Impact of nutritional status on vaccine-induced immunity in children living in South Africa: Investigating the B-cell repertoire and metabolic hormones.

OBJECTIVES: We explored the role of metabolic hormones and the B-cell repertoire in the association between nutritional status and vaccine responses. METHODS: In this prospective cohort study, nested within a larger randomized open-label trial, 211 South African children received two doses of measles vaccine and two or three doses of pneumococcal conjugate vaccine (PCV). Metabolic markers (leptin, ghrelin and adiponectin) and distribution of B-cell subsets (n = 106) were assessed at 18 months of age. RESULTS: Children with a weight-for-height z-score (WHZ) ≤ -1 standard deviation (SD) at booster vaccination had a decreased mean serotype-specific PCV IgG response compared with those with WHZ > -1 and <+1 SD or WHZ ≥ +1 SD at 9 months post-booster (18 months of age). (Naive) pre-germinal center B-cells were associated with pneumococcal antibody decay between one to nine months post-booster. Predictive performance of elastic net models for the combined effect of B-cell subsets, metabolic hormones and nutritional status (in addition to age, sex, and randomization group) on measles and PCV vaccine response had an average area under the receiver operating curve of 0.9 and 0.7, respectively. CONCLUSIONS: The combined effect of B-cell subsets, metabolic hormones and nutritional status correlated well with the vaccination response for measles and most PCV serotypes. CLINICALTRIALS: gov registration of parent studies: NCT02943902 and NCT03330171.

Predictors of TB disease in HIV-exposed children from Southern Africa.

BACKGROUND: P1041 was a randomised, placebo-controlled isoniazid prophylaxis trial in South Africa. We studied predictors for TB in HIV-exposed children participating in the P1041 trial.METHODS: We included data from entry until Week 108. Predictors considered were type of housing, overcrowding, age, sex, ethnicity, tobacco exposure, weight-for-age percentile Z-score (WAZ), CD4%, viral load (VL), antiretroviral therapy (ART) and number of household smokers.RESULTS: Of 543 HIV-positive (HIV+) and 808 HIV-exposed uninfected (HEU) infants at entry, median age was 96 days (interquartile range: 92-105). Of 1,351 caregivers, 125 (9%) had a smoking history, and 62/1,351 reported current smoking. In 594/1,351 (44%) households, there was at least one smoker. Smoking caregivers consumed 1-5 cigarettes daily. In the HIV+ cohort, significant baseline TB predictors after adjusting covariates were as follows: WAZ (adjusted hazard ratio [aHR] 0.76, P = 0.002) and log10 HIV RNA copies/ml (aHR 1.50, P = 0.009). Higher CD4% (aHR 0.88, P = 0.002) and ART (aHR 0.50, P = 0.006) were protective. In the HEU cohort, smoking exposure was associated with reduced TB-free survival on univariate analysis, but not after adjustment in the multivariate model.CONCLUSION: Low WAZ and high VL were strong predictors of TB disease or death. Rising CD4 percentage and being on ART were protective in the HIV+ cohort.

High-throughput nanofluidic real-time PCR to discriminate Pneumococcal Conjugate Vaccine (PCV)-associated serogroups 6, 18, and 22 to serotypes using modified oligonucleotides.

Current real-time high-throughput Polymerase Chain Reaction (qPCR) methods do not distinguish serotypes 6A from 6B, 18C from 18A/B and 22F from 22A. We established a nanofluidic real-time PCR (Fluidigm) for serotyping that included Dual-Priming-Oligonucleotides (DPO), a Locked-Nucleic-Acid (LNA) probe and TaqMan assay-sets for high-throughput serotyping. The designed assay-sets target capsular gene wciP in serogroup 6, wciX and wxcM in serogroup 18, and wcwA in serogroup 22. An algorithm combining results from published assay-sets (6A/B/C/D; 6C/D; 18A/B/C; 22A/F) and designed assay-sets for 6A/C; 18B/C/F; 18C/F, 18F and 22F was validated through blind analysis of 1973 archived clinical samples collected from South African children ≤ 5-years-old (2009-2011), previously serotyped with the culture-based Quellung method. All assay-sets were efficient (92-101%), had low variation between replicates (R2 > 0.98), and were able to detect targets at a limit of detection (LOD) of < 100 Colony-Forming-Units (CFU)/mL of sample. There was high concordance (Kappa = 0.73-0.92); sensitivity (85-100%) and specificity (96-100%) for Fluidigm compared with Quellung for serotyping 6A; 6B; 6C; 18C and 22F. Fluidigm distinguishes vaccine-serotypes 6A, 6B, 18C, next-generation PCV-serotype 22F and non-vaccine-serotypes 6C, 6D, 18A, 18B, 18F and 22A. Discriminating single serotypes is important for assessing serotype replacement and the impact of PCVs on vaccine- and non-vaccine serotypes.

