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Prevenar™ vaccination: Review of the global data, 2006
Vaccine 25 (2007) 3085–3089
PrevenarTM vaccination: Review of the global data, 2006 Kimberly J. Center ∗ Global Medical Affairs, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA, USA Available online 18 January 2007
Abstract The 7-valent pneumococcal conjugate vaccine, PrevenarTM , was first licensed in the United States in 2000 for the prevention of invasive pneumococcal disease (IPD) caused by the serotypes included in the vaccine. It is presently approved in more than 70 countries, and more than 100 million doses of vaccine have been distributed to date. Within 1 year of routine use in the US, incidence of vaccine-serotype IPD had fallen dramatically among children younger than 2 years, with indirect effects noted among other age groups as well. The most recent data available from the US demonstrates that vaccine-serotype IPD has declined by 94% among the age group recommended for vaccination, and indirect effects have been documented in every unvaccinated age group, including among neonates and young infants. Additionally, declines in other pneumococcal-associated respiratory tract diseases have been reported, highlighting the extended benefits of a Prevenar vaccination program. Subsequently, the vaccine has been introduced into the national immunization programs of several other countries, including Canada, Australia, and The Netherlands. While an increase in disease caused by serotypes not included in the vaccine has been observed (“replacement disease”), the overall impact of this increase has, to date, been small in comparison to the substantial reduction in overall disease burden that has resulted since Prevenar introduction. © 2007 Elsevier Ltd. All rights reserved. Keywords: Invasive pneumococcal disease; Pneumococcal conjugate vaccine; Vaccination
1. Introduction Invasive disease caused by Streptococcus pneumoniae is a major public health concern. The World Health Organization (WHO) estimated that in 2002 there were 716,000 deaths among children less than 5 attributable to S. pneumoniae, making it the most common cause of vaccine-preventable death in this age group [1]. Although the highest ageassociated incidence of invasive pneumococcal disease (IPD) occurs in children younger than 2 years of age, no prophylactic intervention was available for this age group until the licensure of Prevenar in 2000. In contrast to the pure polysaccharide pneumococcal vaccines, which have limited immunogenicity in infants and young children, the conjugate vaccine stimulates a robust T cell-dependent immune response that allows for generation of protective anti-pneumococcal antibody even in young infants.
∗
Tel.: +1 484 865 2004; fax: +1 484 865 4199. E-mail address: [email protected].
0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.01.021
The pivotal trial leading to licensure was conducted at Northern California Kaiser Permanente beginning in 1995; the final analysis documented vaccine efficacy for fully vaccinated subjects of 97.4% (95% CI: 82.7–99.9%), with efficacy in the intent-to-treat analysis of 93.9% (95% CI: 79.6–98.5%) [2]. Prevenar was licensed in the United States in February 2000 and subsequently recommended for all infants in October 2000 [3]. Presently, the vaccine is approved in more than 70 countries worldwide, with more than 100 million doses distributed to date. In addition to the US 13 other countries, including Canada, the United Kingdom, the Netherlands, and Australia, have instituted national Prevenar immunization programs, and data demonstrating the profound effect of these programs have begun to emerge from countries in which the vaccine is widely used. However, documentation of the safety of new vaccines is also of paramount importance given the nature and scale of vaccination as a public health intervention. Finally, considerations of cost are important in the practical implementation of vaccination programs. This paper will review the relevant data regarding the changing epidemiology of pneumococcal disease follow-
3086
K.J. Center / Vaccine 25 (2007) 3085–3089
ing the introduction of Prevenar, including indirect effects in unvaccinated populations, the available safety information, and recent pharmacoeconomic analyses that considerably improve the cost–benefit profile of Prevenar compared with that predicted prior to its licensure.
2. Epidemiology of invasive pneumococcal disease in the era of conjugate vaccination S. pneumoniae is a major pediatric pathogen, especially for children younger than 2 years of age, for whom the age-related incidence of IPD is highest. Prior to the introduction of Prevenar in the United States, reported incidence rates of IPD in children younger than 2 years were approximately 188/100,000 [4] and the large majority of these cases (approximately 80–85%) were caused by the seven serotypes included in Prevenar. Data regarding both the documented burden of IPD and the serotype distribution of pneumococci causing invasive disease in other regions of the world vary considerably, based on several factors including standard medical practices (i.e., frequency of culture confirmation of disease, frequency of antibiotic pretreatment, etc.), available infrastructure (i.e., ability to make an etiologic diagnosis, presence of surveillance and/or reporting networks, etc.), and geographic variability in the distribution of pneumococcal serotypes. However, reviews of the existing literature suggest both that in at least some parts of the world, the burden of disease is higher [5–7], and the serotype coverage afforded by Prevenar may be better [6,8–10], than has previously been assumed.
