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
AnnevonGottberg,M.B., B.Ch., Ph.D., LindadeGouveia,N.D., M.T.,
StefanoTempia,D.V.M., Ph.D., VanessaQuan,M.B., B.Ch., M.P.H.,
SusanMeiring,M.B., Ch.B., ClairevonMollendorf,M.B., B.Ch.,
ShabirA.Madhi,M.B., B.Ch., Ph.D., ElizabethR.Zell,M.Stat.,
JenniferR.Verani,M.D., M.P.H., KatherineL.OBrien,M.D., M.P.H.,
CynthiaG.Whitney,M.D., M.P.H., KeithP.Klugman,M.B., B.Ch., Ph.D.,
and CherylCohen,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 From the Centre for Respiratory Diseases
in 2009 with a three-dose schedule for infants at 6, 14, and 36 weeks of age; a and Meningitis, National Institute for Com-
municable Diseases (NICD), National
13-valent vaccine (PCV13) replaced PCV7 in 2011. In 2012, it was estimated that Health Laboratory Service (NHLS) (A.G.,
81% of 12-month-old children had received three doses of vaccine. We assessed the L.G., V.Q., S.M., C.M., S.A.M., C.C.),
effect of vaccination on invasive pneumococcal disease. Medical Research Council, Respiratory
and Meningeal Pathogens Research Unit
(A.G., L.G., S.A.M.), and Department of
METHODS Science and Technology/National Re-
We conducted national, active, laboratory-based surveillance for invasive pneumo- search Foundation, Vaccine-Preventable
Diseases (S.A.M.), University of the Wit-
coccal disease. We calculated the change in the incidence of the disease from a watersrand all in Johannesburg; the
prevaccine (baseline) period (2005 through 2008) to postvaccine years 2011 and Influenza Division (S.T.) and Division of
2012, with a focus on high-risk age groups. Bacterial Diseases (E.R.Z., J.R.V., C.G.W.),
Centers for Disease Control and Preven-
tion, and Hubert Department of Global
RESULTS Health, Rollins School of Public Health,
Surveillance identified 35,192 cases of invasive pneumococcal disease. The rates and Division of Infectious Diseases,
School of Medicine, Emory University
among children younger than 2 years of age declined from 54.8 to 17.0 cases per (K.P.K.) all in Atlanta; and the Johns
100,000 person-years from the baseline period to 2012, including a decline from Hopkins Bloomberg School of Public
32.1 to 3.4 cases per 100,000 person-years in disease caused by PCV7 serotypes Health, Johns Hopkins University, Balti-
more (K.L.O.). Address reprint requests
(89%; 95% confidence interval [CI], 92 to 86). Among children not infected to Dr. von Gottberg at the Centre for Re-
with the human immunodeficiency virus (HIV), the estimated incidence of invasive spiratory Diseases and Meningitis, Na-
pneumococcal disease caused by PCV7 serotypes decreased by 85% (95% CI, 89 to tional Institute for Communicable Dis-
eases, Private Bag X4, Sandringham, 2131,
79), whereas disease caused by nonvaccine serotypes increased by 33% (95% CI, Gauteng, South Africa, or at annev@nicd
15 to 48). Among adults 25 to 44 years of age, the rate of PCV7-serotype disease .ac.za.
declined by 57% (95% CI, 63 to 50), from 3.7 to 1.6 cases per 100,000 person- *Investigators in the Group for Enteric,
years. Respiratory, and Meningeal Disease Sur-
veillance in South Africa (GERMS-SA)
CONCLUSIONS are listed in the Supplementary Appen-
dix, available at NEJM.org.
Rates of invasive pneumococcal disease among children in South Africa fell sub-
stantially by 2012. Reductions in the rates of disease caused by PCV7 serotypes N Engl J Med 2014;371:1889-99.
DOI: 10.1056/NEJMoa1401914
among both children and adults most likely reflect the direct and indirect effects Copyright 2014 Massachusetts Medical Society.
of vaccination. (Funded by the National Institute for Communicable Diseases of
the National Health Laboratory Service and others.)

