On August 31, 2022, the Food and Drug Administration (FDA) approved two new bivalent COVID-19 booster vaccines by Pfizer and Moderna respectively.
Both vaccines target the original virus strain, as well as the latest prevalent strains of Omicron—the BA.4 and BA.5 subvariants. These strains are currently responsible for almost all new cases of COVID-19 infection in the United States.
Moderna’s new bivalent booster has been authorized for use among people aged 18 years or older, while Pfizer’s booster has been approved for persons aged 12 years or older.
All Safety Data Rests on Just 8 Mice
I was surprised to see this piece of news, because no clinical data related to these two BA.4/5 bivalent vaccines could be found.
For instance, in terms of clinical trials, for Moderna’s new Omicron boosters, there are only data on one-month serum neutralizing antibodies for the BA1 bivalent vaccine (not the approved BA.4/5 bivalent vaccine), and no data on the clinical protection rates. The approved BA.4/5 vaccine, on the other hand, has had no human trial so far. And their animal trial data have not been made public, either.
The FDA’s authorization of a vaccine containing the BA.4/5 subvariants based on partial data from another vaccine containing the BA.1 subvariant’s mRNA sequence is baffling.
Regarding the new Pfizer vaccine, an article published in the Science Magazine revealed that data from only eight mice vaccinated with the BA.4/5 bivalent vaccine as the third dose were available at the June FDA meeting. However, these data hadn’t been made public when the Pfizer BA.4/5 bivalent vaccine was approved by the FDA.
This is quite unusual, for such a new type of vaccine, one that has been newly applied in response to such a rapidly changing virus.
In response, the FDA stated that during a pandemic, if they wait for all the data to come in, they would miss the opportunity to save people.
FDA officials also compared the production of COVID-19 vaccines with the approach of updating the annual flu vaccines and concluded that all the evidence supported their decision.
2 Major Risks Are Associated With Designing New Booster Vaccines
Although the FDA’s starting point and intentions appear to be good, they do not make up for the lack of scientific evidence. Scientists have long been concerned about the uncertainty of COVID vaccine design in light of the fast mutation of new Omicron subvariants.
1. Fast Mutation of Virus Strains Renders Vaccine Design Difficult
For example, an article published in June 2022 in the journal Nature pointed out that rapidly mutating variants further complicate vaccine updates. Emerging variants and erratic immune responses mean that it is still difficult to determine what a new vaccine should be like.
The graph below shows the rapid changes in the Omicron subvariants. Back in March 2022, there was a lot of interest in BA.1, and it was assumed that BA.1 was a problem that people would be dealing with in the future.
However, circumstances changed with the passage of time. The Omicron virus strain has been producing one new generation almost every two months, and currently, the BA.4 and BA.5 subvariants account for over 90 percent of new infections.
In fact, virologists were previously very concerned about the SARS-CoV-2 virus’s rapid mutation. They believed that it was quite possible that a completely new variant would pop up from one of the SARS-CoV-2 family tree branches. If the upcoming vaccines were based on the original Omicron BA.1 subvariant, it was likely that the prevalent Omicron strains would be different when they are administered later in 2022.
Unfortunately, this scenario became true.
Furthermore, scientists have also warned that updating COVID-19 vaccines is not as simple as just swapping the mRNA based on the genetic material of the old virus strain and replacing it with the mRNA of another variant.
To give a layman’s example, when making clothes, you can cut off part of the fabric and patch it up with a new piece of fabric. However, this is not the case with updating vaccines.
Any biological phenomenon that involves the human body and can change its structure and/or function is complex, multidimensional, and multifaceted.
If a new SARS-CoV-2 viral RNA sequence is added directly to the original vaccine platform and administered into the body, will the desired effect occur?
2. Risk of ADE Effect, With the Vaccine Aggravating the Infection
We are afraid that the consequences would be much more complex than people may think. One of the key reasons is that vaccine-induced antibodies are not one single type but rather a heterogeneous group of proteins. There are “good” and “bad” antibodies.
When the mRNA vaccine enters the body, the body’s immune system can generate various antibodies against the full-length fragment of the mRNA of the spike protein.
The neutralizing antibodies are protective and bind tightly to the spike proteins on the surface of the virus and thus surround the virus. Surrounded viruses will be removed by immune cells successfully.
Therefore, neutralizing antibodies are “good antibodies” and are tested for potency in phase III clinical trials of the vaccines.
However, there are antibodies that, instead of protecting the individual against infection, actually promote infection. These “bad antibodies” also bind to proteins on the surface of the virus, but rather loosely, so that they do not have the power to assist in the removal of the virus. Instead, they assist in the entry of the virus into the body’s cells through some mechanisms, thus enhancing the viral infection. And this is called antibody-dependent enhancement (ADE).
ADE has an effect of promoting infection rather than protecting against infection.
It can be said that the vaccine produces protective antibodies when injected into the body, which is the ideal state. However, the actual situation can produce different antibodies, both good and bad ones, acting as a double-edged sword.
ADE has been found to be present in more than 40 viruses. It was first found in the dengue virus and later found in SARS and MERS.
