Continued occurrence of serotype 1 pneumococcal meningitis in two regions located in the meningitis belt in Ghana five years after introduction of 13-valent pneumococcal conjugate vaccine
Continued occurrence of serotype 1 pneumococcal meningitis in two regions located in the meningitis belt in Ghana five years after introduction of 13-valent pneumococcal conjugate vaccine
Catherine H. Bozio 0 1
Abass Abdul-Karim 1
John Abenyeri 1
Braimah Abubakari 1
Winfred Ofosu 1
Justina Zoya 1
Mahamoudou Ouattara 0 1
Velusamy Srinivasan 0 1
Jeni T. Vuong 0 1
David Opare 1
Franklin Asiedu-Bekoe 1
Fernanda C. Lessa 0 1
0 Division of Bacterial Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention , Atlanta, GA , United States of America, 2 Epidemic Intelligence Service, Centers for Disease Control and Prevention , Atlanta, GA , United States of America, 3 Zonal Public Health Laboratory , Tamale, Ghana, 4 Northern Regional Directorate, Tamale, Ghana, 5 Upper West Regional Directorate, Wa , Ghana , 6 National Public Health Reference Laboratory, Ghana Health Service , Accra, Ghana, 7 Ghana Health Service, Accra , Ghana
1 Editor: Jose Melo-Cristino, Universidade de Lisboa Faculdade de Medicina , PORTUGAL
Data Availability Statement: All relevant data are
included within the paper and its Supporting
Funding: This work was part of a public health
response and supported by U.S. Global Health
Competing interests: The authors have declared
that no competing interests exist.
Increases in pneumococcal meningitis were reported from Ghanaian regions that lie in the
meningitis belt in 2016±2017, despite introduction of 13-valent pneumococcal conjugate
vaccine (PCV13) in 2012 using a 3-dose schedule (6, 10, and 14 weeks). We describe
pneumococcal meningitis epidemiology in the Ghanaian Northern and Upper West regions
across two meningitis seasons.
Suspected meningitis cases were identified using World Health Organization standard
definitions. Pneumococcal meningitis was confirmed if pneumococcus was the sole pathogen
detected by polymerase chain reaction, culture, or latex agglutination in cerebrospinal fluid
collected from a person with suspected meningitis during December 2015-March 2017.
Pneumococcal serotyping was done using PCR. Annual age-specific pneumococcal
meningitis incidence (cases per 100,000 population) was calculated, adjusting for suspected
meningitis cases lacking confirmatory testing.
Among 153 pneumococcal meningitis cases, 137 (89.5%) were serotyped; 100 (73.0%)
were PCV13-type, including 85 (62.0%) that were serotype 1, a PCV13-targeted serotype.
5 years accounted for 96.7% (148/153) of cases. Comparing 2015±2016
and 2016±2017 seasons, the proportion of non-serotype 1 PCV13-type cases decreased
from 20.0% (9/45) to 4.1% (3/74) (p = 0.008), whereas the proportion that was serotype 1
was stable (71.1% (32/45) vs. 58.1% (43/74); p = 0.16). Estimated adjusted pneumococcal
meningitis incidence was 1.8 in children aged <5 years and ranged from 6.8±10.5 in older
children and adults.
High pneumococcal meningitis incidence with a large proportion of serotype 1 disease in
older children and adults suggests infant PCV13 vaccination has not induced herd
protection with this schedule in this high-transmission setting.
Seasonal increases in pneumococcal meningitis have been reported in the African meningitis
belt prior to pneumococcal conjugate vaccine (PCV) introduction, with case-fatality ratios as
high as 50% in some age groups [
]. The African meningitis belt spans from Senegal to
Ethiopia and experiences annual seasonal meningitis outbreaks with large-scale epidemics every
8±12 years [
]. These outbreaks typically occur during the dry season, as humidity, dry
harmattan wind, and dusty conditions increase the risk of bacterial meningitis [
]. Ghana has
three regions (Northern, Upper West, and Upper East regions) in the meningitis belt. Between
2002 and 2003 (pre-PCV introduction), Ghana experienced epidemics of pneumococcal
meningitis similar to those in Burkina Faso, which borders the Upper East and Upper West
Regions of Ghana. In both of these countries, the outbreaks were caused by serotype 1
pneumococci, occurred early in the meningitis season, and affected mainly children aged <5 years
]. With the support of Gavi, the Vaccine Alliance, Ghana introduced 13-valent PCV
(PCV13; serotypes 1, 3, 4, 5, 6A, 6B, 7F, 9V, 14, 18C, 19A, 19F, and 23F) in their national infant
immunization program in 2012 using a three-dose primary series schedule (3+0) at 6, 10, and
14 weeks of age without a booster or catch-up campaign. In 2013±2016, administrative
coverage estimates for three PCV13 doses were 88±93% .
