Journal Article > ResearchFull Text
Lancet Infect Dis. 2005 December 1; Volume 5 (Issue 12); DOI:10.1016/S1473-3099(05)70296-6
Olliaro PL, Guerin PJ, Gerstl S, Haaskjold AA, Rottingen JA, et al.
Lancet Infect Dis. 2005 December 1; Volume 5 (Issue 12); DOI:10.1016/S1473-3099(05)70296-6
The state of Bihar in India carries the largest share of the world's burden of antimony-resistant visceral leishmaniasis. We analysed clinical studies done in Bihar with different treatments between 1980 and 2004. Overall, 53 studies were included (all but one published), of which 15 were comparative (randomised, quasi-randomised, or non-randomised), 23 dose-finding, and 15 non-comparative. Data from comparative studies were pooled when appropriate for meta-analysis. Overall, these studies enrolled 7263 patients in 123 treatment arms. Adequacy of methods used to do the studies and report on them varied. Unresponsiveness to antimony has developed steadily in the past to such an extent that antimony must now be replaced, despite attempts to stop its progression by increasing dose and duration of therapy. The classic second-line treatments are unsuited: pentamidine is toxic and its efficacy has also declined, and amphotericin B deoxycholate is effective but requires hospitalisation for long periods and toxicity is common. Liposomal amphotericin B is very effective and safe but currently unaffordable because of its high price. Miltefosine-the first oral drug for visceral leishmaniasis-is now registered and marketed in India and is effective, but should be used under supervision to prevent misuse. Paromomycin (or aminosidine) is effective and safe, and although not yet available, a regulatory submission is due soon. To preserve the limited armamentarium of drugs to treat visceral leishmaniasis, drugs should not be deployed unprotected; combinations can make drugs last longer, improve treatment, and reduce costs to households and health systems. India, Bangladesh, and Nepal agreed recently to undertake measures towards the elimination of visceral leishmaniasis. The lessons learnt in Bihar could help inform policy decisions both regionally and elsewhere.
Journal Article > CommentaryFull Text
Nature. 2022 February 9; Volume 602 (Issue 7896); 207-210.; DOI:10.1038/d41586-022-00324-y
Swaminathan S, Pecoul B, Abdullah H, Christou C, Gray G, et al.
Nature. 2022 February 9; Volume 602 (Issue 7896); 207-210.; DOI:10.1038/d41586-022-00324-y
Journal Article > ResearchFull Text
Vaccine. 2020 June 1; Volume 38 (Issue 31); DOI:10.1016/j.vaccine.2020.04.066
Boum Y II, Juan-Giner A, Hitchings MD, Soumah A, Strecker T, et al.
Vaccine. 2020 June 1; Volume 38 (Issue 31); DOI:10.1016/j.vaccine.2020.04.066
Background
As part of a Phase III trial with the Ebola vaccine rVSVΔG-ZEBOV-GP in Guinea, we invited frontline workers (FLWs) to participate in a sub-study to provide additional information on the immunogenicity of the vaccine.
Methods
We conducted an open‐label, non‐randomized, single-arm immunogenicity evaluation of one dose of rVSVΔG-ZEBOV-GP among healthy FLWs in Guinea. FLWs who refused vaccination were offered to participate as a control group. We followed participants for 84 days with a subset followed-up for 180 days. The primary endpoint was immune response, as measured by ELISA for ZEBOV-glycoprotein–specific antibodies (ELISA-GP) at 28 days. We also conducted neutralization, whole virion ELISA and enzyme-linked immunospot (ELISPOT) assay for cellular response.
Results
A total of 1172 participants received one dose of vaccine and were followed-up for 84 days, among them 114 participants were followed-up for 180 days. Additionally, 99 participants were included in the control group and followed up for 180 days. Overall, 86.4% (95% CI 84.1–88.4) of vaccinated participants seroresponded at 28 days post-vaccination (ELISA- GP) with 65% of these seroresponding at 14 days post-vaccination. Among those who seroresponded at 28 days, 90.7% (95% CI 82.0–95.4) were still seropositive at 180 days. The proportion of seropositivity in the unvaccinated group was 0.0% (95% CI 0.0–3.8) at 28 days and 5.4% (95% CI 2.1–13.1) at 180 days post-vaccination. We found weak correlation between ELISA-GP and neutralization at baseline but significant pairwise correlation at 28 days post-vaccination. Among samples analysed for cellular response, only 1 (2.2%) exhibited responses towards the Zaire Ebola glycoprotein (Ebola GP ≥ 10) at baseline, 10 (13.5%) at day 28 post-vaccination and 27 (48.2%) at Day 180.
