All Eggs in One Basket, One Critical Misstep Made? | Multiple studies breakdown
- The approval and recommendation process
Let’s have a very quick recap of the events that lead to the authorization and recommendation of the BA.5 bivalent vaccine.
On June 28, the FDA Vaccine and Related biological products advisory committee held a meeting with representatives from Pfizer, Moderna, and Novavax and voted to recommend the inclusion of an Omicron component for the COVID-19 booster vaccines in the US. Including Dr. Paul Offit; two members disagree with the recommendation. FDA further specifies that the new booster vaccine should have the original and BA.5 omicron components and not the BA.1 omicron components, with an understanding that the vaccine manufacturers will not have human clinical data on the BA.4/5 bivalent vaccine before the Fall booster campaign.
On August 22 and 23rd, Pfizer and Moderna separately submitted their BA.4/5 bivalent vaccine EUA application to the FDA.
Then the FDA did not hold any more advisory committee meetings and authorized the new booster from both companies on August 31.
The CDC Advisory Committee on Immunization Practice (ACIP) held their meeting the next day and voted to recommend the bivalents vaccine for their respective age groups. Dr. Walensky signed off that same night.
The whole process was extremely fast, so why is there such an urgency? What is the added benefit of fast-tracking the new booster without human clinical data?
- Personal Benefits
According to the CDC’s presentation, it concluded that the benefits of bivalents vaccines increase immune response. The booster also further increases the high levels of protection against severe disease. Notice that the CDC recognized the rapid waning of protection against asymptomatic or mild disease. They made no claims on how well the updated booster can protect against mild disease and transmission. (Oliver 68)
Even though the BA.1 bivalent vaccine stimulates higher levels of antibody production than the original booster, they do not know the incremental increase in vaccine effectiveness of the BA.4/5 booster due to the lack of human clinical trial data. There is no available data to support the estimation of the new booster’s duration of protection. Although they think it may have a longer duration. (Oliver 69)
In a most recent PBS News interview with Dr. Fauci on September 2nd, he expressed that the benefits vary considerably depending upon one’s risk. An elderly person or someone with an underlying condition would benefit more than a young, healthy person. I agree with Dr. Fauci’s statement. The only catch is that currently, there are no quantitative assessments of clinical benefit, which seems the regulatory agencies may have lowered the bar for these new boosters.
Argument:
Throughout the ACIP meeting, a few committee members voiced reservations about the BA.4/5 bivalent vaccine due to the lack of human clinical data. CDC representative emphasized that the new booster is an extension of the COVID mRNA vaccines that have been used for more than two years, and there are extensive data collected regarding its safety and effectiveness. The booster does not need human clinical data, just like how the annual flu vaccines are not tested in humans every year before its marketed.
This argument makes sense, but have we learned enough about the mRNA vaccine to apply the same annual flu vaccine principle to it?
According to a review article written by a renowned American physician and vaccine expert, Dr. Stanley Plotkin, who also co-authored a vaccine book with Dr. Paul Offit, not all vaccine immune responses are correlated to the same degree of protection.
He stated in one of the six central principles, “It is important to define protection against what. Correlates may differ quantitatively and qualitatively, depending on whether the objective is to prevent system infection, mucosal infection, disease, or severe disease.
During the early phase of the mRNA vaccine roll-out, the vaccine’s goal was to prevent infection, but with waning immunity and virus mutation, the goals have changed to prevent severe disease and death. Until today, there is still no robust knowledge of how COVID vaccine antibody responses correlate to preventing disease or severe disease. While the bivalent vaccines have quantitatively shown a higher number than the original vaccine, the truly clinical impact remains unpredictable.
Dr. Plotkin also stated that the literature on the correlates of protection against influenza is rich. But even with such extensive experience with inactivated flu vaccines, the young and the old have different degrees of correlation. For instance, in adults up to about 50 years old, serum IgG antibodies correlate well with protection.
But more compelling evidence suggests cytotoxic T cells and granzyme B production correlate better with protection than antibodies do in the elderly.
Both Moderna and Pfizer only presented antibody levels as their evidence of immunogenicity. Their evidence would be much more convincing if they could present cellular immunity data. It is baffling that companies with so many resources are still reluctant to release these data to the public.
In addition, Pfizer’s other bivalent vaccine trials in humans have only been conducted in people aged 18 and above. Based on our rich experience with the seasonal flu vaccine, we know there are age differences. Yet, their BA.4/5 bivalent vaccine received authorization and recommendation for people as young as 12.
