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Peter Attia MD#137 - Paul Offit, M.D.: An expert perspective on COVID-19 vaccines
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CHAPTERS
- 0:11 – 4:21
Episode Overview and Guest Introduction
Peter Attia introduces Paul Offit, a pediatric infectious disease specialist, vaccine expert and co-inventor of the rotavirus vaccine. He explains why he waited to record, and previews the four vaccine strategies and the risks they will cover.
- •Offit's roles at CHOP, Penn and the FDA vaccine advisory committee
- •Attia waited until the COVID vaccine pipeline was clearer
- •Episode covers four vaccine strategies, major companies and risks
- •Preview of what 2021 might look like
- 4:21 – 7:59
A Childhood in a Polio-Era Hospital Ward
Offit recounts being born with clubfeet and a failed surgery at age five that landed him in a chronic care hospital in the 1950s. He describes the isolation of the ward, with its polio patients and one weekly visiting hour. He says these scars shaped his path into pediatrics and child advocacy.
- •Born with clubfeet; his father insisted on a surgery that failed
- •Six weeks in a chronic care children's hospital during the polio era
- •Only one visiting hour a week; he waited by the window for his parents
- •Returned as a medical student and cried at that same window
- •His career and books are motivated by standing up for vulnerable children
- 7:59 – 17:07
Wakefield's Fraud and the Anti-Vaccine Movement
Attia raises the fraudulent Wakefield paper, and Offit says he comes down on the angry side. They discuss how Wakefield misrepresented clinical and biological data, how he eventually lost mainstream media, and why parents misremember or seek hope. Offit notes that MMR and autism has been studied in 18 studies across seven countries.
- •Offit calls Wakefield a knowing fraud who misrepresented clinical and biological data
- •Brian Deer's work showed the biopsy findings were contaminant, per Attia
- •Wakefield's downfall helped marginalize anti-vaccine voices in mainstream media
- •Eighteen studies in seven countries found no link between MMR and autism
- •Parents look for reasons, and Wakefield offered hope and took advantage of them
- 17:07 – 21:18
Offit's Work: The Vaccine Education Center and Rotavirus
Offit describes his 26-year effort to create the RotaTeq vaccine and the founding of the Vaccine Education Center. He explains what rotavirus is, how many children it sickens and kills, and why deaths differ so much between the US and the developing world.
- •Twenty-six years spent creating the bovine-human reassortant RotaTeq vaccine
- •Vaccine Education Center created to answer public and press questions about vaccines
- •Rotavirus hospitalized about 75,000 US children yearly, and killed about 500,000 worldwide
- •Deaths differ because of resources like IV access, not disease severity
- •Seeing how hard vaccines are to make and how easy to damn them drove his passion
- 21:18 – 27:19
Building the Rotavirus Vaccine and the RotaShield Lesson
Offit explains the Jennerian approach of using animal rotavirus strains, and why natural immunity is short-lived for mucosal viruses. He then describes RotaShield, which caused rare intussusception that went undetected before licensure, and draws a humility lesson for COVID vaccines.
- •Natural infection gave protection against moderate to severe disease but not lifelong
- •Cow-human reassortant viruses were used as an oral vaccine
- •RotaShield caused intussusception in roughly 1 in 10,000 to 1 in 30,000 recipients
- •The rare effect was missed pre-licensure despite 50 years of study
- •Offit says COVID vaccine strategies call for real humility
- 27:19 – 32:37
Vaccine Trial Phases, Timeline and Cost
Offit walks through preclinical work and phases one to three for vaccines, including trial sizes and the use of surrogate immune markers. He and Attia note that a normal vaccine takes 15 to 20 years and at least a billion dollars.
- •Preclinical animal studies provide proof of concept
- •Phase one is 20 to 100 people with dose ranging
- •Phase two involves hundreds of people and still uses surrogate markers
- •Phase three is tens of thousands; rotavirus trial had 70,000 babies
- •Normal timeline is 15 to 20 years and at least a billion dollars
- 32:37 – 37:08
Operation Warp Speed and the Genetic Plug-and-Play Vaccines
Offit credits the government's Operation Warp Speed for removing financial risk, making a vaccine in about a year and a quarter possible. He then explains the spike protein and how mRNA, DNA and adenovirus-vector vaccines all deliver the spike gene, making them the easiest to build and produce.
- •Government paid for phase three trials and at-risk mass production
- •A vaccine within roughly a year and a quarter is described as unimaginably fast
- •Spike protein is the target because it attaches the virus to cells
- •mRNA, DNA and vector vaccines are genetic plug-and-play platforms
- •They come first because they are easiest to construct and mass produce
- 37:08 – 44:21
mRNA Vaccines: Moderna, Pfizer and the Cold Chain
The discussion covers the instability of mRNA, lipid encapsulation, and the differing storage needs of Moderna's and Pfizer's vaccines. Offit also explains the odd persistence of viral mRNA in PCR tests, and raises worries about how distribution in real-world pharmacies could affect effectiveness.
