Effects of Vaccination on Invasive Pneumococcal Disease in South Africa

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1 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* ABSTRACT BACKGROUND In South Africa, a 7-valent pneumococcal conjugate vaccine () was introduced in 29 with a three-dose schedule for infants at 6, 14, and 36 weeks of age; a 13-valent vaccine () replaced in 211. In 212, 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 (25 through 28) to postvaccine years 211 and 212, 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. cases per 1, person-years from the baseline period to 212, including a decline from 32.1 to 3.4 cases per 1, person-years in disease caused by 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 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 -serotype disease declined by 57% (95% CI, 63 to 5), from 3.7 to 1.6 cases per 1, personyears. CONCLUSIONS Rates of invasive pneumococcal disease among children in South Africa fell substantially by 212. Reductions in the rates of disease caused by 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 214;371: DOI: 1.156/NEJMoa Copyright 214 Massachusetts Medical Society. n engl j med 371;2 nejm.org November 13,

2 The 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, 1, 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 29, South Africa became the first African country to incorporate vaccination with PCV in its routine infant immunization program. 6 The 7-valent PCV () 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 211, a 13-valent PCV () replaced. The direct and indirect benefits of the reduction in disease among young children who receive the vaccine 7,8 and among older children and adults, 8-1 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 countries 13 ; 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 in preventing invasive pneumococcal disease caused by serotypes was 9% (95% CI, 14 to 99) among HIVuninfected children but only 57% (95% CI, 371 to 96) among HIV-infected children. 15 In 28, 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 2. 16,17 In South Africa, the group at secondhighest risk for invasive pneumococcal disease, after young children, are persons 25 to 44 years of age who have HIV infection 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 29, 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. Methods 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 212, 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. 2 HIV prevalence among pregnant women was stable, at 3%, from 24 through ,22 HIV infection rates among infants younger than 2 months of age who were born to HIV-infected women declined from 9.6% in 28 to 2.8% in 211, as a result of improved prevention of mother-to-child transmission. 21 Since the implementation of comprehensive HIV AIDS treatment programs in 23, 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 1% for 29, 64% for 21, 72% for 211, and 81% for Surveillance for Invasive Pneumococcal Disease Laboratory-based surveillance for invasive pneumococcal disease in South Africa began in Since 23, enhanced surveillance at 24 sentinel 189 n engl j med 371;2 nejm.org November 13, 214

3 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 25 through December 212. 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.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 serotypes (4, 6B, 9V, 14, 18C, 19F, and 23F); 6A, analyzed separately to confirm previously described cross-protection 28 ; serotypes not included in (1, 3, 5, 7F, and 19A); and nonvaccine serotypes (all serotypes not in ). We assumed that the age-specific proportion of serotypes and antimicrobial susceptibility 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 28 through 212 (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 28 through 212. We used the age-specific and serotype-specific estimates of relative risk for 28 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 25 through 27. We calculated the age-stratified annual incidence of invasive pneumococcal disease (overall and HIV-specific) per 1, people by dividing the number of cases of invasive pneumococcal disease by the midyear population estimates and multiplying the quotient by 1,. 2,3 We assessed the effect of the introduction of 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 vaccine 29 ), 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 (25 28) and the rate in each of the two postvaccine years (211 and 212). We excluded the PCV introduction period of To estimate the effect of, we included analyses for 211 (during which there was minimal use of ). For overall populations and for HIV-infected populations, we measured the difference between changes in the rates of invasive pneumococcal disease caused by serotypes and changes in the rates of disease caused by nonvaccine serotypes in an attempt to account for the effects of ART from 28 through 212. 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;2 nejm.org November 13,

