COVID-19
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Immune responses and vaccines
Trials and results
John Jacobs, 28.11.2020 |
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Studies
Developing a vaccine is a risky adventure for pharmaceutical companies since these require huge and expensive trials, without any guarantees for success. In 2007, long-term research and expensive research for another immune disease, HIV, was terminated due to safety concerns. I do not agree with people who in the current, undisclosed and unapproved state of evidence state that any doubts about vaccination is only cold feet. I rely on evidence-based medicine and am think that any intervention given should be shown to have efficacy for that specific purpose. Vaccines should be proven to be safe and effective in people who are (naturally) infected with the virus.
The requirements for COVID-19 vaccines are not extremely high. The FDA (US) provides two options for primary vaccine outcome measures: (i) at least 50% protection against disease or (ii) at least 50% protection against severe disease and death. The European counterpart EMA does not mention specific objectives but will have similar thoughts. In addition, a variety of secondary outcome measures may be added to investigate other important functions of the vaccine. The primary outcome measure is the most important because it is the most sensitive in statistical analysis. Statistically, for multifactorial analysis, mathematical compensation must be done because multiple outcomes are sufficient. To get an idea of this, compare it to dice the probability of three sixes is 1/216 (~ 0.5%), but the probability of three sixes or three fives is 2/216 = 1/103 (~ 1%).
The ten phase 3 clinical studies are large double-blind studies with one or two vaccine groups and control groups. The number of participants per vaccine study varies from over 24,000 to 90,000. The studies are so large because it is considered unethical to intentionally infect subjects with SARS-2. This results in many people being vaccinated, to have a small percentage that will become infected with the virus. The downside of this is that if a vaccine is dangerous in combination with infection, it immediately puts 10,000s people at risk because they live in a world where SARS-2 haunts. The Chinese companies have turned to South America, Africa, and Indonesia for studies, because SARS-2 is eliminated from China.
I am convinced that everyone who develops SARS-2 vaccines, cares about protecting people, but people may have conflicting interests. This is most clearly illustrated by the Chinese companies. Now that China has driven the virus out of the country with lockdown and TTI, the vaccinated Chinese people are not infected, and their vaccines cannot be tested in their homeland. This conflict of interest can also play a role like government advisors who are also involved. Also, for this reason, it is crucial that those discussions and arguments are published. I will do this also, since I am also involved in a study of chronic COVID-19.
The requirements for COVID-19 vaccines are not extremely high. The FDA (US) provides two options for primary vaccine outcome measures: (i) at least 50% protection against disease or (ii) at least 50% protection against severe disease and death. The European counterpart EMA does not mention specific objectives but will have similar thoughts. In addition, a variety of secondary outcome measures may be added to investigate other important functions of the vaccine. The primary outcome measure is the most important because it is the most sensitive in statistical analysis. Statistically, for multifactorial analysis, mathematical compensation must be done because multiple outcomes are sufficient. To get an idea of this, compare it to dice the probability of three sixes is 1/216 (~ 0.5%), but the probability of three sixes or three fives is 2/216 = 1/103 (~ 1%).
The ten phase 3 clinical studies are large double-blind studies with one or two vaccine groups and control groups. The number of participants per vaccine study varies from over 24,000 to 90,000. The studies are so large because it is considered unethical to intentionally infect subjects with SARS-2. This results in many people being vaccinated, to have a small percentage that will become infected with the virus. The downside of this is that if a vaccine is dangerous in combination with infection, it immediately puts 10,000s people at risk because they live in a world where SARS-2 haunts. The Chinese companies have turned to South America, Africa, and Indonesia for studies, because SARS-2 is eliminated from China.
I am convinced that everyone who develops SARS-2 vaccines, cares about protecting people, but people may have conflicting interests. This is most clearly illustrated by the Chinese companies. Now that China has driven the virus out of the country with lockdown and TTI, the vaccinated Chinese people are not infected, and their vaccines cannot be tested in their homeland. This conflict of interest can also play a role like government advisors who are also involved. Also, for this reason, it is crucial that those discussions and arguments are published. I will do this also, since I am also involved in a study of chronic COVID-19.
Results
Most companies aim for 50% protection against disease. Their power analysis for trial design are based on this. The press releases from Pfizer/BioNTech and Moderna suggest that these vaccines are doing much better than this. The press releases of the RNA vaccines herald loud possible effects of more than 90%, both on disease and on serious illness. With a 90% reduction with a COVID-19 vaccine, mortality after infection (IFR) is close to a severe flu epidemic (0.1%). These unexpected huge differences in preventive medicine, may suggest that these studies are also powerful enough to analyze secondary outcomes, such as protection against serious illness and death. The results from the secondary outcome measures may be unclear, for example because a vaccine was mainly given to people who did not become seriously ill. Then a follow-up study can be carried out in groups with a high risk of sufficient statistical power for an unambiguous answer.
How to think about press releases is illustrated by the story of the Oxford/AstraZeneca vaccine. They mentioned an average protection of 70%, with 62% for the RCT dose 62% and the deviating, lower (!) doses 90%. In the scientific method, a new analysis after the results are known is not evidence, but "harked’” as in an explorative study (HARK = Hypothesis After Results are Known). It now appears that this 90% has only been applied to people under 55. So, the phase 3 trial should be judged as 62% on average. That average includes many young people who appear to be well above average protected. This implies that protection for the elderly is below average, and probably less than 50% of the population.
My experience with press releases, including my own research, is that they like scientific scrutiny. Until the scientific results are published and critically reviewed by independent experts, we cannot be sure that there is a vaccine that works. However, the reported unexpectedly excellent results from reputable companies are unlikely to be too far from reality. So it is likely that some of these vaccines will enable Europe to start vaccination of vulnerable people in 2021.
