Annual Report March 2006 – March 2007

Respiratory & Meningeal & Pathogens Research UnitDepartmental Staff Compliment

Directors: Professor Keith P Klugman/ Assoc. Prof. Shabir A MadhiStaffing at NICD: One Senior Pathologist, 1 Senior Scientist, 1 Laboratory Manager, 3 Scientists, 2 Senior Medical Technologists, 1Medical Technologist, 1 Junior Technologist, 1 Data Clerk, and 1 Personal Assistant to the Director.Staffing at Chris Hani Baragwanath Hospital: Co-Director: Associate Professor Shabir Madhi.One Senior Medical Officer, 11 Research Medical Officers, 1 Senior Scientist, 1 Physician, 1 Statistician, 1 Scientist, 1 Study Co-coordinator, 19 Professional nurses, 4 Enrolled nurses, , 5 Nursing Assistants, 1 Nurse, 5 Laboratory Technologists, 1 Clinical Trial co-coordinator, 6 Field Workers, 9 Research assistants, 4 Counselors, 3 Data clerks, 3 Administrators, 2 Drivers, 1 Cleaner.

Departmental Research Interests

Acute Respiratory infections are the leading cause of death in children in developing countries and the leading infectious cause of death in all ages. The Respiratory and Meningeal Pathogens Research Unit (RMPRU) is mandated to study the causes of respiratory and meningeal infections. Both clinical and basic research is conducted with the aim of improving the diagnosis, management and prevention of these diseases.

The structure of the Unit has changed to accommodate the move of the surveillance arm of the Unit to NICD. The Unit’s functions are broadly sub-divided into epidemiological and basic science research (with a focus on antimicrobial resistance) and clinical research largely focusing on vaccinology. The aspect of the research unit affiliated to Wits is based at Chris Hani Baragwanath hospital under the supervision of Prof Madhi while the surveillance arm is at NICD at Rietfontein under the supervision of Dr. von Gottberg. Prof Klugman retains overall responsibility for the MRC Unit at both sites and Prof Madhi has been appointed as a co-director of the Unit. The division of the unit based at CHB has a total staff complement of 95, whom with the exception of one posted funded through MRC funds, are funded exclusively through grant-funds.

The research currently underway at the clinical/vaccinology division of the Unit based at CHB hospital include studies on: 1. the molecular and clinical epidemiology of newly discovered respiratory viruses such as echovirus, coronavirus, bocavirus and rhinovirus. Additionally, the role of pneumococcal coinfections in severe episodes of such viral infections is being probed; 2. The effect of HIV exposure and treatment with anti retroviral drugs on the quantitative and qualitative antibody responses to conjugate bacterial vaccines aimed at preventing respiratory tract infections; 3. affordable and implemental interventions in reducing neonatal sepsis, a large proportion of which is attributed to respiratory disease due to S. agalactiae, is underway; 4. the epidemiology of pneumococcal pneumonia in adults and the role of newer diagnostic modalities in improving on making a pathogen specific diagnosis in adults with suspected pneumococcal pneumonia; 5. prevention of tuberculosis in HIV infected children by way of primary prophylaxis with Isoniazid between 3 and 24 months of age; 6. The molecular and clinical epidemiology of Staph aureus infections; 7. Defining the correlates of protection against nasopharyngeal colonization by pneumococci and the mechanism of protection induced by conjugate pneumococcal vaccines.

During 2006 Profs Madhi and Klugman completed the chapter on Acute Respiratory Infections for the World Bank book on Disease and Mortality in Sub-Saharan Africa. Research from the Unit has led to the proposition of a new algorithm to measure the burden of pneumococcal disease preventable by conjugate vaccine. The Unit’s expanded national surveillance for respiratory pathogens continues to be supported by CDC/USAID. We documented and published in the Bulletin of WHO the impact of Haemophilus influenzae type b (Hib) vaccine on invasive disease in South Africa. The burden of invasive Hib has been greatly reduced by the introduction of conjugate Hib vaccine, despite the impact of the HIV epidemic which has increased invasive Haemophilus influenzae disease burden due to serotypes other than type b. The Unit has demonstrated for the first time the clinical and molecular epidemiology of human metapneumovirus infection in children in a developing country. During 2006 studies the Unit was successful in attracting funding through the Gates Foundation Grand Challenges. This has allowed us to extend our study funded by NIH, USA on the immunological responses to pneumococcal conjugate vaccine in HIV infected children, and we have enrolled the majority of adults in an NIH funded study to measure the burden of vaccine–preventable disease in HIV–infected adults. Another major ongoing study in the Unit is the recruitment of infants at birth to evaluate the impact of chlorhexidine washes for the mother and infant on neonatal sepsis.

Research Projects

Human metapneumovirus pneumonia in HIV-infected and -uninfected childrenProject leader: Prof S Madhi. Researcher: Mr Herbert Ludewick. Collaborator: Professor Guy Boivin, University of Quebec, Canada.In addition to the study published on the molecular epidemiology of human metapneumovirus over three consecutive epidemics in South Africa in Emerging Infectious Diseases in 2005, the first of its kind from any developing country, we have now also published on the role of pneumococcus in the pathogenesis of severe hMPV infections in Journal of Infectious Diseases. Additionally, differences in the clinical characteristics between HIV infected and HIV uninfected children have been described and are currently in press.

Risk factors and clinical course of pneumococcal invasive disease in HIV infected and uninfected adults and childrenProject leaders: Professor Charles Feldman, Prof Shabir Madhi. Collaborators: Dr Victor Yu, University of Pittsburgh, Dr Leslie McGee, Emory University, Atlanta. Funded by the MRC/NHLS/Wits.This definitive study was conducted in collaboration with Dr Victor Yu (University of Cleveland). The Unit contributed cases of pneumonia, and adults with meningitis in collaboration with Prof C Feldman. The study from 2002 included pneumococcal meningitis in children. The initial study on bacteraemic pneumonia was published in 2003 in Clinical Infectious Diseases. Further analyses of the HIV - infected population included in the study have been completed. An analysis of combination therapy showed that this was associated with decreased mortality in severely ill patients and was published in 2004. The impact of serotypes on mortality has been submitted during 2006 to Clinical Infectious Diseases and the analysis of the molecular relatedness of the strains has been completed

Impact of Hib conjugates vaccine on the burden of invasive Haemophilus influenzae type b. Project leaders: Dr A von Gottberg. Collaborators: Dr A Schuchat, Dr S Schrag, CDC, Atlanta, USA. Funding MRC/NHLS/Wits, USAID/CDC/PEPFAR.Following our initial studies on the long term level of protection afforded by Hib vaccine in HIV- infected children, a national study on the effect of HibCV on the burden of invasive Hib disease in South Africa was published in the Bulletin of the WHO in 2006.