A call to action: Temporal trends of COVID-19 deaths in the South African Muslim community.

Letter by Omar on letter by Jassat et al. (Jassat W, Brey Z, Parker S, et al. A call to action: Temporal trends of COVID-19 deaths in the South African Muslim community. S Afr Med J 2021;111(8):692-694. https://doi.org/10.7196/SAMJ.2021.v111i8.15878); and response by Jassat et al.

COVID-19 herd immunity v. learning to live with the virus.

Mutations of SARS-CoV-2 have been associated with increased transmissibility and occasionally reduced sensitivity to neutralising antibody activity induced by past ancestry virus infection or current COVID-19 vaccines. Nevertheless, COVID-19 vaccines have consistently demonstrated high efficacy and effectiveness against COVID-19 severe disease, hospitalisation and death, including disease caused by designated variants of concern. In contrast, COVID-19 vaccines are more heterogeneous in reducing the risk of infection and mild COVID19, and are modestly effective in interrupting virus transmission. Ongoing mutations of SARS-CoV-2 resulting in increased transmissibility and relative evasion of neutralising antibody activity induced by past virus infection or COVID-19 vaccines are likely. The duration of protection induced by COVID-19 vaccines is modelled to be relatively short in protecting against infection and mild COVID-19, but is likely to be 2 - 3 years against severe disease. Current experience from the UK and Israel demonstrates that even with high levels of COVID19 vaccine coverage (>85% of the adult population), resurgences with new variants of concern remain a strong probability. Nevertheless, such resurgences are not mirrored by high rates of hospitalisation and death compared with what was experienced in relatively COVID-19 vaccine-naive populations. Even though COVID-19 vaccines are unlikely to result in a herd immunity state, their ability to protect against severe COVID-19 and death could allow for a return to normalcy once a large enough proportion of the adult population in a country has been vaccinated.

Sepsis in previously healthy neonates discharged home after delivery in Soweto, South Africa.

BACKGROUND: There is a paucity of data on the aetiology of neonatal sepsis in sub-Saharan Africa. OBJECTIVES: To investigate the incidence, aetiology and outcomes of physician-diagnosed sepsis in hospitalised neonates who had previously been discharged home after delivery in Soweto, South Africa. METHODS: A retrospective review using data abstracted from clinical and laboratory databases identified physician-diagnosed sepsis cases in neonates admitted to the general paediatric wards at Chris Hani Baragwanath Academic Hospital from January 2015 to September 2016. Neonates with physician-diagnosed sepsis were categorised into two groups based on putative pathogens recovered from blood and/or cerebrospinal fluid specimens: (i) culture-confirmed sepsis; and (ii) culture-negative sepsis. RESULTS: Of 1 826 neonatal admissions, 1 025 (56.2%) had physician-diagnosed sepsis: 166 (16.2%) with culture-confirmed sepsis and 859 (83.8%) with culture-negative neonatal sepsis. The commonest pathogens causing culture-confirmed neonatal sepsis were Streptococcus viridans (n=53; 26.5%), S. agalactiae (n=38; 19.0%), and Staphylococcus aureus (n=25; 12.5%). The case fatality rates for culture-confirmed sepsis and culture-negative sepsis were 10.8% (18/166) and 2.6% (22/859), respectively. The odds of death occurring during hospitalisation was 10-fold (95% confidence interval 3.7 - 26.9) higher in neonates with culture-confirmed sepsis compared with culture-negative sepsis. CONCLUSIONS: In our setting, physician-diagnosed sepsis represents a huge disease burden in previously healthy neonates hospitalised from home. Most sepsis cases were attributed to S. viridans, S. agalactiae and S. aureus.

COVID-19 vaccines - less obfuscation, more transparency and action.

Letter by Venter et al. on editorial  by Schoub (Dial down the rhetoric over COVID-19 vaccines. S Afr Med J 2021;111(6):522-523. https://doi.org/10.7196/SAMJ.2021.v111i6.15740).

Asymptomatic COVID-19 in South Africa - implications for the control of transmission.

Asymptomatic COVID-19 may contribute significantly to the pandemic trajectory based on global biological, epidemiological and modelling evidence. A retrospective analysis was done to determine the proportion of asymptomatic COVID-19 in the workplace during the lockdown period from 27 March to 31 May 2020. We found that nearly 45% of cases were asymptomatic at the time of the first test. This high proportion of asymptomatic COVID-19 cases has implications for interventions, such as enforcing quarantine of all close contacts of COVID-19 cases regardless of symptoms.