3 Pieces of Experimental Evidence of the ADE Effect
Several scholars have published articles in various authoritative journals discussing the possible ADE risks induced by the development of new COVID-19 vaccines.
A review published in 2020 in the International Journal of Infectious Diseases summarized the mechanisms of the ADE in relation to the SARS-CoV-2 virus. In this review, a total of five potential ADE mechanisms were identified and discussed including the binding of antibody Fc fragments to cellular surface receptors and complement activation.
A 2020 article in the journal Nature Microbiology suggested two consequences of ADE: increased viral infection and exacerbation of the disease after infection.
The two papers mentioned above are theoretical discussions. So what is the experimental evidence for the ADE?
The SARS vaccine development is a wonderful example. After the SARS outbreak took place in 2003, people started to study SARS vaccines. And as a result, researchers found the ADE effect in in vitro, primate, and human experiments.
Due to the ADE effect, the development of SARS vaccines eventually failed.
Example 1: ADE Infection in Mice
Dr. Gary Nabel from the Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health analyzed the impact of the spike proteins of different SARS virus strains on the ADE effect in 2004.
They injected some mice with the spike proteins of SARS virus strains Urbani and SZ3, and two different viral chimeras, SU and US.
In total, there were only 17 amino acid differences in these spike protein fragments, of which only five amino acid differences were found in the receptor binding regions of these fragments.
The results of the neutralizing antibody experiments revealed that the antibodies produced in the mice after being induced by the virus strain Urbani’s spike protein fragments acted as a neutralizer. That is, this is the production of the aforementioned good antibodies, and they protect normal cells from infection, as shown by the leftmost column in the graph below.
If the viral strain Urbani is altered by introducing a spike receptor binding region from another viral strain SZ3, it will form a chimeric virus US. The originally generated antibodies produced by the old virus strain (Urbani) in mice would no longer act as a neutralizing agent. Instead, they have an ADE effect. That is, the antibodies not only have no protective effect, but they also enhance the infection of cells by the “mutated” virus, as shown by the longest upside down column in the graph.
This is a similar situation for COVID. When the COVID-19 vaccines based on Wuhan strain in early 2020 were applied globally since 2021, the antibodies generated to that old strain did not necessarily protect people against the newly mutated SARS-CoV-2 viruses but may rather enhance those later mutants of alpha, gamma, delta, or omicron.
Example 2: ADE Infection in SARS Patients
Another is an in vitro cell experiment conducted by scholars from Japan and China.
The researchers used the antibody-containing sera from SARS patients in their study. It was found that antibodies produced against certain antigenic fragments had the ability to neutralize the virus and effectively prevent infection, while some fragment-induced antibodies would enhance infection in in vitro studies.
As shown in the below graph, the blue bars represent the ability of different antibodies to prevent the virus from entering cells. Therefore, the leftmost antibody is protective of the cells. However, the two other antibodies not only had no protective power, but they also promoted viral infection of cells, which is the ADE phenomenon.
Example 3: ADE of Pathology
In the third study using rhesus monkeys, the investigators administered SARS-inactivated vaccine intramuscularly to the monkeys with a booster injection on day 14. The SARS virus was dropped into the nasal cavity of the animals on day 14 after the booster injection.
The animals were then executed after six days, and their lung tissues were collected for testing to determine if the vaccine was protective of the animals.
As it turned out, after post-vaccination exposure to the virus, protected monkeys had slightly widened lung septum, with no significant abnormalities.
After post-vaccination exposure to the virus, the monkeys experiencing the ADE effect had widened lung septum, pulmonary septal rupture, macrophage and lymphocyte infiltration, intra-alveolar fibrin, and edema.
Unvaccinated and SARS-infected monkeys had widened lung septum, and visible macrophage infiltration with alveolar epithelial hyperplasia.
This study provides pathological evidence for the occurrence of the ADE phenomenon in primates exposed to the SARS virus after vaccination.
New Bivalent Omicron Booster Vaccines May Increase the Risk of ADE Effect
Based on the research evidence, it is clear that when the virus mutates, especially after the mutation of the receptor-binding region of the viral spike protein, the antibodies produced by using it to immunize animals may not block the virus from entering the cells. Rather, unfavorable effects of enhanced infection or increased disease severity occur instead.
For instance, viruses originally enter cells through only one gate, the ACE2 receptor. However, these variant viral antibodies open a “side door” for these viruses to infect human cells through other means.
Even if it was not easy for a certain virus to invade human cells, with the assistance of these “bad antibodies,” the viral infection becomes easier.
The most common mutated region is the RBD receptor binding region, and it is also the main mutated part of BA.1, BA.4, and BA.5 subvariants.
All the above information answers our key question: After a virus mutates, the mutated virus gene cannot be simply replaced to make a new vaccine that can be widely used in a population.
This is because the antibodies produced after the viral gene change are very complex, and the bad antibodies play the opposite of the intended role. Therefore, the development of a new vaccine has to be studied and analyzed to determine what type of antibodies the vaccine induces and whether there will be a promotion of viral infection.
