Wednesday, September 10, 2014

Zmapp success


       It has been a longtime, since Ebola outbreak has been a concern, for it has been the largest of date in terms of cases, fatalities and geographical spread. I have come across internet and media content designating the current situation as "race wiping", which makes no sense. I have previously talked about the known facts (Link). In this post, I wish to visit the topic again with focus on some new research and findings. As of on 31 August 2014 (WHO report), 3685 cases and 1841 deaths have been reported in the current outbreak of Ebola virus disease by the Ministries of Health of Guinea, Liberia and Sierra Leone. From the data available, the case fatality ratio appears to be about 50%.

       Of all the interventions possible, the most optimistic choice has been Zmapp cocktail. It is a trivalent monoclonal antibody combination which has not been clinically tested. However, considering the grave situation, the product was cleared for use based on compassionate use. The original study used a combination of c13C6, h-13F6, and c6D8 in the cocktail. In a recent study published in Nature, by testing several combinations the most active component was found to be c13C6. The study further tested further combinations and compared it with classic combinations. In the study, The combination of c13C6, c2G4, c4G7 was found to be the best. The most striking feature in the paper is that the therapeutic was significantly effective 3 days to 5 days post infection in a primate model. Moreover the successful use of Zmapp, in treating 2 American patients testifies to the fact.

Photo 1: Workers and authors who died
in EBOV outbreak. Link
   A high coverage genomic sequencing analysis of Ebola outbreak, has predicted that the Sierra Leone outbreak is shot from the introduction of two genetically distinct viruses from Guinea. The sad part of the story is that the workers at Kenema Government Hospital (KGH), 6 authors of the science paper, died by contracting EBOV. The study sequenced 99 Ebola virus genomes collected from 78 Ebola patients in Sierra Leone during the first 24 days of the outbreak. The sequencing had a 2000X coverage, The paper reports 395 mutations, including 50 fixed nonsynonymous changes with 8 at positions with high levels of conservation. As Stephen Gire, a research scientist in the Sabeti lab at the Broad Institute and Harvard puts it “We’ve uncovered more than 300 genetic clues about what sets this outbreak apart from previous outbreaks. Although we don’t know whether these differences are related to the severity of the current outbreak, by sharing these data with the research community, we hope to speed up our understanding of this epidemic and support global efforts to contain it.”. Source

    There has been an observation made in previous outbreaks that the survivors of Ebola infection are resistant to at least the same strain of the virus and their serum can protect fresh patients. In 1995 EBOV outbreak in Democratic Republic of the Congo, the doctors, out of option had used recover's serum, to try and save other sick patients out of desperation. Though it was met with high debate the method had seemed to help. This probably forms the basis for claiming that blood from a survivor should be treated as a priority (See Nature news here).

    Given the fact that the antibodies are protective, and with a pilot animal trial results now published, and sequences (of at least a few) in hand it appears that Zmapp is going to be the best available answer for countering the outbreak. Of course at the end the large data that would come from use of the monoclonal cocktail will help us know if this is going to be a viable option for future as well.
Qiu X, Wong G, Audet J, Bello A, Fernando L, Alimonti JB, Fausther-Bovendo H, Wei H, Aviles J, Hiatt E, Johnson A, Morton J, Swope K, Bohorov O, Bohorova N, Goodman C, Kim D, Pauly MH, Velasco J, Pettitt J, Olinger GG, Whaley K, Xu B, Strong JE, Zeitlin L, & Kobinger GP (2014). Reversion of advanced Ebola virus disease in nonhuman primates with ZMapp. Nature PMID: 25171469

Stephen K. Gire etal.(2014). Genomic surveillance elucidates Ebola virus origin and transmission during the 2014 outbreak Science DOI: 10.1126/science.1259657