scholarly journals Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination in children and adolescents in Africa: A randomised, placebo-controlled, multicentre Phase II clinical trial

PLoS Medicine ◽  
2022 ◽  
Vol 19 (1) ◽  
pp. e1003865
Author(s):  
Zacchaeus Anywaine ◽  
Houreratou Barry ◽  
Omu Anzala ◽  
Gaudensia Mutua ◽  
Sodiomon B. Sirima ◽  
...  
Keyword(s):  
Immune Responses ◽  
Phase Ii ◽  
Dose Regimen ◽  
Ebola Virus ◽  
Geometric Mean ◽  
Central Africa ◽  
Paediatric Population ◽  
Multicentre Phase ◽  
Link Type ◽  
Western Africa

Background Reoccurring Ebola outbreaks in West and Central Africa have led to serious illness and death in thousands of adults and children. The objective of this study was to assess safety, tolerability, and immunogenicity of the heterologous 2-dose Ad26.ZEBOV, MVA-BN-Filo vaccination regimen in adolescents and children in Africa. Methods and findings In this multicentre, randomised, observer-blind, placebo-controlled Phase II study, 131 adolescents (12 to 17 years old) and 132 children (4 to 11 years old) were enrolled from Eastern and Western Africa and randomised 5:1 to receive study vaccines or placebo. Vaccine groups received intramuscular injections of Ad26.ZEBOV (5 × 1010 viral particles) and MVA-BN-Filo (1 × 108 infectious units) 28 or 56 days apart; placebo recipients received saline. Primary outcomes were safety and tolerability. Solicited adverse events (AEs) were recorded until 7 days after each vaccination and serious AEs (SAEs) throughout the study. Secondary and exploratory outcomes were humoral immune responses (binding and neutralising Ebola virus [EBOV] glycoprotein [GP]-specific antibodies), up to 1 year after the first dose. Enrolment began on February 26, 2016, and the date of last participant last visit was November 28, 2018. Of the 263 participants enrolled, 217 (109 adolescents, 108 children) received the 2-dose regimen, and 43 (20 adolescents, 23 children) received 2 placebo doses. Median age was 14.0 (range 11 to 17) and 7.0 (range 4 to 11) years for adolescents and children, respectively. Fifty-four percent of the adolescents and 51% of the children were male. All participants were Africans, and, although there was a slight male preponderance overall, the groups were well balanced. No vaccine-related SAEs were reported; solicited AEs were mostly mild/moderate. Twenty-one days post-MVA-BN-Filo vaccination, binding antibody responses against EBOV GP were observed in 100% of vaccinees (106 adolescents, 104 children). Geometric mean concentrations tended to be higher after the 56-day interval (adolescents 13,532 ELISA units [EU]/mL, children 17,388 EU/mL) than the 28-day interval (adolescents 6,993 EU/mL, children 8,007 EU/mL). Humoral responses persisted at least up to Day 365. A limitation of the study is that the follow-up period was limited to 365 days for the majority of the participants, and so it was not possible to determine whether immune responses persisted beyond this time period. Additionally, formal statistical comparisons were not preplanned but were only performed post hoc. Conclusions The heterologous 2-dose vaccination was well tolerated in African adolescents and children with no vaccine-related SAEs. All vaccinees displayed anti-EBOV GP antibodies after the 2-dose regimen, with higher responses in the 56-day interval groups. The frequency of pyrexia after vaccine or placebo was higher in children than in adolescents. These data supported the prophylactic indication against EBOV disease in a paediatric population, as licenced in the EU. Trial registration ClinicalTrials.gov NCT02564523.

scholarly journals Safety and immunogenicity of 2-dose heterologous Ad26.ZEBOV, MVA-BN-Filo Ebola vaccination in healthy and HIV-infected adults: A randomised, placebo-controlled Phase II clinical trial in Africa

PLoS Medicine ◽  
2021 ◽  
Vol 18 (10) ◽  
pp. e1003813
Author(s):  
Houreratou Barry ◽  
Gaudensia Mutua ◽  
Hannah Kibuuka ◽  
Zacchaeus Anywaine ◽  
Sodiomon B. Sirima ◽  
...  
Keyword(s):  
Phase Ii ◽  
Ebola Virus ◽  
Healthy Adult ◽  
Geometric Mean ◽  
Booster Vaccination ◽  
Healthy Adults ◽  
Immune Memory ◽  
The European Union ◽  
Anamnestic Response ◽  
Link Type