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 The n e w e ng l a n d j o u r na l
T
he majority of deaths associated
with childhood pneumococcal disease oc-
cur in Africa.1,2 In randomized trials con-
ducted in Africa,3,4 a pneumococcal conjugate vac-
cine (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 in-
fants who were infected with HIV (65% efficacy;
95% CI, 24 to 86).3,5 In 2009, South Africa be-
came the first African country to incorporate
vaccination with PCV in its routine infant im-
munization program.6 The 7-valent PCV (PCV7)
was introduced with the use of a novel three-
dose 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 chil-
dren and adults,8-10 respectively have been seen
in many high-income countries. Most antibiotic-
resistant pneumococci are of serotypes contained
in PCVs; thus, reductions in rates of antibiotic-
resistant 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 ben-
efits of PCV may be different. In addition, indi-
rect effects may be attenuated among persons in
African countries who have coexisting diseases,
such as HIV infection.14 In a casecontrol study
in South Africa, the estimated effectiveness of
three or more doses of PCV7 in preventing inva-
sive pneumococcal disease caused by PCV7 sero-
types was 90% (95% CI, 14 to 99) among HIV-
uninfected 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 dis-
easeassociated hospitalizations than did HIV-
uninfected children, by a factor of approximately
20.16,17 In South Africa, the group at second-
highest risk for invasive pneumococcal disease,
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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 ap-
proximately 52 million; 4% (approximately 2 mil-
lion 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 preven-
tion of mother-to-child transmission.21 Since the
implementation of comprehensive HIVAIDS treat-
ment programs in 2003, access to antiretroviral
treatment (ART) has steadily improved.23 Esti-
mates 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 pneu-
mococcal disease in South Africa began in 1999.25
Since 2003, enhanced surveillance at 24 sentinel
 Vaccination and Pneumococcal Disease in South Africa
hospitals located in all nine provinces has in-
volved the collection of additional information,
including admission date, HIV serologic status,
discharge diagnosis, and outcome (see the Sup-
plementary Appendix, available with the full text
of this article at NEJM.org). Persons with inva-
sive pneumococcal disease were defined as hos-
pitalized persons from whom Streptococcus pneu-
moniae 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). Sero-
type 6C was distinguished from 6A throughout.26
We determined antimicrobial minimum inhibi-
tory 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 ceftriax-
one were at least 1 mg per liter.27 Multidrug re-
sistance was classified as nonsusceptibility to
three or more of the following drug classes:
chloramphenicol, tetracycline, rifampin, trime-
thoprimsulfamethoxazole, penicillin or ceftri-
axone, 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 sup-
port 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 previ-
ously described cross-protection28; PCV13 sero-
types not included in PCV7 (1, 3, 5, 7F, and 19A);
and nonvaccine serotypes (all serotypes not in
PCV13). We assumed that the age-specific pro-
portion of serotypes and antimicrobial suscepti-
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bility among cases of disease with missing pneu-
mococcal isolates was the same as the proportion
among cases with available data each year.7,29
We imputed the HIV-infection status for pa-
tients with invasive pneumococcal disease who
were not tested for HIV at enhanced-surveillance
sites from 2008 through 2012 (see the Supplemen-
tary Appendix). We then estimated the age-spe-
cific, year-specific, and serotype-specific relative
risk of hospitalization for invasive pneumococ-
cal disease due to HIV infection from 2008
through 2012. We used the age-specific and se-
rotype-specific estimates of relative risk for 2008
to estimate the age-specific, year-specific, and
serotype-specific numbers of HIV-positive per-
sons 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 inci-
dence 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 as-
sessed the effect of the introduction of PCV7 on
invasive pneumococcal disease, focusing a priori
on persons younger than 2 years of age (vacci-
nated age group) and those 25 to 44 years of age
(the group with the highest rates of adult inva-
sive 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 (20052008) and the rate in
each of the two postvaccine years (2011 and 2012).
We excluded the PCV introduction period of
20092010. To estimate the effect of PCV7, we
included analyses for 2011 (during which there
was minimal use of PCV13). For overall popula-
tions and for HIV-infected populations, we mea-
sured 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 se-
rotypes and that increases in nonvaccine sero-
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. Two-
sided 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 Supple-
mentary 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 (base-
line) period (2005 through 2008) to 5.7 cases per
100,000 person-years in 2012 (40%; 95% confi-
dence interval [CI], 42 to 37). The largest ab-
solute differences and percentage changes in rates
occurred among persons younger than 2 years of
age and among those 25 to 44 years of age (Ta-
ble1 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 person-
years in the baseline period to 17.0 cases per
100,000 in 2012 (Table1 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 base-
line period to 2011. Comparing the baseline pe-
riod with 2012, there was a nonsignificant in-
crease 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 n engl j med 371;20nejm.org November 13, 2014
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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 de-
creased by 36% (95% CI, 50 to 17), from 87.8
to 56.6 cases per 100,000 person-years; the larg-
est 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 dis-
ease caused by nonvaccine serotypes increased
by 33% (95% CI, 15 to 48) (Fig.3A, and Table S4
in the Supplementary Appendix). Among HIV-
infected children, the incidence of PCV7-serotype
disease declined by 86% (95% CI, 91 to 78),
which was similar to the decline among HIV-
uninfected children, but the rate of disease was
25 times as high as the rate among HIV-unin-
fected children. The incidence of disease caused
by nonvaccine serotypes did not change signifi-
cantly among HIV-infected children. The abso-
lute 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 inva-
sive pneumococcal disease (all serotypes com-
bined) among persons 25 to 44 years of age
(34%; 95% CI, 39 to 29) (Table1 and Fig.1B
and 2B), driven mostly by reductions in PCV7-
serotype 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 Supple-
mentary Appendix). Decreases in nonvaccine-
serotype disease were not significant (Table1).
Significant reductions were observed in the rates
 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 PCV7.*