3. Impact on pneumococcal disease Data are now emerging demonstrating the impact of Prevenar in routine use on pneumococcal disease. Follows is a brief review of selected impact data. 3.1. United States Surveillance for IPD in the United States is conducted by the Active Bacterial Core Surveillance system (ABCs) of the US Centers for Disease Control and Prevention (CDC), a laboratory-based system that surveys a population of approximately 16 million in 10 states. A comparison of IPD rates in 2003 (the most recent year for which data are available) to those of 1998/1999 reveals not only a 75% decline in invasive pneumococcal disease caused by all pneumococcal serotypes and a 94% decline in IPD caused by vaccine serotypes in children less than 5 years of age (the age group for which the vaccine is indicated), but also reports declines in IPD in persons ≥5 years, and most notably in those persons ≥65 years, demonstrating considerable herd effect [11]. In fact, the authors noted that the herd effect of routine Prevenar vaccination in the US is so profound that twice as many IPD cases
in 2003 were prevented through indirect effects (i.e., through interruption of pneumococcal transmission) than through the direct effect of protecting vaccinated children, and that indirect effects might be expected to increase as vaccine coverage increases. It was estimated that for all ages, routine use of Prevenar prevented 29,599 cases of vaccine-serotype IPD in the US; this reduction was slightly offset by a small increase in the number of cases caused by nonvaccine serotypes (4721) for a net reduction of 24,878 cases of IPD in 2003 compared with the 1998/1999 baseline. New data also suggest that the herd effect of widespread, routine immunization of infants 2–23 months with Prevenar has extended to infants younger than 2 months of age (too young to be eligible for vaccination, or having received at most a single dose of vaccine) [12]. Following Prevenar introduction, the mean rates of IPD decreased significantly for all infants aged 0–90 days, from 11.8/100,000 live births to 7.2/100,000; of note, rates of vaccine-serotype IPD decreased significantly, from 7.3/100,000 live births to 2.4/100,000 (p < 0.001), while IPD caused by nonvaccine serotypes remained stable (p = 0.55). Finally, there has historically been a higher incidence of IPD among black versus white individuals, which has been seen across all age groups; the reason for this disparity is unclear, and likely multifactorial. However, several studies now report that following Prevenar introduction, racial differences in the rates of IPD between whites and blacks have been drastically diminished or even eliminated [12–14], including among adults and infants aged 0–90 days. 3.2. Canada Prevenar was licensed in Canada in 2001. It was recommended for all infants in a four-dose schedule by the National Advisory Committee on Immunization (NACI) in early 2002 [15], and this recommendation was recently reiterated [16]. Alberta was one of the first Canadian provinces to adopt the NACI recommendation and subsequently is among the first populations to observe both direct and indirect effects on IPD in the region. The Calgary Area S. pneumoniae Epidemiology Research (CASPER) team, who conduct prospective population-based surveillance for invasive pneumococcal disease occurring in the Calgary Health Region (population, approximately 1 million), recently reported their IPD surveillance findings from 1998 to 2004 [17]. For children aged ≤23 months, when compared to a baseline average rate between 1998 and 2001, the rate of IPD caused by vaccine serotypes decreased by 92.6% to 3.9 cases/100,000 population (p < 0.001), by vaccine and vaccine-related serotypes by 93.4% (p < 0.001), and by any serotype by 81.6% to 11.7 cases/100,000 (p = 0.02); the rate of IPD caused by nonvaccine serotypes was unchanged (p = 0.61). Similar, though less dramatic, reductions in IPD were observed in adults 65 years or older; in this population, the rate of IPD caused by Prevenar serotypes in 2004 decreased by 62.7% to 8.5 cases/100,000 (p = 0.007). Declines were observed in IPD
K.J. Center / Vaccine 25 (2007) 3085–3089
caused by any serotype and by serotypes included in the pneumococcal polysaccharide vaccine (PPV23) but not in Prevenar, but these reductions were not statistically significant. Finally, a significant increase in IPD caused by serotypes not included in the 23-valent polysaccharide vaccine was observed (p = 0.03), but this did not offset the reduction in disease associated with the indirect effects of infant vaccination with Prevenar [17]. Similar, though less remarkable, results have been reported from the province of British Columbia (BC), with a population of 4.2 million, including 203,435 children aged <5 years. A selective immunization program of high-risk and Aboriginal children aged 2–59 months was started there in April 2003; this program was expanded to include all infants in September 2003. Since vaccine introduction, surveillance in the province has demonstrated a 67% reduction in pediatric IPD; in 2002 and 2005, the overall IPD rates in children <5 years of age were 53 cases and 18 cases per 100,000 population, respectively [18]. BC has not yet observed the anticipated changes in IPD among older adults that have been documented in the United States [11,13,19], although the baseline IPD rate is low compared to the US (16–20 cases/100,000 versus 60 cases/100,000, possibly due to underreporting in a passive surveillance system) [18], and so changes in the occurrence of IPD in this population may be more difficult to find. 3.3. Europe Effectiveness data from Europe are limited, though reports have recently been published from Spain and France. 