Conclusions
We found one dose of rVSVΔG-ZEBOV-GP to be highly immunogenic at 28- and 180-days post vaccination among frontline workers in Guinea. We also found a cellular response that increased with time.
As part of a Phase III trial with the Ebola vaccine rVSVΔG-ZEBOV-GP in Guinea, we invited frontline workers (FLWs) to participate in a sub-study to provide additional information on the immunogenicity of the vaccine.
Methods
We conducted an open‐label, non‐randomized, single-arm immunogenicity evaluation of one dose of rVSVΔG-ZEBOV-GP among healthy FLWs in Guinea. FLWs who refused vaccination were offered to participate as a control group. We followed participants for 84 days with a subset followed-up for 180 days. The primary endpoint was immune response, as measured by ELISA for ZEBOV-glycoprotein–specific antibodies (ELISA-GP) at 28 days. We also conducted neutralization, whole virion ELISA and enzyme-linked immunospot (ELISPOT) assay for cellular response.
Results
A total of 1172 participants received one dose of vaccine and were followed-up for 84 days, among them 114 participants were followed-up for 180 days. Additionally, 99 participants were included in the control group and followed up for 180 days. Overall, 86.4% (95% CI 84.1–88.4) of vaccinated participants seroresponded at 28 days post-vaccination (ELISA- GP) with 65% of these seroresponding at 14 days post-vaccination. Among those who seroresponded at 28 days, 90.7% (95% CI 82.0–95.4) were still seropositive at 180 days. The proportion of seropositivity in the unvaccinated group was 0.0% (95% CI 0.0–3.8) at 28 days and 5.4% (95% CI 2.1–13.1) at 180 days post-vaccination. We found weak correlation between ELISA-GP and neutralization at baseline but significant pairwise correlation at 28 days post-vaccination. Among samples analysed for cellular response, only 1 (2.2%) exhibited responses towards the Zaire Ebola glycoprotein (Ebola GP ≥ 10) at baseline, 10 (13.5%) at day 28 post-vaccination and 27 (48.2%) at Day 180.
Conclusions
We found one dose of rVSVΔG-ZEBOV-GP to be highly immunogenic at 28- and 180-days post vaccination among frontline workers in Guinea. We also found a cellular response that increased with time.
Journal Article > CommentaryFull Text
PLOS Med. 2015 May 11; Volume 12 (Issue 5); DOI:10.1371/journal.pmed.1001831
Balsegaram M, Brechot C, Farrar J, Heymann D, Ganguly N, et al.
PLOS Med. 2015 May 11; Volume 12 (Issue 5); DOI:10.1371/journal.pmed.1001831
Journal Article > CommentaryFull Text
Lancet. 2015 November 18; Volume 387 (Issue 10014); DOI:10.1016/S0140-6736(15)00547-4
Mendelson M, Rottingen JA, Gopinathan U, Hamer DH, Wertheim H, et al.
Lancet. 2015 November 18; Volume 387 (Issue 10014); DOI:10.1016/S0140-6736(15)00547-4
Journal Article > ResearchFull Text
Lancet. 2017 February 1; Volume 389 (Issue 10068); 505-518.; DOI:10.1016/S0140-6736(16)32621-6
Henao-Restrepo AM, Camacho A, Longini I, Watson CH, Edmunds WJ, et al.
Lancet. 2017 February 1; Volume 389 (Issue 10068); 505-518.; DOI:10.1016/S0140-6736(16)32621-6
BACKGROUND
rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa.
METHODS
We did an open-label, cluster-randomised ring vaccination trial (Ebola ça Suffit!) in the communities of Conakry and eight surrounding prefectures in the Basse-Guinée region of Guinea, and in Tomkolili and Bombali in Sierra Leone. We assessed the efficacy of a single intramuscular dose of rVSV-ZEBOV (2×107 plaque-forming units administered in the deltoid muscle) in the prevention of laboratory confirmed Ebola virus disease. After confirmation of a case of Ebola virus disease, we definitively enumerated on a list a ring (cluster) of all their contacts and contacts of contacts including named contacts and contacts of contacts who were absent at the time of the trial team visit. The list was archived, then we randomly assigned clusters (1:1) to either immediate vaccination or delayed vaccination (21 days later) of all eligible individuals (eg, those aged ≥18 years and not pregnant, breastfeeding, or severely ill). An independent statistician generated the assignment sequence using block randomisation with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 individuals vs >20 individuals). Ebola response teams and laboratory workers were unaware of assignments. After a recommendation by an independent data and safety monitoring board, randomisation was stopped and immediate vaccination was also offered to children aged 6–17 years and all identified rings. The prespecified primary outcome was a laboratory confirmed case of Ebola virus disease with onset 10 days or more from randomisation. The primary analysis compared the incidence of Ebola virus disease in eligible and vaccinated individuals assigned to immediate vaccination versus eligible contacts and contacts of contacts assigned to delayed vaccination. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193.
