Sanjay G. Lala

Burden of Invasive Group B Streptococcus Disease and Early Neurological Sequelae in South African Infants

Introduction Group B Streptococcus (GBS) is a leading cause of neonatal sepsis and meningitis. We aimed to evaluate the burden of invasive early-onset (0–6 days of life, EOD) and late-onset (7–89 days, LOD) GBS disease and subsequent neurological sequelae in infants from a setting with a high prevalence (29.5%) of HIV among pregnant women. Methods A case-control study was undertaken at three secondary-tertiary care public hospitals in Johannesburg. Invasive cases in infants <3 months age were identified by surveillance of laboratories from November 2012 to February 2014. Neurodevelopmental screening was done in surviving cases and controls at 3 and 6 months of age. Results We identified 122 cases of invasive GBS disease over a 12 month period. Although the incidence (per 1,000 live births) of EOD was similar between HIV-exposed and HIV-unexposed infants (1.13 vs. 1.46; p = 0.487), there was a 4.67-fold (95%CI: 2.24–9.74) greater risk for LOD in HIV-exposed infants (2.27 vs. 0.49; p<0.001). Overall, serotypes Ia, Ib and III constituted 75.8% and 92.5% of EOD and LOD, respectively. Risk factors for EOD included offensive draining liquor (adjusted Odds Ratio: 27.37; 95%CI: 1.94–386.50) and maternal GBS bacteriuria (aOR: 8.41; 95%CI: 1.44–49.15), which was also a risk-factor for LOD (aOR: 3.49; 95%CI: 1.17–10.40). The overall case fatality rate among cases was 18.0%. The adjusted odds for neurological sequelae at 6 months age was 13.18-fold (95%CI: 1.44–120.95) greater in cases (13.2%) than controls (0.4%). Discussion The high burden of invasive GBS disease in South Africa, which is also associated with high case fatality rates and significant neurological sequelae among survivors, is partly due to the heightened risk for LOD in infants born to HIV-infected women. An effective trivalent GBS conjugate vaccine targeted at pregnant women could prevent invasive GBS disease in this setting.

HIV-1 Is Associated With Lower Group B Streptococcus Capsular and Surface-Protein IgG Antibody Levels and Reduced Transplacental Antibody Transfer in Pregnant Women.

BACKGROUND Human immunodeficiency virus (HIV)-exposed infants are at increased risk of invasive Group B Streptococcus (GBS) disease; however, the reason for this increased susceptibility has not been characterized. METHODS We compared GBS capsular and surface-protein maternal immunoglobin G antibody concentrations and cord-maternal ratios between HIV-infected and HIV-uninfected mother-newborn dyads. RESULTS Median capsular antibody concentrations (µg/mL) were lower in HIV-infected than HIV-uninfected women for serotypes Ib (P = .033) and V (P = .040); and for pilus island (PI)-1 (P = .016), PI-2a (P = .015), PI-2b (P = .015), and fibrinogen-binding protein A (P < .001). For serotypes Ia and III, cord-maternal ratios were 37.4% (P < .001) and 32.5% (P = .027) lower in HIV-infected compared to HIV-uninfected mother-newborn dyads. The adjusted odds of having capsular antibody concentration ≥2 µg/mL when comparing HIV-infected to -uninfected women were 0.33 (95% confidence interval [CI], .15-.75) and 0.34 (95% CI, .12-1.00) for serotypes Ia and III, respectively. Antibody levels and cord-maternal ratios were independent of CD4(+) lymphocyte counts or HIV-1 viral load. CONCLUSIONS The lower GBS antibody concentrations and reduced transplacental antibody transfer in HIV-infected women, which likely contribute to their infants being at heightened susceptibility for invasive GBS disease, could possibly be mitigated by vaccination with a GBS conjugate vaccine currently under clinical development.

Correlates of protection of serotype-specific capsular antibody and invasive Group B Streptococcus disease in South African infants.

