0:00

This week in virology,

0:02

the podcast about viruses,

0:04

the kind that make

0:07

you sick. From Microb

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TV, this is Twiv.

0:11

This week in virology,

0:13

episode 1209, recorded

0:16

on April 11,

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2025. I'm Vincent Rackin

0:20

Yellow and you're listening

0:23

to the podcast

0:25

all about viruses.

0:27

Joining me today from Ann

0:29

Arbor, Michigan, Kathy Spindler.

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Hi, everybody. Here it's 9

0:34

degrees Celsius, 50 degrees Fahrenheit,

0:36

and blue sky clouds, very

0:38

nice after a couple gray,

0:41

rainy days. Oh, look, 9 degrees see

0:43

here in Chelsea as well. Cloudy,

0:45

it's apparently raining.

0:47

It's been raining for many

0:49

days. Also joining us from

0:52

Western, Massachusetts, Alan Dove. Good

0:54

to be here. It's currently

0:56

46 Fahrenheit 8C Overcast. It

0:58

is fortunately, you know, warm

1:00

enough that the snow that

1:02

was on the ground when

1:04

I woke up this morning

1:06

had melted pretty quickly. Gosh,

1:08

it's April. We're sick of

1:10

the snow already. But you

1:12

haven't had much snow lately, right?

1:14

No, no, no. It was just, it

1:17

was a brief flurries that we got

1:19

last night. I got up this morning.

1:21

I looked out the window. I said,

1:23

great. but then it was gone. You

1:25

didn't have to pull out the wovell?

1:28

No, I didn't need the wovell, didn't

1:30

need the electric snowblower, so it's

1:32

all good. Also joining us from

1:34

Madison, New Jersey, Brian Barker. Hi,

1:37

it is exactly the same weather

1:39

that Allen has, so I also

1:41

have 46 Fahrenheit, 8 Celsius, and

1:43

gray and rainy, and blah. It's

1:46

supposed to be a good weekend to

1:48

stay inside. I'm actually probably going to

1:50

spend the weekend going to a museum.

1:52

And I think, or at least tomorrow,

1:54

going to a museum. And you know

1:56

what? I think it's a good museum

1:58

kind of weekend too. that's also

2:01

an excellent idea. Well, so

2:03

last weekend was a rainy

2:05

weekend here as well. If

2:07

you appreciate these programs, if

2:10

you enjoy that, we'd love

2:12

to have your support to

2:14

produce them because we don't

2:16

do advertising. And furthermore, for

2:19

you, MicroTV is of 501c3

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non-profit, so your donations are

2:23

federal US tax deductible. Go

2:25

to MicroB.TV slash contribute. It's

2:28

happening with ASV, Kathy. Pretty

2:30

much the same news as

2:32

before. The deadline for ASV

2:34

CARES and Kitty Corp is

2:36

May 9th. I had been

2:39

telling you the wrong date

2:41

for a long time, which

2:43

may have gotten some of

2:45

you active sooner, but now

2:48

that the concurrent workshop assignments

2:50

are out, you can plan

2:52

your day and figure out

2:54

what hours you might need

2:57

your kids to be at.

2:59

And you can also... apply

3:01

for ASV cares if you're

3:03

not going to use the

3:05

on-site daycare. So those are

3:08

May 9th and then early

3:10

bird registration for the meeting

3:12

itself, which is, as we

3:14

know, in Montreal, Canada is

3:17

May 12th. So you don't

3:19

want to wait till after

3:21

then because it costs more

3:23

to register. Little bit of

3:26

news. Just two items. First

3:28

one. is an article in

3:30

MSN Novavax in Selloff after

3:32

RFK Junior's comments on COVID

3:34

vaccine. This is just a

3:37

bunch of bullet points, right?

3:39

Because it's for financial people.

3:41

So, you know, Novavax, FDA

3:43

declined to approve the Novavax

3:46

vaccine to license it. It's

3:48

been on the EUA ever

3:50

since the pandemic. Do

3:53

we know why they declined?

3:55

Was it just they didn't

3:57

have enough people to get

3:59

around to looking at the

4:01

data and then approving it?

4:03

Or did they look at

4:05

it and say, no? I

4:07

don't think it was the

4:09

latter, but I don't know

4:11

if it was the former.

4:13

I know, but I can't

4:15

tell you. Oh, okay. No,

4:17

not many other people know.

4:19

Okay. So RFQA says, we're

4:21

looking at that vaccine. It's

4:23

a single antigen vaccine. For

4:25

respiratory illnesses, the single antigen

4:27

vaccines have never worked. We're

4:29

actually shifting our priorities to

4:31

multiple antigen vaccines and NIH

4:33

is already working on a

4:35

number of those. Now this

4:37

is just silliness at its

4:39

highest. First of all, RFK,

4:41

I thought you said no

4:43

vaccine works. Now you're saying

4:45

multiple antigen vaccines work? Okay,

4:47

but in fact, it's not

4:49

true that single antigen vaccines

4:51

don't work. The COVID vaccine

4:53

works very well. Right. Saved

4:55

millions of lives. Shingrix. works

4:57

well, single antigen, RSV, single

4:59

antigen. Anyone else? Influenza. Influenza

5:01

is just H-A, right? Well,

5:03

yeah. Or oh, some, yeah,

5:05

okay, you're right. Some, depending

5:07

on which one you're talking

5:09

about. Right, yeah. So, I

5:11

don't know where he gets

5:14

this stuff from, and people

5:16

listen to him. That's not

5:18

true. There's not a reason

5:20

to reject Novavax, because it

5:22

was EU8, it was used

5:24

extensively, and it, all the,

5:26

papers Daniel did it, induced

5:28

antibodies as well as the

5:30

MRNA vaccine, and it was

5:32

equally protective against disease. So

5:34

it seemed like the only

5:36

data that we didn't have

5:38

yet was how durable it

5:40

was, and there was some

5:42

thought that maybe it would

5:44

be more durable. Yeah, that's

5:46

what we were all speculating

5:48

on, but I don't know

5:50

what's happening here. Novax is

5:52

like, hey, we got all

5:54

the data you need. Why

5:56

didn't you approve it? So

5:58

it's very frustrating. dire wolves.

6:00

Yeah this is just a

6:02

quick follow-up to a side

6:04

conversation we had a couple

6:06

of weeks ago about the

6:08

woolly mice so that the

6:10

woolly mice were very very

6:12

cute and I think we

6:14

even talked at the time

6:16

about how they weren't particularly

6:18

a scientific breakthrough but they

6:20

were adorable. Yes the only

6:22

key thing about them was

6:24

that they were adorable. Yes.

6:26

Yes, and colossal biosciences, the

6:28

company that did that, just

6:30

went viral again for supposedly

6:32

resurrecting dire wolves, which they

6:34

very carefully orchestrated the PR

6:36

around this. There's no peer-reviewed

6:38

paper, but probably all of

6:40

our listeners heard this. It

6:42

was on TV. They've got,

6:44

you know, a little, cute

6:46

little fluffy white puppies that

6:49

they're showing off and saying

6:51

these are dire wolves. They're

6:53

not. They're gray wolves genetically

6:55

engineered with a couple dozen

6:57

gene changes that may or

6:59

may not be related to

7:01

characteristics of dire wolves and

7:03

I'm linking to a science

7:05

article that goes into the

7:07

details on this. Did they

7:09

use any frog DNA? I.

7:11

Those in the know will

7:13

understand that. Do you guys

7:15

know what I'm talking about

7:17

Alan? No, I don't. I

7:19

don't. Jurassic Park. Oh yes.

7:21

Yes. Yes. You know, they

7:23

didn't have all the, they

7:25

got a little bit of

7:27

dinosaur DNA from Amber, right?

7:29

Right. Mosquitoes. And then the

7:31

rest, they used Frogdee. Right.

7:33

Right. Why would you use

7:35

Frogdean? Of all things. Yeah.

7:37

No. But the funny thing

7:39

is there's a sequence in

7:41

that book. And if you

7:43

blast it, it's just PBR

7:45

322. And speaking of going

7:47

through freezers, I just threw

7:49

away some really pure preps

7:51

of PBR 322. PBR 322

7:53

is one of the original

7:55

cloning plasmids. widely used tool

7:57

in the lab. Yeah, it

7:59

was really useful. At a

8:01

couple of nice restriction sites

8:03

in empicillin resistance or tetracycling

8:05

resistance, which you could use

8:07

to select for colonies that

8:09

received it. I used it

8:11

myself when I was in

8:13

grad school. I probably have

8:15

used it. Yeah. And one

8:17

more article in Reuter is

8:19

also bullet pointed by Kennedy.

8:21

Set September deadline to identify

8:24

cause of rising U.S. autism

8:26

autism risks. I'm very frustrated

8:28

about this one. Yeah. I

8:30

mean, this has been studied

8:32

for decades. Okay. It's a

8:34

complicated genetic problem. You can't

8:36

put a deadline on it.

8:38

You can't put a deadline

8:40

on it and the premise

8:42

is wrong. The idea that

8:44

the deadline also, September? Yeah.

8:46

Yeah, the premise is that

8:48

there's some, you know, recent

8:50

tremendous rise in the incidence

8:52

of autism, which is at

8:54

best debatable, probably wrong. There's

8:56

a rise in diagnosis of

8:58

it because we've gotten better

9:00

at diagnosing it. And if

9:02

you look at the demographic

9:04

data, you find that people

9:06

who, you know, are older

9:08

who have it are more

9:10

likely to have been diagnosed

9:12

later in life. because they

9:14

weren't diagnosed as kids. But

9:16

this is not some sudden

9:18

change that's caused by some

9:20

thing that's changed in the

9:22

modern world, which is what

9:24

RFK wants to try to

9:26

say that it's due to

9:28

vaccines or, you know, some

9:30

other thing, and if we

9:32

just went back to the

9:34

way we were in primitive

9:36

times, then everything would be

9:38

better. Not the case. No,

9:40

everything would not be better.

9:42

No. Nothing would be. Hardly.

9:44

In fact, I did a

9:46

lecture on measles in my

9:48

emerging infectious disease class this

9:50

week. My students are appalled.

9:52

They can't believe that anyone

9:54

thinks such a thing is

9:56

a good idea. All right.

9:59

Today is Norovirus Day. Yes.

10:01

I don't know. You guys

10:03

remember the Dixon story about

10:05

Norovirus? Oh, yes. So it

10:07

used to be called Norwalk

10:09

virus. And one twivery. So

10:11

the Norwalk Connecticut. And people

10:13

got all pissed off because

10:15

it's Norwalk Ohio. We were

10:17

first identified. People in Connecticut

10:19

didn't like it associated with

10:21

them. Of course, Norwalk was

10:23

gotten rid of. Now it's

10:25

Noro. I think it's just

10:27

one one actual isolate is

10:29

still the Norwalk isolate, most

10:31

likely. It's still called Norwalk.

10:33

Isolate. Yeah, maybe. That doesn't

10:35

mean you can't get Noraviruses

10:37

in Norwalk, Connecticut. I'm sure

10:39

you can. Dixon was always

10:41

funny about that. We said

10:43

that he'll never forget that.

10:45

Anyway, we start with a

10:47

snippet. So today we're going

10:49

to talk about potential vaccine

10:51

and potential maybe therapeutic monoclonal

10:53

antibodies. And these are both

10:55

related to the same underlying

10:57

work. It's the same vaccine,

10:59

right? No, I don't think

11:01

so. Very close, if not

11:03

the same. Very, very closely,

11:05

yeah. I don't think so.

11:07

I was, actually, well, we'll

11:09

get into it. Okay. Yeah.

11:11

Okay. G1. It's a G1

11:13

vaccine. Oh, right, right. Well,

11:15

actually in that paper, they

11:17

made G2 vaccine, too, I

11:19

thought. Or they referred to

11:21

a G2 vaccine. Right. We're

11:23

getting ahead of ourselves. Yeah.