3.3.1. Spain Prevenar became available in Spain in June 2001 but was not recommended for all infants in a four-dose schedule until October 2002; despite this universal recommendation, vaccine uptake has remained low. de Aristegui Fernandez et al. [20] present the surveillance findings of the autonomous regions of the Basque Country (28–45% vaccine uptake in a 3 + 1 schedule) and Navarre (35–37% uptake) during the 2-year post-licensure period 1 June 2001 to 31 May 2003, compared with the 3-year period immediately preceding the introduction of Prevenar (1 May 1998 to 31 May 2001). For children aged ≤23 months, when compared to a baseline average rate of 93.5 cases/100,000 population between 1998 and 2001, the rate of IPD decreased by 39.7% to 56.3 cases/100,000 population (p < 0.05) during the second year of surveillance; similar reductions were observed among children <12 months of age (64.3% [p < 0.01] reduction) and among the total population of children aged 0–59 months (37.5% reduction, p < 0.01). Among children younger than 2 years, the absolute reduction in IPD was entirely driven by a reduction in disease caused by serotypes contained in Prevenar, which accounted for 74.1 cases/100,000 children in the years prior to vaccine introduction and 49.5 cases/100,000 in the 2-year period postlicensure; the rate of disease caused by nonvaccine serotypes remained unchanged
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for the same time period (19.2 cases/100,000 population versus 18.7 cases/100,000 population). Notably, after Prevenar introduction there has also been a reduction in disease caused by penicillin- and cefotaxime-nonsusceptible isolates among children <5 years, with reductions of 58.2 and 24.9%, respectively. A major limitation of this study is that IPD is not a reportable disease in these regions, so it is likely that case ascertainment in both periods may be incomplete; this uncertainty highlights the importance of active, laboratory-based surveillance for IPD including serotyping and susceptibility testing. However, despite these limitations, the observed reductions in disease, even with relatively low vaccine uptake rates, are impressive and would be expected to improve as vaccination becomes more widespread, given the additional benefit of herd protection that has been observed elsewhere. 3.3.2. France The results of surveillance conducted by the Institut de Veille Sanitaire (EPIBAC Network) have recently been released [21], demonstrating significant reductions in pneumococcal bacteremia and meningitis among children <2 years for the first time since introduction of Prevenar in 2003, where the vaccine has been recommended for use in those children considered to be at increased risk of disease. Compared with the pre-vaccine period (1998–2002), 38.6% and 28.7% reductions have been observed in 2005 for pneumococcal meningitis and bacteremia overall, respectively, in children <2 years old (p < 0.001). These results document the impact of Prevenar on IPD in the targeted age group despite the absence of a universal recommendation, but highlight the importance of a universal vaccination program to realize the full spectrum of benefits associated with this vaccine. 3.4. Australia Finally, data regarding the impact of Prevenar are available from Australia, where in 2001 Prevenar was recommended for all Aboriginal infants, for whom the incidence of IPD is among the highest in the world. Compared to a baseline (2001) incidence of 219.2 cases of IPD/100,000 population, the incidence of IPD among Aboriginal children less than 2 years old was 91.5/100,000 in 2004, representing both a 2.9-fold decrease in disease in this population and parity with the non-indigenous population (IPD incidence: 93.6/100,000); notably, a 74% reduction in vaccine-serotype IPD was observed during the same surveillance period [22]. It is expected that further significant reductions in the incidence of IPD will be observed in Australia with the implementation of universal Prevenar vaccination for all infants that started in January 2005.
4. Safety considerations Documentation of the safety of any new vaccine is also of paramount importance given the nature and scale of vac-
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cination as a public health intervention, and Prevenar is no different. The safety profile of Prevenar was established prior to licensure in 5 clinical trials involving more than 18,000 infants and children [Wyeth, data on file], and the vaccine is considered to be generally well tolerated, with a profile comparable to other routinely used infant vaccines. Recently, the results of a large postmarketing evaluation of the safety of Prevenar given concomitantly with other recommended vaccines as part of routine care have been presented [23,24]. The primary endpoint of this study of 65,927 infants who received the primary series of Prevenar in the first year of life was a comparison of commonly occurring systemic events (including fever, seizure, etc.) in the period immediately following immunization (0–30 days) to the rate of the same events occurring later after immunization (31–60 days); this primary evaluation revealed no new safety information [23]. Secondary endpoints of the study involved evaluation of less commonly occurring events or events with longer time to onset, as well as analyses of mortality, as compared to historical controls; these analyses also did not suggest any new safety consideration that would alter the risk-benefit balance of the vaccine [24]. Additional data regarding the safety of Prevenar in routine use are available from the Vaccine Adverse Event Reporting System (VAERS), a passive safety surveillance system in the US that is jointly operated by FDA and CDC [25]. In the 2 years following licensure in the US, VAERS received 4154 reports of adverse events following Prevenar immunization, of which 74.3% included administration of multiple vaccines concomitantly. Based on an estimated distribution of 31.2 million doses in the same time period, the authors reported an overall adverse event rate of 13.2/100,000 doses, and of 1.9/100,000 for serious events; these event rates are similar to those for other routinely recommended vaccines [25]. The major weakness of this surveillance system is its passive nature; however, the findings of the first 2 years are reassuring. More than 100 million doses of Prevenar have now been distributed worldwide, and to date, routine pharmacovigilance does not suggest any new or emerging safety concern.
