Genomic diversity and antimicrobial susceptibility of invasive Neisseria meningitidis in South Africa, 2016-2021.

BACKGROUND: Invasive meningococcal isolates in South Africa have in previous years (<2008) been characterized by serogroup B, C, W and Y lineages over time, with penicillin intermediate resistance (peni) at 6%. We describe the population structure and genomic markers of peni among invasive meningococcal isolates in South Africa, 2016-2021. METHODS: Meningococcal isolates were collected through national, laboratory-based invasive meningococcal disease (IMD) surveillance. Phenotypic antimicrobial susceptibility testing and whole-genome sequencing were performed, and the mechanism of reduced penicillin susceptibility was assessed in silico. RESULTS: Of 585 IMD cases reported during the study period, culture and PCR-based capsular group was determined for 477/585 (82%); and 241/477 (51%) were sequenced. Predominant serogroups included NmB (210/477; 44%), NmW (116/477; 24%), NmY (96/477; 20%) and NmC (48/477; 10%). Predominant clonal complexes (CC) were CC41/44 in NmB (27/113; 24%), CC11 in NmW (46/56; 82%), CC167 in NmY (23/44; 53%), and CC865 in NmC (9/24; 38%). Peni was detected in 16% (42/262) of isolates, and was due to the presence of a penA mosaic, with the majority harboring penA7, penA9 or penA14. CONCLUSION: IMD lineages circulating in South Africa were consistent with those circulating prior to 2008, however peni was higher than previously reported, and occurred in a variety of lineages.

Household Transmission of Severe Acute Respiratory Syndrome Coronavirus 2 From Adult Index Cases With and Without Human Immunodeficiency Virus in South Africa, 2020-2021: A Case-Ascertained, Prospective, Observational Household Transmission Study.

BACKGROUND: In South Africa, 19% of adults are living with human immunodeficiency virus (HIV; LWH). Few data on the influence of HIV on severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) household transmission are available. METHODS: We performed a case-ascertained, prospective household transmission study of symptomatic adult index SARS-CoV-2 cases LWH and not living with HIV (NLWH) and their contacts from October 2020 to September 2021. Households were followed up 3 times a week for 6 weeks to collect nasal swabs for SARS-CoV-2 testing. We estimated household cumulative infection risk (HCIR) and duration of SARS-CoV-2 positivity (at a cycle threshold value <30 as proxy for high viral load). RESULTS: HCIR was 59% (220 of 373), not differing by index HIV status (60% LWH vs 58% NLWH). HCIR increased with index case age (35-59 years: adjusted OR [aOR], 3.4; 95% CI, 1.5-7.8 and ≥60 years: aOR, 3.1; 95% CI, 1.0-10.1) compared with 18-34 years and with contacts' age, 13-17 years (aOR, 7.1; 95% CI, 1.5-33.9) and 18-34 years (aOR, 4.4; 95% CI, 1.0-18.4) compared with <5 years. Mean positivity was longer in cases LWH (adjusted hazard ratio, 0.4; 95% CI, .1-.9). CONCLUSIONS: Index HIV status was not associated with higher HCIR, but cases LWH had longer positivity duration. Adults aged >35 years were more likely to transmit and individuals aged 13-34 to be infected SARS-CoV-2 in the household. As HIV infection may increase transmission, health services must maintain HIV testing and antiretroviral therapy initiation.

Excess Invasive Meningococcal Disease Associated With Seasonal Influenza, South Africa, 2003-2018.

BACKGROUND: Invasive meningococcal disease (IMD) is a devastating illness with high mortality rates. Like influenza, endemic IMD is seasonal, peaking in winter. Studies suggest that circulation of influenza virus may influence the timing and magnitude of IMD winter peaks. METHODS: This ecological study used weekly data from 2 nationwide surveillance programs: Viral Watch (proportion of outpatient influenza-positive cases from throat or nasal swab samples) and GERMS-SA (laboratory-confirmed cases of IMD), occurring across South Africa from 2003 through 2018 in all age bands. A bivariate time series analysis using wavelet transform was conducted to determine cocirculation of the diseases and the time lag between the peak seasons. We modeled excess meningococcal disease cases attributable to influenza cocirculation, using univariate regression spline models. Stata and R statistical software packages were used for the analysis. RESULTS: A total of 5256 laboratory-confirmed IMD cases were reported, with an average annual incidence of 0.23 episodes per 100 000 population and a mean seasonal peak during week 32 (±3 weeks). Forty-two percent of swab samples (10 421 of 24 741) were positive for influenza during the study period. The mean peak for all influenza occurred at week 26 (±4 weeks). There was an average lag time of 5 weeks between annual influenza and IMD seasons. Overall, 5% (1%-9%) of IMD cases can be attributable to influenza cocirculation, with, on average, 17 excess IMD cases per year attributable to influenza. CONCLUSIONS: A quantifiable proportion of IMD in South Africa is associated with influenza cocirculation; therefore, seasonal influenza vaccination may have an effect on preventing a small portion of IMD in addition to preventing influenza.

