Is The Covid-19 Vaccine Effective?

vaccineMadhava Setty, MD – Are you going to decline the Covid-19 vaccine if it is offered to you? Why or why not? No matter how certain you are in your reasoning there will no doubt be someone else who feels exactly the opposite to you and will be just as certain of their position. We trust different sources of information, we have had different experiences with vaccines and we have different impressions of the threat of SARS-COV2 to us and our species.

I would suggest that those in the “vaccine cautionary” community would decline the vaccine based on their ideas around its potential risks. On the other hand, supporters of the vaccine are more likely to focus on its potential benefits. The debate has largely been centered around the disagreement people have about the risks. In this essay I will consider the uncertainty I and others have about its benefits.

Is the Medical Community biased about the Vaccine?

As a contributor to Collective Evolution I am well aware of the “cautionary” perspective on vaccinations and CDC directives. As a physician, I have a reasonable understanding of how those in the medical community regard the “best of what modern science has to offer”.

I am part of a Physician group on social media where doctors can seek advice from each other around all matters Covid-19, from interesting cases to rare side effects to how to address special concerns raised by patients. It has been alarming to realize how unilateral the support of vaccination is in this community.

I mean no disrespect to my medical colleagues. Many of those in this community have seen their patients die from this very real virus. They have had to struggle with the divergent directives coming from the CDC. They have had to work through many weeks where Personal Protective Equipment (PPE) was in short supply as their hospital wards rapidly reached capacity and overflowed.

Now that the Pfizer and Moderna vaccines have met minimum requirements for efficacy under the Emergency Use Authorization (EUA), they are faced with yet another impediment to getting themselves and their patients through this pandemic: growing skepticism around the vaccine coming from the very same people they are endeavoring to help. Their frustration around the situation is understandable, but is it biasing them?

Before consenting to any intervention it is important to understand its relative risks and benefits. As I mentioned earlier, there has been much concern in the “vaccine cautionary” sphere about side-effects and deaths.

Here I will take a closer look at what we know about the benefits of the vaccine based on Pfizer-Biontech’s  briefing document to the FDA’s Vaccines and Related Biological Products Advisory Committee. How confident can we be in the efficacy of the vaccine? Has the manufacturer done its due diligence in its analysis and in being transparent? These are the central questions that need to be answered.

Understanding False Positives and Negatives

There has been a lot of discussion about the rate of “false-positives” with regard to the Polymerase Chain Reaction (PCR) test for confirming infection with SARS-COV2. The PCR test can return a positive result even if only trace fragments of the virus are present.

Fragments of the virus on a nasal swab is not necessarily representative of an active infection or transmissibility. Moreover the sensitivity of this test is dependent on the number of amplification cycles, or the cycle threshold (Ct), used.  The Ct is not standardized. It is not unreasonable to say that there will be a percentage of people who test positive that do not have the disease. Nevertheless, without a better test we as the public must treat all positive PCR tests as an indication of an infection. We must assume the test is right. The rate of false positives, whatever it is, is directly proportional to the overestimation of the prevalence of the disease.

Here I would like to discuss the significance of “false-negatives”. These are people who get a negative PCR result but may still be infected. The rate of false negatives is directly proportional to the underestimation of disease prevalence.

This aspect of the inaccuracy of our primary diagnostic test gets relatively little attention for practical reasons. If you are suffering symptoms consistent with Covid-19 but have a negative PCR test we assume that you have Covid-19 anyway. In other words, if someone is symptomatic we assume that the test is wrong, i.e. that it is a false-negative, and necessary measures are taken. We quarantine and isolate until we feel healthy again whether we have Covid-19 or not.

Because we are in the midst of a pandemic we have no choice but to make these assumptions. We are responding appropriately given the limitations of the test. Because of the assumptions we are forced to make, we are exaggerating the prevalence of the disease and our response to it to some extent. It is the nature of the situation we are in.

How do we know that the Vaccine is 95% effective?

