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Peter Attia MD#115–David Watkins, PhD: Immunology, monoclonal antibodies, & vaccine strategies for COVID-19
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CHAPTERS
- 0:11 – 4:39
Episode Preview and the Freezer Truck Disaster
Peter Attia introduces Professor David Watkins and previews the episode's immunology primer and focus on monoclonal antibodies. Watkins then describes how a truck carrying his freezers from Miami to Washington, DC caught fire and destroyed over a hundred thousand samples.
- •Preview of the Immunology 101 discussion and vaccine categories
- •Watkins' move from the University of Miami to GW Medical School
- •Truck fire in North Carolina destroyed samples from some thirty years of research
- •Work with the insurer on regenerating the most important samples
- 4:39 – 11:04
Watkins' Path from the West Indies to Immunology and HIV
Attia explains why he and colleagues approached Watkins, a question about how long immunity lasts after infection. Watkins traces his path from Uganda and the West Indies through evolutionary biology, HIV, and Brazil and tropical viruses. He names the adaptive immune response as the biggest step in immune evolution.
- •Question of how long immunity lasts after infection
- •Born in Uganda, raised in the West Indies, schooled in South Wales
- •Training as an evolutionary biologist who found HIV a dramatic example of evolution
- •Love of Brazil led to work on Zika and dengue
- •T and B cells are found even in amphibians, so adaptive immunity is ancient
- 11:04 – 16:57
Immunology 101: Innate Response and How B Cells Make Antibodies
Watkins walks through how infection triggers the innate response and then the adaptive arms, focusing on B cells. He describes affinity maturation in lymph nodes, defines antigen as a piece of the virus recognized as non-self, and explains how this underlies vaccination.
- •Virus infection triggers sensors and interferons that turn on adaptive immunity
- •B cells mutate their receptors with each division and are selected for tighter binding
- •Antigen means a recognizable piece of virus that the body sees as not self
- •Pre-made antibodies protect on re-exposure, the basis of vaccination
- 16:57 – 25:56
Neutralizing Antibodies, IgM vs IgG, and Variability in Response
Watkins explains that only neutralizing antibodies block the virus from entering cells, and Attia asks about IgM, IgG and IgA. They discuss a study in which nearly 20% of seropositive people made no neutralizing antibodies, and the open question of reinfection.
- •Neutralizing antibodies cover the part of the spike that binds the human cell receptor
- •IgM appears first and signals recent infection, then IgG follows
- •A Rockefeller study found almost 20% of about 70 people lacked neutralizing antibodies
- •Titers varied widely, from 1 in 100 to 1 in 5,000 dilutions
- •Whether people without neutralizing antibodies can be reinfected remains unknown
- 25:56 – 32:44
Yellow Fever 17D Vaccine and Attenuated Viruses
Watkins describes a study of the attenuated yellow fever 17D vaccine, which produced strong neutralizing responses against the vaccine virus. Responses against wild-type virus from a monkey varied, and some people made none. He also notes the rare risk of illness from the attenuated vaccine.
- •17D is an attenuated virus cultured through many rounds of tissue culture
- •Vaccinated people made neutralizing antibodies at around 1 in 5,000 dilution
- •Some individuals made no response to a primary wild-type isolate
- •Rare serious illness occurs in about one in 300,000 recipients
- 32:44 – 36:24
Memory B Cells, Plasma Cells, and Why Antibody Tests Don't Show Neutralization
Attia summarizes the B cell story, and Watkins adds how affinity-matured cells become memory B cells or bone marrow plasma cells. They establish that common IgG/IgM serology tests measure binding antibody, not neutralization, and Watkins explains why neutralization assays are difficult.
- •Plasma cells in bone marrow act as antibody factories
- •Standard serology measures antibody bound to a viral piece, not neutralizing ability
- •Attia says this was a surprise to him as a physician
- •Neutralization assays require incubating serum with live virus and watching cells for days
- 36:24 – 51:02
T Cells: How CD8 Killer Cells Destroy Infected Cells
Watkins explains the power of cytotoxic CD8 T cells, using the SIV monkey experiment in which T cells wiped out the infecting virus and selected for mutants. He describes how MHC molecules display viral pieces so killer cells can shut down virus factories, and the role of helper cells and MHC diversity.
- •CD8 T cells wiped out virus targeting eight amino acids in SIV-infected monkeys
- •Antibodies cannot act once the virus is inside a cell
- •MHC molecules display viral pieces like flags on infected cells
- •Both arms of immunity are needed, supported by CD4 helper cells
- •MHC diversity explains why transplants are rejected and varies who the virus escapes from
- 51:02 – 56:49
Why HIV Has No Vaccine: Variability and Sugar Shield
Attia asks why HIV lacks a vaccine, and Watkins explains that most vaccines rely on neutralizing antibodies, which are very hard to induce against HIV. He cites massive viral diversity from error-prone replication in a chronic infection, few envelope copies, and a sugar shield.
