The
n e w e ng l a n d j o u r na l
of
m e dic i n e
Original Article
Effects of Vaccination on Invasive Pneumococcal Disease in South Africa Anne von Gottberg, M.B., B.Ch., Ph.D., Linda de Gouveia, N.D., M.T., Stefano Tempia, D.V.M., Ph.D., Vanessa Quan, M.B., B.Ch., M.P.H., Susan Meiring, M.B., Ch.B., Claire von Mollendorf, M.B., B.Ch., Shabir A. Madhi, M.B., B.Ch., Ph.D., Elizabeth R. Zell, M.Stat., Jennifer R. Verani, M.D., M.P.H., Katherine L. O’Brien, M.D., M.P.H., Cynthia G. Whitney, M.D., M.P.H., Keith P. Klugman, M.B., B.Ch., Ph.D., and Cheryl Cohen, M.B., B.Ch., for the GERMS-SA Investigators*
A BS T R AC T BACKGROUND
In South Africa, a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2009 with a three-dose schedule for infants at 6, 14, and 36 weeks of age; a 13-valent vaccine (PCV13) replaced PCV7 in 2011. In 2012, it was estimated that 81% of 12-month-old children had received three doses of vaccine. We assessed the effect of vaccination on invasive pneumococcal disease. METHODS
We conducted national, active, laboratory-based surveillance for invasive pneumococcal disease. We calculated the change in the incidence of the disease from a prevaccine (baseline) period (2005 through 2008) to postvaccine years 2011 and 2012, with a focus on high-risk age groups. RESULTS
Surveillance identified 35,192 cases of invasive pneumococcal disease. The rates among children younger than 2 years of age declined from 54.8 to 17.0 cases per 100,000 person-years from the baseline period to 2012, including a decline from 32.1 to 3.4 cases per 100,000 person-years in disease caused by PCV7 serotypes (−89%; 95% confidence interval [CI], −92 to −86). Among children not infected with the human immunodeficiency virus (HIV), the estimated incidence of invasive pneumococcal disease caused by PCV7 serotypes decreased by 85% (95% CI, −89 to −79), whereas disease caused by nonvaccine serotypes increased by 33% (95% CI, 15 to 48). Among adults 25 to 44 years of age, the rate of PCV7-serotype disease declined by 57% (95% CI, −63 to −50), from 3.7 to 1.6 cases per 100,000 personyears. CONCLUSIONS
Rates of invasive pneumococcal disease among children in South Africa fell substantially by 2012. Reductions in the rates of disease caused by PCV7 serotypes among both children and adults most likely reflect the direct and indirect effects of vaccination. (Funded by the National Institute for Communicable Diseases of the National Health Laboratory Service and others.)
From the Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases (NICD), National Health Laboratory Service (NHLS) (A.G., L.G., V.Q., S.M., C.M., S.A.M., C.C.), Medical Research Council, Respiratory and Meningeal Pathogens Research Unit (A.G., L.G., S.A.M.), and Department of Science and Technology/National Research Foundation, Vaccine-Preventable Diseases (S.A.M.), University of the Witwatersrand — all in Johannesburg; the Influenza Division (S.T.) and Division of Bacterial Diseases (E.R.Z., J.R.V., C.G.W.), Centers for Disease Control and Prevention, and Hubert Department of Global Health, Rollins School of Public Health, and Division of Infectious Diseases, School of Medicine, Emory University (K.P.K.) — all in Atlanta; and the Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore (K.L.O.). Address reprint requests to Dr. von Gottberg at the Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, Private Bag X4, Sandringham, 2131, Gauteng, South Africa, or at annev@nicd .ac.za. *Investigators in the Group for Enteric, Respiratory, and Meningeal Disease Surveillance in South Africa (GERMS-SA) are listed in the Supplementary Appendix, available at NEJM.org. N Engl J Med 2014;371:1889-99. DOI: 10.1056/NEJMoa1401914 Copyright © 2014 Massachusetts Medical Society.
