Single priming and booster dose of ten-valent and 13-valent pneumococcal conjugate vaccines and Streptococcus pneumoniae colonisation in children in South Africa: a single-centre, open-label, randomised trial.

BACKGROUND: Pneumococcal conjugate vaccine (PCV) immunisation has reduced vaccine-serotype colonisation and invasive pneumococcal disease in South Africa, providing the opportunity to consider transitioning from a two-dose (2 + 1) to one-dose (1 + 1) primary series and a booster dose. METHODS: In this single-centre, open-label, randomised trial done in South Africa, infants aged 35-49 days without HIV infection, without childhood immunisations except for BCG and polio, and with gestation age at delivery of at least 37 weeks of age, a birthweight of at least 2500 g, and weight of at least 3500 g at the time of enrolment were randomly assigned (1:1:1:1:1:1), through block randomisation (block size of 30), to receive a single priming dose of ten-valent PCV (PCV10) or 13-valent PCV (PCV13) at either 6 weeks (6-week 1 + 1 group) or 14 weeks (14-week 1 + 1 group), compared with two priming doses at 6 weeks and 14 weeks (2 + 1 group), followed by a booster dose at 9 months of age in all groups. The primary objective of the trial has been published previously. We report the secondary objective of the effect of alternative doses of PCV10 and PCV13 on serotype-specific Streptococcus pneumoniae colonisation at 9 months, 15 months, and 18 months of age and a further exploratory analysis in which we assessed non-inferiority of serotype-specific serum IgG geometric mean concentrations 1 month after the booster (10 months of age) and the percentage of participants with serotype-specific IgG titre above the putative thresholds associated with a risk reduction of serotype-specific colonisation between the 1 + 1 and 2 + 1 groups for both vaccines. Non-inferiority was established if the lower limit of the 95% CI for the difference between the proportion of participants (1 + 1 group vs 2 + 1 group) above the putative thresholds was greater than or equal to -10%. All analyses were done in the modified intention-to-treat population, which included all participants who received PCV10 or PCV13 according to assigned randomisation group and for whom laboratory results were available. The trial is registered with ClinicalTrials.gov, NCT02943902. FINDINGS: 1564 nasopharyngeal swabs were available for molecular serotyping from 600 infants who were enrolled (100 were randomly assigned to each of the six study groups) between Jan 9 and Sept 20, 2017. There was no significant difference in the prevalence of overall or non-vaccine serotype colonisation between all PCV13 or PCV10 groups. PCV13 serotype colonisation was lower at 15 months of age in the 14-week 1 + 1 group than in the 2 + 1 group (seven [8%] of 85 vs 17 [20%] of 87; odds ratio 0·61 [95% CI 0·38-0·97], p=0·037), but no difference was seen at 9 months (nine [11%] of 86 vs ten [11%] of 89; 0·92 [0·60-1·55], p=0·87) or 18 months (nine [11%] of 85 vs 11 [14%] of 87; 0·78 [0·45-1·22], p=0·61). Compared with the PCV13 2 + 1 group, both PCV13 1 + 1 groups did not meet the non-inferiority criteria for serotype-specific anti-capsular antibody concentrations above the putative thresholds purportedly associated with risk reduction for colonisation; however, the PCV10 14-week 1 + 1 group was non-inferior to the PCV10 2 + 1 group. INTERPRETATION: The serotype-specific colonisation data reported in this study together with the primary immunogenicity endpoints of the control trial support transitioning to a reduced 1 + 1 schedule in South Africa. Ongoing monitoring of colonisation should, however, be undertaken immediately before and after transitioning to a PCV 1 + 1 schedule to serve as an early indicator of whether PCV 1 + 1 could lead to an increase in vaccine-serotype disease. FUNDING: The Bill & Melinda Gates Foundation.

Evolution of the Gut Microbiome in HIV-Exposed Uninfected and Unexposed Infants during the First Year of Life.

