School of Medicine accredited by the American 

Medical Association for continuing medical 

education.

Thank you very much,

Doctor Nahmias,

Dr Bloom,

You notice I've just promoted you 

and 

members of the faculty 

students,

visitors of Emory University.

I consider it a great privilege to have this 

opportunity to be the Aaron Brown 

lecturer.

And what I would like to do this morning is to 

share with you some of the recent and 

very exciting developments in the field of 

viral hepatitis.

First,

let us define the term viral hepatitis,

and I think it's important to indicate 

that the term viral hepatitis 

really reflects not one 

disease but at least two 

diseases,

I say,

at least because the closing slide 

the last slide,

which I will show you may indicate 

that there may be more than two causes of viral 

hepatitis.

But the two most common causes of viral 

hepatitis are,

as you know,

viral hepatitis type A,

which was formally and probably still 

is called infectious hepatitis and 

viral hepatitis type B,

which is was formally and my guess is it's 

still called serum hepatitis,

but the terminology type A and type B 

hepatitis is the accepted terminology,

and it should be used because if one 

uses the terminology serum hepatitis,

it gives you the impression that the only 

way that you can get serum hepatitis 

is as a result of a blood transfusion or 

as a result of an inoculation with a 

contaminated needle.

And it's been well demonstrated in recent 

years that Type B hepatitis or 

serum hepatitis also 

spreads from person to person 

as a result of very close and very physical 

type of contact with sharing of 

excretions,

and so that it does not require a 

needle and inoculation or a blood 

transfusion.

Now in the late 

1940s and 1949 to be 

exact when doctor enters and his 

colleagues,

Dr Robbins and Dr Weller,

cultivated poliovirus and tissue culture.

This was an historic occasion because in 

the wake of this very outstanding event,

shortly thereafter,

specific tests became available for the 

specific diagnosis of poliomyelitis.

And as many of you know,

by the mid 1950s,

it was then possible to actually develop 

a vaccine for the prevention of 

poliomyelitis.

The same model of cultivating 

viruses in tissue culture has 

been used for a variety of viruses,

and shortly after polio virus was 

cultivated in tissue culture.

A variety of other viruses was 

successfully cultivated also,

and so it then became possible to 

cultivate respiratory viruses of various 

types.

Measles virus,

rubella virus,

herpes simplex virus.

Many,

many viruses were then successfully cultivated 

in the cell culture and in the 

wake of many of these developments,

we then had a measles vaccine,

and then we had a rebel a vaccine,

and then we had the mumps vaccine.

While in the 1950s,

when many,

many investigators,

many virologists were attempting to 

cultivate various 

viruses,

many obviously also tried to 

cultivate either Type A or type 

B hepatitis Because it was well 

known and well recognized in the 1950s,

especially in the wake of the experience 

during not only the Second World War but many,

many other wars,

that viral hepatitis was one of the most important 

unsolved problems in the field of preventive medicine.

And so with this new technology,

many investigators tried 

to cultivate Type A and type B 

hepatitis,

And I believe I can tell you that as of 

today,

which is May the 1st,

No one has successfully 

reproducible cultivated either 

Type A or type B hepatitis 

in cell culture.

There have been many,

many reports,

but none of the reports have been confirmed.

Now,

if you review the pattern of 

control of a variety of infectious diseases 

and development of vaccines,

et cetera,

one finds that once the virus 

is cultivated and once the vaccine and the specific 

tests that developed,

it is then that we have extraordinary 

progress.

And yet,

in spite of the fact at neither Taipei 

nor Type B,

hepatitis virus has been cultivated.

As many of you in this audience probably know 

from reading the literature,

there have been exciting and extraordinary 

developments Over the past 5 to 

10 years.

Now,

what has happened in the 19 fifties 

and in the early 19 sixties.

Many,

many investigators try to transmit 

Type A or Type B,

hepatitis,

two primates,

non non human primates.

And all of these efforts failed 

Until somewhere around the mid 

1960s,

I think it was roughly 1965.

It was Dr Dihn Heart and his colleagues 

reported that they had successfully 

transmitted Taipei hepatitis 

to marmoset monkeys.

Dr.

Dihn Hart's findings were not confirmed 

initially,

and the reason they weren't confirmed initially is because 

we know now,

in retrospect,

that the agent that Dr Dihn heart transmitted 

to marmoset monkeys was not the 

same as the human hepatitis virus 

that many of us knew about and 

worked with.

It was an entirely different agent,

But by the late 1960s,

that then became obvious not only 

in Dr.

Dihn Hearts Laboratory,

but many other investigators and other 

laboratories successfully then 

transmitted the type A 

hepatitis to marmoset monkeys.

Now,

before going into the details of some 

of the recent developments within the last two 

years regarding uh 

regarding type hepatitis,

I'd like to first with the With the first 

slide illustrate some of the 

differences between Type A and 

type B hepatitis.