n engl j med 371;20 nejm.org November 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at THE UNIVERSITY OF IOWA on November 13, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1889
The
T
n e w e ng l a n d j o u r na l
he majority of deaths associated with childhood pneumococcal disease occur in Africa.1,2 In randomized trials conducted in Africa,3,4 a pneumococcal conjugate vaccine (PCV) was given to infants when they were 6, 10, and 14 weeks of age, without a booster dose. The vaccine showed efficacy for the prevention of invasive pneumococcal disease caused by the nine serotypes contained in the vaccine among infants who were not infected with the human immunodeficiency virus (HIV) (83% efficacy; 95% confidence interval [CI], 39 to 97) and among infants who were infected with HIV (65% efficacy; 95% CI, 24 to 86).3,5 In 2009, South Africa became the first African country to incorporate vaccination with PCV in its routine infant immunization program.6 The 7-valent PCV (PCV7) was introduced with the use of a novel threedose schedule, with two primary doses, given to infants at 6 and 14 weeks of age, and a booster given at 9 months of age. In April 2011, a 13-valent PCV (PCV13) replaced PCV7. The direct and indirect benefits of PCV7 — the reduction in disease among young children who receive the vaccine7,8 and among older children and adults,8-10 respectively — have been seen in many high-income countries. Most antibioticresistant pneumococci are of serotypes contained in PCVs; thus, reductions in rates of antibioticresistant invasive pneumococcal disease are seen after the introduction of PCVs.11,12 Children in African countries, however, have higher rates of pneumococcal disease and serotype carriage than children in other countries13; therefore, the benefits of PCV may be different. In addition, indirect effects may be attenuated among persons in African countries who have coexisting diseases, such as HIV infection.14 In a case–control study in South Africa, the estimated effectiveness of three or more doses of PCV7 in preventing invasive pneumococcal disease caused by PCV7 serotypes was 90% (95% CI, 14 to 99) among HIVuninfected children but only 57% (95% CI, −371 to 96) among HIV-infected children.15 In 2008, HIV-infected children younger than 1 year of age had a higher rate of invasive pneumococcal disease–associated hospitalizations than did HIVuninfected children, by a factor of approximately 20.16,17 In South Africa, the group at secondhighest risk for invasive pneumococcal disease,
1890
of
m e dic i n e
after young children, are persons 25 to 44 years of age who have HIV infection.17-19 Benefits of PCV for the total population of a country in Africa and a population with a high prevalence of HIV infection have not yet been reported. Before 2009, at one sentinel site in South Africa, the rate of invasive pneumococcal disease decreased by 41% among HIV-infected children who were younger than 2 years of age; the decrease was attributed to treatment of HIV infection.16 The additional benefit of PCV in the prevention of pneumococcal disease beyond the benefits afforded by HIV programs is unknown. The Group for Enteric, Respiratory, and Meningeal Disease Surveillance in South Africa (GERMS-SA) conducted a surveillance study to estimate the effect of PCV introduction on HIV-infected and HIV-uninfected persons in South Africa.
Me thods Population under Surveillance
We used observational data to examine trends in the rates of invasive pneumococcal disease in all age groups before and after the introduction of PCV, with stratification according to HIV status. In 2012, the population of South Africa was approximately 52 million; 4% (approximately 2 million persons) were younger than 2 years of age, and 31% (approximately 16 million) were 25 to 44 years of age.20 HIV prevalence among pregnant women was stable, at 30%, from 2004 through 2012.21,22 HIV infection rates among infants younger than 2 months of age who were born to HIV-infected women declined from 9.6% in 2008 to 2.8% in 2011, as a result of improved prevention of mother-to-child transmission.21 Since the implementation of comprehensive HIV–AIDS treatment programs in 2003, access to antiretroviral treatment (ART) has steadily improved.23 Estimates of the percentage of infants who received the third dose of PCV before they were 12 months of age are 10% for 2009, 64% for 2010, 72% for 2011, and 81% for 2012.24 Surveillance for Invasive Pneumococcal Disease
Laboratory-based surveillance for invasive pneumococcal disease in South Africa began in 1999.25 Since 2003, enhanced surveillance at 24 sentinel
n engl j med 371;20 nejm.org November 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at THE UNIVERSITY OF IOWA on November 13, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
Vaccination and Pneumococcal Disease in South Africa
hospitals located in all nine provinces has involved the collection of additional information, including admission date, HIV serologic status, discharge diagnosis, and outcome (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Persons with invasive pneumococcal disease were defined as hospitalized persons from whom Streptococcus pneumoniae was cultured from specimens that are normally sterile (e.g., cerebrospinal fluid, blood, or joint fluid) sometime during the period from January 2005 through December 2012. Duplicate isolates cultured within 21 days after the initial positive culture were excluded. Serotyping and Susceptibility Testing