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Analysis of the genetic diversity of Neisseria meningitides in South AfricaProject leaders: Dr Anne von Gottberg, Mr Garry Coulson, Mignon du Plessis. Funded by the MRC/NHLS/WITS.A molecular epidemiology study of Neisseria meningitides (the meningococcus) in South Africa, for the period July 1999 to July 2002 has been completed. Over 600 isolates have been characterized by pulsed-field gel electrophoresis and over 40 representative isolates of interest were further characterized by multi-locus sequence typing. The results of this study indicate that for each of the five serogroups studied (A, B, C, W135 and Y), hypervirulent clones/clonal complexes, known to have repeatedly caused epidemics and outbreaks worldwide, are circulating in the South African population. The continuous monitoring of the changing epidemiology in South Africa of the clonal composition of meningococci in South Africa has direct implications for public health decisions, with regard to the development of effective control and intervention strategies. These data will be published in Emerging Infectious Diseases Journal early in 2007.

Telithromycin resistance mechanisms in the pneumococcusProject leader: Nicole Wolter. Funded by the MRC/NHLS/WITS.Macrolides are commonly used for the treatment of pneumococcal infection. However, due to the global increase in macrolide resistance alternatives are being developed. Telithromycin, a semi-synthetic derivative of erythromycin, is the first ketolide to be approved for clinical use. The structural modifications of this antibiotic enable it to form a stronger bond with the ribosome than erythromycin and it can therefore overcome the common macrolide resistance mechanisms, erm (B) and mef (A). Although pneumococcal resistance to telithromycin remains rare, resistant isolates are emerging. The mechanism of resistance in a rare highly telithromycin-resistant isolate was investigated. The isolate was found to contain erm (B) with a truncated leader peptide and a mutant ribosomal protein L4. By transformation of susceptible strains, this study showed that high-level telithromycin resistance is conferred by erm (B), wild-type or mutant, in combination with a 69GTG71 to TPS mutation in ribosomal protein L4. This work has been submitted to Antimicrobial Agents and Chemotherapy for publication. A telithromycin-resistant isolate with a 136 bp deletion in arm (B) is currently being investigated for the mechanism of telithromycin resistance.

Macrolide resistance in Streptococcus pneumoniae causing invasive disease in South Africa: 2000 – 2005Project leader: Nicole Wolter. Funded by the MRC/NHLS/WITS.Resistance to macrolides in Streptococcus pneumoniae is conferred by two predominant mechanisms namely, active drug efflux and target-site modification. Drug efflux occurs due to acquisition of the me (A) gene which confers resistance to 14- and 15-membered macrolides (M-phenotype). Target modification occurs predominantly due to acquisition of erm (B). This gene encodes a ribosomal methylase that methylates A2058 of 23S rRNA, conferring cross-resistance to the macrolide-lincosamide-streptogramin B antibiotics (MLSB phenotype). Target modification may also arise from mutations in the genes encoding domain V of 23S rRNA and the ribosomal proteins L4 and L22. There is an increase in macrolide resistance globally, and the predominant mechanism of resistance varies geographically. In this study, macrolide resistance in invasive pneumococcal isolates collected in South Africa for the period 2000-2005 will be investigated. Preliminary data show an increase in macrolide resistance from 9% in 2000 to 14% in 2005. The predominant phenotype is the MLSB phenotype (75%). Serotype 14 is most prevalent in macrolide-resistant strains. Random isolates from 2005 will be genotypically screened for the presence of erm(B) and mef(A) genes.

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Molecular epidemiology of South African serotype 3 pneumococciProject leaders: Anne von Gottberg, Kedibone Mothibeli, Mignon du Plessis. Funded by MRC/NHLS/WITS.Pneumococcal serotype 3 is an important cause of invasive disease worldwide. Patients infected with this serotype have also been shown to have higher fatality rates compared to those infected with other invasive serotypes such as 1 and 14. The aim of this study was to investigate the genetic clonality of South African pneumococcal serotype 3 isolates. For this purpose, a total of 102 serotype 3 isolates were selected from isolates recovered from specimens of patients of all ages from Gauteng province. All specimens were collected from January 2000 to December 2002. These 102 isolates from blood and/or CSF have been analyzed by pulsed-field gel electrophoresis (PFGE). A total of 18 isolates selected from each of the PFGE clusters were further analyzed by multi locus sequence typing (MLST). The results suggest that South African serotype 3 isolates are clonally diverse, and that the predominant clone circulating among the South African serotype 3 isolates differs from the predominant global clone of serotype 3.

Molecular epidemiology of multidrug-resistant pneumococcal serotype 19A isolates from South AfricaProject leaders: Kedibone Mothibeli, Mignon du Plessis, Anne von Gottberg, Funded by the MRC/NHLS/WITS. In 1977, the first penicillin- and multidrug-resistant serotype 19A strain was isolated from a patient in South Africa. Serotype 19A continues to be prevalent in South Africa in young children and is often associated with multidrug resistance. To determine if this 1977 clone is still circulating among recent multidrug-resistant serotype 19A strains, we compared multidrug-resistant serotype 19A isolates collected from June 1999 to December 2004 in South Africa with this 1977 strain. During the study period 14 177 cases of IPD were reported. Of these, 13 064 (92%) had viable isolates available for further testing and 885 (7%) were identified as serotype 19A. Reduced susceptibility to penicillin was detected in 235 (27%) of these isolates, 25 (11%) of which were multidrug-resistant. PFGE was performed on all multidrug-resistant strains. PFGE analysis demonstrated diversity among these isolates. MLST of 15 randomly selected isolates revealed several sequence types (ST), none of which were the same as the 1977 clone.

Penicillin non-susceptibility in meningococcal isolates causing invasive disease in South AfricaProject leaders: Mignon du Plessis, Anne von Gottberg, Linda de Gouveia. Funded by MRC/NHLS/Wits.Neisseria meningitidis non-susceptible to penicillin (MIC ≥0.12g/ml) has been reported in several parts of the world, but to our knowledge not from the African continent. In some countries, non-susceptible invasive isolates have been associated with a single clone. Data were analyzed from January 2000 through December 2005 from a national laboratory-based surveillance program in South Africa. 2130 cases of invasive meningococcal disease were reported during the 6 years analyzed, with an average annual incidence rate of 0.77/100 000 population. Of these cases, 1579 (74%) had viable isolates available for further testing, of which 97 (6%) tested non-susceptible to penicillin. Prevalence rates fluctuated over the years and genotyping showed that penicillin-resistant meningococcal isolates analyzed in this study were not clonal and were represented by all serogroups distributed throughout all provinces and age groups.

Molecular characterization of serogroup B meningococcal isolates causing invasive disease in South AfricaProject leaders: Anne von Gottberg, Mignon du Plessis, Linda de Gouveia. Collaborator: Dr. Gary Zlotnick (Wyeth Pharmaceuticals). Funding: WyethCurrently there is no licensed vaccine for prevention of bacterial meningitis caused by serogroup B N. meningitidis. Outer membrane protein LP2086 has been shown to elicit a good antibody response in animal models and is therefore a promising vaccine candidate. The aim of this study is to investigate the prevalence, distribution and sequence diversity of LP2086 in both serogroup B and other serogroups of meningococci circulating in South Africa.

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Evaluation of Real-Time PCR and a Luminex-based assay for diagnosis of pneumococcal diseaseProject leaders: CDC (Respiratory Diseases Branch and Meningitis and Special Pathogens Branch). Collaborators: Mignon du Plessis, Olga Perovic (Jhb Hospital), Jeannette Wadula (Bara). Funding: CDCThe purpose of this study is to evaluate 5 Real-Time PCR assays and a Luminex-based assay for detection of S. pneumoniae using isolates and clinical specimens from different sources. Blood and CSF specimens are currently being collected from CH Baragwanath and Johannesburg Hospitals and will be sent over to the CDC for testing.

