Clinical Therapeutics/Volume ], Number ], 2015
Recent Developments and Future Directions of Pneumococcal Vaccine Recommendations Katherine M. Tromp, PharmD; Marcus W. Campbell, PharmD; and Alejandro Vazquez, PharmD LECOM, Bradenton, Florida ABSTRACT Purpose: The goal of this article was to review the key clinical trials that resulted in the recent recommendation from the Advisory Committee on Immunization Practices (ACIP) to vaccinate all adults aged Z65 years with the 13-valent pneumococcal polysaccharide conjugate vaccine (PCV13) in addition to the previously recommended 23-valent pneumococcal polysaccharide vaccine (PPSV23). Methods: Pertinent articles were identified through searches of EMBASE and MEDLINE by using the terms pneumococcal polysaccharide conjugate vaccine, pneumococcal vaccine, and PCV13. Searches were limited to articles published between January 1, 2013, and January 31, 2015, and were limited to clinical trials. Resources from the Centers for Disease Control and Prevention’s ACIP recommendations and cited references were also reviewed. Findings: Recent clinical trials have focused on the order of administration of PPSV23 and PCV13, comparisons in immunogenicity of PPSV23 and PCV13, and efficacy of PCV13 in adults aged Z65 years. Immunogenicity trials have shown that PCV13 elicits an equal or greater immune response than PPSV23 for most of the serotypes that both vaccines share. The evidence suggests that PCV13 should be administered before PPSV23 when possible. Most recently, clinical data demonstrated the efficacy of PCV13 in adults aged Z65 years. Implications: Recent randomized clinical trials and disease trends have prompted the ACIP to recommend that all adults aged Z65 years receive a single dose of PCV13. This is in addition to the previous recommended single dose of PPSV23 in the same population. The ACIP and the Centers for Disease Control and Prevention plan to monitor disease trends and clinical data to determine if this recommendation will need to be changed in the future. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved.
] 2015
Key words: pneumococcal, vaccine, immunization, pneumonia.
INTRODUCTION Community-acquired pneumonia (CAP) causes significant morbidity and mortality in the United States. It results in as many as 400,000 hospitalizations annually and is associated with a case fatality rate of 5% to 7%.1,2 Streptococcus pneumoniae causes 25% to 40% of CAP cases in adults, making it the leading cause of this disease. In addition, S pneumoniae bacteria cause invasive pneumococcal disease (IPD) when the bacteria infect the spinal cord fluid and blood, resulting in meningitis and bacteremia.3 The incidence and mortality associated with pneumonia increase as a person ages.4,5 Many serotypes of S pneumoniae exist, and a number of these serotypes can be found in 2 existing pneumococcal vaccines. The 2 currently available are the 23-valent pneumococcal polysaccharide vaccine (PPSV23) and the 13-valent pneumococcal polysaccharide conjugate vaccine (PCV13). The first polysaccharide pneumococcal vaccine was licensed in 1977, and the first polysaccharide conjugate vaccine was licensed in 2000 (Figure 1). PPSV23 contains polysaccharide antigen from 23 serotypes of pneumococcal bacteria. In addition, the vaccine results in cross-sensitivity and protection to other types of bacteria. PCV13 contains capsular polysaccharide of 13 serotypes of S pneumoniae and is conjugated with a nontoxic form of diphtheria toxin.1 Twelve of the 13 serotypes in PCV13 are also found in PPSV23. Although PCV13 only contains 1 additional Accepted for publication March 31, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.03.025 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
1
Clinical Therapeutics
1977
First polysaccharide pneumococcal vaccine (PPSV14) introduced
1983
1997 PPSV23 introduced
PPSV23 shows efficacy in high-risk groups
2000
2010 PCV7 approved in infants and children
PCV13 approved for use in infants and children, also recommended by ACIP
2011
FDA approves PCV13 for use in adults aged >50 years
2014
ACIP recommends PCV13 for all adults aged ≥65 years
Figure 1. Timeline of developments in pneumococcal immunization, displaying some of the important dates in the development, approval, and recommendations of pneumococcal vaccines. PPSV14 ¼ 14valent polysaccharide vaccine; PPSV23 ¼ 23-valent pneumococcal polysaccharide vaccine; PCV7 ¼ 7-valent pneumococcal polysaccharide conjugate vaccine; PCV13 ¼ 13-valent pneumococcal polysaccharide conjugate vaccine; ACIP ¼ Advisory Committee on Immunization Practices; FDA ¼ US Food and Drug Administration.
serotype compared with PPSV23, it elicits an immune response via T-cell activation. T-cell activation may result in longer lasting immunity with subsequent doses and/or natural exposure to the serotypes found in the vaccine.4 It is believed that this contributes to increased immunogenicity.6,7 Conversely, PPSV23 elicits an immune response that is T-cell independent. It works by directly stimulating B cells. This type of vaccine results in less immunogenicity and less of a booster effect than conjugated vaccines.1 The polysaccharide conjugate vaccine initially was indicated for infants and toddlers at ages 2, 4, 6, and 12 to 15 months.8 The first polysaccharide conjugate vaccine contained 7 serotypes. In 2010, a 13-serotype version was approved. Between 2010 and 2013, the incidence of IPD caused by serotypes in the vaccine declined by 50% in persons aged Z65 years. Despite the decline, there were still 413,000 cases of IPD in 2013. Due to the morbidity and mortality associated with IPD, it was necessary to determine if PCV13 could be safely and effectively used in adults aged Z65 years. The aim of the present article was to review the key clinical trials that resulted in the recent recommendation from the Advisory Committee on Immunization Practices (ACIP) to vaccinate all adults aged Z65 years by using both PCV13 and PPSV23. These clinical trials are summarized in the Table. Before August 2014, the ACIP only routinely recommended the use of PPSV23 in adults aged Z65 years.