In the 2015±2016 meningitis season, a large outbreak of serotype 1 pneumococcal
meningitis occurred in the Brong-Ahafo region in Ghana, which falls outside of the meningitis belt.
Nearly 60% of pneumococcal meningitis cases occurred in persons aged 5±29 years, with
children aged <5 years accounting for 4.7% of cases [
]. In contrast, the Northern, Upper West,
and Upper East regions experienced an increase in pneumococcal meningitis early in the
]. In February 2017, districts in the Upper West and Northern regions reported an
increased number of suspected meningitis cases, with four districts (two in each region)
crossing the World Health Organization (WHO) established epidemic threshold of 10 cases per
100,000 population . Most of these initial cases were confirmed to be due to pneumococcus.
We describe the epidemiology of pneumococcal meningitis across two meningitis seasons
(2015±2016, 2016±2017) in the Upper West and Northern regions of Ghana, five years after
PCV13 introduction into the routine infant immunization program.
Case-based meningitis surveillance has been ongoing in the three northern regions of Ghana
since 2013. Detailed epidemiological data (including outcome status) are collected using a
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standardized case report form for each patient who meets the WHO standard definition of
suspected meningitis . Cerebrospinal fluid (CSF) specimens collected from patients with
suspected meningitis are sent to district- or regional-level laboratories, along with a case report
form, for bacteriologic testing, which includes latex agglutination, Gram stain, and, where
available, culture. Laboratory test results are entered on the case report form. CSF specimens
and case report forms are transmitted to the Tamale Zonal Public Health laboratory (hereafter
referred to as Tamale laboratory), the reference laboratory for meningitis in Ghana, where
direct real-time polymerase chain reaction (PCR) for detection and serotyping/serogrouping
of vaccine-preventable bacterial pathogens are performed. Laboratory data are compiled into a
laboratory line list that can be merged with the surveillance data using a unique epidemiologic
number that is assigned to each suspected case.
We used case-based surveillance data to identify suspected meningitis cases with dates of
symptom onset from December 1, 2015 through March 31, 2017. We then compiled
casebased surveillance data with Tamale laboratory data. Using WHO guidelines , a suspected
case of bacterial meningitis was defined as sudden onset of fever (>38.5ÊC rectal or >38.0ÊC
axillary) plus neck stiffness, bulging fontanelle, convulsions, altered consciousness or other
meningeal signs, in a resident of any district located in the Upper West or Northern regions. A
confirmed case of bacterial meningitis was defined as a suspected case with a bacterial
pathogen detected by PCR, culture, or latex agglutination. However, a pneumococcal meningitis
case was considered to be confirmed only if pneumococcus was the single pathogen detected.
The meningitis surveillance is considered a public health activity and was granted a
nonresearch by the U.S. Centers for Disease Control and Prevention (CDC) Institutional Review
Board. The surveillance protocol was approved by Ghana Health Services Ethical Review
Committee as research with minimal risk and informed consent was waived (GHS-ERC
16.07.2016). No additional data beyond what is part of routine surveillance was obtained. A
unique identifier was assigned for each patient by the Regional Public Health Surveillance
Frozen CSF specimens from local hospitals were transported to the Tamale laboratory on ice
packs and stored at -20ÊC until testing. No isolates were sent to the Tamale laboratory. PCR
assays were used for detection of Streptococcus pneumoniae, Neisseria meningitidis, and
Haemophilus influenzae, using gene targets of lytA, sodC, and hpd, respectively [
]. A cycle
threshold (Ct) value 36 was considered positive for each bacterium.