11:25

So there are authors from

11:27

the same company, VACSART, on

11:29

both papers. So it's closely

11:31

related. Okay. Kathy, you want

11:33

to summarize? Sure. So, I

11:36

think there's only one author

11:38

overlapped. between this first paper

11:40

and the second paper. And

11:42

it's the first author, Becca

11:44

Flittner, who is a co-cor

11:46

responding author here with James

11:48

Cummings, and they're both from

11:50

Vaxart. There's one author from

11:52

University of Maryland, but everybody

11:54

else is from. from this

11:56

vaccine company, which is in

11:58

South San Francisco. And so

12:00

this snippet is a report

12:02

of a clinical trial producing

12:04

a vaccine that might work

12:06

against neurovirus, and it's just

12:08

the phase one trial, which

12:10

is really just the safety

12:12

trial. And this factor, or

12:14

something like it, is what

12:16

I had in my notes,

12:18

was used in the patients

12:20

that are used in the

12:22

second paper that we're going

12:24

to talk about. So the

12:26

premise of this first paper

12:28

is that immunizing adults for

12:30

things in general is a

12:32

challenge because their immune systems

12:34

are waning. Immune system function

12:36

declines with age. You know

12:38

what I really like about

12:40

what you just said, Kathy?

12:42

Yes. You said it was

12:44

a problem in adults? Oh,

12:46

yes. Does that mean I'm

12:48

not an adult? Older adults.

12:50

Older adults. And noravirus itself

12:52

is a challenge because there's

12:54

many types to immunize against

12:56

and people have been trying.

12:58

And there's, we'll talk more

13:00

about this for the second

13:02

paper. And in the United

13:04

States, adults that are over

13:06

age 65 are at the

13:08

greatest risk for noravirus associated

13:11

mortality. So that's why they're

13:13

trying out this vaccine that

13:15

they hope will be a

13:17

good. platform for vaccines for

13:19

other things in older adults

13:21

and in particular for neurovirus.

13:23

And so they develop a

13:25

thermostable vaccine that's an oral

13:27

tablet that's enterically coded and

13:29

adenovirus-based. So it's going to

13:31

be related to some of

13:33

the adenovirus vaccines we've talked

13:35

about before. It's based on

13:37

an adenovirus type 5 backbone.

13:39

It's a non-replicating vector and

13:41

they also include a double-stranded

13:43

RNA adjuvant. And so this

13:45

whole backbone and adjuvant and

13:47

everything also expresses the neurovirus

13:49

VP1 which is the capsid,

13:51

main capsid protein. And they

13:53

give it to adults 55

13:55

to 80 years old, and

13:57

it's going to, because it's

13:59

enteric and goes through the

14:01

gut, it's designed to release

14:03

the vector into the intestinal

14:05

Ilium. And this. previously was

14:07

shown to be safe in

14:09

people ages 18 to 49

14:11

and it generated cellular and

14:13

humoral responses. And so now

14:15

they're just trying it in

14:17

an older age group. So

14:19

randomized placebo-controlled trial, 63 adults

14:21

completed the trial, there were

14:23

only mild to moderate adverse

14:25

effects, and the overall take-home

14:27

message is that they... produce

14:29

this vaccine that safely generated

14:31

strong durable neurovirus specific systemic

14:33

cellular and mucosal immune responses.

14:35

But again, this is only

14:37

the phase one trial, so

14:39

they have a ways to

14:41

go with more individuals, etc.

14:43

Okay. So you did say

14:46

most of the debts occur

14:48

in older individuals, right? Over

14:50

65. Right. Yeah, so the

14:52

vaccine's got to work in

14:54

them where, you know, not

14:56

all vaccines work well in

14:58

older people. They call it

15:00

the vaccine efficacy gap. Yeah,

15:02

they say in the introduction

15:04

90% of neurovirus associated deaths

15:06

or people over 65 in

15:08

long-term care facilities particularly. So

15:10

these are going to be

15:12

people that probably have other

15:14

other issues too. When we

15:16

finished recording, remind me to

15:18

tell you a story. I

15:20

don't want to put it

15:22

in the recording. Okay. The

15:24

vaccine efficacy gap, mind the

15:26

gap. That's what this is

15:28

about. There's no what mind

15:30

the gap is? Yes. Oh,

15:32

yes. Been there. Sometimes people

15:34

don't know. Like my, I

15:36

said to the class, my

15:38

classes we bam lamb and

15:40

in the vab, the monoclono

15:42

we used to call a

15:44

bam-bam. And I look at

15:46

him and I say, does

15:48

anybody know what bam-bam was?

15:50

This one guy said, yeah,

15:52

it was. Not a Flintstone's

15:54

character. So very good. Yeah.

15:56

As long before your time.

15:58

So often I say things

16:00

and I wonder if they

16:02

get it because I'm increasingly

16:04

gapped away from the students,

16:06

right? Okay. So, you know,

16:08

we'll see this more in

16:10

the next paper where we

16:12

get some information. But there's

16:14

so many genogroups and types

16:16

of neuroviruses. It's very hard

16:18

to make a vaccine that

16:21

covers all of them. In

16:23

this paper, they want to

16:25

do a mucosal vaccine because,

16:27

you know, mucosal antibodies correlate

16:29

with protection against neurovirus disease,

16:31

disease, not infection disease. And

16:33

it does seem particularly important

16:35

because this is a mucosal

16:37

entering pathogen and mucosal replicating

16:39

pathogen, potentially mucosal spread pathogen.

16:41

So thinking about getting the

16:43

mucosal immune response involved here

16:45

instead of a systemic immune

16:47

response is going to be

16:49

quite important. Yeah, but I'm

16:51

going to tell you that

16:53

IPV is a really good

16:55

vaccine against polio virus. But

16:57

you know, the difference is,

16:59

IP, we're trying to prevent

17:01

invasion into the CNS. We're

17:03

not trying to prevent gut

17:05

replication. We're not trying to

17:07

prevent gut replication. We don't

17:09

care about that. Because once

17:11

it gets in the blood,

17:13

then it could get in

17:15

the CNS. So that's why

17:17

IPV works. You don't have

17:19

to have a mucosa risk.

17:21

Whereas with norovirus, the gut

17:23

virus, the gut replication is

17:25

the gut replication. Two

17:27

buckets got yes, you know,

17:30

showing up in diarrhea All

17:32

right, so this vaccine is

17:34

called VX a G1.1 Let's

17:36

say it's a yes Kathy

17:38

said it has it come

17:41

at five vector and then

17:43

it's a G1.1 VP1 antigen

17:45

with with double-stranded RNA. So

17:47

I guess it's all in

17:50

the tablet It's very interesting

17:52

This is a really cool

17:54

technology. And they've got this

17:56

tablet coated so it'll make

17:58

it through the stomach into

18:01

the intestine. And then this.

18:03

thing uncoats and then the

18:05

adenovirus can presumably infect cells

18:07

in the intestinal, you know,

18:09

epithelium, and then you get,

18:12

since it's a non-replicating virus,

18:14

it's going to go in,

18:16

in fact, produce the noravirus

18:18

protein, give you the adogen,

18:21

and they also have it

18:23

producing this double-stranded RNA, which

18:25

is a built-in edge of

18:27

it, which I just think

18:29

the whole thing is very

18:32

clever. I view the intestine

18:34

as a fast flowing system,

18:36

right? Right. And this, finally,

18:38

this tablet gets into the

18:41

intestine and dissolves. It's got

18:43

to infect the intestinal cells,

18:45

the coastal epithelial cells, right?

18:47

Isn't the RNA going to

18:49

get diffused away? I don't

18:52

know how that actually... I

18:54

mean, the whole point of

18:56

the intestine is that it's

18:58

going to try and have

19:00

contact with the whole contents

19:03

of it. Yeah. Right. And

19:05

it's not a pipe. flexing

19:07

around and you know, you

19:09

know, a bosom peep. Right.

19:12

It's moving, it's moving things

19:14

through by Parastaltus, so you've

19:16

got all this movement. No,

19:18

I got them in the

19:20

story. Yeah. There's a, there's

19:23

a bagel store downstairs. There's

19:25

a picture of a bagel.

19:27

A bagel. Yeah, I mean,

19:29

it works. You're going to

19:32

see. They did a previous.

19:34

safety study, it was fine.

19:36

And this study, you're going

19:38

to see it works. But

19:40

I just don't know why.

19:43

Well, I mean, it's infecting

19:45

the cells the same way

19:47

noravirus would infect the cells.

19:49

Right? This is how noravirus

19:51

gets in. Yeah, I know,

19:54

but this is the tablet

19:56

with virus and adjuvant. Yeah.

19:58

So the vector is going

20:00

to make. Yes. That's what

20:03

I think is so clever

20:05

about it. The vector, the

20:07

vector produces the target antigen,

20:09

the norovirus antigen. The effect

20:11

is over that problem, yeah.

20:14

And it also produces this

20:16

double-stranded RNA right in the

20:18

cell. The cell is going

20:20

to produce that. Is double-stranded

20:23

RNA a TLR3? Okay, because

20:25

that's what they have in

20:27

this picture. I spent way

20:29

too much time trying to

20:31

find out more details about

20:34

this vector, but I did

20:36

eventually get one that shows

20:38

an adenovirus with a trans

20:40

gene and the TLR3 agonist,

20:42

which then I had somehow

20:45

figured was the double-stranded RNA.

20:47

It must be an early

20:49

promoter driving that, right? They

20:51

don't, so it looks pretty

20:54

much like what they used

20:56

to call gutless adenovirus. Right.

20:58

Which we all did. As

21:00

you want a, I think.

21:02

Okay. Maybe. I spent too

21:05

much time and still didn't

21:07

get there, so I don't

21:09

know. I'm not going to

21:11

say what they have. All

21:14

right, so bring the adjuvant

21:16

in the vector, that's the

21:18

key. Very good. Okay, so

21:20

this study, they have 65

21:22

people in the US, 55

21:25

to 80 years old, and

21:27

they're randomized to get vaccine

21:29

or placebo. We have, in

21:31

the end, we have fewer

21:33

people because people drop out.

21:36

And the primary outcome is

21:38

safety and tolerability. And then

21:40

they're going to look at

21:42

responses as well. So all

21:45

the... Solicited events, right? The

21:47

ones you ask about were

21:49

mild to moderate headache. Listen

21:51

to this, this is funny,

21:53

headache, malaise fatigue, they're the

21:56

most common in both the

21:58

vaccine and the placebo group.

22:00

Yes. Yeah, and about the

22:02

same frequency. Yeah. Totally. So

22:05

people get headaches. They get

22:07

malaise and fatigue, whether or

22:09

not. So these are not

22:11

caused by the vaccine. And

22:13

that's the thing. If it's

22:16

the same rate in the

22:18

placebo, then it's not vaccine

22:20

related. Then 17 unsolicited treat.

22:22

adverse events were mild or

22:24

moderate in severity. I

22:28

didn't look at the supplemental figure.

22:30

Does anyone know what they were?

22:32

I didn't look you. Okay, don't

22:35

worry about that. And again, the

22:37

incidents of these unsolicited, the same

22:39

in the vaccine in the placebo

22:42

group. So the summary is when

22:44

you get to this age group,

22:46

people, stuff happens. What kinds of

22:49

things happening? Well, I wouldn't even

22:51

say when you get to this

22:53

age group, I mean, everybody, you

22:55

go out into life and sometimes

22:58

you get a headache and sometimes

23:00

you, you know, yeah, well, you

23:02

might get appendicitis, you might have

23:05

to, after the first dose, did

23:07

you have any of these things?