5. Pharmacoeconomic considerations The final consideration relevant to the implementation of universal immunization programs is that of cost, the importance of which cannot be underestimated. An analysis of cost–benefit of Prevenar performed prior to licensure demonstrated a societal cost of US$ 80,000 per life-year saved, with an estimated 116 deaths from pneumococcal disease prevented; this analysis only considered the direct effects of immunization of the target population [26]. However, a more recent evaluation, taking into account the profound indirect (herd) effect that has been observed in the US, estimates a societal cost of US$ 7500 per life-year saved, with an estimated 5159 deaths prevented [27]; these estimates represent considerably larger reductions than predicted by the previ-
ous evaluation. Additionally, the authors report that if one includes the potential indirect effect of Prevenar on pneumonia among elderly adults, universal immunization with Prevenar became cost saving [27]. When placed in the context of other standard preventive measures recommended for whole populations, then, the cost–benefit that could be realized by routine Prevenar immunization would seem to weigh in favor of routine use.
6. Conclusion In summary, emerging clinical data continue to demonstrate the value of Prevenar; the early US experience of profound reductions in invasive pneumococcal disease among children has begun to be replicated by other countries, and new data are emerging demonstrating the extension of herd effect to unimmunized populations as well in places where the vaccine is routinely used. The phenomenon of replacement disease is of concern and warrants ongoing vigilance, but has not to date threatened the overall large benefit of the vaccine for the population as a whole. While the safety of any vaccine product is continuously monitored, the experience with Prevenar to date suggests no new safety concerns. Challenges still exist, including raising worldwide awareness of the burden of invasive pneumococcal disease and demonstrating the cost effectiveness of universal Prevenar vaccination programs. However, with the availability of this life-saving pneumococcal conjugate vaccine for infants, and the overwhelming evidence of its effectiveness, it is imperative that its use become commonplace so that more children’s lives may be saved, and the public health improved.
References [1] CDC. Vaccine preventable deaths and the global immunization vision and strategy, 2006–2015. Morbid Mortal Weekly Rep 2006;55(18):511–5. [2] Black S, Shinefield H, Fireman B, Lewis E, Ray P, Hansen JR, et al. Efficacy, safety and immunogenicity of heptavalent pneumococcal conjugate vaccine in children. Pediatr Infect Dis J 2000;19:187–95. [3] CDC. Preventing pneumococcal disease among infants and young children: Recommendations of the Advisory Committee on Immunization Practices (ACIP). Morbid Mortal Weekly Rep 2000;49(RR-9):1–35. [4] CDC. Active bacterial core surveillance report—Streptococcus pneumoniae, 1999. Available at: http://www.cdc.gov/ncidod/dbmd/abcs/ survreports.htm. [5] Vergison A, Tuerlinckx D, Verhagen J, Malfroot A, for the Belgian Invasive Pneumococcal Disease Study Group. Epidemiologic features of invasive pneumococcal disease in Belgian children: passive surveillance is not enough. Pediatrics 2006;118(3):e801–9. [6] McIntosh EGD, Fritzell B, Fletcher MA. Burden of paediatric invasive pneumococcal disease in Europe, 2005. Epidemiol Infect 2006:1–13 [epub ahead of print]. [7] Tregnaghi M, Ceballos A, Ruttimann R, Ussher J, Tregnaghi P, Peeters P, et al. Active epidemiologic surveillance of pneumonia and invasive pneumococcal disease in ambulatory and hospitalized infants in Cordoba, Argentina. Pediatr Infect Dis J 2006;25(4):370–2.
K.J. Center / Vaccine 25 (2007) 3085–3089 [8] Garcia S, Levine OS, Cherian T, Gabastou JM, Andrus J, Working Group Members. Pneumococcal disease and vaccination in the Americas: an agenda for accelerated vaccine introduction. Rev Panam Salud Publica 2006;19:340–8. [9] Ho PL, Que TL, Chiu SS, Yung RW, Ng TK, Tsang DN, et al. Fluoroquinolone and other antimicrobial resistance in invasive pneumococci, Hong Kong, 1995–2001. Emerg Infect Dis 2004;10:1250–7. [10] Kennedy WA, Chang S, Kilgore PE, Anh DD, Kim JS, Baiqing D, et al. Serotypes and antibiotic susceptibility of invasive pneumococcal isolates in Asia. In: Presented at the 43rd Annual Meeting of the Infectious Diseases Society of America. 2005 [Abstract #560]. [11] CDC. Direct and indirect effects of routine vaccination of children with 7-valent pneumococcal conjugate vaccine on incidence of invasive pneumococcal disease—United States, 1998–2003. Morbid Mortal Weekly Rep 2005;54(36):893–7. [12] Poehling KA, Talbot TR, Griffin MR, Craig AS, Whitney CG, Zell E, et al. Invasive pneumococcal disease among infants before and after introduction of pneumococcal conjugate vaccine. JAMA 2006;295:1468–74. [13] Flannery B, Heffernan RT, Harrison LH, Ray SM, Reingold AL, Hadler J, et al. Changes in invasive pneumococcal disease among HIV-infected adults living the era of childhood pneumococcal immunization. Ann Intern Med 2006;144:1–9. [14] Talbot TR, Peohling KA, Hartert TV, Arbogast PG, Halasa NB, Mitchel E, et al. Elimination of racial differences in invasive pneumococcal disease in young children after introduction of the conjugate pneumococcal vaccine. Pediatr Infect Dis J 2004;23:726–31. [15] National Advisory Committee on Immunization (NACI). Statement on recommended use of pneumococcal conjugate vaccine. Can Commun Dis Rep 2002;28(ACS-2):1–32. [16] National Advisory Committee on Immunization (NACI). Update on the recommendations for the routine use of pneumococcal conjugate vaccine for infants. Can Commun Dis Rep 2006;32(ACS-4):1–7. [17] Kellner JD, Church DL, MacDonald J, Tyrrell GJ, Scheifele D. Progress in the prevention of pneumococcal infection. CMAJ 2005;173(10):1149–51. [18] Paulus S, David ST, Tang W, Winters M, Buxton J, Henry B, et al. Incidence of invasive pneumococcal disease after introduc-
