Background. We evaluated the immunogenicity of trivalent inactivated influenza vaccine (IIV3) in pregnant women with and those without human immunodeficiency virus (HIV) infection and the persistence ...of hemagglutination-inhibiting antibodies in mothers and infants. Methods. Antibodies were measured before vaccination, 1 month after vaccination, at delivery, and at postpartum week 24 in mothers and within 1 week of birth and at 8, 16, and 24 weeks of age in infants. Results. We enrolled 98 HIV-uninfected and 100 HIV-infected pregnant women, including 93% with a CD4⁺ T-cell count of ≥200 cells/μL. Compared with HIV-uninfected women, HIV-infected women had lower seroconversion rates (ranging from 63%-92% vs 36%-40%), lower antibody titers through postpartum week 24, and overlapping antibody half-lives (ranging from 106-121 vs 87-153 days). Infant titers were lower than the maternal titers within 1 week of delivery, regardless of vaccine strain and HIV exposure status. Compared with HIV-unexposed infants, HIV-exposed infants had a similar transplacental influenza virus antibody transfer ratio, lower titers, and a lower frequency of titers ≥1:40 (ranging from 82%-95% vs 43%-79%) at birth and higher antibody half-lives (ranging from 43-45 vs 56-65 days). Conclusions. Compared with HIV-uninfected pregnant women, HIV-infected pregnant women had lower antibody responses and persistence. Compared with HIV-unexposed infants, HIV-exposed infants had lower antibody levels at birth but similar antibody levels after 8 weeks of life. Early IIV3 administration during pregnancy did not decrease antibody titers among infants at birth.
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BFBNIB, NMLJ, NUK, PNG, SAZU, UL, UM, UPUK
Background. Influenza immunization of pregnant women protects their young infants against laboratory-confirmed influenza infection. Influenza infection might predispose to subsequent bacterial ...infections that cause severe pneumonia. In a secondary analysis of a randomized clinical trial (RCT), we evaluated the effect of maternal vaccination on infant hospitalizations for all-cause acute lower respiratory tract infection (ALRI). Methods. Infants born to women who participated in a double-blind placebo-controlled RCT in 2011 and 2012 on the efficacy of trivalent inactivated influenza vaccine (IIV) during pregnancy were followed during the first 6 months of life. Results. The study included 1026 infants born to IIV recipients and 1023 born to placebo recipients. There were 52 ALRI hospitalizations (median age, 72 days). The incidence (per 1000 infant-months) of ALRI hospitalizations was lower in infants born to IIV recipients (3.4 95% confidence interval {CI}, 2.2–5.4; 19 cases) compared with placebo recipients (6.0 95% CI, 4.3–8.5; 33 cases) with a vaccine efficacy of 43.1% (P = .050). Thirty of the ALRI hospitalizations occurred during the first 90 days of life, 9 in the IIV group (3.0 95% CI, 1.6–5.9) and 21 in the placebo group (7.2 95% CI, 4.7–11.0) (incidence rate ratio, 0.43 95% CI, .19–.93) for a vaccine efficacy of 57.5% (P = .032). The incidence of ALRI hospitalizations was similar in the IIV and placebo group for infants >3 months of age. Forty-four of the hospitalized infants were tested for influenza virus infection and 1 tested positive. Conclusions. Using an RCT as a vaccine probe, influenza vaccination during pregnancy decreased all-cause ALRI hospitalization during the first 3 months of life, suggesting possible protection against subsequent bacterial infections that influenza infection might predispose to. Clinical Trial Registration. NCT01306669.
