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Peter Attia MD#160 - Paul Offit, MD: Latest on COVID-19 vaccines and their safety, herd immunity, & viral variants
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CHAPTERS
- 0:02 – 5:39
Status of the Four Vaccine Strategies
Attia asks for a lay of the land on the four vaccine strategies. Offit surveys where the mRNA, adenovirus-vector, purified-protein and killed or live-attenuated vaccines stand, and the two discuss the history of vaccine approaches back to cowpox and Pasteur.
- •The FDA advisory committee approved the Pfizer mRNA vaccine on Dec 10 and Moderna's on Dec 17; over 120 million people have had at least one mRNA dose
- •Adenovirus-vector vaccines include AstraZeneca/Oxford and J&J's Ad26, which had been used in about 200,000 Ebola doses
- •Novavax uses a baculovirus system like the one used to make FluBlok, and China's vaccine is a killed whole-virus product
- •Cowpox in the late 1700s was the oldest vaccine, followed by Pasteur's killed rabies vaccine
- 5:39 – 13:51
Is mRNA Too Experimental? DNA Alteration and Long-Term Safety
Attia raises the common objection that mRNA vaccines are experimental and could have long-term effects. Offit explains why mRNA cannot alter DNA and argues that serious vaccine side effects have historically appeared within weeks.
- •mRNA vaccines are a genetic strategy, which is why people hear it as gene therapy
- •mRNA cannot alter DNA because it lacks a nuclear access signal, reverse transcriptase and integrase
- •Offit cites narcolepsy with Pandemrix, vaccine-strain polio, Guillain-Barré and yellow fever disease as examples of serious effects that appeared within weeks
- •He says vaccines are followed for about two months after the last dose for this reason
- 13:51 – 20:11
HIV as a Counterpoint and Lessons from Failed Vaccines
Attia asks about HIV and why a vaccine has failed. Offit describes how HIV mutates during a single infection and infects T helper cells, and what earlier vaccine efforts taught researchers.
- •HIV keeps mutating its surface glycoprotein during a single infection
- •It replicates in T helper cells, which orchestrate the immune response
- •Merck's multibillion-dollar adenovirus-vector HIV vaccine failed and in some ways was worse for the vaccinated
- •Offit says lessons carried over from adenovirus work for Ebola, and he compares HIV to the elusive universal flu vaccine
- 20:11 – 28:06
Where SARS-CoV-2 Falls on the Mutation Spectrum and Variants of Concern
Attia places influenza and polio at opposite ends of the mutation spectrum and asks where the coronavirus fits. Offit explains that it mutates more slowly than flu, and discusses how variants will be monitored for immune escape.
- •Flu mutates constantly, while measles has never mutated away from its 1960s vaccine; SARS-CoV-2 falls in between
- •Variants arise mainly as the virus becomes more contagious, starting with D614G
- •B117 is close enough to the original strain for vaccines to work well, and immunity still protects against severe disease from other variants
- •Escape would be signaled by fully immunized or previously infected people being hospitalized or dying, and tested by neutralization of variants in the lab
- •Neutralization assays ignore T helper cell responses, which tend to be broader
- 28:06 – 35:12
Incubation Period, Immune Memory and Durable Immunity
Offit explains how incubation period shapes whether a virus can be eliminated, placing SARS-CoV-2 in between. The two then walk through antigen presentation and memory cells, and why mRNA vaccines are seen as strong immunogens.
- •Longer-incubation viruses like measles can be eliminated, while shorter-incubation mucosal infections can only be modified
- •SARS-CoV-2's six-day incubation puts it in between, and Offit says immunization or natural infection are the two choices going forward
- •Antigen-presenting cells activate T helper cells, which drive antibody production and cytotoxic T cells
- •Work by Shane Crotty and others suggests memory cells last after natural infection, and mRNA vaccines stimulate T cell responses
- •Lymph node enlargement after vaccination reflects a powerful immune response, as Attia's MRI experience illustrated
- 35:12 – 36:47
One Dose or Two: Why the Second mRNA Dose Matters
Attia asks why J&J works after one injection while the mRNA vaccines need two. Offit says adenovirus vaccines induce cellular immunity after one dose and stresses the importance of the second mRNA dose.