And that is,

as many of you know,

following exposure to 

Taipei.

The incubation period is relatively 

short.

It's usually about 15 to 30 days,

and at the end of the incubation period there is a prompt 

rise in serum Trans Am in its 

activity,

and the duration of abnormal Trans am in ice 

activity is very,

very short.

In striking contrast,

type B hepatitis and I refer to 

RMS one in R.

M s to strain here 

following exposure to type B hepatitis,

whether it be a blood transfusion,

accidental inoculation or whatnot.

The incubation period instead of being approximately 

30 days,

is closer to 60 days,

and it may be even much longer.

And the Trans am in its activity is much different.

There's a gradual rise in S G,

O.

T or S GPT,

and then it gradually falls down.

If it is going to fall down and come back to normal.

And the duration of abnormal trans am in its 

activity is much more prolonged than 

type than it is in Taipei.

Now,

at the time that my colleagues and I 

separated the two types of hepatitis 

in the institution where we were working Type A from 

Taipei.

Originally,

it was all thought to be in so called infectious 

hepatitis.

But then when we identified the M S one and the 

M s to strain,

Realizing that MS two or 

type was also infectious by mouth and 

infectious by contact at this 

time In the early 

1960s,

it was just impossible to make a 

precise,

specific diagnosis of 

either type A or type if we knew 

about the exposure.

Utilizing these non specific factors 

that you see here,

then we could assume that one was 

Type A and the other was type B.

It was important,

of course,

because we had known for many,

many years based on human 

volunteer studies that had been carried out during the 

Second World War by various 

investigators.

That one attack of Taipei hepatitis was 

followed by immunity to type but not the 

type.

And an attack of tip was followed by immunity 

to thought to be followed by immunity to 

type.

And subsequently we confirmed this,

but not to Taipei.

So there was homologous immunity,

but there was no heterogeneous immunity,

and so it was extremely important to 

try to develop some specific 

test to specifically 

identify both A and B 

Now.

The breakthrough in Taipei came in recent 

years first,

as I tried to indicate with the 

transmission of the agent to 

marmoset monkeys.

The second breakthrough came several 

years ago when doctors could pickin and 

Purcell and Fine Stone and their colleagues 

using a technique.

And we can take that slide off.

Please slide up,

please.

Using a technique known as immune 

electron microscopy had an 

opportunity to study the stools of 

patients with acute hepatitis 

And in these tools they were able to 

identify virus like 

particles,

which were 27 nm and 

27 nm in diameter.

These particles were present only during the 

acute phase,

and the reason they were able to detect these particles is 

that in this technology of immune electron 

microscopy by adding antibody 

to the filtration,

it was possible to cause an aggregation 

of the few particles that were present in stool 

in,

and they were able to demonstrate that this was clearly 

associated with Type A infection,

and it was not associated with type,

and it was not associated with other 

infectious diseases.

And so here was a test that was 

available to actually detect 

virus like particles,

presumably type a virus in the stools of 

patients who had type hepatitis.

But obviously this was a research tool.

It wasn't very practical.

Another way to make a diagnosis of Type a 

hepatitis and this was done by Dr 

Hillman and his colleagues several years ago 

and reported in several journals was to actually 

do a neutralization test using 

marmoset monkeys.

But of course,

this,

too is a very expensive and very hot,

and as a research tool,

These 27 nmeter particles which 

doctors find stone and 

colleagues detected in the stools of patients with 

type hepatitis,

as you will see in the next slide were 

also detected in 

infected marmoset serum.

And this is a figure from a 

paper by Dr Hillerman and his colleagues.

And what you see here on this slide,

this is their CR Costa 

Rican 3 26 strain of human hepatitis A 

virus which they prepared by 

seizing chloride density gradient 

separation from infected marmoset 

serum.

They infected the marmosets.

And during the acute stage,

when there was supposed to be very mia,

They were able to detect these particles 

which are 27 nm in diameter,

and look exactly the same as those 

described by Dr Fine Stone.

The next the slide will show you 

what happened when they took 

infected liver homogeneous 

and then looked at that.

And you can see that in the infected liver,

homogeneous state of the marmoset liver,

the same virus like particles were present.

They then used these 

infected livers and we can take the 

slide off,

please.

They then use these infected livers,

prepared an extract of the infected 

liver to use it as an 

antigen to see if it 

could detect be using it in 

an antibody test.

And initially they did a complement fixation 

antibody test and then subsequent to that they 

did a test,

which is called an Immune Adherence antibody 

test,

and in the paper that will be published 

Next month or this month.

In May of 1975 

in the Proceedings of the Society for Experimental 

Biology and Medicine,

Dr Hillman and his colleagues report the 

results of this immune adherence 

antibody test.

The results are very impressive.

They were able to demonstrate that persons 

who were developing type hepatitis 

had no detectable antibody before exposure,

but developed high levels of antibody 

some weeks after onset 

of hepatitis.