23:09

Yeah, I had a headache. Yeah,

23:11

that's written down, right, which is

23:14

the way it should be. These

23:16

are, this is a placebo controlled

23:18

trial, folks. Yep. So. To say

23:21

that no vaccine has ever been

23:23

tested in a placebo-controlled trial, it's

23:25

just false information, misinformation and a

23:27

lie actually. I just gave up

23:30

with a great idea. What's that?

23:32

I think from my class in

23:34

the fall, I think we're going

23:37

to do a placebo-controlled trial of

23:39

what things the class makes you

23:41

do. I give my students and

23:43

students and some other class like

23:46

a thing. Did you have a

23:48

headache? Did you have this? Yes.

23:50

And see what my class, what

23:53

side effects my class might do.

23:55

Oh, also ask them if their

23:57

teeth feel fuzzy. Okay. Oh, their

23:59

teeth feel fuzzy, yeah. I mean,

24:02

I think a pandasitis is amazing,

24:04

right? That this can happen in

24:06

this, it's not a huge population.

24:09

Right? Okay, then they looked at

24:11

serum antibody responses, IGA and IGA.

24:13

And by the way, this is

24:15

looking at days 129, 57, 210

24:18

post-vaccination. How many days, how many

24:20

months is 210? A little over

24:22

six? Yeah, six would be 180,

24:25

right. So like almost seven months.

24:27

Seven months. Seven months. Seven months.

24:31

Okay, so you know, the

24:34

antibodies went up and they

24:36

do a comparison with everybody

24:39

as antibodies, the neurovirus is

24:41

already, right? So they do

24:43

fold rise over pre-vaccination baseline

24:46

values for everyone. And the

24:48

notable numbers, CMIJ remained elevated

24:51

on day 57. And on

24:53

day 210. both the high

24:55

and medium dose cohorts had

24:58

over twofold serum IGM over

25:00

the baseline concentration. Although these

25:03

values were not significantly different

25:05

from placebo. So you know

25:07

you expect these titers to

25:10

go down by 210 days

25:12

if not sooner. Yeah and

25:15

it's also important to note

25:17

that here they're looking at

25:19

serum yes and not at

25:22

the immune coastal site they're

25:24

looking at blood. Yeah and

25:27

unfortunately they don't look at...

25:30

memory cells at all in

25:32

this paper, right? But, you

25:34

know, they say it lasts

25:37

a long time because you're

25:39

looking at months, but you're

25:41

not going to have high

25:44

titers six months and more

25:46

afterwards, but you should have

25:48

memory cells, right? But they

25:51

didn't look at that. Okay.

25:53

IGE also is pretty much

25:55

the same. So you're my

25:58

G. There is specifically anti-VP1

26:00

IGE. Day 57. The IGG

26:02

antibody was increased in the

26:05

high medium in low dose

26:07

groups compared with the placebo.

26:09

It remained elevated on day

26:12

210. And importantly, and I

26:14

didn't mention this for the

26:16

other, for the IGA and

26:19

the IGG, there's no difference

26:21

in the age group. So

26:23

they had two different groups,

26:26

55 to 65 and 66

26:28

to 80. And the responses

26:30

were the same. So that

26:33

says this is doing pretty

26:35

well in the... elderly. Which

26:37

is interesting because you kind

26:40

of expect based on other

26:42

vaccines or I kind of

26:45

expect based on other vaccines

26:47

you might see less response

26:49

in the older people. Yeah,

26:52

yeah, it's very surprising. Maybe

26:54

if they had looked at

26:56

T cells they would see

26:59

a difference. Maybe. And we

27:01

pointed out that this is

27:03

dose dependent, right? Yeah. They'll

27:06

have to pick what dose

27:08

they want to use going

27:10

forward. based on this. Okay,

27:13

so these are binding antibodies.

27:15

What about virus binding? So

27:17

they they say they use,

27:20

they have virus-like particles and

27:22

they measure their binding, inhibition

27:24

of their binding to a

27:27

histoblud group antigen. All right?

27:29

It's a surrogate neutralization assay

27:31

because it's very hard to

27:34

do. Neutralization assays with the

27:36

neuroviruses. You can grow them

27:38

in gut-organoid cultures, but not

27:41

in your standard cell lines,

27:43

so it's not so easy

27:45

to do. And so this

27:48

histo-blood group antigen binding to

27:50

viruses relevant to infection. So

27:53

if you can block that.

27:55

the antibodies may be important,

27:57

right? And so again, they

28:00

see increases in antibodies that

28:02

block this interaction. on day

28:04

29 and day 57. No

28:07

differences in the two age

28:09

groups either, 55 to 65

28:11

and 66 to 80. So

28:14

they think that this this

28:16

antibody gives you good functional

28:18

antibody responses again in serum.

28:21

They also look at the

28:23

avidity of the antibody, the

28:25

binding strength over time from

28:28

day 1 to 29. It

28:31

goes up, as you might

28:34

expect it to do. They

28:36

want to know, these experiments,

28:38

they're not distinguishing between IGG

28:41

and IGA, so they want

28:43

to know which one plays

28:46

a greater role in these

28:48

blocking assays that they're doing.

28:50

So they actually purify IGA

28:53

and IGD. separately from the

28:55

Sierra of some of the

28:57

participants. And then they do

29:00

a neutralization, surrogate neutralization tighter

29:02

and normalize it per microgram

29:05

of IGA. So for the

29:07

total antibody, and for IGA,

29:09

the number is 2.8. So

29:12

for IGA, it was 0.

29:14

Looks like IGA is making

29:17

a greater contribution to neutralization

29:19

than IGG. Which is reassuring.

29:21

Is that fair to say

29:24

from this, Brea? Yeah, that's

29:26

what I think I would

29:29

say. And it is reassuring

29:31

and it sort of goes

29:33

with this idea of using

29:36

perhaps a mucousal vaccine. It

29:38

makes you think, okay, perhaps

29:41

we are getting a mucosal

29:43

response as IGA is often

29:45

thought of as a isotype

29:48

that is often found in

29:50

the mucosal. even though they're

29:53

not measuring the mucosa here.

29:55

Right. See them again. Yeah.

29:57

All right. Then they want

30:00

to know if this vaccine

30:02

can generate B cell responses

30:04

in old people. So they

30:07

quantify antibody secreting cells in

30:09

the blood. And what they

30:12

find is an antibody secreting

30:14

B cells, they would be.

30:16

and they quantify them in

30:19

the different age groups and

30:21

there's no difference. They make

30:24

the same numbers of antibody

30:26

secreting cells in both. And

30:28

they do also see another

30:31

dose-dependent response. Yeah. Okay, they

30:33

say antigen-specific mucosal homing plasma

30:36

blasts have been investigated as

30:38

a proxy marker of mucosal

30:40

immune So the plasma blast

30:43

is a plasma blast. So

30:45

a plasma blast is an

30:48

activated B cell. So. It

30:50

is now sort of become

30:52

more like a plasma cell,

30:55

but the most important thing

30:57

here is that this cell

31:00

has proteins on its surface

31:02

that help it travel to

31:04

mucosyl sites. So we know

31:07

that there are certain proteins

31:09

on the surface of lymphocytes

31:11

that mean that when they're

31:14

in the blood, they're getting

31:16

ready to go to the

31:19

mucosyl sites. And since it's

31:21

often... can be challenging to

31:23

actually get a sample from

31:26

a mucosal site and people

31:28

often do what they do

31:31

where they're getting serum samples.

31:33

They will look in the

31:35

blood to see how many

31:38

of the lymphocytes have these

31:40

proteins that mean that those

31:43

lymphocytes are heading towards a

31:45

mucosal site. Okay, so they

31:47

find that the IGA producing

31:50

plasma blasts are in circulation

31:52

and they have the ability...

31:55

to migrate to the gut

31:57

mucosa. Yeah, so it's sort

31:59

of like we've activated B

32:02

cells and the B cells

32:04

that we've activated have been

32:07

have the capacity to go

32:09

to the mucosa. So perhaps

32:11

we are getting a mucosal

32:14

response here. Next they looked

32:16

at T cell responses. And

32:18

they find activated CD4 and

32:21

CDA T cells with the

32:23

right marker. which went up

32:26

in the circulation a week

32:28

after oral vaccination. All right,

32:30

so finally, is it in

32:33

the mucosa? So they look

32:35

in saliva. So they find

32:38

that salivary VP1 specific IGA

32:40

went up in all vaccine

32:42

dosage groups. On day two,

32:45

two, ten, the salivary IJ

32:47

remain elevated compared with placebo,

32:50

but you know, it's not

32:52

huge. It's a little bit.

32:54

No differences in salivary IJ

32:57

between the age groups. So

32:59

they say, yeah, this vaccine

33:02

can give us long-lived salivary

33:04

responses. Are there B cells

33:06

in the oral mucosa, Brian?

33:09

In the oral, I would

33:11

say, yeah. I believe so.

33:14

There definitely are B cells

33:16

in places like the tonsil.

33:18

Yeah. And some of the

33:21

lymphoid tissue that is in

33:23

the malt and malt. Okay,

33:26

so that that could respond

33:28

to a contraction, right? Okay.

33:30

Another place they look besides

33:33

saliva is the nasal lining

33:35

fluid. So these are distal

33:37

mucosa sites, right? Because they're

33:40

immunizing the gut. Yeah, I

33:42

was thinking about that and

33:45

I mean part of the

33:47

problem is that getting samples

33:49

at least of directly you

33:52

know of the small intestine

33:54

would be tricky. Obviously you

33:57

can get some samples lower

33:59

down a little bit more

34:01

easily. But I would also

34:04

imagine that if you really

34:06

think about neurovirus infection, the

34:09

virus is probably coming in

34:11

through the mouth, say, through

34:13

ingestion, and so you want

34:16

to have antibodies that might

34:18

be able to neutralize pretty

34:21

early. So this is a,

34:23

I was thinking that would

34:25

be a good reason to

34:28

perhaps check this early and

34:30

it's just a site you

34:33

can get samples from pretty

34:35

easily. But this would be

34:37

a good place for neutralization

34:40

to happen in a perfect

34:42

world. So they also cite

34:44

some earlier research, I think

34:47

it was in the intro

34:49

or the discussion, that apparently

34:52

IGA, anti-anoravirus IGA, in the

34:54

saliva, correlates with immunity. And

34:56

we also know that when

34:59

you immunize one mucusal site,

35:01

sometimes you get responses at

35:04

other mucosal sites because that's

35:06

what you would want to

35:08

do with this vaccine. You

35:11

immunize the gut and then

35:13

you get antibodies in the

35:16

saliva or the nasal lining

35:18

fluid. And so this is

35:20

basically nasal secretions, not saliva.

35:23

That's different, right. So they

35:25

measure. nasal VP one specific

35:28

IGA. It goes up in

35:30

all groups one month and

35:32

remains elevated. Day 210 there's

35:35

still higher but only in

35:37

the high dose group. So

35:40

you can also find it

35:42

in the nasal wash. You

35:44

get antibodies in the nasal

35:47

wash. They also,

35:49

they finally, they looked at

35:51

both saliva and nasal wash.