Immunogenicity and functionality of antibody induced by pneumococcal conjugate vaccine in HIV- infected infantsProject leaders: CDC (Respiratory Diseases Branch and Meningitis and Special Pathogens Branch). Collaborators: Mignon du Plessis, Olga Perovic (Jhb Hospital), Jeannette Wadula (Bara). Funding: CDCWe obtained initial funding for this study from WHO. We used cohorts of children in whom we had data on immunogenicity. HIV status was determined in an unlinked anonymous way. This collection of sera was started in 2001 and completed in 2002. The analysis of the results was completed in 2004. The Unit has sought and obtained a CIPRA grant to expand this study and a large multi- year project has been designed. An antibody functionality laboratory has been set up by Dr Peter Adrian who joined the Unit again after a number of years in Europe. He attended training during 2003 with our collaborator in Finland. The first series of experiments have been completed and the data were accepted and published during 2005 in PIDJ.

Impact of cotrimoxazole prophylaxis on resistance in respiratory pathogensProject leaders: Dr A von Gottberg, Dr V Quan, L de Gouveia. Collaborators: Dr Anne Schuchat, CDC, Allison Taylor, Emory University. Funding: CDC-USAIDThe widespread introduction of cotrimoxazole for prophylaxis of opportunistic infections in HIV- infected people has major implications for the development of resistance and the selection of multiresistant bacterial clones. We have, with CDC and Emory University, expanded our national surveillance network to monitor the impact on resistance and the effectiveness of the intervention on pneumococcal disease. Funding has been secured from USAID via the CDC. Enhanced surveillance commenced in 2003. Currently there are 10 sites involved nationally. Data are disseminated to participants by quarterly reports and LINK newsletter. An analysis conducted in 2004 shows dramatic increases in cotrimoxazole resistance in pneumococcal isolates. This study will be submitted for publication in 2007. Group for Enteric-Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA).

Differences in blood culturing practices in rural and urban areas of South AfricaProject leader: Dr Anne von Gottberg, Project coordinators: Dr Vanessa Quan and Ms Linda de Gouveia Funding: Gates Foundation PNEUMO_ADIP.It has recently been suggested that the burden of invasive bacterial disease in Africa is greater than was previously thought, but there are many obstacles to accurately measuring this disease burden. In South Africa there are good data on invasive pneumococcal disease for some urban centres, but limited information of disease burden exists outside of these areas.We proposed to improve the quality of surveillance data in South Africa, by collecting details of laboratory and clinical blood culturing practices throughout the country. We will investigate the quality of laboratory processing of specimens. Twenty-one hospitals throughout the country have been approached to request doctors working in these hospitals to fill in a questionnaire with regard to microbiology laboratory diagnostics, specifically blood cultures, pneumococcal disease burden and the availability of possible intervention strategies.These data will assist in the interpretation of ongoing surveillance for invasive pneumococcal disease. We also hope to strengthen laboratory networks in South Africa. Funding for the proposal has been received from the Gates Foundation Pneumo-ADIP.

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Molecular Epidemiology of Haemophilus influenzaeProject leaders: Anne von Gottberg, Linda de Gouveia, Mignon du Plessis. Funding: CDC_USAID.H. influenzae type b vaccine was introduced in routine childhood immunizations in 1999 and a national surveillance network was established to document the impact of the vaccine on Hib disease. In the first five years after vaccine introduction, rates of invasive Hib disease declined by 67% in children < 1 year and by 79% in children aged 1 to 4 years. Even though the number of cases has decreased, there is an increase in the prevalence of multidrug-resistant isolates (ampicillin, chloramphenicol, trimethoprim-sulfamethoxazole) and HIV infection is contributing to the remaining Hib disease in South Africa. We aim to determine the genotype of these Hib isolates using pulsed-field gel electrophoresis. In addition, there appears to be an increase in the number of beta-lactamase-producing isolates. We suspect that the increased beta-lactamase production may be co-selected by tmp-smx and this hypothesis will be explored.

Pneumococcal Antigen-Positive Non-Viable Blood Cultures at Chris Hani Baragwanath HospitalProject leaders: Anne von Gottberg, Linda de Gouveia, Mignon du Plessis. Funding: CDC_USAID.Both blood culture and latex antigen testing are known to lack sensitivity, whereas PCR has been shown to be highly sensitive in identifying organisms in human specimens. We analyzed all blood cultures that were positive by either culture or latex for S. pneumoniae on the BacT/Alert System and compared these results with PCR. During 2003 and 2004, we identified 694 and 547 cases of pneumococcal bacteremia, respectively. Latex testing was performed on all culture-negative bloods (103/694 cases in 2003 and 129/547 cases in 2004) using the Wellcogen* Bacterial Antigen Kit. Fifty randomly selected latex-positive, culture-negative bloods were selected for PCR confirmation. All fifty samples were PCR positive for S. pneumoniae. Data from patient files showed that the most common clinical presentation was lower respiratory tract infection (54/103 and 84/129 culture-negative cases for 2003 and 2004, respectively), and the majority of patients were aged between 22 and 44 years. These results indicate that pneumococcal latex antigen testing provides rapid and specific identification in autolysed blood samples with no viable growth. Moreover, PCR authenticates the results of latex testing and confirms that the results are not false positives. Culture-negative, latex-positive bloods are now routinely screened by PCR for the presence of pneumococci. We aim to utilize a PCR-based serotyping method to type these non-viable isolates directly from DNA extracted from the blood cultures.

Role of CRP and procalcitonin to enhance the specificity of bacterial pneumonia diagnosis in childrenProject leader: Prof Shabir Madhi. Sponsor: WHO and PneumoADIP.The usefulness of procalcitonin and CRP to improve the specificity of radiographic confirmed pneumonia in the measurement of the pneumococcal conjugate vaccine efficacy against pneumonia was accepted and published in PloS Medicine in 2005. The study has since been expanded through funding from the Gates Foundation PneumoADIP and WHO to determine whether procalcitonin and CRP may be used as an alternative to CXRs in evaluating the efficacy of a pneumococcal conjugate vaccine in children. These data were analyzed in 2005 and submitted for publication in 2006. A new algorithm for the measurement of the burden of pneumococcal disease preventable by conjugate vaccine has been accepted for publication in Vaccine in 2007.

Role of pediatric serotypes in the aetiology of adult pneumonia in SowetoProject Leaders: Dr Werner Albrich, Dr Alan Karstaedt, Dr Shabir Madhi. Funding NHLS/Wits/MRC; NIH CFAR. Collaborators: Dr Jim Curran, Emory University.

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A protocol submitted to NIH for funding in collaboration with the Center for Aids Research (CFAR) Unit at Emory University to investigate the role of paediatric serotypes of pneumococci in the aetiology of adult pneumonia in Soweto has been funded. A 3 year project has been developed to measure the potential for interruption of transmission of pneumococci from children to adults in order to decrease the burden of pneumonia and antibiotic resistance in both children and adults in Soweto. Dr Werner Albrech has lead this study during 2006 and more than 400 patients have been enrolled.