RESULTS Immunogenicity of PCV13 and PPSV23 Two studies have researched the immunogenicity of PCV13 compared with PPSV23, 1 in vaccine-naive patients and 1 in previously vaccinated patients.6,7 The goal of these studies was to test the ability of the conjugated 13-valent vaccine to produce an immunogenicity equal to or greater than that of the
2
polysaccharide vaccines, not only in the period directly after immunization but also over time. Because PPSV23 has been scrutinized for its lack of evidence regarding protection over time, the results of both studies would prove to be integral in this type of protection. One of these studies focused specifically on vaccinenaive adults.7 Two adult populations were studied. The main arm of the study examined the response of adults aged 60 to 64 years. The enrollees were randomly divided into 2 even groups, 1 of which received PCV13 vaccination, while the other received PPSV23 vaccination. The other arm included adults aged 50 to 59 years and compared the immunogenicity of PCV13 between the older and younger groups. Subjects were not excluded for having chronic conditions that could increase the risk of developing pneumonia. The exclusion criteria included unstable chronic disease, as well as malignancies, advanced chronic obstructive pulmonary disease, renal disease, cardiac disease, and impaired immune function. Follow-up visits occurred at 1 month and 1 year postvaccination. In the main arm of the study, 818 patients were evaluated for the immunogenicity of their respective vaccines (411 in the PCV13 arm and 407 in the PPSV23 arm).7 The study found that PCV13 was noninferior to PPSV23 in all common serotypes and that the younger group (aged 50–59 years) had a statistically significantly higher immunogenicity response for 9 of the serotypes included in PCV13. It also found a more profound response in the younger group, compared with the older group, in terms of persistence of immune response 1 year after vaccination. The second immunogenicity study examined the response to revaccination in subjects previously vaccinated with PPSV23 as well as the effect of PCV13 administration 1 year after the study was initiated.6 The subjects enrolled had received PPSV23 vaccination at least 5 years before enrollment and were at least 70 years
Volume ] Number ]
] 2015
Table. Summary of recent clinical trials regarding pneumococcal immunization. Author/Trial Jackson et al.6
Jackson et al.7
Jackson et al.4
Patient Population
Trial Duration
470 years of age; previously vaccinated with PPSV23 at least 5 years earlier
13 months
60–64 years of age, vaccine naive
12 months
Extension study in vaccine-naive adults 60–64 years of age
5-year extension
Treatment Group
Key Findings
Sequential vaccination separated by 1 year (2 arms): PPSV23 - PCV13 PCV13 - PCV13
PCV13-PCV13
Single vaccination: PCV13 vs PPSV23
Repeat vaccination 4 years’ postinitial vaccination (3 arms): PCV13 - PCV13 PCV13 - PPSV23 PPSV23- PPSV23
OPA titers were assessed 1 month after each sequential vaccination
OPA titers were assessed 1 month and 1 year after vaccination
OPA titers were assessed 1 month after repeat vaccination
3
K.M. Tromp et al.
group had significantly higher OPA titers in 10 of 12 common serotypes; the remaining 2 were noninferior PCV13 had significantly higher 1month postvaccination OPA titers in 8 of 12 common serotypes; the remaining 4 were comparable A repeat PCV13 had OPA titers that were significantly higher for 7 of 13 serotypes than after the initial vaccination Repeat PPSV23 had OPA titers that were significantly lower for 9 of 13 serotypes than after the initial vaccination
Comments
(continued)
Author/Trial Greenberg et al.5
CAPiTA11
Patient Population Vaccinenaive adults 60–64 years of age
Adults 465 years of age
Trial Duration 13 months
3 years
Treatment Group Repeat vaccination 12 months’ postinitial vaccination (3 arms): PCV13 - PCV13 PCV13 -PPSV23 PPSV23-PPSV23
PCV13 vs placebo
Key Findings
Comments
Initial PCV13
augmented OPA titer to subsequent administration for many serotypes whereby initial PPSV23 decreased OPA titer response PCV13 group compared with control 45.6% ↓ (95% CI, 21.8–62.5) VTpneumococcal CAP 45.0% ↓ (95% CI, 14.2–65.3) VTnonbacteremic pneumococcal pneumonia 75.0% ↓ (95% CI, 41.4–90.8) decrease in VT-IPD
OPA titers were assessed 1 month after each sequential vaccination
Similar serious AEs and deaths; ↑ local reactions in the PCV13 group.
PPSV23 ¼ 23-valent pneumococcal polysaccharide vaccine; PCV13 ¼ 13-valent pneumococcal polysaccharide conjugate vaccine; OPA ¼ opsonophagocytic activity; CAPiTA ¼ Community-Acquired Pneumonia Immunization Trial in Adults; VT ¼ vaccine-type, AEs ¼ adverse events.
