I originally published When Does a Human Life Begin? 17 Timepoints here at DNA Science in 2013. My intent was to inform…
Science and medical writers have been under an avalanche of information for nearly a year now, as we translate technical information about COVID-19 for the public. Links to the latest journal articles overload our inboxes, but, at the beginning and now during another surge, tracking down experts to interview has been difficult. They’re simply too busy saving lives.
A critical resource for me has been the series of JAMA Live Q+A webinars for the media hosted by Howard Bauchner, editor-in-chief of the Journal of the American Medical Association. It is wonderful to hear the top clinicians and researchers speak freely, at length, and in context, or meander – a nice contrast to the echoing soundbites of mainstream media.
JAMA webinar speakers have included the career scientists who’ve already led us through the waters of HIV/AIDS, hepatitis, influenza, Ebola, zika, SARS, and other epidemics and pandemics. Anthony Fauci is a frequent guest – I wrote up his talk with FDA’s Peter Marks here.
The webinars also feature the young clinicians battling our new enemy. Early on, Maurizio Cecconi’s session, “Coronavirus in Italy: Report From the Front Lines,” brought me to tears. The head of the Anaesthesia and Intensive Care Department at Humanitas Research Hospital in Milan, Dr. Cecconi described, at the webinar and in a report (both accessible here), the admission of “patient zero” to the ICU in Lombardy, on February 20, 2020, and how his infection was traced to a local friend who’d had contact with an infected person from China. The 38-year-old was initially not very ill and partied a lot. And the rest is medical history.
Recently Dr. Bauchner spoke with Paul Offit, who directs the Vaccine Education Center and is an attending physician in the Division of Infectious Diseases at Children’s Hospital of Philadelphia. He’s on the FDA Advisory panel that will meet December 10 to discuss Pfizer’s COVID-19 vaccine and on the 17th to consider Moderna’s.
Dr. Offit is best known for co-inventing a vaccine against rotavirus, a diarrheal disease that has claimed millions of lives. It became available in the US in 2006, and is on the World Health Organization’s list of essential medicines. The clinical trials for the rotavirus vaccine RotaTeq took four years and involved 70,000 participants – much more typical than the lightning speed of the COVID vaccine trajectory.
Here’s the Q+A from December 2, lightly edited, with my explanations in parentheses. I’ve omitted the discussion of who gets vaccine when – that’s all over the news.
Dr. Bauchner: Are the two COVID vaccines that FDA will consider soon safe? We believe they work. But that’s not the issue that will persuade people to be vaccinated.
Dr. Offit: Most people who will eventually be getting a vaccine are healthy and young and unlikely to die from this virus. What we can say now is at least in tens of thousands of people, there have been no uncommon serious side effects within 2 months of getting the dose. But there are serious side effects to vaccines, and they occur within 6 weeks. Yellow fever caused yellow fever in one in a million people after they’d received the vaccine. People may have allergic reactions to gelatin or latex in vaccines, or intussusception (a twisted intestine, in an early rotavirus vaccine). And oral polio vaccine was a rare cause of polio in one in 1.4 million doses.
We are testing these vaccines with one foot in the water. We’ll have tens of millions of people, more than that, getting vaccine before the general population gets it. That will build a bigger safety profile.
The vaccine data so far are the tip of the iceberg. We still have to look at the base to see if anything is cracking and whether the tip is true. That being said, 20,000 people receiving a vaccine isn’t the same as 20 million. We will only find out the rare adverse events after approval of the vaccines. Another side to this is the choice not to get vaccinated, but that choice is not risk-free. It is taking a different risk.
In the medical world, safety means benefits outweigh the risks, but not absolute safety. We have to be open-minded to the fact that serous adverse events might happen.
Dr. Bauchner: The Pfizer and Moderna vaccines are mRNA; all the others you mention are more traditional, with the virus manipulated in some way, inactivated or attenuated. Does the fact that these first two vaccines are mRNA make you more or less concerned?
Dr. Offit: More concerned. We have no commercial experience with them. The vaccines are naked pieces of mRNA encapsulated in a complex lipid delivery system that enables the cell to take it up. If you injected the mRNA straight, ribonucleases (enzymes that dismantle RNA) would dissolve it. Once in the cell, the mRNA begins self-reproducing. It’s now making the coronavirus spike protein, which, for the most part, gets inserted into the cell membrane and to a lesser extent into the circulation.
The foreign proteins will be broken up into 15 to 20 “mers” (pieces) and placed on the cell so helper and cytotoxic T cells see them. The mers are also on antigen-presenting cells (which alert the immune system), and myocytes (muscle cells) too, perhaps just the ones that are damaged from the injection. We don’t know exactly.