HIV-exposed uninfected infants (HEU) have abnormal immunologic functions and increased infectious morbidity in the first 6 months of life, which gradually decreases thereafter. The mechanisms underlying HEU immune dysfunctions are unknown. We hypothesized that unique characteristics of the HEU gut microbiota associated with maternal HIV status may underlie the HEU immunologic dysfunctions. We characterized the infant gut, maternal gut, and breast milk microbiomes of mother-infant pairs, including 123 with HEU and 117 with HIV-uninfected infants (HUU), from South Africa. Pan-bacterial 16S rRNA gene sequencing was performed on (i) infant stool at 6, 28, and 62 weeks; (ii) maternal stool at delivery and 62 weeks; and (iii) breast milk at 6 weeks. Infant gut alpha and beta diversities were similar between groups. Microbial composition significantly differed, including 12 genera, 5 families and 1 phylum at 6 weeks; 12 genera and 2 families at 28 weeks; and 2 genera and 2 families at 62 weeks of life. Maternal gut microbiomes significantly differed in beta diversity and microbial composition, and breast milk microbiomes differed in microbial composition only. Infant gut microbiotas extensively overlapped with maternal gut and minimally with breast milk microbiotas. Nevertheless, exclusively breastfed HEU and HUU had less divergent microbiomes than nonexclusively breastfed infants. Feeding pattern and maternal gut microbiome imprint the HEU gut microbiome. Compared to HUU, the HEU gut microbiome prominently differs in early infancy, including increased abundance of taxa previously observed to be present in excess in adults with HIV. The HEU and HUU gut microbiome compositions converge over time, mirroring the kinetics of HEU infectious morbidity risk. IMPORTANCE HIV-exposed uninfected infants (HEU) are highly vulnerable to infections in the first 6 months of life, and this vulnerability decreases to the age of 24 months. Because the microbiome plays a critical role in the education of the infant immune system, which protects them against infections, we characterized the gut microbiomes of HEU and HIV-unexposed infants (HUU) in the first year of life. The HEU and HUU gut microbiomes showed prominent differences at 6 and 28 weeks of life but converged at 62 weeks of life, mirroring the time course of the HEU excess infectious morbidity and suggesting a potential association between the infant gut microbiome structure and susceptibility to infections. Infant gut microbiotas extensively overlapped with maternal gut and minimally with breast milk microbiotas. Moreover, exclusively breastfed HEU and HUU had less divergent microbiomes at 6 and 28 weeks than nonexclusively breastfed HEU and HUU. The factors that affect the HEU gut microbiome, maternal gut microbiome and exclusive breastfeeding, may be targeted by interventions.

Epidemiology of Human Metapneumovirus-associated Lower Respiratory Tract Infections in African Children: Systematic Review and Meta-analysis.

BACKGROUND: Human metapneumovirus (hMPV) has been associated with upper and lower respiratory tract infections (LRTI) in children and adults. This systematic review evaluated the epidemiology of hMPV-associated LRTI, including severe acute respiratory infection (SARI) hospitalization or clinically diagnosed severe pneumonia, in African children under 5 years of age. METHODS: We searched Science Direct, PubMed, Cochrane Central, Scopus, and WHO regional databases using the terms "("Human metapneumovirus" AND "Africa") OR ("hMPV" AND "Africa")" up to September 17, 2020. Other sources included ClinicalTrials.gov to obtain unpublished data. Studies were included if children were less than 5 years of age and hospitalized with hMPV-associated LRTI, SARI or if clinically diagnosed with severe pneumonia in the community. The main outcomes were prevalence of hMPV identified among children with hospitalized LRTI or SARI. We further calculated odds ratios for hMPV in cases with LRTI compared with non-LRTI controls. Pooled results were calculated using a random-effects model. RESULTS: Thirty studies were eligible for inclusion in the review. The prevalence of hMPV-LRTI/SARI among hospitalized and severe pneumonia cases was 4.7% [95% confidence interval (CI): 3.9-5.6, I2 = 95.0]. The case-control studies indicated that hMPV was 2.0-fold (95% CI: 0.9-4.4) more likely to be identified in LRTI cases (10.3%) than controls (6.0%). Three of 5 studies reported hMPV-associated LRTI case fatality risk, with a pooled estimate of 1.3% (95% CI: 0.3-2.9; I2 = 49). CONCLUSIONS: hMPV was associated with approximately 5% of LRTI/SARI hospitalizations or severe pneumonia cases in Africa.

Short-term immunogenicity and safety of hepatitis-A and varicella vaccines in HIV-exposed uninfected and HIV-unexposed South African children.