Pneumococci were serotyped with the use of the quellung reaction (Statens Serum Institut). Serotype 6C was distinguished from 6A throughout.26 We determined antimicrobial minimum inhibitory concentrations (MICs) with the use of broth microdilution methods. Isolates were classified as nonsusceptible if the MICs for penicillin were at least 0.12 mg per liter and those for ceftriaxone were at least 1 mg per liter.27 Multidrug resistance was classified as nonsusceptibility to three or more of the following drug classes: chloramphenicol, tetracycline, rifampin, trimethoprim–sulfamethoxazole, penicillin or ceftriaxone, and erythromycin or clindamycin. Study Oversight
The study was approved by the research ethics committee at the University of the Witwatersrand, Johannesburg, South Africa. The study protocol was also approved by local hospital or provincial ethics committees, as required. All authors vouch for the completeness and accuracy of the data and analyses presented. There was no commercial support for this study. Statistical Analysis
For analysis of trends, serotypes were categorized as PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F); 6A, analyzed separately to confirm previously described cross-protection28; PCV13 serotypes not included in PCV7 (1, 3, 5, 7F, and 19A); and nonvaccine serotypes (all serotypes not in PCV13). We assumed that the age-specific proportion of serotypes and antimicrobial suscepti-
bility among cases of disease with missing pneumococcal isolates was the same as the proportion among cases with available data each year.7,29 We imputed the HIV-infection status for patients with invasive pneumococcal disease who were not tested for HIV at enhanced-surveillance sites from 2008 through 2012 (see the Supplementary Appendix). We then estimated the age-specific, year-specific, and serotype-specific relative risk of hospitalization for invasive pneumococcal disease due to HIV infection from 2008 through 2012. We used the age-specific and serotype-specific estimates of relative risk for 2008 to estimate the age-specific, year-specific, and serotype-specific numbers of HIV-positive persons and HIV-negative persons among the cases of invasive pneumococcal disease identified in South Africa from 2005 through 2007. We calculated the age-stratified annual incidence of invasive pneumococcal disease (overall and HIV-specific) per 100,000 people by dividing the number of cases of invasive pneumococcal disease by the midyear population estimates and multiplying the quotient by 100,000.20,30 We assessed the effect of the introduction of PCV7 on invasive pneumococcal disease, focusing a priori on persons younger than 2 years of age (vaccinated age group) and those 25 to 44 years of age (the group with the highest rates of adult invasive pneumococcal disease in South Africa and the earliest indirect effects of the vaccine29), by calculating the percentage change in the rate of invasive pneumococcal disease and the absolute difference between the average rate in the period before vaccination (2005–2008) and the rate in each of the two postvaccine years (2011 and 2012). We excluded the PCV introduction period of 2009–2010. To estimate the effect of PCV7, we included analyses for 2011 (during which there was minimal use of PCV13). For overall populations and for HIV-infected populations, we measured the difference between changes in the rates of invasive pneumococcal disease caused by PCV7 serotypes and changes in the rates of disease caused by nonvaccine serotypes in an attempt to account for the effects of ART from 2008 through 2012. We assumed that PCV would not cause reductions in the rates of invasive pneumococcal disease caused by nonvaccine serotypes and that increases in nonvaccine sero-
n engl j med 371;20 nejm.org November 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at THE UNIVERSITY OF IOWA on November 13, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1891
The
n e w e ng l a n d j o u r na l
types (replacement disease) were unlikely to be substantial this early in the PCV program.16 The difference in rates and the associated 95% confidence intervals were used to assess the significance of the observed changes in invasive pneumococcal disease. The chi-square test was used to evaluate differences in proportions. Twosided P values of less than 0.05 were considered to indicate statistical significance. Stata software, version 12 (StataCorp), was used for analysis.
R e sult s Overall Incidence of Invasive Pneumococcal Disease
During the 8-year study period (2005 through 2012), we identified a total of 35,192 cases of invasive pneumococcal disease. Isolates were available for 24,552 (70%) (Fig. S1 in the Supplementary Appendix). Age was unknown for 1648 cases (5%). The rate of invasive pneumococcal disease among all ages dropped from 9.4 cases per 100,000 person-years in the pre-PCV (baseline) period (2005 through 2008) to 5.7 cases per 100,000 person-years in 2012 (−40%; 95% confidence interval [CI], −42 to −37). The largest absolute differences and percentage changes in rates occurred among persons younger than 2 years of age and among those 25 to 44 years of age (Table 1 and Fig. 1). Changes in the Incidence of Invasive Pneumococcal Disease among Children Younger than 2 Years of Age