35:53

Yeah, but the saliva we

35:55

already did, nasal was pretty

35:57

much the same, yeah. And

35:59

finally, They have

36:01

this idea that BP1 specific

36:04

IGA positive circulating antibody secreting

36:06

cells, which they see a

36:08

week after the vaccination are

36:11

probably associated with subsequent increases

36:13

in IGA responses that they

36:15

see. And so they look

36:17

at peripheral ASC frequencies a

36:20

week after and a month

36:22

after post immunization. and in

36:24

fact they go up. So

36:27

they say these peripheral ASEs

36:29

that we induce with our

36:31

vaccine may be early plasma

36:33

blasts with the capacity to

36:36

move to mucosal tissues and

36:38

become local antigen-specific secretary IGA-producing

36:40

cells. So overall this looks

36:43

pretty good to me, my

36:45

untrained eye. It's a orally

36:47

delivered vaccine. It induces, it

36:49

induces, it induces vaccine it

36:52

induces, it induces vaccine it

36:54

induces. Antibodies, not only in

36:56

the serum, but in the

36:59

upper respiratory tract, especially IGA

37:01

antibodies that can interfere with

37:03

the neurovirus binding. There's not

37:05

a being old, doesn't hurt

37:08

you here. You do as

37:10

well as younger people in

37:12

terms of responses. And so

37:15

they say that we've got

37:17

to go on forward, but

37:19

this is only... Monovalent G1.1

37:21

in this paper. They say

37:24

we need to look at

37:26

other. And it said, in

37:28

fact, the larger phase two

37:31

is ongoing, which uses G1.1

37:33

and G2.4, right? Well, the

37:35

results in this paper are

37:37

G1 specific. So we're going

37:40

to hear more about this,

37:42

I'm sure. Now, this is

37:44

a good question now. It's

37:47

not a good question. It's

37:49

just a question. So who's

37:51

going to get this vaccine?

37:53

Assuming it's licensed. Depends on

37:56

price. depends on you know

37:58

I think the priority would

38:00

be people who are older

38:03

people in long-term care facilities

38:05

because that's yeah it's most

38:07

likely to die they should

38:09

all get it yeah I

38:12

mean I think that with

38:14

some of the data that

38:16

we had especially with the

38:19

COVID vaccine it looked like

38:21

a higher population percentage of

38:23

people being vaccinated really helped

38:25

some of those at-risk communities

38:28

as well. And so I

38:30

wonder if worrying not so

38:32

much about age group, but...

38:35

populations and maybe populations in

38:37

congregate settings. So people in

38:39

those long-term care facilities, maybe

38:42

people on college campuses, maybe

38:44

kids in daycares, places where

38:46

you could imagine a lot

38:48

of transmission happening. If we

38:51

could block transmission in those

38:53

sorts of settings, that might

38:55

be protective of most of

38:58

the high-risk people in the

39:00

population. And I think

39:02

it makes an enormous difference

39:05

that this is an oral

39:07

vaccine. Yeah, which I personally

39:09

suspect is going to get

39:12

around a lot of vaccine

39:14

hesitancy. Yeah, I agree. It

39:17

certainly drastically simplifies the logistics

39:19

of distributing this thing because

39:21

anybody can hand out pills.

39:24

And it's a, you know,

39:26

you can mail this to

39:29

people. It's a stable tablet.

39:31

The diagram I did find

39:33

about the vector itself shows

39:36

the shipping is just in

39:38

a pouch and says self-administration

39:41

and then I'm laughing because

39:43

the last part of the

39:45

picture is two stick figures.

39:48

One is a guy in

39:50

purple and then the other

39:52

is a woman in green

39:55

and they're both dancing and

39:57

she's got a cane. One

40:01

more thing, what was I going

40:03

to say here? It's gone. Well,

40:05

these are probably going to be

40:08

at least by-valent vaccines going forward.

40:10

So that's good because what's his

40:13

face would object to them? Right.

40:15

Multiple antigens. Yes, multiple antigens. Yeah.

40:17

Yeah. Yeah. I mean, don't. All

40:20

of them really have multiple antigens

40:22

because of ant- or at least

40:25

if we're talking epitopes. Oh wait

40:27

a minute. Are you expecting him

40:29

to know what the hell all

40:32

that is? I know. Oh my

40:34

gosh, epitope. You go up to

40:37

him and say epitope. He'll think,

40:39

he'll put you in jail. But

40:41

if I just started talking about

40:44

epitopes, then I would be like,

40:46

see, it has multiple. It has

40:49

multiple thinggies. Yeah, what did he

40:51

call it? Geez,

40:53

let me go back to

40:55

the single antigen he calls.

40:57

Is that what he used

41:00

the word single antigen? The

41:02

single antigen vaccine. Someone got

41:04

in the word antigen. That's

41:06

even worse. Single antigen. I

41:08

mean, I think he means

41:10

like a single protein, like

41:12

a spike, right? Right. Right.

41:14

But that's many antigens. Well,

41:16

it's many epitopes, perhaps, in

41:18

an antigen. So it's all

41:21

multiple. Yeah. Oh boy.

41:23

Okay. We have another neurovirus

41:25

paper for your digestion. I

41:27

think, can you summarize that

41:30

for us? We all studied

41:32

it, now we're going to

41:34

regurgitate the details. The title

41:36

is Broadly neutralizing Antibodies Targeting

41:38

Pandemic G24 Variants. or 7G2

41:41

genotypes of human neurovirus. And

41:43

there are three co-first authors,

41:45

Jun Park and Lisa Linda

41:47

Smith, both from University of

41:50

Texas Austin and Adam Ollia

41:52

from this Vax art. And

41:54

then there are two. co-senior

41:56

authors George Giorgio and Ralph

41:59

Berrick at University of North

42:01

Carolina at Chapel Hill. So

42:03

yeah, there's also contributions from

42:05

NIAID, the Vaccine Research Center,

42:07

that is, the Centers for

42:10

Disease Control and Prevention. I

42:12

can't read my writing. Oh,

42:14

Utrecht University and the Frederick

42:16

Cancer Center, and that's an

42:19

NIH thing. And then as

42:21

I said, the Vaxart in

42:23

South San Francisco. So. This

42:25

paper, in very short terms,

42:27

uses really highly sophisticated techniques

42:30

to identify antibodies that will

42:32

neutralize a broad range of

42:34

neurovirus variants. And so, again,

42:36

to reiterate, this is a

42:39

really bad infectious gastroenteritis. 700

42:41

million infections worldwide causes tens

42:43

of thousands of deaths. And

42:45

again, the problem with getting

42:48

a vaccine is the genetic

42:50

diversity and then a lack

42:52

of knowledge, and it's that

42:54

knowledge gap that they're working

42:56

on filling here. And the

42:59

knowledge gap is really about

43:01

what are the conserved epitopes

43:03

that the antibodies will bind

43:05

to and neutralize the virus.

43:08

And they make a point

43:10

that there are some suggestions

43:12

that people do make some

43:14

long-term protective immunity to neuroviruses.

43:17

For example, young children rarely

43:19

get repeat infection with the

43:21

same genotype or... or variant

43:23

neurovirus. And there's a lack

43:25

of infections in adults in

43:28

years when there are not

43:30

new strains emerging. So that's

43:32

some evidence that, yes, we

43:34

could conceivably make some good

43:37

vaccines if we had the

43:39

right anogens to elicit antibodies.

43:41

So how to do this?

43:43

So they took advantage of

43:46

the fact that there were

43:48

immunized people that had been

43:50

immunized with this adenovirus. based

43:52

vaccine that expresses the noravirus

43:54

protein VP1 and also has

43:57

this RNA double-stranded RNA. argument

43:59

and so yeah I did

44:01

misspeak the first paper they

44:03

did only use the genotype

44:06

one and geno group whatever

44:08

they call it one and

44:10

here it's genotype two that

44:12

they're using and so they

44:15

take advantage like immunize the

44:17

population and then they screen

44:19

these pop this population and

44:21

find serum from two recipients

44:23

that had robust responses to

44:26

the vaccine, and one of

44:28

them elicited antibodies that could

44:30

neutralize several viral variants within

44:32

a genotype, and the other

44:35

individual developed antibodies that could

44:37

neutralize across genotypes. And so,

44:39

and these individuals were somewhere

44:41

around 37 years of age,

44:44

so not this older age

44:46

group that the previous paper

44:48

had. chose these two people

44:50

and then characterized their the

44:52

monoclonal antibodies from them. Yeah,

44:55

so they used a variety

44:57

of techniques that we'll discuss

44:59

and the bottom line is

45:01

that they identified some of

45:04

these antibodies and one in

45:06

particular called VX22 if you

45:08

want to remember one of

45:10

them VX22 it could block

45:13

more than seven genotypes of

45:15

the major class the G2

45:17

genotype. They used an approach

45:19

called with a set of

45:21

words where I knew all

45:24

the words but had never

45:26

heard them together before. Antibody

45:28

evolution trajectory analysis, which is

45:30

that they used phylogenetics to

45:33

identify the antibody pathway to

45:35

get particularly to this VX22

45:37

antibody. And then they used

45:39

crystallography as another analysis to

45:42

identify a highly conserved cross-neutralizing

45:44

and epitope that all together

45:46

this points to good targets

45:48

for design. for future anogens

45:50

to produce vaccines. And they

45:53

show that, at least their

45:55

evidence, points to the way

45:57

that VX22 is working is

45:59

by disrupting the virus particle,

46:02

so causing it to disassemble

46:04

such that it can't cause

46:06

infection. And then another term

46:08

that they use that I

46:11

had not really heard before,

46:13

and I want to hear...

46:15

the other people's take on

46:17

what it means to be

46:19

doing back boosting. How does

46:22

that differ from just doing

46:24

boosting? But I think they're

46:26

trying to connote something by

46:28

calling it back boosting. But

46:31

anyway, so again, it's not

46:33

putting a pillow in your

46:35

chair. Right. The bottom line

46:37

is that they've really used

46:40

this technology to guide that

46:42

could guide the design of

46:44

imminogens that could make broadly

46:46

product. protective neurovirus vaccines. There's

46:48

that word and there's another

46:51

word that'll come up. We'll

46:53

get to it. Okay, so

46:55

just to remind everyone why

46:57

we care about neurovirus. Globally,

47:00

700 million factions a year,

47:02

tens of thousands of deaths,

47:04

okay, so it's substantial medical

47:06

burden. We got, they're divided

47:09

into genogroups, at least four

47:11

infect humans, and genogroup two.

47:13

causes more than 90% of

47:15

infections. Okay, Geno Group 2,

47:17

remember that, that's the big

47:20

one. And just as far

47:22

as why we care about

47:24

neurovirus, they talk about this

47:26

in the other paper too.

47:29

Even without the deaths, the

47:31

infections are not pleasant. Yeah.

47:33

We don't have enough buckets

47:35

for everyone. Exactly. And this

47:37

is something that will, a

47:40

lot of, I think most

47:42

people have probably experienced it,

47:44

whether they knew it or

47:46

not. What is it the

47:49

most common food-born disease or

47:51

the most common food-born virus,

47:53

certainly? So you eat out

47:55

of a restaurant and a

47:58

couple of days later you

48:00

just you can't go more

48:02

than 10 feet from the

48:04

bathroom And that's the experience

48:06

of a noravirus infection that'll

48:09

go on for a few

48:11

days And you probably can't

48:13

make it to work if

48:15

you need to get out

48:18

somewhere that just completely hampers

48:20

everything So I think one

48:22

of these papers cited a

48:24

figure of direct medical costs

48:27

in excess of a billion

48:29

dollars a year just in

48:31

the US and that's just

48:33

direct medical costs That doesn't

48:35

account for... 10.6 annually. 10.6

48:38

billion. And that's just direct

48:40

medical costs. So that doesn't

48:42

account for all the missed

48:44

work and they, you know,

48:47

other stuff and they're buying

48:49

extra buckets. So it's the

48:51

biggest cause of gastranoritis. And

48:53

of any bacterial viral, it's

48:56

the biggest one. Yeah. This

48:58

virus is bad news. We'd

49:00

like to be rid of

49:02

it. over 90% of infections.

49:04

And there's a genotype, G2.4,

49:07

that does 50 to 80%

49:09

of the outbreaks. And this

49:11

varies. So you get variants

49:13

and they cause new outbreaks

49:16

because they're antigenically different. Right.

49:18

But as Kathy said in

49:20

her summary, you don't get

49:22

repeat infections with the same

49:25

variant. So that means there's

49:27

some hope for preventing infection

49:29

with a vaccine. All right.