Another important question is how long will vaccines protect? Immunity after natural infection by coronaviruses, such as the common cold, appears to last less than a year. However, the first vaccinations were less than half a year ago, so they cannot answer this. Annual vaccination of the entire population is a major operation, several times a year may be too ambitious.
How to think about press releases is illustrated by the story of the Oxford/AstraZeneca vaccine. They mentioned an average protection of 70%, with 62% for the RCT dose 62% and the deviating, lower (!) doses 90%. In the scientific method, a new analysis after the results are known is not evidence, but "harked’” as in an explorative study (HARK = Hypothesis After Results are Known). It now appears that this 90% has only been applied to people under 55. So, the phase 3 trial should be judged as 62% on average. That average includes many young people who appear to be well above average protected. This implies that protection for the elderly is below average, and probably less than 50% of the population.
My experience with press releases, including my own research, is that they like scientific scrutiny. Until the scientific results are published and critically reviewed by independent experts, we cannot be sure that there is a vaccine that works. However, the reported unexpectedly excellent results from reputable companies are unlikely to be too far from reality. So it is likely that some of these vaccines will enable Europe to start vaccination of vulnerable people in 2021.
Another important question is how long will vaccines protect? Immunity after natural infection by coronaviruses, such as the common cold, appears to last less than a year. However, the first vaccinations were less than half a year ago, so they cannot answer this. Annual vaccination of the entire population is a major operation, several times a year may be too ambitious.
Who will be vaccinated?
The Dutch Health council mentions three ethical incentives to vaccinate with priority:
- Vaccinate vulnerable people
- Ring vaccination to prevent infections of vulnerable people.
- Prevent disruption of society
Vaccinate vulnerable people
The goal is to reduce serious COVID-19 illness and mortality. People over 60 years old are prioritized as well as people with underlying serious diseases of, for example, heart or respiratory tract or with diabetes mellitus. It is crucial that these vaccines do protect the vulnerable people and / or do protect against serious illness. These might be secondary outcomes that have yet to be analyzed, along with the primary outcomes.
Ring vaccination
Ring vaccination is herd immunity on a small scale. If vulnerable people cannot be vaccinated themselves, the ring of people around them might be vaccinated: the informal caregivers and health workers who are their contacts and their risks of infection. This advice from the Dutch Health Council is based on the assumption that vaccinated people are not only protected from disease, but also from infection. If this would be the case, they would not transmit the virus to the vulnerable people they care of. However, the MEB and virologists know that corona vaccines are unlikely to protect against infection. Virus titers differ greatly in vaccinated monkeys (Yu, Doremalen, Mercado), although the results could differ between vaccines (Corbet). We should be precautious about this, since monkeys have different immune interaction with SARS-2 and are protected against reinfection.
The Dutch Health Council states that various vaccine manufacturers are looking at immunity from infection in their RCTs. However, in the phase 3 studies, only the BBV152 vaccine trial looked at the rate of asymptomatic infections as a secondary outcome. There are no plans in the EU to purchase this vaccine. It is striking that most vaccine manufacturers are not interested in testing if their vaccine can prevent asymptomatic disease, while many countries suggest they would be interested in buying these. It is tempting to suggests that the vaccine developers do not think their vaccine would protect against infection.
In short, this implies that herd immunity by ring vaccination of care workers will not be effective. Vaccinating care-workers will protect these from disease upon infection, but they could still transmit disease to vulnerable people. If care-workers would be vaccinated it would be even more crucial to test if they carry the virus, since no one would report asymptomatic disease without being tested.
The Dutch Health Council states that various vaccine manufacturers are looking at immunity from infection in their RCTs. However, in the phase 3 studies, only the BBV152 vaccine trial looked at the rate of asymptomatic infections as a secondary outcome. There are no plans in the EU to purchase this vaccine. It is striking that most vaccine manufacturers are not interested in testing if their vaccine can prevent asymptomatic disease, while many countries suggest they would be interested in buying these. It is tempting to suggests that the vaccine developers do not think their vaccine would protect against infection.
In short, this implies that herd immunity by ring vaccination of care workers will not be effective. Vaccinating care-workers will protect these from disease upon infection, but they could still transmit disease to vulnerable people. If care-workers would be vaccinated it would be even more crucial to test if they carry the virus, since no one would report asymptomatic disease without being tested.
Disruption of society
I highly value most advices of the Dutch health council, but I miss the rational of this third option. It appears to be a worse-case scenario of a society disrupted by a COVID-19 epidemic, in which vaccination would be used to protect essential people for society. TTI, lockdown and personal protection measures will control the epidemic. Vaccinating people in early infection would be unwise but is likely to occur in an uncontrolled epidemic. This makes the use of vaccines no more than a WC scenario to be flushed away rapidly.
Roll out of vaccines
Vaccinating infected people might be dangerous, even when using good and safe vaccines. All vaccination studies, screen people for SARS-2 infection. Most vaccines require about a month to induce sufficient protective immunity from disease. An effective and safe vaccination campaign could only be launched if the epidemic is locally controlled by TTI and / or lockdown.
Mandatory vaccination
Some politicians underestimate the duration and complexity of rolling out a vaccine and call for mandatory vaccination. We should state that (i) we do not yet have a vaccine and do not know whether it is safe, (ii) mandatory vaccination is uneasy with personal freedom, (iii) its legal basis is disputed, (iv) logistics to roll out a vaccination campaign will take a long time (v) there is no scientific reason to force vaccination to everyone as long as we do not know whether a vaccine contributes to herd immunity and it even seems to be unlikely.
John Jacobs
28 november 2020
28 november 2020