Clinical Therapeutics
4 Table. (continued).
Volume ] Number ]
K.M. Tromp et al. of age. As with the study that focused on vaccine-naive patients,7 enrollees were not excluded for having chronic diseases that could increase the risk of developing pneumonia. Similar exclusion criteria were outlined (stable chronic disease, lack of malignancies, advanced chronic obstructive pulmonary disease, renal and cardiac disease, and impaired immune function). Study participants were limited to only having 1 instance of PPSV23 vaccination and were not permitted to have had a previous PCV13 vaccination. Subjects were vaccinated and required to return for measurement of antipneumococcal opsonophagocytic activity (OPA) titers 1 month later. The antibody response tested via OPA is believed to correlate with the level of protection provided by the vaccine.7 The OPA assays used in this study were validated previously.6 The study evaluated 879 patients (431 received PCV13 and 448 received PPSV23) for immunogenicity for the first vaccination. At follow-up, as in the previously mentioned study,7 PCV13 was found to be noninferior to PPSV23 in the common serotypes. One year after vaccination, 745 subjects were evaluated (372 received PCV13 first and 373 received PPSV23 first) for immunogenicity.6 Two groups were studied: subjects who received PCV13 first, with a second PCV13 vaccination (PCV13/PCV13), and subjects who received PPSV23 first, with a subsequent PCV13 vaccination (PPSV23/PCV13). Patients who received PPSV23 first had a statistically significant reduction in immunogenicity compared with those who received PCV13 first. The results of these 2 studies show that PCV13, while it protects for fewer serotypes than PPSV23, has greater immunogenicity potential than PPSV23, framing the importance of including PCV13 in pneumococcal vaccine recommendations.
Sequential Administration of PCV13 and PPSV23 Greenberg et al5 conducted a randomized, modified double-blind study in 720 pneumococcal vaccinenaive adults aged 60 to 64 years to evaluate the effect of sequential administration of PCV13 and PPSV23 on the antipneumococcal OPA titers. Patients were randomly assigned to receive either PCV13 followed by a subsequent dose of PCV13 one year later, PCV13 followed by a subsequent dose of PPSV23 one year later, or PPSV23 followed by a subsequent dose of PCV13 one year later. Blood samples were analyzed for titers before and 1 month after administration of each vaccine. The results showed a better OPA
] 2015
immune response in patients who received an initial dose of PCV13 followed by a dose of PPSV23 compared with those patients who received an initial dose of PPSV23 followed by a dose of PCV13. Additional studies have evaluated the sequence of conjugated vaccine followed by PPSV23 with the injections separated by variable intervals of 2, 6, 12, and 36 to 48 months. Results from previous trials suggest that the PPSV23 immune response was not improved after administration of the conjugate vaccine (the first pneumococcal conjugate vaccine [PCV7] or PCV13, depending on the year of the trial).4,9,10 Similar to Greenberg et al,5 Jackson et al4 also evaluated the immunogenicity effect of PCV13 administered before and after PPSV23. Specifically, the study examined the immune response after a second dose of a pneumococcal vaccine in 3 groups: PCV13 after a previous PCV13 dose, PPSV23 after a previous PPSV23 dose, and PCV13 after a previous PPSV23 dose. The study was an extension of the previous immunogenicity trial discussed in detail earlier.7 Participants from the previous study who continued with this study included 405 subjects from the original 60- to 64-year-old group and 214 subjects from the 50- to 59-year-old group.4 Those in the older age group were split 1:1 to receive either PPSV23 or PCV13 if they had previously received PCV13, and PPSV23 only if they had previously received PPSV23; those in the younger age group in the initial study received a second dose of PCV13. Antipneumococcal OPA was evaluated to determine immune response to the second immunization. OPA titers were measured before vaccine administration and 1 month after administration. Tolerability was also evaluated at administration through 6 months’ postvaccination. The study found that a second dose of PCV13, given 4 years later, resulted in OPA titers that were significantly higher than those after initial immunization for 7 of the 13 serotypes in the participants in the 60- to 64-year-old group and 6 of the 13 serotypes in the participants in the 50- to 59-year-old group. 4 Most of the other serotypes were found to be noninferior. Alternatively, patients who received a second dose of PPSV23 exhibited lower OPA titers in 9 of the 13 serotypes and noninferior OPA titers for the other serotypes compared with initial immunization with PPSV23. Patients who received PPSV23 after receiving PCV13 demonstrated increased OPA titers in 10 of the 13 serotypes compared with those with initial PPSV23
5
Clinical Therapeutics
ACIP Recommendations for use in persons aged ≥65 years
Pneumococcal vaccine-naive persons
Previous vaccination with PPSV23
Administer PCV13 first Administer PPSV23 6 to 12 months later Minimum acceptable time between PCV13 and PPSV23 is 8 weeks Do not coadminister the vaccines
PCV13 should be given at least 12 months after PPSV23 administration Patients who are indicated to receive a second dose of PPSV23 should wait 6 to 12 months after receiving PCV13 and 5 years after receiving their previous dose of PPSV23 Only 1 dose of PCV13 and 1 dose of PPSV23 are indicated in persons aged ≥65 years
Figure 2. Current Advisory Committee on Immunization Practices (ACIP) recommendations for persons Z65 years of age. This figure shows the recommendations for adults aged Z65 years who are either pneumococcal vaccine-naive or who have been previously vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPSV23). PCV13 ¼ 13-valent pneumococcal polysaccharide conjugate vaccine. immunization. The study determined that revaccination with PCV13 or PPSV23 resulted in antipneumococcal recall in adults previously vaccinated with PCV13. Conversely, revaccination with PPSV23 after initial PPSV23 resulted in a lower response than initial vaccination for most serotypes. These data suggest that PCV13 should be administered before PPSV23 to elicit a stronger response in most of the shared serotypes. It is important to note that to-date, no studies have compared the optimal interval between PCV13 and PPSV23 vaccination.
Efficacy of PCV13 in Adults Aged Z65 Years CAPiTA (Community-Acquired Pneumonia Immunization Trial in Adults) was a parallel-group, randomized, placebo-controlled, double-blind study designed to evaluate the efficacy of PCV13 in the prevention of first episode vaccine-type (VT) pneumococcal CAP in healthy adults. CAPiTA was conducted in compliance with requirements set forth by the US Food and Drug Administration as part of an accelerated approval process to address an unmet medical need in older adults, and enrollment began in the fall of 2008.3 Across 75 primary care centers associated with the University Medical Center Utrecht in the Netherlands, researchers enrolled 84,496 pneumococcal vaccine-naive subjects aged Z65 years. Subjects were randomized to receive either PCV13 or placebo.