Serotyping and/or serogrouping was done only on CSF specimens positive for any of the
pathogens tested by PCR. S. pneumoniae serotyping was done directly from S.
pneumoniaepositive CSF specimens, using seven sequential triplex PCR reactions to detect 37 serotypes
]. Briefly, the surface of the cryovials containing CSF specimen was carefully disinfected
with paper towel treated in 10% of commercial bleach and vortexed for 5±10 seconds to
homogenize the CSF. Two μl of the homogenized CSF specimen were added into PCR tube
containing 23μl of master mix, 2X Quanta Biosciences PerfeCTa qPCR ToughMix (Thermo
Fisher Inc.) and double the original concentration of primers and probes described in Pimenta
et al. [
]. PCR was performed and results were analyzed on AriaMx instrument and software
(Agilent Technologies, Santa Clara, USA).
Pneumococcal meningitis was defined as PCV13-type if any of the following S. pneumoniae
serotypes were identified in a S. pneumoniae-positive CSF specimen: 1, 3, 4, 5, 6A, 6B, 7F, 9V/
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9A, 14, 18C/18F/18B/18A, 19A, 19F, or 23F; all other pneumococcal meningitis was defined as
non-PCV13 type. Age groups were categorized as <5, 5±14, 15±29, 30±59, and 60 years.
Annual overall and age-specific pneumococcal meningitis incidence rates (cases per 100,000
population) were calculated based on data from epidemiologic week 14 in 2016 through
epidemiologic week 13 in 2017, using the population estimated from the twenty districts where
pneumococcal meningitis patients resided. To adjust for lack of confirmatory testing in some
patients, the total number of confirmed pneumococcal meningitis cases in each age and region
stratum was divided by the number of suspected cases in that stratum with CSF tested at the
Tamale laboratory; this proportion was then applied to cases without CSF samples sent to the
Tamale laboratory within that age and region stratum (hereafter referred to as ªimputedº
results). Two numerators were used for rate calculations: 1) S. pneumoniae detected by PCR,
culture, or latex agglutination, and 2) Observed plus imputed S. pneumoniae meningitis cases.
Cases were summed across region by age stratum to obtain age-specific incidence rates.
Proportions were compared across demographic variables using Pearson's chi-square or Fisher's
exact test. When comparing proportions of PCV13-type pneumococcal meningitis including
and excluding serotype 1 between two meningitis seasons, Bonferroni's correction was applied
to adjust the p-value for multiple comparisons. A p-value less than 0.05 was considered
statistically significant; the Bonferroni-corrected p-value threshold was 0.0125. All analyses were
conducted using SAS 9 4 (Cary, NC).
From December 1, 2015 through March 31, 2017, 1,614 suspected meningitis cases were
reported in the Upper West and Northern regions, of which 1,552 (96.2%) had CSF specimens
collected (Table 1). The proportion of suspected meningitis cases with CSF collected did not
significantly differ by age or region (both p>0.05). Of 1,552 CSF specimens collected, 796
(51.3%) were sent to the Tamale laboratory for further analysis. The proportions of CSF
specimens received at the Tamale laboratory were significantly lower in children aged <5 years
(40.4%) and adults aged 60 years (42.1%), compared to the other age groups (p<0.0001).
Tamale laboratory received significantly more CSF specimens from the Northern Region,
where the laboratory is located, compared to the Upper West region (70.2% vs. 41.8%;
Among the 153 confirmed pneumococcal meningitis cases, 148 (96.7%) occurred in
persons aged 5 years. Of the 98 pneumococcal meningitis cases with a known outcome status,
28 (28.6%) patients died. The case-fatality ratio for pneumococcal meningitis was similar in
older children and adults: 0% (0/2) in children aged <5 years, 27.6% (8/29) in ages 5±14 years,
25.0% (8/32) in ages 15±29 years, 25.8% (8/31) in ages 30±59 years, and 100% (4/4) in ages
Of the 153 pneumococcal meningitis cases, 92 were positive by PCR, six by culture, three by
latex agglutination, and 52 by multiple methods; 16 (10.5%) did not have a CSF specimen
available at Tamale laboratory for serotyping. Of the 137 pneumococcal meningitis cases
serotyped, 100 (73.0%) were PCV13-type, 35 (25.5%) were non-PCV13 type, and two (1.5%) had
multiple serotypes detected and were considered inconclusive. Of the 100 PCV13-type
pneumococcal meningitis cases, 85 (85.0%) were serotype 1; followed by serotype 5 (4.0%), serotype
23F (3.0%), serotype 18C/18F/18B/18A (2.0%), serotype 3 (1.0%), serotype 4 (1.0%), serotype
6A/6B (1.0%), serotype 14 (1.0%), serotype 19A (1.0%), and serotype 19F (1.0%). Of the 35
non-PCV13 serotypes, 19 (54.3%) were serotype 12F/12A/12B/44/46 and 16 (45.7%) were
negative for the serotypes included in the PCR reaction. Of the 85 serotype 1 pneumococcal
meningitis cases, one (1.2%) occurred in persons aged <5 years, 33 (38.8%) in persons aged 5±14
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S. N. H. >1
pneumoniae meningitidis influenzae pathogen
Confirmed by direct real-time polymerase chain reaction (PCR), culture, or latex agglutination as Streptococcus pneumoniae, Neisseria meningitidis, and/or
²Of the 14 specimens that had more than 1 pathogen detected, 10 had N. meningitidis and S. pneumoniae detected, and 4 had S. pneumoniae and H. influenzae detected.
