Ebola: vaccines ready for trials
Ebola vaccines
Maxim Russo, <url>Already in February, large-scale clinical trials of vaccines against Ebola will begin in West Africa.
This was announced on January 9 at a press conference in Geneva by Marie-Paul Kini, Assistant Director General of the World Health Organization. At the moment, trials of two vaccines, the most ready for use, are planned.
Meanwhile, news is coming in from the scene: the rapid spread of the disease has stopped. The epidemic has stopped in Nigeria, the situation has improved significantly in Liberia, and the difficult situation remains only in Sierra Leone and Guinea. This is good news, but it will complicate vaccine trials. It will be difficult to determine what caused the decline in morbidity: natural causes or the effective action of vaccines.
Most often, modern safe vaccination consists in introducing into the body not weakened cultures of the disease virus, but only individual proteins of this virus. The presence of protein allows the body to adjust the immune system to fight this virus by creating memory cells – a special type of lymphocytes. If then the virus-the causative agent of the disease enters the body, the immune system will already be ready to fight back against it. Proteins for vaccination are produced, as a rule, by specially grown cell cultures, for example, yeast, which are genetically modified to force the production of the desired protein.
But in the case of Ebola, both vaccines, which are currently being tested, work a little differently. Their developers have created genetically modified viruses in a special way, in which the gene of one of the proteins of the Ebola virus is embedded. The modified virus is able to integrate into the genome of a cell and make it produce this protein. In the future, everything happens as described above: the protein teaches the immune system to produce the necessary antibodies, memory cells are created and the body is ready for the penetration of the disease virus.
One of the vaccines (cAd3-EBO Z), which is being developed by the British pharmaceutical company GlaxoSmithKline, is based on the use of chimpanzee adenovirus – cAd3. As usually happens in such cases, the virus changes in such a way that it cannot reproduce in the human body, but is able to penetrate the cellular genome only once. The modified virus carries the gene of one of the envelope proteins of the Ebola virus, on which the vaccine action is based. The first clinical trial conducted in Maryland in the fall showed the effectiveness of the vaccine: all twenty participants began to develop antibodies to the Ebola virus. In a trial that began a little later in Oxford, the "modified Ankara cowpox virus" (MVA), widely known in medicine, was used. It was created back in the 1970s by Professor Anton Mayr in Germany and is used as a carrier in vaccines against a number of diseases. The MVA virus has lost about 10% of the genome compared to its ancestor, the cowpox virus. Therefore, it is not capable of self-replication, and its use is safe. Now the developers of the Ebola vaccine are analyzing test data in Maryland and Oxford in order to select the necessary dose and, in particular, determine whether a single or double vaccination is necessary.
Another vaccine is known as VSV-EBOV. Its development was carried out in the laboratory of the National Health Agency of Canada, in 2010 the license for the vaccine was sold to a small American company NewLink Genetics, and now Merck Inc. is working on the vaccine. This vaccine uses a virus that causes cow disease, which manifests itself mainly in the appearance of vesicular rashes on the mucous membranes in the oral cavity (in humans, the virus causes a slight malaise similar to the flu). This is the Indiana vesicular stomatitis virus (VCV). It is already being used in attempts to develop a remedy against cancer or human immunodeficiency virus.
In October 2014, the Wellcome Trust conducted clinical trials of this vaccine on volunteers in Europe, the USA, Kenya and Gabon, but they were discontinued because some participants began to have joint pain. However, due to the danger of Ebola disease, they decided to continue developing the vaccine later. It has been shown that one dose of the vaccine is sufficient for the emergence of immunity to Ebola disease in experimental monkeys – crab-eating macaques.
Both GlaxoSmithKline and Merck Inc announce the possibility of delivering millions of doses of their vaccines to Africa for large-scale clinical trials in the near future. The exact number of them will be determined when the specialists of each of the companies decide on the optimal individual dose of the vaccine.
The rapid spread of the epidemic in the second half of 2014 forced WHO to reduce the usual sequence of clinical trials of vaccines. Usually, the first phase begins, where the safety of the drug and immune reactions are tested on a very small number of volunteers. In the second phase, the number of participants increases and the required dose is specified. Finally, only then they move on to the third phase, where in a randomized double-blind trial on a large number of people, sometimes on tens of thousands, they are convinced of the effectiveness. In this case, for Ebola vaccines, WHO allows immediately after the first phase, which they have successfully passed, to move on to the third.
Marie-Paul Kini also told what the design of clinical trials will be, that is, the plan of how the study will take place. It will be different in three African countries. Double–blind randomized trials will be conducted in Liberia - the "gold standard" of modern evidence-based medicine. It is planned to include three groups, each of nine thousand people. One will receive the cAd3-EBOV vaccine, the other will receive the VSV–EBOV vaccine, and the third will become a control. Initially, it was planned that health workers of Liberia would take part in the trials, as the group at greatest risk, but then they decided to recruit participants from the entire population.
In Sierra Leone, the "stepped-wedge design" will be applied, in which some patients begin to receive the vaccine earlier than others. An indicator of effectiveness is the lower number of cases among those who received the vaccine earlier. This method takes longer to obtain statistically significant results, but is considered by many to be more ethical because all participants eventually receive the vaccine. In Sierra Leone, it is planned to involve about 6,000 people in the study.
In Guinea, they will resort to the "ring" technique, which once helped to finally eradicate smallpox. The vaccine will be given to people who make up the circle of closest contacts of an Ebola patient (the "ring"). It is planned to divide all participants into two large groups, in one the vaccine will be given earlier than in the second. Each of the two groups will include up to 90 rings, each ring will have approximately 50 people. Thus, the total test will cover about 9,000 people.
The third participant, Janssen Pharmaceuticals, Johnson & Johnson Corporation, is slightly behind the two leaders of the race of Ebola vaccine developers. The vaccine she creates contains two components. The first is based on a modified human adenovirus – the Dutch biotech firm Crucell, a division of Janssen Pharmaceuticals, is working on it. The second one is created from the already mentioned modified cowpox virus Ankara, by the efforts of the Bavarian Nordic company, whose headquarters are located in Denmark. At the moment, the results of the efforts of all these companies are undergoing the first phase of clinical trials at the Jenner Institute in Oxford. If successful, the vaccine, which has been designated Advac/MVA-BN, will also take part in large-scale trials in Africa. Preliminary studies show that she needs more time to develop immunity, but as a result, immunity turns out to be more resistant. Perhaps the use of this vaccine will prove promising for pre-immunization of people who are at risk of being exposed to Ebola infection in the future, for example, medical workers. And in the centers of the epidemic, more "fast" vaccines will work. Another advantage of the Advac / MVA-BN vaccine is that it is stored at a temperature of 2 ° C to 8 ° C, whereas other vaccines require stronger cooling. This will make the Advac/MVA-BN vaccine more convenient for use in remote rural areas.
The first results of the third phase of clinical trials should be expected in about six months. But depending on the current results, they may be interrupted if it turns out that the vaccine has too strong side effects, or if it becomes clear in advance that it does not give statistically reliable positive results. If it is seen that the effectiveness of the vaccine is very high, the test may be recognized as successful before a predetermined time.
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