Once preliminary studies have been completed, clinical trials of vaccines have three phases. In phase 1, the vaccine is given to fewer than 100 volunteers, at low doses, and the main objective is to establish that it is safe. In Phase 2, it is expanded to a few hundred, and protection against the disease begins to be measured. In Phase 3, thousands of people are given the vaccine to calculate the protection percentage (by comparing the volunteers who receive the vaccine with those who receive the placebo, and looking at how many have been infected in each group after a while), and also to detect rare complications that would have been missed in the other phases. A vaccine that passes all three phases will have a known efficacy, more or less high, and above all, it will be safe. Phase 4 is the permanent monitoring that takes place once the vaccine has been marketed.
No minimum efficacy rate for vaccine approvals
For influenza or malaria, some of the marketed vaccines have efficacies of between 10% and 16%
The covid-19 pandemic has brought about dramatic advances in the field of vaccines. Not only has the process been accelerated to the maximum, but never before, for any disease, have there been so many candidates and with so many possibilities of being effective. In addition, it has been possible to complete the development of technologies that were still in the experimental phase. The main reason for this has been the massive investment in research, but it has also been influenced by the luck of having found a virus that is much more stable than others, which has made the work easier. This is why the covid-19 vaccine is an exception in the history of these drugs.
Since Edward Jenner created the first vaccine - for smallpox, in 1796 - some twenty vaccines have been developed against viral diseases, and a dozen against those caused by bacteria. In the 19th century the first twelve appeared, against serious problems such as cholera, rabies, tetanus and bubonic plague. During the 20th century most of the vaccines we use today were commercialized. However, during our century we have also had major successes, such as vaccines against papillomavirus, malaria, dengue fever, and Ebola.
Initially, the vaccines were made from dead or attenuated microbes, which were capable of provoking an immune response but not the disease. Later, they began to use only parts of the microbe (one or more proteins, either on their own or modified in the laboratory). These two methods have given us all the vaccines that have been administered so far, and they are also being used for covid-19: about twenty candidates made with proteins and ten from attenuated SARS-Cov-2 have already entered clinical trials.
New vaccination strategies
But the real revolution brought about by the covid-19 was to be able to finish perfecting new production methods that were still under study. For example, using genes from the virus (pieces of RNA or DNA) to make human cells make the viral proteins that stimulate antibody production themselves. This is what Moderna and Pfizer, the pharmaceutical companies that have announced the first positive results of the final clinical tests, have done. Another new system is to make a second virus, duly inactive, act as a messenger and transport the microbe's genetic material. A Russian and a Chinese vaccine, as well as Astra Zeneca's and Johnson & Johnson's, all already in Phase 3, are following this route.
Initial data from these trials, which are expected to be completed less than a year after research begins, show protection for more than 90 percent of those vaccinated. For comparison, the first malaria vaccine, RTS,S, obtained after more than fifty years of research, is only 26-50% effective. Despite such low figures, it was approved because of the urgency of curbing a disease that kills nearly half a million people every year. The same goes for the flu vaccine, which some seasons has had an efficacy of 10% and others of 60%, but which is considered useful because of the many lives it saves. At the other extreme we would find the rVSV-ZEBOV vaccine against Ebola, which is 97.5% effective.
There is, then, no single limit beyond which a vaccine is considered sufficiently effective to be marketed: it depends on the needs generated by each disease. Nor is there a minimum of positive results. The Ebola vaccine was urgently approved last year after a trial with just over 3,000 volunteers when it was found that there were ten infected people in the control group and none in the group that had received the vaccine immediately. In contrast, the covid-19 phase 3 trials involve nearly 50,000 volunteers, and Pfizer has calculated the efficacy from only eight infections in the vaccinated group - compared to 162 in the placebo group (95% of those infected).
In the coming months, we will probably learn more about the efficacy and safety of the twelve candidate vaccines that are already in Phase 3. There are also more than forty in phase 1 and 2, which should be progressing. It is very possible, therefore, that next year we will have dozens of vaccines on the street, some more effective than others, which will finally allow us to control the pandemic.
(Salvador Macip is a researcher at the University of Leicester and at the UOC)