This paper,

which is going to be published this month and 

which was first presented at a meeting in Milan 

late in December on the face of it 

sounds like a very,

very important contribution now.

I was at that meeting in Milan when I heard Dr 

Hilleman present this paper,

and as soon as we return to the 

States,

I asked Dr Hillman if he would 

permit us to use some of the antigen 

to try to confirm try to repeat some of the 

observations that he had made with this 

particular,

uh,

with this test.

During the last 20 years,

while my colleagues and I have been involved 

with studying hepatitis both Type A and Type 

B,

we have accumulated a bank of 

serum specimens where we have collected 

specimens before,

during and some weeks,

some months and some years after 

onset of both Type A and type B 

hepatitis.

And so I selected out of our deep freeze 

473 specimens 

From patients,

20 patients who have had type a 

hepatitis specimens collected 

before,

during and for some years there after 

we coded these specimens and a member of 

my laboratory then took the coded 

specimens and repeated the same test 

that Dr Hillman and his colleagues had carried out 

And why I can summarize it very briefly 

by telling you that not a single one of 

the 20 patients had detectable antibody 

before onset of acute hepatitis 

and 20 out of 20 developed 

antibody immune adherence 

antibody To type a 

hepatitis within 1-4 

weeks after so that it was 100 

and the pattern is illustrated on the 

next line And as you can see from this 

slide,

this is one of the 20 patients here.

You have the onset of type A hepatitis 

at this point at about four weeks.

Note that there was no detectable antibody 

immune adherence antibody before onset of 

hepatitis.

Note that within a matter of a week or two,

after onset of hepatitis levels 

began to rise And reached 

the extraordinary level of equal to or greater 

than 81 920 

In one of these patients.

When we finally completed the titillation,

it was 1,

320,000.

So these are fantastic levels of antibiotic.

You will then note as we 

check all of the serum specimens.

And in this particular patient,

we have a nine year follow up.

We still have an antibody tighter of 1-6 

49 years later.

And so these observations 

confirmed everything that Dr Hellerman reported 

and more details about this Will 

be published in the May 29 issue of the New England 

Journal of Medicine.

I have too much to cover so that I can't go into too 

much detail about it.

But both Dr Hillerman's article in the May issue 

of proxy Shock and our article in the New England 

Journal of Medicine later this month,

I can give you the additional details regarding 

this test.

It seems obvious,

as you look at this slide,

that this is an extraordinary,

extraordinarily good test to 

try to determine susceptibility.

If there's no detectable antibody,

the likelihood is that that person is susceptible 

to type the hepatitis.

It's a good test to try to determine immunity to 

Taipei.

It's a good test to use for an essay of 

gamma globulin standard gamma globulin,

to determine what the tighter of hepatitis A 

embody is in gamma globulin.

It's a good test,

of course,

to be used by virologists who are attempting to 

cultivate Type A virus and tissue 

culture because this is an excellent 

marker and it is a relatively simple test 

to do and can be done in most laboratories 

because the tests that are being now being 

done for Type B hepatitis in in many,

many laboratories throughout the country,

this is essentially the basics of it 

are an urgent antibiotic complement 

complex with a group O 

positive human red cells,

and it causes an and the 

illumination type of phenomenon in these red 

cells.

It's very simple to do and very simple to raise,

so that here we have a new and 

very exciting development,

as is as concerns Taipei 

hepatitis prospects 

for prevention of type A hepatitis by active 

immunization,

I'd have to say Right now there are no prospects for 

prevention of type A hepatitis by active 

immunization because it will require 

cultivating this particular virus in tissue 

cultures so that enough energon will be 

available to be used for,

uh,

use of,

uh,

as a vaccine.

And as of the present time,

no one has successfully cultivated it.

When we take that slide off,

please,

I'd like to very quickly now leave type A 

and then move over to type hepatitis.

Now,

as many of you know,

one of the most exciting developments regarding 

type B hepatitis was the 

discovery of Australia,

an urgent By Dr.

Bloomberg and his colleagues and they.

Although this occurred in the early 

1960s,

it became obvious to most everyone 

who reads the literature by the late 

1960s now initially when 

Australia,

when it was shown that Australia an urgent 

was associated with hepatitis,

it wasn't known as to whether it was 

associated with be only or 

a only or both.

And in the original reports by Bloomberg and 

by Cokie and by others,

it was found,

at least in their experience,

based on the criteria that they used.

It was found to be associated with both Type A and 

Type B,

but they had to rely on the clinicians to give 

them the diagnosis of type and type.

And most clinicians would not make a 

diagnosis of type if 

there weren't a history of an inoculation for a blood 

transfusion,

so that those patients who had Type B 

hepatitis,

which was acquired as a result of 

intimate contact,

whether it be a venereal type of 

transmission or into close contact 

with sharing of secretions,

those patients,

we're not called type.

