Dr. Paul Offit is one of the most notable vaccine experts in the U.S. A member of the FDA’s Vaccines and Related Biological Products Advisory Committee for COVID-19 vaccines, Offit is the co-inventor of a rotavirus vaccine.
In a conversation with JAMA editor-in-chief Dr. Howard Bauchner, Offit shared his opinion on a range of subjects related to the Pfizer (NYSE:PFE) and Moderna (NSDQ:MRNA) vaccine candidates.
1. The performance similarity between the top two vaccines is reassuring
Both the Pfizer and Moderna vaccines rely on mRNA and had an efficacy rate of approximately 95% in Phase 3 clinical trials. The similarity in results is reassuring to Offit.
The two vaccines differ from each other in meaningful ways. Pfizer’s uses a 30-μg dose of mRNA, and Moderna’s uses a 100-μg amount. The two vaccines also have different nucleoside analogs and use unique lipid delivery systems. “That is why one is much more amenable to shipping and storing at –20° C whereas the other is shipping and storing at –70 to –80° C,” Offit said.
And yet, the two vaccines had “essentially the same results across the board,” Offit said. “It’s exactly what you would have wanted to see.”
2. Vaccines’ ability to protect against COVID-19 may be less in the real world
The 95% efficacy data from the Moderna and Pfizer vaccines is impressive. Early in the year, the possibility of having a single COVID-19 vaccine that is so efficacious, let alone two, by the end of the year seemed remote.
But one thing to keep in mind is that the vaccines’ ability to protect against COVID-19 may be less in the real world. While vaccine recipients may have 95% protection a week or two after receiving the second vaccine dose, the immune response will likely fade to some extent over time. The Moderna and Pfizer clinical trials were “looking at the best possible data,” Offit said. “People worry reasonably” about vaccine recipients’ immunity six months to a year later.
Another concern is the possibility that vaccine trial participants don’t reflect the general population. (Read on for more on that topic.)
3. COVID-19 vaccines will likely induce incomplete, short-term immunity
Viruses with short incubation periods where viremia is not part of the pathogenesis induce immunity that is generally short-lived, Offit said. That doesn’t necessarily mean immunity is measured in months, but in immunity that lasts for “years, not decades,” he added.
Additionally, the vaccines are likely to offer incomplete immunity. That is, they are unlikely to completely prevent the novel coronavirus from replicating in the body.
To be sure, COVID-19 vaccines are likely to offer significant protection against the virus. “I mean, if all you want to do is keep people out of the hospital and keep them out of the morgue, I think this vaccine can certainly do that — even if there is some fading of immunity over that six-month, one-year [or] two-year period after people get the vaccine,” Offit said.
4. Volunteer bias could have been an issue in the Pfizer and Moderna trials
In the Pfizer and Moderna trials, the incidence of COVID-19 was in the range of 0.7–0.85%. “That’s low,” Offit noted, saying said he would have expected the incidence to be around 3–3.5%.
“When you see it low like that, you worry that you are seeing something called ‘volunteer bias,’” Offit said. In other words, volunteers for the trials may be more attentive to their health and hygiene measures like mask-wearing and social distancing than the general population. If that is the case, the participants exposed to COVID-19 likely received a relatively small inoculum of the virus. “It may be easier to protect against a low-inoculum disease than a high-inoculum disease,” Offit said. When healthcare workers administer the vaccine in the real world, it may not be “as effective as you had hoped,” he added. “That’s another thing people are worried about.”
5. Vaccine safety can be a complicated subject
One of the prime drivers of vaccine hesitancy in the public is the fear that vaccines are not safe.
But the Moderna and Pfizer vaccines apparently have a good safety profile. “When these vaccines roll out, you’re going to be able to say that, at least in tens of thousands of people, there was no uncommon serious side effect that was seen within two months of getting a dose,” Offit said.
That finding is noteworthy because serious vaccine side effects tend to occur within six weeks of getting a dose. The Pfizer and Moderna vaccines are two-dose vaccines with adverse events that are most apparent after the second dose. But the side effects for both doses were generally mild for both the Pfizer and Moderna vaccines.
Examples of severe vaccine-linked side effects include the onset of Guillain-Barré syndrome following the flu vaccine in roughly one in one million patients and viscerotropic disease following the yellow fever vaccine in approximately the same proportion of people. Those both occurred relatively quickly.
“Gelatin allergies or latex allergies occur virtually immediately” following administration of vaccines that contain those substances, Offitt said.
Still, researchers may uncover serious side effects as the vaccines are administered to millions of people.
The notion of safety as it pertains to vaccines doesn’t mean that there is no risk at all. “The term ‘safety’ in the medical world means that benefits outweigh what are, at this point, theoretical risks,” Offit said.
One unknown factor is the use of mRNA in the Pfizer and Moderna vaccines. “We have no commercial experience with the messenger RNA vaccine,” Offit said.
6. Offit believes placebo recipients should be offered the vaccine
One moral quandary is that a significant number of clinical volunteers for COVID-19 vaccinations have received placebos. While refraining from giving that subset of volunteers a vaccine for as long as possible would result in the cleanest clinical trial data, it isn’t ethical to withhold the vaccine from them, Offit said. A clinical trial volunteer who is over 65 with comorbidities who received the placebo is at a high risk of having a severe COVID-19 infection.
7. Acute reactions from COVID vaccines could cause short-term problems
While the Moderna and Pfizer vaccines promise to be generally safe, somewhere around 10–20% of people who receive them are likely to have an acute reaction. “Now that could end up overwhelming the healthcare system at the same time that you don’t want people coming into clinics,” Bauchner said.
The fact that a portion of people receiving the vaccines will have a low-grade fever, headaches, muscle aches and fatigue makes it possible for at least some to miss work, Offit acknowledged. “You’re not going to vaccinate your whole emergency department [at once] and have them potentially be out the next day,” he said.
But the problem is likely a relatively minor one. “I wish the immune system had a better public relations team,” Offit quipped. The relatively minor side effects are “a natural consequence of having an activated immune system,” he said.
Filed Under: Drug Discovery, Drug Discovery and Development, Infectious Disease