Background We investigated safety, tolerability, and immunogenicity of the heterologous 2-dose Ebola vaccination regimen in healthy and HIV-infected adults with different intervals between Ebola vaccinations. Methods and findings In this randomised, observer-blind, placebo-controlled Phase II trial, 668 healthy 18- to 70-year-olds and 142 HIV-infected 18- to 50-year-olds were enrolled from 1 site in Kenya and 2 sites each in Burkina Faso, Cote d’Ivoire, and Uganda. Participants received intramuscular Ad26.ZEBOV followed by MVA-BN-Filo at 28-, 56-, or 84-day intervals, or saline. Females represented 31.4% of the healthy adult cohort in contrast to 69.7% of the HIV-infected cohort. A subset of healthy adults received booster vaccination with Ad26.ZEBOV or saline at Day 365. Following vaccinations, adverse events (AEs) were collected until 42 days post last vaccination and serious AEs (SAEs) were recorded from signing of the ICF until the end of the study. The primary endpoint was safety, and the secondary endpoint was immunogenicity. Anti-Ebola virus glycoprotein (EBOV GP) binding and neutralising antibodies were measured at baseline and at predefined time points throughout the study. The first participant was enrolled on 9 November 2015, and the date of last participant’s last visit was 12 February 2019. No vaccine-related SAEs and mainly mild-to-moderate AEs were observed among the participants. The most frequent solicited AEs were injection-site pain (local), and fatigue, headache, and myalgia (systemic), respectively. Twenty-one days post-MVA-BN-Filo vaccination, geometric mean concentrations (GMCs) with 95% confidence intervals (CIs) of EBOV GP binding antibodies in healthy adults in 28-, 56-, and 84-day interval groups were 3,085 EU/mL (2,648 to 3,594), 7,518 EU/mL (6,468 to 8,740), and 7,300 EU/mL (5,116 to 10,417), respectively. In HIV-infected adults in 28- and 56-day interval groups, GMCs were 4,207 EU/mL (3,233 to 5,474) and 5,283 EU/mL (4,094 to 6,817), respectively. Antibody responses were observed until Day 365. Ad26.ZEBOV booster vaccination after 1 year induced an anamnestic response. Study limitations include that some healthy adult participants either did not receive dose 2 or received dose 2 outside of their protocol-defined interval and that the follow-up period was limited to 365 days for most participants. Conclusions Ad26.ZEBOV, MVA-BN-Filo vaccination was well tolerated and immunogenic in healthy and HIV-infected African adults. Increasing the interval between vaccinations from 28 to 56 days improved the magnitude of humoral immune responses. Antibody levels persisted to at least 1 year, and Ad26.ZEBOV booster vaccination demonstrated the presence of vaccination-induced immune memory. These data supported the approval by the European Union for prophylaxis against EBOV disease in adults and children ≥1 year of age. Trial registration ClinicalTrials.gov NCT02564523

Ebola

2020 ◽  
pp. 223-240
Author(s):  
Michael B. A. Oldstone
Keyword(s):  
Virus Infection ◽  
West Africa ◽  
Ebola Virus ◽  
Central Africa ◽  
Hemorrhagic Fever ◽  
Natural Reservoir ◽  
Western Africa ◽  
Fruit Bat ◽  
Contaminated Blood ◽  
Ebola Virus Infection

This chapter examines the Ebola virus in detail. Since 1976, with the exception of the 2013–2016 epidemic in West Africa, all outbreaks of Ebola virus infection have occurred in central Africa. The initial 1976 eruption of Ebola in Zaire in central Africa provided lessons for how to control future outbreaks of this disease. Unfortunately, those lessons were not well learned or sufficiently applied to the massive Ebola outbreak that followed in 2013–2016 in western Africa. Ebola virus can spread either through the air or by exposure to contaminated blood of infected humans. The clinical course of Ebola virus infection is that of a severe hemorrhagic fever. An Ebola vaccine was developed and administered to over 40,000 individuals for the 2018–2019 outbreak. However, the vaccine’s effectiveness in the outbreak has not been formally assessed, and critical scientific assessment will be difficult to achieve. Ultimately, Ebola virus remains endemic in Africa. Whether the fruit bat is the only natural reservoir for such viruses, how Ebola is transmitted, and where it lurks are still unresolved.

scholarly journals Randomized, Open-Label Study of the Impact of Age on Booster Responses to the 10-Valent Pneumococcal Nontypeable Haemophilus influenzae Protein D Conjugate Vaccine in Children in India