Streptococcus pneumoniae Serotypes Associated with Death, South Africa, 2012-2018.

The Streptococcus pneumoniae polysaccharide capsule plays a role in disease severity. We assessed the association of serotype with case-fatality ratio (CFR) in invasive pneumococcal disease (IPD) and meningitis in South Africa, 2012-2018 (vaccine era), using multivariable logistic regression by manual backward elimination. The most common serotypes causing IPD were 8 and 19A. In patients <15 years of age, serotypes associated with increased CFR in IPD, compared with serotype 8 and controlling for confounding factors, were 11A, 13, 19F, 15A, and 6A. None of these serotypes were associated with increased CFR in meningitis. Among IPD patients >15 years of age, serotype 15B/C was associated with increased CFR. Among meningitis patients of all ages, serotype 1 was associated with increased CFR. PCV13 serotypes 1, 3, 6A, 19A, and 19F should be monitored, and serotypes 8, 12F, 15A, and 15B/C should be considered for inclusion in vaccines to reduce deaths caused by S. pneumoniae.

The Burden of Invasive Bacterial Disease and the Impact of 10-Valent Pneumococcal Conjugate Vaccine in Children <5 years hospitalized for Meningitis in Lusaka, Zambia, 2010-2019.

BACKGROUND: Despite the availability of vaccines, invasive bacterial diseases remain a public health concern and cause childhood morbidity and mortality. We investigated the characteristics of etiological agents causing bacterial meningitis in children <5 years in the years pre- (2010-2012) and post- (2014-2019) 10-valent pneumococcal conjugate vaccine (PCV10) introduction in Zambia. METHODS: Streptococcus pneumoniae (Spn), Haemophilus influenzae (Hi), and Neisseria meningitidis (Nm) from cerebrospinal fluid (CSF) were identified by microbiological culture and/or real-time polymerase chain reaction. RESULTS: During the surveillance period, a total of 3811 children were admitted with suspected meningitis, 16% (598 of 3811) of which were probable cases. Bacterial meningitis was confirmed in 37% (221 of 598) of the probable cases. Spn pneumoniae, Hi, and Nm accounted for 67% (148 of 221), 14% (31 of 221), and 19% (42 of 221) of confirmed cases, respectively. Thirty-six percent of pneumococcal meningitis was caused by 10-valent pneumococcal conjugate vaccine (PCV10) serotypes, 16% 13-valent pneumococcal conjugate vaccine and 39% by nonvaccine serotype (NVS). There was an association between the introduction of PCV10 vaccination and a decrease in both Spn meningitis and the proportion of PVC10 serotypes in the postvaccination period. Antimicrobial susceptibility of 47 Spn isolates revealed 34% (16 of 47) penicillin resistance. The 31 serotyped Hi accounted for 74% type b (Hib) and 10% type a (Hia). All 42 serogrouped Nm belonged to serogroup W. CONCLUSIONS: There was a decline in pneumococcal meningitis and proportion of PCV10 serotypes in the postvaccination period. However, the serotype replacement with non-PCV10 serotypes and penicillin resistance warrant continued surveillance to inform policy.

Decline in Vaccine-Type Streptococcus pneumoniae Serotypes Following Pneumococcal Conjugate Vaccine Introduction in Madagascar.