Role of the pneumococcus in viral infectionsProject Leader: Prof Shabir Madhi.Using the vaccine as a probe the relationship of bacterial superinfection to the pathogenesis of viral pneumonia was further sought in additional analyses of the 9- valent conjugate vaccine trial during 2005. The initial data were published in 2004 in Nature Medicine. The results prove a major role for pneumococcal superinfection in viral pneumonia hospitalization in children. The data have led to an analysis led by Dr Klugman into the role of the pneumococcus and other bacteria in morbidity and mortality associated with influenza in 1918. The role of the pneumococcus in metapneumovirus related pneumonia was investigated in 2005, and published in 2006 in the Journal of Infectious Diseases...

The impact of local fluoroquinolone use in non-responding otitis media (NROM)Project leader: Dr Adrian Brink. Project coordinateurs: Dr Anne von Gottberg, Linda de Gouveia, Dr Mignon du Plessis, Nicole Wolter.Fluoroquinolones are being used as topical solution in children undergoing tympanocentesis. Isolates of Streptococcus pneumoniae isolated from middle ear fluid of such children are currently being tested for fluoroquinolone resistance and first step mutants. MICs were performed by Etest on those isolates that had the smallest fluoroquinolone disk zone sizes. All of the isolates were found to be susceptible to levofloxavin, ofloxacin and ciprofloxacin. Isolates with the highest MICs were selected for sequencing of the QRDR regions.

Investigation of the Streptococcus pneumoniae-derived toxin, pneumolysin, as a target of macrolide antimicrobial agentsProject leader: Dr A von Gottberg. Collaborators: Profs R Anderson, C Feldman A significant percentage of patients with severe pneumococcal disease who receive appropriate antimicrobial chemotherapy still die. Proposed alternative treatment strategies may be of considerable potential value in pneumococcal disease. A pneumolysin deficient strain will be used to determine the influence, if any, of macrolides on the synthesis of pneumolysin, as well as the impact of cigarette smoke on pneumococcal growth. It was found that macrolides inhibit the production of pneumolysin at concentrations far below the MIC. These data have been submitted for publication in the Journal of Chemotherapy.

Investigation into epidemiology of N. meningitidis serogroup W135 in GautengProject leaders: Anne von Gottberg, Elizabeth Prentice.Investigation of the epidemiology of cases of N. meningitidis in Gauteng province began in March 2005. Serogroup W135 replaced serogroup A as the predominant serogroup in this province in 2004. As many of the 2004 isolates were related to the ‘Hajj-strain’, further epidemiological information on meningococcal meningitis cases was deemed necessary. The present investigation was designed as a case-control study, where patients were questioned about known risk factors for meningococcal disease, their socio-economic status, travel history and vaccination history. These data are being finalized for publication.

Preventing serious neonatal and maternal peripartum infections in developing country settings with a high prevalence of HIV infection: Assessment of the disease burden and evaluation of an affordable intervention in Soweto, South Africa.Project leaders: Dr Shabir Madhi, Dr Clare Cutland, Dr Stephanie Schrag (CDC). Sponsor: CDC/Gates Foundation.

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This study was initiated in April 2004, with planned completion in 2008. More than 6000 ? Clare to give the number) participants have been enrolled onto this randomised, controlled trial to evaluate the efficacy of chlorhexidine wipes of the birth canal in labour and of the infant in reducing 1) vertical transmission of leading pathogens from mother to infant during labour and delivery and 2) incidence of neonatal sepsis and maternal peripartum infection.

Surveillance of culture-confirmed invasive infections among young infants and post-partum mothers at Chris Hani Baragwanath HospitalProject leaders: Dr Clare Cutland, Dr Michael Thigpen (CDC). Collaborator: Mani Khoosal, Dr. J Wadula, Microbiology, CHBH, Dr Anne Schuchat (CDC).This study entails prospective laboratory-based, active surveillance of culture-confirmed invasive infections among young infants who are admitted to CHBH within the first 3 months of life, and post-partum women hospitalized within 14 days of delivery. Surveillance has been ongoing since January 2004.

Durability of antibody response and measure of anamnestic responses to a nonavalent pneumococcal conjugate vaccine among HIV infected and HIV uninfected childrenProject leader: Prof Shabir Madhi. Funder: Wyeth vaccines This study has been performed to try to assess the durability of the efficacy of the PncC vaccine, particularly among HIV infected children. The study involved those children who had participated in the phase 3 Pnc conjugate vaccine efficacy trial that were recruited between March 1998 and October 2000. The current age of the children that participated in the vaccine efficacy trial ranges between 3-5.5 years (mean 4 years). These children would have been randomised to receive there primary series of PncCv or placebo at 6, 10 and 14 weeks of age. In addition to this a second cohort of HIV infected children, who were not participants of the initial vaccine trial, between the ages of 3-6 years received two vaccines 1 month apart respectively.Recruitment and sample collection was completed in May 2005. Completion of specimen processing and release of results by early 2006. One manuscript published, and a second is in preparation.

Fluoroquinolone-resistant pneumococci causing invasive disease have emerged in South Africa in childrenProject leaders: Anne von Gottberg, Linda de Gouveia, Mignon du Plessis; collaborators: NICD Epidemiology and National Microbiology Surveillance Units; Drs Andrew Whitelaw and Rena Hoffman, Groote Schuur Hospital, Cape TownThese resistant isolates were associated with MDR-TB treatment in children (von Gottberg A et al, PIDJ 2003, 22:1020-1, and oral presentation at International Symposium on Pneumococci and Pneumococcal Diseases, April 2-6, Alice Springs, Central Australia. 2006.). A carriage study at Sizwe Hospital completed in August 2006 demonstrated no pneumococcal carriage in adult patients, but 47% (9/19) of children were colonized with pneumococci. All these pneumococci were resistant to fluoroquinolones, and were identified as the same strain causing invasive disease in 2003 in the same hospital. A second carriage study is proposed in the Western Cape, and these data are to be finalized for publication.

Postgraduate students

Name Study Level

Gender Population group

Funder Status of study

Leigh Dini PhD Female White 2nd year (PT)

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Peter Suwirakwenda Nyasulu

MSc Male Black Will submit in January 2007

Sithembiso Velaphi PhD Male Black 2nd yr (PT)Herbert Ludwick PhD Male Colored 3rd Yr-

submitting thesis in 2007

Name Study Level Title of thesis Institution where registered

Progress thus far

Nicole Wolter PhD Novel mechanisms of resistance to protein synthesis inhibitors in Streptococcus pneumoniae

Wits 3rd yearWriting up – will submit mid-2007

Kedibone Mothibeli

MSc Molecular epidemiology of pneumococcal serotype 3and serotype 19A isolates from South Africa.

Wits 3rd yearWriting up – will submit early 2007

Anne von Gottberg PhD Studies on bacterial respiratory pathogens causing bacteraemia and meningitis in South Africa.

