HPV Vaccine: How close are we to wiping out cervical cancer?

[Kristin] (0:00 - 0:07)
She says, I like to call it the common cold of the vagina. That's why it's so important to normalize it.

[Regina] (0:08 - 0:14)
Oh, the common cold of the vagina. I love that. That quote is gold, by the way.

[Kristin] (0:19 - 0:42)
Welcome to Normal Curves. This is a podcast for anyone who wants to learn about scientific studies and the statistics behind them. It's like a journal club, except we pick topics that are fun, relevant, and sometimes a little spicy.

We evaluate the evidence, and we also give you the tools that you need to evaluate scientific studies on your own. I'm Kristin Sainani. I'm a professor at Stanford University.

[Regina] (0:42 - 0:48)
And I'm Regina Nuzzo. I'm a professor at Gallaudet University and a part-time lecturer at Stanford.

[Kristin] (0:49 - 0:53)
We are not medical doctors, we are PhDs, so nothing in this podcast should be construed as medical advice.

[Regina] (0:53 - 0:59)
Also, this podcast is separate from our day jobs at Stanford and Gallaudet University.

[Kristin] (0:59 - 1:26)
Regina, today I want to talk about the HPV vaccine. And yes, I am bringing sex into this episode, because HPV is a sexually transmitted infection. So today we're talking about sex, cancer, and statistics.

[Regina]
We are hitting all of the bases, I am so proud of that.

[Kristin]
Did you know, Regina, that nearly all cases of cervical cancer are caused by a virus? It's called human papillomavirus, or HPV.

[Regina] (1:26 - 1:41)
Hmm. A single cause is really incredible, when you think about it. Because even a cancer, like lung cancer, where a lot of it is caused by smoking, even non-smokers get lung cancer, too.

But here we're talking about a single cause.

[Kristin] (1:41 - 1:51)
Cervical cancer is unique in this way, and the amazing thing is that we have a way to get rid of that cause. We have a highly effective vaccine against HPV.

[Regina] (1:51 - 2:02)
So if the vaccine works, we could just get rid of cervical cancer entirely, like no more, ever again? Just eradicate it from the globe?

[Kristin] (2:03 - 2:18)
Yeah, in theory. And actually, that's the claim that we're going to look at today. Regina, I'm going big and bold with the claim.

Here it is. Cervical cancer will be eradicated in most of the world by the end of the century. We're going to explore the promise of that and, of course, the obstacles.

[Regina] (2:19 - 2:20)
That is bold. I’ll give you that.

[Kristin] (2:20 - 2:56)
You know, cervical cancer kills about 350,000 women worldwide every year, and it's not just about women, because HPV also causes other cancers, including throat and penile cancers.

[Regina]
Interesting.

So this affects men as well?

[Kristin]
Absolutely. In terms of statistics today, we're going to talk about disease surveillance, case reports, and mathematical models, including Markov models.

We'll also talk about a fascinating phenomenon called mass psychogenic illness.

[Regina] (2:56 - 2:59)
This is going to be good.

[Kristin] (2:59 - 3:18)
Regina, the HPV vaccine has been in the news lately because of some lawsuits that were just dismissed. We're going to come back to those at the very end of this episode. But what got me thinking about this topic was a recent headline that read, No cervical cancer cases detected in vaccinated women following HPV immunization.

[Regina] (3:19 - 3:26)
No cervical cancer cases in vaccinated women, but which vaccinated? In the whole world?

[Kristin] (3:27 - 4:06)
No. Yeah, the headline is a bit misleading because it's a rather narrow case. It's a specific group of vaccinated women in Scotland.

Scotland has had a school-based vaccination program since 2008 for girls aged 12 to 13 with catch-up shots for older teens. The zero cases was in all of Scotland from 2008 to 2020, but specifically in girls vaccinated by age 13.

[Regina]
And why did they stop in 2020?

Did something happen?

[Kristin]
No, no. It's just because there's always a lag because it takes time to compile and analyze the data.

So we always are a few years behind on cancer statistics.

[Regina] (4:07 - 4:17)
Oh, right. So there's zero cases. That was in women who had been vaccinated on time.

But what about if they did not get the vaccine or got it later?

[Kristin] (4:18 - 4:35)
So among those who were similar in age and unvaccinated, there were eight cases of cervical cancer per 100,000 women per year in Scotland. And in women who were fully vaccinated but got the vaccine late, after age 13, the rate was three cases per 100,000 women.

[Regina] (4:35 - 4:43)
Wow. So it looks like the vaccine was effective, but also the age that you get the vaccine is important.

[Kristin] (4:43 - 4:48)
Yeah. The vaccine works best if you give it to girls before they are sexually active.

[Regina] (4:49 - 4:57)
Because vaccines prevent future infections, don't help with existing ones after you've already started having sex.

[Kristin] (4:57 - 5:03)
That's exactly right. And women are often exposed to at least one strain of HPV soon after they become sexually active.

[Regina] (5:04 - 5:24)
Interesting. But, Kristin, I'm doing the math in my head with the dates you gave us. And you said 2008 to 2020, that is only 12 years of follow up.

And you said they were vaccinated as teens. So they are 20s, early 30s at the most. They're still young.

[Kristin] (5:25 - 5:38)
Yeah. Good catch, Regina. I mean, I guess it's important to give the caveats here.

They're still young and they could get cancer in the future. But, you know, I would say zero cases so far. Great proof of principle.

It's pretty striking.

[Regina] (5:39 - 5:39)
I'll give it. It's a good start. Good start.

[Kristin] (5:39 - 5:54)
Yes. Yeah. Quick technical note, Regina, when we talk about cancer rates today, they are all age standardized rates, which means they correct for any differences in the ages of the groups we're comparing.

Regina, I'm saving the deep dive on age standardization for a future episode, though.

[Regina] (5:55 - 6:06)
Oh, yes. That is a great topic. Kristin, maybe now you can give us a little background on HPV.

It's a virus. But what is it?

[Kristin] (6:06 - 6:35)
Oh, I would love to. And actually, Regina, I would love to talk about some history of science first.

[Regina]
I love the history of science. Yes.

[Kristin]
All right. So let's go back to 1842. There was an Italian surgeon who did one of the earliest cancer surveillance studies.

He analyzed death records from Verona. He looked at a combination of uterine and cervical cancer because they were lumped together at the time, but it's largely reflective of cervical cancer. He found that nuns had much lower rates of those cancers than married or widowed women.

[Regina] (6:36 - 6:45)
Oh, interesting. And one important difference between nuns and married women, I'm guessing, is having sex.

[Kristin] (6:45 - 7:07)
Ah, yes.This was an early hint that sex might be a risk factor for cervical cancer. Interestingly, he also noticed that breast cancer was more common in the nuns than in married or widowed women. And he had some interesting theories about why that might be.

He thought it might be because their corsets were too tight or because they were squeezing their breasts while praying.

[Regina] (7:09 - 7:36)
Do you squeeze your breasts while praying? Do you squeeze your breasts while doing anything? Did anyone?

[Kristin]
I don't think so.

[Regina]
Do you squeeze their breasts while doing anything other than, I guess, if you're on OnlyFans and you're squeezing your breasts? Okay, so I'm guessing what he did not know is that not having children is a risk factor for breast cancer.