Perhaps, we could reasonably assume that the new vaccine is not likely to pose additional risk to these young people, but what are the bases for accessing the incremental benefit?
- Personal Risks
Myocarditis is a known risk for both COVID infection and COVID vaccination. A recent detailed analysis of nearly 43 million people was published on August 22nd in the American Heart Association journal Circulation. Seven working days ahead of the FDA issuing EUA to the bivalent vaccine.
In brief, this article concluded that in men under 40 years old, the risk of myocarditis after receiving the second dose of the Moderna vaccine is higher than in those infected with COVID. There are also uncertainly with sequential vaccine doses.
In fact, Germany, and France, have restricted the use of the Moderna vaccine in men under thirty years old. Finland, Sweden, and Denmark also have a similar age restriction in Moderna use for young males. These restrictions were initiated in late 2021, and it does not seem the US FDA and CDC have considered that option.
Argument:
Someone may argue that we could not directly compare European and American vaccine practices because our healthcare systems are very different.
This is absolutely correct!
American hospitals stay are known to be the most expensive among developed countries.
According to a published poster abstract in a 2019 American College of Cardiology meeting, the average hospital charge for myocarditis hospitalization was $110,568 in 2014, with an average length of stay of 7.4 days.
While there are no publicly available similar data from European countries, a review article from Germany described the average hospitalization cost of the acute phase of myocardial infarction, commonly known as heart attack, which is a much more severe heart injury than myocarditis, to be only between 6790 and 8919 euros per admission.
Even in the worst exchange rate for the US dollars in 2014, an average heart attack hospital stay in Germany would only cost as much as 12500 US dollars, roughly ten times less than a myocarditis hospitalization stays in the US.
Even though Germany has a much lower hospitalization stay cost than the US, they still choose on the cautionary side to protect their young males from rare vaccine injuries. Why have US regulatory bodies not taken that into consideration?
When both the risk and incremental benefits of the new bivalent vaccine in young males are arguable, even the cost-saving effect of COVID or COVID-vaccine-related myocarditis hospitalization stay becomes questionable.
- Public Benefits
The main public benefit of giving the new bivalent vaccine early in September before human data is available in November or December is the potential additional hospitalization and death reduction by 137,000 and 9700 cases, respectively, based on complex computer modeling prediction. (Oliver 51)
In addition, the model also predicted that authorizing the new booster to 18 and above would lead to at least a 20% and 15% reduction in hospitalizations and deaths, respectively, versus a recommendation for individuals ages 50 and above only.
Again, this model still omits the public benefits of authorization and recommendation for all people 12 to 17.
If there is anything we have learned about the pandemic and the virus, it is extremely difficult to make precise predictions due to its dynamic nature. I have also mistakenly been too optimistic about the end of the pandemic back in March in one of my videos.
A study was published in early 2021 to assess the reliability of COVID-19 modeling techniques. It suggested that some models were relatively accurate while others were not. The longer the period covered by the model, the likely more accurate the estimates tend to be.
Note that CDC models are estimated until April 2023.
Argument:
But do we absolutely need this new booster to provide public benefits? Why can’t we use the old one with human clinical data?
A new modeling study in pre-print led by Deborah Cromer, a mathematical modeler at the University of South Wales (UNSW) in Sydney, Australia, suggested that the differences between the original booster and variant-based booster appeared to be very subtle, according to the study.
It also suggested that even though boosters are more effective when they resemble the circulating variants, they add little extra protection when the population immunity is already high, which is the case in the US with all prior vaccinations and infections.
According to Dr. John Moore, a vaccine scientist at Weill Cornell Medicine in New York City, “This is not some kind of super-shield against infection compared to what you could have got two weeks ago or a month ago,”
- All Eggs in One Basket and FDA’s Misstep
The CDC has relaxed most of the guidance for testing, distancing, and quarantine. It is betting on a higher uptake of the new bivalent vaccine to prevent the anticipated winter COVID surge.
CDC’s survey of 171 people showed that 72% of respondents were willing to get an updated booster; my poll appears to have a very different result.
Many respondents believe protection from previous doses is enough, and an updated booster is not effective. Some are also worried about the side effects of the updated vaccine. It is, in part, likely due to a lack of human clinical data.
Even though there were still plenty of monovalent COVID vaccines left, and with more than two years of effectiveness and safety data, the FDA decided to remove its authorization for individuals 12 years and up.
At this point, FDA and CDC have put everyone in the bivalent basket. Let’s hope their bet on the bivalent vaccine is good enough to save the public and not a misstep in wasting vaccine resources and eroding trust in the public.