They were called infectious hepatitis 

because the dogma at 

that time was that the only way you could get 

type B hepatitis was buying inoculation.

And that is why the original reports 

regarding the Australian androgen 

suggested that it was present both in Type A and 

Type B,

and that is why the nomenclature initially 

was hepatitis associated antigen 

H A.

But then Dr Prince and his 

colleagues and Dr Giles of our 

staff and our colleagues showed very 

clearly that this particular 

Anderson was associated only with B 

and not with a and as a 

result of that,

the nomenclature,

of course,

changed again,

and it was called hepatitis B and urgent.

Now that next slide will show you What one 

can see if one looks under 

the in an electron microscope 

and looks at a sample of serum 

taken from a carrier with 

type B hepatitis or taken 

from a person who happens to be during the acute 

stages of type B hepatitis,

In contrast with the photograph of 

Type A,

which you saw a few moments ago where you 

have all of the particles of the same,

They're all 27 nm in diameter.

Here you will note you have 

particles that seems to have an outer 

coat and an inner core,

and it measures approximately 42 

nanometers in diameter.

And then you have these smaller particles 

about 20 nanometers in diameter,

and then you have these elongated,

cylindrical type particles,

Also 20 nm in diameter.

But much longer well,

again,

to make a very,

very long story very,

very short because of the limitation of time.

It is now clear,

I think,

to most persons working in this field that 

this particle is 42 nanometer particle,

which was first described by Dr Dane D.

A.

N E.

And his colleagues some years ago from 

from London that this 42 

nanometer particle is in all probability,

the hepatitis B virus.

The other particles that you see here,

the Australia an urgent or the hepatitis B 

and these are the particles,

which are essentially the same as 

the surface part of the Dane 

particle,

so that this hepatitis B virus 

As at least two components,

it has a core,

and it has an outer coat.

The outer coat is the 

hepatitis surface.

Be surface,

an urgent or the Australia energy.

In the new clinic,

asset is in the inner core and there are 

immunologically distinct.

These are immunologically distinct addictions,

as has been shown by various investigators,

especially Dr Hoofnagle and his colleagues at the 

Bureau of Biologics,

so that we now have to talk in terms of 

not only the hepatitis.

We can't talk in terms of a hepatitis B at urgent 

because we now have a hepatitis B 

surface antigen and we haven't hepatitis 

B core antigen.

And as you can see from this slide 

here,

the Committee on viral hepatitis of the National Academy of 

Sciences felt that the nomenclature had to be 

clarified.

And so instead of talking in terms of 

I'd like I didn't mean to press that.

So can we come back instead of talking in 

terms of Australia,

an urgent or hepatitis B antigen,

we have to talk in terms of hepatitis B,

surface antigen,

H B s,

a G and the antibody to this hepatitis 

B surface antigen is anti 

HBs and then hepatitis B,

core antigen and anti 

HBC.

And then,

of course,

we refer to the Dane particle being the 

hepatitis B virus.

It's a little more complicated than that because it has been 

shown that there are,

as you will see in the next slide.

There are sub uh,

there are specificities of the hepatitis B 

surface antigen so that we 

have.

We can have a hepatitis B surface image 

and and they all have this group specific 

determining small a and 

subtype specific determinants D,

N.

Y and W and R so 

that a patient who receives a blood transfusion 

that is added and positive may 

receive a transfusion that contains 

H B S,

a G A D W or A D 

R A Y w or a 

Y R.

This is extremely important because 

it's an important epidemiological 

finding because these 

subtypes breed true,

the recipient of a DW will get a D 

W and not a yw.

And so if you have a patient who has hepatitis 

and was presumably exposed to someone else,

if the subtypes are the same,

then the circumstantial evidence is that 

it really came from that person.

If the subtypes are different,

then the circumstantial evidence is that it came 

from someone else,

so that from the point of view of epidemiological 

surveys,

this is extremely important.

The crucial question is what happens as far 

as what will happen as far as protection 

against hepatitis will a person 

who has had hepatitis B caused by a 

D.

W B immune to hepatitis B 

caused by a Y W well,

the LTD available evidence would 

suggest yes.

In all probability,

there is protection between these various 

types.

More information has to be collected and 

more information will be needed.

I think the saving grace will be the fact that 

there is this common determinant.

Small A With all of these,

now we'll go to the next slide.

We now happen to be in a very 

unusual situation 

where not only do we have,

as I described earlier,

and these are more recent developments a specific 

test to diagnose Taipei infection.

But now we have a variety of specific tests 

to diagnose type B infections.

Now there are a number of ways you can a number of tests that 

can be done.

Obviously the Trans Am in eight hours have been 

available a long,

long time so that you can do S g o 

T.

As you follow a patient who has been exposed.

A new observation by Dr Kaplan and 

Dr Jared and his colleagues within the past few 

years in an article that was published in The 

Journal of Virology,

indicates that you can actually detect 

DNA proliferates activity in 

association with type B hepatitis.