Age and Serotype Baseline 2011 2012 Baseline to 2011 Baseline to 2012

Absolute Difference Relative Difference Absolute Difference Relative Difference

in Rate in Rate in Rate in Rate

no. of cases cases/100,000 person-yr cases/100,000 person-yr

(cases/100,000 person-yr) (95% CI) % (95% CI) (95% CI) % (95% CI)
<2 yr
All serotypes 1142 (54.8) 470 (21.7) 369 (17.0) 33.1 (36.9 to 29.4) 60 (65 to 56) 37.8 (41.4 to 34.2) 69 (72 to 65)
PCV7 serotypes 669 (32.1) 138 (6.4) 74 (3.4) 25.8 (28.4 to 23.1) 80 (84 to 76) 28.7 (31.3 to 26.2) 89 (92 to 86)
Serotype 6A 131 (6.3) 52 (2.4) 20 (0.9) 3.9 (5.2 to 2.6) 62 (73 to 47) 5.4 (6.5 to 4.2) 85 (91 to 76)
Additional PCV13 156 (7.5) 126 (5.8) 70 (3.2) 1.7 (3.2 to 0.1) 22 (39 to 1) 4.3 (5.7 to 2.9) 57 (68 to 42)
serotypes
Nonvaccine 186 (8.9) 155 (7.1) 205 (9.5) 1.8 (3.5 to 0.6) 20 (36 to 0.2) 0.5 (1.3 to +2.4) 6 (16 to 23)
serotypes
2544 yr
All serotypes 1712 (11.9) 1516 (9.6) 1262 (7.9) 2.2 (3.0 to 1.5) 18 (24 to 13) 4.0 (4.7 to 3.3) 34 (39 to 29)
PCV7 serotypes 537 (3.7) 369 (2.3) 257 (1.6) 1.4 (1.8 to 1.0) 37 (45 to 28) 2.1 (2.5 to 1.8) 57 (63 to 50)
Serotype 6A 110 (0.8) 117 (0.7) 66 (0.4) 0.02 (0.2 to 0.2) 3 (26 to 28) 0.4 (0.5 to 0.2) 46 (61 to 26)
Additional PCV13 505 (3.5) 511 (3.3) 384 (2.4) 0.3 (0.7 to 0.2) 7 (18 to 5) 1.1 (1.5 to 0.2) 32 (40 to 22)
serotypes
Nonvaccine 559 (3.9) 519 (3.3) 555 (3.5) 0.6 (1.0 to 0.1) 15 (25 to 4) 0.4 (0.9 to 0.01) 11 (21 to 4)

The New England Journal of Medicine

n engl j med 371;20nejm.org November 13, 2014
serotypes

* 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 prevac-
cine 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.
Vaccination and Pneumococcal Disease in South Africa