Among children younger than 2 years of age, the incidence of invasive pneumococcal disease (all serotypes combined) declined by 69% (95% CI, −72 to −65), from 54.8 cases per 100,000 personyears in the baseline period to 17.0 cases per 100,000 in 2012 (Table 1 and Fig. 1A and 2A). The greatest declines were in the incidence of PCV7-serotype disease (−89%; 95% CI, −92 to −86), with each PCV7 serotype and vaccine-related serotype 6A declining significantly from the baseline period to 2011. Comparing the baseline period with 2012, there was a nonsignificant increase of 6% (95% CI, −16 to 23) in the incidence of disease caused by nonvaccine serotypes. By 2012, the incidence of disease caused by PCV13 serotypes not included in PCV7 had declined significantly among children (−57%; 95% CI, −68 to −42), driven by declines in serotype 19A 1892
of
m e dic i n e
(−70%; 95% CI, −81 to −55) (Table S2 in the Supplementary Appendix). The only other PCV13 serotype that changed significantly in 2012 as compared with the baseline period was serotype 1 (−57%; 95% CI, −79 to −16). Among children younger than 10 weeks of age, disease rates decreased by 36% (95% CI, −50 to −17), from 87.8 to 56.6 cases per 100,000 person-years; the largest decline was in PCV7-serotype disease (−78%; 95% CI, −88 to −60), whereas rates of disease caused by nonvaccine serotypes did not change significantly (an increase of 2%; 95% CI, −49 to 36) (Fig. S2 in the Supplementary Appendix). Among HIV-uninfected children younger than 2 years of age, the incidence of invasive pneumococcal disease caused by PCV7 serotypes decreased by 85% (95% CI, −89 to −79) from baseline to 2012, whereas the incidence of disease caused by nonvaccine serotypes increased by 33% (95% CI, 15 to 48) (Fig. 3A, and Table S4 in the Supplementary Appendix). Among HIVinfected children, the incidence of PCV7-serotype disease declined by 86% (95% CI, −91 to −78), which was similar to the decline among HIVuninfected children, but the rate of disease was 25 times as high as the rate among HIV-uninfected children. The incidence of disease caused by nonvaccine serotypes did not change significantly among HIV-infected children. The absolute differences in the percent reductions in PCV7-serotype disease and nonvaccine-serotype disease among HIV-infected children younger than 2 years of age were 38 percentage points (77% minus 39%) in 2011 and 55 percentage points (86% minus 31%) in 2012. Changes in the Incidence of Invasive Pneumococcal Disease among Adults 25 to 44 Years of Age
From the baseline period to 2012, significant reductions were observed in the incidence of invasive pneumococcal disease (all serotypes combined) among persons 25 to 44 years of age (−34%; 95% CI, −39 to −29) (Table 1 and Fig. 1B and 2B), driven mostly by reductions in PCV7serotype disease (−57%; 95% CI, −63 to −50). The incidence of disease caused by all individual PCV7 serotypes and vaccine-related serotype 6A declined significantly (Table S3 in the Supplementary Appendix). Decreases in nonvaccineserotype disease were not significant (Table 1). Significant reductions were observed in the rates
n engl j med 371;20 nejm.org November 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at THE UNIVERSITY OF IOWA on November 13, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
131 (6.3)
156 (7.5)
186 (8.9)
Serotype 6A
Additional PCV13 serotypes†
Nonvaccine serotypes
1142 (54.8)
669 (32.1)
559 (3.9)
Nonvaccine serotypes
519 (3.3)
511 (3.3)
117 (0.7)
369 (2.3)
1516 (9.6)
155 (7.1)
126 (5.8)
52 (2.4)
138 (6.4)
470 (21.7)
555 (3.5)
384 (2.4)
66 (0.4)
257 (1.6)
1262 (7.9)
205 (9.5)
70 (3.2)
20 (0.9)
74 (3.4)
369 (17.0)
2012
−0.6 (−1.0 to −0.1)
−0.3 (−0.7 to 0.2)
−0.02 (−0.2 to 0.2)
−1.4 (−1.8 to −1.0)
−2.2 (−3.0 to −1.5)
−1.8 (−3.5 to −0.6)
−1.7 (−3.2 to −0.1)
−3.9 (−5.2 to −2.6)
−25.8 (−28.4 to −23.1)
−33.1 (−36.9 to −29.4)
cases/100,000 person-yr (95% CI)
Absolute Difference in Rate
−15 (−25 to −4)
−7 (−18 to 5)
−3 (−26 to 28)
−37 (−45 to −28)
−18 (−24 to −13)
−20 (−36 to −0.2)
−22 (−39 to −1)
−62 (−73 to −47)
−80 (−84 to −76)
−60 (−65 to −56)
% (95% CI)
Relative Difference in Rate
Baseline to 2011
−0.4 (−0.9 to 0.01)
−1.1 (−1.5 to −0.2)
−0.4 (−0.5 to −0.2)
−2.1 (−2.5 to −1.8)
−4.0 (−4.7 to −3.3)
0.5 (−1.3 to +2.4)
−4.3 (−5.7 to −2.9)
−5.4 (−6.5 to −4.2)
−28.7 (−31.3 to −26.2)
−37.8 (−41.4 to −34.2)
cases/100,000 person-yr (95% CI)
Absolute Difference in Rate
−11 (−21 to 4)
−32 (−40 to −22)
−46 (−61 to −26)
−57 (−63 to −50)
−34 (−39 to −29)
6 (−16 to 23)
−57 (−68 to −42)
−85 (−91 to −76)
−89 (−92 to −86)
−69 (−72 to −65)
% (95% CI)
Relative Difference in Rate
Baseline to 2012
* The rate of disease is the number of cases per 100,000 person-years. The baseline case numbers and rates were calculated as the average of the numbers and rates during the prevaccine period (2005 through 2008). The 7-valent pneumococcal vaccine (PCV7) was introduced in 2009, and the 13-valent pneumococcal vaccine (PCV13) was introduced in 2011. † Additional PCV13 serotypes are PCV13 serotypes not included in PCV7.