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tion of the universal infant immunization program, British Columbia (2002–2005). Can Commun Dis Rep 2006;32(14):157–61. Lexau CA, Lynfield R, Danila R, Pilishvili T, Facklam R, Farley MM, et al. Changing epidemiology of invasive pneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine. JAMA 2005;294(16):2043–51. de Aristegui Fernandez J, Bernaola Iturbe E, Pocheville I, Garc´ıa Calvo C, Arranz L, Dur´an G, et al. Reduction of pediatric invasive pneumococcal disease in the Basque Country and Navarre after the introduction of the heptavalent pneumococcal conjugate vaccine. Basque Country/Navarre Invasive Pneumococcal Disease Study Group. Eur J Clin Microbiol Infect Dis 2007, in press. Reseau Epibac (surveillance des infections invasives a` Haemophilus influenzae, . . .). Donn´ees e´ pid´emiologiques 2005 (25 Octobre 2006). URL: http://www.invs.sante.fr/surveillance/epibac/publications.htm. Accessed 19 January 2006. Roche PW, Krause VL, Bartlett M, Coleman D, Cook H, Davis C, et al. Invasive pneumococcal disease in Australia, 2004. Commun Dis Intell 2006;30(1):80–92. Black S, France EK, Lewis E, Hansen J, Schwalbe J, Fireman B, et al. Postmarketing assessment of Prevnar® , 7-valent pneumococcal conjugate vaccine (PNCV7). In: Presented at the Pediatric Academic Societies’ 2006 Annual Meeting. 2006 [Abstract #3528.181]. Black S, France EK, Center KJ, Hansen J, Lewis E, Graepel J, et al. Postmarketing assessment of uncommon events following Prevnar® , 7-valent pneumococcal conjugate vaccine. In: Presented at the 44th Annual Meeting of the Infectious Diseases Society of America. 2006 [Abstract #641]. Wise RP, Iskander J, Pratt RD, Campbell S, Ball R, Pless RP, et al. Postlicensure safety surveillance for 7-valent pneumococcal conjugate vaccine. JAMA 2004;292(14):1702–10. Lieu TA, Ray GT, Black SB, Butler JC, Klein JO, Breiman RF, et al. Projected cost-effectiveness of pneumococcal conjugate vaccination of healthy infants and young children. JAMA 2000;283:1460–8. Ray GT, Whitney CG, Fireman BH, Ciuryla V, Black SB. Costeffectiveness of pneumococcal conjugate vaccine: evidence from the first 5 years of use in the United States incorporating herd effects. Pediatr Infect Dis J 2006;25(6):494–501.
PrevenarTM vaccination: Review of the global data, 2006 Kimberly J. Center ∗ Global Medical Affairs, Wyeth Pharmaceuticals, 500 Arcola Road, Collegeville, PA, USA Available online 18 January 2007
Abstract The 7-valent pneumococcal conjugate vaccine, PrevenarTM , was first licensed in the United States in 2000 for the prevention of invasive pneumococcal disease (IPD) caused by the serotypes included in the vaccine. It is presently approved in more than 70 countries, and more than 100 million doses of vaccine have been distributed to date. Within 1 year of routine use in the US, incidence of vaccine-serotype IPD had fallen dramatically among children younger than 2 years, with indirect effects noted among other age groups as well. The most recent data available from the US demonstrates that vaccine-serotype IPD has declined by 94% among the age group recommended for vaccination, and indirect effects have been documented in every unvaccinated age group, including among neonates and young infants. Additionally, declines in other pneumococcal-associated respiratory tract diseases have been reported, highlighting the extended benefits of a Prevenar vaccination program. Subsequently, the vaccine has been introduced into the national immunization programs of several other countries, including Canada, Australia, and The Netherlands. While an increase in disease caused by serotypes not included in the vaccine has been observed (“replacement disease”), the overall impact of this increase has, to date, been small in comparison to the substantial reduction in overall disease burden that has resulted since Prevenar introduction. © 2007 Elsevier Ltd. All rights reserved. Keywords: Invasive pneumococcal disease; Pneumococcal conjugate vaccine; Vaccination
1. Introduction Invasive disease caused by Streptococcus pneumoniae is a major public health concern. The World Health Organization (WHO) estimated that in 2002 there were 716,000 deaths among children less than 5 attributable to S. pneumoniae, making it the most common cause of vaccine-preventable death in this age group [1]. Although the highest ageassociated incidence of invasive pneumococcal disease (IPD) occurs in children younger than 2 years of age, no prophylactic intervention was available for this age group until the licensure of Prevenar in 2000. In contrast to the pure polysaccharide pneumococcal vaccines, which have limited immunogenicity in infants and young children, the conjugate vaccine stimulates a robust T cell-dependent immune response that allows for generation of protective anti-pneumococcal antibody even in young infants.