6
Surveillance of the enrolled subjects for the development of CAP and IPD was conducted at 58 hospitals surrounding the areas of enrollment.3,11 The mean time for follow-up was set to exceed 3 years, and observation of study subjects was completed in August 2013. The trial demonstrated that those in the PCV13 arm were 45.6% less likely to develop VT-pneumococcal CAP (CI, 21.8–62.5; P o 0.001). Analysis of secondary outcomes demonstrated 45.0% (CI, 14.2–65.3; P = 0.007) efficacy of PCV13 against VT-nonbacteremic pneumococcal pneumonia and 75.0% (CI, 41.4–90.8; P o 0.007) efficacy against VT-IPD.11 The trial also measured adverse events.11 All participants were monitored for 1 month after vaccination for serious adverse events, and no difference was seen between groups (P ¼ 0.61). A safety subgroup was analyzed to determine the frequency of nonserious adverse events within 1 month of vaccination and serious adverse events for 6 months after vaccination. There were 1006 participants in the PCV13 subgroup and 1005 in the placebo subgroup. There were statistically significantly more adverse events in the PCV13 subgroup than in the placebo subgroup (188 events compared with 144 events; P ¼ 0.01); however, the difference in serious adverse events 6 months after vaccination was not deemed significant (70 events compared with 60 events; P ¼ 0.41). Volume ] Number ]
K.M. Tromp et al.
FUTURE DIRECTIONS Based on clinical data and disease trends, PCV13 is now recommended for all adults aged Z65 years (Figure 2). This recommendation is in addition to the previous recommendation of vaccinating all adults aged Z65 years with PPSV23. If an adult aged Z65 years has not been vaccinated with either pneumococcal vaccine, PCV13 should be administered first. PPSV23 should be administered 6 to 12 months after administration of PCV13; if that is not possible, PPSV23 can be administered as early as 8 weeks after PCV13. For patients who already have received the PPSV23 immunization, they should wait 12 months before receiving PCV13.8 The most recent recommendation to administer PCV13 to all adults aged Z65 years will be reevaluated by the ACIP in 2018.8 The Centers for Disease Control and Prevention will evaluate the implementation and impact of the new recommendation and continue to monitor trends in CAP and IPD. Monitoring will also be performed to compare the outcomes of those who do get immunized versus those who do not. Although the next review of this information is estimated to be conducted in 2018, the ACIP will continuously monitor information about the pneumococcal vaccines and will change recommendations as necessary.
ACKNOWLEDGMENTS All authors contributed equally to this paper. Katherine Tromp wrote the Abstract, Introduction, Future directions, and Figure 2. Marcus Campbell wrote the Methods and the Table. Alex Vazquez created Figure 1. All three authors contributed equally to the Results.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
REFERENCES 1. Centers for Disease Control and Prevention. In: Atkinson W, Wolfe S, Hamborsky J, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 12th ed. second printing. Washington, DC: Public Health Foundation; 2012.
2. Huang SS, Johnson KM, Ray GT, et al. Healthcare utilization and cost of pneumococcal disease in the United States. Vaccine. 2011;29:3398–3412. 3. Hak E, Grobbee DE, Sanders EAM, et al. Rationale and design of CAPITA: A RCT of 12-valent conjugated pneumococcal vaccine efficacy among older adults. Neth J Med. 2008;66:378–382. 4. Jackson LA, Gurtman A, van Cleeff M, et al. Influence of initial vaccination with 13-valent pneumococcal conjugate vaccine or 23-valent pneumococcal polysaccharide vaccine on anti-pneumococcal responses following subsequent pneumococcal vaccination in adults 50 years and older. Vaccine. 2013;31:3594–3602. 5. Greenberg RN, Gurtman A, Frenck RW, et al. Sequential administration of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naïve adults 60–64 years of age. Vaccine. 2014;32:2364–2374. 6. Jackson LA, Gurtman A, Rice K, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 70 years of age and older previously vaccinated with 23-valent pneumococcal polysaccharide vaccine. Vaccine. 2013;31:3585–3593. 7. Jackson LA, Gurtman A, van Cleeff M, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naïve adults. Vaccine. 2013;31:3577–3584. 8. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged Z65 years: Recommendations of the Advisory Committee on Immunization Practice (ACIP). MMWR Morb Mortal Wkly Rep. 2014;63:822–825. 9. Goldblatt D, Southern J, Andrews N, et al. The immunogenicity of 7-valent pneumococcal conjugate vaccine versus 23-valent polysaccharide vaccine in adults aged 50-80 years. Clin Infect Dis. 2009;49:1318–1325. 10. Miernyk KM, Butler JC, Bulkow LR, et al. Immunogenicity and reactogenicity of pneumococcal polysaccharide and conjugate vaccines in Alaska native adults 55-70 years of age. Clin Infect Dis. 2009;49:241–248. 11. Bonten MJM, Huijts SM, Bolkenbaas M, et al. Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults. N Engl J Med. 2015;372:1114–1125.