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Although group B Streptococcus (GBS) is a leading cause of severe invasive disease in young infants worldwide, epidemiologic data and knowledge about risk factors for the disease are lacking from ...low- to middle-income countries. To determine the epidemiology of invasive GBS disease among young infants in a setting with high maternal HIV infection, we conducted hospital-based surveillance during 2004-2008 in Soweto, South Africa. Overall GBS incidence was 2.72 cases/1,000 live births (1.50 and 1.22, respectively, among infants with early-onset disease EOD and late-onset LOD disease). Risk for EOD and LOD was higher for HIV-exposed than HIV-unexposed infants. GBS serotypes Ia and III accounted for 84.0% of cases, and 16.9% of infected infants died. We estimate that use of trivalent GBS vaccine (serotypes Ia, Ib, and III) could prevent 2,105 invasive GBS cases and 278 deaths annually among infants in South Africa; therefore, vaccination of all pregnant women in this country should be explored.
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DOBA, IZUM, KILJ, NUK, ODKLJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
People living with HIV are at an increased risk of fatal outcome when admitted to hospital for severe COVID-19 compared with HIV-negative individuals. We aimed to assess safety and immunogenicity of ...the ChAdOx1 nCoV-19 (AZD1222) vaccine in people with HIV and HIV-negative individuals in South Africa.
In this ongoing, double-blind, placebo-controlled, phase 1B/2A trial (COV005), people with HIV and HIV-negative participants aged 18–65 years were enrolled at seven South African locations and were randomly allocated (1:1) with full allocation concealment to receive a prime-boost regimen of ChAdOx1 nCoV-19, with two doses given 28 days apart. Eligibility criteria for people with HIV included being on antiretroviral therapy for at least 3 months, with a plasma HIV viral load of less than 1000 copies per mL. In this interim analysis, safety and reactogenicity was assessed in all individuals who received at least one dose of ChAdOx1 nCov 19 between enrolment and Jan 15, 2021. Primary immunogenicity analyses included participants who received two doses of trial intervention and were SARS-CoV-2 seronegative at baseline. This trial is registered with ClinicalTrials.gov, NCT04444674, and the Pan African Clinicals Trials Registry, PACTR202006922165132.
Between June 24 and Nov 12, 2020, 104 people with HIV and 70 HIV-negative individuals were enrolled. 102 people with HIV (52 vaccine; 50 placebo) and 56 HIV-negative participants (28 vaccine; 28 placebo) received the priming dose, 100 people with HIV (51 vaccine; 49 placebo) and 46 HIV-negative participants (24 vaccine; 22 placebo) received two doses (priming and booster). In participants seronegative for SARS-CoV-2 at baseline, there were 164 adverse events in those with HIV (86 vaccine; 78 placebo) and 237 in HIV-negative participants (95 vaccine; 142 placebo). Of seven serious adverse events, one severe fever in a HIV-negative participant was definitely related to trial intervention and one severely elevated alanine aminotranferase in a participant with HIV was unlikely related; five others were deemed unrelated. One HIV-negative participant died (unlikely related). People with HIV and HIV-negative participants showed vaccine-induced serum IgG responses against wild-type Wuhan-1 Asp614Gly (also known as D614G). For participants seronegative for SARS-CoV-2 antigens at baseline, full-length spike geometric mean concentration (GMC) at day 28 was 163·7 binding antibody units (BAU)/mL (95% CI 89·9–298·1) for people with HIV (n=36) and 112·3 BAU/mL (61·7–204·4) for HIV-negative participants (n=23), with a rising day 42 GMC booster response in both groups. Baseline SARS-CoV-2 seropositive people with HIV demonstrated higher antibody responses after each vaccine dose than did people with HIV who were seronegative at baseline. High-level binding antibody cross-reactivity for the full-length spike and receptor-binding domain of the beta variant (B.1.351) was seen regardless of HIV status. In people with HIV who developed high titre responses, predominantly those who were receptor-binding domain seropositive at enrolment, neutralising activity against beta was retained.
ChAdOx1 nCoV-19 was well tolerated, showing favourable safety and immunogenicity in people with HIV, including heightened immunogenicity in SARS-CoV-2 baseline-seropositive participants. People with HIV showed cross-reactive binding antibodies to the beta variant and Asp614Gly wild-type, and high responders retained neutralisation against beta.
