Preliminary results of Pfizer booster shot of Phase III trials announced

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Preliminary results of Pfizer booster shot of Phase III trials announced

Preliminary results of Pfizer booster shot of Phase III trials announced.

1. Background introduction

Developed countries are in the process of determining or launching COVID-19 vaccine booster vaccination, which mainly involves the third dose of mRNA vaccine. In this process, the data on the necessity, effectiveness, or safety of the booster shot is still in a state of accumulation from scratch.

For the effectiveness and safety of a vaccine, the most reliable and important data comes from a randomized double-blind phase III clinical trial. However, unlike the effectiveness of the first two injections of mRNA vaccines verified in Phase III clinical trials, the data before the booster injections are mainly derived from the immune bridging test.

Unlike the large-scale phase III clinical trials that directly detect the protective effects of vaccines, the immune bridging test uses the detection of immune response as the end point.

By proving that the third shot induces an immune response that is not inferior to the first two shots, it is indirectly inferred that the third shot can be obtained.

Same protection as the first two stitches. This kind of speculation has its scientific principles, but due to the lack of a clear validity data, there are still limitations in analyzing the benefits of the booster needle.

2. Make up the gap

Pfizer and BioNTech announced the first phase III clinical trials of the COVID-19 booster shot on October 21, which provided very critical effectiveness data.

The data currently published are all from Pfizer and BioNTech press releases. Many details have not been disclosed, but the trial framework and primary endpoint data are basically clear.

Preliminary results of Pfizer booster shot of Phase III trials announced.

In terms of trial design, this trial recruited more than 10,000 subjects over the age of 16 who had completed the first two doses of Pfizer vaccine. Half of the volunteers received the third dose of Pfizer vaccine and the other half received a placebo.

The average age of the more than 10,000 subjects was 53 years old, most of them were between 16-55 years old (55.5%), and the elderly over 65 years old accounted for 23.3%. When subjects received the third shot, the median time to completion of the second shot was 11 months.

The difference in infection cases between the booster shot group and the non-booster shot group was tracked from 7 days after the third injection (the estimated time required for the occurrence of immune response). In the analysis of the results, the median follow-up time was 2.5 months.

It was found that 5 cases of symptomatic infection occurred in the booster shot group and 109 cases in the non-booster shot group. Based on this data calculation, the effectiveness of the booster shot to prevent symptomatic infection is 95.6% (95% confidence interval: 89.3, 98.6).

From the safety data point of view, no new adverse reactions were found, and the proportion of adverse reactions was similar to that of other clinical trials of the vaccine (the press release did not announce the specific proportions.

The previous immune bridging test of 300 people showed that common adverse reactions were similar to those of the second injection. Phase III clinical trials are similar, and it is speculated that the Phase III clinical trials of booster shots are also similar).

3. Pfizer vaccine is more prominent

Judging from this result, Pfizer’s booster shot has shown very clear effectiveness, and the safety is no problem. More importantly, these data are derived from a randomized double-blind phase III clinical trial, which greatly enhances the data intensity of Pfizer/BioNTech’s booster shot.

Enhance the effectiveness of 95.6% of the needle. From a professional analysis, the key is not that the numbers are good-looking, but that this is a randomized double-blind phase three clinical trial with the least interference factors.

Different from the immune bridging test, this is actually calculated based on the effectiveness of the vaccine’s protective effect, not a guess based on the amount of antibodies. Different from the real-world effectiveness tracking of Pfizer’s third shot previously announced by Israel, the randomized double-blind design avoids other differences between the vaccinated population and the non-vaccinated population as much as possible, resulting in a bias in effectiveness estimation.

Moreover, 10,000 subjects were involved in the Phase III clinical trial, and more than 5,000 people were vaccinated with booster injections, providing a large amount of safety data. One of the most criticized aspects of Pfizer’s FDA application for booster shots is that the safety data came from the immune bridging test of 300 people. Of course, a few weeks later, Moderna applied for 171 people, which made people no longer feel embarrassed to criticize Pfizer.

Theoretically speaking, whether 171 or 300 is good, we can see common adverse reactions, such as how many people have fever and how many people feel tired. However, the small number of people means that the error of many analyses will be relatively large.

The rare adverse reaction that requires the most attention of the mRNA vaccine is myocarditis, which is difficult to confirm in clinical trials in terms of the incidence (the incidence of the second shot is higher in young men, the highest is estimated to be one in five thousand).

However, a large number of Phase III clinical trials, even if such rare adverse reactions are not found, can provide a good exclusion-it is clear that this is indeed a rare adverse reaction with an incidence rate of less than one in a thousand.

In addition, although rare adverse reactions mainly rely on post-market follow-up, such follow-up often has the problem of not being reported in time, or even the number of reports is low. It is extremely important to have a more complete clinical trial data collection.

Previously, Pfizer had accumulated the most third-shot data with Israel’s first booster injection, and had taken a great initiative in the booster injection competition-Johnson & Johnson and AstraZeneca had two adenovirus vaccines because of rare thrombosis problems.

It is difficult to become an booster shot choice in developed countries. Compared with Moderna, Pfizer’s “massive” data helps it even better. With the success of Phase III clinical trials of the only booster shot so far, it will only further widen the gap.