Address correspondence to: Katherine M. Tromp, PharmD, LECOM, 5000 Lakewood Ranch Boulevard, Bradenton, FL 34211. E-mail: ktromp@ lecom.edu
] 2015
7
Recent Developments and Future Directions of Pneumococcal Vaccine Recommendations Katherine M. Tromp, PharmD; Marcus W. Campbell, PharmD; and Alejandro Vazquez, PharmD LECOM, Bradenton, Florida ABSTRACT Purpose: The goal of this article was to review the key clinical trials that resulted in the recent recommendation from the Advisory Committee on Immunization Practices (ACIP) to vaccinate all adults aged Z65 years with the 13-valent pneumococcal polysaccharide conjugate vaccine (PCV13) in addition to the previously recommended 23-valent pneumococcal polysaccharide vaccine (PPSV23). Methods: Pertinent articles were identified through searches of EMBASE and MEDLINE by using the terms pneumococcal polysaccharide conjugate vaccine, pneumococcal vaccine, and PCV13. Searches were limited to articles published between January 1, 2013, and January 31, 2015, and were limited to clinical trials. Resources from the Centers for Disease Control and Prevention’s ACIP recommendations and cited references were also reviewed. Findings: Recent clinical trials have focused on the order of administration of PPSV23 and PCV13, comparisons in immunogenicity of PPSV23 and PCV13, and efficacy of PCV13 in adults aged Z65 years. Immunogenicity trials have shown that PCV13 elicits an equal or greater immune response than PPSV23 for most of the serotypes that both vaccines share. The evidence suggests that PCV13 should be administered before PPSV23 when possible. Most recently, clinical data demonstrated the efficacy of PCV13 in adults aged Z65 years. Implications: Recent randomized clinical trials and disease trends have prompted the ACIP to recommend that all adults aged Z65 years receive a single dose of PCV13. This is in addition to the previous recommended single dose of PPSV23 in the same population. The ACIP and the Centers for Disease Control and Prevention plan to monitor disease trends and clinical data to determine if this recommendation will need to be changed in the future. (Clin Ther. 2015;]:]]]–]]]) & 2015 Elsevier HS Journals, Inc. All rights reserved.
] 2015
Key words: pneumococcal, vaccine, immunization, pneumonia.
INTRODUCTION Community-acquired pneumonia (CAP) causes significant morbidity and mortality in the United States. It results in as many as 400,000 hospitalizations annually and is associated with a case fatality rate of 5% to 7%.1,2 Streptococcus pneumoniae causes 25% to 40% of CAP cases in adults, making it the leading cause of this disease. In addition, S pneumoniae bacteria cause invasive pneumococcal disease (IPD) when the bacteria infect the spinal cord fluid and blood, resulting in meningitis and bacteremia.3 The incidence and mortality associated with pneumonia increase as a person ages.4,5 Many serotypes of S pneumoniae exist, and a number of these serotypes can be found in 2 existing pneumococcal vaccines. The 2 currently available are the 23-valent pneumococcal polysaccharide vaccine (PPSV23) and the 13-valent pneumococcal polysaccharide conjugate vaccine (PCV13). The first polysaccharide pneumococcal vaccine was licensed in 1977, and the first polysaccharide conjugate vaccine was licensed in 2000 (Figure 1). PPSV23 contains polysaccharide antigen from 23 serotypes of pneumococcal bacteria. In addition, the vaccine results in cross-sensitivity and protection to other types of bacteria. PCV13 contains capsular polysaccharide of 13 serotypes of S pneumoniae and is conjugated with a nontoxic form of diphtheria toxin.1 Twelve of the 13 serotypes in PCV13 are also found in PPSV23. Although PCV13 only contains 1 additional Accepted for publication March 31, 2015. http://dx.doi.org/10.1016/j.clinthera.2015.03.025 0149-2918/$ - see front matter & 2015 Elsevier HS Journals, Inc. All rights reserved.
1
Clinical Therapeutics
1977
First polysaccharide pneumococcal vaccine (PPSV14) introduced
1983
1997 PPSV23 introduced
PPSV23 shows efficacy in high-risk groups
2000
2010 PCV7 approved in infants and children
PCV13 approved for use in infants and children, also recommended by ACIP
2011
FDA approves PCV13 for use in adults aged >50 years
2014
ACIP recommends PCV13 for all adults aged ≥65 years
Figure 1. Timeline of developments in pneumococcal immunization, displaying some of the important dates in the development, approval, and recommendations of pneumococcal vaccines. PPSV14 ¼ 14valent polysaccharide vaccine; PPSV23 ¼ 23-valent pneumococcal polysaccharide vaccine; PCV7 ¼ 7-valent pneumococcal polysaccharide conjugate vaccine; PCV13 ¼ 13-valent pneumococcal polysaccharide conjugate vaccine; ACIP ¼ Advisory Committee on Immunization Practices; FDA ¼ US Food and Drug Administration.
serotype compared with PPSV23, it elicits an immune response via T-cell activation. T-cell activation may result in longer lasting immunity with subsequent doses and/or natural exposure to the serotypes found in the vaccine.4 It is believed that this contributes to increased immunogenicity.6,7 Conversely, PPSV23 elicits an immune response that is T-cell independent. It works by directly stimulating B cells. This type of vaccine results in less immunogenicity and less of a booster effect than conjugated vaccines.1 The polysaccharide conjugate vaccine initially was indicated for infants and toddlers at ages 2, 4, 6, and 12 to 15 months.8 The first polysaccharide conjugate vaccine contained 7 serotypes. In 2010, a 13-serotype version was approved. Between 2010 and 2013, the incidence of IPD caused by serotypes in the vaccine declined by 50% in persons aged Z65 years. Despite the decline, there were still 413,000 cases of IPD in 2013. Due to the morbidity and mortality associated with IPD, it was necessary to determine if PCV13 could be safely and effectively used in adults aged Z65 years. The aim of the present article was to review the key clinical trials that resulted in the recent recommendation from the Advisory Committee on Immunization Practices (ACIP) to vaccinate all adults aged Z65 years by using both PCV13 and PPSV23. These clinical trials are summarized in the Table. Before August 2014, the ACIP only routinely recommended the use of PPSV23 in adults aged Z65 years.