BACKGROUND: The 10-valent conjugate vaccine (PCV10) was introduced into the Extended Program on Immunization in Madagascar. We assessed the impact of PCV10 on the targeted pneumococcal serotypes among children < 5 years of age at Centre Hospitalier Universitaire Mère Enfant Tsaralalàna. METHOD: Between 2012 and December 2018, cerebrospinal fluid (CSF) samples were collected and tested for S. pneumoniae by culture, and antigen tests. The Sentinel Site Laboratory (SSL) referred available CSF samples to the Regional Reference Laboratory (RRL) for real-time polymerase chain reaction confirmatory testing and serotyping. RESULTS: In total, 3616 CSF specimens were collected. The SSL referred 2716 to the RRL; 125 were positive for S. pneumoniae. At the RRL, 115 samples that tested positive for S. pneumoniae were serotyped; PCV10 serotypes accounted for 20%. Compared to the pre-PCV period, the proportion of S. pneumoniae detected declined from 22% to 6.6%, (P < .05), the proportion of PCV10 serotypes as the cause of pneumococcal meningitis cases declined by 26% following vaccine introduction. CONCLUSIONS: In our findings, PCV10 introduction resulted in a decline of meningitis caused by S. pneumoniae and PCV10 vaccine serotypes.

The Role of Molecular Testing in Pediatric Meningitis Surveillance in Southern and East African Countries, 2008-2017.

BACKGROUND: As part of the global Invasive Bacterial Vaccine-Preventable Diseases Surveillance Network, 12 African countries referred cerebrospinal fluid (CSF) samples to South Africa's regional reference laboratory. We evaluated the utility of real-time polymerase chain reaction (PCR) in detecting and serotyping/grouping Haemophilus influenzae, Neisseria meningitidis, and Streptococcus pneumoniae (HNS). METHODS: From 2008 to 2017, CSF samples collected from children <5 years old with suspected meningitis underwent routine microbiology testing in-country, and 11 680 samples were submitted for HNS PCR at the regional reference laboratory. Unconditional logistic regression, with adjustment for geographic location, was performed to identify factors associated with PCR positivity. RESULTS: The overall HNS PCR positivity rate for all countries was 10% (1195 of 11 626 samples). In samples with both PCR and culture results, HNS PCR positivity was 11% (744 of 6747 samples), and HNS culture positivity was 3% (207 of 6747). Molecular serotype/serogroup was assigned in 75% of PCR-positive specimens (762 of 1016). Compared with PCR-negative CSF samples, PCR-positive samples were more often turbid (adjusted odds ratio, 6.80; 95% confidence interval, 5.67-8.17) and xanthochromic (1.72; 1.29-2.28), had elevated white blood cell counts (6.13; 4.71-7.99) and high protein concentrations (5.80; 4.34-7.75), and were more often HNS culture positive (32.70; 23.18-46.12). CONCLUSION: PCR increased detection of vaccine-preventable bacterial meningitis in countries where confirmation of suspected meningitis cases is impeded by limited culture capacity.

The Global Landscape of Pediatric Bacterial Meningitis Data Reported to the World Health Organization-Coordinated Invasive Bacterial Vaccine-Preventable Disease Surveillance Network, 2014-2019.

BACKGROUND: The World Health Organization (WHO) coordinates the Global Invasive Bacterial Vaccine-Preventable Diseases (IB-VPD) Surveillance Network to support vaccine introduction decisions and use. The network was established to strengthen surveillance and laboratory confirmation of meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. METHODS: Sentinel hospitals report cases of children <5 years of age hospitalized for suspected meningitis. Laboratories report confirmatory testing results and strain characterization tested by polymerase chain reaction. In 2019, the network included 123 laboratories that follow validated, standardized testing and reporting strategies. RESULTS: From 2014 through 2019, >137 000 suspected meningitis cases were reported by 58 participating countries, with 44.6% (n = 61 386) reported from countries in the WHO African Region. More than half (56.6%, n = 77 873) were among children <1 year of age, and 4.0% (n = 4010) died among those with reported disease outcome. Among suspected meningitis cases, 8.6% (n = 11 798) were classified as probable bacterial meningitis. One of 3 bacterial pathogens was identified in 30.3% (n = 3576) of these cases, namely S. pneumoniae (n = 2177 [60.9%]), H. influenzae (n = 633 [17.7%]), and N. meningitidis (n = 766 [21.4%]). Among confirmed bacterial meningitis cases with outcome reported, 11.0% died; case fatality ratio varied by pathogen (S. pneumoniae, 12.2%; H. influenzae, 6.1%; N. meningitidis, 11.0%). Among the 277 children who died with confirmed bacterial meningitis, 189 (68.2%) had confirmed S. pneumoniae. The proportion of pneumococcal cases with pneumococcal conjugate vaccine (PCV) serotypes decreased as the number of countries implementing PCV increased, from 77.8% (n = 273) to 47.5% (n = 248). Of 397 H. influenzae specimens serotyped, 49.1% (n = 195) were type b. Predominant N. meningitidis serogroups varied by region. CONCLUSIONS: This multitier, global surveillance network has supported countries in detecting and serotyping the 3 principal invasive bacterial pathogens that cause pediatric meningitis. Streptococcus pneumoniae was the most common bacterial pathogen detected globally despite the growing number of countries that have nationally introduced PCV. The large proportions of deaths due to S. pneumoniae reflect the high proportion of meningitis cases caused by this pathogen. This global network demonstrated a strong correlation between PCV introduction status and reduction in the proportion of pneumococcal meningitis infections caused by vaccine serotypes. Maintaining case-based, active surveillance with laboratory confirmation for prioritized vaccine-preventable diseases remains a critical component of the global agenda in public health.The World Health Organization (WHO)-coordinated Invasive Bacterial Vaccine-Preventable Disease (IB-VPD) Surveillance Network reported data from 2014 to 2019, contributing to the estimates of the disease burden and serotypes of pediatric meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis.