∗
Tel.: +1 484 865 2004; fax: +1 484 865 4199. E-mail address: [email protected].
0264-410X/$ – see front matter © 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.vaccine.2007.01.021
The pivotal trial leading to licensure was conducted at Northern California Kaiser Permanente beginning in 1995; the final analysis documented vaccine efficacy for fully vaccinated subjects of 97.4% (95% CI: 82.7–99.9%), with efficacy in the intent-to-treat analysis of 93.9% (95% CI: 79.6–98.5%) [2]. Prevenar was licensed in the United States in February 2000 and subsequently recommended for all infants in October 2000 [3]. Presently, the vaccine is approved in more than 70 countries worldwide, with more than 100 million doses distributed to date. In addition to the US 13 other countries, including Canada, the United Kingdom, the Netherlands, and Australia, have instituted national Prevenar immunization programs, and data demonstrating the profound effect of these programs have begun to emerge from countries in which the vaccine is widely used. However, documentation of the safety of new vaccines is also of paramount importance given the nature and scale of vaccination as a public health intervention. Finally, considerations of cost are important in the practical implementation of vaccination programs. This paper will review the relevant data regarding the changing epidemiology of pneumococcal disease follow-
3086
K.J. Center / Vaccine 25 (2007) 3085–3089
ing the introduction of Prevenar, including indirect effects in unvaccinated populations, the available safety information, and recent pharmacoeconomic analyses that considerably improve the cost–benefit profile of Prevenar compared with that predicted prior to its licensure.
2. Epidemiology of invasive pneumococcal disease in the era of conjugate vaccination S. pneumoniae is a major pediatric pathogen, especially for children younger than 2 years of age, for whom the age-related incidence of IPD is highest. Prior to the introduction of Prevenar in the United States, reported incidence rates of IPD in children younger than 2 years were approximately 188/100,000 [4] and the large majority of these cases (approximately 80–85%) were caused by the seven serotypes included in Prevenar. Data regarding both the documented burden of IPD and the serotype distribution of pneumococci causing invasive disease in other regions of the world vary considerably, based on several factors including standard medical practices (i.e., frequency of culture confirmation of disease, frequency of antibiotic pretreatment, etc.), available infrastructure (i.e., ability to make an etiologic diagnosis, presence of surveillance and/or reporting networks, etc.), and geographic variability in the distribution of pneumococcal serotypes. However, reviews of the existing literature suggest both that in at least some parts of the world, the burden of disease is higher [5–7], and the serotype coverage afforded by Prevenar may be better [6,8–10], than has previously been assumed.
3. Impact on pneumococcal disease Data are now emerging demonstrating the impact of Prevenar in routine use on pneumococcal disease. Follows is a brief review of selected impact data. 3.1. United States Surveillance for IPD in the United States is conducted by the Active Bacterial Core Surveillance system (ABCs) of the US Centers for Disease Control and Prevention (CDC), a laboratory-based system that surveys a population of approximately 16 million in 10 states. A comparison of IPD rates in 2003 (the most recent year for which data are available) to those of 1998/1999 reveals not only a 75% decline in invasive pneumococcal disease caused by all pneumococcal serotypes and a 94% decline in IPD caused by vaccine serotypes in children less than 5 years of age (the age group for which the vaccine is indicated), but also reports declines in IPD in persons ≥5 years, and most notably in those persons ≥65 years, demonstrating considerable herd effect [11]. In fact, the authors noted that the herd effect of routine Prevenar vaccination in the US is so profound that twice as many IPD cases
in 2003 were prevented through indirect effects (i.e., through interruption of pneumococcal transmission) than through the direct effect of protecting vaccinated children, and that indirect effects might be expected to increase as vaccine coverage increases. It was estimated that for all ages, routine use of Prevenar prevented 29,599 cases of vaccine-serotype IPD in the US; this reduction was slightly offset by a small increase in the number of cases caused by nonvaccine serotypes (4721) for a net reduction of 24,878 cases of IPD in 2003 compared with the 1998/1999 baseline. New data also suggest that the herd effect of widespread, routine immunization of infants 2–23 months with Prevenar has extended to infants younger than 2 months of age (too young to be eligible for vaccination, or having received at most a single dose of vaccine) [12]. Following Prevenar introduction, the mean rates of IPD decreased significantly for all infants aged 0–90 days, from 11.8/100,000 live births to 7.2/100,000; of note, rates of vaccine-serotype IPD decreased significantly, from 7.3/100,000 live births to 2.4/100,000 (p < 0.001), while IPD caused by nonvaccine serotypes remained stable (p = 0.55). Finally, there has historically been a higher incidence of IPD among black versus white individuals, which has been seen across all age groups; the reason for this disparity is unclear, and likely multifactorial. However, several studies now report that following Prevenar introduction, racial differences in the rates of IPD between whites and blacks have been drastically diminished or even eliminated [12–14], including among adults and infants aged 0–90 days. 3.2. Canada Prevenar was licensed in Canada in 2001. It was recommended for all infants in a four-dose schedule by the National Advisory Committee on Immunization (NACI) in early 2002 [15], and this recommendation was recently reiterated [16]. Alberta was one of the first Canadian provinces to adopt the NACI recommendation and subsequently is among the first populations to observe both direct and indirect effects on IPD in the region. The Calgary Area S. pneumoniae Epidemiology Research (CASPER) team, who conduct prospective population-based surveillance for invasive pneumococcal disease occurring in the Calgary Health Region (population, approximately 1 million), recently reported their IPD surveillance findings from 1998 to 2004 [17]. For children aged ≤23 months, when compared to a baseline average rate between 1998 and 2001, the rate of IPD caused by vaccine serotypes decreased by 92.6% to 3.9 cases/100,000 population (p < 0.001), by vaccine and vaccine-related serotypes by 93.4% (p < 0.001), and by any serotype by 81.6% to 11.7 cases/100,000 (p = 0.02); the rate of IPD caused by nonvaccine serotypes was unchanged (p = 0.61). Similar, though less dramatic, reductions in IPD were observed in adults 65 years or older; in this population, the rate of IPD caused by Prevenar serotypes in 2004 decreased by 62.7% to 8.5 cases/100,000 (p = 0.007). Declines were observed in IPD