49:31

I don't know if we

49:33

mentioned this, but when you

49:36

make VP1 of this virus,

49:38

it assembles into a virus-like

49:40

particle, right? VLLP. And that's

49:42

what's happening with these oral

49:45

vaccines, they're delivering the gene

49:47

into cells, and they're assembling

49:49

presumably into VLLPs. And these

49:51

are immunologically indistinguishable from native

49:54

neurovirus, virus, and identify the

49:56

epitopes. on the particle that

49:58

react with antibodies because you

50:00

can't grow them in cells

50:02

and culture for the most

50:05

part except for intestinal enteroids

50:07

which just doing a lot

50:09

of neutralization assays is just

50:11

not not a convenient system

50:14

to work with and so

50:16

these they do use surrogate

50:18

neutralization assays like we said

50:20

in the other paper to

50:23

look at virus binding to

50:25

blood group antigens and other

50:27

glycans as surrogates so they

50:29

say five neurovirus vaccines are

50:31

in clinical development a G2.4.1,

50:34

one, either, so they can

50:36

do two things. They can

50:38

give you VLPs. You just,

50:40

I don't know how they

50:43

would do it, maybe in

50:45

a tablet also, or the

50:47

adenovirus vectors that encode the

50:49

VP1, which will make the

50:52

GPs. Oh, I see, and

50:54

adults, the VLPs are given

50:56

intramuscularly. And so they give,

50:58

they don't work so well.

51:00

Okay. We need to do

51:03

better. And that could be

51:05

a ucosal versus systemic delivery

51:07

thing. And they say we

51:09

don't really know much about

51:12

the antigenic structure. We'll have

51:14

a few neutralizing monoclono antibodies

51:16

and we know they're epitopes.

51:18

And they gives this example.

51:21

It's very interesting. G2.4 Hong

51:23

Kong 2019 variant emerged with

51:25

antigenic changes in at least

51:27

six known epitopes. That's

51:30

a lot, six known epitopes.

51:32

And no human monoclonals have

51:35

been reported to neutralize this

51:37

HK 2019 variant. So even

51:40

though it hasn't spread extensively,

51:42

they're worried that it will

51:44

because it's so different antigenically.

51:47

And furthermore, no antibodies of

51:49

any type that neutralized more

51:52

than two G2 viruses have

51:54

been reported. So they say

51:56

we need to. better understand

51:59

the antibody response to guide.

52:01

vaccine design. So that's the

52:04

rationale for this paper, essentially.

52:06

And so what they do

52:08

is they tap two healthy

52:11

young adults and they immunize

52:13

them with a single dose

52:16

of an ad-5-based oral vaccine

52:18

similar to the one we

52:21

talked about, except this has

52:23

got VP1 of G2. So

52:25

this is from a clinical

52:28

ongoing clinical trial. Yeah, so

52:30

different genogroup, G1 versus G2,

52:33

and this, so this one

52:35

is G2, and it's that

52:37

particularly frequent, genogroup, and particularly

52:40

frequent strain. Right. Now, but

52:42

this is the same company,

52:45

same platform. It's the tablet

52:47

targeting the Ilium, yada yada

52:49

yada yada. Yadi yada. Had

52:52

no virus factor. So just

52:54

to make it clear. I

52:57

think that. reading the materials

52:59

and methods, they had access

53:02

to this population that Vaxhart

53:04

had immunized and they screened

53:06

a bunch of them and

53:09

picked these two based on

53:11

their responses. Right. Yeah, that

53:14

could be. Yeah. This was

53:16

not too random individuals. No.

53:18

The results make it sound

53:21

that way though. Yes. We

53:23

just grabbed two people and

53:26

they had these great responses.

53:28

No. We immunized them and

53:30

then... Right. Yeah. I mean,

53:33

it says two donors were

53:35

selected for detailed studies because

53:38

of exceptionally high G24 neutralization

53:40

bread participant A or cross

53:43

G2 neutralization bread participant B.

53:45

So A and B are

53:47

off or dealt with separately

53:50

because they have different findings

53:52

with both. Right. And so

53:55

in A, the vaccination boosted

53:57

the... ligand binding blockades here.

53:59

Remember, this is the surrogate

54:02

neutralization assay. To all test

54:04

the G24 variants circulating from

54:07

1987 to 2019. What a

54:09

pain that you have to

54:11

circumscribe it so much. And

54:14

then the participant B had

54:16

exceptional cross-genotype blocking. serum breath

54:19

across 7G2 and 2G1 genotypes

54:21

before he was vaccinated. Oh

54:24

my God, this person must

54:26

have been a world traveler.

54:28

Although maybe not, maybe you

54:31

got one good... Yeah, maybe

54:33

he had one good B

54:36

cell that made some antibody

54:38

that was very, very cross-reactive.

54:40

They're both females and A

54:43

was 28 and B was

54:45

37. Then she is a

54:48

world traveler. Right. You know,

54:50

the interesting thing is the,

54:53

the participant B, all these

54:55

antibodies were, were modestly boosted

54:57

by vaccination. It's very interesting.

55:00

And they say there's probably

55:02

immune imprinting going on, which

55:05

we have evidence for, because

55:07

they say both owners, the

55:09

greatest fold increase in blockade

55:12

was observed against. the vaccine

55:14

strain, whereas the highest tighter

55:17

was to the ancestral G24

55:19

variants and they say that's

55:21

probably immune imprinting. So the

55:24

first the first neurovirus you

55:26

see that's what you respond

55:29

to with subsequent challenges unless

55:31

they are different enough and

55:34

you know how different we

55:36

don't we're not sure. Okay

55:38

so then they go on

55:41

to... They say, we're going

55:43

to de-convalute the antigen-specific antibody

55:46

repertoire. Basically, they want to

55:48

know what antibodies are binding

55:50

to what epitopes in these

55:53

individuals. But they do it.

55:55

They use bottom-up liquid chromatography,

55:58

tandem mass spec, Heavy chain

56:00

variable transfer. and single cell

56:02

VH light chain variable domain

56:05

paired B cell receptor reads,

56:07

which they got from peripheral

56:10

B cells on day eight.

56:12

So these individuals, they make

56:15

these libraries from them and

56:17

get all of these reads

56:19

out of them. Yeah, so

56:22

basically they found exactly what

56:24

the DNA of those individuals

56:27

looked like, and then they

56:29

compared the protein fragments. to

56:31

make sure that they were

56:34

getting a match of the

56:36

actual DNA sequence in the

56:39

individual donors. So this way

56:41

they could determine the compositions

56:43

of these antigen-specific IGG clonotypes

56:46

and their abundance in serum.

56:48

So they purify the antibodies

56:51

using immobilized VLPs and then

56:53

they sequence the immunoglobulin gene

56:56

sequencing. They say this revealed

56:58

an oligoclono and polarized anti-G2.4

57:00

serological repertoire with the top

57:03

five most abundant clono types

57:05

constituting more than 60% of

57:08

the anti-G2.4 vaccination repertoire. And

57:10

then comparing the pre-imposed vaccination

57:12

serum repertoire, so they compare

57:15

this before and after. vaccination,

57:17

that vaccination back boosted all

57:20

antigen specific clonotypes that were

57:22

present at day one. So,

57:24

yeah, it's just boosting, it's

57:27

just memory, right? Yeah, yeah.

57:29

What do you call the

57:32

back boosting? I don't really

57:34

know why they're calling it

57:37

a back boost either. I

57:39

think they're just trying to

57:41

emphasize that these were, these

57:44

were pre-existing, that this is,

57:46

this is a memory response,

57:49

but it's a little convoluted.

57:51

Yeah. Isn't boosting. always boosting

57:53

is always something that was

57:56

there already yes yeah you

57:58

don't need both words, it's

58:01

true. Anyway, so vaccination

58:04

increases the antibodies

58:07

and the clonotypes

58:10

present at day one

58:12

already. And these these

58:15

vaccine boasted

58:17

antibodies comprise 65%

58:20

of the post

58:22

vaccination serum

58:24

responses. So really.

58:26

I don't know how universal this is

58:29

because it's two people, but I

58:31

suppose you're going to at one

58:33

point immunize people who have never

58:35

seen noravirus. Is that possible? Nah.

58:37

Babies? Are you going to immunize

58:39

babies? I don't think you're going

58:42

to immunize babies. So it's going

58:44

to be older people. Well, is it

58:46

really severe in young kids? No. Well,

58:48

I don't know, babies, you know, depends

58:51

where you are. Right, because that

58:53

might be a reason for immunized

58:55

babies. But, well, we know, I

58:57

mean, we know just from this

58:59

paper and the fact that they

59:01

picked these two out of a

59:03

group that this is not the

59:06

usual response. Yes. Yeah.

59:08

Yeah, I mean, you're gonna have

59:10

a de novo. So, Brian, we

59:12

did a paper recently where they

59:14

called it a de novo response.

59:17

Yes. And you said that

59:19

we usually call it what? I

59:22

would call that a response

59:24

from a naive. So. Yeah, so I

59:26

don't know. I mean, the point here

59:28

is that they're using

59:30

these as tools and they

59:32

get some interesting antibodies. So

59:35

it doesn't matter. Right. Right.

59:37

What they had before, but I

59:40

mean, if you want to figure

59:42

out a way to induce

59:44

these antibodies in a naive person,

59:46

then. That's a different story. Yeah,

59:49

I mean, there are a couple of

59:51

ways that people think about those types

59:53

of things, but before you can get

59:55

that complicated, you need to know what

59:57

is the target like goal antibody and

59:59

what. is the antigen that

1:00:02

that antibody binds so

1:00:04

that you can try

1:00:06

to use that as

1:00:08

your immunogen so that

1:00:10

and get this goal

1:00:12

amazing antibody and it

1:00:15

might be more complicated

1:00:17

than that but you

1:00:19

at least have to

1:00:21

know what the goal

1:00:23

is and what the

1:00:25

antigen is before you

1:00:27

can do anything else

1:00:30

complicated. Yeah if you

1:00:32

don't know what you're

1:00:34

aiming for you're not

1:00:36

going to hit it

1:00:38

and this paper is

1:00:40

trying to figure out

1:00:42

what to aim for

1:00:45

I think. to try

1:00:47

and find antibodies that

1:00:49

have broad G2 activity.

1:00:51

And they have a

1:00:53

way of doing that,

1:00:55

which I'm not going

1:00:57

to go into. But...

1:01:00

The participant B was

1:01:02

the one who had

1:01:04

like neutralization of all

1:01:06

sorts of different strains.

1:01:08

Yeah. So they find

1:01:10

that vaccination of B

1:01:12

increases the abundance of

1:01:15

G23 and G24 colonotypes.

1:01:17

by more than threefold

1:01:19

on day 29 compared

1:01:21

with day one. And

1:01:23

these account for over

1:01:25

75% of their serum

1:01:27

response. Those two clonotypes.

1:01:30

And a big fraction

1:01:32

of those were boosted

1:01:34

by vaccination. I'm going

1:01:36

to take out the

1:01:38

back, boosted by vaccination,

1:01:40

which they say suggests

1:01:42

recall responses from memory

1:01:45

B cells. Yeah, that's

1:01:47

what it is. Recall

1:01:49

memory B cells elicited

1:01:51

by earlier. Exposures. For

1:01:53

participant A, okay, here's

1:01:55

another the other word,

1:01:57

Kathy, that bothers me.

1:02:00

Thirteen monoclonals comprising, 70%

1:02:02

of the anti-G24 serum

1:02:04

repertoire were recombinently expressed.

1:02:06

Do you like recombinently?

1:02:08

Do you like recombinently?

1:02:10

No, I understand what

1:02:12

it means. Yeah. I

1:02:15

mean any kind of

1:02:17

expression that they're doing

1:02:19

here. they had to

1:02:21

do by recombination. Just

1:02:23

recombinately is a funny

1:02:25

word. Yeah. Or anyway.

