Use of ChAd3-EBO-Z Ebola virus vaccine in Malian and US adults, and boosting of Malian adults with MVA-BN-Filo: a phase 1, single-blind, randomised trial, a phase 1b, open-label and double-blind, dose-escalation trial, and a nested, randomised, double-blind, placebo-controlled trial

SummaryBackgroundThe 2014 west African Zaire Ebola virus epidemic prompted worldwide partners to accelerate clinical development of replication-defective chimpanzee adenovirus 3 vector vaccine expressing Zaire Ebola virus glycoprotein (ChAd3-EBO-Z). We aimed to investigate the safety, tolerability, and immunogenicity of ChAd3-EBO-Z in Malian and US adults, and assess the effect of boosting of Malians with modified vaccinia Ankara expressing Zaire Ebola virus glycoprotein and other filovirus antigens (MVA-BN-Filo).MethodsIn the phase 1, single-blind, randomised trial of ChAd3-EBO-Z in the USA, we recruited adults aged 18–65 years from the University of Maryland medical community and the Baltimore community. In the phase 1b, open-label and double-blind, dose-escalation trial of ChAd3-EBO-Z in Mali, we recruited adults 18–50 years of age from six hospitals and health centres in Bamako (Mali), some of whom were also eligible for a nested, randomised, double-blind, placebo-controlled trial of MVA-BN-Filo. For randomised segments of the Malian trial and for the US trial, we randomly allocated participants (1:1; block size of six [Malian] or four [US]; ARB produced computer-generated randomisation lists; clinical staff did randomisation) to different single doses of intramuscular immunisation with ChAd3-EBO-Z: Malians received 1 × 1010 viral particle units (pu), 2·5 × 1010 pu, 5 × 1010 pu, or 1 × 1011 pu; US participants received 1 × 1010 pu or 1 × 1011 pu. We randomly allocated Malians in the nested trial (1:1) to receive a single dose of 2 × 108 plaque-forming units of MVA-BN-Filo or saline placebo. In the double-blind segments of the Malian trial, investigators, clinical staff, participants, and immunology laboratory staff were masked, but the study pharmacist (MK), vaccine administrator, and study statistician (ARB) were unmasked. In the US trial, investigators were not masked, but participants were. Analyses were per protocol. The primary outcome was safety, measured with occurrence of adverse events for 7 days after vaccination. Both trials are registered with ClinicalTrials.gov, numbers NCT02231866 (US) and NCT02267109 (Malian).FindingsBetween Oct 8, 2014, and Feb 16, 2015, we randomly allocated 91 participants in Mali (ten [11%] to 1 × 1010 pu, 35 [38%] to 2·5 × 1010 pu, 35 [38%] to 5 × 1010 pu, and 11 [12%] to 1 × 1011 pu) and 20 in the USA (ten [50%] to 1 × 1010 pu and ten [50%] to 1 × 1011 pu), and boosted 52 Malians with MVA-BN-Filo (27 [52%]) or saline (25 [48%]). We identified no safety concerns with either vaccine: seven (8%) of 91 participants in Mali (five [5%] received 5 × 1010 and two [2%] received 1 × 1011 pu) and four (20%) of 20 in the USA (all received 1 × 1011 pu) given ChAd3-EBO-Z had fever lasting for less than 24 h, and 15 (56%) of 27 Malians boosted with MVA-BN-Filo had injection-site pain or tenderness.Interpretation1 × 1011 pu single-dose ChAd3-EBO-Z could suffice for phase 3 efficacy trials of ring-vaccination containment needing short-term, high-level protection to interrupt transmission. MVA-BN-Filo boosting, although a complex regimen, could confer long-lived protection if needed (eg, for health-care workers).FundingWellcome Trust, Medical Research Council UK, Department for International Development UK, National Cancer Institute, Frederick National Laboratory for Cancer Research, Federal Funds from National Institute of Allergy and Infectious Diseases

Background Rates of Adverse Pregnancy Outcomes for Assessing the Safety of Maternal Vaccine Trials in Sub-Saharan Africa

<div><h3>Background</h3><p>Maternal immunization has gained traction as a strategy to diminish maternal and young infant mortality attributable to infectious diseases. Background rates of adverse pregnancy outcomes are crucial to interpret results of clinical trials in Sub-Saharan Africa.</p> <h3>Methods</h3><p>We developed a mathematical model that calculates a clinical trial's expected number of neonatal and maternal deaths at an interim safety assessment based on the person-time observed during different risk windows. This model was compared to crude multiplication of the maternal mortality ratio and neonatal mortality rate by the number of live births. Systematic reviews of severe acute maternal morbidity (SAMM), low birth weight (LBW), prematurity, and major congenital malformations (MCM) in Sub-Saharan African countries were also performed.</p> <h3>Findings</h3><p>Accounting for the person-time observed during different risk periods yields lower, more conservative estimates of expected maternal and neonatal deaths, particularly at an interim safety evaluation soon after a large number of deliveries. Median incidence of SAMM in 16 reports was 40.7 (IQR: 10.6–73.3) per 1,000 total births, and the most common causes were hemorrhage (34%), dystocia (22%), and severe hypertensive disorders of pregnancy (22%). Proportions of liveborn infants who were LBW (median 13.3%, IQR: 9.9–16.4) or premature (median 15.4%, IQR: 10.6–19.1) were similar across geographic region, study design, and institutional setting. The median incidence of MCM per 1,000 live births was 14.4 (IQR: 5.5–17.6), with the musculoskeletal system comprising 30%.</p> <h3>Interpretation</h3><p>Some clinical trials assessing whether maternal immunization can improve pregnancy and young infant outcomes in the developing world have made ethics-based decisions not to use a pure placebo control. Consequently, reliable background rates of adverse pregnancy outcomes are necessary to distinguish between vaccine benefits and safety concerns. Local studies that quantify population-based background rates of adverse pregnancy outcomes will improve safety assessment of interventions during pregnancy.</p> </div

The incidence of severe acute maternal morbidity in 16 studies in Sub-Saharan Africa published between 1995 and 2012.