Le COVID-19 a symptomatique pourrait contribuer significativement à la trajectoire de la pandémie en se basant sur des preuves mondiales, biologique et épidémiologiques, et en modélisant les preuves. Une analyse rétrospective a été réalisée afin de décrire la proportion d'infections asymptomatiques de SARS-CoV-2 parmi les clusters essentiels sur les lieux de travail en Afrique du Sud où des investigations de flambée ont été réalisées durant la période de confinement très restrictive du 27 mars au 31 mai 2020. Près de 45% des cas étaient asymptomatique lors du premier test. Cette proportion élevée des cas de COVID-19 asymptomatiques a des implications en ce qui concerne les interventions nonpharmaceutique comme le renforcement de la quarantaine de tous les contacts étroits des cas de SARS-CoV-2 sans tenir compte des symptômes.

Incidence of febrile seizures and associated factors in children in Soweto, South Africa.

BACKGROUND: Febrile seizures (FSs) are a common cause of paediatric emergencies, but there is limited research on the aetiology and epidemiology of FSs, especially in Africa. OBJECTIVES: To determine the incidence of FS hospitalisations in children aged 6 - 59 months in Soweto, South Africa, and factors associated with FS hospitalisations. METHOD: In a secondary data analysis using a cohort of children enrolled in a 9-valent pneumococcal conjugate vaccine efficacy trial conducted in Soweto during 1998 - 2005, the incidence of FS hospitalisation was calculated and stratified by age group. Regression analysis was used to investigate factors associated with FS at the time of hospitalisation. Influenza A, influenza B, respiratory syncytial virus (RSV), adenovirus and parainfluenza were investigated for among those with respiratory symptoms using immunofluorescent assays. RESULTS: FSs accounted for 780 (11.0%) of 7 126 hospitalisations during the study period. The overall incidence of FSs was 4.4 (95% confidence interval (CI) 4.10 - 4.97) per 1 000 person-years, with the highest incidence in children aged 12 - 23 months (7.25; 95% CI 6.44 - 8.14). Among hospitalised children, FS hospitalisation was associated with HIV-negative status (odds ratio (OR) 6.25; 95% CI 4.34 - 8.99), body temperature ≥39ºC (OR 2.03; 95% CI 1.56 - 2.64) and concurrent diagnosis of acute otitis media (OR 2.16; 95% CI 1.74 - 2.67). Influenza A was identified in 44/515 FS hospitalisations (8.5%) compared with 123/3 794 non-FS hospitalisations (3.2%) (OR 2.22; 95% CI 1.56 - 3.16). In contrast, RSV detection was less commonly identified in children with FSs (21; 4.1%) than without (419; 11.0%) (OR 0.36; 95% CI 0.24 - 0.54). CONCLUSIONS: FSs contributed significantly to the burden of paediatric hospitalisations in Soweto, and were strongly associated with influenza A virus infection.

COVID-19 herd immunity v. learning to live with the virus

Mutations of SARS-CoV-2 have been associated with increased transmissibility and occasionally reduced sensitivity to neutralising antibody activity induced by past ancestry virus infection or current COVID-19 vaccines. Nevertheless, COVID-19 vaccines have consistently demonstrated high efficacy and effectiveness against COVID-19 severe disease, hospitalisation and death, including disease caused by designated variants of concern. In contrast, COVID-19 vaccines are more heterogeneous in reducing the risk of infection and mild COVID19, and are modestly effective in interrupting virus transmission. Ongoing mutations of SARS-CoV-2 resulting in increased transmissibility and relative evasion of neutralising antibody activity induced by past virus infection or COVID-19 vaccines are likely. The duration of protection induced by COVID-19 vaccines is modelled to be relatively short in protecting against infection and mild COVID-19, but is likely to be 2 - 3 years against severe disease. Current experience from the UK and Israel demonstrates that even with high levels of COVID19 vaccine coverage (>85% of the adult population), resurgences with new variants of concern remain a strong probability. Nevertheless, such resurgences are not mirrored by high rates of hospitalisation and death compared with what was experienced in relatively COVID-19 vaccine-naive populations. Even though COVID-19 vaccines are unlikely to result in a herd immunity state, their ability to protect against severe COVID-19 and death could allow for a return to normalcy once a large enough proportion of the adult population in a country has been vaccinated