110 (0.8)
505 (3.5)
Additional PCV13 serotypes†
537 (3.7)
PCV7 serotypes
Serotype 6A
1712 (11.9)
All serotypes
25–44 yr
2011
no. of cases (cases/100,000 person-yr)
Baseline
PCV7 serotypes
All serotypes
n e w e ng l a n d j o u r na l
of
m e dic i n e
Original Article
Effects of Vaccination on Invasive Pneumococcal Disease in South Africa Anne von Gottberg, M.B., B.Ch., Ph.D., Linda de Gouveia, N.D., M.T., Stefano Tempia, D.V.M., Ph.D., Vanessa Quan, M.B., B.Ch., M.P.H., Susan Meiring, M.B., Ch.B., Claire von Mollendorf, M.B., B.Ch., Shabir A. Madhi, M.B., B.Ch., Ph.D., Elizabeth R. Zell, M.Stat., Jennifer R. Verani, M.D., M.P.H., Katherine L. O’Brien, M.D., M.P.H., Cynthia G. Whitney, M.D., M.P.H., Keith P. Klugman, M.B., B.Ch., Ph.D., and Cheryl Cohen, M.B., B.Ch., for the GERMS-SA Investigators*
A BS T R AC T BACKGROUND
In South Africa, a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2009 with a three-dose schedule for infants at 6, 14, and 36 weeks of age; a 13-valent vaccine (PCV13) replaced PCV7 in 2011. In 2012, it was estimated that 81% of 12-month-old children had received three doses of vaccine. We assessed the effect of vaccination on invasive pneumococcal disease. METHODS
We conducted national, active, laboratory-based surveillance for invasive pneumococcal disease. We calculated the change in the incidence of the disease from a prevaccine (baseline) period (2005 through 2008) to postvaccine years 2011 and 2012, with a focus on high-risk age groups. RESULTS
Surveillance identified 35,192 cases of invasive pneumococcal disease. The rates among children younger than 2 years of age declined from 54.8 to 17.0 cases per 100,000 person-years from the baseline period to 2012, including a decline from 32.1 to 3.4 cases per 100,000 person-years in disease caused by PCV7 serotypes (−89%; 95% confidence interval [CI], −92 to −86). Among children not infected with the human immunodeficiency virus (HIV), the estimated incidence of invasive pneumococcal disease caused by PCV7 serotypes decreased by 85% (95% CI, −89 to −79), whereas disease caused by nonvaccine serotypes increased by 33% (95% CI, 15 to 48). Among adults 25 to 44 years of age, the rate of PCV7-serotype disease declined by 57% (95% CI, −63 to −50), from 3.7 to 1.6 cases per 100,000 personyears. CONCLUSIONS
Rates of invasive pneumococcal disease among children in South Africa fell substantially by 2012. Reductions in the rates of disease caused by PCV7 serotypes among both children and adults most likely reflect the direct and indirect effects of vaccination. (Funded by the National Institute for Communicable Diseases of the National Health Laboratory Service and others.)
From the Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases (NICD), National Health Laboratory Service (NHLS) (A.G., L.G., V.Q., S.M., C.M., S.A.M., C.C.), Medical Research Council, Respiratory and Meningeal Pathogens Research Unit (A.G., L.G., S.A.M.), and Department of Science and Technology/National Research Foundation, Vaccine-Preventable Diseases (S.A.M.), University of the Witwatersrand — all in Johannesburg; the Influenza Division (S.T.) and Division of Bacterial Diseases (E.R.Z., J.R.V., C.G.W.), Centers for Disease Control and Prevention, and Hubert Department of Global Health, Rollins School of Public Health, and Division of Infectious Diseases, School of Medicine, Emory University (K.P.K.) — all in Atlanta; and the Johns Hopkins Bloomberg School of Public Health, Johns Hopkins University, Baltimore (K.L.O.). Address reprint requests to Dr. von Gottberg at the Centre for Respiratory Diseases and Meningitis, National Institute for Communicable Diseases, Private Bag X4, Sandringham, 2131, Gauteng, South Africa, or at annev@nicd .ac.za. *Investigators in the Group for Enteric, Respiratory, and Meningeal Disease Surveillance in South Africa (GERMS-SA) are listed in the Supplementary Appendix, available at NEJM.org. N Engl J Med 2014;371:1889-99. DOI: 10.1056/NEJMoa1401914 Copyright © 2014 Massachusetts Medical Society.
