Papers by Thandie mwalukomo
Expansion of pneumococcal serotype 23F and 14 lineages with genotypic changes in capsule polysaccharide locus and virulence gene profiles post introduction of pneumococcal conjugate vaccine in Blantyre, Malawi
Microbial genomics, Jun 19, 2024
Clonal Expansion of a <i>Streptococcus pneumoniae</i> Serotype 3 Capsule Variant Sequence Type 700 With Enhanced Vaccine Escape Potential After 13-Valent Pneumococcal Conjugate Vaccine Introduction
The journal of infectious diseases (Online. University of Chicago Press)/The Journal of infectious diseases, Mar 26, 2024
Nature Communications, Nov 16, 2023
Streptococcus pneumoniae causes substantial mortality among children under 5-years-old worldwide.... more Streptococcus pneumoniae causes substantial mortality among children under 5-years-old worldwide. Polysaccharide conjugate vaccines (PCVs) are highly effective at reducing vaccine serotype disease, but emergence of non-vaccine serotypes and persistent nasopharyngeal carriage threaten this success. We investigated the hypothesis that following vaccine, adapted pneumococcal genotypes emerge with the potential for vaccine escape. We genome sequenced 2804 penumococcal isolates, collected 4-8 years after introduction of PCV13 in Blantyre, Malawi. We developed a pipeline to cluster the pneumococcal population based on metabolic core genes into "Metabolic genotypes" (MTs). We show that S. pneumoniae population genetics are characterised by emergence of MTs with distinct virulence and antimicrobial resistance (AMR) profiles. Preliminary in vitro and murine experiments revealed that representative isolates from emerging MTs differed in growth, haemolytic, epithelial infection, and murine colonisation characteristics. Our results suggest that in the context of PCV13 introduction, pneumococcal population dynamics had shifted, a phenomenon that could further undermine vaccine control and promote spread of AMR. Streptococcus pneumoniae (the pneumococcus), a common commensal of the upper respiratory tract, is responsible for a high burden of severe pneumonia, septicaemia and meningitis 1,2 , mainly affecting children under 5-years-old, the immunocompromised and the elderly. Pneumococcal disease causes almost 300,000 deaths annually in under-5's worldwide, and disproportionally affects people in resourcepoor settings, where 57% of the total pneumococcal deaths occur 3. This high burden of pneumococcal disease is largely vaccine preventable 1,4. Indeed, reports from The Gambia, South Africa, Kenya and Malawi 5-9 show that pneumococcal conjugate vaccines (PCV), targeting the polysaccharide capsule of the most common diseasecausing pneumococcal serotypes (currently PCV10 or PCV13), have been highly effective in reducing invasive pneumococcal disease (IPD). However, the highly adaptable nature of S. pneumoniae has the
bioRxiv (Cold Spring Harbor Laboratory), Mar 26, 2024
Expansion of pneumococcal serotype 23F and 14 lineages with genotypic changes in capsule polysacc... more Expansion of pneumococcal serotype 23F and 14 lineages with genotypic changes in capsule polysaccharide locus and virulence gene profiles post introduction of pneumococcal conjugate vaccine in Blantyre, Malawi
Effect of Long Duration of Art on Pneumococcal Carriage in Hiv Infected Adults Following PCV13 Introduction Into the Infant Schedule in Malawi
BMC Medicine, Dec 1, 2019
Background: In November 2011, Malawi introduced the 13-valent pneumococcal conjugate vaccine (PCV... more Background: In November 2011, Malawi introduced the 13-valent pneumococcal conjugate vaccine (PCV13) into the routine infant schedule. Four to 7 years after introduction (2015-2018), rolling prospective nasopharyngeal carriage surveys were performed in the city of Blantyre. Carriage of Streptococcus pneumoniae vaccine serotypes (VT) remained higher than reported in high-income countries, and impact was asymmetric across age groups. Methods: A dynamic transmission model was fit to survey data using a Bayesian Markov-chain Monte Carlo approach, to obtain insights into the determinants of post-PCV13 age-specific VT carriage. Results: Accumulation of naturally acquired immunity with age and age-specific transmission potential were both key to reproducing the observed data. VT carriage reduction peaked sequentially over time, earlier in younger and later in older age groups. Estimated vaccine efficacy (protection against carriage) was 66.87% (95% CI 50.49-82.26%), similar to previous estimates. Ten-year projected vaccine impact (VT carriage reduction) among 0-9 years old was lower than observed in other settings, at 76.23% (CI 95% 68.02-81.96%), with sensitivity analyses demonstrating this to be mainly driven by a high local force of infection. Conclusions: There are both vaccine-related and host-related determinants of post-PCV13 pneumococcal VT transmission in Blantyre with vaccine impact determined by an age-specific, local force of infection. These findings are likely to be generalisable to other Sub-Saharan African countries in which PCV impact on carriage (and therefore herd protection) has been lower than desired, and have implications for the interpretation of post-PCV carriage studies and future vaccination programs.