Wits 1st year completed

Azola Fali PhD To be decided To register in 2007

Clare Cutland PhD Epidemiology and prevention of sepsis in young infants and the potential impact of maternal HIV infection on neonatal sepsis

Wits 1st year completed

Dr Michelle Groome

Masters in Biostatistics and Epidemiology

Wits Registration in 2007

Morongwe Maraba M. Tech Quantitative and qualitative assessment of antibody response to PCV in HIV infected and uninfected children

Vaal University of Technology

1st Year completed

2006 Publications

1. Anderson R, Steel HC, Cockeran R, Smith AM, von Gottberg A, de Gouveia L, Brink A, Klugman KP, Mitchell TJ, Feldman C.(2006) Clarithromycin alone and in combination with ceftriaxone inhibits the production of pneumolysin by both macrolide-susceptible and

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macrolide-resistant strains of Streptococcus pneumoniae. J Antimicrob Chermother; in press.

2. Frean J, Arntzen L, Klugman K (2006) Susceptibility of Bacillus anthracis to moxifloxacin. South Afr J Epidemiol Infect; 20: 119 – 120.

3. Hermans PW, Adrian PV, Albert C, Estevao S, Hoogenboezem T, Luijendijk IH, Kamphausen T, Hammerschmidt S (2006) The streptococcal lipoprotein rotamase A (SlrA) is a functional peptidyl-prolyl isomerase involved in pneumococcal colonization. J Biol Chem. 2006; 281: 968-76.

4. Klugman KP, Levin BR (2006) one enzyme inactivates two antibiotics. Nat Med; 12: 19 – 20.

5. Klugman KP, Madhi SA (2006) Conjugate vaccines as probes to define the burden of pneumococcal and Haemophilus influenzae type b pneumonia as well as the role of viruses in the pathogenesis of pneumonia. In Scheld WM, Hooper DC, Hughes JM (Eds.) Emerging Infections 7, ASM Press, Washington, DC pp 215-224.

6. Klugman KP, Yu VL (2006) No impact of penicillin resistance on mortality. Clin Infect Dis 2006; 43: 261-2.

7. Laxminarayan R, Bhutta Z, Duse A, Jenkins P, O’Brien T, Okeke I, Pablo-Mendez A, Klugman KP (2006) Drug resistance. In Jamison DT, Breman JG, Meesham AR, Alleyne G, Claeson M, Evans DB, Jha P, Mills A, Musgrove P (Eds.) Disease Control Priorities Project, 2nd Ed., World Bank, Washington DC, pp 1031 – 1051.

8. Levine OS, O’Brien KL, Knoll M, Adegbola RA, Black S, Cherian T, Dagan R, Goldblatt D, Grange A, Greenwood B, Hennessy T, Klugman KP, Madhi SA, Mulholland K, Nohynek H, Santosham M, Saha SK, Scott JA, Sow S, Whitney CG, Cutts F (2006) Pneumococcal vaccination in developing countries. Lancet; 367: 1880 - 1882.

9. Madhi S, Klugman KP (2006) acute respiratory infections. In Disease and Mortality in Sub-Saharan Africa, 2nd Ed., Jamison DT, Feachem RG, Makgoba MW, Bos ER, Baingana FK, Hofman KJ, Rogo KO (Eds.), The World Bank, Washington DC, pp 149 - 162.

10. Madhi SA, Adrian P, Kuwanda L, Jassat W, Jones S, Little T, Soininen A, Cutland C, Klugman KP (2006) Long-term immunogenicity and efficacy of a 9-valent conjugate pneumococcal vaccine in human immunodeficient virus infected and non-infected children in the absence of a booster dose of vaccine. Vaccine 2006 Sep 20, epub ahead of print.

11. Madhi SA, Cutland C, Zhu Y, Hackell JG, Newman F, Blackburn N, Murphy BR, Belshe RB, Karron RA, Deatly A, Gruber WC, Wright PF (2006) Transmissibility, infectivity and immunogenicity of a live human parainfluenza type 3 virus vaccine (HPIV3cp45) among susceptible infants and toddlers. Vaccine 2006; 24: 2432-9.

12. Madhi SA, Ludewick H, Kuwanda L, Niekerk N, Cutland C, Little T, Klugman KP (2006) Pneumococcal coinfection with human metapneumovirus. J Infect Dis 2006; 193: 1236-43.

13. Madhi SA, Kohler M, Kuwanda L, Cutland C, Klugman KP (2006) Usefulness of C-reactive protein to define pneumococcal conjugate vaccine efficacy in the prevention of pneumonia. Pediatr Infect Dis J; 25: 30 - 36.

14. Madhi SA, Kuwanda L, Cutland C, Klugman KP (2006) Five-year cohort study of hospitalization for respiratory syncytial virus associated lower respiratory tract infection in African children. J Clin Virol; 36: 215 – 221.

15. Madhi SA, Ludwick H, Kuwanda L, van Niekerk N, Cutland C, Little T, Klugman KP (2006). Pneumococcal co-infection with human metapneumovirus. J Infect Dis; 193: 1236 -1243.

16. Obaro S, Madhi SA (2006) Pneumonia Vaccines and Childhood Pneumonia: Are we winning, refining or redefining? Lancet Infect Dis 2006; 6: 150-61.

17. Tillotson GS, Carroll J, Klugman KP (2006) Antimicrobial Resistance - Fluoroquinolones and the Tiger's Tail. J Chemother 2006; 18: 328-30.

18. Tuomanen E and Klugman KP (2006) Pneumococcal infections. In Tropical Infectious Diseases: Principles, Pathogens, and Practice, 2nd Ed., Guerrant, RI, Walker DH, Weller PF (Eds.), Elsevier, New York, Vol 1, pp 349-355.

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19. Van Rie A, Madhi SA, Heera JR, Meddows-Taylor S, Wendelboe AM, Anthony F, Violari A, Tiemessen CT (2006) Influence of intrauterine exposure to Human Immunodeficiency Virus on infant interferon gamma production to BCG and Mycobacterium tuberculosis antigens. Clin Vaccine Immunol 2006; 13: 246-252.

20. von Gottberg A, de Gouveia L, Madhi SA, du Plessis M, Quan V, Soma K, Huebner R, Flannery B, Schuchat A, Klugman KP for the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA) (2006) Impact of conjugate Haemophilus influenzae type b (Hib) vaccine introduction in South Africa. Bull WHO; 84: 811 - 818.

21. Wadula, J, von Gottberg, A, Kilner, D, de Jong, G. Cohen, C. Keddy, K, Creewe-Brown, H (2006) Nosocomial outbreak of extended-spectrum β-lactamase-producing Salmonella Isangi in pediatric wards. Ped Inf Dis J 2006; 25: 843-852.

22. Wolter N, Smith AM, Farrell DJ, Klugman KP (2006) Heterogeneous macrolide resistance and gene conversion in the pneumococcus. Antimicrob Agents Chemother; 50: 359-361.

23. Wright PF, Karron RA, Madhi SA, Treanor JJ, King JC, O’Shea A, Ikizler MR, Zhu Y, Collins PL, Cutlland C, Randolph VB, Deatly A, Gruber WC, Murphy BR (2006) The interferon antagonist NS2 protein of respiratory syncytial virus is an important virulence determinant for humans J.Infect Dis 2006; 193: 573-81.

