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No serious adverse event occurred. In the hours and days following the injection, some volunteers experienced fever or muscle pain; these reactions were expected and participants were informed about them during the medical consultation which took place before their inclusion in the study. Around 10 to 15 days after receiving the injection, some volunteers also experienced mild to moderate joint pain, mostly in the hands and feet, with an inflammation similar to rheumatisms. Not a single volunteer had to miss work or be hospitalized. These symptoms disappeared after a few days or a few weeks, even without treatment. Skin rashes and small vesicles appeared on the hands or feet of about 10% of the volunteers, also disappearing after less than two weeks.
Joint pain was not part of the expected side effects and was not included in the prior information given to volunteers. As a precautionary measure, the injections were stopped a week earlier than planned in the protocol, in order to study this phenomenon and consult with other centres that are testing the experimental vaccine. In the context of clinical trials, the safety of volunteers is always a priority. Several investigations were launched to ensure that the identified symptoms were benign and transient. The 59 volunteers who received an injection of vaccine or placebo were contacted again to check if they had felt such a type of pain without reporting it. Eventually, it turned out that 11 out of the 51 vaccinated volunteers experienced pain in one or more joints. Additional observations and analyses showed that these joint pains were caused by an inflammation – induced by the vaccination – similar to rheumatism.
First, these joint pains always occurred at the same time, around 10 days after the injection. Second, complementary analyses allowed us to drop a long list of other possible causes of joint inflammation. Finally, and most importantly, vaccine particles were found in some of the inflamed joints, demonstrating that the pain was caused by joint inflammation. The onset of joint pain after infection or after injection of a live vaccine is a common phenomenon occurring, for instance, in one out of five vaccinations against rubella. Such inflammations usually disappear spontaneously with no consequences, although in certain cases this process can take a few weeks or months. Similarly, we found particles of VSV-ZEBOV in vesicles that formed on the skin of some volunteers. Hence, causality is formally demonstrated.
The VSV-ZEBOV vaccine is a live virus which does not remain where it is injected. It enters the bloodstream and probably binds to white blood cells which spread it through the body. That is how it boosts the immune system. The vaccine is then removed from the blood in a few days, but is able to persist longer in other parts of the body – for about 2 to 3 weeks. This is what all live vaccines do, such as those against measles or rubella. The vaccine particles can thus reach other parts of the body, stay there for a few days and trigger an inflammatory response. This response can be painful, but allows for the clearing of the virus and returning to a normal physiological state.
The Geneva team is constantly exchanging information with the other research centres conducting similar studies in Canada, Gabon, Germany and the United States. At first, these other teams did not observe joint inflammations, and it was tricky to understand why. But later, several teams made the same observations among some of their volunteers, although less frequently than at the HUG. These differences can be explained in several ways. First, many volunteers for the clinical trial at the HUG work in the healthcare sector or for international organizations and may therefore be particularly aware of their body's reactions: they report precisely on anything they notice, as indeed we asked them to, even if it may have nothing to do with the vaccination. Second, we have adopted a research strategy which delves into more detail than in the other centres. Finally, the HUG have a top level virology laboratory which is able to confirm within a few hours the presence of a vaccine in a sample, which was very helpful.
Yes, it was modified although the regulatory authorities declared that the clinical trial could proceed with the same high doses, given that the observed side-effects were not threatening for the volunteers' health. Since the immune response to VSV-ZEBOV is probably very good – the vaccine was able to induce the production of antibodies in volunteers during a pilot study in the USA – the second part of the clinical trial at the HUG is testing a lower dose of the vaccine (300,000 vaccine particles, between 30 and 160 times less than in the first part of the study). With that dose, the VSV-ZEBOV vaccine candidate should be better tolerated, while hopefully still triggering the production of antibodies. This change in the clinical trial protocol was approved by Swissmedic and three relevant ethics and safety committees. Injections resumed on 5 January 2015 with this lower dose of the vaccine candidate – or placebo.
No, not yet. We are currently analyzing the large amount of collected data.