VERIFY: New COVID booster approved from final study of mice, not humans

According to documents on the CDC website, human tests of Moderna’s version of the new booster are still “ongoing.” Right now, there is only final evidence from “8-10 mice” per group.”

The FDA’s website shows for Pfizer the agency also relayed on the final study evidence from “8 mice.” But human trials are also ongoing. So far, the new boosters “showed a similar local reaction and systemic event profile.” That means side effects appear to be about the same including “mild to moderate injection site pain, fatigue, and muscle pain.”

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“To advance the Omicron BA.4/BA.5 bivalent vaccine as rapidly as possible, regulators, including the FDA, WHO and EMA, have advised that our submissions be based on safety and immunogenicity data generated in adults with an Omicron BA.1 bivalent vaccine and supported by BA.4/BA.5 bivalent pre-clinical data and BA.4/BA.5 bivalent quality and manufacturing data. These packages follow a similar model to that provided to public health officials who evaluate seasonal flu vaccines each year. Moving forward, this approach may help address the pressing need for vaccines that provide a high level of protection against current and emerging variants of concern so that we can remain vigilant against this evolving virus. The FDA has authorized our Omicron BA.4/BA.5 bivalent vaccine based on clinical data generated in adults with an Omicron BA.1 bivalent vaccine, pre-clinical data with a BA.4/BA.5 bivalent vaccine and BA.4/BA.5 bivalent quality and manufacturing data. Pre-clinical data showed a booster dose of Pfizer and BioNTech’s Omicron BA.4/BA.5- bivalent vaccine generated a strong neutralizing antibody response against Omicron BA.1, BA.2 and BA.4/BA.5 variants, as well as the original wild-type strain. A clinical study investigating the safety, tolerability and immunogenicity of the Omicron BA.4/BA.5 bivalent vaccine in individuals 12 years of age and older is ongoing. Data will be shared with regulators when available. We are facing a virus with an exceptionally high mutation rate, which the nimble mRNA platform is well situated to address. Only the mRNA sequence requires updating to match emerging strains, and utilizing a bivalent vaccine aims to provide broader coverage against known and future COVID-19 variants of concern.”

Related:

COVID Boosters Are Critical, But Using Only Animal Data Is a Needless Gamble

Numerous issues are at play here. First, compared to the original virus or amongst themselves, subvariants like BA.1, BA.4 and BA.5 can vary considerably in terms of their acute effects in humans, like the havoc they wreak on the immune system and their capacity to evolve and spread. Almost all new COVID-19 variants, including the Omicron subvariants, have not been fully characterized yet. Simply put, we do not know enough about these subvariants to bypass testing them in humans, prior to making their booster vaccines available to millions. We are also just beginning to understand their long-haul effects.

Second, substituting the efficacy data in mice, or any artificial animal model, for human data is extraordinary under any circumstances. It is not a secret that scientific findings in animals often fail to translate to medical discoveries in humans. In fact, 90 percent of experimental drugs tested on animals do not work in humans due to either safety or efficacy issues. In most contexts, animal data used to inform clinical applications need to be met with the utmost skepticism.

Separately, it is hard to reconcile this FDA approach with the landmark decision taken at the March 2020 meeting of the International Coalition of Medicines Regulatory Authorities (ICMRA) — more specifically during the Global regulatory workshop on COVID-19 vaccine development. There, global regulators stipulated that, “It is not required to demonstrate the efficacy of the SARS-CoV-2 vaccine candidate in animal challenge models prior to proceeding to FIH [first in humans] clinical trials.” That important policy decision was a vital step to accelerate the development of successful vaccines in the first place. Ostensibly, now the reverse is being promoted by the FDA.

In retrospect, much of the COVID-19 animal data generated during the pandemic produced more questions than answers. Had it not been for the world’s full attention on developing vaccines, relying only on artificial animal models for directions and “next steps” could have been catastrophic from the standpoint of saving time or generating actionable information. For instance, studying COVID-19 in mice, the most widespread model in the world, is misleading. Mice — unlike humans — are not naturally susceptible to COVID-19 due to a key structural difference between the two species in their host-pathogen interaction. For example, a cell surface receptor (ACE2) that serves as a doorway for coronaviruses to infect cells is unresponsive in mice. Murine models had to be artificially modified or “humanized” before they could be infected.

Furthermore, non-human primates (NHPs), considered closer to humans than other species, showed very mild clinical symptoms in response to SARS-CoV-2, practically rendering them unreliable as research models for COVID-19. No fatalities from disease burden were registered in SARS-CoV-2 infected NHPs, making them also inappropriate for modeling COVID-19-induced multisystem organ failure, a hallmark of COVID-19-related deaths. In fact, an objective examination of the many artificial animal models used to study COVID-19 reveals disparate characteristics — with hardly any capturing the sequela of COVID-19 infections in humans. Radical structural, physiological, anatomic, digestive, genomic, metabolic and behavioral differences underlie those discrepancies among species.

In fairness, the FDA has taken concrete steps to explore innovative technologies that could reduce the reliance on artificial animal models. These include advancing the science and applications of Microphysiological Systems (MPS) — a category of sophisticated research tools, like Organ-Chips, also known as alternative methods to animal experimentation. These advanced systems are made possible by the convergence of many disciplines such as biophysics, regenerative medicine and electrical engineering. For instance, the FDA was a co-host of an inaugural World Summit focusing on MPS earlier in 2022. The agency also sustains programs like the Predictive Toxicology Roadmap and ISTAND with somewhat similar objectives. More recently, a new initiative, although poorly funded, has been conceived by the FDA “to implement a cross-agency New Alternative Methods Program.” In its budget proposal for fiscal year 2023, the agency expressly stated that, “New alternative methods have the potential to provide both more timely and more predictive information to accelerate product development and enhance emergency preparedness.” In addition to Organ-Chips, alternative methods include artificial intelligence (AI) or machine learning approaches as well as three-dimensional (3D) bioprinting techniques, which are sophisticated engineering methods for the fabrication of biomedical parts that replicate the features of natural human tissues.