24. Zar HJ, Madhi SA (2006) Childhood pneumonia--progress and challenges. S Afr Med J 2006; 96: 890-900.

25. Berkelman R, Cassell G, Specter S, Hamburg M, Klugman K (2006) The “Achilles heel” of global efforts to combat infectious diseases. Clin Infect Dis; 42: 1503 - 1504.

26. McGee L, Tenover FC, Beall B, Klugman KP (2006) The Emergence, Spread and Extinction of Bacterial Pathogenic Clones. In Cassell GH, Baquero F, Nombela C, Gutiérrez-Fuentes JA (Eds.) Introduction to the Evolutionary Biology of Bacterial and Fungal Pathogens, ASM Press, Washington, DC, in press.

27. Klugman KP, Feldman C (2006) Pneumococcal infections. In Brachman PS, AbrutynE (Eds.) Bacterial Infections of Humans: Epidemiology and Control, 4th Ed., Springer, New York, in press

28. Klugman KP (2006) Fluoroquinolone treatment of pneumococcal infections. Southern Afr J Epidemiol Infect, in press.

29. Klugman KP, Madhi SA, Feldman C (2006) HIV and pneumococcal disease. Curr Opinion Infect Dis, in press.

30. Klugman KP (2006) Clinical impact of antibiotic resistance in respiratory tract infections. Int J Antimicrob Agents, in press.

31. Coulson GB, von Gottberg A, du Plessis M, Smith AM, de Gouveia L, Klugman KP for the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA) (2006) Epidemiology of meningococcal disease in South Africa 1999 - 2002. Emerg Infect Dis, in press.

32. Wolter N, Smith AM, Low DE, Klugman KP (2006) High level telithromycin resistance in a clinical isolate of Streptococcus pneumoniae. Antimicrob Agents Chemother, in press.

33. Madhi SA, Klugman KP (2006) World health organization definition of “radiologically – confirmed pneumonia” may underestimate the true public health value of conjugate pneumococcal vaccines. Vaccine, 18 Sep 2006, epub ahead of print.

Details of Conferences AttendancesInvited Lectures, Papers Presented and Consultancies Professor Keith P Klugman

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Jan 2006 Invited Speaker, US / Japan Cooperative Medical Science Program, Acute Respiratory Infections Panel meeting, Galveston, TX

Feb 2006 Invited Speaker, 13th Conference on Retroviruses and Opportunistic Infections (CROI), Denver, CO

Feb 2006 Invited Participant, Public and Scientific Affairs Board Meeting of the American Society for Microbiology, Washington, DC

Mar 2006 Inaugural Lecture, William H Foege Professor of Global Health, Emory University, Atlanta, GA

Apr 2006 Invited Lecture, Pediatric Grand Rounds, SUNY Downstate Medical Center, Brooklyn, New York, NY

Apr 2006 Invited Lecture, Department of Epidemiology, Harvard School of Public Health, Boston, MA

Apr 2006 Member of Advisory Board, Invited Chair of Session and Speaker, 5 th

International Symposium on Pneumococci and Pneumococcal Diseases (ISPPD), Alice Springs, Australia

Apr 2006 Chairperson of the 9th Meeting of the Pneumococcal Molecular Epidemiology Network, Alice Springs, Australia.

Apr 2006 Invited Lecture, 75th Anniversary Meeting of the Turkish Society of Microbiology, Istanbul, Turkey

Apr 2006 - Invited Member Executive Committee Meeting of the International Union of Date Microbiological Societies, Istanbul, Turkey. Jun 2006 Invited Participant, European Commission Workshop on International

Collaboration on Antibiotic Resistance, Specifically the Burden of Resistance, Brussels, Belgium.

Jun 2006 Invited Reviewer, Gates Foundation/Wellcome Trust Grand Challenge Grant on Novel Drugs for Tuberculosis, Imperial College, London, UK.

Jun 2006 Invited Lecture, 12th International Congress on Infectious Diseases, Lisbon, Portugal.

Jun 2006 Invited Participant, WHO Conference on Essential Care and Prevention Interventions for People Living with HIV; Reviewing the Evidence and Developing Guidelines, Montreux, Switzerland.

Jun 2006 Chair of ASM International Committee Delegation to WHO, Geneva, Switzerland, and to Merieux Foundation, Lyon, France.

Jul 2006 Invited Lecture, 2nd Federation of European Microbioloical Societies (FEMS) Congress, Madrid, Spain.

Aug 2006 Invited Lectures, Research Rounds 21, Whistler, BC, Canada.Aug 2006 Invited Participant, Retreat of International Education Committee of ASM,

Washington, DC.Sep 2006 Invited Lecture to Deans Council of School of Public Health of Emory University,

CDC, Atlanta, GASep 2006 Chair of Satellite Symposium and Invited Lecture, European Respiratory Society

Annual Congress, Munich, Germany.Sep 2006 Invited Chair of Session and Lecture, 46th Interscience Conference on

Antimicrobial Agents and Chemotherapy (ICAAC), San Francisco, CAOct 2006 Invited Lecture, Molecular Microbiology Group, Department of Microbiology,

Emory University, Atlanta, GA.Oct 2006 Invited Lecture, Department of Pulmonolgy, School of Medicine, Emory

University, Atlanta, GA.Oct 2006 Member of Council Policy Committee Meeting, ASM, Washington, DCOct 2006 Invited Chair of Session, Wellcome Trust Vaccinology Frontiers Meeting, Hartley

Wintney, Hamshire, UK.Oct 2006 Invited Chair of Session, 44th Infectious Diseases Society of America (IDSA)

Annual Meeting, Toronto, Canada.

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Oct 2006 Invited Expert, Expert Review of Estimates of Morbidity and Mortality Associated with Haemophilus influenzae type b (Hib) and Streptococcus pneumoniae (SP), WHO Initiative for Vaccine Research, London, UK.

Oct 2006 Chair, Expert Consultation on Serotype Composition of Pneumococcal Conjugate Vaccines for Use in Resource Poor Developing Countries, WHO Initiative for Vaccine Research, Geneva, Switzerland.

Nov 2006 Invited Participant, UK Public Health Strategy Meeting of the Wellcome Trust, London, UK.

Nov 2006 Invited Speaker, 2nd Asia- Pacific Pneumococcal Disease Conference, Kuala Lumpur, Malaysia.

Nov 2006 Chair of Session and Speaker, 55th Annual Meeting of the American Society of Tropical Medicine and Hygiene, Atlanta, GA

Sep 2006 Invited Speaker, All 4 Kids Congress, South African Paediatric Association, Sun City.

Dec 2006 Invited Speaker and Co-Chair of Session, 2nd Regional Pneumococcal Symposium, Sao Paulo, Brazil.

Associate Professor Shabir Madhi

Invited talks

1. 5th International Symposium on Pneumococci and Pneumococcal Diseases. Alice Springs, Australia; 2-6 April 2006. Bacterial Pneumonia- do current diagnostic definitions (chest-radiograph alveolar consolidation) cover the full spectrum prevented by vaccination. (SY3.09)

2. 24th Annual Meeting of the European Society for Paediatric Infectious Diseases (ESPID).Basel, Switzerland May 3-5 2006. Pneumococcal co-infections in Viral associated Pneumonia (ESPID Young Investigators Award Invited Presentation).