4 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.5 were considered to indicate statistical significance. Stata software, version 12 (StataCorp), was used for analysis. Results Overall Incidence of Invasive Pneumococcal Disease During the 8-year study period (25 through 212), we identified a total of 35,192 cases of invasive pneumococcal disease. Isolates were available for 24,552 (7%) (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 1, person-years in the pre-pcv (baseline) period (25 through 28) to 5.7 cases per 1, person-years in 212 ( 4%; 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 1, personyears in the baseline period to 17. cases per 1, in 212 (Table 1 and Fig. 1A and 2A). The greatest declines were in the incidence of -serotype disease ( 89%; 95% CI, 92 to 86), with each serotype and vaccine-related serotype 6A declining significantly from the baseline period to 211. Comparing the baseline period with 212, there was a nonsignificant increase of 6% (95% CI, 16 to 23) in the incidence of disease caused by nonvaccine serotypes. By 212, the incidence of disease caused by serotypes not included in had declined significantly among children ( 57%; 95% CI, 68 to 42), driven by declines in serotype 19A ( 7%; 95% CI, 81 to 55) (Table S2 in the Supplementary Appendix). The only other serotype that changed significantly in 212 as compared with the baseline period was serotype 1 ( 57%; 95% CI, 79 to 16). Among children younger than 1 weeks of age, disease rates decreased by 36% (95% CI, 5 to 17), from 87.8 to 56.6 cases per 1, person-years; the largest decline was in -serotype disease ( 78%; 95% CI, 88 to 6), 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 serotypes decreased by 85% (95% CI, 89 to 79) from baseline to 212, 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 -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 -serotype disease and nonvaccine-serotype disease among HIV-infected children younger than 2 years of age were 38 percentage points (77% minus 39%) in 211 and 55 percentage points (86% minus 31%) in 212. Changes in the Incidence of Invasive Pneumococcal Disease among Adults 25 to 44 Years of Age From the baseline period to 212, 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 - serotype disease ( 57%; 95% CI, 63 to 5). The incidence of disease caused by all individual 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 1892 n engl j med 371;2 nejm.org November 13, 214

5 Vaccination and Pneumococcal Disease in South Africa Table 1. Rate of Invasive Pneumococcal Disease among Children Younger than 2 Years of Age and Adults 25 to 44 Years of Age in South Africa before and after the Introduction of.* Age and Serotype Baseline Baseline to 211 Baseline to 212 Absolute Difference in Rate Relative Difference in Rate Absolute Difference in Rate Relative Difference in Rate no. of cases (cases/1, person-yr) cases/1, person-yr (95% CI) % (95% CI) cases/1, person-yr (95% CI) % (95% CI) <2 yr All serotypes 1142 (54.8) 47 (21.7) 369 (17.) 33.1 ( 36.9 to 29.4) 6 ( 65 to 56) 37.8 ( 41.4 to 34.2) 69 ( 72 to 65) serotypes 669 (32.1) 138 (6.4) 74 (3.4) 25.8 ( 28.4 to 23.1) 8 ( 84 to 76) 28.7 ( 31.3 to 26.2) 89 ( 92 to 86) Serotype 6A 131 (6.3) 52 (2.4) 2 (.9) 3.9 ( 5.2 to 2.6) 62 ( 73 to 47) 5.4 ( 6.5 to 4.2) 85 ( 91 to 76) Additional serotypes Nonvaccine serotypes yr 156 (7.5) 126 (5.8) 7 (3.2) 1.7 ( 3.2 to.1) 22 ( 39 to 1) 4.3 ( 5.7 to 2.9) 57 ( 68 to 42) 186 (8.9) 155 (7.1) 25 (9.5) 1.8 ( 3.5 to.6) 2 ( 36 to.2).5 ( 1.3 to +2.4) 6 ( 16 to 23) All serotypes 1712 (11.9) 1516 (9.6) 1262 (7.9) 2.2 ( 3. to 1.5) 18 ( 24 to 13) 4. ( 4.7 to 3.3) 34 ( 39 to 29) serotypes 537 (3.7) 369 (2.3) 257 (1.6) 1.4 ( 1.8 to 1.) 37 ( 45 to 28) 2.1 ( 2.5 to 1.8) 57 ( 63 to 5) Serotype 6A 11 (.8) 117 (.7) 66 (.4).2 (.2 to.2) 3 ( 26 to 28).4 (.5 to.2) 46 ( 61 to 26) Additional serotypes Nonvaccine serotypes 55 (3.5) 511 (3.3) 384 (2.4).3 (.7 to.2) 7 ( 18 to 5) 1.1 ( 1.5 to.2) 32 ( 4 to 22) 559 (3.9) 519 (3.3) 555 (3.5).6 ( 1. to.1) 15 ( 25 to 4).4 (.9 to.1) 11 ( 21 to 4) * The rate of disease is the number of cases per 1, person-years. The baseline case numbers and rates were calculated as the average of the numbers and rates during the prevaccine period (25 through 28). The 7-valent pneumococcal vaccine () was introduced in 29, and the 13-valent pneumococcal vaccine () was introduced in 211. Additional serotypes are serotypes not included in. n engl j med 371;2 nejm.org November 13,