Human Immunodeficiency Virus Infection Is Associated With Increased Meningococcal Carriage Acquisition Among First-year Students in 2 South African Universities.

BACKGROUND: Invasive meningococcal disease clusters occur among university students and may reflect higher carriage prevalence among this population. We aimed to measure meningococcal carriage prevalence, acquisition, and risk factors among first-year university students in South Africa. METHODS: In summer-autumn 2017, after consenting to participate, we collected oropharyngeal swabs and questionnaires on carriage risk factors and tested students for HIV at 2 universities, during registration week (survey 1) and 6-8 weeks later (survey 2). Meningococci were detected by culture and polymerase chain reaction. RESULTS: We enrolled 2120 students at registration. Mean age was 18.5 years, 59% (1252/2120) were female and 0.8% (16/1984) had HIV. Seventy-eight percent of students returned for survey 2 (1655/2120). Among the cohort, carriage prevalence was 4.7% (77/1655) at registration, increasing to 7.9% (130/1655) at survey 2: 5.0% (83) acquired new carriage, 2.8% (47) had persistent carriage, 1.8% (30) cleared the initial carriage, and 90.3% (1495) remained carriage free. At both surveys, nongenogroupable meningococci predominated, followed by genogroups Y, B, W, and C. On multinomial analysis, risk factors for carriage acquisition included attending nightclubs (adjusted relative risk ratio [aRRR], 2.1; 95% CI, 1.1-4.0), having intimate kissing partners (aRRR, 1.8; 95% CI, 1.1-2.9) and HIV (aRRR, 5.0; 95% CI, 1.1-24.4). CONCLUSIONS: Meningococcal carriage among first-year university students increased after 2 months. Sociobehavioral risk factors were associated with increased carriage for all analyses. HIV was associated with carriage acquisition. Until vaccination programs become mandatory in South African universities, data suggest that students with HIV could benefit most from meningococcal vaccination.

Pneumococcal serotype determines growth and capsule size in human cerebrospinal fluid.

BACKGROUND: The polysaccharide capsule is a major virulence factor of S. pneumoniae in diseases such as meningitis. While some capsular serotypes are more often found in invasive disease, high case fatality rates are associated with those serotypes more commonly found in asymptomatic colonization. We tested whether growth patterns and capsule size in human cerebrospinal fluid depends on serotype using a clinical isolate of S. pneumoniae and its capsule switch mutants. RESULTS: We found that the growth pattern differed markedly from that in culture medium by lacking the exponential and lysis phases. Growth in human cerebrospinal fluid was reduced when strains lost their capsules. When a capsule was present, growth was serotype-specific: high carriage serotypes (6B, 9 V, 19F and 23F) grew better than low carriage serotypes (7F, 14, 15B/C and 18C). Growth correlated with the case-fatality rates of serotypes reported in the literature. Capsule size in human cerebrospinal fluid also depended on serotype. CONCLUSIONS: We propose that serotype-specific differences in disease severity observed in meningitis patients may, at least in part, be explained by differences in growth and capsule size in human cerebrospinal fluid. This information could be useful to guide future vaccine design.