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1893
 The n e w e ng l a n d j o u r na l of m e dic i n e

to 40 percentage points in 2012 (Table S4 in the

A Age <15 Years
60 Age Group Supplementary Appendix). From baseline to 2012,
55 PCV7 <2 Yr the reduction in the disease rate (all serotypes
Cases per 100,000 Person-Yr

50 24 Yr combined) among HIV-infected adults exceeded

45 59 Yr
40 the rate reduction among HIV-uninfected adults
1014 Yr
35 by a factor of almost 180.
30 PCV13
25
20 Changes in the Rates of Invasive Pneumococcal
15 Disease among Persons in Other Age Groups
10
5 Declines in the rates of invasive pneumococcal
0
2005 2006 2007 2008 2009 2010 2011 2012 disease (all serotypes combined) were also seen
among children who were 2 to 4 years of age
B Age 15 Years (60%; 95% CI, 67 to 51) and among those 5 to
60 Age Group 9 years of age (44%; 95% CI, 54 to 33)
55 1524 Yr
Cases per 100,000 Person-Yr

50 2544 Yr
45 4564 Yr
40
35
>64 Yr
30
25
PCV7 PCV13
20
15
10
5
0 significant changes in the incidence of disease
2005 2006 2007 2008 2009 2010 2011
Figure 1. Incidence of Invasive Pneumococcal Disease in South Africa
from 2005 through 2012, According to Age Group.
The period from 2005 through 2008 constitutes the pre-PCV period. The
7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2009,
and the 13-valent pneumococcal conjugate vaccine (PCV13) in 2011. 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
PCV13 (32%; 95% CI, 40 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 PCV7-serotype disease
declined significantly from the baseline period
to 2012 (52%; 95% CI, 72 to 19) (Table S4
and Fig. S3A in the Supplementary Appendix).
Among HIV-infected adults, the largest reduc-
tions were in the rate of PCV7-serotype disease
(59%; 95% CI, 65 to 52) (Table S4 and Fig.
S3B in the Supplementary Appendix). The abso-
lute difference in rate reduction between disease
caused by PCV7 serotypes and disease caused by
nonvaccine serotypes among HIV-infected adults
was 18 percentage points in 2011 and increased
(Fig.1A). The incidence of invasive pneumococ-
cal disease among children who were 10 to 14
years of age was low and decreased nonsignifi-
cantly (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 (30%; 95% CI, 42 to 15) (Fig.1B). No
2012 from the baseline period to 2012 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 2012, among children
younger than 2 years of age, the rate of invasive
pneumococcal disease caused by penicillin-non-
susceptible 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 Supplemen-
tary Appendix). The rate of disease caused by
ceftriaxone-nonsusceptible isolates and ceftriax-
one-susceptible isolates also declined (85% [95%
CI, 91 to 77] and 66% [95% CI, 70 to 62],
respectively), as did the rate of disease caused by
multidrug-resistant isolates and non-multidrug-
resistant isolates (84% [95% CI, 88 to 79]
and 38% [95% CI, 43 to 33], respectively).
These changes were predominantly due to de-
clines in the proportion of penicillin-nonsuscep-
tible PCV7 serotypes, from 70% of isolates (348
of 498) in 2009 to 47% (41 of 87) in 2012
(P<0.001) (Fig.4).

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 Vaccination and Pneumococcal Disease in South Africa

Discussion All serotypes PCV7 serotypes Non-PCV13 serotypes

Additional PCV13 serotypes Serotype 6A
We used a laboratory-based surveillance system
in South Africa, a middle-income country, to A Age <2 Years
60
document reductions of 89% in the incidence of 55 PCV7

Cases per 100,000 Person-Yr

invasive pneumococcal disease caused by PCV7 50
serotypes and 82% in the incidence of disease 45
40
caused by penicillin-nonsusceptible serotypes 35
within 4 years after PCV introduction among 30
PCV13
25
children younger than 2 years of age. Some of 20
these reductions were most likely due to im- 15
10
provements in the care of HIV-infected persons, 5
reflected by declines of 20% in the incidence of 0
2005 2006 2007 2008 2009 2010 2011 2012
invasive pneumococcal disease caused by non-
vaccine serotypes between the baseline period B Age 25 to 44 Years
and 2011. However, the 20% decrease in the in- 60
cidence of disease caused by nonvaccine sero- 55