6 A Age <15 Years 6 Age Group 55 <2 Yr Yr Yr Yr Cases per 1, Person-Yr B Age 15 Years 6 Age Group Yr Yr Yr 4 35 >64 Yr Cases per 1, Person-Yr Figure 1. Incidence of Invasive Pneumococcal Disease in South Africa from 25 through 212, According to Age Group. The period from 25 through 28 constitutes the pre-pcv period. The 7-valent pneumococcal conjugate vaccine () was introduced in 29, and the 13-valent pneumococcal conjugate vaccine () in 211. Of 35,192 cases of invasive pneumococcal disease, 1648 (5%) were excluded because the age was not known. of disease due to the additional serotypes in ( 32%; 95% CI, 4 to 22), including serotypes 1 ( 33%; 95% CI, 46 to 17) and 19A ( 31%; 95% CI, 45 to 12) (Table S3 in the Supplementary Appendix). Among HIV-uninfected adults who were 25 to 44 years of age, the rate of -serotype disease declined significantly from the baseline period to 212 ( 52%; 95% CI, 72 to 19) (Table S4 and Fig. S3A in the Supplementary Appendix). Among HIV-infected adults, the largest reductions were in the rate of -serotype disease ( 59%; 95% CI, 65 to 52) (Table S4 and Fig. S3B in the Supplementary Appendix). The absolute difference in rate reduction between disease caused by serotypes and disease caused by nonvaccine serotypes among HIV-infected adults was 18 percentage points in 211 and increased to 4 percentage points in 212 (Table S4 in the Supplementary Appendix). From baseline to 212, the reduction in the disease rate (all serotypes combined) among HIV-infected adults exceeded the rate reduction among HIV-uninfected adults by a factor of almost 18. Changes in the Rates of Invasive Pneumococcal Disease among Persons in Other Age Groups Declines in the rates of invasive pneumococcal disease (all serotypes combined) were also seen among children who were 2 to 4 years of age ( 6%; 95% CI, 67 to 51) and among those 5 to 9 years of age ( 44%; 95% CI, 54 to 33) (Fig. 1A). The incidence of invasive pneumococcal disease among children who were 1 to 14 years of age was low and decreased nonsignificantly ( 6%; 95% CI, 28 to 23). Reductions in the rates of invasive pneumococcal disease were observed among persons who were 15 to 24 years of age ( 3%; 95% CI, 42 to 15) (Fig. 1B). No significant changes in the incidence of disease from the baseline period to 212 were observed among persons older than 64 years of age (1%; 95% CI, 26 to 22), whereas small but significant reductions were documented among persons who were 45 to 64 years of age ( 14%; 95% CI, 23 to 3). Antimicrobial-Nonsusceptible Pneumococcal Disease From the baseline period to 212, among children younger than 2 years of age, the rate of invasive pneumococcal disease caused by penicillin-nonsusceptible isolates declined by 82% (95% CI, 85 to 78), and the rate of disease caused by penicillin-susceptible isolates declined by 47% (95% CI, 55 to 38) (Fig. S4 in the Supplementary Appendix). The rate of disease caused by ceftriaxone-nonsusceptible isolates and ceftriaxone-susceptible isolates also declined ( 85% [95% CI, 91 to 77] and 66% [95% CI, 7 to 62], respectively), as did the rate of disease caused by multidrug-resistant isolates and non-multidrugresistant isolates ( 84% [95% CI, 88 to 79] and 38% [95% CI, 43 to 33], respectively). These changes were predominantly due to declines in the proportion of penicillin-nonsusceptible serotypes, from 7% of isolates (348 of 498) in 29 to 47% (41 of 87) in 212 (P<.1) (Fig. 4) n engl j med 371;2 nejm.org November 13, 214

