Friday, November 28, 2014

Confirmed: GSK Ebola Vaccine Candidate Seemed Less Efficacious At Low-Doses -- Than Merck's

These important caveats apply: These are very small Phase I trials, looking primarily at safety. We can infer almost nothing about a trial involving only 20 people -- as to broad scale efficacy -- and dosing. And we will begin to see efficacy trials (Phase III) in January 2015.

Even so, it would seem that NewLink/Merck's livestock-virus derived container (developed by researchers at the Canadian Institutes of Health Research labs, initially) showed more robust immune responses -- at lower doses -- than the GSK simian-derived container (originally developed at the US NIH/NIAID). So, it is a rumor no longer. However, it may be reversed by wider scale efficacy testing, come January 2015. Or it may be confirmed. All in, I like Merck's chances here. From, this morning, then do go read it all (but you may safely ignore some of the hype around GSK -- that's some home-town cheerleading, going on):

. . . .Dr. Daniel Bausch of Tulane School of Public Health and Tropical Medicine in New Orleans, however, expressed reservations about GSK’s vaccine, stating that the better immune response resulted from the administration of a larger dose, which was also associated with minor side effects of fever and leucopenia. Also, more importantly, the sample size of 20 was too small to establish the efficacy of the vaccine. . . .

Phase I trial results are expected to come out next month, and if the results are positive, the two companies will move on to later-stage trials. Phase III trials to test the efficacy of the vaccine are expected to begin in the first quarter of next year. . . .

Time to go workout (shed the tryptophan's lethargy!), and then get some dim sum -- in a great local historic district.

1 comment:

Birdman said...

Once again, you have your finger on the pulse of the ebola vaccine development achievements.

Unfortunately we have not yet seen the immunogenicity results from the VSV-ZEBOV human studies; in particular the GP ELISA data. I fully expect higher titers from the VSV vaccine considering that this vector appears to be "hotter" than the Ad or MVA vectors. I also expect slightly more complaints of minor fever, chills, myalgia, etc with the VSV vector; but do not expect these will be severe. I am of the opinion that the post vaccination signs and symptoms are often a good correlate of immunogenicity.

It is clear from the Ledgerwood 2014 NEJM paper that the Low Dose ChAd3-EBOL (2e10) was clearly inferior, and unacceptable, in anti-GP IgG production (331) and CD8 response and High Dose (2e11) was better (2037) but still unacceptable and only likely to confer 85-90% protection, at best. Sullivan showed 100% protection in NHP with GP ELISA titers >3700. I do accept that the GP ELISA results are only a correlate of protection but believe it is the best we have at this time.

Sullivan, N.J., Martin, J.E., Graham, B.S., Nabel, G.J., 2009. Correlates of protective immunity for Ebola vaccines: implications for regulatory approval by the animal rule. Nat. Rev. Microbiol. 7, 393–400. doi:10.1038/nrmicro2129

It is also important to look at the Ledgerwood anti-vector immunity which was completely played down in the paper even though very clear inverse correlations were seen (author claims "not achieving statistical significance" in most cases) for anti-ChAd3 preexisting immunity vs the anti-GP and CD8 responses generated following vaccination.

Pre-existing anti ChAd3 immunity is a serious issue as it is with most other Ad vectors. If Ledgerwood et al. had removed from the analysis the subjects that did not have preexisting anti-Ad3 antibodies I believe they would have had clearer and significant inverse correlations to anti-ebola responses.

It seems obvious that GSK also has realized these weaknesses and this is why they have recruited Bavarian Nordic into the picture to use their MVA vaccine as a heterologous boost...although it appears not to have been included in the USG indemnification declaration for 3 ebola vaccines that was released yesterday:

I assume that GSK and BN will petition Secretary Burwell for an amendment which includes heterologous boosting of ChAd3-EBOL with MVA-mBN226B.

Any prime boost regimen may be viable, but, NOT during an outbreak where logistics are a nightmare and trying to find subjects for a second immunization is nearly impossible.