RESULTS Immunogenicity of PCV13 and PPSV23 Two studies have researched the immunogenicity of PCV13 compared with PPSV23, 1 in vaccine-naive patients and 1 in previously vaccinated patients.6,7 The goal of these studies was to test the ability of the conjugated 13-valent vaccine to produce an immunogenicity equal to or greater than that of the
2
polysaccharide vaccines, not only in the period directly after immunization but also over time. Because PPSV23 has been scrutinized for its lack of evidence regarding protection over time, the results of both studies would prove to be integral in this type of protection. One of these studies focused specifically on vaccinenaive adults.7 Two adult populations were studied. The main arm of the study examined the response of adults aged 60 to 64 years. The enrollees were randomly divided into 2 even groups, 1 of which received PCV13 vaccination, while the other received PPSV23 vaccination. The other arm included adults aged 50 to 59 years and compared the immunogenicity of PCV13 between the older and younger groups. Subjects were not excluded for having chronic conditions that could increase the risk of developing pneumonia. The exclusion criteria included unstable chronic disease, as well as malignancies, advanced chronic obstructive pulmonary disease, renal disease, cardiac disease, and impaired immune function. Follow-up visits occurred at 1 month and 1 year postvaccination. In the main arm of the study, 818 patients were evaluated for the immunogenicity of their respective vaccines (411 in the PCV13 arm and 407 in the PPSV23 arm).7 The study found that PCV13 was noninferior to PPSV23 in all common serotypes and that the younger group (aged 50–59 years) had a statistically significantly higher immunogenicity response for 9 of the serotypes included in PCV13. It also found a more profound response in the younger group, compared with the older group, in terms of persistence of immune response 1 year after vaccination. The second immunogenicity study examined the response to revaccination in subjects previously vaccinated with PPSV23 as well as the effect of PCV13 administration 1 year after the study was initiated.6 The subjects enrolled had received PPSV23 vaccination at least 5 years before enrollment and were at least 70 years
Volume ] Number ]
] 2015
Table. Summary of recent clinical trials regarding pneumococcal immunization. Author/Trial Jackson et al.6
Jackson et al.7
Jackson et al.4
Patient Population
Trial Duration
470 years of age; previously vaccinated with PPSV23 at least 5 years earlier
13 months
60–64 years of age, vaccine naive
12 months
Extension study in vaccine-naive adults 60–64 years of age
5-year extension
Treatment Group
Key Findings
Sequential vaccination separated by 1 year (2 arms): PPSV23 - PCV13 PCV13 - PCV13
PCV13-PCV13
Single vaccination: PCV13 vs PPSV23
Repeat vaccination 4 years’ postinitial vaccination (3 arms): PCV13 - PCV13 PCV13 - PPSV23 PPSV23- PPSV23
OPA titers were assessed 1 month after each sequential vaccination
OPA titers were assessed 1 month and 1 year after vaccination
OPA titers were assessed 1 month after repeat vaccination
3
K.M. Tromp et al.
group had significantly higher OPA titers in 10 of 12 common serotypes; the remaining 2 were noninferior PCV13 had significantly higher 1month postvaccination OPA titers in 8 of 12 common serotypes; the remaining 4 were comparable A repeat PCV13 had OPA titers that were significantly higher for 7 of 13 serotypes than after the initial vaccination Repeat PPSV23 had OPA titers that were significantly lower for 9 of 13 serotypes than after the initial vaccination
Comments
(continued)
Author/Trial Greenberg et al.5
CAPiTA11
Patient Population Vaccinenaive adults 60–64 years of age
Adults 465 years of age
Trial Duration 13 months
3 years
Treatment Group Repeat vaccination 12 months’ postinitial vaccination (3 arms): PCV13 - PCV13 PCV13 -PPSV23 PPSV23-PPSV23
PCV13 vs placebo
Key Findings
Comments
Initial PCV13
augmented OPA titer to subsequent administration for many serotypes whereby initial PPSV23 decreased OPA titer response PCV13 group compared with control 45.6% ↓ (95% CI, 21.8–62.5) VTpneumococcal CAP 45.0% ↓ (95% CI, 14.2–65.3) VTnonbacteremic pneumococcal pneumonia 75.0% ↓ (95% CI, 41.4–90.8) decrease in VT-IPD
OPA titers were assessed 1 month after each sequential vaccination
Similar serious AEs and deaths; ↑ local reactions in the PCV13 group.
PPSV23 ¼ 23-valent pneumococcal polysaccharide vaccine; PCV13 ¼ 13-valent pneumococcal polysaccharide conjugate vaccine; OPA ¼ opsonophagocytic activity; CAPiTA ¼ Community-Acquired Pneumonia Immunization Trial in Adults; VT ¼ vaccine-type, AEs ¼ adverse events.
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4 Table. (continued).
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K.M. Tromp et al. of age. As with the study that focused on vaccine-naive patients,7 enrollees were not excluded for having chronic diseases that could increase the risk of developing pneumonia. Similar exclusion criteria were outlined (stable chronic disease, lack of malignancies, advanced chronic obstructive pulmonary disease, renal and cardiac disease, and impaired immune function). Study participants were limited to only having 1 instance of PPSV23 vaccination and were not permitted to have had a previous PCV13 vaccination. Subjects were vaccinated and required to return for measurement of antipneumococcal opsonophagocytic activity (OPA) titers 1 month later. The antibody response tested via OPA is believed to correlate with the level of protection provided by the vaccine.7 The OPA assays used in this study were validated previously.6 The study evaluated 879 patients (431 received PCV13 and 448 received PPSV23) for immunogenicity for the first vaccination. At follow-up, as in the previously mentioned study,7 PCV13 was found to be noninferior to PPSV23 in the common serotypes. One year after vaccination, 745 subjects were evaluated (372 received PCV13 first and 373 received PPSV23 first) for immunogenicity.6 Two groups were studied: subjects who received PCV13 first, with a second PCV13 vaccination (PCV13/PCV13), and subjects who received PPSV23 first, with a subsequent PCV13 vaccination (PPSV23/PCV13). Patients who received PPSV23 first had a statistically significant reduction in immunogenicity compared with those who received PCV13 first. The results of these 2 studies show that PCV13, while it protects for fewer serotypes than PPSV23, has greater immunogenicity potential than PPSV23, framing the importance of including PCV13 in pneumococcal vaccine recommendations.