years, 28 (32.9%) in persons aged 15±29 years, 19 (22.4%) in persons aged 30±59 years, and
three (3.5%) in persons aged 60 years; age was not reported for one person. Among the four
confirmed pneumococcal meningitis cases in children aged <5 years, two were PCV13-type:
one was serotype 1 and one was 19F; both had unknown PCV13 vaccination status.
During the first meningitis season (December 1, 2015-June 30, 2016 [epidemiologic weeks
48±26 in 2015±2016]), 897 suspected meningitis cases were reported; 373 CSF specimens were
sent to the Tamale laboratory, of which 59 had pneumococcus detected. Thirty-seven of these
59 pneumococcal meningitis cases were included in a previous publication describing the 2016
meningitis outbreak in Ghana [
]. In comparison, during the second meningitis season
(December 1, 2016-March 31, 2017 [epidemiologic weeks 48±13 in 2016±2017]), 473
suspected meningitis cases were reported; 354 CSF specimens were sent to the Tamale laboratory,
of which 75 had pneumococcus detected (Fig 1). The proportion of PCV13 serotypes among
serotyped pneumococcal meningitis cases significantly decreased from 91.1% (41/45) to 62.2%
(46/74) (p = 0.0004). The proportion that were non-serotype 1 PCV13-type decreased from
20.0% (9/45) to 4.1% (3/74) (p = 0.008) between the two meningitis seasons, while the
proportion that were serotype 1 was stable (71.1% (32/45) in season 1 vs. 58.1% (43/74) in season 2
(p = 0.16)). However, the proportion of serotyped pneumococcal meningitis due to 12F/12A/
12B/44/46, a non-PCV13 serotype, increased from 4.4% (2/45) in the first season to 18.9% (14/
74) in the second season; however, this increase was not significant after Bonferroni
Among serotyped pneumococcal cases in persons aged 5 years, 97 (74.0%) were
PCV13-type, including 80 (64.0%) serotype 1. Further, the proportion that were serotype 1
ranged from 48.7% in persons aged 30±59 years to 75.0% in persons aged 5±14 years, but the
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Fig 1. Epidemiologic curve of confirmed pneumococcal meningitis cases, serotyped cases, PCV13 serotypes, and
serotype 1 by epidemiologic week between December 1, 2015 and March 31, 2017. S. pneumoniae detected in
cerebrospinal fluid (CSF) by direct real-time polymerase chain reaction or latex or isolated from CSF by culture.
overall pneumococcal serotype distribution was not statistically different across age groups
(p = 0.058) (Fig 2).
From epidemiologic weeks 14±13 in 2016±2017, 85 confirmed pneumococcal meningitis
cases were reported from 20 districts for an annual observed incidence of 4.33/100,000
(Table 2). Children aged <5 years had the lowest observed pneumococcal meningitis incidence
(0.64 cases per 100,000), compared to other age groups. After adjusting for suspected
meningitis cases lacking confirmatory testing, the imputed incidence increased by 1.4±2.8 times. These
increases were highest among persons aged <5 and 60 years (2.8 and 2.3 times higher,
respectively), as they had the lowest proportions of cases with CSF collected for which
specimens were received at the Tamale laboratory. The imputed incidence was highest in adults
aged 60 years and 30±59 years (10.45 and 10.51 per 100,000 population, respectively)
Fig 2. Serotype distribution of pneumococcal meningitis cases by age group, December 1, 2015-March 31, 2017.