Impact of 10-Valent Pneumococcal Conjugate Vaccine on Bacterial Meningitis in Madagascar.

BACKGROUND: The 10-valent pneumococcal conjugate vaccine (PCV10) was introduced in Madagascar in 2012. The objective of this study was to determine the impact of PCV10 on bacterial meningitis in hospitalized children <5 years of age. METHODS: During 2010-2017, data from the hospital admission logbook were recorded for bacterial meningitis and pneumonia hospitalizations in children <5 years of age. Between April 2011 and December 2017, 3312 cerebrospinal fluid (CSF) samples collected from children who fulfilled the World Health Organization case definition of suspected bacterial meningitis were analyzed at the sentinel site laboratory (SSL) by microscopy, culture, and antigen detection tests. A total of 2065 CSF samples were referred to the regional reference laboratory for real-time polymerase chain reaction (RT-PCR) analysis. 2010-2011 was defined as the prevaccine period, 2012 as vaccine introduction year, and 2013-2017 the postvaccine period. The number of cases, causative agent, and pneumonia hospitalizations were compared before and after PCV10 introduction. RESULTS: In the prevaccine period, bacterial meningitis and pneumonia hospitalizations accounted for 4.5% and 24.5% of all hospitalizations while there were 2.6% and 19%, respectively, in the postvaccine period (P < .001). In samples tested at the SSL, 154 were positive with 80% Streptococcus pneumoniae and 20% other bacteria. Pneumococcal meningitis diagnosed by RT-PCR declined from 14% in 2012 to 3% in 2017. Also, 14% of children with pneumococcal meningitis died. CONCLUSIONS: Following PCV10 introduction, pneumococcal meningitis, bacterial meningitis, and pneumonia hospitalizations declined. Surveillance should continue to monitor the impact of PCV10.

Declining Incidence of Invasive Meningococcal Disease in South Africa: 2003-2016.

BACKGROUND: Invasive meningococcal disease (IMD) is endemic to South Africa, where vaccine use is negligible. We describe the epidemiology of IMD in South Africa. METHODS: IMD cases were identified through a national, laboratory-based surveillance program, GERMS-SA, from 2003-2016. Clinical data on outcomes and human immunodeficiency virus (HIV) statuses were available from 26 sentinel hospital sites. We conducted space-time analyses to detect clusters of serogroup-specific IMD cases. RESULTS: Over 14 years, 5249 IMD cases were identified. The incidence was 0.97 cases per 100 000 persons in 2003, peaked at 1.4 cases per 100 000 persons in 2006, and declined to 0.23 cases per 100 000 persons in 2016. Serogroups were confirmed in 3917 (75%) cases: serogroup A was present in 4.7% of cases, B in 23.3%, C in 9.4%; W in 49.5%; Y in 12.3%, X in 0.3%; Z in 0.1% and 0.4% of cases were non-groupable. We identified 8 serogroup-specific, geo-temporal clusters of disease. Isolate susceptibility was 100% to ceftriaxone, 95% to penicillin, and 99.9% to ciprofloxacin. The in-hospital case-fatality rate was 17% (247/1479). Of those tested, 36% (337/947) of IMD cases were HIV-coinfected. The IMD incidence in HIV-infected persons was higher for all age categories, with an age-adjusted relative risk ratio (aRRR) of 2.5 (95% confidence interval [CI] 2.2-2.8; P < .001) from 2012-2016. No patients reported previous meningococcal vaccine exposure. Patients with serogroup W were 3 times more likely to present with severe disease than those with serogroup B (aRRR 2.7, 95% CI 1.1-6.3); HIV coinfection was twice as common with W and Y diseases (aRRR W = 1.8, 95% CI 1.1-2.9; aRRR Y = 1.9, 95% CI 1.0-3.4). CONCLUSIONS: In the absence of significant vaccine use, IMD in South Africa decreased by 76% from 2003-2016. HIV was associated with an increased risk of IMD, especially for serogroup W and Y diseases.

Pediatric Bacterial Meningitis Surveillance in the World Health Organization African Region Using the Invasive Bacterial Vaccine-Preventable Disease Surveillance Network, 2011-2016.