[Kristin] (7:36 - 7:50)
Right, exactly.

It is not the tight corsets.

But it was interesting that he noticed that pattern even that early on. All right. Back to cervical cancer.

We're now going to fast forward to the 1960s. By then, there were several studies linking cervical cancer to sex, which, of course, sparked some moral panic.

[Regina] (7:52 - 7:56)
I bet it did. Sex is bad. Do not have sex.

[Kristin] (7:57 - 8:17)
Yes, exactly. Regina, I love old papers. Sometimes they're so fun.

So I have to share this editorial I found, 1964, Canadian Medical Association Journal. I'm going to put a link in the show notes because it's hilarious. The title of the paper is Cleanliness, Continence, Constancy, and Cervical Carcinoma.

[Regina] (8:17 - 8:21)
They really reached pretty far to get that alliteration, didn't they?

[Kristin] (8:21 - 8:22)
Beautiful alliteration, yes.

[Regina] (8:23 - 8:28)
What does it even mean, continence? Are they talking about holding your urine?

[Kristin] (8:28 - 8:47)
Let me translate here. So cleanliness is referring to male penile hygiene. Okay. Continence is not what we think of today.

It's a slightly archaic word for abstinence. So no sex. Constancy means monogamy.

And of course, cervical carcinoma is cervical cancer.

[Regina] (8:47 - 9:02)
Mm-hmm. Can we go back to that penile hygiene?

[Kristin]
Sure.

[Regina]
I want to talk about washing the penis now, because now that I'm thinking about it, I'm wondering, does it actually help prevent cancer?

[Kristin] (9:03 - 9:09)
No, it doesn't. But the authors of that editorial were kind of obsessed with it. They actually compared it to dental hygiene.

[Regina] (9:11 - 9:13)
Of course they were. Were these men?

[Kristin] (9:14 - 9:22)
I'm guessing they were men. Well, I don't know, because there were no authors listed, because it was an editorial. But I'm guessing the editorial board in 1964 probably was all men, yes.

[Regina] (9:24 - 9:33)
They were definitely men, and they were obsessed with their penises, and they just wanted an excuse to go up and wash it. Hey, honey, I'm washing my penis. Don't open the door.

[Kristin] (9:34 - 10:08)
They were trying to encourage monogamy and abstinence first, but they were like, well, but if we can't get them to do that, at least we can get them to do penile hygiene.

[Regina]
Okay. We can at least get the men to use soap every now and then.

[Kristin]
All right. I only have time to share one of the fun quotes from the paper.

So they were talking about that male circumcision could reduce the risk of cervical cancer, but they said it was hard to get good data on that because, quote, in early surveys, it was discovered that wives were hard put to say definitely whether or not their husbands were circumcised.

[Regina] (10:11 - 10:24)
I'm picturing Betty Draper from Mad Men, and I can totally picture Betty Draper not knowing whether Don was circumcised. Not looking down at all. Yes.

[Kristin] (10:25 - 10:36)
Yes. I got a chuckle out of that, though. Yes.

Old papers. So good. All right.

By the 1960s, now scientists suspected that a sexually transmitted infection was behind cervical cancer. At first, though, Regina, they thought it was herpes.

[Regina] (10:36 - 10:44)
Well, I guess that makes sense, because if you've got one sexually transmitted infection, you're more likely to have another, right?

[Kristin] (10:44 - 11:09)
Yeah. It's classic confounding. If you have herpes, you're more likely to have HPV. It was actually a German scientist in the 1970s named Harald zur Hausen who figured out that it was HPV and not herpes.

And he figured this out because he knew of some rare reports of penile warts turning cancerous. So he thought maybe the same virus that causes the warts, which is HPV, maybe that's also behind cervical cancer.

[Regina] (11:09 - 11:15)
Penile warts. I bet he was super fun at dinner parties. I would invite him. Tell me more about penile warts.

[Kristin] (11:15 - 11:49)
Yes. And then he was able to isolate HPV DNA from tumors, and then many other people followed up on this research.

So now, fast forward to 1999. There was a landmark paper. They isolated HPV DNA from 99.7% of a large sample of cervical tumors from all over the world. And the paper is titled, Human Papilloma Virus is a Necessary Cause of Invasive Cervical Cancer Worldwide.

[Regina] (11:49 - 11:54)
Wow. I like that title because it really gets to the point.

[Kristin] (11:55 - 12:12)
It's a great title, much better than most scientific papers, maybe not quite as good as the Constancy and Continence, but it's a great take-home message. I like that title, yes. And zur Hausen won the Nobel Prize for his work on HPV in 2008.

[Regina]
Oh, good for him.

[Kristin]
Well-deserved, yes.

[Regina] (12:12 - 12:31)
Kristin, now tell me a little more about HPV because I've learned now it causes penile warts. It does, yes. Does it also cause warts on the vulva?

[Kristin]
Yeah, all over the genital areas, yes.

[Regina]
What about warts on the hands and feet? Because now I'm thinking about all of this and witches and their noses. Is it the same virus?

[Kristin] (12:33 - 12:41)
It is the same virus, different strains. Different strains of the virus infect the hands and feet than infect the genitals.

[Regina] (12:41 - 12:49)
I don't know why witches and noses. You know, I had learned the old wives' tale growing up that you get warts when you touch toads.

[Kristin] (12:50 - 12:52)
Oh, really?

[Regina]
When you hold toads. Yeah.

[Kristin]
I did not learn that.

[Regina] (12:52 - 13:01)
I always thought it was because toads have bumpy, lumpy skin. Okay, so you're telling me toads were the unfairly maligned victims in this slander story.

[Kristin] (13:01 - 13:26)
They were, yeah, because toads do not cause warts. It's HPV. So, there are about 200 strains of HPV.

Only 40 of those infect the genital areas, and most of them are harmless. A few cause genital warts, and about 14 cause cancer. The two most important for cancer are HPV 16 and 18.

Those two cause about 70% of all cervical cancers.

[Regina] (13:27 - 13:42)
HPV 16 and 18, those are their names, I'm guessing?

[Kristin]
Yes, that's how they name the different strains, their numbers.

[Regina]
Getting back to genitals, I have heard that genital HPV is really common.

Is that true?

[Kristin] (13:43 - 13:55)
Yeah, it's true. Almost everyone gets it. And actually, there was one study that estimated that even individuals who have just a single sexual partner in their lifetime, they still have about a 60% chance of being infected.

[Regina] (13:56 - 14:08)
Yikes. First of all, it's hard for me to imagine a lot of people having just one sexual partner in their lifetime, but you still have a 60% chance of being, I guess, their sexual partner.

[Kristin] (14:08 - 14:11)
Right, presumably their partner had more than one partner, yes, probably.

[Regina] (14:12 - 14:13)
The math has got to work out somehow.

[Kristin] (14:13 - 14:29)
Yeah, but it is super common, and I found this great quote in Cosmo. This was an OB-GYN talking about HPV, and she says, I like to call it the common cold of the vagina. That's why it's so important to normalize it.

[Regina] (14:30 - 14:37)
Oh, the common cold of the vagina. I love that. That quote is gold, by the way.

[Kristin] (14:38 - 14:47)
Pure gold. I mean, Regina, you and I have both written for magazines, and when you're interviewing scientists, you are just sitting there on the phone waiting for a quote like that, and sometimes you never get it.

