FDA authorised new mRNA formula for kids without a clinical trial
By Maryanne Demasi, PhD
In October 2021, Pfizer requested the permission of the US Food and Drug Administration (FDA) to amend the formulation of its covid-19 vaccine for children aged 5-11 yrs.
Pfizer wanted to switch the “phosphate- buffered saline” used in previous adult formulations, to “tromethamine (Tris) buffer” and to exclude both sodium chloride and potassium chloride, claiming it “improved the stability profile of the vaccine.”
A Pfizer spokesperson said, “This allows the mRNA to resist being degraded for a longer period of time before administration - meaning the pediatric vaccine can be stored [at] 2-8°C in commonly available refrigerators for up to 10 weeks.”
The FDA granted Pfizer’s request stating that Tris buffer was “a commonly used buffer in other FDA-approved vaccines.”
But there was a problem. There were no clinical studies of the new formula in children. The FDA only looked at the “analytical comparability” and did not request any safety or efficacy studies of the newly formulated vaccine prior to it being rolled out to millions of children.
Experts aghast
“It’s extraordinary,” said Nikolai Petrovsky, Chairman and Research director of Vaxine Pty Ltd, an Adelaide-based biotechnology company focused on vaccine development, including a covid-19 vaccine.
“I’ve been doing vaccine development for a long time and normally regulators say the minute you change something in a formulation that may change its behaviour in a material way, you have to go back to square one and establish safety all over again, to show the change mightn’t have adverse consequences. The FDA apparently did not do this in this case,” he said.
The silence from the medical community is deafening said Petrovsky. “Why is no one questioning this? It’s the regulator's job to act on the side of caution and assume any change could have harmful effects until proven otherwise.”
As a vaccinologist, Petrovsky said that altering a vaccine formula, especially for new technology such as mRNA, has too many unknowns.
“Pfizer said they changed the formula for stability – well, does that mean the mRNA in the new stabilised paediatric formulation is more potent or going to last in the body longer? If so, you may see big differences in biological outcomes. And what else is the change in buffer doing to those complex lipid nanoparticles in the mRNA formulations?” asks Petrovsky.
The FDA defended its decision saying that Tris buffer has been used in other vaccines (incl Moderna) and proven to be safe, but Petrovsky says that misses the point. “No-one is questioning the safety of the buffer – it’s about how it might change the properties of this particular mRNA vaccine in its lipid nanoparticles,” he said.
“If you have a biologic that is stable for two weeks, and then you swap the buffer so that it becomes stable for 10 weeks, then you don’t have the same biologic because they don’t have the same half-life. You’ve done something that has completely changed the way this biologic behaves. How do we know that that biologic isn't going to behave differently in the body? How do we know it hasn't changed its safety?” added Petrovsky.
Tom Jefferson, senior associate tutor at the University of Oxford, agrees. “It’s not acceptable. What the manufacturer has done, is taken steps which I think are not scientifically based and are ethically challenging. If you have a vaccine, it’s made in vats like a big soup. If you change the phosphate buffer, then you change your formulation and so you have to test it sufficiently. Manufacturing a vaccine is very different to making a drug.”
Most drugs are highly stable, small chemical molecules that can be easily analysed with a mass spectrometer but biologics - like vaccines - are on another level.
“Biologics have a trillion times more complexity than small molecule drugs, biologics can exhibit completely different properties depending on how the protein, or in this case, mRNA chain folds up. That's why you need different FDA departments to regulate them, because the things that go wrong with biologics are much more complex than the things that go wrong with small molecule drugs,” said Petrovsky.
Now, the FDA is set to green-light more changes to the covid-19 vaccine in the absence of clinical data. On 28 June 2022, the FDA’s advisory panel voted to recommended that manufacturers update the design of their booster shots to include components tailored to combat the currently dominant omicron BA.4 and BA.5 variants.
Notably, Peter Marks, head of the FDA’s Center for Biologics Evaluation and Research told Reuters that the agency would “not require companies to submit clinical trial data on the modified vaccines.” Instead, the agency would rely on the previous data from clinical trials of vaccines designed to combat the BA.1 variant.
Will history repeat?
Jefferson says that we are not learning from past mistakes, pointing to the Pandemrix scandal. The Pandemrix vaccine was initially developed as a pandemic “mock-up” vaccine using the H5N1 strain with the purpose of being ready to tweak in the event of a pandemic.
In 2009, when the ‘swine flu’ outbreak occurred, the vaccine’s formulation was altered to accommodate the circulating H1N1 strain.
There was insufficient testing of the newly formulated vaccine in paediatric populations and by the following year, Scandinavian researchers noticed increased cases of narcolepsy in children - an incurable neurological disease that causes alteration of the sleep-wake cycles and may cause lack of muscle control.
Despite denials from the European regulator and the vaccine manufacturer, multiple academic and government-led studies subsequently judged that the link between Pandemrix and narcolepsy was likely to be ‘causal’.
Another example of how tweaking a vaccine can result in dramatic clinical outcomes, is the experience with Merck’s MMRV vaccine, which combined the measles/mumps/rubella vaccine with the varicella (chicken pox) vaccine.
Authorities noticed that when the two vaccines were combined, it resulted in higher rates of febrile seizures in 1yr olds, compared to administering the two vaccines separately.
Despite being based on two existing vaccines, simply mixing the two into a single shot, was enough of a change to make a big difference in real world harms. The MMRV vaccine was soon suspended for that age group and is now administered as two separate shots.
It’s still unclear what impact, if any, there has been on safety since the change in covid-19 vaccine formulation for 5-11yr olds, but since then, Pfizer has swapped the buffers in the adult vaccine (Comirnaty), too.