- •The J&J Ad26 vaccine induces cellular immunity after a single dose, while mRNA vaccines need a second dose
- •Offit says he doesn't know why this difference exists
- •Some respected epidemiologists have argued for first-dose-first strategies, citing about 80% protection after one dose versus 90–95% after two
- •Offit worries people will confuse one-dose J&J with the two-dose mRNA regimen and settle for less durable protection against drifting variants
- 36:47 – 41:34
Relative vs. Absolute Risk Reduction
Attia argues that the press and vaccine makers failed to distinguish relative from absolute risk reduction, using J&J versus Pfizer and Moderna as the example. Offit adds the Pfizer trial numbers and a street-crossing analogy.
- •Headline efficacy figures were 95–96% for mRNA vaccines versus about 66% for J&J
- •Attia says absolute risk reduction was about 1.7% for J&J, 1.2% for Moderna and under 1% for Pfizer
- •Offit recalls roughly 165 placebo cases versus eight vaccine cases in the Pfizer trial of about 40,000 people
- •A low absolute risk reduction means a lower NNT for J&J, which Attia put at about 60
- •Offit compares relative and absolute risk to crossing the street versus standing on the lawn
- 41:34 – 46:59
The J&J Pause Over Brain Blood Clots
Attia and Offit discuss the pause of the J&J vaccine after reports of rare clotting. They weigh roughly 1 case per million against the deaths prevented and Offit's worry about public confidence.
- •Six serious clotting episodes, all in women and one fatal, were reported among about 6.9 million people given J&J
- •Offit estimates around 1,850 deaths prevented per million vaccinated against about one clot case
- •The pause alerted doctors not to treat with heparin and to watch for headache, chest pain, shortness of breath and leg pain within two weeks
- •Offit fears the pause will chill uptake of all COVID vaccines, noting cities stopped giving the vaccine
- 46:59 – 59:41
Herd Immunity and the Vaccine Hesitancy Debate
Attia asks what herd immunity requires. Offit says the virus will be controlled rather than eliminated, needing about 80% immunity, and the two debate natural infection, personal choice, mandates and obligations to vulnerable people.
- •Offit compares control of SARS-CoV-2 to rotavirus, which dropped sharply after vaccination but was not eliminated
- •He expects at least 80% immunity is needed and that vaccination will continue for years, as with polio
- •Offit says natural infection may not match vaccination in durability, and a single vaccine dose for the previously infected is reasonable
- •Offit and Attia agree on requiring vaccination for hospital workers but differ on individual choice in general
- •Offit tells the story of Luke, a child with leukemia who spoke at the California hearings on vaccine exemptions
- 59:41 – 1:07:18
Timeline to Herd Immunity, Vaccinating Children and Boosters
Offit estimates how long it will take to reach herd immunity and says next winter will be the test. They discuss vaccinating children, including the severity of MIS-C, and when the need for boosters will become clear.
- •Offit calculates roughly another 120 million people need full immunization, possibly within three or four months at three million doses a day
- •The test of herd immunity will be whether winter brings a surge
- •Vaccination of children is expected to extend to age six by early next year, and Offit describes MIS-C as frightening
- •Offit says that vaccinating older adults is already lowering deaths
- •Offit expects booster needs to be clearer in about two years and doubts immunity lasts decades
- 1:07:18 – 1:11:06
Theories on the Origin of SARS-CoV-2
Attia raises the natural spillover and lab-escape theories. Offit discusses gain-of-function research, says he doubts humans could have made this virus, and holds that the question is knowable with early sequence data.
- •The two competing theories are spillover from bats via an intermediate species and an accidental lab escape near Wuhan
- •Offit notes gain-of-function studies exist but doubts humans were smart enough to make this virus
- •He says the question is knowable via early sequences and sera, as with tracing HIV to Cameroon in the 1930s
- •His bias is a bat-to-human jump through an unidentified intermediate host, and he says China has not been open with data
- 1:11:06 – 1:26:48
Preparing for the Next Pandemic and Lessons from Failures
Attia and Offit discuss the likelihood of future coronavirus pandemics and what should change. They cover international surveillance and vaccine sharing, and what they see as the biggest failure: testing.
- •Offit says SARS, MERS and SARS-CoV-2 show another pandemic virus will emerge
- •Asymptomatic transmission made this virus far harder to contain than SARS or MERS
- •Offit calls for international surveillance and collaboration, and for vaccine access for all countries, noting mRNA doses are only micrograms
- •Heidi Larson's work finds France least confident in vaccines, and Offit distinguishes vaccine skeptics from cynics
- •Both identify the failure of early testing as a key mistake, including the CDC's flawed test and the lack of other test makers