- •mRNA is labile and encapsulated in a lipid delivery system
- •Moderna stores at minus 20, Pfizer at minus 70 to minus 80
- •NIH partnered only with Moderna and holds the patent on its construct
- •Offit worries real-world handling could reduce effectiveness compared to the trials
- •PCR positivity for months reflects mRNA, not infectious virus
- 44:21 – 51:16
Trial Data Timing, Emergency Use Authorization and Safety Follow-Up
Offit explains how data monitoring boards decide when a trial has enough cases, and why these vaccines will go through emergency use authorization rather than full licensure. He argues that two months of safety follow-up has historically been enough to detect serious vaccine side effects.
- •The company doesn't know who got vaccine or placebo; a Data Safety Monitoring Board does
- •About 150 cases are needed to reject the null hypothesis
- •EUA is a permission to use without full data, chosen because of limited time
- •Offit gives examples of serious vaccine side effects that were identified within two months
- •Effectiveness is likely at least short term, with boosters as worst case
- 51:16 – 58:04
Adenovirus-Vector Vaccines, Clinical Holds and Russian and Chinese Products
Offit describes his safety worries about replication-defective adenovirus vaccines, including clinical holds on Johnson & Johnson and AstraZeneca trials and the Jesse Gelsinger history. He also covers the Chinese and Russian vaccines and what is known about Merck's candidates.
- •Vector vaccines need about ten billion particles per dose and can cause fever and chills
- •Clinical holds involved J&J and AstraZeneca, the latter for neurological issues
- •The Jesse Gelsinger case involved a far larger adenovirus dose
- •China and Russia approved adenovirus vaccines without phase three results, per Offit
- •Merck is working on vesicular stomatitis virus and measles vector candidates
- 58:04 – 1:03:35
Purified Protein and Inactivated Vaccine Strategies
Offit explains the recombinant protein approach used in hepatitis B, HPV and Flublok vaccines, and why it is considered the most benign. He points to Novavax and Sanofi/GSK, notes Shingrix's adjuvants, and mentions that inactivated vaccines are coming from China.
- •Recombinant protein vaccines have decades of commercial experience
- •Novavax and Sanofi/GSK use the purified protein approach
- •Shingrix works better than the live vaccine thanks to strong adjuvants
- •Novavax's adjuvant is similar, so it might suit older people
- •Inactivated vaccines appear to come out of China
- 1:03:35 – 1:12:55
Genetic Drift, Immunity Questions and Fading Antibodies
Offit predicts SARS-CoV-2 will behave more like measles than influenza, so vaccines may not need yearly updating. They discuss whether prior human coronavirus exposure protects, neutralizing antibodies, memory cells, and why fading antibodies shouldn't cause alarm, along with male-female differences and blood type.
- •As a single-stranded RNA virus it mutates, but Offit predicts measles-like stability
- •Offit doesn't think earlier human coronavirus infections offer meaningful protection
- •Neutralizing antibodies against the spike's receptor binding domain are the goal
- •Memory B and T cells matter for medium-incubation diseases, so fading antibodies aren't alarming
- •Blood type protection is considered unproven
- 1:12:55 – 1:21:56
Distribution, Rationing and Whether Offit Would Take the Vaccine
Offit describes priority groups that add up to roughly half of US adults and the challenges of rationing, two-dose logistics and ultra-cold storage. He says he would take the vaccine after seeing the data, and explains that vasculitis and long-term effects of the virus concern him most.
- •First-tier groups total about 150 million adults, needing 300 million doses
- •Department of Defense leads distribution under Operation Warp Speed, with states apportioning
- •Offit says hospital mandates are not fair for novel vaccine strategies yet
- •He would take the vaccine once he sees data representing people his age
- •Vasculitis and long-term effects make the virus more than a flu-like illness
- 1:21:56 – 1:29:46
Vaccinating Children and the Role of Fever
Offit says children are less likely to be severely affected, with deaths comparable to flu, so there is no compelling push for a child vaccine. He discusses placebo groups, immuno-bridging, and expanded access, then explains his view that treating fever with Tylenol or ibuprofen can weaken the immune response.
- •Under-21s are about 26% of the population but 0.08% of deaths
- •Child trials could use placebo controls or immuno-bridging studies
- •Vaccinating control groups after EUA loses safety and efficacy information
- •Fever helps the immune system work better, and suppressing it can worsen illness
- •Febrile seizures are benign, but environmental fevers like heatstroke are dangerous
- 1:29:46 – 1:36:05
Why Some Vaccines Fail: RSV, Measles and Fusion Proteins, and Closing
Offit explains that early inactivated RSV and measles vaccines in the 1960s caused worse disease on exposure, which is a concern for fusion proteins like that of SARS-CoV-2. Attia and Offit then wrap up, stressing that the vaccine rollout will be gradual rather than a binary switch.
- •Formaldehyde-inactivated RSV vaccine made children more likely to get pneumonia and some died
- •The 1963 inactivated measles vaccine caused atypical pneumonia
- •SARS-CoV-2 also has a fusion protein, so the shape of the vaccine protein matters
- •Offit worries about altered protein conformation across all platforms
- •Both emphasize the rollout will be gradual with ongoing learning