It's transient,

and we'll discuss that in a moment.

The other tests you can do is for hepatitis B 

surface antigen antibody to the 

core and antibody to the surface antigens.

And so if you have a patient who was exposed to 

Tybee at day zero.

And if you follow that patient prospectively,

I must tell you that the black area 

refers means that it is.

The test is abnormal or the Anderson is 

detectable.

The stippled area means that we 

looked for it,

but it wasn't there.

It's either normal or non detectable.

And so,

as you can see from the slide,

the most common type of type B hepatitis,

which is one in which you have acute 

hepatitis and the patient recovers and then 

becomes immune.

The first thing that becomes abnormal,

usually within one month,

is hepatitis B.

Surface antigen becomes detectable,

then DNA polymerase activity,

then at about 2 to 3 months,

is when there's evidence of abnormal 

liver function tests.

Serum Trans Am in its becomes abnormal.

You will note that the first antibody 

to be detectable is the antibody to the 

core,

and some weeks or some months later,

antibody to the hepatitis B surface 

energy again making a 

very,

very long story very,

very short.

It turns out that the protective 

antibody,

the neutralizing antibody,

is this antibody to the surface,

and it's this antibody,

which is the protective one.

The antibody to the core is 

not has not been shown to be the protective 

antibody.

And Dr Hoofnagle and uh,

Garrity and Barker and their colleagues at the Bureau of 

Biologics have have tested more 

than 100 chronic carriers of the hepatitis 

B added in.

And 100% of these carriers have 

antibodies to the core,

but they don't have detectable antibody to the 

surface energy.

That doesn't mean that they will necessarily get a 

second attack of type B hepatitis.

But there's no detectable antibody to the surface.

And this is what happens following a parental 

exposure and,

as you can see in the next slide 

following exposure by contact with a 

carrier.

The only difference is is that the incubation period is 

obviously longer.

Some several months after exposure to a 

carrier again,

the first thing is an agent,

then DNA polymerase,

then abnormal S C o T.

Then add the body to the core in 

this particular,

uh,

person.

There was no antibody to the 

hepatitis B surface antigen detected 

by this technique.

This is passive hemoglobin ation,

but that is not as sensitive as radio Immuno 

asset.

You will note that later,

uh,

following exposure again.

There was an antibody to the hepatitis B surface 

antigen,

But in any event,

this is what happens in a contact infection 

type.

And the final illustration I'd like to show you is 

an example.

In an example of,

uh,

of the chronic carrier state.

This is extremely uncommon.

It happens most 

especially in adults Of 

adults who get acute hepatitis.

The odds are that well over 

95,

possibly even 98%,,

Will recover from their hepatitis and will not be 

carriers,

but a small percentage,

whether it's 1% or less than 1% or 

2%,

we're really not sure it requires much 

more.

Many more prospective studies will end up 

as chronic carriers,

and here's an example of a chronic carrier again,

exposure at this point.

First,

Anderson DNA people embrace,

which is prolonged for many,

many years.

S G o.

T,

which was abnormal for 10 months and then 

became came down to normal.

This is an asymptomatic carrier,

But note eight years.

7 or eight years later,

the antigen is still present and it may be present for a 

lifetime,

and the body to the core consistently 

present and a body to the surface and 

not detectable in this particular situation.

You may have that slide off,

please.

Now.

Well,

let me look at the next slide,

please.

First,

if I may,

Yes.

What reason?

I want to show you this slide is that here 

is here is a person who had 

both type B and type A 

hepatitis.

The type A hepatitis occurred 

approximately six months after the type 

B.

To show you what can be done today with 

these new tests.

Note that which I be 

hepatitis occurred at this point here 

we were able to detect hepatitis B surface 

antigen.

We were able to detect antibody to the 

core we were able to 

detect at the appropriate time and the 

body to the hepatitis B surface antigen.

You will note that we tested for 

antibody both by complement,

fixation and immune adherence for 

antibody to hepatitis A virus at this 

point.

But it wasn't detectable,

proving again that these are immunologically 

distinct viruses.

But later,

after an attack of Taipei hepatitis,

the complement fixing and immune adherence 

antibody then became detectable.

And this is exactly what we would have expected.

Lights off,

please.

Now,

this brings us now to a point.

Mhm about prevention of 

type B hepatitis 

Late 1970 early 

1971 my colleagues and I 

described what we 

believed was a hepatitis B 

vaccine.

Now I began this discussion by telling 

you that neither type A nor type B 

hepatitis has been cultivated in cell 

culture,

and in recent years,

the only way that one could really make a 

vaccine for for 

a virus infection like polio,

measles rubella is to actually have 

enough energy and enough material present so that 

you can either inactivated or attenuated.

And that required cultivation.

Mhm.