Children caught in the long shadow of COVID-19

Despite the more transmissible delta variant being associated with higher rates of COVID-19 in unvaccinated adolescents, children have remained relatively spared from severe disease. Nevertheless, children are indirectly affected by the COVID-19 pandemic, which threatens to have far-reaching consequences. The effect of disruptions of seasonal patterns of circulation of respiratory pathogens on future immunity against such pathogens, childhood immunization programmes, and HIV and tuberculosis treatment programmes poses a threat to the future wellbeing of children. Furthermore, the economic devastation caused by the pandemic, including an increase in unemployment, gives rise to numerous challenges, such as food insecurity, which is likely to worsen childhood nutritional status. Also, COVID-19 has ongoing effects on the mental wellbeing of children, driven in part by the interruption of schooling and other opportunities to socialize. An increase in psychological illnesses has manifested in children consequent to the stresses of the pandemic, lockdowns, caregiver deaths. In this article, we highlight the indirect effects of COVID-19 on children, and suggest solutions to mitigate against the long-term sequelae. A focused health, nutrition, education and child protection response is required from government and healthcare practitioners to safeguard the health and wellbeing of South African children.

Antimicrobial susceptibility and serotype distribution of Streptococcus agalactiae rectovaginal colonising isolates from pregnant women at a tertiary hospital in Pretoria, South Africa: An observational descriptive study.

BACKGROUND: Streptococcus agalactiae or group B streptococcus (GBS) is a significant cause of neonatal sepsis. Intrapartum antibiotic prophylaxis is recommended for pregnant women identified to be rectovaginally colonised between 34 and 37 weeks' gestational age to decrease the risk of invasive disease in their newborns. An effective multivalent GBS vaccine may prevent a broader scope of GBS-associated diseases, such as GBS early-onset disease, GBS late-onset disease, spontaneous abortion, stillbirth and maternal bacteraemia. Serotype distribution of GBS isolates is essential to determine the efficacy of such a vaccine. OBJECTIVES: To investigate serotype distribution and antimicrobial susceptibility patterns of GBS isolates cultured from rectovaginal specimens during pregnancy. METHODS: Sixty-nine archived maternal colonising isolates were tested against penicillin, erythromycin, clindamycin, vancomycin and levofloxacin. Minimum inhibitory concentration testing was performed using the ETEST method. Serotyping was performed by the latex agglutination method. RESULTS: The most common serotypes detected were Ia (54%), III (20%), V (16%), II (6%), IV (2%) and Ib (1%). All isolates were fully susceptible to penicillin, vancomycin and levofloxacin. Eight (11%) and 50 (56%) isolates showed intermediate resistance to erythromycin and clindamycin, respectively, and 1 isolate was resistant to erythromycin. The macrolide-lincosamide-streptogramin B (MLSB) phenomenon was noted in 3 (4%) of the isolates. CONCLUSIONS: GBS-colonising isolates remain susceptible to penicillin, which remains the drug of choice for intrapartum antibiotic prophylaxis and treatment of invasive disease in newborns. Macrolides should only be used if clinically indicated due to the high prevalence of intermediate resistance. A pentavalent GBS vaccine currently in phase I trials should provide coverage for 97% of the isolates identified in this study.

Long-COVID: An evolving problem with an extensive impact.

Persistence of symptoms or development of new symptoms relating to SARS-CoV-2 infection late in the course of COVID-19 is an increasingly recognised problem facing the globally infected population and its health systems. 'Long-COVID' or 'COVID long-haulers' generally describes those persons with COVID-19 who experience symptoms for >28 days after diagnosis, whether laboratory confirmed or clinical. Symptoms are as markedly heterogeneous as seen in acute COVID-19 and may be constant, fluctuate, or appear and be replaced by symptoms relating to other systems with varying frequency. Such multisystem involvement requires a holistic approach to management of long-COVID, and descriptions of cohorts from low- and middle-income countries are eagerly awaited. Although many persons with long-COVID will be managed in primary care, others will require greater input from rehabilitation medicine experts. For both eventualities, planning is urgently required to ensure that the South African public health service is ready and able to respond.

Diagnosis and management of community-acquired pneumonia in children: South African Thoracic Society guidelines.