So making a new vaccine is not simply a matter of replacing the “contents” with the mRNA of the BA.4/5 subvariants.
If the newly authorized vaccines are widely used in a population, by the time the next wave of virus variants becomes prevalent, the new variants are likely to be different again from the current BA.4 and BA.5 subvariants. Some of the anti-BA.4 and BA.5 antibodies that remain in the human body may bind to some of the spike proteins on the surface of the new variants and play a neutralizing role. However, it is also possible that some other antibodies play a role in enhancing the infection of the new variants.
The concentration of neutralizing antibodies is one side of the coin. There is another side: the ADE effect, which needs to be carefully weighed.
In fact, this risk has always existed, because the SARS-CoV-2 virus has always been changing, and people have been receiving vaccination with the vaccines against the outdated virus variants of 2020.
To date, regarding the ADE risk, we have not seen any vaccine company publicly state that they have done experiments to exclude the risks of ADE and found that their vaccines do not induce ADE phenomenon involving the Alpha, Beta, and Delta variants.
On the contrary, we often see some clinical data, or epidemiological survey data, where some countries with high rates of vaccination have seen an increase in infection rates instead of a decrease.
A study published in 2021 in the European Journal of Epidemiology examined the relationship between the percentage of the population that are fully vaccinated (i.e. two doses of the COVID-19 vaccines) and new COVID-19 cases across 68 countries and 2,947 counties in the United States.
The findings were surprising.
Those countries with higher rates of full vaccination had higher rather than lower rates of COVID-19 cases per 1 million people in the past seven days, in comparison with countries with low rates of full vaccination.
Let’s take a look at two examples.
Israel has a full vaccination rate of over 60 percent. It has 6,224 new COVID-19 cases per 1 million people, the highest number of all the 68 countries. In Vietnam and South Africa, where the full vaccination rate is 10 percent, the number of new infections per 1 million was 820 and 870, respectively.
This data should in fact lead people to reflect on whether it is possible that the antibodies produced after vaccination may cause ADE to increase the risk of infection.
The new Omicron vaccines will be widely used in the population, so we cannot ignore the experimental exploration of the ADE effect. This is because it is a major issue that affects the lives and health of so many people.
Are the COVID-19 Vaccines Comparable to the Influenza Vaccines?
Some people may ask: the influenza virus has different strains every year, and the influenza vaccine is updated every year and developed at a rapid pace. So can the concept of influenza vaccine development be applied to the development of the COVID-19 vaccines?
My answer is no, although FDA officials have a different answer for this.
First, the influenza vaccines have been on the market since 1945. The influenza vaccines use two technical routes, inactivated and attenuated vaccines, and the technical platform is relatively mature, which belongs to the traditional vaccine development approach.
In contrast, the existing COVID-19 vaccines are mRNA vaccines, which are a relatively new type of vaccines. The known damages of mRNA vaccines to the human body include damage to mitochondria, suppression of the immune system, damage to the repair mechanism of DNA, and damage to the blood system.
The mRNA vaccines were widely used in humans for the first time during this COVID-19 pandemic.
Second, the flu vaccine annual immunization program is not necessarily a gold standard for people to cope with ever-changing viruses.
People seem to be used to being vaccinated every year by a new flu jab made based on the predicted new strain. But how effective is the flu vaccine used every year?
In a comprehensive analysis published in The Lancet in 2012, the effectiveness of influenza vaccine in protecting adults was 59 percent.
How effective are the flu vaccines today?
According to the interim analysis data on the CDC website, influenza vaccine effectiveness was only 34 to 35 percent from 2021 to 2022, far below the WHO requirement of a basic minimum of 50 percent for vaccine protection.
A study in Medical Virology found the same ADE phenomenon for the flu vaccines. The relationship between the decreased protection rate and the ADE phenomenon induced by vaccination should be examined.
What Should be Included in the Assessment of Vaccine Risks by Regulatory Agencies?
The SARS-CoV 2 virus is changing so rapidly, and vaccine designs are mostly using the novel mRNA vaccine platform. Going forward, it should be emphasized that it will be critical for regulators to assess the risk of ADE in animal studies and clinical vaccine studies.
In addition to ADE, another complication risk is enhanced respiratory disease (ERD), a mechanism associated with ADE, and it has been observed in animal studies of SARS and MERS vaccines.
While manufacturing new vaccines, in addition to in vitro cytology experiments and human studies to check the titer of neutralizing antibodies, other relevant immune parameters (e.g. T-cell response and cytokine profile) have to be examined to check whether or not they point to the desired Th1-biased immune response.
It is necessary to use different animal models to detect ADE/ERD related risks to evaluate the safety of a new COVID-19 vaccine. All the above tests are possible before human vaccine trials are performed. All data should also be made public. This current practice of blindly pushing vaccine booster shots without the necessary safety risk assessment may bring health risks to people who receive vaccines in the future. We do not want these things to happen, so these potential adverse events need to be prevented beforehand.
Making vaccines is not a matter as simple as putting together matching puzzle pieces.
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