2014 ◽  
Vol 21 (9) ◽  
pp. 1292-1300 ◽  
Author(s):  
Sanjay Lalwani ◽  
Sukanta Chatterjee ◽  
Jugesh Chhatwal ◽  
Anna Simon ◽  
Sudheer Ravula ◽  
...  
Keyword(s):  
Immune Responses ◽  
Haemophilus Influenzae ◽  
Conjugate Vaccine ◽  
Booster Dose ◽  
Geometric Mean ◽  
Phase Iii ◽  
Open Label ◽  
Link Type ◽  
Catch Up ◽  
The Impact

ABSTRACTIn this phase III, open-label, multicenter, and descriptive study in India, children primed with 3 doses (at ages 6, 10, and 14 weeks) of the 10-valent pneumococcal nontypeableHaemophilus influenzaeprotein D conjugate vaccine (PHiD-CV) were randomized (1:1) to receive a booster dose at 9 to 12 (early booster) or 15 to 18 months old (late booster) in order to evaluate impact of age at booster. We also evaluated a 2-dose catch-up vaccination plus an experimental booster dose in unprimed children age 12 to 18 months. The early booster, late booster, and catch-up vaccinations were administered to 74, 95, and 87 children, respectively; 66, 71, and 81 children, respectively, were included in the immunogenicity according-to-protocol cohort. One month postbooster, for each PHiD-CV serotype, ≥95.2% (early booster) and ≥93.8% (late booster) of the children had antibody concentrations of ≥0.2 μg/ml; ≥96.7% and ≥93.0%, respectively, had opsonophagocytic activity (OPA) titers of ≥8. The postbooster antibody geometric mean concentrations (GMCs) were in similar ranges for early and late boosters; the OPA titers appeared to be lower for most PHiD-CV serotypes (except 6B and 19F) after the early booster. After dose 2 and postbooster, for each PHiD-CV serotype, ≥88.6% and ≥96.3%, respectively, of the catch-up immunogenicity according-to-protocol cohort had antibody concentrations of ≥0.2 μg/ml; ≥71.4% and ≥90.6%, respectively, had OPA titers of ≥8. At least 1 serious adverse event was reported by 2 children in the early booster (skin infection and gastroenteritis) and 1 child in the catch-up group (febrile convulsion and urinary tract infection); all were resolved, and none were considered by the investigators to be vaccine related. PHiD-CV induced robust immune responses regardless of age at booster. Booster vaccination following 2 catch-up doses induced robust immune responses indicative of effective priming and immunological memory. (These studies have been registered atwww.clinicaltrials.govunder registration no. NCT01030822 and NCT00814710; a protocol summary is available atwww.gsk-clinicalstudyregister.com[study ID 112909]).

scholarly journals Vaccination strategy and anti - SARS-CoV-2 S titers in healthcare workers of the INT – IRCCS “Fondazione Pascale” Cancer Center (Naples, Italy)

2021 ◽  
Vol 16 (1) ◽  
Author(s):  
Ernesta Cavalcanti ◽  
Maria Antonietta Isgrò ◽  
Domenica Rea ◽  
Lucia Di Capua ◽  
Giusy Trillò ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Healthcare Workers ◽  
Geometric Mean ◽  
Vaccination Strategy ◽  
Antibody Responses ◽  
Cancer Center ◽  
Serum Samples ◽  
Humoral Immune ◽  
History Of

Abstract Background Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection and the resulting disease, coronavirus disease 2019 (COVID-19), have spread to millions of people globally, requiring the development of billions of different vaccine doses. The SARS-CoV-2 spike mRNA vaccine (named BNT162b2/Pfizer), authorized by the FDA, has shown high efficacy in preventing SARS-CoV-2 infection after administration of two doses in individuals 16 years of age and older. In the present study, we retrospectively evaluated the differences in the SARS-CoV-2 humoral immune response after vaccine administration in the two different cohorts of workers at the INT - IRCCS “Fondazione Pascale” Cancer Center (Naples, Italy): previously infected to SARS-CoV-2 subjects and not infected to SARS-CoV-2 subjects. Methods We determined specific anti-RBD (receptor-binding domain) titers against trimeric spike glycoprotein (S) of SARS-CoV-2 by Roche Elecsys Anti-SARS-CoV-2 S immunoassay in serum samples of 35 healthcare workers with a previous documented history of SARS-CoV-2 infection and 158 healthcare workers without, after 1 and 2 doses of vaccine, respectively. Moreover, geometric mean titers and relative fold changes (FC) were calculated. Results Both previously infected and not infected to SARS-CoV-2 subjects developed significant immune responses to SARS-CoV-2 after the administration of 1 and 2 doses of vaccine, respectively. Anti-S antibody responses to the first dose of vaccine were significantly higher in previously SARS-CoV-2-infected subjects in comparison to titers of not infected subjects after the first as well as the second dose of vaccine. Fold changes for subjects previously infected to SARS-CoV-2 was very modest, given the high basal antibody titer, as well as the upper limit of 2500.0 BAU/mL imposed by the Roche methods. Conversely, for naïve subjects, mean fold change following the first dose was low ($$ \overline{x} $$ x ¯ =1.6), reaching 3.8 FC in 72 subjects (45.6%) following the second dose. Conclusions The results showed that, as early as the first dose, SARS-CoV-2-infected individuals developed a remarkable and statistically significant immune response in comparison to those who did not contract the virus previously, suggesting the possibility of administering only one dose in previously SARS-CoV-2-infected subjects. FC for previously infected subjects should not be taken into account for the generally high pre-vaccination values. Conversely, FC for not infected subjects, after the second dose, were = 3.8 in > 45.0% of vaccinees, and ≤ 3.1 in 19.0%, the latter showing a potential susceptibility to further SARS-CoV-2 infection.