[Regina] (14:47 - 14:51)
Oh, yeah. And you're trying to encourage them, you know, gently nudge them to be more portable.

[Kristin] (14:51 - 14:55)
Oh, we have all sorts of tricks to try to elicit a quote like that, yes. They don't always work.

[Regina] (14:56 - 15:01)
Yeah, it does not always work. Okay, common cold of the vagina, so good, I'm stealing it.

[Kristin] (15:02 - 15:17)
We should steal that, yeah.

Now, of course, Regina, the more sexual partners you have, the more chances you have to pick up one of these higher-risk strains, like HPV-16 or 18, that can cause cancer. This is probabilistic, but someone who has just one partner, they can still get cervical cancer.

[Regina] (15:18 - 15:23)
Kristin, how does the HPV actually spread from person to person?

[Kristin] (15:24 - 15:41)
Good question, but let's keep it PG-13 here, Regina, okay? Okay. It's spread through skin-to-skin contact, not through bodily fluids like HIV is.

So pretty much anywhere with mucous membranes and skin that come into contact during sex.

[Regina] (15:42 - 15:56)
There's a lot of membranes and skin that comes into contact during sex. If you're doing it right, there's a lot, yes. So you are telling me condoms then are not complete protection here.

[Kristin] (15:57 - 16:10)
Correct. They do reduce risk, but they're not totally protective because HPV doesn't just infect the cervix and the penis. It can infect other genital areas and also the mouth and throat.

[Regina] (16:12 - 16:29)
This is interesting, though, because I know that sometimes young people today say that they are still a virgin if they've not had penetrative sex, if they've only had oral sex. So you are saying they could still be at risk for HPV infection.

[Kristin] (16:29 - 16:38)
Yes, they are still at risk of HPV. And Regina, this gets tricky where, like, how do you define sex? And this is reminding me of Bill Clinton, actually.

[Regina] (16:39 - 16:47)
Oh, what was his famous quote? I did not have sexual relations with that woman. Yes.

Sexual relations.

[Kristin] (16:47 - 16:52)
Yes, that's the quote. But even though he didn't, he could still have transmitted HPV anyway.

[Regina] (16:52 - 17:03)
I'd like to just say for Bill Clinton's lawyer who is listening right now, we are not saying he did transmit HPV or anything else. Just for the record.

[Kristin] (17:04 - 17:10)
We are just saying it's biologically possible. I do also want to point out that some of our audience may not be old enough to understand this reference. So I'm telling them to go look it up.

[Regina] (17:11 - 17:18)
Yeah, good history lesson here. Kristin, what about French kissing? Kissing, deep kissing, tongue kissing?

[Kristin] (17:19 - 17:25)
Oh, that's interesting. I'm not sure, but it is mucous membranes, so possibly, I don't know.

[Regina] (17:25 - 17:39)
That was a trick question because I already looked it up.

[Kristin]
Oh, thank you.

[Regina]
I wanted to see if you knew the answer.

[Kristin]
I did not, sorry.

[Regina]
I did look it up and you can. You can spread HPV just through kissing.

[Kristin] (17:39 - 17:40)
No way.

[Regina]
Yes, you can.

[Kristin]
Oh, wow.

[Regina] (17:41 - 17:58)
I've got to say, I am thinking very differently about all my dates now because STI hits a little different when you're talking about doing something like just kissing. So can HPV cause cancer in all these other areas as well that we've been talking about?

[Kristin] (17:58 - 18:13)
Yes, HPV 16 and 18 also cause anal, vaginal, vulvar, and penile cancers, but also oropharyngeal cancers, which are much more common. And this is cancer in the middle of the throat, tonsils, soft palate, and back of the tongue.

[Regina] (18:14 - 18:29)
Throat and mouth cancer. So before oral sex was the common pastime that it is today, didn't those cancers used to be mostly caused by smoking and alcohol, right?

[Kristin] (18:29 - 18:32)
Yes, that's correct. But now it's estimated that 70% of these cancers are due to HPV.

[Regina] (18:33 - 19:00)
Wow. That is fascinating. So who gets this?

My next question. Gay women, straight women, gay men, straight men.

[Kristin]
It's actually a lot of young, straight men.

[Regina]
Good for them.

[Kristin]
Very modern.

[Regina]
Very modern men.

Like I am not happy that they got cancer. But somehow I find this oddly cheering, this trend that we are seeing.

[Kristin] (19:00 - 19:15)
Yeah. I didn't realize this until I was researching this episode, but there are actually now more HPV-related cancers in men than in women in the U.S., largely because of throat cancer. Only a third of HPV-related cancers in the U.S. are cervical cancers, believe it or not.

[Regina] (19:16 - 19:21)
That is wild. So this is affecting men. They need to get vaccinated too, right?

[Kristin] (19:21 - 19:28)
They need to get vaccinated. Yes. And actually, we don't screen for these other cancers the way we do for cervical cancer. So in some ways, they're even more dangerous.

They might be caught at later stages.

[Regina] (19:29 - 19:37)
Okay. So how does HPV infection actually turn into cancer?

[Kristin] (19:38 - 20:08)
Thankfully, it usually doesn't, actually.

Most infections clear on their own, and people never even know they're infected. But sometimes, especially with high-risk strains of the virus, the infection can become persistent. And it can turn off some of the body's cancer defenses, and this leads to abnormal cell growth.

[Regina]
That's the cancer?

[Kristin]
Not the cancer yet, because the cells first become precancerous. They form these lesions called dysplasia.

And even then, the body often clears those up on its own as well. But sometimes, those precancers can progress to cancer.

[Regina] (20:08 - 20:13)
A lot of steps, then, from first infection all the way to cancer.

[Kristin] (20:13 - 20:20)
Exactly. The key is that it takes a long time from infection to cancer. On average, something like 15 to 20 years.

[Regina] (20:21 - 20:26)
And that is why screening works so well, pap smears, because you have time to catch it.

[Kristin] (20:26 - 20:45)
Yeah, you have time to catch the precancers. And doctors can remove the precancer entirely, and then you don't get cancer.

[Regina]
How do they remove them?

[Kristin]
They can burn it off or freeze it off, actually. These are very common. It's something like 200,000 women a year in the U.S. have to get these lesions removed. So it's a burden on women, actually.

[Regina] (20:46 - 21:03)
It's scary and traumatic and costly. This is where a vaccine, then, has the advantage over screening, because you prevent cancer both ways. But with screening, you've got to get something on your cervix burned off or frozen off, and a vaccine is just a shot.

[Kristin] (21:03 - 21:27)
That's right. The vaccine isn't just preventing cancer. It prevents the entire chain of events. All right, let's talk about the vaccine now.

The first vaccine was approved in 2006. And Regina, I remember when this came out, because I was like, this is so amazing. We have a vaccine that prevents cancer.

But I also remember being surprised that it didn't get quite the attention that I would have expected in the media for such a big breakthrough.

[Regina] (21:28 - 21:37)
Do you think that's because it was tinged with sex and sex is bad? And if you have a vaccine, then people might do sex for fun.

[Kristin] (21:39 - 22:02)
I distinctly remember listening to an interview on NPR, and this is one of those times when you're shouting at NPR in the car, because they were interviewing a Catholic representative and she was saying, oh, we're very worried about safety because it's a new vaccine. And I was like, yeah, sure, you're worried about safety. And also, I have a bridge to sell you in Brooklyn.