How could any responsible scientists 

come out with a report of a possible 

develop development of a vaccine 

if nobody has successfully cultivated 

well,

what we were really trying to do at that time was trying to 

determine if the same 

treatment of our M s to 

serum would render 

that serum,

as in non infectious 

as previous study that we had carried 

out with RMS one or type a serum.

We had learned a number of years ago That if we 

took MS one,

which is Taipei,

and diluted it in water,

one part of serum nine parts of water and 

1 to 10 dilution just boiling 

That for one minute was enough to render that material 

non infectious.

And so when the Australia Amazon was 

discovered and when it became possible to 

actually detect the 

hepatitis B surface antigen,

it was important.

At least we felt it was important to try to 

repeat this with RMS to serum.

And we did that and again making a 

long,

long story very,

very short.

It became obvious to us as a result 

of a series of studies That boiling 

that mess to the type B serum in water for one 

minute rendered it non infectious.

But it was still energetic when we 

tested that material before boiling.

It had a tighter of about 1 to 5 

12 with by complement 

fixation,

test for the hepatitis B,

an urgent and when we tested it after boiling,

it was only 12 difference.

It was 1 to 2 56.

Well,

having discovered this accidentally,

we felt that it was very important for us to try to 

determine if this material 

could actually prevent type hepatitis 

under the conditions that the 

conditions under which we were working at that time 

in the institution And so we did 

that and again,

in several papers published in 

1971,

it became obvious to us that this heat 

inactivated material could indeed 

prevent type B hepatitis.

Now,

the next slide will show you a slide you've 

seen before because this is what 

happens in an unimmunized 

person,

whether it be a blood transfusion or whatnot.

Given an unimmunized susceptible person 

exposed to type B,

you get an organ,

you get the n a prelim race.

You get elevated S G O T 

antibody to the core and later you get 

this protective antibody,

the antibody to the surface,

as you will see in the next slide.

After three inoculations of the heat 

inactivated M s to serum,

it became obvious that there was.

First of all,

there were no symptoms at all.

No evidence of abnormal liver function,

no DNA proliferates,

no hepatitis B surface antigen,

no antibody to the core,

which is supposed to be a a reflection 

of replication,

the virus.

But you will note that after the second inoculation of 

the heat and activated material,

there was antibody to the surface energy and which 

persisted.

And about six months later,

after an exposure to the unheated MS 

two again no symptoms but 

continued protection.

And under the conditions of the study,

we were able to protect approximately 

70%.

And this was with a preparation 

where where the energetic content 

was not as potent as obviously could be 

made.

It became obvious then as a result of 

these studies,

that indeed it was possible to make the 

hepatitis B vaccine.

Now,

you may ask,

You may have that slide off.

How is it possible?

Well,

it turns out that if you take a sample of blood from a 

carrier and you do if you do a particle 

count on that blood,

You find that there may be as many as 

10 to the 10 or 10 to the 

12 of these virus like 

particles.

Just visualize all of those zeros.

That means that a carrier who isn't 

ill,

who was just walking around going about 

his or her business,

maybe carrying billions and billions of 

virus particles circulating in the blood.

And it has this extraordinary symbiotic 

relationship between this virus and this human being.

But that material given to a 

person who is susceptible,

whether it be a blood transfusion or an 

intimate contact could spread hepatitis.

And so it became obvious,

then that this was a peculiar virus.

This type hepatitis.

Unlike polio,

where,

during the stage of Vira Mia,

there are just a few virus like particles which you 

can't see under an electron microscope,

and you have to cultivate it And re 

inoculated,

and you finally get a tighter of 10 to the 

67,

possibly 10 to the eight.

Here we have a situation where in true 

life persons are walking around with titles of 

the order of 10 to the 12 

became obvious then to a number of people.

That it would be should be possible then to make a 

vaccine because it was this surface component 

that was important.

And again in the next slide,

yeah,

summarizing again a great deal of material very,

very quickly with the biophysical 

and biochemical techniques that are available 

today.

It's certainly is possible and has been 

possible to purify 

this blood that contains all of 

these particles.

The Dane particles the virus here,

these particles here the hepatitis B surface 

engine and the trick then,

is to try to select out 

these non infectious 

surface the Australia or the hepatitis 

B surface and try to purify this 

preparation and select that out.

And,

of course,

the technology is available and the next slide will 

show you a for a,

the same material treated.

And here we think that can be focused a little better.

Please.

The same material is treated.

And as you can see,

all that remains are these 

non infectious particles.

And it is this then that was used 

by two groups of investigators,

Dr Morris Hillerman and his colleagues at the Merc 

Institute with,

uh,

Therapeutic Research,

and Dr Purcell and his colleagues at the 

National Institute of Allergy.

We can turn that off and infectious diseases,

both groups.

And this was reported at a recent meeting in Washington,

which was held Well,

I believe was March 12-13 of 

this year.

Both groups reported that they had 

prepared a vaccine 

from these purified particles.