Sequential Administration of PCV13 and PPSV23 Greenberg et al5 conducted a randomized, modified double-blind study in 720 pneumococcal vaccinenaive adults aged 60 to 64 years to evaluate the effect of sequential administration of PCV13 and PPSV23 on the antipneumococcal OPA titers. Patients were randomly assigned to receive either PCV13 followed by a subsequent dose of PCV13 one year later, PCV13 followed by a subsequent dose of PPSV23 one year later, or PPSV23 followed by a subsequent dose of PCV13 one year later. Blood samples were analyzed for titers before and 1 month after administration of each vaccine. The results showed a better OPA
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immune response in patients who received an initial dose of PCV13 followed by a dose of PPSV23 compared with those patients who received an initial dose of PPSV23 followed by a dose of PCV13. Additional studies have evaluated the sequence of conjugated vaccine followed by PPSV23 with the injections separated by variable intervals of 2, 6, 12, and 36 to 48 months. Results from previous trials suggest that the PPSV23 immune response was not improved after administration of the conjugate vaccine (the first pneumococcal conjugate vaccine [PCV7] or PCV13, depending on the year of the trial).4,9,10 Similar to Greenberg et al,5 Jackson et al4 also evaluated the immunogenicity effect of PCV13 administered before and after PPSV23. Specifically, the study examined the immune response after a second dose of a pneumococcal vaccine in 3 groups: PCV13 after a previous PCV13 dose, PPSV23 after a previous PPSV23 dose, and PCV13 after a previous PPSV23 dose. The study was an extension of the previous immunogenicity trial discussed in detail earlier.7 Participants from the previous study who continued with this study included 405 subjects from the original 60- to 64-year-old group and 214 subjects from the 50- to 59-year-old group.4 Those in the older age group were split 1:1 to receive either PPSV23 or PCV13 if they had previously received PCV13, and PPSV23 only if they had previously received PPSV23; those in the younger age group in the initial study received a second dose of PCV13. Antipneumococcal OPA was evaluated to determine immune response to the second immunization. OPA titers were measured before vaccine administration and 1 month after administration. Tolerability was also evaluated at administration through 6 months’ postvaccination. The study found that a second dose of PCV13, given 4 years later, resulted in OPA titers that were significantly higher than those after initial immunization for 7 of the 13 serotypes in the participants in the 60- to 64-year-old group and 6 of the 13 serotypes in the participants in the 50- to 59-year-old group. 4 Most of the other serotypes were found to be noninferior. Alternatively, patients who received a second dose of PPSV23 exhibited lower OPA titers in 9 of the 13 serotypes and noninferior OPA titers for the other serotypes compared with initial immunization with PPSV23. Patients who received PPSV23 after receiving PCV13 demonstrated increased OPA titers in 10 of the 13 serotypes compared with those with initial PPSV23
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Clinical Therapeutics
ACIP Recommendations for use in persons aged ≥65 years
Pneumococcal vaccine-naive persons
Previous vaccination with PPSV23
Administer PCV13 first Administer PPSV23 6 to 12 months later Minimum acceptable time between PCV13 and PPSV23 is 8 weeks Do not coadminister the vaccines
PCV13 should be given at least 12 months after PPSV23 administration Patients who are indicated to receive a second dose of PPSV23 should wait 6 to 12 months after receiving PCV13 and 5 years after receiving their previous dose of PPSV23 Only 1 dose of PCV13 and 1 dose of PPSV23 are indicated in persons aged ≥65 years
Figure 2. Current Advisory Committee on Immunization Practices (ACIP) recommendations for persons Z65 years of age. This figure shows the recommendations for adults aged Z65 years who are either pneumococcal vaccine-naive or who have been previously vaccinated with 23-valent pneumococcal polysaccharide vaccine (PPSV23). PCV13 ¼ 13-valent pneumococcal polysaccharide conjugate vaccine. immunization. The study determined that revaccination with PCV13 or PPSV23 resulted in antipneumococcal recall in adults previously vaccinated with PCV13. Conversely, revaccination with PPSV23 after initial PPSV23 resulted in a lower response than initial vaccination for most serotypes. These data suggest that PCV13 should be administered before PPSV23 to elicit a stronger response in most of the shared serotypes. It is important to note that to-date, no studies have compared the optimal interval between PCV13 and PPSV23 vaccination.
Efficacy of PCV13 in Adults Aged Z65 Years CAPiTA (Community-Acquired Pneumonia Immunization Trial in Adults) was a parallel-group, randomized, placebo-controlled, double-blind study designed to evaluate the efficacy of PCV13 in the prevention of first episode vaccine-type (VT) pneumococcal CAP in healthy adults. CAPiTA was conducted in compliance with requirements set forth by the US Food and Drug Administration as part of an accelerated approval process to address an unmet medical need in older adults, and enrollment began in the fall of 2008.3 Across 75 primary care centers associated with the University Medical Center Utrecht in the Netherlands, researchers enrolled 84,496 pneumococcal vaccine-naive subjects aged Z65 years. Subjects were randomized to receive either PCV13 or placebo.