scholarly journals High-dose oral and intravenous rifampicin for the treatment of tuberculous meningitis in predominantly HIV-positive Ugandan adults: a phase II open-label randomised controlled trial

2021 ◽  
Author(s):  
Fiona V Cresswell ◽  
David B Meya ◽  
Enock Kagimu ◽  
Daniel Grint ◽  
Lindsey te Brake ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Geometric Mean ◽  
Standard Of Care ◽  
Hiv Positive ◽  
High Dose ◽  
Open Label ◽  
Dose Oral ◽  
Csf Levels

Abstract Background High-dose rifampicin may improve outcomes of tuberculous meningitis (TBM). Little safety or pharmacokinetic (PK) data exist on high-dose rifampicin in HIV co-infection, and no cerebrospinal fluid (CSF) PK data exist from Africa. We hypothesized that high-dose rifampicin would increase serum and CSF concentrations without excess toxicity. Methods In this phase II open-label trial, Ugandan adults with suspected TBM were randomised to standard-of-care control (PO-10, rifampicin 10mg/kg/day), intravenous rifampicin (IV-20, 20mg/kg/day), or high-dose oral rifampicin (PO-35, 35mg/kg/day). We performed PK sampling on day 2 and 14. The primary outcomes were total exposure (AUC0-24), maximum concentration (Cmax), CSF concentration and grade 3-5 adverse events. Results We enrolled 61 adults, 92% were HIV-positive, median CD4 count was 50cells/µL (IQR 46–56). On day 2, geometric mean plasma AUC0-24hr was 42.9h.mg/L with standard-of-care 10mg/kg dosing, 249h.mg/L for IV-20 and 327h.mg/L for PO-35 (P<0.001). In CSF, standard-of-care achieved undetectable rifampicin concentration in 56% of participants and geometric mean AUC0-24hr 0.27mg/L, compared with 1.74mg/L (95%CI 1.2–2.5) for IV-20 and 2.17mg/L (1.6–2.9) for PO-35 regimens (p<0.001). Achieving CSF concentrations above rifampicin minimal inhibitory concentration (MIC) occurred in 11% (2/18) of standard-of-care, 93% (14/15) of IV-20, and 95% (18/19) of PO-35 participants. Higher serum and CSF levels were sustained at day 14. Adverse events did not differ by dose (p=0.34) Conclusion Current international guidelines result in sub-therapeutic CSF rifampicin concentration for 89% of Ugandan TBM patients. High-dose intravenous and oral rifampicin were safe, and respectively resulted in exposures ~6- and ~8-fold higher than standard-of-care, and CSF levels above the MIC

scholarly journals A phase IV, multi-centre, randomized clinical trial comparing two pertussis-containing vaccines in pregnant women in England and vaccine responses in their infants

BMC Medicine ◽  
2021 ◽  
Vol 19 (1) ◽  
Author(s):  
Christine Elizabeth Jones ◽  
Anna Calvert ◽  
Jo Southern ◽  
Mary Matheson ◽  
Nick Andrews ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Randomized Clinical Trial ◽  
Pertussis Toxin ◽  
Geometric Mean ◽  
Control Group ◽  
Primary Immunization ◽  
Link Type ◽  
In Pregnancy ◽  
Pertussis Antigens ◽  
Phase Iv

