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“We easily run the risk of comparing apples to oranges”
(Daniel Altmann, immunologist)
It is important for researchers to understand why the vaccine appears to work much better with a lower first dose. One explanation could be in the data themselves: the study may not have been large enough to measure the difference between the two schemes. Perhaps that is why effectiveness will stabilize as soon as more Covid-19 cases occur in the test subjects, says Luk Vandenberghe, a virologist at the Massachusetts Eye and Ear Institute and Harvard Medical School in Boston. The “half dose, full dose” results are based on data from 2,741 study participants, while the study arm, which had a weaker efficacy, comprised 8,895 participants. The press release does not indicate in which group of cases they occurred.
Low dose, high effect?
However, if the differences are real and a lower first dose actually works better, researchers are eager to understand why. “I don’t think it’s an anomaly,” says Katie Ewer. The immunologist is working on the vaccine at the Jenner Institute in Oxford. She has two theories as to why a lower first dose could lead to better protection against Covid-19. For example, it is conceivable that a low dose of vaccine will better stimulate the subset of immune cells that contribute to antibody production: T cells.
Another possible explanation is related to the response of the immune system to the chimpanzee virus. The vaccine not only triggers an immune response against the Sars-CoV-2 spike protein, but also against components of the viral vector. The first full dose could mitigate that response, Ewer says. Therefore, he wishes to investigate the antibody reactions against the chimpanzee virus to clarify this question.
Hildegund Ertl, an immunologist at the Wistar Institute in Philadelphia, said the results are in line with her own work on adenovirus vaccines in mice. It also found that a low first dose can lead to better protection when a vaccine must be given twice in total. A lower first dose can accelerate the formation of “memory cells”, which are activated by a second dose of vaccine. Waiting longer between the two shots could have the same effect.
Meanwhile, AstraZeneca hopes to collect more data on the various dosage regimens. The company has also administered the vaccine to about 10,000 people in the United States to date. In the summer, the study had to be temporarily stopped because one of the study participants suspected serious side effects. The company now plans to ask regulators if it can modify the study to include the most effective dosing regimen, Mene Pangalos, vice president of biopharmaceutical research at AstraZeneca, said at a news conference.
Phases of clinical trials
When a new drug is developed, it goes through five clinical phases. To be able to conduct a study in a higher phase, all the previous phases must have been completed successfully.
Phase 0 study: The first experiments are carried out on healthy people. About 10 to 15 people receive subtherapeutic doses, also known as microdoses. The main focus is to examine how the active ingredient behaves in the body.
Phase-I-Studie: Approximately 20 to 80 people receive a dose that could be relevant for further therapeutic use. How tolerable and safe the agent is is checked.
Phase-II-Study: Manufacturers review the therapy concept with about 50 to 200 people and determine the appropriate dosage. At this point, the positive effects of the therapy should already be visible.
Phase-III-Study: Now it is decided whether the responsible authorities approve a drug. The therapeutic efficacy of the drug must be demonstrated in 200 to 10,000 people. This also applies to its safety, adequate pharmaceutical quality, and adequate risk-benefit ratio.
Phase-IV-Study: These long-term follow-ups begin after the drug is approved. This is intended, for example, to detect very rare side effects that are only visible in very large patient populations.