BACKGROUND: Pneumonia remains a major cause of morbidity and mortality amongst South African children. More comprehensive immunisation regimens, strengthening of HIV programmes, improvement in socioeconomic conditions and new preventive strategies have impacted on the epidemiology of pneumonia. Furthermore, sensitive diagnostic tests and better sampling methods in young children improve aetiological diagnosis. OBJECTIVES: To produce revised guidelines for pneumonia in South African children under 5 years of age. METHODS: The Paediatric Assembly of the South African Thoracic Society and the National Institute for Communicable Diseases established seven expert subgroups to revise existing South African guidelines focusing on: (i) epidemiology; (ii) aetiology; (iii) diagnosis; (iv) antibiotic management and supportive therapy; (v) management in intensive care; (vi) prevention; and (vii) considerations in HIV-infected or HIVexposed, uninfected (HEU) children. Each subgroup reviewed the published evidence in their area; in the absence of evidence, expert opinion was accepted. Evidence was graded using the British Thoracic Society (BTS) grading system. Sections were synthesized into an overall guideline which underwent peer review and revision. RECOMMENDATIONS: Recommendations include a diagnostic approach, investigations, management and preventive strategies. Specific recommendations for HIV infected and HEU children are provided. VALIDATION: The guideline is based on available published evidence supplemented by the consensus opinion of SA paediatric experts. Recommendations are consistent with those in published international guidelines.

Measles seroprevalence in pregnant women in Soweto, South Africa: a nested cohort study.

OBJECTIVES: Measles infection causes particularly severe disease in young children who, prior to vaccination, are dependent on maternal antibodies for protection against infection. Measles vaccination was introduced into the South African public immunization programme in 1983 and became widely available in 1992. The aim of this study was to determine measles-specific immunoglobulin G (IgG) levels in pregnant women living with and without HIV born before and after measles vaccine introduction in South Africa. METHODS: Measles IgG antibody level from blood obtained at the time of delivery was compared between women who were born before 1983 (n = 349) and since 1992 (n = 349). Serum samples were tested for measles IgG antibody using an enzyme-linked immunosorbent assay. Geometric mean titres (GMTs) and the proportion with seronegative (<200 mIU/mL) or seropositive titres (≥275 mIU/mL) were compared. RESULTS: Women born since 1992 had lower GMTs [379.7 mIU/mL (95% CI 352.7-448.6)] and fewer were seropositive (55.9%, 195/349) than women born before 1983 [905.8 mIU/mL (95% CI 784.7-1045.5); 76.8%, 268/349], for both comparisons p < 0.001. CONCLUSIONS: We found an association between measles vaccine implementation into the public immunization program in South Africa and peri-partum maternal measles immunity, where women born before vaccine introduction had higher measles IgG antibody titres and were more likely to be seropositive. These findings suggest a need to reconsider the infant measles immunization schedule in settings where women have derived immunity mainly from measles vaccine rather than wild-type virus exposure.

Maternal and neonatal vitamin D status at birth in black South Africans.

BACKGROUND: Vitamin D deficiency (VDD) in pregnant women has been associated with adverse pregnancy and neonatal outcomes. 25-hydroxyvitamin D (25(OH)D) levels are affected by numerous factors, including vitamin D intake, skin pigmentation, latitude and season of the year; they therefore vary by race and country. Vitamin D status in pregnant women and their offspring in South Africa (SA) is not well established. OBJECTIVES: To assess vitamin D status by measuring serum 25(OH)D in pregnant black SA women and their offspring in Johannesburg (latitude 26°S) and to assess whether vitamin D status is affected by maternal HIV infection. METHODS: We prospectively enrolled pregnant women and their healthy neonates, and measured 25(OH)D in maternal and cord blood at delivery. Pregnant women were stratified by their HIV status. Predictors of maternal and neonatal VDD (levels <30 nmol/L) were assessed using multiple logistic regression analysis. RESULTS: A total of 291 pregnant women and their healthy neonates were enrolled over a 21-month period. Mean (standard deviation) maternal and cord blood 25(OH)D levels were 57.0 (29.7) and 41.9 (21.0) nmol/L and the prevalence of VDD was 15.9% and 32.8%, respectively. On average, concentrations of 25(OH)D in cord blood were ~80% of those in the mother. There was no association between cord 25(OH)D and gestational age, but levels were associated with birth weight (p<0.001). There were no differences in maternal or cord blood 25(OH)D levels between those HIV-infected or uninfected. The predictor of VDD in mothers was giving birth in winter (odds ratio (OR) 2.87, 95% confidence interval (CI) 1.47 - 5.61), and in neonates the predictors were maternal age (OR 16.5, 95% CI 1.82 - 149), being born in winter (OR 3.68, 95% CI 2.05 - 6.61), being born by caesarean section (OR 4.92, 95% CI 1.56 - 15.57) and being of low birth weight (OR 1.99, 95% CI 1.13 - 3.50). CONCLUSIONS: Among black SA women delivering in Johannesburg, about one in six mothers and one in three neonates have 25(OH)D levels indicative of VDD. Maternal HIV status appears not to affect levels of 25(OH)D in either the mother or her neonate. Research on the effects of VDD on the outcomes of pregnancy and the best methods to combat the high prevalence of VDD in women of childbearing age in the SA context is required.