BACKGROUND Vaccinating pregnant women may prevent invasive Group B Streptococcus (GBS) disease in their young infants. In a low-middle income setting, we sought to determine an association between natural maternal antibody responses and the development of invasive GBS disease. METHODS We undertook a matched case-control study in Johannesburg, South Africa. Maternal and infant antibody concentrations were compared between serotype-specific Ia and III GBS cases and well-baby controls in which the mother was colonized with the same serotype. RESULTS The median maternal serotype Ia and III antibody concentrations (in μg/mL) were 0.05 (IQR: 0.02-0.24; n=27) and 0.14 (IQR: 0.08-0.33; n=29) in cases, and 0.29 (IQR: 0.06-1.60; n=43) and 0.29 (IQR: 0.13-0.58; n=31) in homotypic controls, respectively. A smaller proportion of cases as compared to homotypic controls had higher serotype Ia and III maternal antibody concentrations. Using Bayesian modeling, we demonstrated that the risk of invasive GBS disease was less than 10% with maternal antibody concentrations ≥ 6 μg/mL and ≥ 3 μg/mL for serotypes Ia and III, respectively. CONCLUSIONS Maternal capsular antibody concentrations are associated with the risk of invasive GBS disease in infants. In a low-middle income setting with a high burden of invasive disease, we have demonstrated a sero-correlate of protection for GBS serotypes Ia and III which could facilitate vaccine licensure.

Maternal hepatitis B and infant infection among pregnant women living with HIV in South Africa

Globally, hepatitis B virus (HBV) infection is the leading cause of liver‐related mortality. Newborn vaccination, maternal antiviral therapy and administering hepatitis B immune globulin shortly after birth can greatly reduce the risk of perinatal and infant infection. However, evidence‐based policy regarding these interventions in Africa is hampered by gaps in knowledge of HBV epidemiology. We describe maternal chronic hepatitis B (CHB) prevalence and infant infection during the first year of life within a cohort of women living with HIV.

The discriminative value of C-reactive protein levels in distinguishing between community-acquired bacteraemic and respiratory virus-associated lower respiratory tract infections in HIV-1-infected and -uninfected children

Abstract This study assessed the value of routine CRP measurements to discriminate between bacterial and viral lower respiratory tract infection (LRTI) in HIV-1-infected and-uninfected children. A total of 570 children, prospectively enrolled, were categorised into four aetiological groups, as follows: (i) bacteraemic pneumonia (n=50), (ii) respiratory virus-associated LRTI (n=146), (iii) bacteraemic and respiratory virus-associated (mixed) LRTI (n=10), and (iv) LRTI of undetermined aetiology (n=364). The discriminative ability of threshold CRP values was evaluated, and values predicting bacteraemic pneumonia were used to construct receiver-operating characteristic (ROC) plots. Median CRP values were significantly higher in bacteraemic pneumonia (195 mg/L, p<0.0001), and threshold CRP values ranging from 10 to 100 mg/L differentiated bacteraemic from virus-associated LRTI (p<0.0001). The discriminative ability of CRP values assessed by ROC plots in pneumonia is 80%, and CRP 10 mg/L identified 90% of all bacteraemic pneumonia. In HIV-1 infection, median CRP values were significantly higher in bacteraemic pneumonia (200 mg/L) but correlated with levels in uninfected children, irrespective of LRTI aetiology. Although CRP responses are significantly different in bacteraemic and virus-associated LRTI, the considerable overlap between these aetiological groups hinders selection of threshold CRP values that are clinically useful in differentiating bacteraemic from virus-associated LRTI pneumonia.