3. 12th International Congress on Infectious Diseases. Lisbon, Portugal June 15-18 2006.Tuberculosis: Recognition and Management in Children with and Without HIV. Session 73.002

4. South African Paediatric Association; All 4 Kids Congress 2006. Sun City, Johannesburg; 7-10 Sept 2006. Management of pneumonia in HIV infected children.

5. British HIV Association Autumn Conference. Queen Elizabeth II Conference Centre; London; 12-13 October 2006. Pneumococcal Diseases and HIV infection in adults and children.

Orals and Posters presented at congresses by other staff

International Conference on Emerging Infectious Diseases, March 19-22, 2006, Atlanta, Georgia, USA.

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1. Emergence of W135 Meningococcal Disease in South Africa. Prentice E, von Gottberg A, Cohen C, de Gouveia L, Coulson G, Klugman KP. Oral presentation 58, Program and Abstracts Book, International Conference on Emerging Infectious Diseases, March 19-22, 2006, Atlanta, Georgia, USA.

2. ‘Perinatal sepsis due to Staphylococcus aureus in Soweto, South Africa’ R.M. Patel, M.C. Thigpen , C. L. Cutland, W. Jassat , M.J. Groome, S.C. Velaphi, M. Khoosal, J. Wadula, S.J. Schrag, S.A. Madhi

5th International Symposium on Pneumococci and Pneumococcal Diseases, April 2-6, 2006, Alice Springs, Central Australia.

1. Telithromycin resistance in a clinical isolates of Streptococcus pneumoniae conferred by a deletion in the promoter region of erm(B). Wolter N, Smith AM, Farrell, DJ, and Klugman KP. Oral presentation SY5.02, Program and Abstract Book, 5th International Symposium on Pneumococci and Pneumococcal Diseases, April 2-6, 2006, Alice Springs, Central Australia.

2. Emergence of fluoroquinolone resistant invasive pneumococcal infections among children, South Africa, 2000-2005. von Gottberg A, Smith AM, de Gouveia L, Whitelaw A, Hoffman R, Klugman KP for the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA). Oral presentation SY13.04, Program and Abstract Book, 5th International Symposium on Pneumococci and Pneumococcal Diseases, April 2-6, 2006, Alice Springs, Central Australia.

3. History of prior antibiotic use before acute hospital admission for invasive pneumococcal disease in South Africa in 2003 and 2004. Quan V, von Gottberg A, de Gouveia L, Klugman KP for the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA). Poster presentation PO13.04, Program and Abstract Book, 5th International Symposium on Pneumococci and Pneumococcal Diseases, April 2-6, 2006, Alice Springs, Central Australia.

4. Probing the association between serotype-specific pneumococcal nasopharyngeal colonization and efficacy of the pneumococcal conjugate vaccine against pneumonia. Madhi SA, Cutland CL, Kuwanda L, de Gouveia L, von Gottberg A, and Klugman KP. Poster presentation PO7.09, Program and Abstract Book, 5th International Symposium on Pneumococci and Pneumococcal Diseases, April 2-6, 2006, Alice Springs, Central Australia.

5. Long-term effects of a 9-valent penumococcal conjugate vaccine (PCV) on nasopharyngeal colonization with pneumococcal serotypes included in the vaccine. Adrian PV, van Niekerk N, Jones S, Cutland CL, von Gottberg A, de Gouveia L, Klugman KP, Madhi SA. Poster presentation PO10.16, Program and Abstract Book, 5th International Symposium on Pneumococci and Pneumococcal Diseases, April 2-6, 2006, Alice Springs, Central Australia.

6. A new method for serotyping pneumococcal strains using quantitative immunoabsorption as measured by ELISA. Eastham V, van Niekerk N, Little T, von Gottberg A, de Gouveia L, Adrian PV, and Madhi SA. PODT.32, Program and Abstract Book, 5th International Symposium on Pneumococci and Pneumococcal Diseases, April 2-6, 2006, Alice Springs, Central Australia.

16th European Congress of Clinical Microbiology and Infectious Disease, April 1-4, 2006, Nice, France.

1. Antimicrobial susceptibility of pneumococcal isolates causing bacteraemic community-acquired pneumonia in the public and private sectors in Gauteng, South Africa. Feldman C, Brink A, von Gottberg A, de Gouveia L, Perovic O, and Klugman KP. Oral

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presentation O228, Abstracts and Posters, 16th European Congress of Clinical Microbiology and Infectious Disease, April 1-4, 2006, Nice, France.

2. Invasive pneumococcal disease in the era of human immunodeficiency virus infection. Perovic O, von Gottberg A, and Feldman C. Oral presentation O221, Abstracts and Posters, 16th European Congress of Clinical Microbiology and Infectious Disease, April 1-4, 2006, Nice, France.

3rd Public Health Conference, May 15-17, 2006, Midrand, South Africa

1. de Gouveia L, Mpembe R, von Gottberg A, Quan V, Prentice E, Klugman KP, for the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA). Surveillance of invasive Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis disease from 2003-2005 in South Africa. Poster presentation, Programme Book, 3rd Public Health Conference, May 15-17, 2006, Midrand, South Africa.

2. Govender N , Quan V, Prentice E, von Gottberg A, Keddy K, and McCarthy K for the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA). A national South African Surveillance Network for bacterial and fungal diseases. Poster presentation, Programme Book, 3rd Public Health Conference, May 15-17, 2006, Midrand, South Africa.

IX International Workshop on Opportunistic Protists (IWOP-9), Lisbon Portugal, June 2006.

Dini LA, du Plessis M, Wong ML, Karstaedt A, Fernandez V, Frean JA. High prevalence of DHPS polymorphisms associated with sulfa resistance in South African Pneumocystis jirovecii strains. Platform presentation at IX International Workshop on Opportunistic Protists (IWOP-9), Lisbon Portugal, June 2006.

WITS Health Sciences Research Day, 23rd Aug 2006

1. N. Wolter , AM Smith, DJ Farrell and KP Klugman Telithromycin resistance in a clinical isolate of Streptococcus pneumoniae conferred by a deletion in the promoter region of erm(B).

2. C. Feldman , R. Anderson, HC Steel, R. Cockeran, A. von Gottberg, L. de Gouveia, A. Smith, A. Brink, TJ Mitchell and KP Klugman. Pneumococcal pneumolysin production is inhibited by clarithromycin, both in the presence and absence of ceftriaxone.

Prize awarded for the best oral presentation in: HIV and Infectious diseases category3. K Mothibeli , L. McGee, M. du Plessis, A. von Gottberg, AM Smith, B. Beall and KP

Klugman. Molecular epidemiology of invasive pneumococcal serotype 3 isolates from Gauteng province and comparison with serotype 3 strains from United States of America (poster presentation).

