21 Days Later

The vaccine is here! The one we dared to dream of! 100% success!

Well… not exactly.

rVSV-ZEBOV is a promising Ebola virus vaccine candidate.

A trial of this vaccine candidate was being carried out in Basse-Guinée, and an interim analysis of this work was published on the 31st July in The Lancet. The data has generated much excitement and enthusiasm, and the coverage has left me with a feeling that perhaps not everyone who should have read the paper, did read the paper…

Ebola vaccine trial proves 100% successful in Guinea

Picture 3

The Ebola vaccine we dared to dream of is here

It looks like a done deal from these stories, but there has been a much more measured reaction to the data by the authors of the paper, those closely involved in the trial, and other media. Caveats abound, as they should with such early and limited data.

The WHO Assistant Director, Marie-Paul Kieny spoke at a press conference: “The data so far – and it’s as I said, an intermediary analysis and the trial is going on – but the data so far, shows that none of the 2,014 persons vaccinated developed Ebola virus disease after 10 days after vaccination.”

The paper itself states: ‘The results of this interim analysis indicate that rVSV-ZEBOV might be highly efficacious and safe in preventing Ebola virus disease, and is most likely effective at the population level when delivered during an Ebola virus disease outbreak via a ring vaccination strategy.’

I’m thrilled that we do have positive results. I work at St. George’s, where I worked on, and where work continues on, a Phase I clinical trial of this vaccine. I want my vaccine to work. I’m not a sociopath; I want any vaccine to work. But I am a skeptic. I want the vaccine to actually work, not just to look like it works, and I want to understand how well it works, and how it can be used effectively and safely.

This is the first published data from a phase III clinical trial of an Ebola virus vaccine candidate. Clinical trials perform the purpose of reducing our uncertainty about an intervention. The more high-quality trials we have, the less uncertain we can be about how well an intervention works. This is one trial. It has reduced our uncertainty. These are interim results – some of the results, from some of the trial – they are not the results of the full trial. There are more data, and more types of data in this trial, and more trials that we need to look at before we can be less uncertain about how well the vaccine works, and how safe the vaccine is.

If it is to be THE Ebola virus vaccine, we also need to work out who should be vaccinated, who shouldn’t, and how this new vaccination program could be managed. Although the results are very hopeful, it is a bit more complicated than 100% success achieved.

Other good news will make vaccine research even more difficult – we will (hopefully) have fewer and fewer patients on whom to test the vaccine. The number of new cases of Ebola virus disease in the week to 26th July was seven – down from the 20-30 cases per week it had been for the two previous months.

The trial

It is a great trial design. This was an open-label, cluster-randomised ring vaccination trial. For each new confirmed case, all the people who had been in close contact with that person, and all the people who had been in contact with them were defined as a cluster. Each cluster was randomly allocated to receive the vaccine immediately or after 21 days. The number of cases of Ebola virus disease in the two groups was then compared.

The results

The figure of 100% efficacy was arrived at by comparing the number of people in the group who were vaccinated immediately and got Ebola virus disease after 10 or more days, with the number of people in the group who were vaccinated after 21 days and got Ebola virus disease after 10 or more days. Data for 48 clusters in which 2014 patients were vaccinated immediately, and 42 clusters in which 1498 patients were vaccinated 21 days later were used in this analysis. There were no cases of Ebola virus disease after 10 days in the immediate vaccination group, whereas in the after 21 days vaccination group there were 16 cases of Ebola virus disease, so vaccine efficacy of 100% (p=0·0036).

But

What about the people who got Ebola virus disease within 10 days after vaccination? 9 of the 2014 immediately vaccinated patients did get Ebola virus disease within 10 days, compared to 16 of the 1498 patients who were not immediately vaccinated. So this study found that the vaccine is not (and of course it was not expected to be) 100% effective in preventing Ebola virus disease from days 0-21.

And that isn’t the only data, or the only data we need.

The study did look at adverse events, and mentions 43 serious adverse events – but analysis is not complete and details were not published in this paper. We need to know more. Side effects of the vaccine might be severe enough and common enough to outweigh the possible benefits of the vaccine, especially in areas where people are at an extremely low risk of infection. Long-term sequelae have not yet been studied.

What about other people? This study did include not children, or some women – we need to look at outcomes in these groups.

What about other doses? Might a smaller dose be equally effective, but have fewer side effects? Phase I preliminary results (full results not yet published) showed a number of adverse events in (unexposed) patients receiving lower doses of the vaccine than was used here, but were they less common and/or less severe?

An electron micrograph of an Ebola viral particle By CDC/ Dr. Frederick A. Murphy

An electron micrograph of an Ebola viral particle
By CDC/ Dr. Frederick A. Murphy

Whom will this vaccine benefit? How many people will have to be vaccinated to prevent one infection? How many to prevent an outbreak? What method of vaccination? How long would any protection last? With our limited pot of money for dealing with health issues, how much should be spent on vaccination against Ebola virus disease, when other preventable diseases kill so many more people?

Due to the positive results of this trial, it has been agreed that it is no longer ethical to have a group of people who are vaccinated after 21 days; instead everyone will be vaccinated immediately. This leaves us without a control group, which makes it difficult to determine how many infections have been prevented. Control groups are also required to study possible side effects. We’re without many patients to study, as the outbreak hopefully comes to an end.

These data is a huge achievement, many thousands of people have worked together to get to this point, and it is very encouraging. BUT, we need more data to further reduce our uncertainty about the efficacy and safety of the vaccine. We don’t know what the outcomes of this trial or other ongoing trials of this vaccine will be. We can now be more hopeful that they will be positive.

We don’t have an Ebola virus vaccine yet, but we do have a promising Ebola virus vaccine candidate.

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