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Surveillance of the enrolled subjects for the development of CAP and IPD was conducted at 58 hospitals surrounding the areas of enrollment.3,11 The mean time for follow-up was set to exceed 3 years, and observation of study subjects was completed in August 2013. The trial demonstrated that those in the PCV13 arm were 45.6% less likely to develop VT-pneumococcal CAP (CI, 21.8–62.5; P o 0.001). Analysis of secondary outcomes demonstrated 45.0% (CI, 14.2–65.3; P = 0.007) efficacy of PCV13 against VT-nonbacteremic pneumococcal pneumonia and 75.0% (CI, 41.4–90.8; P o 0.007) efficacy against VT-IPD.11 The trial also measured adverse events.11 All participants were monitored for 1 month after vaccination for serious adverse events, and no difference was seen between groups (P ¼ 0.61). A safety subgroup was analyzed to determine the frequency of nonserious adverse events within 1 month of vaccination and serious adverse events for 6 months after vaccination. There were 1006 participants in the PCV13 subgroup and 1005 in the placebo subgroup. There were statistically significantly more adverse events in the PCV13 subgroup than in the placebo subgroup (188 events compared with 144 events; P ¼ 0.01); however, the difference in serious adverse events 6 months after vaccination was not deemed significant (70 events compared with 60 events; P ¼ 0.41). Volume ] Number ]
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FUTURE DIRECTIONS Based on clinical data and disease trends, PCV13 is now recommended for all adults aged Z65 years (Figure 2). This recommendation is in addition to the previous recommendation of vaccinating all adults aged Z65 years with PPSV23. If an adult aged Z65 years has not been vaccinated with either pneumococcal vaccine, PCV13 should be administered first. PPSV23 should be administered 6 to 12 months after administration of PCV13; if that is not possible, PPSV23 can be administered as early as 8 weeks after PCV13. For patients who already have received the PPSV23 immunization, they should wait 12 months before receiving PCV13.8 The most recent recommendation to administer PCV13 to all adults aged Z65 years will be reevaluated by the ACIP in 2018.8 The Centers for Disease Control and Prevention will evaluate the implementation and impact of the new recommendation and continue to monitor trends in CAP and IPD. Monitoring will also be performed to compare the outcomes of those who do get immunized versus those who do not. Although the next review of this information is estimated to be conducted in 2018, the ACIP will continuously monitor information about the pneumococcal vaccines and will change recommendations as necessary.
ACKNOWLEDGMENTS All authors contributed equally to this paper. Katherine Tromp wrote the Abstract, Introduction, Future directions, and Figure 2. Marcus Campbell wrote the Methods and the Table. Alex Vazquez created Figure 1. All three authors contributed equally to the Results.
CONFLICTS OF INTEREST The authors have indicated that they have no conflicts of interest regarding the content of this article.
REFERENCES 1. Centers for Disease Control and Prevention. In: Atkinson W, Wolfe S, Hamborsky J, eds. Epidemiology and Prevention of Vaccine-Preventable Diseases. 12th ed. second printing. Washington, DC: Public Health Foundation; 2012.
2. Huang SS, Johnson KM, Ray GT, et al. Healthcare utilization and cost of pneumococcal disease in the United States. Vaccine. 2011;29:3398–3412. 3. Hak E, Grobbee DE, Sanders EAM, et al. Rationale and design of CAPITA: A RCT of 12-valent conjugated pneumococcal vaccine efficacy among older adults. Neth J Med. 2008;66:378–382. 4. Jackson LA, Gurtman A, van Cleeff M, et al. Influence of initial vaccination with 13-valent pneumococcal conjugate vaccine or 23-valent pneumococcal polysaccharide vaccine on anti-pneumococcal responses following subsequent pneumococcal vaccination in adults 50 years and older. Vaccine. 2013;31:3594–3602. 5. Greenberg RN, Gurtman A, Frenck RW, et al. Sequential administration of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naïve adults 60–64 years of age. Vaccine. 2014;32:2364–2374. 6. Jackson LA, Gurtman A, Rice K, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine in adults 70 years of age and older previously vaccinated with 23-valent pneumococcal polysaccharide vaccine. Vaccine. 2013;31:3585–3593. 7. Jackson LA, Gurtman A, van Cleeff M, et al. Immunogenicity and safety of a 13-valent pneumococcal conjugate vaccine compared to a 23-valent pneumococcal polysaccharide vaccine in pneumococcal vaccine-naïve adults. Vaccine. 2013;31:3577–3584. 8. Tomczyk S, Bennett NM, Stoecker C, et al. Use of 13valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged Z65 years: Recommendations of the Advisory Committee on Immunization Practice (ACIP). MMWR Morb Mortal Wkly Rep. 2014;63:822–825. 9. Goldblatt D, Southern J, Andrews N, et al. The immunogenicity of 7-valent pneumococcal conjugate vaccine versus 23-valent polysaccharide vaccine in adults aged 50-80 years. Clin Infect Dis. 2009;49:1318–1325. 10. Miernyk KM, Butler JC, Bulkow LR, et al. Immunogenicity and reactogenicity of pneumococcal polysaccharide and conjugate vaccines in Alaska native adults 55-70 years of age. Clin Infect Dis. 2009;49:241–248. 11. Bonten MJM, Huijts SM, Bolkenbaas M, et al. Polysaccharide conjugate vaccine against pneumococcal pneumonia in adults. N Engl J Med. 2015;372:1114–1125.
Address correspondence to: Katherine M. Tromp, PharmD, LECOM, 5000 Lakewood Ranch Boulevard, Bradenton, FL 34211. E-mail: ktromp@ lecom.edu
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