7 Vaccination and Pneumococcal Disease in South Africa Discussion We used a laboratory-based surveillance system in South Africa, a middle-income country, to document reductions of 89% in the incidence of invasive pneumococcal disease caused by serotypes and 82% in the incidence of disease caused by penicillin-nonsusceptible serotypes within 4 years after PCV introduction among children younger than 2 years of age. Some of these reductions were most likely due to improvements in the care of HIV-infected persons, reflected by declines of 2% in the incidence of invasive pneumococcal disease caused by nonvaccine serotypes between the baseline period and 211. However, the 2% decrease in the incidence of disease caused by nonvaccine serotypes was substantially less than the 8% decrease observed for -serotype disease. In addition, between the baseline period and 212, we observed decreases in invasive pneumococcal disease caused by serotypes of more than 5% among unvaccinated adults 25 to 44 years of age and of more than 3% among children too young to benefit directly from the vaccine, suggesting that PCV use has indirect effects, even in geographic areas of high colonization and high disease burden. In 212, as compared with the prevaccine era, we found a 49% reduction in the rate of invasive pneumococcal disease caused by any serotype and an 85% reduction in the rate of disease caused by serotypes among HIV-uninfected children younger than 2 years of age. Substantial reductions (69%) in the rates of disease caused by any serotype were documented within a year after the introduction of in the United States among all children targeted for vaccination. 29 Among HIV-infected children younger than 2 years of age, we observed declines in disease caused by PCV serotypes and by nonvaccine serotypes, most likely reflecting the combined effects of, ART, and improvements in the prevention of mother-to-child transmission of HIV. Among such children, rates of invasive pneumococcal disease caused by nonvaccine serotypes fell by 31% from the baseline period to 212 and the rates of disease due to serotypes declined by 86%, most likely confirming that HIV-infected children were benefiting from PCV use. Reductions in -serotype disease A Age <2 Years Cases per 1, Person-Yr B Age 25 to 44 Years Cases per 1, Person-Yr All serotypes serotypes Additional serotypes Figure 2. Changes in the Incidence of Invasive Pneumococcal Disease, According to Age and Serotype. was introduced in 29, and in 211. Additional serotypes are serotypes not included in. in 29 and 21, before the introduction of, are also most likely a result of ART. The amount of the reduction in invasive pneumococcal disease among HIV-infected children that can be attributed to the effects of PCV, whether those effects are direct or indirect, is unclear. A previous clinical trial in South Africa 5 involving a different vaccine schedule showed efficacy against invasive pneumococcal disease among both HIV-infected children and HIV-uninfected children. In contrast, a case control study conducted in South Africa did not show vaccine effectiveness with the current schedule (two primary doses plus a booster) among HIV-infected children. 15 We documented that the indirect effects of vaccination are similar in HIV-infected adults and in HIV-uninfected adults (declines of 4% and 52%, respectively, for -serotype disease), Non- serotypes Serotype 6A n engl j med 371;2 nejm.org November 13,

8 A HIV-Uninfected Children <2 Years of Age 35 Cases per 1, Person-Yr B HIV-Infected Children <2 Years of Age 7 Cases per 1, Person-Yr All serotypes serotypes Additional serotypes Non- serotypes Serotype 6A Figure 3. Changes in the Incidence of Invasive Pneumococcal Disease among Children Younger than 2 Years of Age, According to HIV Status and Serotype. was introduced in 29, and in 211. HIV denotes human immunodeficiency virus. findings that are similar to those in the United States. 1,32 The declines that we documented were somewhat smaller than the declines among HIV-infected adults and HIV-uninfected adults 18 to 64 years of age in the United States (which averaged 61%), 32 but because of the high prevalence of HIV infection in South Africa, the public health implications of indirect protection from PCV are greater in South Africa than in the United States. Our data reflect fewer years of vaccine effect (only 4 years) and an effect that is most likely delayed by the lack of a catch-up campaign. There has been speculation that serotype replacement in low-income countries may be greater than that observed in high-income countries. 33 Small increases in the rates of invasive pneumococcal disease caused by nonvaccine serotypes were seen among HIV-uninfected children after introduction of the vaccine. We observed little or no increase in invasive pneumococcal disease caused by nonvaccine serotypes (i.e., serotype replacement) among HIV-infected children; however, serotype replacement may have been masked by ongoing improvements in the care of HIVinfected children and adults, which itself would decrease invasive pneumococcal disease caused by any serotype. In other geographic areas, serotype-replacement disease was usually not detected until at least 5 years after introduction of the vaccine, even in areas of high vaccine coverage. 33 Most middle-income and high-income countries have introduced PCV as a two-dose or three-dose primary series during infancy, with a booster dose at 11 to 18 months of age, whereas low-income countries currently use three primary doses without a booster. 34 In our study, we observed that a dose schedule aligned to Expanded Program on Immunization visits, used elsewhere in Africa, provided protection against overall invasive pneumococcal disease. For most but not all serotypes, the immune response induced by two primary doses is similar to the response induced by three doses. 35,36 Additional data from the United States and the United Kingdom show that fewer than three doses of PCV during infancy may be effective against invasive pneumococcal disease. 28,37 In the United Kingdom, a schedule of two primary doses plus a booster has resulted in a substantial decline in invasive pneumococcal disease caused by vaccine serotypes. 8,38 Waning immunity may still be important in South Africa, and ongoing surveillance will be necessary to characterize vaccination failures. 5 has also shown effectiveness in reducing antimicrobial-resistant invasive pneumococcal disease. 11,39 Levels of pneumococcal nonsusceptibility to penicillin and to multiple anitmicrobial agents have been high in South Africa, and in the prevaccine era, 83% of multidrug-resistant isolates were serotypes contained in. 31,4 Our data indicate that overall rates of invasive pneumococcal disease characterized by drug-nonsusceptible isolates declined by more than 5%. In children younger than 2 years of age, among 1896 n engl j med 371;2 nejm.org November 13, 214