The Bill & Melinda Gates Foundation, South African Medical Research Council, UK Research and Innovation, UK National Institute for Health Research, and the South African Medical Research Council.
Abstract
Within 2 years after the start of the coronavirus disease 2019 (COVID-19) pandemic, novel severe acute respiratory syndrome coronavirus 2 vaccines were developed, rigorously evaluated in ...large phase 3 trials, and administered to more than 5 billion individuals globally. However, adverse events of special interest (AESIs) have been described post-implementation, including myocarditis after receipt of messenger RNA (mRNA) vaccines and thrombosis with thrombocytopenia syndrome after receipt of adenoviral vector vaccines. AESIs are rare (<1 to 10/100 000 vaccinees) and less frequent than COVID-19 complications, though they have associated morbidity and mortality. The diversity of COVID-19 vaccine platforms (eg, mRNA, viral vector, protein) and rates of AESIs both between and within platforms (eg, higher rate of myocarditis after mRNA-1273 vs BNT162b2 vaccines) present an important opportunity to advance vaccine safety science. The International Network of Special Immunization Services has been formed with experts in vaccine safety, systems biology, and other relevant disciplines to study cases of AESIs and matched controls to uncover the pathogenesis of rare AESIs and inform vaccine development.
Seizing the opportunity coronavirus disease 2019 (COVID-19) vaccination programs present to advance vaccine safety science, a new international network aims to apply a systems biology “adversomics” approach to characterize the mechanisms that underlie rare adverse events following immunization with potential to improve vaccine safety
Summary Background Neonates born to women infected with HIV are at increased risk for invasive group B streptococcus (GBS) disease. We aimed to compare safety and immunogenicity of trivalent ...glycoconjugate GBS vaccine in pregnant women with and without HIV in Malawi and South Africa. Methods In our non-randomised phase 2, open-label, multicentre study, we recruited pregnant women attending two antenatal clinics, one in Blantyre, Malawi, and one in Soweto, Johannesburg, South Africa. Participants were divided into three groups on the basis of their HIV infection status (no infection, infection and high CD4 cell count >350 cells per μL, and infection and low CD4 cell count >50 to ≤350 cells per μL) and received a 5 μg dose of glycoconjugate GBS vaccine (serotypes Ia, Ib, and III, with CRM197 Novartis Vaccines, Siena, Italy) intramuscularly at 24–35 weeks' gestation. GBS serotype-specific antibody concentrations were measured before vaccination (day 1), day 15, day 31, and at delivery, and in infants at birth and day 42 of life. The primary outcomes were safety in mothers and infants and the amount of placental transfer of GBS serotype-specific antibodies from mothers to their infants. All immunogenicity and safety analyses were done on the full analysis set, including participants who, or whose mother, correctly received the vaccine and who provided at least one valid assessable serum sample. This study is registered with ClinicalTrials.gov , number NCT01412801. Findings 270 women and 266 infants were enrolled between Sept 26, 2011, and Dec 4, 2012 (90 women and 87 infants without HIV, 89 and 88 with HIV and high CD4 cell counts, and 91 and 91 with HIV and low CD4 cell counts, respectively). Seven women were lost to follow-up, six withdrew consent, one died, and two relocated. Eight infants died or were stillborn and two were lost to follow-up. Across serotypes, fold change in antibody concentrations were higher for the HIV-uninfected group than the HIV-infected groups. Transfer ratios were similar across all three groups (0·49–0·72; transfer ratio is infant geometric mean antibody concentration in blood collected within 72 h of birth divided by maternal geometric mean antibody concentration in blood collected at delivery); however, at birth, maternally derived serotype-specific antibody concentrations were lower for infants born to women infected with HIV (0·52–1·62 μg/mL) than for those born to women not infected with HIV (2·67–3·91 μg/mL). 