[Regina] (22:03 - 22:12)
OK, so maybe the problem with sex and morality, but they're just hiding behind the safety.

[Kristin] (22:12 - 22:12)
Yeah, I think the sex was the big elephant in the room there. Yes.

[Regina] (22:13 - 22:20)
So this was not a new or weird vaccine. Pretty typical vaccine technology, right?

[Kristin] (22:20 - 22:42)
Super old school. HPV is a DNA virus. It mutates slowly, unlike flu or COVID.

So you don't have to keep updating it. And it's not an mRNA vaccine. It's just the old fashioned vaccine where you make a synthetic protein that looks like the protein on the surface of the virus and your body learns to make antibodies against that protein.

So if you ever become exposed, your immune system takes that infection out right away.

[Regina] (22:43 - 22:48)
And the original vaccine covered what, one of the HPV strains or all of them?

[Kristin] (22:48 - 23:01)
The first version was Gardasil 4, and it protected against four strains, 16 and 18, which we talked about are the two that cause 70 percent of cervical cancers, but also 6 and 11, which are the two that cause genital warts.

[Regina] (23:03 - 23:18)
If we can do something to rid the world of genital warts, I think we should go ahead and do it.

[Kristin]
I agree, Regina.

[Regina]
Yes, it's not cancer, but it might actually help motivate people to get the vaccine if it helps prevent something they find to be embarrassing.

[Kristin] (23:20 - 23:35)
I should note that the vaccine has been updated. We now have Gardasil 9, which has an additional five cancer causing strains in the vaccine. So it protects against 90 percent of all cervical cancers.

In some parts of the world, though, they're still using a cheaper vaccine that only protects against 16 and 18.

[Regina] (23:36 - 23:44)
Kristin, in the U.S., at what age is it recommended that the boys and girls get this vaccine?

[Kristin] (23:44 - 24:03)
Ages 11 to 12. And that timing is really important. As we talked about with the Scotland study, there was an interesting modeling study in 2017 that estimated that over half of the HPV infections that eventually go on to cause cancer, over half of these are acquired before the age of 21.

[Regina] (24:05 - 24:10)
OK, common cold of the vagina right here. You need to vaccinate early.

[Kristin] (24:10 - 24:19)
Yeah, exactly. I should note that the U.S. has allowed catch-up vaccination originally up to age 26 and more recently up to age 45 for women.

[Regina] (24:19 - 24:20)
Oh, wow. So is it still worth getting it late?

[Kristin] (24:20 - 24:40)
It's less effective as you get older, but it might still protect against high risk strains of the virus that you haven't yet been exposed to. And actually, Regina, when they raised the age to 45, I was still young enough. So I went out and got it.

[Regina]
Really?

[Kristin]
Yeah, I mean, shots don't bother me. So I was like, why not? Just in case.

[Regina] (24:41 - 24:42)
Just in case.

[Kristin] (24:42 - 25:27)
But Regina, most women our age and even a decade behind us have not been vaccinated.

[Regina]
Right.

[Kristin]
All right.

The vaccine has now been out for almost 20 years, and we have plenty of evidence that it works. HPV infections are way down, even in unvaccinated people.

[Regina]
Oh, herd immunity.

[Kristin]
Yeah, exactly. And there have also been dramatic declines in cervical dysplasia, those pre-cancers.

[Regina]
Oh, which is important, like we talked about.

[Kristin]
Yeah, absolutely. And now we are finally able to show that, indeed, the vaccine prevents cancer. We have plenty of studies now similar to the Scotland study.

And the vaccine appears to offer long-lasting protection. They are still seeing high antibody levels against HPV 18 and 16 in women vaccinated over a decade ago.

[Regina] (25:28 - 25:37)
So the vaccine works, but then how do we get from we've got an effective vaccine to we've wiped out cervical cancer from the face of the earth?

[Kristin] (25:37 - 26:16)
Just a few steps, Regina, just a few steps in the middle, yes. This is where we need a global effort. And actually, the World Health Organization, the WHO, has a strategy for global eradication.

They published this plan in 2020, and I want to talk about it next.

[Regina]
I want to hear about their plan, but let's take a short break first.

[Kristin]
Regina, I've mentioned before on this podcast our introductory statistics course, Demystifying Data, which is on Stanford Online.

I want to give our listeners a little bit more information about that course.

[Regina] (26:16 - 26:26)
It's a self-paced course where we do a lot of really fun case studies. It's for stats novices, but also people who might have had a stats course in the past, but want a deeper understanding now.

[Kristin] (26:27 - 26:40)
You can get a Stanford professional certificate as well as CME credit. You can find a link to that course on our website, normalcurves.com, and our listeners get a discount. The discount code is normalcurves10.

That's all lowercase.

[Regina] (26:48 - 26:56)
Welcome back to Normal Curves. We were about to talk about the WHO's plan to eradicate cervical cancer from the globe.

[Kristin] (26:56 - 27:04)
Regina, I want to clarify that the WHO defines eradication as fewer than four cases per 100,000 women per year.

[Regina] (27:05 - 27:10)
So it's not quite the same as like with smallpox. We're not talking about getting down to zero.

[Kristin] (27:10 - 27:51)
Right. We're talking about getting to the point where it's considered a rare cancer. For context, in 2020, the global rate was about 14 per 100,000 women.

So what does the plan involve then? They have three targets that they want to reach by 2030. It's called the 90-70-90 plan.

90% of girls vaccinated by age 15, 70% of women screened twice in their lives, and 90% of women with pre-cancers or cancers treated. We still need screening and treatment, Regina, because if you think about it, most women on Earth now were too old to have gotten the vaccine, and all of these women still need to be screened. They're not protected.

[Regina] (27:51 - 28:04)
So multiple strategies to get there, not just the vaccine, the vaccine with other things. But those goals really sound ambitious. 2030, it's like right around the corner.

[Kristin] (28:04 - 28:23)
Yes, quite ambitious. And whether or not those targets are realistic is a question we're going to tackle later. But first, I just want to talk about where does the 90-70-90 even come from?

How do scientists set these kinds of public health targets? A lot of it comes from mathematical models.

[Regina] (28:24 - 28:35)
I love models because we can play with different scenarios in this big picture way. It's something you can't do with regular old individual studies or clinical trials.

[Kristin] (28:36 - 28:53)
Exactly. Scientists use mathematical models to try out different scenarios, like different screening strategies or different strategies for achieving eradication. Regina, can we take a statistical detour now and talk about how these models work?

[Regina]
Oh, absolutely. Please.

[Kristin]
All right. I want to talk about Markov models and micro simulation models.

[Regina] (28:53 - 28:59)
I love Markov models, just for the record. And I remember these from grad school, Stanford.

[Kristin] (28:59 - 29:07)
Me too. I had a whole stats course about Markov models. And Regina, actually, I have a dating story from that class.

I met a boyfriend in that class.

[Regina] (29:07 - 29:12)
No way. Really?

[Kristin]
Yeah.

[Regina]
Not the one that you were dating when I met you, though.

[Kristin] (29:12 - 29:19)
No, this was before that one. And he was more nerdy, I think, than the one you're thinking about.