Includes pneumococcal samples negative for the 37 serotypes tested by PCR.
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(cases per 100,000 population)
Despite Ghana's introduction of PCV13 in 2012 and subsequent high vaccination coverage,
vaccine-type pneumococci continues to be a main cause of bacterial meningitis in the
Northern and Upper West regions. Although children aged <5 years had the lowest burden of
pneumococcal meningitis, most pneumococcal meningitis cases and serotype 1 cases occurred in
persons aged 5 years, who were not age-eligible to have received PCV13. Additionally, across
the two meningitis seasons, the proportion of pneumococcal meningitis cases caused by
serotype 1 did not change although the proportion caused by other PCV13-types declined. These
findings suggest that, while PCV13 introduction produced the anticipated direct effect in
Ghana, herd immunity, at least for serotype 1, has not yet been established.
From pre-PCV introduction data in West African countries, including Ghana [
1, 4, 5, 13
pneumococcal meningitis affected all ages, with highest rates in children aged <5 years. From
2015±2017, Ghanaian children aged <5 years had dramatically lower rates compared to those
pre-PCV introduction, suggesting PCV13's direct effect. In Ghana's neighboring country,
Burkina Faso, where PCV13 was introduced in 2013 using a 3+0 schedule, children aged <1 and
1±4 years had the largest decreases in rates for confirmed pneumococcal meningitis,
PCV13-type pneumococcal meningitis, and serotype 1 pneumococcal meningitis by 2015 .
In Mozambique, following PCV10 introduction using a 3+0 schedule, the proportion of
confirmed bacterial meningitis cases that were pneumococcal decreased from 33.6% in 2013 to
1.9% in 2015 among children aged <5 years [
]. Finally, in South Africa, the incidence of
serotype 1 invasive pneumococcal disease (IPD) (cases per 100,000 population) decreased
significantly in children aged <1 year (2003±2008: 1.8 cases vs 2013: 0.3 cases) and 1±4 years
(2003±2008: 1.3 cases vs 2013: 0.3 cases), after PCV13 introduction using a schedule of two
primary doses and one booster dose (2+1) [
Despite high PCV13 vaccine coverage in young children, the burden of PCV13-type
pneumococcal meningitis, especially serotype 1, remains high in older children and adults in
Ghana, suggesting that herd effects for serotype 1 have not yet been established. A higher
prevalence of risk factors for other bacterial diseases spread through droplets among adults may
contribute to this shift in the age distribution of disease burden [
]. During the 2015±2016
pneumococcal meningitis outbreak in Ghana's Brong-Ahafo region, 94.1% of confirmed
pneumococcal meningitis cases were aged 5 years; among persons aged 5 years, 71.4% had
serotype 1 disease [
]. In Burkina Faso, serotype 1 pneumococcal meningitis incidence in
children aged 5±14 years also remained stable after PCV13 introduction using a 3+0 schedule
]. In contrast, in South Africa, which adopted a 2+1 schedule, serotype 1 IPD incidence
decreased significantly by 2013 across all age groups except persons aged >64 years [
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The lack of indirect effect of PCV for serotype 1 using a 3+0 schedule observed in countries
in the meningitis belt raises concerns. A trial of PCV9 (which includes serotype 1) efficacy in
the Gambia showed that PCV9 was not effective against serotype 1 disease, although this was
based on only six isolates [
]. In a randomized trial comparing four PCV13 schedules, the
immune response (one month after the primary series) against serotype 1 with the 2-3-4
month schedule (which is most similar to Ghana's and Burkina Faso's schedules) was inferior
compared to the 2-4-6 month, 3±5 month, and 2±4 month schedules [
]. Waning immunity
for serotype 1 is a concern for PCV13 schedules without a booster dose [
]. In the 12 IPD
cases of serotype 1 vaccine failures identified from PCV9 trials in Africa, the median age was
20.9 months (range 18.4±27.5 months), which may reflect failures in the absence of a booster
dose . Additionally, in a PCV10 trial, opsonophagocytic activity against serotype 1 was
lower relative to other PCV-types one month after the primary series [
], which can impact
both carriage and disease. Thus, a booster dose after the primary series may be needed to
provide sufficient protection against serotype 1 disease.