9 Vaccination and Pneumococcal Disease in South Africa whom the prevalence of nonsusceptibility has consistently been higher than that among adults, 4 these reductions were greater than 8% for penicillin, ceftriaxone, and multidrug resistance. We did not evaluate antibiotic use, but recommendations for cotrimoxazole prophylaxis among HIV-exposed or HIV-infected children did not change during the study period, although the number of children who were given prophylaxis probably decreased. 41 Our study has several limitations. First, laboratory-based surveillance, as reported here, underestimates the full burden of pneumococcal disease. 17 The incidence of invasive pneumococcal disease at a sentinel site with a defined population was four to five times as high as the incidence that we documented. 16,19 Second, the analysis of the effect of PCV on pneumococcal disease in persons with HIV infection is limited by the large numbers of patients in whom HIV serostatus is unknown in the early years. Third, serotype and antimicrobial susceptibility were imputed for almost a third of cases on the assumption that the data were missing at random. Finally, if disease caused by increases in nonvaccine serotypes was masked among HIV-infected infants owing to the effects of HIV treatment, we may have overestimated vaccine effects in this group by examining the effect of the vaccine on invasive pneumococcal disease caused by vaccine serotypes as compared with the effect on disease caused by nonvaccine serotypes. An earlier study at one site documented declines in the rate of invasive pneumococcal disease in the pre-pcv era (27 and 28) due to HIV interventions, 16 which may have been masked by ongoing improvements and increased case ascertainment at other sites throughout the country in our larger, national study. However, increases in the sensitivity of the surveillance would result in underestimates of the PCV effects. Preventing pneumococcal disease is a priority throughout Africa as we strive to reduce infant deaths across the continent. Our study shows that the introduction of PCV in South Africa is associated with a substantial decrease in the incidence of invasive pneumococcal disease in children, which is a marker of the overall effect of the vaccine on pneumococcal disease. No. of Isolates Figure 4. Number of Penicillin-Nonsusceptible Isolates Causing Invasive Pneumococcal Disease among Children Younger than 2 Years of Age, According to Serotype. The bar for the period (the pre-pcv period) shows the proportion of all detections of approximately 1 isolates per year, selected randomly from all available samples for each year (127 isolates from 91 samples for 25, 125 from 826 samples for 26, 116 from 81 samples for 27, and 134 from 881 samples for 28). The same broth microdilution methods were used that were used on all viable isolates from 29 onward. 31 The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the Centers for Disease Control and Prevention. Supported by the National Institute for Communicable Diseases of the National Health Laboratory Service, the President s Emergency Plan for AIDS Relief, the U.S. Agency for International Development s Antimicrobial Resistance Initiative, and the Centers for Disease Control and Prevention (cooperative agreements U62/CCU2291, 5U2GPS1328, and U6/ CCU2288). Dr. von Gottberg reports receiving grant support through her institution from Pfizer; Dr. von Mollendorf, receiving honoraria for presentations from Pfizer and salary support from the Global Alliance for Vaccines and Immunization through the Program for Appropriate Technology in Health; Dr. Madhi, receiving fees from GlaxoSmithKline and Pfizer for serving on advisory boards, lecture fees from GlaxoSmithKline, Pfizer, and Sanofi Pasteur, and grant support through his institution from GlaxoSmithKline, Pfizer, and Novartis; Dr. O Brien, receiving grant support from GlaxoSmithKline and Pfizer; and Dr. Klugman, receiving fees from Pfizer and GlaxoSmithKline for serving on advisory boards and grant support from Pfizer. No other potential conflict of interest relevant to this article was reported. Disclosure forms provided by the authors are available with the full text of this article at NEJM.org. We thank all laboratory and clinical staff throughout South Africa for contributing to national surveillance; Mignon du Plessis, Olga Hattingh, Kedibone Mothibeli, Ruth Mpembe, Happy Skosana, and Nicole Wolter for providing technical expertise and assistance; Penny Crowther-Gibson, Thembi Mthembu, and Judith Tshabalala for providing data management; and the Corporate Data Warehouse, National Health Laboratory Service, Sandringham, South Africa, for providing data for quarterly and annual audits. serotypes Serotype 6A Additional serotypes Non- serotypes n engl j med 371;2 nejm.org November 13,

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