K.J. Center / Vaccine 25 (2007) 3085–3089
caused by any serotype and by serotypes included in the pneumococcal polysaccharide vaccine (PPV23) but not in Prevenar, but these reductions were not statistically significant. Finally, a significant increase in IPD caused by serotypes not included in the 23-valent polysaccharide vaccine was observed (p = 0.03), but this did not offset the reduction in disease associated with the indirect effects of infant vaccination with Prevenar [17]. Similar, though less remarkable, results have been reported from the province of British Columbia (BC), with a population of 4.2 million, including 203,435 children aged <5 years. A selective immunization program of high-risk and Aboriginal children aged 2–59 months was started there in April 2003; this program was expanded to include all infants in September 2003. Since vaccine introduction, surveillance in the province has demonstrated a 67% reduction in pediatric IPD; in 2002 and 2005, the overall IPD rates in children <5 years of age were 53 cases and 18 cases per 100,000 population, respectively [18]. BC has not yet observed the anticipated changes in IPD among older adults that have been documented in the United States [11,13,19], although the baseline IPD rate is low compared to the US (16–20 cases/100,000 versus 60 cases/100,000, possibly due to underreporting in a passive surveillance system) [18], and so changes in the occurrence of IPD in this population may be more difficult to find. 3.3. Europe Effectiveness data from Europe are limited, though reports have recently been published from Spain and France. 3.3.1. Spain Prevenar became available in Spain in June 2001 but was not recommended for all infants in a four-dose schedule until October 2002; despite this universal recommendation, vaccine uptake has remained low. de Aristegui Fernandez et al. [20] present the surveillance findings of the autonomous regions of the Basque Country (28–45% vaccine uptake in a 3 + 1 schedule) and Navarre (35–37% uptake) during the 2-year post-licensure period 1 June 2001 to 31 May 2003, compared with the 3-year period immediately preceding the introduction of Prevenar (1 May 1998 to 31 May 2001). For children aged ≤23 months, when compared to a baseline average rate of 93.5 cases/100,000 population between 1998 and 2001, the rate of IPD decreased by 39.7% to 56.3 cases/100,000 population (p < 0.05) during the second year of surveillance; similar reductions were observed among children <12 months of age (64.3% [p < 0.01] reduction) and among the total population of children aged 0–59 months (37.5% reduction, p < 0.01). Among children younger than 2 years, the absolute reduction in IPD was entirely driven by a reduction in disease caused by serotypes contained in Prevenar, which accounted for 74.1 cases/100,000 children in the years prior to vaccine introduction and 49.5 cases/100,000 in the 2-year period postlicensure; the rate of disease caused by nonvaccine serotypes remained unchanged
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for the same time period (19.2 cases/100,000 population versus 18.7 cases/100,000 population). Notably, after Prevenar introduction there has also been a reduction in disease caused by penicillin- and cefotaxime-nonsusceptible isolates among children <5 years, with reductions of 58.2 and 24.9%, respectively. A major limitation of this study is that IPD is not a reportable disease in these regions, so it is likely that case ascertainment in both periods may be incomplete; this uncertainty highlights the importance of active, laboratory-based surveillance for IPD including serotyping and susceptibility testing. However, despite these limitations, the observed reductions in disease, even with relatively low vaccine uptake rates, are impressive and would be expected to improve as vaccination becomes more widespread, given the additional benefit of herd protection that has been observed elsewhere. 3.3.2. France The results of surveillance conducted by the Institut de Veille Sanitaire (EPIBAC Network) have recently been released [21], demonstrating significant reductions in pneumococcal bacteremia and meningitis among children <2 years for the first time since introduction of Prevenar in 2003, where the vaccine has been recommended for use in those children considered to be at increased risk of disease. Compared with the pre-vaccine period (1998–2002), 38.6% and 28.7% reductions have been observed in 2005 for pneumococcal meningitis and bacteremia overall, respectively, in children <2 years old (p < 0.001). These results document the impact of Prevenar on IPD in the targeted age group despite the absence of a universal recommendation, but highlight the importance of a universal vaccination program to realize the full spectrum of benefits associated with this vaccine. 3.4. Australia Finally, data regarding the impact of Prevenar are available from Australia, where in 2001 Prevenar was recommended for all Aboriginal infants, for whom the incidence of IPD is among the highest in the world. Compared to a baseline (2001) incidence of 219.2 cases of IPD/100,000 population, the incidence of IPD among Aboriginal children less than 2 years old was 91.5/100,000 in 2004, representing both a 2.9-fold decrease in disease in this population and parity with the non-indigenous population (IPD incidence: 93.6/100,000); notably, a 74% reduction in vaccine-serotype IPD was observed during the same surveillance period [22]. It is expected that further significant reductions in the incidence of IPD will be observed in Australia with the implementation of universal Prevenar vaccination for all infants that started in January 2005.