Association between maternal Group B Streptococcus surface-protein antibody concentrations and invasive disease in their infants

Objectives: Group B Streptococcus (GBS) surface-proteins have been shown to be immunogenic and potential vaccine candidates. We aim to determine the association between maternal IgG antibodies to select GBS surface-proteins and invasive GBS disease in their infants. Methods: Using a matched case–control study, maternal antibody levels for GBS-immunogenic bacterial adhesin, fibrinogen-binding protein A and pilus-island (PI) PI-1, PI-2a, PI-2b were compared between infants with invasive GBS disease and well-baby controls. Results: The absolute risk of disease did not differ between cases and colonized controls with increasing antibody concentrations for these surface-proteins. There was, however, a relative risk reduction in invasive disease associated with fibrinogen-binding protein A, with an adjusted odds ratio of 0.04 (95% CI: 0.01–0.69) at antibody levels ≥10,000 AU/ml. Conclusion: We have not demonstrated an association between naturally occurring fibrinogen-binding protein A, GBS-immunogenic bacterial adhesin, and PI surface-protein antibodies and the risk of invasive disease in young infants. These surface-proteins may not be suitable GBS vaccine candidates.

Temporal Changes in Invasive Group B Streptococcus Serotypes: Implications for Vaccine Development.

Introduction There is a paucity of longitudinal data on the serotype-specific burden of invasive group B Streptococcus (GBS) disease from low-middle income countries, which could inform selection of vaccine epitopes. Methods From 2005 to 2014, infants less than 90 days of age with invasive GBS disease were identified through sentinel laboratory and hospital admission surveillance at Chris Hani Baragwanath Academic Hospital in Soweto, South Africa. Results We identified 820 cases of invasive GBS disease, including 55% among newborns <7 days age (i.e. early-onset disease; EOD). The overall incidence (per 1,000 live births) of invasive GBS disease was 2.59 (95% CI: 2.42–2.77), including 1.41 (95% CI: 1.28–1.55) for EOD and 1.18 (95% CI: 1.06–1.30) in infants 7–89 days age (late-onset disease). Year-on-year, from 2005 to 2014, we observed a 9.4% increase in incidence of serotype Ia invasive disease (RR: 1.09; 95% CI: 1.04–1.15; p<0.001), and a 7.4% decline in serotype III invasive disease (RR: 0.93; 95% CI: 0.90–0.96; p<0.001). Overall, serotypes Ia (28.2%), III (55.4%) and V (7.9%) were the commonest disease causing serotypes. Conclusions The incidence of invasive GBS disease has remained persistently high in our setting, with some changes in serotype distribution, albeit mainly involving the same group of dominant serotypes.

Group B Streptococcus: developing a correlate of protection for a vaccine against neonatal infections.

Purpose of review Maternal vaccination to prevent invasive Group B Streptococcus (GBS) disease in infants is an important alternative strategy to intrapartum antibiotic prophylaxis. Licensure of GBS vaccines could be expedited using immunological correlates of protection. Recent findings Between 2014 and 2015, we identified two studies that demonstrated an inverse association between invasive GBS disease and maternal serotype III capsular antibody levels greater than 1 &mgr;g/ml and greater than 3 &mgr;g/ml, and higher maternal antibody levels were associated with protection against serotype Ia disease. Furthermore, serotype Ia and III antibody levels greater than 3 &mgr;g/ml were associated with a reduced risk of GBS colonization in pregnant women. Experimental studies have investigated the use of GBS surface proteins as vaccine candidates. Although the immunogenic potential of pilus island and other surface proteins has been shown in animal-model studies, no association between maternal pilus island antibody levels and invasive GBS disease was demonstrated in infants. Additionally, several novel innate immune mediators that prevent GBS infection have been described in human and experimental studies. Summary Recent studies suggest that maternal capsular antibody thresholds may be used as immunological correlates of protection for vaccine licensure. Surface proteins, as candidate vaccines or conjugates to the polysaccharide-protein vaccine, may broaden protection against invasive GBS disease.

Integrated Source Case Investigation for Tuberculosis (TB) and HIV in the Caregivers and Household Contacts of Hospitalised Young Children Diagnosed with TB in South Africa: An Observational Study.