[Regina] (29:19 - 29:21)
Yeah. I knew the bad boy boyfriend.

[Kristin] (29:22 - 29:32)
The motorcycle driving. Yes. This other one, though, our first date was actually studying Markov models.

[Regina]
Oh, no way. That's kind of sexy, though.

[Kristin] (29:33 - 29:36)
Isn't it though?

[Regina]
I will give you that. Yes, yes.

[Kristin] (29:36 - 29:47)
All right. Anyway, Markov models invented by a Russian mathematician, Andrey Markov. He showed that you could predict the next letter in a text by looking only at the letter before it.

[Regina] (29:47 - 29:50)
Oh, kind of like a really dumb autocomplete.

[Kristin] (29:50 - 30:21)
It's like a low power precursor to modern auto texting. Yes. Markov models are used for modeling all kinds of health problems, not just cervical cancer.

The way they work is you define a bunch of different health states, like you are HPV negative or you have a high risk HPV infection or you have a precancerous lesion or you have cancer. And at every time step, this is usually every month or every year, you have a certain probability of moving from one state to another. I think of it like a board game where at every turn you roll the dice to see if you move forward, backward or stay put.

[Regina] (30:22 - 30:46)
Oh, I like that board game thing. I always used to think of it as a choose your own adventure story. Remember those books?

[Kristin]
Oh, yeah.

[Regina]
Page 25. What do you do next?

If you stab the goblin, turn to page 50. If you run away in fear, turn to page 45. Yeah.

[Kristin]
Yeah. We loved those when we were kids. Yeah.

[Regina]
Yeah. But this is probabilistic. You don't get to choose.

[Kristin] (30:46 - 31:36)
You don't. Yeah. Probabilistic.

But I still like that analogy because at each decision point, your next move doesn't depend on the last move. And that's how a Markov model works. Yes.

And Regina, once we have these health states and these probabilities, we can layer on vaccination and treatment strategies. And those, of course, would affect those transition probabilities. Now, the limitation of the Markov models that we learned back a while ago is they look at groups of people at once.

And nowadays, with modern computing power, we can actually do better than this. We can simulate the life courses of individual people. It allows you to build in more detail and nuance because now each woman can have her own probabilities.

And these can change over time, depending on how her virtual life evolves. And these are what we call micro simulation models. The micro is the individual person part.

[Regina] (31:37 - 31:54)
I love this so much. You get to play God and run millions of little parallel universes with millions of little fake people having their fake lives. It kind of feels like a video game, like SimCity.

But at the end, you get an answer to a medical question.

[Kristin] (31:54 - 32:48)
I mean, I never played SimCity, but it does seem similar. Yes. Let's walk through a simple example, Regina.

All right. Say the model simulates a girl named Anne. She enters the simulation at age 12.

First question, is she vaccinated? Maybe the data show that 70 percent of girls at her age and her region get the vaccine. So the model goes ahead and flips a virtual coin with a 70 percent chance of heads.

And let's say it comes up heads. Well, now Anne's vaccinated.

[Regina]
Good for Anne.

How's her sex life going to go?

[Kristin]
Well, let's say girls in her area have an 80 percent chance of being sexually active by age 19. So at age 19, the model flips a virtual coin and it comes out heads.

And so now, boom, she's sexually active. Then it flips another coin and we find out, whoops, she's been exposed to HPV. But because she's had the vaccine, she has only a five percent chance of becoming infected.

So the model flips a coin. Turns out she's not infected.

[Regina] (32:49 - 32:56)
Hmm. Does she find a loving spouse, though? Does she have good sex?

Does she have good orgasms? Is she happy? That's what I want to know.

[Kristin] (32:56 - 33:15)
You know, the model doesn't play out all of that, doesn't tell us any of that. But sometimes it keeps track of quality of life, which actually would go down if Anne got a pre-cancer or a cancer. And then the model keeps going.

Did Anne get a pap smear at 25? Did she get an HPV test at 30? Did she get a new sexual partner?

Did she follow up after an abnormal result?

[Regina] (33:15 - 33:25)
And so I can see why you need computing power for this, because we're not just doing it for Anne. We're doing it for lots and lots of women.

[Kristin] (33:25 - 34:19)
Yeah, exactly. And then we're taking all the outputs and counting up all the cases of cancer that occurred in these virtual women. And how many tests did they experience? How many false positives?

What the costs of all this were. And that allows us then to compare the costs and benefits of different screening protocols or different eradication strategies.

[Regina]
But how do they figure out the probabilities that we were talking about?

[Kristin]
Right. These are based on empirical data from all sorts of sources, behavioral surveys, clinical trials, as well as national cancer data. Just to give a fun example, some things we need to know are like, when do teens start having sex?

How many sexual partners do most people have? And these are going to be country specific. So I found some numbers from a model in Australia because they published the underlying numbers.

They used a median age of sexual debut of 16 to 17 and a median number of lifetime sexual partners of four for women and seven for men. And interestingly, the values in the U.S. are pretty similar.

[Regina] (34:19 - 34:33)
OK, I'm doing my math in my head. OK, first of all, 16 to 17 for a sexual debut, a median of four for women and seven for men. That's interesting.

[Kristin] (34:34 - 34:42)
Yeah, I mean, you'd think they have to be balanced, but actually they don't have to be balanced because men, I think, span a wider range of ages than women, right?

[Regina] (34:43 - 34:49)
Yeah. I'm also wondering if some women just don't report their true number. We talked about social desirability bias.

[Kristin] (34:50 - 35:08)
Yes, underreporting could be. Now, of course, everyone at home is just like we talked about in that episode. They’re going to compare themselves.

Where do I fall relative to the median? And actually, this is an interesting one, Regina. Opinions may differ about whether it's better to be on the left side or the right side for this one.

[Regina] (35:10 - 35:32)
It depends on your life goals, I think.

OK, but getting back to the models, the most important thing we're supposed to be talking about here, there are a lot of assumptions stacked on top of each other in this idealistic world, right, with Anne and her friends. How do we know if the model produces anything matching reality?

[Kristin] (35:32 - 35:48)
Great question, Regina. The models are actually calibrated, and what that means is we run kind of a basic version of the model using past data, and we can check whether the model spits out the right numbers for the number of cancer cases in those years, for example. And if it's off, we might have to tweak the parameters a little bit.

[Regina] (35:49 - 36:06)
Ah, so you've fine-tuned it to match the past. Yes. But isn't there a risk that it only works because you've massaged everything to get it just right, to, like, overfit it to reality?

What if the whole thing unravels the minute you just, like, touch a dial?

[Kristin] (36:06 - 36:20)
That's why researchers actually also test how much the results change when they tweak the inputs. That's called a sensitivity analysis. We can try out different values.

You know, what if sexual debut was a little older or younger, for example, than 17?

[Regina] (36:20 - 36:28)
So you're basically checking if the model has a meltdown, like a nervous breakdown when you poke it a little bit.

[Kristin] (36:28 - 36:34)
That's exactly right, yes, yes. And, Regina, another way to build confidence is to use multiple independent models to look at the same question.

[Regina] (36:34 - 36:43)
Ah, yes, always reassuring when you use different methods or different models, and they all converge on the same answer. It makes the evidence feel a little more solid, yeah.