n engl j med 371;20 nejm.org November 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at THE UNIVERSITY OF IOWA on November 13, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1889
The
T
n e w e ng l a n d j o u r na l
he majority of deaths associated with childhood pneumococcal disease occur in Africa.1,2 In randomized trials conducted in Africa,3,4 a pneumococcal conjugate vaccine (PCV) was given to infants when they were 6, 10, and 14 weeks of age, without a booster dose. The vaccine showed efficacy for the prevention of invasive pneumococcal disease caused by the nine serotypes contained in the vaccine among infants who were not infected with the human immunodeficiency virus (HIV) (83% efficacy; 95% confidence interval [CI], 39 to 97) and among infants who were infected with HIV (65% efficacy; 95% CI, 24 to 86).3,5 In 2009, South Africa became the first African country to incorporate vaccination with PCV in its routine infant immunization program.6 The 7-valent PCV (PCV7) was introduced with the use of a novel threedose schedule, with two primary doses, given to infants at 6 and 14 weeks of age, and a booster given at 9 months of age. In April 2011, a 13-valent PCV (PCV13) replaced PCV7. The direct and indirect benefits of PCV7 — the reduction in disease among young children who receive the vaccine7,8 and among older children and adults,8-10 respectively — have been seen in many high-income countries. Most antibioticresistant pneumococci are of serotypes contained in PCVs; thus, reductions in rates of antibioticresistant invasive pneumococcal disease are seen after the introduction of PCVs.11,12 Children in African countries, however, have higher rates of pneumococcal disease and serotype carriage than children in other countries13; therefore, the benefits of PCV may be different. In addition, indirect effects may be attenuated among persons in African countries who have coexisting diseases, such as HIV infection.14 In a case–control study in South Africa, the estimated effectiveness of three or more doses of PCV7 in preventing invasive pneumococcal disease caused by PCV7 serotypes was 90% (95% CI, 14 to 99) among HIVuninfected children but only 57% (95% CI, −371 to 96) among HIV-infected children.15 In 2008, HIV-infected children younger than 1 year of age had a higher rate of invasive pneumococcal disease–associated hospitalizations than did HIVuninfected children, by a factor of approximately 20.16,17 In South Africa, the group at secondhighest risk for invasive pneumococcal disease,
1890
of
m e dic i n e
after young children, are persons 25 to 44 years of age who have HIV infection.17-19 Benefits of PCV for the total population of a country in Africa and a population with a high prevalence of HIV infection have not yet been reported. Before 2009, at one sentinel site in South Africa, the rate of invasive pneumococcal disease decreased by 41% among HIV-infected children who were younger than 2 years of age; the decrease was attributed to treatment of HIV infection.16 The additional benefit of PCV in the prevention of pneumococcal disease beyond the benefits afforded by HIV programs is unknown. The Group for Enteric, Respiratory, and Meningeal Disease Surveillance in South Africa (GERMS-SA) conducted a surveillance study to estimate the effect of PCV introduction on HIV-infected and HIV-uninfected persons in South Africa.
Me thods Population under Surveillance
We used observational data to examine trends in the rates of invasive pneumococcal disease in all age groups before and after the introduction of PCV, with stratification according to HIV status. In 2012, the population of South Africa was approximately 52 million; 4% (approximately 2 million persons) were younger than 2 years of age, and 31% (approximately 16 million) were 25 to 44 years of age.20 HIV prevalence among pregnant women was stable, at 30%, from 2004 through 2012.21,22 HIV infection rates among infants younger than 2 months of age who were born to HIV-infected women declined from 9.6% in 2008 to 2.8% in 2011, as a result of improved prevention of mother-to-child transmission.21 Since the implementation of comprehensive HIV–AIDS treatment programs in 2003, access to antiretroviral treatment (ART) has steadily improved.23 Estimates of the percentage of infants who received the third dose of PCV before they were 12 months of age are 10% for 2009, 64% for 2010, 72% for 2011, and 81% for 2012.24 Surveillance for Invasive Pneumococcal Disease
Laboratory-based surveillance for invasive pneumococcal disease in South Africa began in 1999.25 Since 2003, enhanced surveillance at 24 sentinel
n engl j med 371;20 nejm.org November 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at THE UNIVERSITY OF IOWA on November 13, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
Vaccination and Pneumococcal Disease in South Africa
hospitals located in all nine provinces has involved the collection of additional information, including admission date, HIV serologic status, discharge diagnosis, and outcome (see the Supplementary Appendix, available with the full text of this article at NEJM.org). Persons with invasive pneumococcal disease were defined as hospitalized persons from whom Streptococcus pneumoniae was cultured from specimens that are normally sterile (e.g., cerebrospinal fluid, blood, or joint fluid) sometime during the period from January 2005 through December 2012. Duplicate isolates cultured within 21 days after the initial positive culture were excluded. Serotyping and Susceptibility Testing
