Discrete probability (crash course, cont.) (14 min)

Hi, my name is Paul Offit . I'm the Chief
of the Division of Infectious Diseases at

Children's Hospital, Philadelphia and a
professor at the Perelman School of

Medicine at the University of
Pennsylvania. And I'm introducing now the

first of a series of lectures about
vaccines. What we want to try and

accomplish in these lectures is to
understand what vaccines are, how they're,

how they are made how they work, and why
they are still important. So, I thought

probably the best way to start would be
talk to about kind of the story of

vaccines, history of vaccines and starting
just from the very beginning because I

think we can learn from that history. Now,
you can divide up vaccine history into a

kind of a series of era or epics and the
first will be the whole animal era. So,

that really starts with the first vaccine
which is the smallpox vaccine developed by

Edward Jenner in the late 1700s. So Edward
Jenner was a, a physician who worked in

Southern English. He was a country
physician and what he noticed was that

every two or three years, a smallpox would
sweep across the Southern English country

side, leaving many people dead, about one
out of every three people who got smallpox

died from the disease at least a, a third
of people who, who contracted smallpox

were also left blind from the disease and
virtually everybody who got small pox were

left with these deep, disfiguring pock
marks. But what Jenner noticed and had

actually been noticed decades before him
by a farmer named Benjamin Jesty, was that

women who milk the cows didn't seem to get
smallpox and, and, what he tried to, to,

to, to reason, was that the reason that
they didn't get small pox was because when

they would milk cows and cows would have
these blisters on their udders and they

would then get these blisters on their
hands or on their wrists and, and that

seemed to protect them against smallpox,
that those two things were related. That

somehow, getting blisters on your hands
and, and on your wrists from milking cows

was somehow related to being protected
from smallpox. Now, this was 1796. This

was decades before anybody understood what
viruses were. It was actually many decades

before really anybody understood the germ
theory and what that was, that specific

germs cause specific diseases. So, what
Jenner was doing was really just pure

phenomenology. He didn't know what we know
now which was that cowpox or the, the

virus causing those blisters on the udders
of cows was, was, was close enough for

so-called antigenically related enough to
human smallpox so that immunization with

one could protect you from disease with
the other. So, what he did was he took

these blisters from actually a, a,
milkmaid who was in is his employ,

employee named Sarah Nelms. He then
injected a, a boy, a little boy with named

James Fipps, with, with this with this
fluid from the, from the, from the blister

and then what he did is he injected that
boy with, with something called

variolation, now this isn't vaccination,
it's variolation and this was noted

centuries before that people who, who, who
got small pox, when they survived, you

could actually take that blister you could
dry it out, grind it up and then you, you

inject it into the vein or you could
actually inhale it. So, this was called an

inoculation or variolation and in fact you
Benjamin Franklin and then actually here,

when you're here at the University of
Pennsylvania, you're, you're asked to at

least mention Benjamin Franklin once in
your talk. But Benjamin Franklin in 1736

regretted that his five-year-old son had
died of smallpox and that he had failed to

variolate him. And remember this is 1736.
This is 60 years before Jenner. So, what,

what really Franklin is talking about is
he's talking about taking, taking sort of

dried-up crusts from people with smallpox
and inoculating them and then hopefully

that would protect the person and it did.
I mean, you were six to seven folds less

likely to get smallpox if you were
variolated. But, you know, v ariolation

came with a price. There were occasionally
people who died from that variolation

event. In any case, whenever you got
variolated, you developed the, a very the

large red painful blister at the sight
where you got variolated. So, that's,

that's what Jenner did. He said, he sort
of reasoned that if I, if I vaccinate

somebody with, with now we know as cow pox
and then I varioalte them, I'm just

curious to see ho, how bad that
variolation blister looks. And what he

found was when he variolated people who
had been vaccinated with, with, with cow

pox then in fact, they had a very minimal
or no reaction at all and he assumed then

that, that meant that they were protected
and he was right. So, this, this is a

picture of, of, of Jenner, actually shown
on the left and they're, they're, they're,

the, the phrase is the origin of the
vaccine and the word vaccine comes from,

from the Latin word vacca, there's no
actually hard v-sound in Latin so vacca

means cow vaccine, or vaccania literally
means of the cow. So, this, this is where

the word vaccine comes from, it comes from
the fact that Edward Jenner used cow pox,

to protect against what we now know is an
antigenically related human smallpox. And

it works. So, so, small pox I think is
probably the, the, the most powerful

vaccine story around. This is a, a virus
which probably has killed five hundred

million people in the world's history and
because of the smallpox vaccine, the last

case of naturally occurring small pox
occurred in Somalia in, in 1977. So, this

is a, is, is the only example actually
where vaccine has eliminated a virus from

the face of the earth but, you know, I
think it's still possible to, to do that

with other viruses most likely viruses
like a polio virus or measles virus. Now,

as we move along in the story and we're
still in the whole animal era. Remember

Jenner used a cow, really, as, as his
source of, of vaccine. In this, that case,

it was cow pox virus. And we sort of fast
forwa rd on 100 years to the late 1800s

for the next vaccine which is the rabies
vaccine. And that was developed by Louis

