It is not easy to determine its effectiveness. First, researchers need to know if simply giving someone an injection is helpful. Large numbers of people participate in medical trials, half of whom receive it and the other half a placebo
By Adam Kleczkowski November 16, 2020 Share on FacebookShare Share on TwitterTweet Share on WhatsAppShare
PHOTO FILE: A woman holds a small vial labeled “COVID-19 Vaccine” and a medical syringe in this illustration taken on April 10, 2020. REUTERS / Dado Ruvic
Pfizer and BioNTech have just released the interim results of the trial of their vaccine against the COVID-19 disease. Although it is not the only one in the final stages of testing, the sheer scale of its trial and its extremely careful design, not to mention its promising results, have generated more than understandable excitement around the world. Now that we are getting closer and closer to the long-awaited start of vaccination, it is worth learning how statistics help physicians establish vaccine safety.
How effective are vaccines?
It is not easy to determine the efficacy of a vaccine. First, researchers need to know if simply giving someone an injection is helpful. Large numbers of people participate in medical trials, half of whom receive the vaccine and the other half a placebo. The participants then have to expose themselves to infection, with the expectation that most of the patients in the control group will become ill, but that the vaccine will protect at least some of the treated group.
In certain situations, as with HIV or Ebola, even the fact of administering a placebo is ethically very controversial, since we are talking about a very high mortality rate in these cases. In the coronavirus disease, scientists are forced to rely on natural infection, since, to date, there are no studies that intentionally expose participants to the coronavirus. As a result, the vaccine efficacy estimate is based on the relatively small number of people who contracted COVID-19 from contact with other infected people.
The efficacy of the vaccine reflects the percentage of the number of people who fell ill within the group who had been vaccinated and the group who had not received the vaccine. The Pfizer / BioNTech trial had nearly 44,000 participants, of whom 21,999 received the vaccine.
Researchers use statistical analysis to mark milestones where they can be increasingly confident that the vaccine works, or not, as dropper cases emerge. If the number of participants were small, it would not be clear whether the differences between the placebo group and the treated group would be real or just a product of chance.
Statisticians resort to the so-called study of statistical power to find out how many cases we need to observe. For the Pfizer and BioNTech vaccine, it was determined that testing would continue until a total of 164 cases were recorded, all based on the assumption that the vaccine would be 60% effective. For this calculation, the efficacy of the seasonal influenza vaccine was taken as a reference. However, and given that the figures exceeded expectations, the laboratory decided to publish the results that were already available in one of the intermediate analysis points.
94 cases were reported, and the division of the approximately 86 cases in the placebo group and the 8 cases among the vaccinated patients yielded an efficacy of 90%. Thus, we would be facing a level of protection against the virus more than remarkable. Even though the study is conducted from a relatively small number of cases, the statistical analysis allows the researchers to extrapolate the results to what might happen once the vaccine is on the market.
People of different ages and ethnic groups participated in the trial, but more studies are still needed to assess whether vaccination would protect the most vulnerable groups.
The ultimate efficacy may be lower, as administering the treatment is complex for many logistical reasons, including the fact that messenger RNA vaccines, such as Pfizer's, must be stored at very low temperatures. In the real world, the vaccine could not be kept at the proper temperature and could therefore go bad.
How safe is the vaccine?
In the event that the vaccine was administered widely, both the medical community and society as a whole could be reassured about its safety.
The Pfizer vaccine was administered to 21,999 people. Some transmitted a reaction similar to that experienced after getting vaccinated against seasonal flu. So far, no serious side effects have been reported. However, how can we be certain that this will continue to be the case when the drug reaches millions of people?
To do this, statisticians developed the rule of three. According to this rule, if 21,999 participants were vaccinated and did not have any side effects, that is, a safety of 95% was demonstrated, it is expected that the chances of the vaccine having side effects will be below three ( hence the name) divided by 21,999 and will therefore be less than 1 in 10,000. The chances of side effects appearing even lower, but the researchers prefer to go further in the trial to confirm this.
Safety is as important as efficacy. If we keep the probability of 1 in 10,000 and move it to the 300 million people who are expected to be vaccinated in the United States alone, the number of people who would suffer the side effects would rise to 30,000, a high number. It is clear that doctors have to ensure that they will not cause harm, and that any serious side effect attributable to the vaccine would greatly damage their prestige and significantly affect their uptake.
How should the vaccine be used to be effective and safe?
Health authorities are now working on how to incorporate vaccination into their national programs, but the details depend on different factors. The UK Government has already purchased 40 million doses of the Pfizer vaccine, which, taking into account that it is administered in two doses, would vaccinate 20 million people, that is, the entire 55-year-old population onwards. However, vaccination will not be quick, as both production and distribution of vaccines will take time.
The UK government has commissioned 40 million doses of the Pfizer vaccine. (Alberto Pezzali / Pool via REUTERS)
The strategy also depends on what the vaccination program aims to achieve. Children's vaccines, such as measles, are given to newborns to maintain herd immunity. In this case, we are talking about the fact that only a relatively small percentage of the population needs to be vaccinated. Given the rapid spread of COVID-19 and the extremely high levels of infection, the vaccine should reach a much larger number of people.
Predictions regarding the level of immunity required to achieve herd immunity depend on our calculation of the COVID-19 basic reproductive number, R₀. In the absence of any other control measure, this value is around 3, so at least 67% of the population would need to be totally immune to stop the epidemic from growing. If the goal were to eradicate the virus, even higher values would have to be achieved.
This level is hardly achievable with an efficacy of 60%, even when it is decided to vaccinate the entire population. The R₀ = 3 value assumes a return to pre-pandemic behavior. If we maintained a certain level of restrictions and continued to use masks, R₀ could be lower and group immunity would become easier to achieve.
Among the positives, it should be noted that our simple models may be being too pessimistic about levels to talk about group immunity. Furthermore, if it turns out that around 20% of the population would have already contracted COVID-19, the level of vaccination required could be infinitely more affordable.
Another option would be to administer the vaccine to segments of the population that have a high risk of infection (health workers and caregivers) or that present a high risk of death (vulnerable people, patients in nursing homes). In fact, this is precisely the recommended strategy in the UK.
Are we close to winning the battle against the virus?
The results of the Pfizer vaccine trial are very promising. But the truth is that the road to eradicating the coronavirus can be long and difficult. In addition to establishing the potential of the vaccine to protect us against the virus, we must know if it provides us with permanent immunity or if it must be administered repeatedly, as is the case with vaccines against tetanus or seasonal flu.
Policymakers and researchers must also balance what is needed to curb the pandemic and fears of side effects along with doubts about the vaccine. While these concerns can be easy to dismiss, they must be taken seriously if vaccination is to be successful.
Adam Kleczkowski is Professor of Mathematics and Statistics at the University of Strathclyde (Scotland)
Article originally published on The Conversation