Pneumococci were serotyped with the use of the quellung reaction (Statens Serum Institut). Serotype 6C was distinguished from 6A throughout.26 We determined antimicrobial minimum inhibitory concentrations (MICs) with the use of broth microdilution methods. Isolates were classified as nonsusceptible if the MICs for penicillin were at least 0.12 mg per liter and those for ceftriaxone were at least 1 mg per liter.27 Multidrug resistance was classified as nonsusceptibility to three or more of the following drug classes: chloramphenicol, tetracycline, rifampin, trimethoprim–sulfamethoxazole, penicillin or ceftriaxone, and erythromycin or clindamycin. Study Oversight
The study was approved by the research ethics committee at the University of the Witwatersrand, Johannesburg, South Africa. The study protocol was also approved by local hospital or provincial ethics committees, as required. All authors vouch for the completeness and accuracy of the data and analyses presented. There was no commercial support for this study. Statistical Analysis
For analysis of trends, serotypes were categorized as PCV7 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F); 6A, analyzed separately to confirm previously described cross-protection28; PCV13 serotypes not included in PCV7 (1, 3, 5, 7F, and 19A); and nonvaccine serotypes (all serotypes not in PCV13). We assumed that the age-specific proportion of serotypes and antimicrobial suscepti-
bility among cases of disease with missing pneumococcal isolates was the same as the proportion among cases with available data each year.7,29 We imputed the HIV-infection status for patients with invasive pneumococcal disease who were not tested for HIV at enhanced-surveillance sites from 2008 through 2012 (see the Supplementary Appendix). We then estimated the age-specific, year-specific, and serotype-specific relative risk of hospitalization for invasive pneumococcal disease due to HIV infection from 2008 through 2012. We used the age-specific and serotype-specific estimates of relative risk for 2008 to estimate the age-specific, year-specific, and serotype-specific numbers of HIV-positive persons and HIV-negative persons among the cases of invasive pneumococcal disease identified in South Africa from 2005 through 2007. We calculated the age-stratified annual incidence of invasive pneumococcal disease (overall and HIV-specific) per 100,000 people by dividing the number of cases of invasive pneumococcal disease by the midyear population estimates and multiplying the quotient by 100,000.20,30 We assessed the effect of the introduction of PCV7 on invasive pneumococcal disease, focusing a priori on persons younger than 2 years of age (vaccinated age group) and those 25 to 44 years of age (the group with the highest rates of adult invasive pneumococcal disease in South Africa and the earliest indirect effects of the vaccine29), by calculating the percentage change in the rate of invasive pneumococcal disease and the absolute difference between the average rate in the period before vaccination (2005–2008) and the rate in each of the two postvaccine years (2011 and 2012). We excluded the PCV introduction period of 2009–2010. To estimate the effect of PCV7, we included analyses for 2011 (during which there was minimal use of PCV13). For overall populations and for HIV-infected populations, we measured the difference between changes in the rates of invasive pneumococcal disease caused by PCV7 serotypes and changes in the rates of disease caused by nonvaccine serotypes in an attempt to account for the effects of ART from 2008 through 2012. We assumed that PCV would not cause reductions in the rates of invasive pneumococcal disease caused by nonvaccine serotypes and that increases in nonvaccine sero-
n engl j med 371;20 nejm.org November 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at THE UNIVERSITY OF IOWA on November 13, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
1891
The
n e w e ng l a n d j o u r na l
types (replacement disease) were unlikely to be substantial this early in the PCV program.16 The difference in rates and the associated 95% confidence intervals were used to assess the significance of the observed changes in invasive pneumococcal disease. The chi-square test was used to evaluate differences in proportions. Twosided P values of less than 0.05 were considered to indicate statistical significance. Stata software, version 12 (StataCorp), was used for analysis.
R e sult s Overall Incidence of Invasive Pneumococcal Disease
During the 8-year study period (2005 through 2012), we identified a total of 35,192 cases of invasive pneumococcal disease. Isolates were available for 24,552 (70%) (Fig. S1 in the Supplementary Appendix). Age was unknown for 1648 cases (5%). The rate of invasive pneumococcal disease among all ages dropped from 9.4 cases per 100,000 person-years in the pre-PCV (baseline) period (2005 through 2008) to 5.7 cases per 100,000 person-years in 2012 (−40%; 95% confidence interval [CI], −42 to −37). The largest absolute differences and percentage changes in rates occurred among persons younger than 2 years of age and among those 25 to 44 years of age (Table 1 and Fig. 1). Changes in the Incidence of Invasive Pneumococcal Disease among Children Younger than 2 Years of Age