The New England Journal of Medicine, Mar 4, 2010
Background Streptococcus pneumoniae is a leading and serious coinfection in adults with human imm... more Background Streptococcus pneumoniae is a leading and serious coinfection in adults with human immunodeficiency virus (HIV) infection, particularly in Africa. Prevention of this disease by vaccination with the current 23-valent polysaccharide vaccine is suboptimal. Protein conjugate vaccines offer a further option for protection, but data on their clinical efficacy in adults are needed. Methods In this double-blind, randomized, placebo-controlled clinical efficacy trial, we studied the efficacy of a 7-valent conjugate pneumococcal vaccine in predominantly HIV-infected Malawian adolescents and adults who had recovered from documented invasive pneumococcal disease. Two doses of vaccine were given 4 weeks apart. The primary end point was a further episode of pneumococcal infection caused by vaccine serotypes or serotype 6A. Results From February 2003 through October 2007, we followed 496 patients (of whom 44% were male and 88% were HIV-seropositive) for 798 person-years of observation. There were 67 episodes of pneumococcal disease in 52 patients, all in the HIV-infected subgroup. In 24 patients, there were 19 episodes that were caused by vaccine serotypes and 5 episodes that were caused by the 6A serotype. Of these episodes, 5 occurred in the vaccine group and 19 in the placebo group, for a vaccine efficacy of 74% (95% confidence interval [CI], 30 to 90). There were 73 deaths from any cause in the vaccine group and 63 in the placebo group (hazard ratio in the vaccine group, 1.18; 95% CI, 0.84 to 1.66). The number of serious adverse events within 14 days after vaccination was significantly lower in the vaccine group than in the placebo group (3 vs. 17, P = 0.002), and the number of minor adverse events was significantly higher in the vaccine group (41 vs. 13, P = 0.003). Conclusions The 7-valent pneumococcal conjugate vaccine protected HIV-infected adults from recurrent pneumococcal infection caused by vaccine serotypes or serotype 6A. (Current Controlled Trials number, ISRCTN54494731.
Risk factors for pneumococcal carriage in adults living with HIV on antiretroviral therapy in the infant pneumococcal vaccine era in Malawi
AIDS, Aug 19, 2022
Objective: Adults living with HIV (ALWHIV) on antiretroviral therapy (ART) are at high risk of pn... more Objective: Adults living with HIV (ALWHIV) on antiretroviral therapy (ART) are at high risk of pneumococcal carriage and disease. To help evaluate carriage risk in African ALWHIV at least 4 years after infant pneumococcal conjugate vaccination introduction in 2011, we assessed association between pneumococcal carriage and potential risk factors. Methods: Nasopharyngeal swabs were collected from adults aged 18–40 years attending an ART clinic during rolling, cross-sectional surveys in Blantyre, Malawi between 2015 and 2019. We fitted generalized additive models to estimate the risk of sex, social economic status (SES), living with a child less than 5 years, and ART duration on carriage. Results: Of 2067 adults, median age was 33 years (range 28–37), 1427 (69.0%) were women, 1087 (61.4%) were in low–middle socioeconomic-status (SES), 910 (44.0%) were living with a child less than 5 years, and median ART duration was 3 years (range 0.004–17). We estimated 38.2 and 60.6% reductions in overall and vaccine-serotype carriage prevalence. Overall carriage was associated with low SES, living with a child less than 5 years and shorter duration on ART. By contrast, vaccine-type carriage was associated with living without a child less than 5 years and male sex. Conclusion: Despite temporal reductions in overall and vaccine-serotype carriage, there is evidence of incomplete vaccine-serotype indirect protection. A targeted-vaccination campaign should be considered for ALWHIV, along with other public health measures to further reduce vaccine-serotype carriage and therefore disease.
