#137 - Paul Offit, M.D.: An expert perspective on COVID-19 vaccines

KEYPOINTS

• 01

  A childhood hospital stay shaped Offit's career

  In the 1950s Offit had a clubfoot operation that the surgeon himself advised against, and it failed. He then spent about six weeks in a chronic-care children's hospital ward of about 20 children, many with polio, some in iron lungs. Parents could visit one hour a week, on Sundays from 2 to 3. He says the experience pushed him toward pediatrics and preventing childhood disease.

• 02

  The modern anti-vaccine movement grew from fraud

  Andrew Wakefield's Lancet paper on 12 children was not just wrong but 'knowing fraud', misrepresenting both clinical and biological data. Since then, many studies have found no link between MMR and autism. Offit cites an Autism Science Foundation survey showing about 85% of parents of autistic children no longer believe vaccines caused it. He worries that COVID disrupted routine childhood vaccination, which had been near the 95% needed for measles.

• 03

  Rotavirus shows why big trials and caution matter

  Before vaccines, rotavirus hospitalized about 75,000 US children a year and killed about 500,000 children worldwide, up to 2,000 a day, mostly under age two. Offit's rotavirus vaccine took 26 years. Its final trial enrolled about 70,000 babies, half on placebo, partly because RotaShield, an earlier vaccine, was pulled within about 10 months of licensure. It caused intussusception (bowel blockage) in roughly 1 in 10,000 to 1 in 30,000 recipients, which pre-licensure trials were too small to detect.

• 04

  Normal vaccine development takes 15–20 years and at least $1 billion

  Phase 1 tests doses in about 20–100 people. Phase 2 expands to hundreds or thousands. Phase 3 involves tens of thousands. Operation Warp Speed compressed this by running steps in parallel and paying to manufacture tens of millions of doses before knowing whether they worked, a financial risk no company would normally take.

• 05

  The mRNA candidates differ in dose and cold chain

  Moderna's vaccine came out of NIH work and uses 100 micrograms per dose in a two-dose series. Pfizer's uses a lower dose but must ship and be stored at -70 to -80°C, compared with Moderna's -20°C, an 'ultra-cold chain' challenge.

• 06

  How the phase 3 trials judge efficacy

  With about 30,000 people randomized one-to-one, the trials needed roughly 150–160 symptomatic cases to show statistically robust efficacy. Offit, who sits on the FDA's vaccine advisory committee (meeting October 22), explained why the first vaccines would come via Emergency Use Authorization rather than full licensure, simply because of time.

• 07

  Adenovirus vectors carry real but rare risks

  The adenovirus vaccines deliver about 10 billion particles per dose. Offit recalls Jesse Gelsinger, who died about 20 years earlier at Penn of a massive cytokine reaction to an Ad5 gene-therapy vector. The vaccine dose is about 1/300th of what Gelsinger received, but rare events surface only in millions of people. AstraZeneca's trial holds were for neurological events, including transverse myelitis (about 1 in 200,000 in the general population), which was judged likely coincidental.

• 08

  Coronaviruses don't change type the way flu does

  Measles has never really changed serotype, so the 1963 vaccine still works. The four common cold coronaviruses, identified in the 1960s, cause about 15–20% of the respiratory illness seen in hospitals. Offit hoped SARS-CoV-2 would behave more like measles, so that a vaccine that works now still works years later.

• 09

  Other platforms were coming too

  Purified-protein vaccines use the approach behind the hepatitis B vaccine (since the early 1990s), the HPV vaccine (around 2006) and the flu vaccine Flublok, so their record is long. Merck was a step behind, with candidates including a replication-competent vesicular stomatitis virus vector. Russia's vaccine (Ad5 then Ad26) was announced by Putin in late August before any phase 3 results.

• 10

  Vaccines may do better than natural infection

  Short incubation periods let infection outrun memory cells. Measles' 10–14 days gives memory cells time to activate. Offit sees some hope that a vaccine could induce better immunity than infection does.