Prize awarded for the best poster presentation in: HIV and Infectious diseases category, Prize = R10 000 travel grant

4. M. du Plessis , A. von Gottberg, C. Cohen, L. de Gouveia, G. Coulson and KP Klugman for GERMS-SA. Penicillin non-susceptibility in meningococcal isolates causing invasive disease in South Africa (poster presentation)

5. Peter V. Adrian , Nadia van Niekerk, Clare L. Cutland, Anne von Gottberg, and Shabir A. Madhi

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Relationship between nasopharyngeal colonization with Streptococcus pneumoniae, Haemophilus influenzae, and Staphylococcus aureus, in relation to HIV status, and vaccination with a 9-valent pneumococcal conjugate vaccine (PCV) (poster presentation)6. Adrian, PV 1, van Niekerk, N1, Jones, S1, Cutland, CL1, von Gottberg, A2, de Gouveia,

L2, Klugman, KP3, Madhi, SA1 Long Term Effects of a 9-valent Pneumococcal Conjugate Vaccine (PCV) on Nasopharyngeal Colonization with Pneumococcal Serotypes Included in the Vaccine(poster presentation)V. Eastham,1N. van Niekerk1, T. Little1, A. von Gottberg2, L. de Gouveia2, P.V. Adrian 1 S.A. Madhi1

7. A novel method for serotyping pneumococcal strains using quantitative immunoabsorption as measured by ELISA(poster presentation)

The American College of Chest Physicians (ACCP) 72nd Annual Medical Conference October 21-26, 2006, in Salt Lake City, UT, USA.

Charles Feldman, Anne von Gottberg, Willem Sturm, Alan Karstaedt, Nelesh Govender, Andrew Whitelaw, Linda de Gouveia, Keith Klugman for the Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA). Nosocomial Invasive Pneumococcal Disease (IPD). Poster presentation, in abstracts of the American College of Chest Physicians (ACCP) 72nd Annual Medical Conference October 21-26, in Salt Lake City, UT, USA.This poster was awarded a “top ten” poster award at the Congress.

1st e’Goli Branch Mini Congress, 5 November 2006, University of Johannesburg, Auckland Park, Johannesburg, South Africa

Linda de Gouveia, Anne von Gottberg, Ruth Mpembe, Olga Hattingh, and Keith Klugman, for GERMS-SA. Bacterial meningitis in children younger than 5 years in South Africa in 2005. Society of Medical Laboratory Technologists of South Africa (SMLTSA) 1st e’Goli Branch Mini Congress, 5 November 2006, University of Johannesburg, Auckland Park, Johannesburg, South Africa.

Oral Presentations at Group for Enteric, Respiratory and Meningeal Disease Surveillance in South Africa (GERMS-SA) Principal Investigators Meeting held at NICD (7-8th November 2006)

Molecular epidemiology of meningococcal disease in South Africa (M. du Plessis) Epidemiology of serotype 3 Streptococcus pneumoniae in South Africa (K. Mothibeli) Pneumococcal macrolide resistance: 2000-2005 (N. Wolter) Pediatric bacterial meningitis in South Africa (A. von Gottberg)Risk factors for mortality in patients with invasive pneumococcal disease from South Africa (P. Nyasulu)

Presentations at NICD Academic Day (27-28th November 2006)

Penicillin non-susceptibility in meningococcal isolates causing invasive disease in South Africa (Oral presentation: M. du Plessis)Outbreak of serotype 1 invasive pneumococcal disease in South Africa in 2003 (Oral presentation: A. von Gottberg)High-level telithromycin resistance in a clinical isolate of Streptococcus pneumoniae (Oral presentation: N. Wolter)Bacterial meningitis in children in South Africa (Poster presentation: L. de Gouveia)Molecular epidemiology of multi-drug resistant pneumococcal serotype 19A isolates from South Africa (Poster presentation: K. Mothibeli)

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Research Translation:

The chapter on Acute Respiratory Infections for the World Bank book on Disease and Mortality in Sub-Saharan Africa sets a benchmark for intervention by that organization. The proposition of a new algorithm to measure the burden of pneumococcal disease preventable by conjugate vaccine has already been adopted by the only major vaccine trial of conjugate vaccination to be performed in South America... The Unit’s expanded national surveillance for respiratory pathogens has validated the decision of the DOH to invest in Hib vaccination of children in South Africa. The data on pneumococcal disease burden provide a basis for the introduction of conjugate pneumococcal vaccine and measures the impact of antiretrovirals on the evolution of the pneumococcus as an opportunistic infection in South Africa, Dr Anne von Gottberg contributed to the finalization of Meningococcal Disease Guidelines with the Meningococcal Guideline Working Group. The members of the Unit participated in numerous South African and international policy discussions – see consultancies above.

Details of any other Activities, Research Outputs and Outcomes, Achievements or Awards

Associate Professor Shabir Madhi

Prof Shabir Madhi was awarded the European Society for Infectious Diseases, Young Investigators Award for 2006.

Prof Shabir Madhi was awarded the Faculty of Health Sciences Prize (University of the Witwatersrand) for Research. This is the most prestigious prize offered by the Faculty of Health Sciences at the University of the Witwatersrand, and is awarded in recognition of excellence in research.

The prize goes to the researcher (under 40 years of age), usually the first author on the publication, whose publication in an international peer-reviewed journal is considered to have made the most impact on the biomedical community of scientists. The publication must be of exceptional quality within the discipline and is judged to be of winning standard considering the Impact Factor of the journal in which the paper appeared, the rank of the journal in the discipline, and the quality of the research paper itself. The Impact Factor is an indication of the likely impact a journal may have in the scientific community as calculated by the Institute for Scientific Information.2006

Prof KP Klugman

Prof Klugman was given Honorary Membership of the South African Paediatric Association.

Dr A Smith

Dr Anthony Smith was awarded the Faculty of Health Sciences (University of the Witwatersrand) Prize for Research. This is the most prestigious prize offered by the Faculty of Health Sciences at the University of the Witwatersrand, and is awarded in recognition of excellence in research.

The prize goes to the researcher (under 40 years of age), usually the first author on the publication, whose publication in an international peer-reviewed journal is considered to have made the most impact on the biomedical community of scientists. The publication must be of exceptional quality within the discipline and is judged to be of winning standard considering the Impact Factor of the

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journal in which the paper appeared, the rank of the journal in the discipline, and the quality of the research paper itself. The Impact Factor is an indication of the likely impact a journal may have in the scientific community as calculated by the Institute for Scientific Information.

A statement of total income and expenditure for the year, demonstrating accountability for funds provided and expected budget for the following year

Current funding

Source Amount Purpose (eg. details of the project or work funded)

Funded elements

MRC R507,304 OperatingMRC R144,797 SalariesWITS R251,550 SalariesNICD R1m Salaries and

operationalCDC/Gates Foundation

R4.2m Preventing serious neonatal and maternal peripartum infections in developing country settings with a high prevalence of HIV infection: Assessment of the disease burden and evaluation of an affordable intervention in Soweto, South Africa.

Salaries, laboratory assays, subject follow-up costs

CIPRA R1.8m Immunogenicity and functionality of antibody induced by pneumococcal conjugate vaccine in HIV- infected infants

Salaries, laboratory assays, subject follow-up costs

NIH $1m over 3 years Adult burden of bacterial pneumonia Salaries, laboratory assays

Grand Challenge R2.5m Defining the correlates of protection against nasopharyngeal colonization by pneumococci and the mechanism of protection induced by conjugate pneumococcal vaccines

Salaries, laboratory assays, subject follow-up costs

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