4. Safety considerations Documentation of the safety of any new vaccine is also of paramount importance given the nature and scale of vac-
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cination as a public health intervention, and Prevenar is no different. The safety profile of Prevenar was established prior to licensure in 5 clinical trials involving more than 18,000 infants and children [Wyeth, data on file], and the vaccine is considered to be generally well tolerated, with a profile comparable to other routinely used infant vaccines. Recently, the results of a large postmarketing evaluation of the safety of Prevenar given concomitantly with other recommended vaccines as part of routine care have been presented [23,24]. The primary endpoint of this study of 65,927 infants who received the primary series of Prevenar in the first year of life was a comparison of commonly occurring systemic events (including fever, seizure, etc.) in the period immediately following immunization (0–30 days) to the rate of the same events occurring later after immunization (31–60 days); this primary evaluation revealed no new safety information [23]. Secondary endpoints of the study involved evaluation of less commonly occurring events or events with longer time to onset, as well as analyses of mortality, as compared to historical controls; these analyses also did not suggest any new safety consideration that would alter the risk-benefit balance of the vaccine [24]. Additional data regarding the safety of Prevenar in routine use are available from the Vaccine Adverse Event Reporting System (VAERS), a passive safety surveillance system in the US that is jointly operated by FDA and CDC [25]. In the 2 years following licensure in the US, VAERS received 4154 reports of adverse events following Prevenar immunization, of which 74.3% included administration of multiple vaccines concomitantly. Based on an estimated distribution of 31.2 million doses in the same time period, the authors reported an overall adverse event rate of 13.2/100,000 doses, and of 1.9/100,000 for serious events; these event rates are similar to those for other routinely recommended vaccines [25]. The major weakness of this surveillance system is its passive nature; however, the findings of the first 2 years are reassuring. More than 100 million doses of Prevenar have now been distributed worldwide, and to date, routine pharmacovigilance does not suggest any new or emerging safety concern.
5. Pharmacoeconomic considerations The final consideration relevant to the implementation of universal immunization programs is that of cost, the importance of which cannot be underestimated. An analysis of cost–benefit of Prevenar performed prior to licensure demonstrated a societal cost of US$ 80,000 per life-year saved, with an estimated 116 deaths from pneumococcal disease prevented; this analysis only considered the direct effects of immunization of the target population [26]. However, a more recent evaluation, taking into account the profound indirect (herd) effect that has been observed in the US, estimates a societal cost of US$ 7500 per life-year saved, with an estimated 5159 deaths prevented [27]; these estimates represent considerably larger reductions than predicted by the previ-
ous evaluation. Additionally, the authors report that if one includes the potential indirect effect of Prevenar on pneumonia among elderly adults, universal immunization with Prevenar became cost saving [27]. When placed in the context of other standard preventive measures recommended for whole populations, then, the cost–benefit that could be realized by routine Prevenar immunization would seem to weigh in favor of routine use.
6. Conclusion In summary, emerging clinical data continue to demonstrate the value of Prevenar; the early US experience of profound reductions in invasive pneumococcal disease among children has begun to be replicated by other countries, and new data are emerging demonstrating the extension of herd effect to unimmunized populations as well in places where the vaccine is routinely used. The phenomenon of replacement disease is of concern and warrants ongoing vigilance, but has not to date threatened the overall large benefit of the vaccine for the population as a whole. While the safety of any vaccine product is continuously monitored, the experience with Prevenar to date suggests no new safety concerns. Challenges still exist, including raising worldwide awareness of the burden of invasive pneumococcal disease and demonstrating the cost effectiveness of universal Prevenar vaccination programs. However, with the availability of this life-saving pneumococcal conjugate vaccine for infants, and the overwhelming evidence of its effectiveness, it is imperative that its use become commonplace so that more children’s lives may be saved, and the public health improved.
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