BACKGROUND: Bacterial meningitis is a major cause of morbidity and mortality in sub-Saharan Africa. We analyzed data from the World Health Organization's (WHO) Invasive Bacterial Vaccine-preventable Diseases Surveillance Network (2011-2016) to describe the epidemiology of laboratory-confirmed Streptococcus pneumoniae (Spn), Neisseria meningitidis, and Haemophilus influenzae meningitis within the WHO African Region. We also evaluated declines in vaccine-type pneumococcal meningitis following pneumococcal conjugate vaccine (PCV) introduction. METHODS: Reports of meningitis in children <5 years old from sentinel surveillance hospitals in 26 countries were classified as suspected, probable, or confirmed. Confirmed meningitis cases were analyzed by age group and subregion (South-East and West-Central). We described case fatality ratios (CFRs), pathogen distribution, and annual changes in serotype and serogroup, including changes in vaccine-type Spn meningitis following PCV introduction. RESULTS: Among 49 844 reported meningitis cases, 1670 (3.3%) were laboratory-confirmed. Spn (1007/1670 [60.3%]) was the most commonly detected pathogen; vaccine-type Spn meningitis cases declined over time. CFR was the highest for Spn meningitis: 12.9% (46/357) in the South-East subregion and 30.9% (89/288) in the West-Central subregion. Meningitis caused by N. meningitidis was more common in West-Central than South-East Africa (321/954 [33.6%] vs 110/716 [15.4%]; P < .0001). Haemophilus influenzae (232/1670 [13.9%]) was the least prevalent organism. CONCLUSIONS: Spn was the most common cause of pediatric bacterial meningitis in the African region even after reported cases declined following PCV introduction. Sustaining robust surveillance is essential to monitor changes in pathogen distribution and to inform and guide vaccination policies.

Pneumococcal Conjugate Vaccine Impact on Meningitis and Pneumonia Among Children Aged <5 Years-Zimbabwe, 2010-2016.

BACKGROUND: Streptococcus pneumoniae is a leading cause of pneumonia and meningitis in children aged <5 years. Zimbabwe introduced 13-valent pneumococcal conjugate vaccine (PCV13) in 2012 using a 3-dose infant schedule with no booster dose or catch-up campaign. We evaluated the impact of PCV13 on pediatric pneumonia and meningitis. METHODS: We examined annual changes in the proportion of hospitalizations due to pneumonia and meningitis among children aged <5 years at Harare Central Hospital (HCH) pre-PCV13 (January 2010-June 2012) and post-PCV13 (July 2013-December 2016) using a negative binomial regression model, adjusting for seasonality. We also evaluated post-PCV13 changes in serotype distribution among children with confirmed pneumococcal meningitis at HCH and acute respiratory infection (ARI) trends using Ministry of Health outpatient data. RESULTS: Pneumonia hospitalizations among children aged <5 years steadily declined pre-PCV13; no significant change in annual decline was observed post-PCV13. Post-PCV13 introduction, meningitis hospitalization decreased 30% annually (95% confidence interval [CI], -42, -14) among children aged 12-59 months, and no change was observed among children aged 0-11 months. Pneumococcal meningitis caused by PCV13 serotypes decreased from 100% in 2011 to 50% in 2016. Annual severe and moderate outpatient ARI decreased by 30% (95% CI, -33, -26) and 7% (95% CI, -11, -2), respectively, post-PCV13 introduction. CONCLUSIONS: We observed declines in pediatric meningitis hospitalizations, PCV13-type pneumococcal meningitis, and severe and moderate ARI outpatient visits post-PCV13 introduction. Low specificity of discharge codes, changes in referral patterns, and improvements in human immunodeficiency virus care may have contributed to the lack of additional declines in pneumonia hospitalizations post-PCV13 introduction.

Invasive Disease Caused Simultaneously by Dual Serotypes of Streptococcus pneumoniae.

There are at least 98 known pneumococcal serotypes. Invasive pneumococcal disease (IPD) is usually caused by a single serotype, and dual-serotype IPD is rare. To assess factors associated with dual-serotype IPD, patient information obtained through laboratory-based surveillance for IPD from 2005 through 2014 in South Africa was reviewed. Genomes of isolate pairs from coinfected individuals were sequenced to determine their molecular characteristics. For 30 (91%) of 33 patients with dual serotypes, one or both isolates were a pneumococcal conjugate vaccine (PCV13) serotype. Dual-serotype IPD was associated with children <5 years of age (adjusted odds ratio [aOR], 4.7; 95% confidence interval [95% CI], 1.8 to 11.7), underlying illness (other than HIV) (aOR, 2.8; 95% CI, 1.1 to 6.6) and death (aOR, 2.5; 95% CI, 1.08 to 6.09). For each coinfecting pair, isolates were genotypically unrelated, and their genotypes were common among isolates of the same serotype in South Africa. Of 701 accessory genes identified among dual-serotype IPD isolates, four were common between isolate pairs. Coinfecting isolate pairs had different genotypic backgrounds. The association of dual serotypes with death warrants increased awareness of IPD coinfection caused by two or more serotypes.