Cases per 100,000 Person-Yr

50
types was substantially less than the 80% de- 45
crease observed for PCV7-serotype disease. In 40
addition, between the baseline period and 2012, 35
30
we observed decreases in invasive pneumococcal 25
PCV7 PCV13
disease caused by PCV7 serotypes of more than 20
15
50% among unvaccinated adults 25 to 44 years 10
of age and of more than 30% among children 5
0
too young to benefit directly from the vaccine, 2005 2006 2007 2008 2009 2010 2011 2012
suggesting that PCV use has indirect effects,
even in geographic areas of high colonization Figure 2. Changes in the Incidence of Invasive Pneumococcal Disease, Ac-
and high disease burden. cording to Age and Serotype.
In 2012, as compared with the prevaccine era, PCV7 was introduced in 2009, and PCV13 in 2011. Additional PCV13 sero-
we found a 49% reduction in the rate of invasive types are PCV13 serotypes not included in PCV7.
pneumococcal disease caused by any serotype
and an 85% reduction in the rate of disease
caused by PCV7 serotypes among HIV-uninfect- in 2009 and 2010, before the introduction of
ed children younger than 2 years of age. Sub- PCV13, are also most likely a result of ART. The
stantial reductions (69%) in the rates of disease amount of the reduction in invasive pneumococ-
caused by any serotype were documented within cal disease among HIV-infected children that can
a year after the introduction of PCV7 in the United be attributed to the effects of PCV, whether
States among all children targeted for vaccina- those effects are direct or indirect, is unclear. A
tion.29 Among HIV-infected children younger previous clinical trial in South Africa5 involving
than 2 years of age, we observed declines in a different vaccine schedule showed efficacy
disease caused by PCV serotypes and by nonvac- against invasive pneumococcal disease among
cine serotypes, most likely reflecting the combined both HIV-infected children and HIV-uninfected
effects of PCV7, ART, and improvements in the children. In contrast, a casecontrol study con-
prevention of mother-to-child transmission of ducted in South Africa did not show vaccine ef-
HIV. Among such children, rates of invasive pneu- fectiveness with the current schedule (two pri-
mococcal disease caused by nonvaccine sero- mary doses plus a booster) among HIV-infected
types fell by 31% from the baseline period to children.15
2012 and the rates of disease due to PCV7 sero- We documented that the indirect effects of
types declined by 86%, most likely confirming vaccination are similar in HIV-infected adults and
that HIV-infected children were benefiting from in HIV-uninfected adults (declines of 40% and
PCV use. Reductions in PCV13-serotype disease 52%, respectively, for PCV7-serotype disease),

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 The n e w e ng l a n d j o u r na l of m e dic i n e

All serotypes PCV7 serotypes Non-PCV13 serotypes

er than that observed in high-income countries.33
Additional PCV13 serotypes Serotype 6A Small increases in the rates of invasive pneumo-
coccal disease caused by nonvaccine serotypes
A HIV-Uninfected Children <2 Years of Age were seen among HIV-uninfected children after
35
PCV7
introduction of the vaccine. We observed little or
30 no increase in invasive pneumococcal disease
Cases per 100,000 Person-Yr

25
caused by nonvaccine serotypes (i.e., serotype
PCV13
replacement) among HIV-infected children; how-
20 ever, serotype replacement may have been masked
15 by ongoing improvements in the care of HIV-
infected children and adults, which itself would
10
decrease invasive pneumococcal disease caused
5 by any serotype. In other geographic areas, sero-
0 type-replacement disease was usually not detected
2005 2006 2007 2008 2009 2010 2011 2012 until at least 5 years after introduction of the
vaccine, even in areas of high vaccine coverage.33
B HIV-Infected Children <2 Years of Age Most middle-income and high-income coun-
700 tries have introduced PCV as a two-dose or
PCV7
600 three-dose primary series during infancy, with a
Cases per 100,000 Person-Yr