With this in mind I would like to discuss a post in the opinion blog of the British Medical Journal (BMJ) that appeared earlier this month. The author, Peter Doshi (PhD and Associate Editor at the BMJ), takes a rigorous look at the results reported by Pfizer regarding the efficacy of their mRNA vaccine. The success of their vaccine has been widely publicized to be 95%. Where exactly does this figure come from?

During the four weeks of observation (three weeks between 1st and 2nd dose followed by 7 days), 162 participants who received the placebo expressed symptoms of Covid-19 and tested positive by PCR. Compare that with only 8 in the group that received their experimental vaccine.

The chance of getting Covid 19 after receiving the vaccine was about 20 times lower than if you got the placebo. This is the basis of the claim that their vaccine was 95% effective, well over the 50% threshold required for Emergency Use Authorization that allows their product to be deployed despite the fact that the two-year Phase III trial is still 20 months from completion.

How did Pfizer handle study participants in the “Suspected Covid-19” group?

It is less commonly known that of the nearly 38,000 participants in the Pfizer study, 3,410 fell into a group labeled “suspected Covid-19”. These are people who developed symptoms consistent with disease but tested negative by PCR. 1,594 of those in this group received the vaccine and 1,816 received the placebo. It should be quite clear that how we regard this much bigger group of symptomatic participants will have an enormous impact on the true efficacy of the vaccine.

In other words, if we assume that the PCR test was accurate in all of these people and that they didn’t have Covid-19 and developed symptoms from another virus, the flu for example, then the vaccine would in fact be 95% effective as reported. On the other hand, if the PCR test was wrong every time and they all in fact had Covid-19, the efficacy of the vaccine would be much different: 1602 (1594 + 8) in the vaccine wing vs. 1978 (1816 + 162) in the placebo wing results in a vaccine efficacy of only 19%.

The PCR test (like any test) can be wrong some of the time and right some of the time. No test is 100% accurate, however in this situation the accuracy of the PCR test has a very large impact on how we interpret the results of the vaccine trial. The true efficacy of the Pfizer vaccine can be known only if we know how many symptomatic people in each wing had Covid-19 despite testing negative by PCR.

It is likely that the percentage of false negatives are different in each arm. As the FDA briefing document on the Pfizer study and the BMJ piece correctly note, there should be fewer false negatives in the vaccine group. Why? It is because there is a greater chance of developing Covid-19 symptoms after receiving the vaccine compared to getting a placebo. Reactogenicity, or the acute response of the body to the vaccine, is common.

Most of the acute inflammatory reaction to the vaccine occurs in the first seven days after receiving the vaccine. Looking more closely at the data, 409 patients in the vaccine group developed symptoms in the first seven days after inoculation. Compare this to 287 in the placebo group. If we assume that any participant who expressed symptoms in the first seven days must be suffering from the side effects of the vaccine or the placebo and not a new Covid-19 infection, the efficacy of the vaccine would still only be 29% if everyone else in that group was a false negative. This is admittedly a very large assumption but it is not outside the realm of possibility.

There are other more extreme possibilities. If all of the vaccinated participants who were suspected of Covid-19 truly did not have the disease and all of the unvaccinated (placebo) participants who were suspect did have the disease we would have a true miracle vaccine. Why? It would mean that only 8 people got the disease in the vaccinated group compared to 1978 in the placebo group. This would mean that the vaccine was approximately 99.6% effective. On the other hand, if all those who got vaccinated in the suspected group got Covid-19 and those who got the placebo didn’t, the vaccine would be not just ineffective, it would be dangerous.

Putting aside extreme and unlikely possibilities, the matter of the 3,412 “suspected Covid-19” participants and our assumptions about them still has very large implications. Let us say hypothetically that we as a nation decide to vaccinate our entire population with the Pfizer vaccine assuming that it has a 95% efficacy in preventing the disease.