Abstract Background Pertussis vaccines containing three or five pertussis antigens are recommended in pregnancy in many countries, but no studies have compared the effect on infants’ antigen-specific immunoglobulin G (IgG) concentrations. The aim of this study was to compare anti-pertussis IgG responses following primary immunization in infants of mothers vaccinated with TdaP5-IPV (low dose diphtheria toxoid, tetanus toxoid, acellular pertussis [five antigens] and inactivated polio) or TdaP3-IPV in pregnancy (three pertussis antigens). Methods This multi-centre phase IV randomized clinical trial was conducted in a tertiary referral centre and primary care sites in England. Women were randomized to receive TdaP5-IPV (n = 77) or TdaP3-IPV (n = 77) at 28–32 gestational weeks. A non-randomized control group of 44 women who had not received a pertussis-containing vaccine in pregnancy and their 47 infants were enrolled post-partum. Results Following infant primary immunization, there was no difference in the geometric mean concentrations (GMCs) of anti-pertussis toxin, filamentous haemagglutinin or pertactin IgG between infants born to women vaccinated with TdaP5-IPV (n = 67) or TdaP3-IPV (n = 63). However, the GMC of anti-pertussis toxin IgG was lower in infants born to TdaP5-IPV- and TdaP3-IPV-vaccinated mothers compared to infants born to unvaccinated mothers (n = 45) (geometric mean ratio 0.71 [0.56–0.90] and 0.78 [0.61–0.98], respectively); by 13 months of age, this difference was no longer observed. Conclusion Blunting of anti-pertussis toxin IgG response following primary immunization occurs in infants born to women vaccinated with TdaP5-IPV and TdaP3-IPV, with no difference between maternal vaccines. The blunting effect had resolved by 13 months of age. These results may be helpful for countries considering which pertussis-containing vaccine to recommend for use in pregnancy. Trial registration ClinicalTrials.gov, NCT02145624, registered 23 May 2014

scholarly journals Vinorelbine alternating oral and intravenous plus carboplatinin advanced non-small-cell lung cancer: results of a multicentre phase II study

2004 ◽  
Vol 15 (6) ◽  
pp. 921-927 ◽  
Author(s):  
M.E.R. O’Brien ◽  
A. Szczesna ◽  
H. Karnicka ◽  
P. Zatloukal ◽  
T. Eisen ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Phase Ii ◽  
Cell Lung Cancer ◽  
Phase Ii Study ◽  
Small Cell ◽  
Small Cell Lung ◽  
Multicentre Phase

scholarly journals Safety and Immunogenicity of a Novel Staphylococcus aureus Vaccine: Results from the First Study of the Vaccine Dose Range in Humans

2010 ◽  
Vol 17 (12) ◽  
pp. 1868-1874 ◽  
Author(s):  
Clayton Harro ◽  
Robert Betts ◽  
Walter Orenstein ◽  
Eun-Jeong Kwak ◽  
Howard E. Greenberg ◽  
...  
Keyword(s):  
Staphylococcus Aureus ◽  
Immune Response ◽  
Adverse Events ◽  
Immune Responses ◽  
Geometric Mean ◽  
Dose Range ◽  
Vaccine Dose ◽  
Double Blind Study ◽  
Mean Concentration ◽  
Positive Immune Response

ABSTRACT Merck V710 is a novel vaccine containing the conserved Staphylococcus aureus iron surface determinant B shown to be protective in animal models. A phase I, multicenter, double-blind study of the dose range was conducted to assess the immunogenicity and safety of an adjuvanted liquid formulation of V710. A total of 124 adults (18 to 55 years of age) were randomized 1:1:1:1 to receive one 0.5-ml intramuscular injection of V710 (5 μg, 30 μg, or 90 μg) or saline placebo. A positive immune response was defined as at least a 2-fold increase in IsdB-specific IgG levels from baseline levels. Local and systemic adverse events were assessed for 5 and 14 days, respectively, following vaccination. Positive immune responses were detected in 12 (67%) of the 18 subjects in the groups receiving 30 and 90 μg V710 tested at day 10. At day 14, a significantly greater proportion of subjects manifested a positive immune response with higher geometric mean concentrations in the V710 30-μg (86%; geometric mean concentration of 116 μg/ml) and 90-μg (87%; geometric mean concentration of 131 μg/ml) dose groups than in the V710 5-μg (29%; geometric mean concentration of 51 μg/ml) or placebo (4%; geometric mean concentration of 23 μg/ml) groups. Immune responses were durable through day 84. Subjects <40 and ≥40 years of age had comparable immune responses. The most common adverse events were injection-site pain, nausea, fatigue, and headache, usually of mild intensity. No immediate reactions or serious adverse events were reported. In this first study of V710 in humans, a single 30-μg or 90-μg dose was more immunogenic than the 5-μg dose or placebo. Immune responses were evident by 10 to 14 days after vaccination in most responders.

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