resistant pneumococci in children and, through reduced transmission, in adults.
An unwanted effect of vaccination has been the emergence of what are called "replacement strains." If pneumococci of vaccine serotypes occupy an ecologic niche in the nasopharynx, and if potential colonization by some of these pneumococci is reduced, then others might appear to take their place. For me, this was not an intuitive leap. I thought that there was such complexity of nasopharyngeal flora and so much potential for other streptococci to occupy an ecologic niche that there was no reason to assume other encapsulated pneumococci would rise to the occasion. Clearly, I was wrong. Whereas disease due to the chief infecting serotypes has shown a tremendous decline, there has been a substantial increase in nonvaccine serotypes such as 11, 15, and 19A. In the case of type 11, the increase began from a tiny denominator, and the impact is still minor, but types 15 and 19A have become more prominent; what is even more worrisome is that these strains also carry antibiotic resistance.1,5 This problem is compounded by the fact that, through genetic transformation, pneumococci can switch capsules. For poorly understood reasons, certain strains, such as original types 6B, 9V, and 23F, have a special capacity for worldwide spread. If these strains acquire genes for nonvaccine capsules, new types may emerge that can both escape containment by vaccine and spread throughout the world. Thus, the prognosis for a lasting suppression of pneumococcal disease is guarded.
There are many ramifications of the observations on antibiotic-resistant pneumococci. If pneumococci return to their earlier, pristine, antibiotic-susceptible state, the medical profession can be more at ease regarding the choice of empirical therapy for respiratory infections, such as the recommendation for a macrolide as empirical therapy for pneumonia in outpatients, given the decline in the proportion of macrolide-resistant pneumococci in the community. In this context, it is worth noting that the 2005 Swedish guidelines continue to recommend oral penicillin for outpatient treatment of pneumonia10; in nearly all instances, conventional doses of penicillins overcome the observed in vitro resistance.11
The herd effect, although important from an epidemiologic perspective, is much less strongly protective than is the direct effect of vaccination. I regularly receive calls from parents who, having delayed vaccinating their children because of widely prevalent but erroneous concepts about the adverse effects of vaccination, are now concerned because an active case of infection has surfaced and their child has been exposed. These parents may have been counting on the benefits of the herd effect. Unfortunately, once there is a direct exposure, the herd effect is no longer applicable. Our task, as physicians, is to ensure that our colleagues and patients understand the complex individual and societal benefits of vaccinations, in order to optimize adherence to vaccination recommendations.
Supported in part by funding from the Department of Veterans Affairs Merit Review program.
Source Information
From the Medical Care Line (Infectious Disease Section), Michael E. DeBakey Veterans Affairs Medical Center, and the Departments of Medicine and Molecular Virology and Microbiology, Baylor College of Medicine — both in Houston.
References
Kyaw MH, Lynfield R, Schaffner W, et al. Effect of introduction of the pneumococcal conjugate vaccine on drug-resistant Streptococcus pneumoniae. N Engl J Med 2006;354:1455-1463.
Black S, Shinefield H, Fireman B, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187-195.
Dagan R, Givon-Lavi N, Zamir O, et al. Reduction of nasopharyngeal carriage of Streptococcus pneumoniae after administration of a 9-valent pneumococcal conjugate vaccine to toddlers attending day care centers. J Infect Dis 2002;185:927-936.
Dagan R, Givon-Lavi N, Zamir O, Fraser D. Effect of a nonavalent conjugate vaccine on carriage of antibiotic-resistant Streptococcus pneumoniae in day-care centers. Pediatr Infect Dis J 2003;22:532-540.
Huang SS, Platt R, Rifas-Shiman SL, Pelton SI, Goldmann D, Finkelstein JA. Post-PCV7 changes in colonizing pneumococcal serotypes in 16 Massachusetts communities, 2001 and 2004. Pediatrics 2005;116:e408-e413.
Eskola J, Kilpi T, Palmu A, et al. Efficacy of a pneumococcal conjugate vaccine against acute otitis media. N Engl J Med 2001;344:403-409.
Givon-Lavi N, Fraser D, Dagan R. Vaccination of day-care center attendees reduces carriage of Streptococcus pneumoniae among their younger siblings. Pediatr Infect Dis J 2003;22:524-532.
Musher DM. How contagious are common respiratory infections? N Engl J Med 2003;348:1256-1266.
Direct and indirect effects of routine vaccination of children with 7-valent conjugate vaccine on incidence of invasive pneumococcal disease -- United States, 1998-2003. MMWR Morb Mortal Wkly Rep 2005;54:893-897.
Hedlund J, Stralin K, Ortqvist A, Holmberg H. Swedish guidelines for the management of community-acquired pneumonia in immunocompetent adults. Scand J Infect Dis 2005;37:791-805.
Musher DM, Bartlett JG, Doern GV. A fresh look at the definition of susceptibility of Streptococcus pneumoniae to beta-lactam antibiotics. Arch Intern Med 2001;161:2538-2544.(Daniel M. Musher, M.D.)