Now,

what I didn't tell you,

which I should have told you,

Is that one of the very important 

breakthroughs as far as hepatitis B 

research came not only with the 

discovery of the Australia and again in the late 

60s,

but also With the ability 

in the early 1970s.

This is 1972 73 

in reports by Dr Barker and his colleagues and others 

the ability to transmit type 

hepatitis to chimpanzees 

now for many,

many years,

many,

many investigators try to transmit Type B 

hepatitis to chimpanzees,

and they failed.

They were unsuccessful.

Now why is it that,

finally,

in 1972 73,

it becomes possible?

It became possible because 

tests became available to determine 

whether chimpanzees were susceptible or whether 

they were immune.

And it turns out that most of the chimpanzees 

that are brought to this country are immune to 

hepatitis.

And so by selecting out those 

susceptible chimpanzees And 

inoculating them,

it became possible then to transmit 

type B hepatitis,

and this was reported by various 

investigators within the past year or two.

Then it became possible for both Dr Purcell and his 

colleagues and Dr Hillerman and his colleagues 

to take that vaccine that they prepared 

inoculate chimpanzees,

which is what they did.

The chimpanzees developed antibody to the 

hepatitis B surface antigen.

They did not develop hepatitis.

The controlled chimpanzees did develop 

hepatitis that is those who were given 

material that was not purified.

And then,

roughly six months later,

when the immunized the 

chimpanzees would challenge,

they resisted infection.

And this has recently been reported,

and those of you who are interested the 

entire July and August 

issue of the American Journal of Medical 

Sciences will be devoted to 

a will be a 

publication of all of the proceedings of this three day 

conference on viral hepatitis that was held at 

the National Academy of Sciences in March of this 

year.

And many of the things that I've tried to relate to 

you are included in that in that 

particular volume,

I I I indicated 

that before I began to speak 

earlier that I I'd like to leave 

enough time for questions.

I see the time is 10 minutes of one or a 

number of areas that I haven't touched.

Or perhaps if we can leave time for questions.

But before doing that,

since there is a pediatric element to this meeting 

and since I'm a pediatrician,

I can't sit down before I at least make some 

brief comments about the vertical transmission of 

Type B hepatitis.

And that is it's been shown very clearly that 

given a situation where a mother a 

woman who is pregnant is either an asymptomatic 

carrier of type or is 

or has acute type hepatitis.

There is a fairly good chance that the 

infant,

her infant,

may possibly be infected in utero.

And if the infant is not infected in utero,

that infant more commonly will be infected 

at the time of birth.

Because,

remember,

at the time of birth,

the mother is a carrier.

This baby is being born in a bath 

of hepatitis B virus.

It's in the blood,

and it's been shown that some weeks or some 

months after birth,

there have been a number of infants who have subsequently 

developed an organ.

Some have gone on to develop clear cut hepatitis.

Others have only become carriers.

Others have escaped the infection so that there is this 

possibility of transmission from Mother 

two infant.

And rather than go into more and more 

details,

I'd like to very much thank you for your attention and stop at 

this point in order that we may have some 

time for questions and for discussion.

Thank you very much.

Mhm.

Okay.

Thank you,

Dr Krugman.

Very much.

Before we go on to the questions.

Just like to announce that after this meeting 

any of you interested in having lunch 

with Dr Krugman will be eating 

especially reserved tables in the 

cafeteria.

Uh,

secondly,

that after that,

to 30 

men will meet with any interested 

people to discuss,

uh,

some cases and,

uh,

some of the recent aspects of immunization 

practices.

This will be held in room seven,

which is in the basement of the Glen Building.

Um,

floor is now open for the comments or 

questions.

Dr.

Columbus?

Yeah.

Improvement.

I believe you plan to 

comment on this.

Time apparently stopped you.

You indicated that there 

is a type specific immunity 

after virus A and after virus 

be infection.

And probably the a determinant on the 

energon is the one that 

is protective.

Therefore,

these areas the WR 

subtypes are are just 

epidemiologic interest,

but not of immunological importance.

Mhm.

What I would like for you to comment on 

is those individuals who had 

a typical type B infection 

who became sociologically positive for the energy and 

energy and disappeared than they have 

repeated attacks of hepatitis.

Many who had at least two attacks.

But they are well defined attacks 

three or four 

and I would like to speculate 

on the alphabet C,

Maybe the well.

I'm glad you asked that question because she reminded me 

about a slide that I wanted to show,

which will not answer your question completely.

But I think it's extremely important from the point 

of view of post transfusion hepatitis,

and that is in this last slide,

and there are now several groups who have observed 

us Here.

We have a group of 204 

transfused patients.

This is from an article by Dr.

Prince and his colleagues.

I was published in Lancet in 1974.