booster dose at 11 to 18 months of age, whereas

500
400
300
200
100
0
2005 2006 2007 2008 2009 2010
Figure 3. Changes in the Incidence of Invasive Pneumococcal Disease
among Children Younger than 2 Years of Age, According to HIV Status
and Serotype.
PCV7 was introduced in 2009, and PCV13 in 2011. HIV denotes human
immunodeficiency virus.
findings that are similar to those in the United
States.10,32 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 preva-
lence of HIV infection in South Africa, the pub-
lic 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 re-
placement in low-income countries may be great-
low-income countries currently use three pri-
PCV13
mary doses without a booster.34 In our study, we
observed that a dose schedule aligned to Ex-
panded Program on Immunization visits, used
elsewhere in Africa, provided protection against
overall invasive pneumococcal disease. For most
but not all serotypes, the immune re-
2011 2012 sponse induced by two primary doses is similar
to the response induced by three doses.35,36 Ad-
ditional 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
PCV7 has also shown effectiveness in reducing
antimicrobial-resistant invasive pneumococcal dis-
ease.11,39 Levels of pneumococcal nonsusceptibil-
ity to penicillin and to multiple anitmicrobial
agents have been high in South Africa, and in the
prevaccine era, 83% of multidrug-resistant iso-
lates were serotypes contained in PCV7.31,40 Our
data indicate that overall rates of invasive pneu-
mococcal disease characterized by drug-nonsus-
ceptible isolates declined by more than 50%. In
children younger than 2 years of age, among

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Copyright 2014 Massachusetts Medical Society. All rights reserved.
 Vaccination and Pneumococcal Disease in South Africa
whom the prevalence of nonsusceptibility has
consistently been higher than that among adults,40
these reductions were greater than 80% for
penicillin, ceftriaxone, and multidrug resistance.
We did not evaluate antibiotic use, but recom-
mendations 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, labo-
ratory-based surveillance, as reported here, un-
derestimates the full burden of pneumococcal
disease.17 The incidence of invasive pneumococ-
cal 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 as-
sumption that the data were missing at random.
Finally, if disease caused by increases in nonvac-
cine 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 vac-
cine serotypes as compared with the effect on
disease caused by nonvaccine serotypes. An ear-
lier study at one site documented declines in the
rate of invasive pneumococcal disease in the
pre-PCV era (2007 and 2008) due to HIV inter-
ventions,16 which may have been masked by on-
going improvements and increased case ascer-
tainment 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 inci-
dence of invasive pneumococcal disease in chil-
dren, which is a marker of the overall effect of
the vaccine on pneumococcal disease.
n engl j med 371;20nejm.org November 13, 2014
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600
PCV7 serotypes
500 Serotype 6A
Additional PCV13 serotypes
400 Non-PCV13 serotypes
No. of Isolates
300
200
100
0
20052008 2009 2010 2011 2012
Figure 4. Number of Penicillin-Nonsusceptible Isolates Causing Invasive
Pneumococcal Disease among Children Younger than 2 Years of Age, Ac-
cording to Serotype.
The bar for the 20052008 period (the pre-PCV period) shows the propor-
tion of all detections of approximately 100 isolates per year, selected ran-
domly from all available samples for each year (127 isolates from 910 sam-
ples for 2005, 125 from 826 samples for 2006, 116 from 810 samples for
2007, and 134 from 881 samples for 2008). The same broth microdilution
methods were used that were used on all viable isolates from 2009 on-
ward.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 Dis-
eases of the National Health Laboratory Service, the Presi-
dents Emergency Plan for AIDS Relief, the U.S. Agency for In-
ternational Developments Antimicrobial Resistance Initiative,
and the Centers for Disease Control and Prevention (coopera-
tive agreements U62/CCU022901, 5U2GPS001328, and U60/
CCU022088).
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, re-
ceiving 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. OBrien, receiving
grant support from GlaxoSmithKline and Pfizer; and Dr. Klug-
man, receiving fees from Pfizer and GlaxoSmithKline for serving
on advisory boards and grant support from Pfizer. No other po-
tential 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 Ples-
sis, 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 Cor-
porate Data Warehouse, National Health Laboratory Service,
Sandringham, South Africa, for providing data for quarterly and
annual audits.
1897
 The n e w e ng l a n d j o u r na l of m e dic i n e

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