1:02:28

So then they characterize

1:02:30

these antibodies. Ten of

1:02:32

them blocked at least

1:02:34

one G24 variant and

1:02:36

none of them blocked

1:02:38

non-G24 strains. And none

1:02:40

of them blocked non-G24

1:02:43

strains. And they picked

1:02:45

one of them. which

1:02:47

was 44% of the

1:02:49

repertoire, and they characterized

1:02:51

it more in more

1:02:53

detail. And they say

1:02:55

that this, the blockade

1:02:58

serum landscape of participant

1:03:00

A was substantially driven

1:03:02

by a single clonotype

1:03:04

VXI, which comprised over

1:03:06

40% of the total

1:03:08

response. VX1. Heart to

1:03:10

distinguish. They're so small.

1:03:13

Yes. So then they,

1:03:15

these G24 neutralizing antibodies,

1:03:17

they put them in

1:03:19

two classes. One, class

1:03:21

one, neutralizes multiple G24

1:03:23

variants except for HK

1:03:25

2019. And class two,

1:03:28

neutralized, diverse G24 variants,

1:03:30

including HK 2019. I

1:03:32

guess the only difference

1:03:34

is HK 2019? Yeah.

1:03:36

More or less. Yeah.

1:03:38

So these these monoclonos

1:03:40

recognize more a site

1:03:43

more conserved across G2.4

1:03:45

than in class one

1:03:47

bean abs. Class two

1:03:49

recognize a site more

1:03:51

conserved than class one.

1:03:54

because of the HK 2019.

1:03:56

So basically class ones recognize

1:03:58

everything. But HK 2019, so

1:04:00

they recognize something that's on

1:04:03

all of them, not HK

1:04:05

2019, and the other ones

1:04:07

recognize something that's on all

1:04:09

of them. Then they have

1:04:11

a collection of VFPs with

1:04:13

amino acid changes in each

1:04:16

of the antigenic site. They

1:04:18

call them epitope mutant VFPs,

1:04:20

which I totally disagree with.

1:04:22

They're not epitope mutate. You

1:04:24

can't mutate an epitope. No.

1:04:26

No, you cannot. Don't argue

1:04:29

with me. You can mutate

1:04:31

the gene that encodes that

1:04:33

episode. Yes, exactly. You could

1:04:35

alter an epitope. You could

1:04:37

alter an epitope. And so

1:04:39

they can identify, you know,

1:04:42

where these monoclonal antibodies are

1:04:44

binding, the class ones, for

1:04:46

example. But I'm not going

1:04:48

to tell you, because it's

1:04:50

not going to mean anything

1:04:52

to you. Then they want

1:04:55

to know the class two

1:04:57

epitopes, but they had to

1:04:59

make more VLPs. They made

1:05:01

a, they called them G2

1:05:03

chimeric VLPs. At least they

1:05:05

didn't call them, Epetope mutant,

1:05:08

VLPs. And they could identify

1:05:10

the epitopes for class two

1:05:12

as well. All right. That's

1:05:14

what I'm going to tell

1:05:16

you about that. Now what

1:05:18

about, can these antibodies block

1:05:21

replication? That's a good question,

1:05:23

right? We've just looked at

1:05:25

the surrogate binding assay so

1:05:27

far, ligand blocking. And so

1:05:29

they select four antibodies, VX1

1:05:31

and 14 from class 1,

1:05:34

and V6 and 10 from

1:05:36

class two. Oh, I guess

1:05:38

VXXXX and 10 from class

1:05:40

two. Oh, I guess VXXXX

1:05:42

and 10 from class two.

1:05:44

Oh, I guess VXXXXXX and

1:05:47

10 from class 2 and

1:05:49

10 from class 2. By

1:05:51

the way, I like Vaxard

1:05:53

as a company name. Yeah,

1:05:55

I do like that name.

1:05:57

It's really good. Good job.

1:06:01

And they use their

1:06:04

enter, their, enter, their,

1:06:06

organoids, their enteric organoids

1:06:09

to measure blockade. And

1:06:11

they use PCR to

1:06:14

measure genome copies. And

1:06:16

all four monoclonals neutralize,

1:06:19

reduce the genomic copies

1:06:21

of G24, S-Y-2-4-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2-2 And

1:06:24

in a gene. Except

1:06:27

for the one with

1:06:29

the typo, the negative

1:06:32

vontrol. Ah, yes. So

1:06:34

basically. Often used in

1:06:37

transylvanian papers. This results

1:06:39

show multiple antigenic landscapes

1:06:42

for broadening G24 neutralizing

1:06:44

responses, including highly accessible

1:06:47

residues residues that lie.

1:06:49

across antigenics. Cites, that

1:06:52

would be the class

1:06:54

one monoclonals and two

1:06:57

residues that are less

1:06:59

surfic exposed but highly

1:07:02

conserved across the G2.

1:07:05

That would be class

1:07:07

two. All right, 16.

1:07:10

For participant B, they

1:07:12

produce most likely an

1:07:15

E. coli, but maybe

1:07:17

somewhere else. 16 monoclonals.

1:07:20

That's 60% of the

1:07:22

anti-G2 for serum IGG

1:07:25

repertoire repertoire. And five

1:07:27

of them that aren't

1:07:30

very good, so they

1:07:32

don't look at those

1:07:35

anymore. The remaining 11

1:07:38

blocked ligand binding to

1:07:40

the vaccine imaging, G24,

1:07:43

S-Y-12, two of them,

1:07:45

G- sorry, VX-22 and

1:07:48

VX-20, blocked ligand binding

1:07:50

of six additional G-2

1:07:53

genotypes. And the

1:07:55

neutralization assay confirms that both.

1:07:57

these monoclonals, VX, 22 and

1:08:00

20, reduce replication in their

1:08:02

cell culture assay. So that's

1:08:04

pretty cool. So that's some,

1:08:07

this is indication that, you

1:08:09

know, human IGG can neutralize

1:08:11

multiple G2 viruses, which is

1:08:13

cool. Yeah, so it looks

1:08:16

like they're starting to find

1:08:18

a part or an epitope

1:08:20

that might. bind to these

1:08:23

broadly neutralizing antibodies that might

1:08:25

be very conserved. And you

1:08:27

can think of lots of

1:08:29

ways that that could be

1:08:32

used going forward. Now, they

1:08:34

want to know how these

1:08:36

antibodies arose in these people,

1:08:38

right? Antibody, evolution, trajectory analysis.

1:08:41

This is the collection of

1:08:43

words that Kathy never saw

1:08:45

together. together. IG 5ML. So

1:08:48

they wanted to find the

1:08:50

unmutated common ancestor that served

1:08:52

as the precursor for all

1:08:54

of these antibodies. And so

1:08:57

they say all members of

1:08:59

this lineage were found on

1:09:01

day eight. They have the

1:09:04

same variable light chain, but

1:09:06

a differently mutated variable heavy

1:09:08

chain. They can produce different

1:09:10

versions of these in some

1:09:13

organism, most likely equal. Many

1:09:15

words to avoid for commonently.

1:09:17

So you can swap VHVL

1:09:20

from the ancestor in the

1:09:22

different intermediates and find out

1:09:24

what the result is. And

1:09:26

it's very interesting when the

1:09:29

unmutated VH of UCA1, which

1:09:31

was the... University Common Ancestor.

1:09:33

Thank you. Was paired with

1:09:36

the conserved mutated VX22 VL.

1:09:38

and UCA too. The antibody

1:09:40

not only had improved G12

1:09:42

blockade, but also gained G23

1:09:45

blockade, which shows that the

1:09:47

VL somatic hyper mutation alone

1:09:49

contributes to G23 blockade. I

1:09:52

thought that was really cool.

1:09:54

Yeah, light change matter. LCCM.

1:09:56

You have a t-shirt with

1:09:58

LCCM on it. Well, maybe

1:10:01

you don't feel strongly enough.

1:10:03

I don't know. So then

1:10:05

they also had an antibodies

1:10:08

with VH sequences corresponding to

1:10:10

intermediate nodes in the tree

1:10:12

that led to VX22, right,

1:10:14

or diverged clonotypes. And so

1:10:17

they can study those and

1:10:19

they conclude that the ancestor

1:10:21

of VX22 likely originated from

1:10:24

an earlier G12 infection and

1:10:26

then subsequent infections resulted in

1:10:28

an altered VL. chain or

1:10:30

a mutative VL gene that

1:10:33

acquired neutralization breath to G23

1:10:35

and then later affinity maturation

1:10:37

of the VH resulted in

1:10:40

expansion of the breath for

1:10:42

VX22 and other members. It's

1:10:44

pretty cool that they can.

1:10:46

Yeah, and this is important

1:10:49

to know because if you're

1:10:51

trying to use this antigen...

1:10:53

as a vaccine or if

1:10:56

you have a goal of

1:10:58

a vaccine strategy of eliciting

1:11:00

this antibody, you need to

1:11:02

know what types of things

1:11:05

need to happen to the

1:11:07

B cell in order to

1:11:09

make this antibody. Is this

1:11:12

a simple somatic hyper mutation

1:11:14

process or is it complicated

1:11:16

where only some paths will

1:11:18

work or will lots of

1:11:21

paths work? And it might

1:11:23

be that... The reason why

1:11:25

this person has this more

1:11:28

rare antibody is because their

1:11:30

B cells were perhaps infected

1:11:32

with a few different versions.

1:11:34

of this virus that sort

1:11:37

of led the B cells

1:11:39

down a path to hypermutate

1:11:41

in this way. And so

1:11:44

if we're going to vaccinate,

1:11:46

perhaps the only way to

1:11:48

actually get your B cell

1:11:50

to go in this route,

1:11:53

to go on this trajectory,

1:11:55

as they would say, is

1:11:57

to give that B cell

1:12:00

the same series of... epitopes

1:12:02

over time. And so maybe

1:12:04

you actually have to do

1:12:06

three epitopes, one after the

1:12:09

other to sort of push

1:12:11

the B cell down this

1:12:13

weird trajectory and get this

1:12:16

amazing antibody that other people

1:12:18

don't make. And so thinking

1:12:20

about what sort of series

1:12:22

of antigens did the B

1:12:25

cell see to push it

1:12:27

to have these hypermutations is

1:12:29

important. And there are some

1:12:32

sort of very large studies

1:12:34

of these types of things

1:12:36

that are done in some

1:12:38

other neutralizing antibody settings. More

1:12:41

optimistically, it's possible, I think

1:12:43

Brian's explanation is pretty likely

1:12:45

that this pathway was how

1:12:48

this person got to this

1:12:50

point, but it may be

1:12:52

possible if you know enough

1:12:54

about the antibodies that you're

1:12:57

getting and about the specific

1:12:59

epitopes they respond to, to

1:13:01

create an epitope that may

1:13:04

not look anything like nor

1:13:06

a virus, but that elicits

1:13:08

this type of response. and

1:13:10

gets you to the end

1:13:13

point without having to go

1:13:15

through those intermediate steps. It's

1:13:17

possible. Yeah, but you got

1:13:20

to know all the stuff

1:13:22

first. You got to know

1:13:24

all the stuff first. This

1:13:26

is the groundwork to get

1:13:29

to either of those outcomes.

1:13:31

All right, so next they

1:13:33

solve the structure of VX22,

1:13:36

which they really like, together

1:13:38

with a domain of VP1

1:13:40

from the vaccine G2D4, S-Y-2012.

1:13:42

And I want to tell

1:13:45

you one thing. Well, just

1:13:47

a few things about that.

1:13:49

This, the epitope, so then

1:13:52

they can see what the

1:13:54

epitope for VX22 is, right?

1:13:56

Because you can visualize the

1:13:58

antibody bound to the virus.

1:14:01

and you know what amino

1:14:03

acids it's touching. So interestingly,

1:14:05

the epitope is distant from

1:14:08

the ligand binding sites, right?