BACKGROUND: HIV-exposed uninfected (HEU) children have increased risk of infectious morbidity during early childhood. We evaluated the short-term immunogenicity and safety of single dose inactivated hepatitis-A virus (HAV) vaccine and live attenuated varicella zoster virus (VZV) vaccine in South African children. METHODS: 195 HIV-unexposed and 64 HEU children received either one dose of HAV or VZV vaccine at 18 months of age. Blood samples were tested for hepatitis-A or VZV antibodies before and one month after vaccination by chemiluminescent microparticle immunoassay and enzyme-linked immunosorbent assay, respectively. All children were evaluated for solicited adverse events (AEs). RESULTS: One-month post-vaccination, a similar percentage of HIV-unexposed (91.8%) and HEU (82.9%) children were seropositive for hepatitis-A (p = 0.144). VZV antibody geometric mean fold-rise was also similar in HIV-unexposed (5.6; 95%CI: 4.6-6.7) and HEU children (5.1; 95%CI: 3.7-7.2); however, only 44% HIV-unexposed and HEU seroconverted (titers > 50 mIU/ml). AEs occurred with similar frequency and severity between groups, except for more systemic AEs after VZV vaccination in HEU than HIV-unexposed children. CONCLUSIONS: Single dose HAV and VZV vaccine was similarly immunogenic in HIV-unexposed and HEU children. We did not identify differences in short-term humoral immunity after administration of either a live attenuated or inactivated vaccine. Seroconversion rates after a single dose of VZV vaccine were, however, lower compared to reports from previous studies (85-89%). CLINICAL TRIALS REGISTRATION: NCT03330171.

Rubella seroprevalence in pregnant women living with and without HIV in Soweto, South Africa.

OBJECTIVES: Rubella infection during pregnancy may cause foetal death or congenital rubella syndrome. In South Africa, the national public immunization programme does not include rubella vaccination. The aim of this study was to evaluate rubella sero-epidemiology in pregnant South African women living with and without HIV. METHODS: Serum samples obtained from women living with HIV (n=552) and without HIV (n=552) were tested for rubella immunoglobulin G antibodies using an ELISA. The proportions of women with seronegative titres (<8IU/ml) and seropositive titres (≥11IU/ml), and geometric mean titres (GMT) were compared by age group and HIV status. RESULTS: The overall proportion of rubella seropositivity was 97.8%. The proportion of seropositive women increased with age group (18-25 years: 97.0%; 26-32 years: 97.7%; 33-40 years: 99.3%; p=0.047 after adjusting for HIV status). Similar proportions of women living with and without HIV were seropositive. CONCLUSIONS: Rubella immunity was high among South African pregnant women living with and without HIV in the absence of rubella vaccination in the public immunization programme. However, a lower percentage of younger women had seropositive titres, indicating the need for routine rubella vaccination after an increase in vaccine coverage rates.

Immunogenicity and Safety of an Early Measles Vaccination Schedule at 6 and 12 Months of Age in Human Immunodeficiency Virus (HIV)-Unexposed and HIV-Exposed, Uninfected South African Children.

BACKGROUND: Measles morbidity and mortality rates are greatest in children <12 months old, with increased susceptibility in human immunodeficiency virus (HIV)-exposed children. We evaluated the immunogenicity and safety of an early 2-dose measles vaccine regimen administered at 6 and 12 months of age in South Africa. METHODS: HIV-unexposed (HU) (n = 212) and HIV-exposed, uninfected (HEU) (n = 71) children received measles vaccination (CAM-70) at 6 and 12 months of age. Measles immunoglobulin G titers were measured by means of enzyme-linked immunosorbent assay before and 1 month after each vaccine dose. RESULTS: The majority of children (88.2% HU and 95.8% HEU; P = .04) were seronegative (<150 mIU/mL) to measles at 4.2 months of age. This was particularly evident among infants of mothers born from 1992 onwards (year of public nationwide measles vaccine availability). One month after the first measles vaccine, 42.3% of HU and 46.4% of HEU children were seropositive (≥330 mIU/mL). After the second dose, the proportion seropositive increased to 99.0% in HU and 95.3% in HEU children. Safety profiles were similar between HU and HEU children. CONCLUSIONS: Early 2-dose measles vaccination at 6 and 12 months of age was safe and induced antibody responses in HU and HEU children, which could partly offset the early loss of maternally derived antibodies in infants born to predominantly measles-vaccinated mothers. CLINICAL TRIALS REGISTRATION: NCT03330171.

Measles Immunity at 4.5 Years of Age Following Vaccination at 9 and 15-18 Months of Age Among Human Immunodeficiency Virus (HIV)-infected, HIV-exposed-uninfected, and HIV-unexposed Children.