[Kristin] (36:44 - 36:55)
And for cervical cancer, we're lucky. We have several well-validated models have been widely used, developed over many years. In particular, there's one from Harvard and another called Policy One Cervix.

[Regina] (36:56 - 37:11)
Well, isn't that catchy? Policy One Cervix. Policy One Cervix.

It sounds a little like some government agency wonk got together with, like, a sci-fi movie and made a baby and had a love child there.

[Kristin] (37:11 - 37:15)
Yeah, maybe modelers are not the best at marketing and creative names.

[Regina] (37:16 - 37:23)
Yeah. But, Kristin, how are they using these models to address our claim today, which is about cervical cancer?

[Kristin] (37:24 - 37:38)
Yes, I'm going to give three examples, Regina. One study done in Australia, one in the U.S., and one looking at 78 lower-income countries. But let's start with Australia, because Australia is actually on track to be one of the first countries to eliminate cervical cancer.

[Regina] (37:39 - 37:46)
And by eradicate, you do not mean zero, right? You mean that threshold of, what was it, fewer than four per 100,000 people?

[Kristin] (37:46 - 38:34)
That's correct, yeah. We want to keep that in mind, that we're not actually meaning zero like in smallpox here. All right, so there was a 2019 paper in The Lancet Public Health.

It used the Policy One Cervix model, now we're all going to remember that name, to predict how soon eradication might occur in Australia. And Australia has an excellent school-based vaccination program, very similar to Scotland. Over 80% of girls and boys have been vaccinated by age 15, so it just misses that 90% WHO target.

They also have excellent screening, way above the 70% WHO target.

[Regina]
Oh, good for them. So what did the model find soon?

[Kristin]
They are on track to eliminate cervical cancer by 2028, according to the model. But of course, that comes with a margin of error, and on the high end, it could be as late as 2035. It is 2025 when we are recording this.

[Regina] (38:34 - 38:36)
Are they going to make it by 2028?

[Kristin] (38:36 - 38:55)
It's really interesting, because these kinds of statistics actually take time to compile, so we won't actually know if they've hit it until a few years after 2028.

[Regina]
Ah, lag, yeah.

[Kristin]
There's a lag.

But we do have data from 2020. By 2020, they were already down to 6.6 cases per 100,000, so I'd say they're roughly on track.

[Regina] (38:55 - 39:00)
Oh, not bad. Not too far from four. Four is our goal.

[Kristin] (39:01 - 39:17)
That's exactly right, yes. And, Regina, they also modeled what would happen if you phased out screening altogether for the women who are young enough to have been offered the vaccine. And if you do that, cases go up a little, but they still stay below the elimination target of that four per 100,000.

[Regina] (39:17 - 39:24)
So you're saying if enough women are vaccinated, you could eventually just ditch the screening altogether? Wow, that'd be wild.

[Kristin] (39:24 - 39:43)
Yeah, at least in Australia. Okay, that's Australia.

What about the U.S.? There was a similar study in the U.S. published in the same journal in 2020. They used two different simulation models. The Harvard model predicted we'd hit elimination by 2038, and policy one cervix said 2046.

[Regina] (39:43 - 39:49)
So on track, but definitely not as good as Australia. Why not? What happened?

[Kristin] (39:50 - 40:01)
We're just not quite hitting their numbers on vaccination. So in the U.S., coverage is still under 80%. And while our screening easily meets the WHO target, we're still a little behind Australia there too.

[Regina] (40:02 - 40:05)
How could we speed things up if we wanted to?

[Kristin] (40:05 - 40:24)
Great question, Regina, because they actually looked at that in the paper. So it turns out their modeling says that if we raise screening rates to 90%, that's way above that 70% target, we could shave almost a decade off the timeline. But weirdly, bumping vaccination up to 90% doesn't speed things up much at all.

[Regina] (40:24 - 40:32)
Vaccination, bumping it up, doesn't speed things up. Does that mean vaccinations are less important?

[Kristin] (40:32 - 40:55)
No, no, no, no, not at all. So remember, we're talking about getting up to 90% coverage for girls that are 11 or 12 now. This is not retroactive, right? We're not going to jump in the DeLorean and go back in time and vaccinate everyone else, right?

So because of that, we're not going to see the benefits of scaling up vaccination for about 20 years. That's why it doesn't move up the eradication date. But of course, it's the key to eradication long-term.

[Regina] (40:56 - 41:04)
Mm, like a retirement account you got to invest now, but it doesn't get you to retirement any faster.

[Kristin] (41:04 - 41:11)
That's right, yes. All right, Regina, the final modeling paper we're going to look at is one that considered low- and middle-income countries.

[Regina] (41:11 - 41:16)
Mm, I'm guessing they have lower screening and vaccination coverage?

[Kristin] (41:16 - 41:51)
Absolutely, yeah. Many of these countries lag way behind, and they correspondingly have much higher cervical cancer rates than higher-income countries. So the WHO, in making this plan for global eradication, they commissioned a group of modelers to model 78 countries using three different models.

It includes that Harvard and the Policy 1 cervix again.

[Regina]
What'd they find?

[Kristin]
The models show that if these countries were able to hit the 90-70-90 target by 2030, then depending on the country, they could hit elimination between about 2048 and 2071.

[Regina] (41:52 - 42:10)
Not as fast as Australia or the U.S., but still within the century. Yeah. Kristin, this shows that eradication is possible if countries can hit these targets we've been talking about, but that seems like a big if to me.

Is it really realistic?

[Kristin] (42:11 - 42:41)
Yeah, I mean, this is a moonshot. These are ambitious goals for sure, Regina. There are countries on track, so there's hope, but it's not universal.

I wanna talk about screening and treatment first. In high-income countries, screening is generally very good, way above that WHO target of 70% of women screened twice in their lives. But in low- and middle-income countries, only about 20% of women have ever been screened for cervical cancer, so it's way below the WHO target.

[Regina] (42:42 - 42:44)
How can they improve that? What's the trick?

[Kristin] (42:44 - 42:51)
One thing that's changing the game, Regina, in screening is that we are moving away from pap smears and adopting HPV testing.

[Regina] (42:52 - 43:10)
I remember having to go in every year for a pap smear. So instead of this annual pap smear exam, replacing it with HPV screening, Kristin, maybe we can talk a little bit about what pap smears are and how this HPV testing is different.

[Kristin] (43:10 - 43:32)
Absolutely, so pap smears detect abnormal cells, whereas the HPV test actually detects the high-risk strains of the virus, like the HPV16 and 18, which are necessary in order to develop cancer. HPV tests are much more accurate, and women that have a negative HPV test can actually go five years without being screened again.

[Regina] (43:32 - 43:33)
Five years instead of yearly?

[Kristin] (43:34 - 44:06)
Yeah, the recommendation in the U.S. is that women in their 20s get a pap smear every three years, but women 30 and older just need an HPV test every five years. And the WHO target is even less than this. They're saying that if you can get women an HPV test twice in their lifetimes, once around age 35 and once around age 45, that's enough to catch the majority of cancers.

[Regina]
Hmm, logistically much more feasible.

[Kristin
Exactly, and another thing that's making this all logistically easier is we now have HPV self-tests that women can do at home.

[Regina] (44:06 - 44:17)
I can test myself for HPV in the privacy of my own home. So, you're saying no stirrups. I don't need to go into a cold room with a hospital gown.