Molecular Characterization of Corynebacterium diphtheriae Outbreak Isolates, South Africa, March-June 2015.

In 2015, a cluster of respiratory diphtheria cases was reported from KwaZulu-Natal Province in South Africa. By using whole-genome analysis, we characterized 21 Corynebacterium diphtheriae isolates collected from 20 patients and contacts during the outbreak (1 patient was infected with 2 variants of C. diphtheriae). In addition, we included 1 cutaneous isolate, 2 endocarditis isolates, and 2 archived clinical isolates (ca. 1980) for comparison. Two novel lineages were identified, namely, toxigenic sequence type (ST) ST-378 (n = 17) and nontoxigenic ST-395 (n = 3). One archived isolate and the cutaneous isolate were ST-395, suggesting ongoing circulation of this lineage for >30 years. The absence of preexisting molecular sequence data limits drawing conclusions pertaining to the origin of these strains; however, these findings provide baseline genotypic data for future cases and outbreaks. Neither ST has been reported in any other country; this ST appears to be endemic only in South Africa.

Imputing the Direct and Indirect Effectiveness of Childhood Pneumococcal Conjugate Vaccine Against Invasive Pneumococcal Disease by Surveying Temporal Changes in Nasopharyngeal Pneumococcal Colonization.

The limited capability in most low- to middle-income countries to study the benefit of pneumococcal conjugate vaccine (PCV) in protecting against invasive pneumococcal disease (IPD) calls for alternate strategies to assess this. We used a mathematical model to predict the direct and indirect effectiveness of PCV by analyzing serotype-specific colonization prevalence and IPD incidence prior to and following childhood PCV immunization in South Africa. We analyzed IPD incidence from 2005 to 2012 and colonization studies undertaken in human immunodeficiency virus (HIV)-uninfected and HIV-infected child-mother dyads from 2007 to 2009 (pre-PCV era), in 2010 (7-valent PCV era), and in 2012 (13-valent PCV era). We compared the model-predicted changes in IPD incidence with observed changes in IPD incidence, according to HIV status, in children aged 3 months-5 years and in women aged 18-45 years. We observed reductions in vaccine-serotype colonization and IPD due to vaccine serotypes among children and women after PCV introduction. Using the changes in vaccine-serotype colonization data, the model-predicted changes in vaccine-serotype IPD incidence rates were similar to the observed changes in PCV-unvaccinated children and adults, but not among children under age 24 months. Surveillance of colonization prior to and following PCV use can be used to impute the indirect protection afforded by PCV in unvaccinated age groups, including those in high-HIV-prevalence settings.

Effects of vaccination on invasive pneumococcal disease in South Africa.

BACKGROUND: In South Africa, a 7-valent pneumococcal conjugate vaccine (PCV7) was introduced in 2009 with a three-dose schedule for infants at 6, 14, and 36 weeks of age; a 13-valent vaccine (PCV13) replaced PCV7 in 2011. In 2012, it was estimated that 81% of 12-month-old children had received three doses of vaccine. We assessed the effect of vaccination on invasive pneumococcal disease. METHODS: We conducted national, active, laboratory-based surveillance for invasive pneumococcal disease. We calculated the change in the incidence of the disease from a prevaccine (baseline) period (2005 through 2008) to postvaccine years 2011 and 2012, with a focus on high-risk age groups. RESULTS: Surveillance identified 35,192 cases of invasive pneumococcal disease. The rates among children younger than 2 years of age declined from 54.8 to 17.0 cases per 100,000 person-years from the baseline period to 2012, including a decline from 32.1 to 3.4 cases per 100,000 person-years in disease caused by PCV7 serotypes (-89%; 95% confidence interval [CI], -92 to -86). Among children not infected with the human immunodeficiency virus (HIV), the estimated incidence of invasive pneumococcal disease caused by PCV7 serotypes decreased by 85% (95% CI, -89 to -79), whereas disease caused by nonvaccine serotypes increased by 33% (95% CI, 15 to 48). Among adults 25 to 44 years of age, the rate of PCV7-serotype disease declined by 57% (95% CI, -63 to -50), from 3.7 to 1.6 cases per 100,000 person-years. CONCLUSIONS: Rates of invasive pneumococcal disease among children in South Africa fell substantially by 2012. Reductions in the rates of disease caused by PCV7 serotypes among both children and adults most likely reflect the direct and indirect effects of vaccination. (Funded by the National Institute for Communicable Diseases of the National Health Laboratory Service and others.).