BACKGROUND: Human immunodeficiency virus (HIV)-infected and HIV-exposed-uninfected (HEU) children may be at increased risk of measles infection due to waning of immunity following vaccination. We evaluated persistence of antibodies to measles vaccination at 4.5 years of age in HIV-unexposed, HEU, and HIV-infected children with CD4+ ≥25% previously randomized to immediate antiretroviral therapy (ART) interrupted at 12 months (HIV/Immed-ART-12), 24 months (HIV/Immed-ART-24), or when clinically/immunologically indicated (HIV/Def-ART). The HIV/Def-ART group initiated ART by median 5.8 (interquartile range, 4.4-10.3) months of age. METHODS: In this study, HIV-unexposed (n = 95), HEU (n = 84), HIV/Immed-ART-12 (n = 70), HIV/Immed-ART-24 (n = 70), and HIV/Def-ART (n = 62) children were scheduled to receive measles vaccination at age 9 and 15-18 months. Antimeasles serum immunoglobulin G titers were quantified using enzyme-linked immunosorbent assay at 4.5 years. RESULTS: Compared with HIV-unexposed children (2860 mIU/mL), measles antibody geometric mean titers (GMTs) were significantly lower in both HIV/Immed-ART-12 (571; P < .001) and HIV/Immed-ART-24 (1136; P < .001) but similar in the HIV/Def-ART (2777) and HEU (3242) groups. Furthermore, compared with HIV-unexposed, antibody titers ≥330 mIU/mL (ie, presumed serocorrelate for protection; 99%) were also significantly lower in HIV/Immed-ART-12 (70%; P < .001) and HIV/Immed-ART-24 (83%; P < .001) but similar in the HIV/Def-ART (90%) and HEU (98%) groups. CONCLUSIONS: HIV-infected children in whom ART was interrupted at either 12 or 24 months had lower GMTs and lower proportions with seroprotective titers than HIV-unexposed children, indicating a potential downside of ART treatment interruption. CLINICAL TRIALS REGISTRATION: NCT00099658 and NCT00102960.

Safety and Immunogenicity of Measles Vaccination in HIV-Infected and HIV-Exposed Uninfected Children: A Systematic Review and Meta-Analysis.

BACKGROUND: HIV-infected and HIV-exposed uninfected (HEU) children have an increased risk of measles that may be due to altered immune responses or suboptimal timing of measles vaccination. We aimed to evaluate the safety and immunogenicity of measles vaccination in HIV-infected and HEU children. METHODS: For this systematic review and meta-analysis, we searched PubMed, Embase, Cochrane Library, CINAHL, Global Health Library and IndMED on May 9, 2018. Studies were included if they reported on safety or seroresponse (either seroprotection/seropositivity/seroconversion) after measles vaccination in HIV-infected or HEU children. We calculated pooled estimates to compare immunogenicity outcomes between HIV-infected, HEU and HIV-unexposed children, using risk ratios [RRs] (with 95%CIs). PROSPERO registration number: CRD42017057411. FINDINGS: Seventy-one studies met the inclusion criteria (15,363 children). Twenty-eight studies reported on safety; vaccine-associated adverse events and deaths were uncommon. Sixty-two studies reported on immunogenicity, 27 were included in the meta-analysis. HIV-infected children had lower seroresponse rates after primary vaccination compared with HIV-unexposed (RR 0.74; 95%CI: 0.61-0.90, I 2  = 85.9%) and HEU children (0.78; 0.69-0.88, I 2  = 77.1%), which was mitigated by antiretroviral therapy and time interval between vaccination and serology. HEU and HIV-unexposed children had similar seroresponses. Vaccination at 6-months resulted in similar proportions of HIV-infected children having seroresponse compared with HIV-unexposed (0.96; 0.77-1.19) and HEU children (1.00; 0.73-1.37, I 2  = 63.7%). INTERPRETATION: Primary measles vaccination at 6-months of age may provide protection against measles during early infancy in settings with high prevalence of maternal HIV-infection, however, further studies are needed to evaluate this strategy in HEU children and HIV-infected children receiving antiretroviral therapy. FUNDING: South African Research Chairs Initiative of the Department of Science and Technology and National Research Foundation in Vaccine Preventable Diseases; Medical Research Council: Respiratory and Meningeal Pathogens Research Unit.