[Kristin] (44:17 - 44:17)
No speculum.

[Regina] (44:18 - 44:21)
And no speculum. Okay, sign me up for that.

[Kristin] (44:21 - 45:02)
Yeah, I think COVID may have helped move these along because people are used to swabbing slightly hard-to-reach areas at home, right?

[Regina]
This is hard to reach.

[Kristin]
A little bit, yep.

But in lower-income countries, you can imagine that if you give women self-tests at home, that is going to be logistically easier, and then you only need to bring women into the clinic if they test positive.

[Regina]
Ah, very cost-effective then.

[Kristin]
Yeah, and they have this cheap test-and-treat method that they can do in low-resource settings.

Basically, they dab vinegar on her cervix, and if there are any abnormal cells, these turn white and they show up right away.

[Regina] (45:03 - 45:07)
No way. Vinegar? Vinegar? Like the thing I used to clean my kitchen sink?

[Kristin] (45:07 - 45:17)
Yeah, it turns these cells white, and you can see the results in minutes. So if the nurse or doctor sees something suspicious, they can treat it on the spot. They can lob it off right there and then.

[Regina] (45:18 - 45:26)
Honestly, this is kind of brilliant. Like, low-cost, easy to do. Can I do this at home myself?

[Kristin] (45:26 - 45:26)
No, I don't know. It'd be tricky.

[Regina] (45:27 - 45:29)
I guess, how am I going to see that, right?

[Kristin] (45:29 - 45:34)
Yeah, you're going to need a speculum then, and you're going to need a good mirror, and it's going to be complicated.

[Regina] (45:34 - 45:37)
Right, and a flashlight. Maybe with a partner. Sexy time, activity.

[Kristin] (45:40 - 45:52)
Whatever floats your boat. But the swabbing at home, and then assuming you don't have a high-risk version of the HPV, you don't even need to go in, because if you don't have high-risk HPV, nothing to worry about.

[Regina] (45:53 - 45:54)
Wow, nice.

[Kristin] (45:54 - 46:38)
All right, so screening, still lots of problems, scaling this up, but at least there are some low-cost solutions out there like this, and countries are trying to scale up screening. Let's talk, though, now about vaccination, because ultimately, you can imagine some scenarios where we get to vaccination only, and we phase out screening, as we talked about. Globally, though, we're behind.

As of 2023 worldwide, only 27% of girls under 15 had received even one dose of the HPV vaccine. Now, that's up from 20% the year before, so it's improving, but we're way off the WHO target. There have been some success stories.

Rwanda and Bhutan have over 90% coverage of the vaccine, believe it or not.

[Regina] (46:38 - 46:42)
Wow, good for them. So they are showing it is possible.

[Kristin] (46:43 - 47:46)
They had to partner with NGOs, pharmaceutical companies, the WHO. They set up school-based programs. They had community outreach.

But it shows that if you really do prioritize and do all of this, it can be done. One thing we haven't talked about, Regina, that might be helpful is that a lot of countries now, even high-income countries like Scotland, are moving to a one-dose schedule.

[Regina]
Just one shot.

[Kristin]
Yeah. In the past, they said that you needed two doses if you vaccinated young enough and three doses if you vaccinated at an older age. But they're finding that actually, if you vaccinate young enough, one dose is sufficient.

Much more practical. But, Regina, vaccines are tricky because it's not just about logistics and resources. The way it largely is with screening.

[Regina]
Are you talking about vaccine hesitancy?

[Kristin]
I am talking about vaccine hesitancy, yes. Quick case in point, Regina, Japan's HPV vaccine coverage is just over 20%.

That is not a resource issue with Japan. It's about vaccine hesitancy and misinformation. And this is where eradication could really be stalled.

[Regina] (47:46 - 47:51)
I am really looking forward to talking about this, but let's take a short break first.

[Kristin] (47:59 - 48:09)
Regina, I've mentioned before on this podcast, our clinical trials course on Stanford Online is called Clinical Trials Design Strategy and Analysis. I want to give our listeners a little bit more information about that course.

[Regina] (48:09 - 48:19)
It's a self-paced course. We cover some really fun case studies designed for people who need to work with clinical trials, including interpreting, running, and understanding them.

[Kristin] (48:19 - 48:32)
You can get a Stanford Professional Certificate as well as CME credit. You can also get a certificate You can find a link to that course on our website, normalcurves.com, and our listeners get a discount. The discount code is normalcurves10.

That's all lowercase.

[Regina] (48:39 - 48:56)
Welcome back to Normal Curves. Today, we're looking at the claim that eradicating cervical cancer from most of the world is within reach by the end of this century. And we were about to talk about vaccine hesitancy.

Kristin, this is a big topic.

[Kristin] (48:56 - 49:33)
Oh, this is such a huge topic. We could spend multiple episodes on this, and I'm sure we will touch on it in future episodes. We're going to talk specifically about HPV vaccine hesitancy, though, today.

The uptake of the HPV vaccine has been spotty, even in high-income countries, unfortunately.

[Regina]
Really? Including the U.S.?

[Kristin]
In the U.S., about 77% of teens have received at least one dose of the vaccine. 62% are fully vaccinated. It's lower than what we see for other vaccines administered at the exact same age. Tdap and meningococcal vaccines are given at the same age, and we have almost 90% coverage for those two.

[Regina] (49:34 - 49:40)
Wow. So maybe it's not just general vaccine hesitancy, but something specific to HPV?

[Kristin] (49:41 - 49:41)
It looks like it.

[Regina] (49:41 - 49:42)
I'm thinking maybe sex?

[Kristin] (49:44 - 50:14)
I think that's definitely part of it. It's interesting, though, because we do vaccinate against another sexually transmitted infection, which is hepatitis B, and we have over 90% coverage on that one in the U.S. Oh, what's the difference, then? It might have to do with timing, because the hep B vaccine is given to newborns because hepatitis B can be passed from mother to child.

In the hospital, after you have a baby, they whisk your newborn away right away and give them the hep B vaccine and a vitamin K shot, actually.

[Regina] (50:16 - 50:32)
So I guess if it's done right after birth, no one's actually thinking about that baby having sex. That's right. Maybe you're not thinking about sex, either.

[Kristin]
Probably thinking about not ever having it again.

[Regina]
So why not do it that way for HPV, then?

[Kristin] (50:32 - 51:05)
Unfortunately, the best timing for the HPV vaccine, for many reasons, is the preteen years and not right after birth.

[Regina]
Too bad.

[Kristin]
Interestingly, Regina, when you ask parents why they didn't vaccinate their kids against HPV, most do not cite sex as the main reason.

We have some data on this because there's a national CDC survey given every year on teen vaccination. Only about 1% of parents say that their main reason for skipping the shot is that they're worried that their kids are going to have more sex. About 10% of parents say they are skipping the shot because their kid is not sexually active.

[Regina] (51:07 - 51:13)
Isn't that exactly when you're supposed to get the vaccine? Yes. Before you have sex?

[Kristin] (51:13 - 51:28)
Yes, or apparently before you even French kiss.

[Regina]
So this is really parents not understanding the point of the vaccine?

[Kristin]
Yeah.

Another 15% say their main reason for skipping it is that they think their child doesn't need it.

[Regina] (51:29 - 51:33)
Is that code for, my kid's not having sex, my kid is not promiscuous?