FINDINGS
In the randomised part of the trial we identified 4539 contacts and contacts of contacts in 51 clusters randomly assigned to immediate vaccination (of whom 3232 were eligible, 2151 consented, and 2119 were immediately vaccinated) and 4557 contacts and contacts of contacts in 47 clusters randomly assigned to delayed vaccination (of whom 3096 were eligible, 2539 consented, and 2041 were vaccinated 21 days after randomisation). No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9–100·0, p=0·0045), and the calculated intraclass correlation coefficient was 0·035. Additionally, we defined 19 non-randomised clusters in which we enumerated 2745 contacts and contacts of contacts, 2006 of whom were eligible and 1677 were immediately vaccinated, including 194 children. The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomisation among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters. The estimated vaccine efficacy here was 100% (95% CI 79·3–100·0, p=0·0033). 52% of contacts and contacts of contacts assigned to immediate vaccination and in non-randomised clusters received the vaccine immediately; vaccination protected both vaccinated and unvaccinated people in those clusters. 5837 individuals in total received the vaccine (5643 adults and 194 children), and all vaccinees were followed up for 84 days. 3149 (53·9%) of 5837 individuals reported at least one adverse event in the 14 days after vaccination; these were typically mild (87·5% of all 7211 adverse events). Headache (1832 [25·4%]), fatigue (1361 [18·9%]), and muscle pain (942 [13·1%]) were the most commonly reported adverse events in this period across all age groups. 80 serious adverse events were identified, of which two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness); all three recovered without sequelae.
INTERPRETATION
The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters.
rVSV-ZEBOV is a recombinant, replication competent vesicular stomatitis virus-based candidate vaccine expressing a surface glycoprotein of Zaire Ebolavirus. We tested the effect of rVSV-ZEBOV in preventing Ebola virus disease in contacts and contacts of contacts of recently confirmed cases in Guinea, west Africa.
METHODS
We did an open-label, cluster-randomised ring vaccination trial (Ebola ça Suffit!) in the communities of Conakry and eight surrounding prefectures in the Basse-Guinée region of Guinea, and in Tomkolili and Bombali in Sierra Leone. We assessed the efficacy of a single intramuscular dose of rVSV-ZEBOV (2×107 plaque-forming units administered in the deltoid muscle) in the prevention of laboratory confirmed Ebola virus disease. After confirmation of a case of Ebola virus disease, we definitively enumerated on a list a ring (cluster) of all their contacts and contacts of contacts including named contacts and contacts of contacts who were absent at the time of the trial team visit. The list was archived, then we randomly assigned clusters (1:1) to either immediate vaccination or delayed vaccination (21 days later) of all eligible individuals (eg, those aged ≥18 years and not pregnant, breastfeeding, or severely ill). An independent statistician generated the assignment sequence using block randomisation with randomly varying blocks, stratified by location (urban vs rural) and size of rings (≤20 individuals vs >20 individuals). Ebola response teams and laboratory workers were unaware of assignments. After a recommendation by an independent data and safety monitoring board, randomisation was stopped and immediate vaccination was also offered to children aged 6–17 years and all identified rings. The prespecified primary outcome was a laboratory confirmed case of Ebola virus disease with onset 10 days or more from randomisation. The primary analysis compared the incidence of Ebola virus disease in eligible and vaccinated individuals assigned to immediate vaccination versus eligible contacts and contacts of contacts assigned to delayed vaccination. This trial is registered with the Pan African Clinical Trials Registry, number PACTR201503001057193.