The relative decline of non-serotype 1 PCV13-types among serotyped pneumococcal
meningitis cases was followed by an increase in serotype 12F/12A/12B/44/46. Serotype 12F was the
second most common serotype in the Brong-Ahafo outbreak in 2016 [
] and is associated with
antimicrobial resistance [
], leading to concerns that this serotype might emerge as a source
of replacement disease post-PCV introduction.
Our analysis has limitations. First, not all CSF specimens collected were sent to Tamale for
PCR testing. In particular, a larger proportion of CSF specimens collected from the Northern
region compared to the Upper West region were received at the Tamale laboratory, although
we accounted for this difference in imputing pneumococcal meningitis rates for suspected
meningitis cases without confirmatory testing. Thus, it is possible that we underestimated the
number of bacterial meningitis cases. Additionally, 13 (8.4%) patients with pneumococcal
meningitis had another pathogen detected. These cases were conservatively excluded from the
analyses due to concerns of potential cross-contamination given that meningitis caused by
more than one bacterial pathogen is rare. Therefore, it is possible that the number of
pneumococcal meningitis cases was underestimated.
Despite high PCV13 vaccination coverage, Ghana continues to experience a substantial
burden of pneumococcal meningitis, primarily affecting older children and adults, in the
Northern and Upper West regions. It is unclear whether PCV vaccination in infancy prevents
pneumococcal meningitis outbreaks, and concerns about waning immunity for serotype 1 in
PCV13-vaccinated persons in countries that adopted a 3+0 schedule have been raised .
Alternative vaccination strategies could be explored to protect persons of all ages from
pneumococcal meningitis, especially that due to serotype 1. Ongoing work to identify the drivers of
carriage and transmission, and continued monitoring of the epidemiology of pneumococcal
meningitis could help to inform development and application of these strategies, particularly
in the African meningitis belt region, where meningitis incidence is high and epidemics occur.
The authors thank the Upper West and Northern regional offices for their support and efforts
in case-based surveillance. We also appreciate Azure Stebleson and Gladys Ayeebo at the
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Tamale Zonal Public Health laboratory for their laboratory technical skills and Chastity
Walker for her assistance with logistics for this public health response.
The findings and conclusions in this report are those of the authors and do not necessarily
represent the official position of the Ghana Health Service or the Centers for Disease Control
Conceptualization: Catherine H. Bozio, Abass Abdul-Karim, Fernanda C. Lessa.
Data curation: Abass Abdul-Karim, John Abenyeri, Braimah Abubakari, Winfred Ofosu,
Justina Zoya, Franklin Asiedu-Bekoe.
Formal analysis: Catherine H. Bozio.
Investigation: Catherine H. Bozio, Abass Abdul-Karim, Mahamoudou Ouattara, Velusamy
Srinivasan, Jeni T. Vuong, David Opare, Fernanda C. Lessa.
Methodology: Catherine H. Bozio, Abass Abdul-Karim, Fernanda C. Lessa.
Supervision: Fernanda C. Lessa.
Validation: Abass Abdul-Karim, David Opare.
Writing ± original draft: Catherine H. Bozio, Abass Abdul-Karim.
Writing ± review & editing: Catherine H. Bozio, Abass Abdul-Karim, John Abenyeri,
Braimah Abubakari, Winfred Ofosu, Justina Zoya, Mahamoudou Ouattara, Velusamy
Srinivasan, Jeni T. Vuong, David Opare, Franklin Asiedu-Bekoe, Fernanda C. Lessa.
9 / 10
1. Gessner BD , Mueller JE , Yaro S. African meningitis belt pneumococcal disease epidemiology indicates a need for an effective serotype 1 containing vaccine, including for older children and adults . BMC Infect Dis . 2010 ; 10 : 22 . https://doi.org/10.1186/ 1471 -2334-10-22 PMID: 20146815; PubMed Central PMCID : PMC2838886 .
2. Greenwood B. Manson Lecture . Meningococcal meningitis in Africa. Trans R Soc Trop Med Hyg . 1999 ; 93 ( 4 ): 341 ± 53 . PMID: 10674069 .