1:14:10

We're using ligand blocking assays

1:14:12

to measure these antibodies, yet

1:14:14

where the antibody binds is

1:14:17

far away from it. So

1:14:19

they thought, could it be

1:14:21

that the antibody breaks up

1:14:23

the virus particle? It's so

1:14:26

far. Maybe if you broke

1:14:28

it up, that would be

1:14:30

the same thing. It couldn't

1:14:33

bind anymore, right? And in

1:14:35

fact. They incubate the antibody

1:14:37

with virus particles and they

1:14:39

look at it and they're

1:14:42

all broken. You always say

1:14:44

that Petra Levin on swim

1:14:46

always says you should always

1:14:49

look in a microscope at

1:14:51

what you're doing. And you

1:14:53

can find out a lot

1:14:55

of things. So it's this

1:14:58

antibody. And they also see

1:15:00

from the structure that the

1:15:02

FAB approaches the epitope at

1:15:05

an upward angle. And they

1:15:07

think, as a result, the

1:15:09

constant region projects downward toward

1:15:11

the virion interior, which they

1:15:14

think either causes substantial steric

1:15:16

clashes with a neighboring domain

1:15:18

or minor clashes with the

1:15:21

heavy chain of the antibody

1:15:23

in a neighboring S and

1:15:25

that's leading to breaking up

1:15:27

of the virus particle. This

1:15:30

is cool because I don't

1:15:32

think I've ever thought about

1:15:34

an antibody doing that. Explosion.

1:15:37

Yeah. which we could leverage

1:15:39

for designing future images that

1:15:41

may have broad protection across

1:15:43

two genotypes. Okay, so those,

1:15:46

a little bit complicated, but

1:15:48

I will summarize for you,

1:15:50

we have a couple of

1:15:53

antibodies here. So in participant

1:15:55

A, half of the serum

1:15:57

repertoire. targets two specific epitopes

1:15:59

on the virus particle, so

1:16:02

these are immune to dominant

1:16:04

sites, and they probably neutralize

1:16:06

by... hindering the ligand interaction

1:16:09

with the virus particle. And

1:16:11

then class two, VX6 and

1:16:13

VXN broadly blocked all tested

1:16:15

G2.4 variants. And they probably

1:16:18

neutralized by long range allosteric

1:16:20

mechanisms, not by breaking up

1:16:22

the virus particle. Those are

1:16:25

from participant A. For participant

1:16:27

B, they got these cool.

1:16:30

monoclonals VX20 and VX22 and VX22

1:16:32

as you saw neutralizes by breaking

1:16:34

the virus particle. So they say

1:16:37

VX20 and 22 are leading candidates

1:16:39

for prophylaxis and therapeutic treatment of

1:16:41

neurovirus associated illness. I guess if

1:16:44

you had an outbreak in a

1:16:46

facility that where a lot of

1:16:48

older people live you could give

1:16:50

everybody a monoclonal right to get

1:16:53

them. something like that. So that

1:16:55

would be in addition to a

1:16:57

vaccine, you know, maybe you didn't

1:17:00

have a chance to get everybody

1:17:02

vaccinated, you could just do that.

1:17:04

I also, you know, when I

1:17:06

was reading this and got to

1:17:09

the end, maybe this is just

1:17:11

that I've, you know, it makes

1:17:13

me feel old, I guess, because

1:17:16

I look at things like figure

1:17:18

four and I'm like, oh, and

1:17:20

then they just threw in a

1:17:22

structure. Yes. Like that didn't used

1:17:25

to be like a whole paper

1:17:27

and a whole thing in and

1:17:29

of itself. While we were on

1:17:32

our way to the store, yeah.

1:17:34

Okay, that's the second paper for

1:17:36

you. So a lot of activity

1:17:38

in Norway, people are always asking

1:17:41

us what's going on with neurovirus.

1:17:43

There you go. There you go.

1:17:45

We get a bunch of vaccines

1:17:48

and monoclonals. And all I want

1:17:50

to say is I hope this

1:17:52

continues. Yeah. Yeah.

1:17:55

Hmm. See, it's for 20. We

1:17:58

can do a couple emails. Kathy,

1:18:00

can you take the first one?

1:18:02

Oh. We don't have one. Oh,

1:18:04

no, this. Yes. Bronwen writes, due

1:18:06

to a team. I was very

1:18:08

excited to listen to 1207 taking

1:18:11

a shot at dementia. because for

1:18:13

once I had already heard about

1:18:15

your featured article in an Australian

1:18:17

newspaper which gave some interesting background

1:18:19

to the research highlighting yet again

1:18:22

that scientific endeavor rarely runs in

1:18:24

a straight line and you often

1:18:26

need a tough hide to be

1:18:28

a good scientist. It was great

1:18:30

to read that further research has

1:18:32

been undertaken with Australian electronic health

1:18:35

records which is awaiting peer review

1:18:37

but had similar results and Brahman

1:18:39

gives the link for that. I'm

1:18:41

hoping the link is not pay

1:18:43

well, but in case it is,

1:18:45

I've included the text, which doesn't

1:18:48

have the external links below, and

1:18:50

provides that. Thank you for making

1:18:52

science accessible. Rats, my screen just,

1:18:54

my, my mouse flew around and

1:18:56

my screen went dark and I

1:18:58

may have it pop right back

1:19:01

up where I can. Access where

1:19:03

I was, if I can find

1:19:05

my mouse. Okay, in real time.

1:19:07

Thank you for making science accessible.

1:19:09

Your message has never been more

1:19:11

important. I'm grateful to be living

1:19:14

in a country where electronic records

1:19:16

can be accessed, and science is

1:19:18

funded and mostly valued. Although we

1:19:20

don't have the same resources as

1:19:22

the US, and cuts to your

1:19:25

funding will also affect Australian research.

1:19:27

And I'm also glad that through

1:19:29

Patreon, I can make a very

1:19:31

small contribution, the cost of a

1:19:33

cup of coffee, to your work

1:19:35

on the other side of the

1:19:38

world, and I encourage all your

1:19:40

listeners to try to do the

1:19:42

same. Thank you also for your

1:19:44

moving commemoration of Dixon-Day Pomey's life

1:19:46

and work, and again, for all

1:19:48

you do. Best wishes, Braunwin. Thank

1:19:51

you, Allen, can you take the

1:19:53

next one? Sure. Sonarisa writes, hello

1:19:55

to all, but Vincent Rich and

1:19:57

Allen specifically. Thanks for the paper

1:19:59

today on the shingles vaccine. Although

1:20:01

I am younger than the target

1:20:04

population for shingles at 44, but

1:20:06

maybe I should talk to my

1:20:08

doctor about getting it as I

1:20:10

have had the misfortune of experiencing

1:20:12

shingles outbreaks twice already in my

1:20:14

life. When, once when I was

1:20:17

only five, and that was horrific,

1:20:19

all through my bid section, yes,

1:20:21

they confirmed it as shingles and

1:20:23

not chicken pox, I had already

1:20:25

had that too. And later at

1:20:28

22, I had a very small

1:20:30

outbreak. Anyway, that was a cool

1:20:32

little bit of research and having

1:20:34

listened to the recent twin on

1:20:36

herpes and Alzheimer's, it was fun

1:20:38

putting the bits together. Thanks always

1:20:41

for all you and the rest

1:20:43

of the microbe TV team do.

1:20:45

I personally love being able to

1:20:47

hear interesting science from across such

1:20:49

a wide array of topics and

1:20:51

connect back between the different podcasts.

1:20:54

Cheers some Risa. Thank you very

1:20:56

much. Young people can get shingles.

1:20:58

Yeah. you know, in her 20s

1:21:00

and she had shingles. But sometimes

1:21:02

it's because people are taking immunosuppressive

1:21:04

therapies for other things and that

1:21:07

can allow early reactivation. And sometimes

1:21:09

bad stuff just happens. Yeah, sometimes

1:21:11

it just happens. So you could

1:21:13

talk to your doctor about... getting

1:21:15

in early. But you know the

1:21:18

problem is that the study was

1:21:20

done with the Zostavacs and you

1:21:22

know now the shingles vaccine is

1:21:24

shingrix different. We don't know if

1:21:26

it will get the same protection.

1:21:28

I don't know. But I think

1:21:31

if you've already if you've had

1:21:33

a shingles episode regardless of your

1:21:35

age you probably ought to get

1:21:37

shingricks so you don't get that

1:21:39

again. Dear Twive Team, I hope

1:21:41

this message finds you well. I've

1:21:44

been meeting to write you for

1:21:46

a while, and the title of

1:21:48

your recent episode with the word

1:21:50

Pluviosity finally gave me the perfect

1:21:52

excuse. When I saw it, I

1:21:54

thought about the word Pluvios. Pluvius

1:21:57

refers to the rainy month that

1:21:59

usually spans not only because of

1:22:01

the fascinating virology meets rainforest discussion,

1:22:03

but also as a listener from

1:22:05

Guadalupe, I was reminded of the

1:22:07

French Republican calendar which replaced the

1:22:10

Gregorian calendar during the revolution, the

1:22:12

same folks who gave the world

1:22:14

the metric system. Pluvius refers to

1:22:16

the rainy month that usually spans

1:22:18

late January to mid-February around my

1:22:21

birthday in fact. Allow me to

1:22:23

briefly introduce myself. My name is

1:22:25

Loique, Dragon. I am originally from

1:22:27

Guadalupe, a French overseas territory in

1:22:29

the Caribbean, and I hold a

1:22:31

PhD in virology. After a few

1:22:34

years as a postdoc in Pennsylvania,

1:22:36

then back to Guadalupe and away

1:22:38

from research, I am now working

1:22:40

on reconnecting with science, particularly through

1:22:42

the world of virology and bacteria

1:22:44

phases, which I find absolutely fascinating

1:22:47

vis-a-vis their potential for science, health,

1:22:49

agriculture, etc. And since there is

1:22:51

not much research here in the

1:22:53

field, your postdoc is a true

1:22:55

inspiration and a key part of

1:22:57

this journey back into the topic.

1:23:00

virology and other fields like microbiology.

1:23:02

For instance, when you mentioned thiomargarita

1:23:04

magnifica in a past episode of

1:23:06

Twim years ago, I nearly jumped

1:23:08

out of my chair. That giant

1:23:10

bacterium was discovered on the very

1:23:13

mangroves of Guadalupe. I was thrilled

1:23:15

that you covered it and I

1:23:17

want to give a special shout

1:23:19

out to Professor Olivier Groth, who

1:23:21

is my microbiology teacher in Guadalupe

1:23:24

and a key member of the

1:23:26

team behind that discovery. It was

1:23:28

a proud moment for us here.

1:23:30

I also had the chance to

1:23:32

meet Dr. Rackinillo years ago in

1:23:34

Hershey, and I've never forgotten the

1:23:37

experience. It meant a lot to

1:23:39

me then, and it continues to

1:23:41

now, especially as I hear your

1:23:43

discussions from my corner of the

1:23:45

world. I thought you might enjoy

1:23:47

knowing that Twive has a regular

1:23:50

listener from Guadalupe, proof that your

1:23:52

voice carries far and wide, even

1:23:54

to places that might not often

1:23:56

make the virology map. Thank you

1:23:58

for the work you do, and

1:24:00

for keeping science accessible, engaging. and

1:24:03

very much alive with warm regards,

1:24:05

Loek. And I will also just

1:24:07

thank the folks who think the

1:24:09

other members of this team who

1:24:11

had highlighted the pronunciation. Fortunately, I

1:24:14

had seen it right before you

1:24:16

did that because I would have

1:24:18

been a little lost. I think

1:24:20

we should do a live twive

1:24:22

from Guadalupe. Maybe in like February.