151 (57%) of 265 women reported at least one solicited adverse reaction: 39 (45%) of 87 women with HIV and low CD4 cell counts, 52 (59%) of 88 women with HIV and high CD4 cell counts, and 60 (67%) of 90 women in the HIV-uninfected group. 49 (18%) of 269 women had at least one adverse event deemed possibly related to the vaccine (six 7% in the HIV and low CD4 cell count group, 12 13% in the HIV and high CD4 cell count group, and 21 23% in the HIV-uninfected group), as did three (1%) of 266 neonates (zero, two 1%, and one 1%); none of these events was regarded as serious. Interpretation The vaccine was less immunogenic in women infected with HIV than it was in those not infected, irrespective of CD4 cell count, resulting in lower levels of serotype-specific maternal antibody transferred to infants, which could reduce vaccine protection against invasive GBS disease. A validated assay and correlate of protection is needed to understand the potential protective value of this vaccine. Funding Novartis Vaccines and Diagnostics division (now part of the GlaxoSmithKline group of companies), Wellcome Trust UK, Medical Research Council: Respiratory and Meningeal Pathogens Research Unit.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
A globally standardized approach in high and low and middle-income countries (LMIC) to actively monitor the safety of vaccines for pregnant women during development and implementation phases is ...critical. Brighton Collaboration’s (BC) Global Alignment of Immunization Safety Assessment in Pregnancy (GAIA) project has developed globally standardized case definitions (CDs) of key obstetric and neonatal terms for the assessment of safety of vaccines in pregnancy. CDs are categorized into levels of diagnostic certainty, facilitating their use in varied settings. This study evaluates the field performance of CDs in LMIC.
Data from pregnant participants of RCTs for trivalent inactivated influenza vaccine conducted at Chris Hani Baragwanath Academic Hospital, South Africa (SA) between 2011 and 2013 were reviewed retrospectively for preterm birth, stillbirth and hypertension CDs and the Gestational age assessment (GA) algorithm. Data from an ongoing pneumococcal vaccine trial (conducted at MRC Unit, The Gambia) were collected prospectively for GA.
For GA, 600 mother-infant dyads from Gambia and 155 mother-infant dyads from SA were reviewed. Level 2B (unsure LMP and US in 2nd trimester) was the most common level seen in Gambia (63%) and level 3B1 (unsure LMP with physical examination) in SA (43%). Preterm deliveries had similar results in SA. The pregnancy-induced hypertension definition performed well, with 96% (54/56) of cases fulfilling ‘level 1’ for ‘preeclampsia with severe features’. 24 stillbirths were identified and 21 records were reviewed; 73.3% (11/15) of the stillbirths classified as antepartum by attending physicians and 83.3% (5/6) of the intrapartum stillbirths did not fulfil the criteria for any level of certainty.
BC CDs for neonatal and maternal outcomes (preterm and hypertension) and GA were sensitive, reliable and feasible to use in RCTs in SA and Gambia. Modifications to the stillbirth CD are required to improve its usefulness in varied settings.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
•Background rates of maternal foetal and neonatal adverse events in South Africa have been assessed to support safety assessment of vaccines.•Retrospective review of paper-based medical records is ...challenging and time-consuming.•Missing data hampered alignment between clinically-reported adverse events and adverse events confirmed with GAIA case definitions.•Brighton Collaboration GAIA case definitions are useful, but some require amendments to improve utilization in real world settings.
Background epidemiologic population data from low- and middle-income countries (LMIC), on maternal, foetal and neonatal adverse outcomes are limited. We aimed to estimate the incidence of maternal, foetal and neonatal adverse outcomes at South African maternal vaccine trial sites as reported directly in the clinical notes as well as using the ‘Global Alignment of Immunization Safety Assessment in Pregnancy’ case definitions (GAIA-CDs). GAIA-CDs were utilized as a tool to standardise data collection and outcome assessment, and the applicability and utility of the GAIA-CDs was evaluated in a LMIC observational study.
