peter attia paul grewal covid-19

A masterclass in immunology, monoclonal antibodies, and vaccine strategies for COVID-19| David Watkins, Ph.D. on The Drive with Peter Attia #115

Key Takeaways

  • “As we stand here with the coronavirus epidemic three months old, I think we should have faith that science will find a solution to this.” – Dr. David Watkins
  • Adaptive immunity is the biggest change in the evolution of the immune system
  • The combination strategies of T cells and B cells control infection
  • Antibodies measured in serum tell us the number of antibodies bound to the receptor but does not mean we can be sure of immunity because we don’t know the presence of neutralizing antibodies
  • In a new study in review on coronavirus, almost 20% do not make neutralizing antibodies despite the presence of IgG or IgA
  • We don’t need a coronavirus vaccine to be perfect for it to be effective

Introduction

Dr. David Watkins, Ph.D. is a professor of pathology at George Washington University School of Medicine.

In this episode of The Drive, Dr. David Watkins provides a clear review of the immune system functions and shares about how HIV and Zika research could apply to the novel coronavirus pandemic.

Host: Peter Attia (@PeterAttiaMD)

How the Immune System Works: Immunology Overview

  • Most viruses will get into any cell that has a receptor on the surface
  • As you age, the immune response is not as effective 
  • Once you get infected with a virus, the virus needs to get into the cell and replicate
  • Infection event triggers an innate immune response
  • Sensors inside cells trigger the production of interferons which turn on the immune system – including adaptive immunity
  • Innate immunity is activated by the presence of an antigen and uses the body’s inherent defense mechanisms such as physical barriers (skin), chemicals in the blood, etc.
  • Adaptive immunity is more complex and involves antibodies and other strategies the body creates in response to the exposure of a specific antigen
    • Adaptive immune response is the biggest change in the evolution of the immune system
    • The evolution of T and B cells allows the immune system to have memory to respond to pathogens
    • The adaptive immune system has two major arms, T cells and B cells

Antibody vs antigen

  • An antigen is a piece of a virus that comes into the body and is recognized as foreign or enemy
  • Antibodies bind to the virus and stop it from infecting cells before it enters

Antibodies – IgG, IgM, IgA

  • Many types of antibodies are used at different mucosal surfaces and offer different tasks in the body
  • Antibodies come online at different times throughout the course of virus
  • IgM is the first antibody that shows up then IgG comes up as IgM is trailing off
  • Antibodies we measure in a person’s serum does not mean we can be sure of immunity because we don’t know the presence of neutralizing antibodies

B Cells: Arm One of Adaptive Immune System

  • Antigen enters the body and stimulates B cells to replicate and fight the virus off
  • B cells have receptors on the surface, recognize the antigen as a virus and bind weakly
  • The recognition stimulates the B cell to divide
  • Every time the B cell divides, it makes an error – some errors make it harder to bind and the B cell dies, some make it better able to bind to the antigen
  • After rounds of mutation, you arrive at an antibody which binds to antigen with high affinity
  • Once B cell gets better at binding, they exit lymph node 7-10 days later and become memory B cells
  • Memory B cells either circulate or go into bone marrow and become factories of antibodies
  • If a B cell becomes neutralizing, you’ll confer protection against virus for a long time

Neutralizing Antibodies

  • Virus neutralization is technical
  • You’ll get many antibodies that bind to the virus but won’t neutralize the virus because they won’t stop it from infecting cells –
  • In other words, some antibodies bind to the virus but don’t affect its ability to infect cells

How Do Vaccines Work?

  • Goal of vaccine is to generate neutralizing antibodies
  • When someone is vaccinated, you give them the virus
  • That virus gets presented to B cells and the individual makes antibodies
  • Next time you see the live virus, antibodies will bind and prevent it from infecting cells

Second Arm of Adaptive Immune System: T Cells

  • You need the multiple approaches offered by B cells and T cells to control infection
  • T cell is instructed to destroy but with a different method of killing than B cells
  • An antibody can interact to stop the virus from getting into the cell but once the virus is in the cell, antibodies cannot get into the cell
    • This is where T cells come in – without harming healthy cells, T cells recognize an infected cell and kill it before it releases the virus  
  • A virus enters a cell and can replicate so many times, it eventually causes the host cell to burst and is released into the bloodstream
    • When a virus binds to a receptor and gets into a cell, it starts to make its own proteins
    • An infected cell is like a virus factory you need to shut down before mass production  
  • Killer T cell can recognize infected cells from uninfected cells and kill them

Will We Have a SARS-CoV-2 Vaccine?

  • It’s unfair to compare SARS-CoV-2 to the flu, in part because we have an annual vaccine to protect against the flu
  • The flu vaccine isn’t perfect but is good enough – a coronavirus vaccine may be similar
  • We won’t know until the future but it’s possible that SARS-CoV-2 has a seasonal component
  • The vaccine must reduce viral load to aid in recovery and reduce transmission
  • We don’t know the duration and level of neutralizing response needed to prevent infection
    • It’s possible antibodies will last 3-6 months and individuals may need booster shots
  • The key experiment is putting vaccine into humans  

Monoclonal antibodies

  • “The most exciting hope is neutralizing antibodies delivered as monoclonal antibodies.” – Dr. David Watkins
  • Vaccinating with monoclonal antibodies is a relatively new area of vaccinology that will be hugely important in coronavirus
  • A logical extension of vaccine – clone neutralizing antibodies from individuals who have beat the virus then test against the virus, animal models, and humans  
    • If successful, monoclonal antibodies could be used for treatment and prevention

Helpful Lessons from HIV Research

Why don’t we have an HIV vaccine?

  • HIV is chronic and highly selected for so mutates frequently
  • Most vaccines are based on immunizing individual with neutralizing antibodies but it’s very difficult to make neutralizing antibody against HIV because there’s enormous variability in the virus
  • Nobody has been able to generate neutralizing antibody against HIV – the antibodies bind but don’t neutralize
  • The biology of HIV cells allow it to spawn and create new methods to outrun death

We want a vaccine for HIV but have additional therapeutic avenues

  • “If everyone who’s sexually active takes Truvada, the epidemic is over.” – Dr. David Watkins
  • Even without an HIV vaccine, a multiple approach strategy (condoms, PrEP) has helped shift the virus to a chronic disease
    • Coronavirus may be the same way – social distancing plus better therapeutic treatments
  • Hepatitis C has a similar story to HIV with enormous variability and while there’s no vaccine, there is a drug treatment that cures it

Legacy of Zika Virus

  • Because Zika virus infects brain tissue, children will have many deficits as they age
  • Vaccine faces the same problems in that you must induce neutralizing antibodies
  • Progress has been made in vaccination in one area but not another:
  • Limited progress has been made in Zika virus vaccine: antibodies that you could inject into monkeys and prevent infection
    • Antibodies injected in monkeys without Zika virus prevented injection in babies
    • However, the vaccine did not work when given to pregnant monkeys who were already infected with Zika virus
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Notes By Maryann

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