1:24:24

Can I go? I mean, I'm

1:24:27

in. This is lovely letter. Thank

1:24:29

you so much. And I love

1:24:31

the, we love to hear. from

1:24:33

listeners everywhere, so I would not

1:24:35

know that you're listening in Guadalupe,

1:24:37

so it's really good to know

1:24:40

this. Yeah, Thayer, Margarita, Magnifica, huge

1:24:42

bacterium, huge, the biggest known, I

1:24:44

think, something like that. Wow. All

1:24:46

right, one more. Charles writes. Not

1:24:48

sure if this is a question

1:24:50

for the regular twiver of the

1:24:53

clinical update. Well, I thought it

1:24:55

was a regular. Not

1:24:58

a great day in Chapel Hill,

1:25:00

North Carolina, 24C, which is nice,

1:25:02

but drizzle, which is not. I

1:25:04

was doing something a bit dangerous

1:25:07

last night, and for the past

1:25:09

few days, I've been thinking about

1:25:11

the measles outbreak and what would

1:25:13

be nice to have to help

1:25:15

combat it. I know a functioning

1:25:18

HHS CDC, FDA, NIH would be

1:25:20

a good start, but that is

1:25:22

out of the question for a

1:25:24

few years. Came up with monoclonal

1:25:27

antibodies for measles as being useful.

1:25:29

The first use would be as

1:25:31

a post- exposure prophylaxis. And in

1:25:33

fact, the child goes to school

1:25:35

exposing a lot of other children.

1:25:38

Those exposed, unvaccinated people could be

1:25:40

giving a monoclonal to prevent disease.

1:25:42

Second and more complex, give monoclonals

1:25:44

for measles to children under 8.5

1:25:46

months of age. See the paper

1:25:49

on 1204, which is long-term dynamics

1:25:51

of measles virus-specific antibiotics and children

1:25:53

vaccinated before 12 months of age.

1:25:55

I remember that. That will be

1:25:58

traveling to an area with a

1:26:00

measles out. I think this would

1:26:02

get around the problem of a

1:26:04

third MMRT, and I hope would

1:26:06

preserve the favorable dynamics of the

1:26:09

measles vaccine given at 12 months.

1:26:11

Complication being that a monoclonal antibody

1:26:13

could interfere with the vaccine if

1:26:15

given to close together. With RFK

1:26:17

Jr., the Trump Musk administration in

1:26:20

charge, we're going to have lots

1:26:22

of opportunities to try different treatments

1:26:24

for measles and other infectious and

1:26:26

preventable diseases. Charles. Yeah,

1:26:29

the paper was we did on

1:26:32

twift. It was all about reexamining

1:26:34

the idea of when in the

1:26:36

first year you could give MMR

1:26:38

where you can't give it less

1:26:41

than six months because you're going

1:26:43

to have interference with maternal antibodies.

1:26:45

But how close to six months

1:26:47

can you go? And they concluded

1:26:49

that 12 months is the right

1:26:52

time. Just a long time to

1:26:54

wait. It's just part of the

1:26:56

problem. I don't know. I mean,

1:26:58

a monoclonal could have, yeah, in

1:27:00

a school situation, but... You know,

1:27:03

if you have a school where

1:27:05

everyone is unvaccinated, I don't think

1:27:07

they're going to take monoclonals. Because

1:27:09

they don't want anything injected into

1:27:11

their bodies. Their parents don't, you

1:27:14

know. I wish you could fast

1:27:16

forward them 15 years and ask

1:27:18

them whether they want this vaccine

1:27:20

or not, and then come back

1:27:23

to the present and give it

1:27:25

to them or not based on

1:27:27

their preference. Because, you know, a

1:27:29

lot of kids... when grown up

1:27:31

would probably would probably prefer to

1:27:34

get this. Yeah, but they're in

1:27:36

the hands of the parents. That's

1:27:38

the way it works. Anyway, thanks

1:27:40

Charles for that. Yeah, I don't

1:27:42

know what the situation is with

1:27:45

measles monoclonals. It's a good question

1:27:47

if anyone knows. I have never

1:27:49

seen a paper. So don't know.

1:27:51

I know that did a podcast

1:27:53

at Georgia State. I

1:27:57

think it was Richard Plimper. Where

1:27:59

is he, Kathy? He's at Georgia

1:28:01

State. He's a state. And he

1:28:03

says there's absolutely no market for

1:28:06

measles antivirus because the vaccine is

1:28:08

so good. Maybe it's the same

1:28:10

for monoclonals. Okay, let's do some

1:28:12

picks of the week. Brian, what

1:28:14

have you got for us? So

1:28:17

I have an article that I

1:28:19

saw on CNN that I was

1:28:21

sort of excited about. You may

1:28:23

recall from some past discussion of

1:28:25

sort of early life on earth,

1:28:28

an experiment called the Yuri Miller

1:28:30

experiment, where two scientists' experiment was

1:28:32

in the 1950s, took a lot

1:28:34

of the chemicals that were thought

1:28:36

to have been found on the

1:28:39

early earth and put them together

1:28:41

in a experiment in a vessel

1:28:43

and added lightning and added lightning

1:28:45

and showed that they could get...

1:28:48

nucleotides and amino acids, particularly Ural

1:28:50

and glycine. And this was sort

1:28:52

of an idea related to how

1:28:54

life began on earth, because some

1:28:56

of these compounds are the compounds

1:28:59

you need for early life. I've

1:29:01

always had a sort of a

1:29:03

soft spot for this paper because

1:29:05

I think it was the first

1:29:07

paper I ever read, because I

1:29:10

heard about it in high school

1:29:12

and I decided I was going

1:29:14

to read it. Not that I

1:29:16

understood anything from a 1950s paper,

1:29:19

but you know, I tried. So

1:29:21

this article says that researchers actually

1:29:23

basically redid this experiment to show

1:29:25

how life on earth could have

1:29:27

started, but they made one fundamental

1:29:30

change, which is that they did

1:29:32

not add lightning as sort of

1:29:34

big exogenous bolts of electricity. Instead,

1:29:36

they looked at electron transfer between

1:29:38

different types of water droplets, which

1:29:41

they call a micro-lighting. All right,

1:29:43

yeah, they call microlatening in terms

1:29:45

of just small electron transfers that

1:29:47

are happening between water droplets of

1:29:49

different sizes. And they show- I

1:29:52

think that's what the rest of

1:29:54

us would call static electrodes. Yeah,

1:29:56

exactly. And they actually showed that

1:29:58

that static electricity, micro-lightening, electron transfer,

1:30:01

whatever you feel like calling it,

1:30:03

was actually enough to allow for

1:30:05

the production of uracil and glycine

1:30:07

from these compounds. And so in

1:30:09

conditions that perhaps mimic what was

1:30:12

seen in the early earth in...

1:30:14

the early Earth's oceans, you can

1:30:16

see that some of these organic

1:30:18

molecules can be spontaneously produced. And

1:30:20

so in a recent paper in

1:30:23

Science Advances, they published all of

1:30:25

this information with sort of this

1:30:27

other, you know, even easier idea,

1:30:29

they wouldn't require, you know, the

1:30:32

right compounds getting struck by lightning,

1:30:34

but... is perhaps even more likely

1:30:36

something to have happened. And I

1:30:38

was just sort of got a

1:30:40

kick out of reading about how

1:30:43

even these sort of classic experiments

1:30:45

are being updated now. Very cool.

1:30:47

I know the guy in England,

1:30:49

Lane, Mark Lane, is that his

1:30:51

name? He's written a bunch of

1:30:54

books on. Oh yeah, yeah, yeah,

1:30:56

Nick Lane. He thinks this is

1:30:58

his own nonsense because he thinks

1:31:00

life originated down on the ocean

1:31:02

floor, you know. And he says,

1:31:05

we don't need no stinking lightning

1:31:07

or anything. Yeah, well, see, now

1:31:09

you don't. I bet there's static

1:31:11

electricity down on the ocean floor.

1:31:14

Maybe. Sure. Yeah. Kathy, what do

1:31:16

you have for us? Well, I

1:31:18

picked today's astronomy picture of the

1:31:20

day. Today is April 11th, and

1:31:22

there's always a permanent link if

1:31:25

you go down to the bottom.

1:31:27

And what it is, is a

1:31:29

cool image that someone caught. They

1:31:31

were doing a video. And in

1:31:33

just one frame, they caught the

1:31:36

international space station. in the Crescent

1:31:38

of Venus. So you can see

1:31:40

the shape of the ISS. And

1:31:42

so as a kind of shout

1:31:45

out to Rich who told us

1:31:47

about these ways to see the

1:31:49

ISS some years back on TWI

1:31:51

put in the link for the

1:31:53

how you sign up for the

1:31:56

NASA alerts for your area and

1:31:58

they have kind of a cutoff.

1:32:00

So they're not going to alert

1:32:02

you for every time it passed.

1:32:04

is over only when it's high

1:32:07

enough up and for long enough

1:32:09

to make it worth your while.

1:32:11

And then there's several apps and

1:32:13

the only one that I'm familiar

1:32:15

with is called Go ISS Watch.

1:32:18

It's at the Apple store and

1:32:20

there's a user's guide that I

1:32:22

put the link in for. And

1:32:24

there's similar links for Android and

1:32:27

so forth. But I get the

1:32:29

alerts from NASA and then I

1:32:31

set an alarm on my clock

1:32:33

and then I... Open up the

1:32:35

app just about the time it's

1:32:38

going over and and then it

1:32:40

shows me you know where to

1:32:42

look and Where the moon is

1:32:44

if the moon is out that

1:32:46

night and stuff like that. So

1:32:49

you you too can see the

1:32:51

ISS I've probably seen it I

1:32:53

don't know between 20 and 30

1:32:55

times now, but yeah I've never

1:32:58

seen it. I want to yeah,

1:33:00

I don't know that I don't

1:33:02

know that I've seen it, but

1:33:04

now I'm going to oh my

1:33:06

goodness we find it Yeah, I

1:33:09

looked and there's not really any

1:33:11

good passes in my area for

1:33:13

the next couple weeks, so it

1:33:15

may be true for you as

1:33:17

well. But set up the NASA

1:33:20

alerts and they usually come 12

1:33:22

hours ahead of time. And you'll

1:33:24

be amazed at how fast it

1:33:26

goes. When you first see it,

1:33:29

it's like, whoa, that's really going

1:33:31

fast. And the app shows you

1:33:33

because it has to do with

1:33:35

where it's picking up the reflected

1:33:37

sunlight. You know, it's usually a

1:33:40

little before. sunrise or a little

1:33:42

after sunset. But then it doesn't,

1:33:44

you're not going to see it

1:33:46

necessarily traverse across the whole sky

1:33:48

depending on where it is. And

1:33:51

so the app will show you

1:33:53

it's just about to go dim

1:33:55

now and you're watching it and

1:33:57

then it goes dim and it's

1:33:59

gone. Yeah, it's cool. And I

1:34:02

always wave to Kate or whoever's,

1:34:04

she's not on the INS anymore.

1:34:06

Yeah. I've seen it a couple

1:34:08

of times. I've also heard it

1:34:11

several times. There's some there's a

1:34:13

ham radio repeater on the ISS

1:34:15

and and hams will contact there.

1:34:17

I've tried to make a contact

1:34:19

through it but haven't succeeded yet

1:34:22

because I don't have my antennas

1:34:24

set up right and I I

1:34:26

usually think of it like too

1:34:28

late in the process and then.

1:34:30

Yeah. When the 50s when I

1:34:33

was a kid, I remember one

1:34:35

night we were living in Patterson,

1:34:37

New Jersey. My father said, the

1:34:39

Sputnik's gonna pass overhead. Let's go

1:34:42

see we all went outside. And

1:34:44

there's this light moving across the

1:34:46

sky. I think it was an

1:34:48

airplane. I don't know. But maybe

1:34:50

it was a Sputnik. Who knows?

1:34:53

It seemed kind of low to

1:34:55

me, I didn't know. You needed

1:34:57

an app. Yeah, 1950s. Yeah, you

1:34:59