What turns it off? In mice it goes on for 10 days. In humans, I don’t know. We’ll find that out.
Dr. Bauchner: Can someone switch to a different vaccine for the second dose?
Dr. Offit: If a vaccine uses adenovirus and then you switch to a vaccine that uses a different adenovirus, make sure there is no cross reactivity that would neutralize the vector. The Pfizer and Moderna vaccines, both based on mRNA, are not interchangeable. They use different doses, mRNA constructs, and lipid formulations.
Dr. Bauchner: How will we learn about whether pregnant women, kids, and people with autoimmune disorders taking biologics can take a COVID vaccine?
Dr. Offit: Pfizer initially enrolled people over 18 and then dropped it to 16 and then to 12. Moderna announced a prospective placebo-controlled study in people aged 12 to 18. Even though pregnant women were not part of the studies, they’re never actually excluded because anyone who gets a vaccine and then finds out she is pregnant will be followed up. So there will be some data. People with an autoimmune disorder are in the trials; they included a variety of co-morbidities and that was one.
Dr. Bauchner: What happens to people who received placebo in the trials? Should they receive active vaccine?
Dr. Offit: Ethically they should. If the vaccine is very clearly shown to work and you have volunteered and perhaps are over 65 or have a co-morbidity, you should get the vaccine. We can still learn from that trial. We can follow both groups, people who got the vaccine early or 6 months later. It’s a good way to see if efficacy fades.
Dr. Bauchner: Ten to 20 percent of vaccinated people get an acute reaction. Could that overwhelm the health care system at a time when we don’t want people coming in to clinics? Especially in the later phases when vaccinations are given at CVS and Walgreens. Will people then go call their primary care providers with reaction symptoms?
Dr. Offit: The Advisory Committee on Immunization Practices (ACIP) addressed that. mRNA vaccines do induce an immune response and you have certain symptoms of activation – muscle aches, fatigue, fever, enough to miss a day of work. I wish the immune system had a better PR team. The symptoms are a natural consequence of an activated immune system. A hospital is not going to vaccinate an entire ER staff at once.
Dr. Bauchner: You developed a vaccine that saved millions of lives, the rotavirus vaccine. Based on that, do you have a sense about how long immunity will last from the COVID vaccines? What are your instincts?
Dr. Offit: The rotavirus vaccine story is that it provides protection for years, not decades, and not sterilizing immunity. But that’s ok. All you want to do is keep people out of the hospital and the morgue. These (COVID) vaccines will do that even if there is a fading of immunity after the second or third year. High frequency of memory B and T cells protect against moderate to severe disease. Memory T cells are the best predictor. That’s what we’ll be looking for on December 10th and 17th when we evaluate the Pfizer and Moderna vaccines. (I recently wrote about T cells in COVID in MedPage Today.)
Dr. Bauchner: Is genetic shift a concern with COVID vaccines, like it is for influenza? (Genetic shift is a sudden, large change in genes that encode proteins that dot a virus’s surface. Genetic drift refers to continual small-scale mutations, such as of a single DNA base).
Dr. Offit: Flu is a segmented virus, so it undergoes shift and drift. This new virus (SARS-CoV-2) mutates because it’s genome is single-stranded RNA. So far there has been no evidence that mutation has caused it to mutate away from a vaccine. Measles virus is also single-stranded RNA and in 60 years it has never mutated away from the vaccine. I predict that will also happen here. But immunity will fade after a year or two. There will be the same need for a booster like for flu, which mutates constantly.
(ME AGAIN) I note in the JAMA webinars the emphasis of the experts on the fact that what we know as scientists is always being amended, by new observations and findings in experiments, including clinical trials. “Settled science” and “clinical proof” have made it into our lexicon, but these terms do not reflect the way that scientific inquiry actually works – and that can lead to unrealistic expectations and even accusations that an expert’s statement is “wrong.” So I’ll end with Dr. Offit’s words on the matter, in the context of COVID.
“We’re always a little uncertain. You have to be humble. There are things I’m sure we don’t know, and we have to be open to the fact that we don’t know everything. We are dealing with a pandemic that has brought us to our knees, with massive joblessness, homelessness, and illness. If these vaccines are in any way like the top line data look, they will be a lifesaver.”
My gratitude to Dr. Bauchner and all of his guests, and all of the journals that have provided unprecedented access, and to the public information officers who track down sources and set up interviews, for keeping us informed.