Molecular characterization of invasive capsule null Neisseria meningitidis in South Africa.

BACKGROUND: The meningococcal capsule is an important virulence determinant. Unencapsulated meningococci lacking capsule biosynthesis genes and containing the capsule null locus (cnl) are predominantly non-pathogenic. Rare cases of invasive meningococcal disease caused by cnl isolates belonging to sequence types (ST) and clonal complexes (cc) ST-845 (cc845), ST-198 (cc198), ST-192 (cc192) and ST-53 (cc53) have been documented. The clinical significance of these isolates however remains unclear. We identified four invasive cnl meningococci through laboratory-based surveillance in South Africa from 2003 through 2013, which we aimed to characterize using whole genome data. RESULTS: One isolate [NG: P1.7-2,30: F1-2: ST-53 (cc53)] contained cnl allele 12, and caused empyema in an adult male with bronchiectasis from tuberculosis, diabetes mellitus and a smoking history. Three isolates were NG: P1.18-11,42-2: FΔ: ST-192 (cc192) and contained cnl allele 2. One patient was an adolescent male with meningitis. The remaining two isolates were from recurrent disease episodes (8 months apart) in a male child with deficiency of the sixth complement component, and with the exception of two single nucleotide polymorphisms, contained identical core genomes. The ST-53 (cc53) isolate possessed alleles for NHBA peptide 191 and fHbp variant 2; whilst the ST-192 (cc192) isolates contained NHBA peptide 704 and fHbp variant 3. All four isolates lacked nadA. Comparison of the South African genomes to 61 additional cnl genomes on the PubMLST Neisseria database ( http://pubmlst.org/neisseria/ ), determined that most putative virulence genes could be found in both invasive and carriage phenotypes. CONCLUSIONS: Although rare, invasive disease by cnl meningococci may be associated with host immunodeficiency and such patients may benefit from protein-based meningococcal vaccines.

Comparing the Yield of Nasopharyngeal Swabs, Nasal Aspirates, and Induced Sputum for Detection of Bordetella pertussis in Hospitalized Infants.

BACKGROUND: Advances in molecular laboratory techniques are changing the landscape of Bordetella pertussis illness diagnosis. Polymerase chain reaction (PCR) assays have greatly improved the sensitivity detection and the turnaround time to diagnosis compared to culture. Moreover, different respiratory specimens, such as flocked nasopharyngeal swabs (NPSs), nasopharyngeal aspirates (NPAs), and induced sputum, have been used for B. pertussis detection, although there is limited head-to-head comparison to evaluating the PCR yield from the 3 sampling methods. METHODS: Hospitalized infants <6 months of age who fulfilled a broad syndromic criteria of respiratory illness were tested for B. pertussis infection by PCR on paired NPSs and NPAs; or paired NPSs and induced sputum. An exploratory analysis of B. pertussis culture was performed on induced sputum specimens and in a subset of NPSs. RESULTS: From November 2014 to May 2015, 484 infants with paired NPSs and NPAs were tested; 15 (3.1%) PCR-confirmed pertussis cases were identified, 13 of which were PCR positive on both samples, while 1 each were positive only on NPS or NPA. From March to October 2015, 320 infants had NPSs and induced sputum collected, and 11 (3.4%) pertussis cases were identified by PCR, including 8 (72.7%) positive on both samples, 1 (9.1%) only positive on NPS, and 2 (18.2%) only positive on induced sputum. The 3 types of specimens had similar negative predictive value >99% and sensitivity >83%. Compared to PCR, culture sensitivity was 60% in induced sputum and 40% in NPSs. CONCLUSIONS: Flocked nasopharyngeal swabs, nasopharyngeal aspirates, and induced sputum performed similarly for the detection of B. pertussis infection in young infants by PCR.