The Lancet HIV, 2018
Background In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high... more Background In sub-Saharan Africa, severely immunocompromised HIV-infected individuals have a high risk of mortality during the first few months after starting antiretroviral therapy (ART). We hypothesise that universally providing readyto-use supplementary food (RUSF) would increase early weight gain, thereby reducing early mortality compared with current guidelines recommending ready-to-use therapeutic food (RUTF) for severely malnourished individuals only. Methods We did a 2 × 2 × 2 factorial, open-label, parallel-group trial at inpatient and outpatient facilities in eight urban or periurban regional hospitals in Kenya, Malawi, Uganda, and Zimbabwe. Eligible participants were ART-naive adults and children aged at least 5 years with confirmed HIV infection and a CD4 cell count of fewer than 100 cells per µL, who were initiating ART at the facilities. We randomly assigned participants (1:1) to initiate ART either with (RUSF) or without (no-RUSF) 12 weeks' of peanut-based RUSF containing 1000 kcal per day and micronutrients, given as two 92 g packets per day for adults and one packet (500 kcal per day) for children aged 5-12 years, regardless of nutritional status. In both groups, individuals received supplementation with RUTF only when severely malnourished (ie, body-mass index [BMI] <16-18 kg/m² or BMI-forage Z scores <-3 for children). We did the randomisation with computer-generated, sequentially numbered tables with different block sizes incorporated within an online database. Randomisation was stratified by centre, age, and two other factorial randomisations, to 12 week adjunctive raltegravir and enhanced anti-infection prophylaxis (reported elsewhere). Clinic visits were scheduled at weeks 2, 4, 8, 12, 18, 24, 36, and 48, and included nurse assessment of vital status and symptoms and dispensing of all medication including ART and RUSF. The primary outcome was mortality at week 24, analysed by intention to treat. Secondary outcomes included absolute changes in weight, BMI, and mid-upper-arm circumference (MUAC). Safety was analysed in all randomly assigned participants. Follow-up was 48 weeks. This trial is registered with ClinicalTrials.gov (NCT01825031) and the ISRCTN registry (43622374).
Basic description of clinical and laboratory data for the 2009/2010 cohort
<p>*At least one of Kaposi's sarcoma, oral candidiasis, wasting, generalized lymphadeno... more <p>*At least one of Kaposi's sarcoma, oral candidiasis, wasting, generalized lymphadenopathy or herpes-zoster.</p
Malawi medical journal : the journal of Medical Association of Malawi, Mar 1, 2009
Systemic vaccination of the BNT162b2 mRNA stimulates humoral response. The aim of our study was t... more Systemic vaccination of the BNT162b2 mRNA stimulates humoral response. The aim of our study was to compare the intensity of humoral immune response, measured by SARS CoV-2 IgG, SARS CoV-2 IgM, and neutralization S-RBD IgG antibodies level, post COVID-19 vaccination versus post SARS COV-2 infection. We analysed 1060 people in the following groups: convalescents, healthy vaccinated, vaccinated with COMIRNATY, AstraZeneca, Moderna, Johnson&Johnson and vaccinated SARS CoV-2 convalescents. A concentration of SARS CoV-2 IgG, SARS CoV-2 IgM, and neutralizing S-RBD IgG was estimated in Bialystok Oncology Center laboratory by chemiluminescent immunoassay-CLIA, MAGLUMI. Results: 1. We observed a raise of antibodies response in both, convalescent SARS CoV-2 and COVID-19 vaccinated groups 2. The level of all antibodies' concentrations in vaccinated COVID-19 convalescents was signi cantly higher. 3. We differentiated an asymptomatic SARS CoV-2 convalescents from control group. Based on our analysis we suggest that it is important to monitor SARS CoV-2 antibodies concentrations as an indicator of asymptomatic COVID-19 infection, and as an equivalent of effectiveness of humoral response in convalescents and vaccinated people. Taking into consideration the time-limited nature of the effects of post infection SARS CoV-2 recovery or vaccination, among others physiological half-life, we suggested monitoring IgG antibodies level as a criterium for next vaccination.
Risk factors for pneumococcal carriage in adults living with HIV on antiretroviral therapy in the infant pneumococcal vaccine era in Malawi
ObjectiveAdults living with HIV (ALWHIV) on antiretroviral therapy (ART) are at high risk of pneu... more ObjectiveAdults living with HIV (ALWHIV) on antiretroviral therapy (ART) are at high risk of pneumococcal carriage and disease. To help evaluate carriage risk in African ALWHIV in the infant pneumococcal conjugate vaccination era, we assessed association between carriage and potential risk factors.MethodsNasopharyngeal swabs were collected from adults aged 18-40 years attending an ART clinic during rolling, cross-sectional surveys in Blantyre, Malawi between 2015-2019. We fitted generalised additive models to estimate the risk of sex, social economic status (SES), living with a child <5y, and ART duration on carriage.ResultsOf 2,067 adults, median age was 33y (range 28-37), 1,427 (69.0%) were females, 1,087 (61.4%) were in low-middle socio-economic-status (SES), 910 (44.0%) were living with a child <5y, and median ART duration was 3.0 years (range 0.004-17). We estimated 38.2% and 60.6% reductions in overall and vaccine-serotype carriage prevalence. Overall carriage was associ...
