Israel’s Institute for Biological Research is considering restarting its ongoing clinical trial from the beginning on the COVID-19 vaccine that it is developing. The step would be taken in the hope of developing a version that is effective with a single dose, Haaretz has learned. According to sources, it became apparent from the first and second phases of the clinical trials on the two-shot Israeli BriLife vaccine that it would be possible to forgo the second shot if patients were given a higher dose in a single injection.
The move would be expected to delay the date on which the BriLife vaccine is available to the public, if it gets final approval. The Nes Tziona-based institute plans to move its clinical trials on the vaccine from Israel to Argentina, Haaretz has also learned, whether it continues based on a two-shots or a single dose.
That’s due to the high rate at which Israelis have already been vaccinated against the virus, which makes it difficult to test the vaccine’s efficiency. In the next two weeks, a delegation headed by physicians from Jerusalem’s Hadassah University Hospital, which is involved in the clinical trial, is expected to go to Argentina to lay the groundwork for the trial to be relocated there.
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The results of the biological institute’s clinic trials on the vaccine have not yet been made public, and it is therefore not clear the extent of the BriLife vaccine’s efficiency compared to the coronavirus vaccines produced by Pfizer and Moderna, for example. The Israeli trials have explored various doses, sources say, revealing major disparities in the vaccine’s efficiency: The highest dose has been found highly efficient against the virus while the lowest dose was not effective at all.
That has led the researchers to believe that their vaccine is capable of providing a high degree of effectiveness but that the key is in the level of the dose. Staffers at the institute think an additional increase in the size of the dose would produce greater efficacy, to such an extent that the second shot could be dispensed with. Because the third and largest phase of the trial, which is due to involve 30,000 participants, has not yet begun, the researchers are seriously considering repeating the first and second clinical phases, which take less time than the third, using a single, higher dose.
"The clinical trial on the vaccine that the biological institute developed continues as planned. The need has never been established to return to Phase 1. All of the volunteers for Phase 2 have been recruited," the Defense Ministry, which has oversight authority over the institute, said in a statement for this article. "An additional, higher dose is in fact being considered," the ministry said. "Argentina is being considered as one of the countries where Phase 3 would be carried out."
An effective single-dose coronavirus vaccine would have a large number of advantages, relating to production capacity, cost and shipping, as well of course in the ultimate advantage of being able to vaccinate the public with a single dose. That would be particularly true if it turns out that booster shots are necessary to maintain immunity and or if adjustments are needed to the vaccine to account for new variants. A one-dose vaccine also might give Israel an advantage on the global vaccine market, although obviously redoing the first and second stage of the clinical trials could delay when it would come to market.
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Vector vaccine technology
Around the beginning of the second phase, in December, the government began its massive vaccination campaign of the Israeli public, using the Pfizer vaccine. But ironically, that made Israel a place where results of a clinical trial became someone “tainted” because it was being carried out in a less infectious environment. The Israeli BriLife vaccine is based on an animal-derived carrier virus called virus stomatitis vesicular, or VSV. It’s a viral vector vaccine, meaning that a modified version of this other virus is used to induce immunity in humans. VSV rarely infects humans, and when it does, it causes mild, passing symptoms – at most a fever and joint pain. In the case of the BriLife vaccine, the VSV virus serves as the vector carrying parts of the protein on the surface of the coronavirus, the spike, and then seeks to induce an immune response to the coronavirus.
VSV was found highly effective as a vector for the ebola vaccine. In January, however, the Merck pharmaceutical company, which developed the ebola vaccine and had begun developing a VSV-based COVID-19 vaccine, announced that it was halting its Phase 1 clinical trials on the coronavirus vaccine after it was found to prompt a weaker immune response than the competitors’ vaccines. That also raised questions regarding the prospects for Israel’s vaccine.
The Phase 1 clinical trial on BriLife began in November on 80 participants, carried out at the Sheba Medical Center at Tel Hashomer and at Hadassah University Hospital at Ein Karem in Jerusalem. It included a group that received a low dose of the vaccine, another receiving a higher dose and a control group that received a placebo that by design was entirely ineffective.
A month and a half later, in mid-December, the institute received permission to proceed to Phase 2, involving 960 participants and eight hospitals in Israel. As noted, the second phase has encountered difficulties due to the massive vaccination campaign using the Pfizer vaccine that began around that time. A number of the Phase 2 participants also asked to be vaccinated with the Pfizer vaccine and dropped out of the clinical trial.
During the second phase, it became clear that the low dose used in the first phase had no efficacy. It was therefore decided to focus on the higher dose and to add a second shot, a booster shot, to the trial. This two-shot, higher-dose regimen apparently demonstrated a sufficient level of efficacy, according to the sources. But scientists at the Nes Tziona institute believe that the best approach would be to administer a single dose at an even higher level.
A $54 million investment
So far 175 million shekels ($54 million) has been invested in the Israeli effort to develop the vaccine, which even if the clinical trials are not restarted from the beginning, will apparently not meet initial time lines. In November, the institute’s director, Prof. Shmuel Shapira, predicted that distribution of the BriLife vaccine would begin early this summer, which now appears unrealistic. In addition, in March Haaretz reported that Shapira, who is considered the driving force behind the vaccine project, is expected to step down from his job this month.
The trials require the approval of the Israeli Health Ministry’s so-called Helsinki clinical trial committee, which last year established a special panel to oversee coronavirus vaccine trials. In November, Shapira said the institute had encountered stricter regulatory constraints in Israel than companies abroad had faced in developing the coronavirus vaccine.
In March, in response to an inquiry from Haaretz about progress in developing the vaccine, the Defense Ministry, said: “As with any vaccine trial, the institute has considered and selected the correct and appropriate dose and at this dose, there is a good and effective immune response, as anticipated.”
On the understanding that Phase 3 of the clinical trial will be carried out abroad, the options are being explored with a number of countries, the ministry noted, but it is not yet clear where and when the trials will begin, the ministry said at the time.
Asked whether the clinic trials would be restarted from the beginning, the ministry said that the clinic trial is proceeding as planned. “The need has never been determined to start from Phase 1. All of the volunteers for Phase 2 have been recruited. The second phase includes an examination of several doses administered in two shots.”