Pasteur and what he did was he noticed
that certainly there were a lot of rabid

dogs that roamed the streets of Paris
where he lived. That when people were

bitten by rabid dogs and started to
develop symptoms of rabies, that they,

they invariably died. Rabies is probably
the most fatal of infectious diseases,

that when you get, first get symptoms of
rabies, the chances that you are going to

go on and die as roughly a 100%. So, there
was a tremendous interest obviously in

trying to find a way to stop it. So, what
he did was he, he took a dog that had, had

died from rabies. He then ground up its
sort of, its brain and its spinal cord. He

injected it into a rabbit, which then
would kill the rabbit. He then took the

spinal cord of the rabbit and he dried it
out for up to two weeks. And he found that

when he then took that dried out rabbit
spinal cord and inoculated it back into

in, into, into rabbits, that he was able
to induce an immune response which is

protective. So, so, the, the, this was a
vaccine that he thought showed a lot of

promise. When he, when he then was
confronted with a little boy who had been

bitten by along the face and, and trunk by
a rabid dog, he then tried this out by

inoculating the child with dried out
rabbit's spinal cord that contains what we

now know was largely killed rabies virus.
He then ejected with a series of

inoculations with the, this spinal cord
that have been less and less dried out.

And frankly, the, the, toward the end of
the inoculation, he has no doubt was

inoculating that child with what was live
rabies virus. But by that time, the child

had developed an immune response from the
killed rabies virus that induced

protection. The problem with, with, with
his, his, his a, his method was that when

you inoculate people with a, with a
substance that is in-part derive from

nervous tissue whether it is brain or
spinal cords. Those br ains and spinal

cords contains something call myelin. And
we all have myelin that, that lines sort

of our nerve, nerve sheets in the brain or
spinal cords. And it's very similar across

species. And you start to develop an
immune response to that myelin which can

cause symptoms such as seizures or
ncephalopathy which just mean brain

dysfunctions or, or paralysis. Now, that
occur in about probably one in every 250

people or 24 percent of those who got this
vaccine. But remember, this was a vaccine

that you gave post-exposure. Meaning you
only gave it to somebody after they have

already been bitten by suspected rabid
dog. And because of the, the, the, the

mortality or death rate from rabies
approached a 100%, people were willing to

take that 0.4 percent risk that they would
get a side effect from, from, from the

vaccine. But, but this is a story that
doesn't end here because the notion of

using nervous tissue to protect against
human disease comes back again as we move

forward. So, this is a picture actually of
Louis Pasteur's up on the left hand

portion of the, the screen watching
someone being inoculated with an

experimental rabies vaccine. But the
rabies vaccine that was developed by Louis

Pasteur has, has, is still used today. And
there's still thousands and thousands of

people that gets rabies every year,
primarily in the developing world and this

vaccine is a life saver. Now, we fast
forward from the late 1800s to the, the

early 1900s, we are still in the whole
animal era. We've gone from, from, from

cows to rabbits and now we are going to go
to monkeys to develop the polio vaccine.

Now, when people think about the polio
vaccine they always think of Jonas Salk

and Albert Sabin in the 1950s but there
actually were polio vaccines that were

developed in the 1930s. There were two,
two groups actually. One was headed by

John Kolmer at Philadelphia General
Hospital that is actually right here on

Penn's campus. And what Kolmer reasoned
was I'm going to take monkeys, inoculate

them with polio virus which I know can
reproduce itself in the brain and spinal

cords of, of, of monkeys. I'm then going
to take that out and homogenize it and,

and treat it with a chemical called
ricinoleate which is sort of a soap

developed from, from the castor bean plant
and, and which makes one of the most

potent toxins known to man. Ricin, this is
a soap of ricin and then another group

working in New York had to buy Maurice
Brodie, took the, the, the same thing to

ground up brains and spinal cords from
monkeys that had been inoculated with

polio and then activate it with
formaldehyde. The problem was because

these slurries that were made from ground
up brains, and spinal cords were able, was

able to protect polio virus from the, the,
the killing effects of formaldehyde and

frankly the less than killing effects of
ricinoleate. There were a number of

children who got those vaccines, who got
polio and in fact, died from polio. So,

that, the tragedies associated with using
whole brains and spinal cords to, to try

and serve as a substrate to make polio
vaccines really set polio vaccine research

back about twenty years. So, that ended
the whole animal era.