3. Codjoe SN , Nabie VA . Climate change and cerebrospinal meningitis in the Ghanaian meningitis belt . Int J Environ Res Public Health . 2014 ; 11 ( 7 ): 6923 ± 39 . Epub 2014/07/09. https://doi.org/10.3390/ ijerph110706923 PMID: 25003550; PubMed Central PMCID : PMC4113853 .
4. Leimkugel J , Adams Forgor A , Gagneux S , Pfluger V , Flierl C , Awine E , et al. An outbreak of serotype 1 Streptococcus pneumoniae meningitis in northern Ghana with features that are characteristic of Neisseria meningitidis meningitis epidemics . J Infect Dis . 2005 ; 192 ( 2 ): 192 ±9. https://doi.org/10.1086/ 431151 PMID: 15962213 .
5. Yaro S , Lourd M , Traore Y , Njanpop-Lafourcade BM , Sawadogo A , Sangare L , et al. Epidemiological and molecular characteristics of a highly lethal pneumococcal meningitis epidemic in Burkina Faso . Clin Infect Dis . 2006 ; 43 ( 6 ): 693 ± 700 . https://doi.org/10.1086/506940 PMID: 16912941 .
6. World Health Organization. WHO-UNICEF estimates of 13-valent Pneumococcal Conjugate Vaccine (PCV13) coverage 2017 . Available from: http://apps.who.int/immunization_monitoring/globalsummary/ timeseries/tswucoveragepcv3.html ( accessed September 7 , 2017 ).
7. Kwambana-Adams BA , Asiedu-Bekoe F , Sarkodie B , Afreh OK , Kuma GK , Owusu-Okyere G , et al. An outbreak of pneumococcal meningitis among older children ( 5 years) and adults after the implementation of an infant vaccination programme with the 13-valent pneumococcal conjugate vaccine in Ghana . BMC Infect Dis . 2016 ; 16 ( 1 ): 575 . https://doi.org/10.1186/s12879-016-1914-3 PMID: 27756235; PubMed Central PMCID : PMC5070171 .
8. Aku FY , Lessa FC , Asiedu-Bekoe F , Balagumyetime P , Ofosu W , Farrar J , et al. Meningitis Outbreak Caused by Vaccine-Preventable Bacterial PathogensÐNorthern Ghana , 2016 . MMWR Morb Mortal Wkly Rep . 2017 ; 66 ( 30 ): 806 ± 10 . https://doi.org/10.15585/mmwr.mm6630a2 PMID: 28771457 .
World Health Organization. Technical Guidelines for Integrated Disease Surveillance and Response in the African Region, 2nd Edition . Brazzaville: 2010 .
World Health Organization-AFRO. Standard operating procedures for enhanced meningitis surveillance in Africa: World Health Organization Regional Office for Africa . 2009 .
11. Vuong J , Collard JM , Whaley MJ , Bassira I , Seidou I , Diarra S , et al. Development of Real-Time PCR Methods for the Detection of Bacterial Meningitis Pathogens without DNA Extraction . PLoS One . 2016 ; 11 ( 2 ):e0147765. https://doi.org/10.1371/journal.pone.0147765 PMID: 26829233; PubMed Central PMCID : PMC4735509 .
12. Pimenta FC , Roundtree A , Soysal A , Bakir M , du Plessis M , Wolter N , et al. Sequential triplex real-time PCR assay for detecting 21 pneumococcal capsular serotypes that account for a high global disease burden . J Clin Microbiol . 2013 ; 51 ( 2 ): 647 ± 52 . https://doi.org/10.1128/JCM.02927-12 PMID: 23224094; PubMed Central PMCID : PMC3553924 .
13. Kambire D , Soeters HM , Ouedraogo-Traore R , Medah I , Sangare L , Yameogo I , et al. Nationwide Trends in Bacterial Meningitis before the Introduction of 13-Valent Pneumococcal Conjugate VaccineBurkina Faso , 2011 ± 2013 . PLoS One . 2016 ; 11 ( 11 ):e0166384. https://doi.org/10.1371/journal.pone. 0166384 PMID: 27832151; PubMed Central PMCID : PMC5104358 .
14. Kambire D , Soeters HM , Ouedraogo-Traore R , Medah I , Sangare L , Yameogo I , et al. Early impact of 13-valent pneumococcal conjugate vaccine on pneumococcal meningitis- Burkina Faso , 2014 ± 2015 . J Infect . 2017 . https://doi.org/10.1016/j.jinf. 2017 . 12 .002 PMID: 29253559 .
