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Earlier this week, the University of Oxford (UK) and British pharmaceutical company AstraZeneca announced that their experimental coronavirus vaccine had been found to be 70.4 percent effective, leading to renewed optimism about the possibility of reducing the spread of the pandemic. A few days later, however, several questions have arisen about the announcement and about some details that could affect the approval process of the new vaccine.
The data provided on Monday looked quite encouraging. Depending on the dose, the experimental vaccine showed an efficacy between 90 and 62 percent, with an average efficacy estimated at 70.4 percent, the percentage most picked up and reported by the media.
Such a marked difference between the doses had given rise to some doubts, difficult to resolve in the absence of more details from AstraZeneca. 90% efficacy was achieved in a group of volunteers who received half the standard dose in the first administration, followed by a second full dose one month later; 62% of the effectiveness was derived from the administration of two equal doses, always one month apart.
In a press release published Monday, AstraZeneca indicated that just under 2,800 volunteers had received the lower dose, compared to 8,900 trial participants who received the two full doses. The disproportion between the two groups was quite unusual for this type of clinical trial, as was the lack of additional information on whether a lower dose led to better efficacy. Representatives for AstraZeneca and the research group had not provided particular explanations, saying they do not yet have convincing answers.
In addition, the press release did not offer other important elements to contextualize the little data provided. For example, he cited the identification of 131 COVID-19 cases in the preliminary phase of the trial, but without specifying how many of these had been detected in different groups of volunteers. Therefore, it was not possible to know how many symptoms were found in the group that received a lower dose, that that received a normal dose, and that that received a different substance (another vaccine) or did nothing (placebo).
Typically, in clinical trials, volunteers are separated into groups receiving different treatments, just to check if a vaccine is effective and how effective it is. The trial implies the presence of at least two groups: the first receives the experimental vaccine, the second a placebo. The researchers then wait a few months to see how many volunteers get sick in each group, thus determining the effectiveness of their solution.
In the last phase (of 3) of the trial, this procedure is usually performed on thousands of volunteers, in order to assess the efficacy of the vaccine on a solid statistical basis. Research centers and pharmaceutical companies then have the possibility to provide preliminary results, therefore with trials still in progress, if they are large enough to request emergency authorizations for their vaccines. That’s what Pfizer-BioNTech and Moderna have done so far, after the very promising results of their experimental mRNA-based vaccines.
However, the preliminary information provided by AstraZeneca on Monday was not as clear as that provided by the competition. In addition to not having provided details on the division of symptoms into the different groups, the company had combined the results of two different clinical trials of step 3, one started in the UK and the other in Brazil. It is quite unusual for the results to be combined in this way, also because each clinical trial has differences and variables to take into account and that can hardly be combined to obtain a single data, such as effectiveness.
Skepticism increased after the news agency published an interview. Reuters in which Menelas Pangalos, AstraZeneca’s head of research and development, explained that the company had in no way thought of experimenting with a lower dose of the vaccine. The investigators in charge of the UK trial had miscalculated the dose, resulting in a first dose being given at a lower than normal concentration. This circumstance was not mentioned in any way in Monday’s press release.
In a later interview published Wednesday by New York Times, Pangalos returned to the question: “The truth is that it could be a very useful mistake. He did not put anyone in danger. It was an error in the dosage. We were all moving very fast. We corrected the error and continued the study, without any change in the research, and agreed with the regulatory authorities to include those volunteers in the study analysis. What had to be revealed? It does not matter if [l’errore] whether deliberate or not. “
Despite Pangalos’ statements, from the formal point of view of the investigation, the error has some relevance. Before proceeding to a clinical trial, the protocols with which it will be carried out are identified, including the methods of drug administration. Formalizing the rules of the game is very important, and it is the basis for good experimentation and its reproducibility. The clinical trial rules initially decided by AstraZeneca and the University of Oxford did not provide for the administration of lower doses of the vaccine: this led to a change in career and consequently to the production of less convincing data, or to the less spoiled by circumstances. .
Further doubts were added when it was found that the volunteers who received the lowest dose were all under the age of 55, thus in an age group statistically less at risk of developing severe symptoms due to a coronavirus infection. The lack of consistent data on the elderly could complicate the licensing of emergency vaccines, as all major regulators have set minimum limits of efficacy for age groups.
Several observers also considered inappropriate the choice of some AstraZeneca executives to provide more details, not contained in the press release, during confidential meetings with investors, to reassure them of the results obtained. It is something that often occurs during drug trials, requiring costly investments by pharmaceutical companies, but the option to do so also for an experimental vaccine in the midst of a pandemic and despite public commitments to transparency of the AstraZeneca itself has picked up some criticism.
Unlike the Moderna and Pfizer-BioNTech vaccines, which employ an mRNA-based technique never before used on a large scale for vaccines, AstraZeneca and the University of Oxford have developed a more traditional vaccine, starting with one of the viruses that cause the common cold in chimpanzees. The genetic material of the protein that the coronavirus uses to bind to the cells of our body and replicate has been transferred to the virus obtained by chimpanzees and made harmless to humans. In this way, the immune system learns to attack the protein, so that it can also cope with any infection caused by the actual coronavirus.
On paper at least, AstraZeneca’s experimental vaccine is cheaper and can be easily stored in the refrigerator for months, compared to Pfizer-BioNTech’s, which must be kept at -70 ° C, therefore in very powerful freezers. . Moderna solution should also be stored in the freezer, but at -20 ° C and remains stable for about a month once thawed, provided it is kept refrigerated.
Therefore, the AstraZeneca vaccine could have an advantage, both in terms of lower cost and storage and logistics methods, but it could be significantly less effective than those of Pfizer-BioNTech and Moderna. Preliminary results presented on their mRNA-based solutions were considered more consistent and reliable, especially since they were derived from clinical trials of step 3 unique, and no longer comes from later experiments.
The confusion surrounding the initial results provided by AstraZeneca does not, of course, imply that an unsafe or ineffective vaccine is licensed, or that this specific vaccine is failing. The data collected in the step 3 they will be the basis for a deeper scientific investigation, which will then be made public and reviewed by outside researchers who have had nothing to do with vaccine development. Some research of this type on the AstraZeneca vaccine has already been published and received with interest by the scientific community, although with some criticism and doubts once again about the choice to collect different data.
Finally, it will be up to the control bodies, such as the United States Food and Drug Administration, to establish that the experimental vaccine meets the requirements to obtain an emergency authorization, making it possible to distribute it while waiting for clearer and more definitive results. To date, there are no elements to fear that the authorities will issue authorizations seeking shortcuts to do it faster, with potential risks to the health of millions of people. An authorization in the absence of robust data would be risky and could lead to a lack of confidence in vaccines, which could make a difference in stopping this pandemic.
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