Comparison of case fatality rates 1997/98 & 2009/10
<p>Comparison of case fatality rates 1997/98 & 2009/10.</p
Summary of patient recruitment strategy and outcomes
<p>Summary of patient recruitment strategy and outcomes.</p
Residual carriage of vaccine-serotype Streptococcus pneumoniae after introduction of a pneumococcal conjugate vaccine in Malawi
BackgroundIn November 2011, Malawi introduced the 13-valent pneumococcal conjugate vaccine (PCV13... more BackgroundIn November 2011, Malawi introduced the 13-valent pneumococcal conjugate vaccine (PCV13) into the routine infant schedule. Four to seven years after introduction (2015-2018), rolling prospective nasopharyngeal carriage surveys were performed in the city of Blantyre. Carriage of Streptococcus pneumoniae vaccine serotypes (VT) remained higher than reported in developed countries, and VT impact was surprisingly asymmetric across age-groups. A dynamic transmission model was fit to survey data using a Bayesian Markov-chain Monte Carlo approach, to obtain insights into the determinants of post-PCV13 age-specific VT carriage.ResultsAccumulation of naturally acquired immunity with age and age-specific transmission potential were both key to reproducing the observed data. VT carriage reduction peaked sequentially over time, earlier in younger and later in older age-groups. Estimated vaccine efficacy (protection against carriage) was 66.87% (95% CI 50.49-82.26%), similar to previous...
Study data and dictionary - Evaluation of Pneumococcal Serotyping of Nasopharyngeal- Carriage Isolates by Latex Agglutination, Whole-Genome Sequencing (PneumoCaT), and DNA Microarray in a High- Pneumococcal-Carriage-Prevalence Population in Malawi
Serotyping results with relevant metadata and dictionary used for evaluating concordance between ... more Serotyping results with relevant metadata and dictionary used for evaluating concordance between three serotyping methods
Malawi Medical Journal, 2016
Streptococcus pneumoniae is a leading and serious coinfection in adults with human immunodeficien... more Streptococcus pneumoniae is a leading and serious coinfection in adults with human immunodeficiency virus (HIV) infection, particularly in Africa. Prevention of this disease by vaccination with the current 23-valent polysaccharide vaccine is suboptimal. Protein conjugate vaccines offer a further option for protection, but data on their clinical efficacy in adults are needed.
The metabolic, virulence and antimicrobial resistance profiles of colonizing Streptococcus pneumoniae shift after pneumococcal vaccine introduction in urban Malawi
Streptococcus pneumoniae accounts for at least 300,000 deaths from pneumonia, septicaemia and men... more Streptococcus pneumoniae accounts for at least 300,000 deaths from pneumonia, septicaemia and meningitis among children under 5-years-old worldwide. Protein-polysaccharide conjugate vaccines (PCVs) are highly effective at reducing vaccine serotype disease but emergence of non-vaccine serotypes and persistent nasopharyngeal carriage threaten to undermine this success. Here, we address the hypothesis that following vaccine introduction in high disease and carriage burden settings, adapted pneumococcal genotypes emerge with the potential to facilitate vaccine escape. We show that beyond serotype replacement, there are marked changes in S. pneumoniae carriage population genetics amongst 2804 isolates sampled 4-8 years after the 2011 introduction of PCV-13 in urban Malawi. These changes are characterised by metabolic genotypes with distinct virulence and antimicrobial resistance (AMR) profiles. This included exclusive genes responsible for metabolism and carbohydrate transport, and toxin...
PLoS ONE, 2014
Introduction: Bloodstream infection (BSI) is one of the principle determinants of the morbidity a... more Introduction: Bloodstream infection (BSI) is one of the principle determinants of the morbidity and mortality associated with advanced HIV infection, especially in sub-Saharan Africa. Over the last 10 years, there has been rapid roll-out of antiretroviral therapy (ART) and cotrimoxazole prophylactic therapy (CPT) in many high HIV prevalence African countries. Methods: A prospective cohort of adults with suspected BSI presenting to Queen's Hospital, Malawi was recruited between 2009 and 2010 to describe causes of and outcomes from BSI. Comparison was made with a cohort pre-dating ART roll-out to investigate whether and how ART and CPT have affected BSI. Malawian census and Ministry of Health ART data were used to estimate minimum incidence of BSI in Blantyre district. Results: 2,007 patients were recruited, 90% were HIV infected. Since 1997/8, culture-confirmed BSI has fallen from 16% of suspected cases to 10% (p,0.001) and case fatality rate from confirmed BSI has fallen from 40% to 14% (p,0.001). Minimum incidence of BSI was estimated at 0.03/1000 years in HIV uninfected vs. 2.16/1000 years in HIV infected adults. Compared to HIV seronegative patients, the estimated incidence rate-ratio for BSI was 80 (95% CI:46-139) in HIV-infected/ untreated adults, 568 (95% CI:302-1069) during the first 3 months of ART and 30 (95% CI:16-59) after 3 months of ART. Conclusions: Following ART roll-out, the incidence of BSI has fallen and clinical outcomes have improved markedly. Nonetheless, BSI incidence remains high in the first 3 months of ART despite CPT. Further interventions to reduce BSIassociated mortality in the first 3 months of ART require urgent evaluation.
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Papers by Thandie mwalukomo