Among children younger than 2 years of age, the incidence of invasive pneumococcal disease (all serotypes combined) declined by 69% (95% CI, −72 to −65), from 54.8 cases per 100,000 personyears in the baseline period to 17.0 cases per 100,000 in 2012 (Table 1 and Fig. 1A and 2A). The greatest declines were in the incidence of PCV7-serotype disease (−89%; 95% CI, −92 to −86), with each PCV7 serotype and vaccine-related serotype 6A declining significantly from the baseline period to 2011. Comparing the baseline period with 2012, there was a nonsignificant increase of 6% (95% CI, −16 to 23) in the incidence of disease caused by nonvaccine serotypes. By 2012, the incidence of disease caused by PCV13 serotypes not included in PCV7 had declined significantly among children (−57%; 95% CI, −68 to −42), driven by declines in serotype 19A 1892
of
m e dic i n e
(−70%; 95% CI, −81 to −55) (Table S2 in the Supplementary Appendix). The only other PCV13 serotype that changed significantly in 2012 as compared with the baseline period was serotype 1 (−57%; 95% CI, −79 to −16). Among children younger than 10 weeks of age, disease rates decreased by 36% (95% CI, −50 to −17), from 87.8 to 56.6 cases per 100,000 person-years; the largest decline was in PCV7-serotype disease (−78%; 95% CI, −88 to −60), whereas rates of disease caused by nonvaccine serotypes did not change significantly (an increase of 2%; 95% CI, −49 to 36) (Fig. S2 in the Supplementary Appendix). Among HIV-uninfected children younger than 2 years of age, the incidence of invasive pneumococcal disease caused by PCV7 serotypes decreased by 85% (95% CI, −89 to −79) from baseline to 2012, whereas the incidence of disease caused by nonvaccine serotypes increased by 33% (95% CI, 15 to 48) (Fig. 3A, and Table S4 in the Supplementary Appendix). Among HIVinfected children, the incidence of PCV7-serotype disease declined by 86% (95% CI, −91 to −78), which was similar to the decline among HIVuninfected children, but the rate of disease was 25 times as high as the rate among HIV-uninfected children. The incidence of disease caused by nonvaccine serotypes did not change significantly among HIV-infected children. The absolute differences in the percent reductions in PCV7-serotype disease and nonvaccine-serotype disease among HIV-infected children younger than 2 years of age were 38 percentage points (77% minus 39%) in 2011 and 55 percentage points (86% minus 31%) in 2012. Changes in the Incidence of Invasive Pneumococcal Disease among Adults 25 to 44 Years of Age
From the baseline period to 2012, significant reductions were observed in the incidence of invasive pneumococcal disease (all serotypes combined) among persons 25 to 44 years of age (−34%; 95% CI, −39 to −29) (Table 1 and Fig. 1B and 2B), driven mostly by reductions in PCV7serotype disease (−57%; 95% CI, −63 to −50). The incidence of disease caused by all individual PCV7 serotypes and vaccine-related serotype 6A declined significantly (Table S3 in the Supplementary Appendix). Decreases in nonvaccineserotype disease were not significant (Table 1). Significant reductions were observed in the rates
n engl j med 371;20 nejm.org November 13, 2014
The New England Journal of Medicine Downloaded from nejm.org at THE UNIVERSITY OF IOWA on November 13, 2014. For personal use only. No other uses without permission. Copyright © 2014 Massachusetts Medical Society. All rights reserved.
131 (6.3)
156 (7.5)
186 (8.9)
Serotype 6A
Additional PCV13 serotypes†
Nonvaccine serotypes
1142 (54.8)
669 (32.1)
559 (3.9)
Nonvaccine serotypes
519 (3.3)
511 (3.3)
117 (0.7)
369 (2.3)
1516 (9.6)
155 (7.1)
126 (5.8)
52 (2.4)
138 (6.4)
470 (21.7)
555 (3.5)
384 (2.4)
66 (0.4)
257 (1.6)
1262 (7.9)
205 (9.5)
70 (3.2)
20 (0.9)
74 (3.4)
369 (17.0)
2012
−0.6 (−1.0 to −0.1)
−0.3 (−0.7 to 0.2)
−0.02 (−0.2 to 0.2)
−1.4 (−1.8 to −1.0)
−2.2 (−3.0 to −1.5)
−1.8 (−3.5 to −0.6)
−1.7 (−3.2 to −0.1)
−3.9 (−5.2 to −2.6)
−25.8 (−28.4 to −23.1)
−33.1 (−36.9 to −29.4)
cases/100,000 person-yr (95% CI)
Absolute Difference in Rate
−15 (−25 to −4)
−7 (−18 to 5)
−3 (−26 to 28)
−37 (−45 to −28)
−18 (−24 to −13)
−20 (−36 to −0.2)
−22 (−39 to −1)
−62 (−73 to −47)
−80 (−84 to −76)
−60 (−65 to −56)
% (95% CI)
Relative Difference in Rate
Baseline to 2011
−0.4 (−0.9 to 0.01)
−1.1 (−1.5 to −0.2)
−0.4 (−0.5 to −0.2)
−2.1 (−2.5 to −1.8)
−4.0 (−4.7 to −3.3)
0.5 (−1.3 to +2.4)
−4.3 (−5.7 to −2.9)
−5.4 (−6.5 to −4.2)
−28.7 (−31.3 to −26.2)
−37.8 (−41.4 to −34.2)
cases/100,000 person-yr (95% CI)
Absolute Difference in Rate
−11 (−21 to 4)
−32 (−40 to −22)
−46 (−61 to −26)
−57 (−63 to −50)
−34 (−39 to −29)
6 (−16 to 23)
−57 (−68 to −42)
−85 (−91 to −76)
−89 (−92 to −86)
−69 (−72 to −65)
% (95% CI)
Relative Difference in Rate
Baseline to 2012
* The rate of disease is the number of cases per 100,000 person-years. The baseline case numbers and rates were calculated as the average of the numbers and rates during the prevaccine period (2005 through 2008). The 7-valent pneumococcal vaccine (PCV7) was introduced in 2009, and the 13-valent pneumococcal vaccine (PCV13) was introduced in 2011. † Additional PCV13 serotypes are PCV13 serotypes not included in PCV7.
110 (0.8)
505 (3.5)
Additional PCV13 serotypes†
537 (3.7)
PCV7 serotypes
Serotype 6A
1712 (11.9)
All serotypes
25–44 yr
2011
no. of cases (cases/100,000 person-yr)
Baseline
PCV7 serotypes
All serotypes