Background Contact tracing, to identify source cases with untreated tuberculosis (TB), is rarely performed in high disease burden settings when the index case is a young child with TB. As TB is strongly associated with HIV infection in these settings, we used source case investigation to determine the prevalence of undiagnosed TB and HIV in the caregivers and household contacts of hospitalised young children diagnosed with TB in South Africa. Methods Caregivers and household contacts of 576 young children (age ≤7 years) with TB diagnosed between May 2010 and August 2012 were screened for TB and HIV. The primary outcome was the detection of laboratory-confirmed, newly-diagnosed TB disease and/or HIV-infection in close contacts. Results Of 576 caregivers, 301 (52·3%) self-reported HIV-positivity. Newly-diagnosed HIV infection was detected in 63 (22·9%) of the remaining 275 caregivers who self-reported an unknown or negative HIV status. Screening identified 133 (23·1%) caregivers eligible for immediate anti-retroviral therapy (ART). Newly-diagnosed TB disease was detected in 23 (4·0%) caregivers. In non-caregiver household contacts (n = 1341), the prevalence of newly-diagnosed HIV infection and TB disease was 10·0% and 3·2% respectively. On average, screening contacts of every nine children with TB resulted in the identification of one case of newly-diagnosed TB disease, three cases of newly diagnosed HIV-infection, and three HIV-infected persons eligible for ART. Conclusion In high burden countries, source case investigation yields high rates of previously undiagnosed HIV and TB infection in the close contacts of hospitalised young children diagnosed with TB. Furthermore, integrated screening identifies many individuals who are eligible for immediate ART. Similar studies, with costing analyses, should be undertaken in other high burden settings–integrated source case investigation for TB and HIV should be routinely undertaken if our findings are confirmed.

Vaccination of HIV-infected pregnant women: implications for protection of their young infants

BackgroundThe prevention of mother to child transmission of HIV has resulted in reduced burden of pediatric HIV-infection, but the prevalence of maternal HIV infection remains high in sub-Saharan African countries. HIV-exposed-uninfected infants have an increased risk of morbidity and mortality due to infectious diseases than HIV-unexposed infants, particularly during the first six months of life, which in part might be due to lower levels of pathogen-specific protective antibodies acquired transplacentally from their mothers. This could be mitigated by vaccinating pregnant women to boost antibody levels; although vaccine responses among HIV-infected pregnant women might differ compared to HIV-uninfected women. We reviewed studies that compared natural and vaccine-induced antibody levels to different epitopes between HIV-infected and HIV-uninfected pregnant women.FindingsMost studies reported lower baseline/pre-vaccination antibody levels in HIV-infected pregnant women, which may not be reversed by antiretroviral therapy during pregnancy. There were only few studies on vaccination of HIV-infected pregnant women, mainly on influenza virus and group B Streptococcus (GBS) vaccines. Immunogenicity studies on influenza vaccines indicated that HIV-infected pregnant women had lower vaccine induced hemagglutination inhibition antibody titers and a decreased likelihood of seroconversion compared to HIV-uninfected women; and while higher CD4+ T-lymphocyte levels were associated with better immune responses to vaccination, HIV viral load was not associated with responses. Furthermore, infants born to influenza vaccinated HIV-infected pregnant women also had lower antibody levels and a lower proportion of HIV-exposed infants had titers above the putative correlate of protection compared to HIV-unexposed infants. The immunogenicity of a CRM197-conjugated trivalent GBS vaccine was also lower in HIV-infected pregnant women compared to HIV-uninfected women, irrespective of CD4+ T-lymphocyte counts.ConclusionsPoorer immunogenicity of vaccines reported in HIV-infected compared to HIV-uninfected pregnant women might compromise the potential benefits to their young infants. Alternate vaccination strategies, including vaccines with higher antigen concentration, adjuvanted vaccines or multiple doses schedules might be required in HIV-infected pregnant women to optimize antibody transferred to their fetuses.