We conducted a retrospective record review of maternity and neonatal case records for births that occurred in Soweto, Inner City- Johannesburg and Metro-East Cape Town, South Africa, between 1st July 2017 and 30th June 2018. Study staff abstracted data from randomly selected medical charts onto standardized study-specific forms. Incidence (per 100,000 population) was calculated for adverse maternal, foetal and neonatal outcomes, which were identified as priority outcomes in vaccine safety studies by the Brighton Collaboration and World Health Organization. Outcomes reported directly in the clinical notes and outcomes which fulfilled GAIA-CDs were compared. Incidence of outcomes was calculated by combining cases which were either reported in clinical notes by attending physicians and/ or fulfilled GAIA-CDs.
Of 9371 pregnant women enrolled, 27·6% were HIV-infected, 19·9% attended antenatal clinic in the 1st trimester of pregnancy and 55·3% had ≥1 ultrasound examination. Fourteen percent of women had hypertensive disease of pregnancy, 1·3% had gestational diabetes mellitus and 16% experienced preterm labour. There were 150 stillbirths (1·6%), 26·8% of infants were preterm and five percent had microcephaly. Data available in clinical notes for some adverse outcomes, including maternal- & neonatal death, severe pre-eclampsia/ eclampsia, were able to fulfil GAIA-CDs criteria for all of the clinically-reported cases, however, missing data required to fulfil other GAIA-CD criteria (including stillbirth, gestational diabetes mellitus and gestational hypertension) led to poor correlation between clinically-reported adverse outcomes and outcomes fulfilling GAIA-CDs. Challenges were also encountered in accurately ascertaining gestational age.
This study contributes to the expanding body of data on background rates of adverse maternal and foetal/ neonatal outcomes in LMICs. Utilization of GAIA-CDs assists with alignment of data, however, some GAIA-CDs require amendment to improve the applicability in LMICs.
This study was funded by Pfizer (Inc).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
About 2·6 million third-trimester stillbirths occur annually worldwide, mostly in low-income and middle-income countries, where the causes of these deaths are rarely investigated.
We did a ...prospective, hospital-based, observational study in Soweto, South Africa, to investigate the causes of stillbirths in fetuses of at least 22 weeks' gestational age or with a birthweight of at least 500 g. Maternal clinical information was abstracted from medical records. Investigations included placental macroscopic and histopathological examination and fetal blood culture (including screening for pathogenic bacteria associated with stillbirth). Cases missing one or more of these investigations were considered to have incomplete samples and were excluded from the analysis of cause of stillbirth. Causes of stillbirths were assessed by individual case reviews by at least two obstetricians, and classified with a modified Stillbirth Collaborative Research Network classification system.
Between Oct 9, 2014, and Nov 8, 2015, we enrolled 354 stillbirths (born to 350 women). Among the women with available data, 133 (38%) of 350 had hypertension, median age was 27 years (IQR 23–33), 51 (18%) of 291 were obese, six (2%) of 344 had syphilis, and 94 (27%) of 350 had HIV. 63 (18%) of 341 fetuses showed intrauterine growth restriction. Of 298 cases (born to 294 mothers) with complete samples, the most common causes of stillbirth were maternal medical conditions (64 21% cases; among them 56 19% with hypertensive disorders and six 2% with diabetes), placental or fetal infections (58 19%; 47 16% with fetal invasive bacterial infection), pathological placental conditions (57 19%; among them 27 9% with fetal membrane and placental inflammation and 26 9% with circulatory abnormalities), and clinical obstetric complications (54 18%; 45 15% with placental abruption). Six (2%) stillbirths were attributed to fetal, genetic, or structural abnormalities. In 55 (18%) cases, no cause of death was identified. The most common bacteria to which stillbirths due to fetal invasive infections were attributed were group B streptococcus (15 5% cases), E coli (12 4%), E faecalis (six 2%), and S aureus (five 2%).
Targeted investigation of stillbirths (even without fetal autopsy) can ascertain a cause of stillbirth in most cases. Further studies using such investigations are needed to inform the prioritisation of interventions to reduce stillbirths globally.
Novartis and GlaxoSmithKline.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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