- •Most licensed vaccines depend on neutralizing antibodies
- •HIV escapes both CD8 T cells and antibodies through mutation
- •Vaccination so far yields binding but not neutralizing antibodies
- •Envelope is covered in sugars and varies by as much as 30%
- 56:49 – 1:05:05
Lessons from HIV and the Hepatitis C Cure
Attia and Watkins discuss how drug therapy changed HIV and how Watkins saw the science unfold over thirty years, from identifying the virus to AZT, combination drugs and PrEP. They then turn to hepatitis C, where curative drugs arrived without a vaccine, and apply the lesson of using multiple approaches to coronavirus.
- •HAART turned HIV from fatal to chronic
- •Condoms, drugs, and PrEP were solutions that did not need a vaccine
- •Hep C replicates to high levels with great variability, yet drugs now cure it
- •Watkins says lessons from HIV help with coronavirus and science will find a solution
- 1:05:05 – 1:08:19
How Bad Is COVID-19 and What Is Still Unknown
The two compare the 1918 flu and HIV pandemics with COVID-19 and debate how much worse it is than flu. Watkins admits his early predictions were wrong and says he is encouraged that escape seems far less than with HIV. Unknowns include the neutralizing titer needed for protection and how long it lasts.
- •Watkins says he has been wrong about every prediction since January
- •He estimates the virus is about ten times worse than seasonal flu, depending on conditions
- •Attia argues from IFR data that it is somewhat lower
- •Evidence of escape is far lower than for HIV, and this is not a chronic virus
- •Protective titer and duration of response are unknown
- 1:08:19 – 1:19:10
Monoclonal Antibodies as the Most Promising Strategy
Watkins explains cloning the best neutralizing antibodies from super responders and producing them at scale for prevention and treatment. They discuss convalescent serum, durability of three to six months, use in the elderly, the Ebola result, and how broadly neutralizing HIV antibodies were found.
- •Antibodies are cloned from memory B cells of top responders and grown in vats
- •Engineering can make them last three to six months
- •They may suit the elderly, who respond poorly to vaccines
- •A monoclonal antibody treatment cut Ebola mortality from about 50% to about 15%
- •Humira shows repeated monoclonal dosing is feasible
- •Broadly neutralizing HIV antibodies come from rare long-term infected individuals
- 1:19:10 – 1:25:27
COVID-19 Vaccine Approaches and Attenuated Vaccine Risks
Attia notes that most coronavirus vaccine efforts use newer approaches rather than inactivated or attenuated viruses. Watkins describes Desrosiers' Nef-attenuated SIV vaccine, which protected animals but could revert or recombine, and mentions the Oxford chimp adenovirus approach. He says the goal is to reduce viral load, not sterilizing immunity.
- •Inactivated and attenuated vaccines make up most existing vaccines
- •Nef-deleted SIV protected monkeys but later became pathogenic or recombined
- •Oxford uses a chimp adenovirus expressing the spike protein
- •Neutralizing titers should be measured in humans, not just monkeys
- •Goal is to cut viral load, symptoms and transmission rather than sterilizing immunity
- 1:25:27 – 1:31:01
Zika Lessons and Why the Vaccine Needn't Be Perfect
Watkins explains that Zika threatens mainly pregnant women and describes monkey experiments in which antibody combinations prevented infection but failed to stop fetal transmission when given after infection. Attia argues a good-enough vaccine that elicits neutralizing antibodies and lowers viral load could greatly reduce harm, and Watkins stresses monoclonals as the new vaccinology.
- •Zika's harm comes from infection in pregnancy and brain tissue
- •Antibody combination gave sterilizing immunity in monkeys but failed after infection in pregnant monkeys
- •Attia says neutralizing antibodies are non-negotiable but the vaccine need not be perfect
- •Lower viral load could reduce transmission and severity, as with flu vaccines
- •Watkins wants to anticipate future SARS-like viruses
- 1:31:01 – 1:37:31
Closing Reflections: Try Everything and Human Data Trumps All
Watkins and Attia reflect on how the pandemic could have been worse, Watkins' view that all vaccine approaches should be tried, and the importance of human data. Attia thanks him, and Watkins expresses hope to study reinfection, followed by Attia's closing membership notes.
- •A 1918-style W-shaped mortality curve would have been far worse
- •Watkins' change of mind about T cell versus antibody vaccines
- •A famous vaccinologist told Watkins that human data trumps everything
- •Watkins hopes to study whether people can be reinfected