<p>SAMM: Severe Acute Maternal Morbidity; MI: Mortality Index (# of maternal deaths divided by the sum of near-miss cases and maternal deaths) TB: Total births; D: Deliveries; Hem: Hemorrhage; Dyst: Dystocia (includes uterine rupture); HTN: Hypertensive diseases of pregnancy (severe pre-eclampsia and eclampsia); Anem: Anemia; Infect: Infection;</p>†<p>Data from the year 2000 published by Vandecruys et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046638#pone.0046638-Vandecruys1" target="_blank">[50]</a> were also published in Cochet et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046638#pone.0046638-Cochet1" target="_blank">[48]</a>. In this table, those data were removed from Vandecruys et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046638#pone.0046638-Vandecruys1" target="_blank">[50]</a> to avoid duplication.</p>*<p>In Prual et al <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046638#pone.0046638-Prual1" target="_blank">[54]</a>, 109 Cesarean sections performed for scarred uterus, fetal distress, and premature rupture of membranes that did not meet criteria for severe dystocia were subtracted from the total number of severe maternal morbidities as these ostensibly did not directly threaten the life of the mother.</p

Summary of literature search and study selection.

<p>A. Severe Acute Maternal Morbidity. B. Low Birth Weight, Prematurity, and Small for Gestational Age. C. Congenital Malformations.</p

The incidence of congenital malformations among liveborn infants in 11 studies in Sub-Saharan Africa published between 1966 and 2009.

<p>CNS = Central Nervous System (ICD-10: Q00–Q07); Resp = Respiratory (ICD-10: Q30–Q34); CV = Cardiovascular (ICD-10: Q20–Q28); MSK = Musculoskeletal system (ICD-10: Q65–79); GI = Digestive system (ICD-10: Q35–Q45); GU = genital organs and urinary system (ICD-10: Q50–Q56, Q60–Q64); HEENT = Eye, ear, face, and neck (ICD-10: Q10–Q18); Chrom = Chromosomal abnormalities (ICD-10: Q90–Q99); Multip = Major congenital malformations in multiple systems.</p>*<p>Denominator given in total births.</p

Expected number of maternal and neonatal deaths and stillbirths for a hypothetical cohort of pregnant women corresponding to 1,000 births in Sub-Saharan Africa and the proportion of live-born infants expected to be low birth weight or premature.

¥<p>Maternal and neonatal deaths were expressed as a fraction of total births by multiplying the maternal mortality ratio (maternal deaths/live births) and the neonatal mortality ratio (neonatal deaths/live birth) by 1 minus the stillbirth rate <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046638#pone.0046638-Cousens1" target="_blank">[44]</a>.</p>†<p>For % LBW and % <37 wks, the median and range for all studies performed in the specified country are presented.</p>*<p>Note –UN Data classifies Cameroon and Chad as falling within the Middle Africa sub-region rather than the West Africa sub-region. However, in this table these countries are kept within the West Africa sub-region to maintain congruity with global burden of disease publications.</p

Publications by country on low birth weight, prematurity, and small for gestational age in sub-Saharan Africa.

<p>Publications by country on low birth weight, prematurity, and small for gestational age in sub-Saharan Africa.</p

Observation-time model vs. Live births model to calculate expected background maternal and neonatal deaths over the course of a clinical trial in 1000 pregnant women in Mali.

<p>Assuming a maternal mortality ratio of 418.8 (327.5–519.8) per 100,000 live births, stillbirth rate of 23 (18–42) per 1,000 total births, early neonatal mortality rate of 33.5 (28.1–39.0) per 1,000 live births, and late neonatal mortality rate of 12.4 (9.9–15.5) per 1,000 live births estimated for Mali by recently published systematic analyses <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046638#pone.0046638-Hogan1" target="_blank">[3]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046638#pone.0046638-Cousens1" target="_blank">[44]</a>, <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046638#pone.0046638-Rajaratnam1" target="_blank">[45]</a>. We assume women are recruited at 28 weeks gestation and deliver exactly 12 weeks later. † 50 pregnant women recruited each week over 20 weeks. ‡500 pregnant women recruited each week over 2 weeks.</p

Background rates of pregnancy outcomes by region of Sub-Saharan Africa.

<p>SAMM = Severe Acute Maternal Morbidity; NND = Neonatal Deaths; LBW = Low Birth Weight; MCM = Major Congenital Malformations.</p>†<p>For Severe Maternal Morbidity, Low Birth Weight, Prematurity, and Major Congenital Malformations, the median and range of a systematic review is presented for the entire region. In Central Africa, only 1 data point was available for Severe Maternal Morbidity <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046638#pone.0046638-MayiTsonga1" target="_blank">[52]</a> and for Major Congenital Malformations <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046638#pone.0046638-Ahuka1" target="_blank">[60]</a>, so no range was presented.</p>¥<p>Maternal and neonatal deaths were expressed as a fraction of total births by multiplying the maternal mortality ratio (maternal deaths/live births) and the early and late neonatal mortality ratios (neonatal deaths/live births) by 1 minus the stillbirth rate <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0046638#pone.0046638-Cousens1" target="_blank">[44]</a>.</p