FINDINGS
In the randomised part of the trial we identified 4539 contacts and contacts of contacts in 51 clusters randomly assigned to immediate vaccination (of whom 3232 were eligible, 2151 consented, and 2119 were immediately vaccinated) and 4557 contacts and contacts of contacts in 47 clusters randomly assigned to delayed vaccination (of whom 3096 were eligible, 2539 consented, and 2041 were vaccinated 21 days after randomisation). No cases of Ebola virus disease occurred 10 days or more after randomisation among randomly assigned contacts and contacts of contacts vaccinated in immediate clusters versus 16 cases (7 clusters affected) among all eligible individuals in delayed clusters. Vaccine efficacy was 100% (95% CI 68·9–100·0, p=0·0045), and the calculated intraclass correlation coefficient was 0·035. Additionally, we defined 19 non-randomised clusters in which we enumerated 2745 contacts and contacts of contacts, 2006 of whom were eligible and 1677 were immediately vaccinated, including 194 children. The evidence from all 117 clusters showed that no cases of Ebola virus disease occurred 10 days or more after randomisation among all immediately vaccinated contacts and contacts of contacts versus 23 cases (11 clusters affected) among all eligible contacts and contacts of contacts in delayed plus all eligible contacts and contacts of contacts never vaccinated in immediate clusters. The estimated vaccine efficacy here was 100% (95% CI 79·3–100·0, p=0·0033). 52% of contacts and contacts of contacts assigned to immediate vaccination and in non-randomised clusters received the vaccine immediately; vaccination protected both vaccinated and unvaccinated people in those clusters. 5837 individuals in total received the vaccine (5643 adults and 194 children), and all vaccinees were followed up for 84 days. 3149 (53·9%) of 5837 individuals reported at least one adverse event in the 14 days after vaccination; these were typically mild (87·5% of all 7211 adverse events). Headache (1832 [25·4%]), fatigue (1361 [18·9%]), and muscle pain (942 [13·1%]) were the most commonly reported adverse events in this period across all age groups. 80 serious adverse events were identified, of which two were judged to be related to vaccination (one febrile reaction and one anaphylaxis) and one possibly related (influenza-like illness); all three recovered without sequelae.
INTERPRETATION
The results add weight to the interim assessment that rVSV-ZEBOV offers substantial protection against Ebola virus disease, with no cases among vaccinated individuals from day 10 after vaccination in both randomised and non-randomised clusters.
Journal Article > CommentaryFull Text
Lancet. 2017 November 11; Volume 390 (Issue 10108); 2211-2214.; DOI:10.1016/S0140-6736(17)31224-2
Perkins MD, Dye C, Balasegaram M, Brechot C, Mombouli JV, et al.
Lancet. 2017 November 11; Volume 390 (Issue 10108); 2211-2214.; DOI:10.1016/S0140-6736(17)31224-2
Diagnostics are crucial in mitigating the effect of disease outbreaks. Because diagnostic development and validation are time consuming, they should be carried out in anticipation of epidemics rather than in response to them. The diagnostic response to the 2014-15 Ebola epidemic, although ultimately effective, was slow and expensive. If a focused mechanism had existed with the technical and financial resources to drive its development ahead of the outbreak, point-of-care Ebola tests supporting a less costly and more mobile response could have been available early on in the diagnosis process. A new partnering model could drive rapid development of tests and surveillance strategies for novel pathogens that emerge in future outbreaks. We look at lessons learned from the Ebola outbreak and propose specific solutions to improve the speed of new assay development and ensure their effective deployment.
Journal Article > CommentaryFull Text
Bull World Health Organ. 2015 December 1; Volume 93 (Issue 12); 867-876.; DOI:10.2471/BLT.15.153171
Hoffman SJ, Caleo GNC, Daulaire N, Elbe S, Matsoso P, et al.
Bull World Health Organ. 2015 December 1; Volume 93 (Issue 12); 867-876.; DOI:10.2471/BLT.15.153171
Global governance and market failures mean that it is not possible to ensure access to antimicrobial medicines of sustainable effectiveness. Many people work to overcome these failures, but their institutions and initiatives are insufficiently coordinated, led and financed. Options for promoting global collective action on antimicrobial access and effectiveness include building institutions, crafting incentives and mobilizing interests. No single option is sufficient to tackle all the challenges associated with antimicrobial resistance. Promising institutional options include monitored milestones and an inter-agency task force. A global pooled fund could be used to craft incentives and a special representative nominated as an interest mobilizer. There are three policy components to the problem of antimicrobials--ensuring access, conservation and innovation. To address all three components, the right mix of options needs to be matched with an effective forum and may need to be supported by an international legal framework.