Moderna is also vaccinating volunteers in previous clinical trials with booster needles, but when this booster needle Phase III clinical trial will produce results is unknown. Many European countries have chosen Pfizer as the booster shot due to the amount of data and the risk of myocarditis (some tracking shows that Moderna’s risk of myocarditis is higher).

Although the United States still recommends that the same vaccine is the first choice for booster shots, as mashups are allowed, from the perspective of market competition, there is not much time left for Moderna.

4. Interpret carefully

Although Pfizer’s Phase III clinical trial of booster shots has filled an important gap, it does not mean that booster shots are really beyond doubt, nor can it be said that Pfizer is the best choice of booster shots.

It can even be said that the interpretation of the Phase III clinical trial of Pfizer booster shot needs to be very cautious. Pharmaceutical companies will want to interpret this result in one direction, but like the data privacy agreement of Internet companies, the devil is in the details (devil is in the details). ).

The third needle interval in Pfizer’s booster shot test is not actually implemented now. The median interval in the trial was 11 months-half of the subjects received booster shots more than 11 months later. In reality, Pfizer’s third injection recommendation is 6 months for non-immunosuppressive people (5 months is more aggressive in Israel).

Will the interval affect the effect of the booster shot? A few weeks away will not be a big problem, but there may be a difference between two months and half a year. Better enhancement effects are often based on the fact that the previous immune response has dropped a lot. Some studies have shown that extending the interval between the first two shots of COVID-19 vaccination can increase the effectiveness is also based on this principle.

From the perspective of Moderna’s booster shot application, if the antibody level is high before the third shot, it corresponds to a small increase in the final antibody and a small total amount (the increase is still greater than before the booster shot, but it was a whole class before. , Now is the whole class of poor students).

It can be inferred that the longer the time, the more the subjects will have lower antibodies, so the enhancement effect achieved in Pfizer’s clinical trial at an interval of 11 months may not be the same as in reality.

What is more worthy of attention is the effectiveness of the vaccine in the placebo group. The placebo group in the booster shot trial was the person who had completed the first two shots and was also fully vaccinated. In terms of infection cases, there are 109 cases in more than 5,000 people in two and a half months, and the infection rate is about 2%, which is very high. Based on this calculation, the annual infection rate will be as high as 10%.

Even if the trial is at the peak of Delta, this infection rate is far higher than the infection rate of the placebo group that was not vaccinated in the Phase III clinical trial in 2020. The interpretation in the Pfizer press release is that the booster needle has restored its effectiveness. But what must be asked is, how much effect is left of Pfizer’s first two shots?

The booster shot is exactly the same vaccine as the first two shots. If the immune protection of the first two shots declines very quickly, then you need to consider whether there is a problem with the vaccine itself-many vaccine effectiveness tracking Moderna did not see the same decline, even Pfizer The decline in the effectiveness of the vaccine seen in Canada is also much smaller (Canada was forced to extend the interval between two doses due to restrictions on vaccine exports from the United States).

Whether it is because the previous two injections are too short (Pfizer is three weeks) or because of the difference in dosage (Pfizer and Moderna are 30 micrograms and 100 micrograms respectively), if Pfizer really has serious persistence problems, and in other It is not seen in the vaccine, so the solution to the persistence problem should not only rely on an additional injection of the same vaccine. Otherwise, maybe the same problem will reappear in a few months.

The published data of Pfizer’s booster shot clinical trial also did not substantially answer the question of the necessity of booster shots. For booster shots, necessity is no less a problem than effectiveness. The benefits of booster vaccination are not compared to those who have not been vaccinated, but to ask what are the further benefits of those who have been vaccinated and have received immune protection?

How many of the 109 infections in the control group were severe? Judging from the standards of Pfizer’s previous phase three clinical trials, due to the low testing standards (nucleic acid testing if there is a potential symptom), the collected cases are mainly mild. If the control group is mild or mildly ill, how important is it to enhance the needle? Why develop and promote the COVID-19 vaccine? Not only because of the extremely strong infectious power of the COVID-19, but more importantly because of the serious illness and death threats after infection.

Including Pfizer vaccine, the purpose of the development of the COVID-19 vaccine is to prevent and reduce the COVID-19 disease. If it is used to effectively protect even a mild cold-like illness, then it may be necessary to examine the original intention and necessity first. Many vaccines may not be able to do this, and even if they can, it may mean that boosters are needed every six months.

Of course, we must pay attention to breakthrough infections after vaccination, especially the severe or even death cases among them, find the patterns among them, and find ways to reduce the occurrence of these cases. For people who are really at high risk, such as immunosuppressed or elderly people, it is worth considering whether it is booster shots or prophylactic use of monoclonal antibodies, as well as other therapeutic drugs. But for the Nationwide booster shot, before admiring the amazing effectiveness provided by Pfizer or Israel, we need to think about our goal. Do we suddenly need a cold vaccine once every six months?

Pfizer press release:
https://www.pfizer.com/news/press-release/press-release-detail/pfizer-and-biontech-announce-phase-3-trial-data-showing

Preliminary results of Pfizer booster shot of Phase III trials announced

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