15. Nhantumbo AA , Weldegebriel G , Katsande R , de Gouveia L , Come CE , Cuco AZ , et al. Surveillance of impact of PCV-10 vaccine on pneumococcal meningitis in Mozambique , 2013 ± 2015 . PLoS One . 2017 ; 12 ( 6 ):e0177746. https://doi.org/10.1371/journal.pone.0177746 PMID: 28604773; PubMed Central PMCID : PMC5467806 .
16. von Mollendorf C , Cohen C , Tempia S , Meiring S , de Gouveia L , Quan V , et al. Epidemiology of Serotype 1 Invasive Pneumococcal Disease, South Africa , 2003 ± 2013 . Emerg Infect Dis . 2016 ; 22 ( 2 ): 261 ± 70 . https://doi.org/10.3201/eid2202.150967 PMID: 26812214; PubMed Central PMCID : PMC4734528 .
17. Muthumbi E , Lowe BS , Muyodi C , Getambu E , Gleeson F , Scott JAG . Risk factors for communityacquired pneumonia among adults in Kenya: a case-control study . Pneumonia (Nathan) . 2017 ; 9 : 17 . Epub 2017/12/07. https://doi.org/10.1186/s41479-017-0041-2 PMID: 29209590; PubMed Central PMCID : PMC5702239 .
18. Saaka M , Okoko BJ , Kohberger RC , Jaffar S , Enwere G , Biney EE , et al. Immunogenicity and serotypespecific efficacy of a 9-valent pneumococcal conjugate vaccine (PCV-9) determined during an efficacy trial in The Gambia . Vaccine. 2008 ; 26 ( 29 ±30): 3719 ± 26 . https://doi.org/10.1016/j.vaccine. 2008 . 04 .066 PMID: 18514974 .
19. Spijkerman J , Veenhoven RH , Wijmenga-Monsuur AJ , Elberse KE , van Gageldonk PG , Knol MJ , et al. Immunogenicity of 13-valent pneumococcal conjugate vaccine administered according to 4 different primary immunization schedules in infants: a randomized clinical trial . JAMA . 2013 ; 310 ( 9 ): 930 ±7. https:// doi.org/10.1001/jama. 2013 .228052 PMID: 24002279 .
20. Jayasinghe S , Menzies R , Chiu C , Toms C , Blyth CC , Krause V , et al. Long-term Impact of a "3 + 0" Schedule for 7- and 13-Valent Pneumococcal Conjugate Vaccines on Invasive Pneumococcal Disease in Australia , 2002 ±2014. Clin Infect Dis . 2017 ; 64 ( 2 ): 175 ± 83 . https://doi.org/10.1093/cid/ciw720 PMID: 27986682 .
21. Klugman KP , Madhi SA , Adegbola RA , Cutts F , Greenwood B , Hausdorff WP . Timing of serotype 1 pneumococcal disease suggests the need for evaluation of a booster dose . Vaccine . 2011 ; 29 ( 18 ): 3372 ±3. https://doi.org/10.1016/j.vaccine. 2011 . 02 .089 PMID: 21396901 .
22. Vesikari T , Wysocki J , Chevallier B , Karvonen A , Czajka H , Arsene JP , et al. Immunogenicity of the 10- valent pneumococcal non-typeable Haemophilus influenzae protein D conjugate vaccine (PHiD-CV) compared to the licensed 7vCRM vaccine . Pediatr Infect Dis J . 2009 ; 28 ( 4 Suppl) : S66 ± 76 . https://doi. org/10.1097/INF.0b013e318199f8ef PMID: 19325449 .
23. Chaguza C , Cornick JE , Andam CP , Gladstone RA , Alaerts M , Musicha P , et al. Population genetic structure, antibiotic resistance, capsule switching and evolution of invasive pneumococci before conjugate vaccination in Malawi . Vaccine. 2017 ; 35 (35 Pt B): 4594 ± 602 . https://doi.org/10.1016/j.vaccine. 2017 . 07 .009 PMID: 28711389; PubMed Central PMCID : PMC5571440 .
World Health Organization. Pneumococcal meningitis outbreaks in sub-Saharan Africa . Weekly Epidemiological Record, No. 23 , 10 June 2016 . 2016 .