In other words, we are assuming that none of those “suspected” of having Covid-19 actually have the disease. This is in fact the assumption that the FDA is making when approving the use of the vaccine under the EUA. We can predict that within a month about 6.3% people will develop Covid-like symptoms from something other than vaccine reactogenicity or the disease itself. This is based on the number of participants who became symptomatic (from something other than reactogenicity) despite getting the vaccine and testing negative (1,185) divided by the total number who got the vaccine (18,801) = 0.063. That’s what happened in the study.

In a population of 300 million, we would expect roughly 19 million people to develop symptoms of Covid from something other than SARS-COV2 within a month. We can agree that we must be extremely confident about whether these 19 million people have the disease or not. Why would we assume they all don’t have Covid-19 when the vaccine trial itself considered them to be “suspected” of having it? We won’t. We shouldn’t, and practically speaking, we will be in the same situation we are in right now.

Pfizer either did not do or report additional testing that would have helped

The real issue here is that we shouldn’t be guessing about such important numbers. What do you suppose Pfizer did, knowing that this larger pool of symptomatic participants could have an enormous impact on the estimation of their vaccine’s efficacy?

In my opinion, they should have tested everyone who developed symptoms for antibodies to help quantify the percentage of false negative PCR tests. If a participant felt like they were coming down with Covid-19 but had a negative PCR test, it seems clear that performing an antibody test would have offered additional clarity. This was either not done or not reported.

We must be careful when interpreting the power of a vaccine study. Although tens of thousands of people were enrolled, the only meaningful numbers with regard to efficacy have to do with those who contracted the disease during the period of observation. This is the only way to assess the efficacy of the vaccine. When Pfizer only considers participants that became symptomatic and tested positive we only have a group of 170 cases to cross compare.

The 3,410 people who became symptomatic but tested negative during the four weeks of observation would represent a much larger set of cohorts and would amplify the power of the study 20 fold if infection could be confirmed or ruled out through additional testing. In other words, the 3,410 symptomatic people should be the ones that Pfizer were hoping would emerge when they enrolled 37,000+ individuals in their study.

I find this lapse in diligence suspicious and at the very least inexplicable, especially in light of the latitude they are granted under the EUA. The fact of the matter is that we do not know if this was done. Pfizer, per their own protocol, will not make this data available until the trial is completed 20 months from now.

Why didn’t Pfizer look harder?

This forces us to ask some sobering questions. If Pfizer is required (or has agreed) to make all data available in two years, would they have conducted antibody tests on the “suspected Covid” group? If those results told a different story it would be quite damning, if not now, eventually. Their product would not be permitted for use under the EUA if a 50% efficacy requirement could not be met. On the other hand, if antibody tests were conducted and the results confirmed the impressive efficacy of the vaccine, why wouldn’t they have made the data available right now?

It should be clear that if Pfizer’s primary goal was to obtain approval under the EUA they would have had little incentive to do further testing to confirm their product’s efficacy. Why would they take the risk of seeking more information on 3,400 participants that could potentially overturn their results that were based on only 170 outcomes? This is where we must be very careful in our assessment of the situation.

If you believe Pfizer and vaccine manufacturers are only out for profit, it would be easy to conclude that they are being manipulative. If you believe that these corporations are seeking to improve public health and safety you may grant them a lot of latitude here. To be truly objective we must ask if they have been scientific in their approach.

At the very least I feel that they have not been diligent, and their position hints at disingenuousness: Pfizer didn’t mention this group of participants in their 92 page report or in their publication in the New England Journal of Medicine. This group was only mentioned in two paragraphs of a 53 page briefing to the Vaccines and Related Biological Products Advisory Committee (VRBPAC) of the FDA submitted December 10, 2020. The FDA, an agency of the department of Health and Human Services that ostensibly serves to protect the public by ensuring the safety of drugs, biological products and medical devices, continues to remain silent around this issue.

The Take Away

The 95% efficacy of the Pfizer vaccine is widely touted by the media and the medical establishment. Why didn’t Pfizer test or report the testing of an enormously important group of participants in their trial? We can predict that without these additional tests deploying the vaccine will not change our behavior nor our attitude to this pandemic.

SF Source Collective Evolution Jan 2021

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