At our meeting in Washington recently,

a similar report appeared,

and that is that these are patients who received many,

many transfusions now that we 

have the technology to specifically diagnose 

B and specifically diagnose A,

It was possible to do studies like this where 

in this group of 204 they were 

able to identify 15 

or 7% of this group 

had type B hepatitis of 

that,

they did serial determinations so that they know about an 

electorate as well as it Eric.

47% were victory.

The incubation period was typical for Type B 10 

weeks.

This is the peak trans am in 8s and the duration of the trans 

am in eight.

The interesting thing is,

is that twice as many 

There were 36 or 18 

who had hepatitis,

also after a relatively long 

incubation period who clearly 

did not have Taipei and did not have 

type.

So that here we have a situation of post 

transfusion hepatitis,

not a not big.

What is it,

is it?

See,

I really don't know,

and I think before we label it as see,

it will be important to carry out 

studies and animals and other studies.

But it's very clear that now that 

we are progressing from commercial donors to 

voluntary donors and now that 

every sample of every unit of blood is 

tested for energy,

it's been obvious in recent years that 

hepatitis B is not going to be very much of a 

problem.

As far as post transfusion hepatitis,

It will become less and less.

It will be a lot less than 7%.

And if you go exclusively to volunteer 

donors and if you 

continue to test as you have to,

of course,

because it's mandated,

the likelihood is that in the future 

most of the hepatitis will be in this particular 

category,

which is neither a nor B.

Now they look for cytomegalovirus and herpes simplex 

virus and others,

and they rule that out.

So this is one factor for a second 

or a third attack,

I believe the other thing that we have to realize is this is 

that there are persons who may have 

type B hepatitis who never recovered.

They may have a have an 

asymptomatic anti terror infection,

the Trans Am in aces.

They're abnormal.

But even though they have no symptoms 

trans am in eights maybe well over 100 not only for 

a year but for two years,

three years or even four years.

And it is conceivable that in persons like 

this,

whatever the excitement factor may be that this 

subclinical as far as symptoms type of 

hepatitis,

could conceivably be activated 

into an overt type of hepatitis.

My guess is that that is another possibility.

But I think I think there may be many,

many factors involved because it is true 

that it is possible for some persons to 

have many,

many attacks of hepatitis.

If you review your experience with this,

you'll find that this experience of more than three 

or four attacks of hepatitis has been 

predominantly associated in drug addicts.

When you leave the drug addict and you study 

the non drug addict population,

it is extraordinarily unusual to have 

hepatitis more than twice.

And I think that to my feeling is that as 

far as the kind of hepatitis that we deal with 

the two major causes,

and my impression will always be A and B 

as far as post transfusion,

it's obvious that there's something else.

And then we have the recurrences,

relapses or what you want to call it?

Time for one more question.

Hey,

why this come up,

right?

Mhm Uh,

there's this very funny discrepancy of the 

development of the antibodies to the 

surface component in that it seems to take 

seven months.

There may be a relation to chronic carriage.

Uh,

is this a matter of our ability 

to detect them the sensitivity of the technique?

Or do you think it's real that it would take seven months for 

an antibody to come up To an infectious agent?

It's a mixture of factors.

No one.

There's no question about the fact that there is a 

delay.

It seems to be related in some patients 

to the declining as the antigen 

declines.

And once the antigen is no longer 

detectable,

the likelihood of having antibody to the surface 

Is,

uh,

that appears now,

if you review many,

many patients who have been followed,

you'll find that some developed antibodies to the surface 

engine within 1-2 months.

Many don't get it for another for 4-6 

months,

it now becomes apparent that some that 

we believed had no antibody when we took the 

specimens out of the deep freeze and tested them by 

radio.

You know,

I say the antibody was there 

in low level,

but when it reached a significantly a 

significant level,

then we were able to detect it by passive human 

coordination.

Because even following patients 

prospectively,

at least in our experience,

we can only detect antibody and about 

80% of those who have clear cut 

type B hepatitis A year or so 

later,

when we test them,

only 50% have antibody.

Now,

I know from our experience that that 

that some of those who lost their antibodies 

subsequently get their antibody again when 

they've been exposed to someone they sort of re infected.

They have no symptoms and they get a boost so that I 

think you've answered the question.

It's the sensitivity of the test when the 

antibody level is too low.

If you use Ph a passive hemagglutinin nation,

I say you may not detect antibodies if you 

use radio.

Um,

you know,

I say you made detective,

And we also know from studies that were carried 

out in the 1950s 

by various investigators,

and it is possible to actually 

transmit hepatitis,

whether it be blood transfusion or whatnot.

When you go back in retrospect and study these serum 

specimens.

The patient who received the blood got hepatitis.

But the material that was tested was negative,

even by radio amino acids,

so that the susceptible human being is a 

much more sensitive indicator 

of whether there is or is not virus there.

And you have to have enough material enough energy in 

there in order to detect it.

Mhm.

Thank you very much.

Dr Krugman,

for coming to Emory again.

Yeah,

Grady Memorial Hospital.

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