[Kristin] (51:34 - 51:43)
You know, I'm guessing that's some of what's going on in that group, Regina. But interestingly, the most common reason parents cite for skipping the shot is concerns about safety.

[Regina] (51:43 - 51:51)
I wonder if it's discomfort with sex, but they're covering it with safety because it seemed a little bit more socially acceptable.

[Kristin] (51:51 - 52:10)
It could be, Regina, it's reminding me of the interview with the Catholic representative who was like, oh, it's just about safety, right? So it could be some of that, yeah. But this finding is backed up by other surveys.

Other surveys have found that even among parents who are not vaccine-hesitant, many still have some concerns about serious side effects with the HPV vaccine.

[Regina] (52:11 - 52:20)
Hmm, what do you think is driving this? Have there been actual safety problems with the vaccine?

[Kristin] (52:20 - 52:52)
No, the HPV vaccine is very safe. Unfortunately, historically, there has been a mix of rumors, scary headlines, and misinformation that have created this kind of cloud of suspicion around the HPV vaccine.

[Regina]
Where did this come from? How did this start?

[Kristin]
So, of course, before the vaccine was approved, they did large clinical trials and they found the vaccine to be safe. But we always want to monitor, after we roll out a vaccine, we want to monitor just in case some rare side effects pop up. I think sometimes, though, Regina, the way the media covers this monitoring, I would characterize it as irresponsible.

[Regina] (52:53 - 52:54)
Imagine that.

[Kristin] (52:54 - 53:21)
Imagine that, yeah. So earlier we talked about a great quote in Cosmo.

[Regina]
Oh, common cold to the vagina.

[Kristin]
Yes, and now I want to give an example of bad journalism and bad quoting. And this is from a CBS report in 2009. They were reporting on a study in JAMA, Journal of the American Medical Association, that looked at data from the Vaccine Adverse Event Reporting System, the VAERS system in the U.S. Mm, VAERS.

[Regina] (53:21 - 53:25)
We hear a lot about that. Do you mind just unpacking what that is for a moment?

[Kristin] (53:25 - 53:42)
Yeah, it's important. VAERS is a Voluntary Self-Report Passive Surveillance System where anyone, doctors, nurses, parents, lawyers, anyone can report anything that happens after a vaccine. So it might be fainting or rashes, but it could also be you got hit by a car.

[Regina] (53:42 - 53:48)
And completely voluntarily, like if you feel like it, you go ahead and file a report.

[Kristin] (53:48 - 54:07)
Exactly. I liken it, Regina, to, you know, at the airport when they come on the announcements and they say, if you see something, say something. And you're supposed to report like if you spot an abandoned backpack.

[Regina]
Right.

[Kristin]
Reports to VAERS are kind of like this, right? We have no evidence that it's a bomb, but we're going to report it just in case.

[Regina] (54:08 - 54:13)
Because if it is a bomb, the consequences are pretty high.

[Kristin] (54:14 - 54:55)
Right, better safe than sorry. But of course, we need the security guard to come and follow up and determine if it's a bomb or just a bag full of forgotten socks.

[Regina]
That's a great analogy, by the way.

[Kristin]
Oh, thanks, Regina.

All right, back to the CBS report so that I can criticize their journalism. Let me read their summary of that 2009 JAMA paper. And again, this was looking at adverse events reported to VAERS about the HPV vaccine.

In Tuesday's Journal of the American Medical Association, the CDC reported more than 12,000 side effects after 23 million doses were distributed. 94% of the problems were not serious, but 6% were, including patients who were hospitalized, permanently disabled, or died. There were 32 deaths, one in over 700,000 doses.

[Regina] (54:55 - 55:03)
That language makes it sound like the vaccines caused the deaths, though.

[Kristin] (55:03 - 55:21)
Right, which is completely misleading. And so they did follow up that summary with a quote from the lead author. And I think the quote was supposed to provide context, but it is an awful quote. Here's what she says.

This is a researcher from the CDC. It really isn't an increase with what we've seen with other vaccines and people of that age group.

[Regina] (55:21 - 55:44)
Oh, that's kind of a tortured nonsense sentence.

[Kristin]
The way scientists talk sometimes, it's awful.

[Regina]
Unfortunate, it's like passive voice and it's indirect.

I think what she is trying to say is there's no signal here. These events occur at some sort of background rate. And in those who were vaccinated, the rate was not significantly higher than the background, right?

[Kristin] (55:44 - 56:11)
Right, that's exactly what she's trying to say. These deaths were not linked to the vaccine. Sadly, young people sometimes die.

And by coincidence, some of those deaths might occur in the days, weeks, or months after a shot. Experts followed up and looked into those deaths. They were from all sorts of causes, prescription drug overdose, diabetes complications, viral meningitis, viral sepsis, and, Regina, the deaths occurred anywhere between two to 405 days after the HPV vaccine.

[Regina] (56:11 - 56:23)
That is a pretty slow-acting killer vaccine.

[Kristin]
Yes, it is.

[Regina]
So you are saying VAERS is a good start, but you've got to follow up with rigorous studies.

[Kristin] (56:23 - 56:55)
Absolutely. And that JAMA report did flag two potential signals. They saw more blood clots and more fainting than would be expected in the background for that age group.

[Regina]
Blood clots, those are dangerous.

[Kristin]
Yeah, very serious. But the blood clots turned out just to be a false signal because they followed up with large, rigorous studies with proper controls, and they did not find an increased risk of blood clots. They did find, though, Regina, that there is more fainting after the shot.

But actually, fainting after a vaccine is pretty common among teens in general, so it's not really specific to the HPV vaccine.

[Regina] (56:55 - 57:13)
I can imagine that, teens being teens.

[Kristin]
A little drama, yes.

[Regina]
Doing their teen thing, yeah.

The problem with these kinds of media reports, though, about this is that in the popular imagination, sometimes those false signals really stick in our memory.

[Kristin] (57:13 - 57:33)
Yeah, that fear sticks. It's really sticky. Yes.

Another thing that's fed into the concerns about safety is this fascinating phenomenon called mass psychogenic illness, sometimes also called mass hysteria. And Regina, I'd like your permission to do a little scientific detour here because it's just super interesting.

[Regina] (57:33 - 57:34)
Oh, it sounds fascinating. Yes, please.

[Kristin] (57:35 - 57:56)
Okay. Mass psychogenic illness is basically a group panic attack, right? So a group of people experience real symptoms, dizziness, fainting, and nausea, but there's no organic medical cause, and it typically starts with a triggering event, like maybe there's a strange smell or someone very publicly falls ill, and it spreads through fear and power of suggestion.

[Regina] (57:56 - 58:01)
Sounds like a party, a bad party.

[Kristin] (58:01 - 58:27)
A bad party with bad drugs. Yes. Well, the case reports in the literature are such great reads.

I'll put links in the show notes to a few of them. There are cases reported in the military, in public transportation situations, at workplaces. But I'm going to ask you now, Regina, to make a wild guess in terms of what group, age and gender, do you think this most complicated commonly occurs in?

[Regina] (58:29 - 58:32)
You're asking me to bring out all my stereotypes.

[Kristin] (58:32 - 58:32)
Sorry.

[Regina] (58:32 - 58:40)
And I'm going to go ahead and put them all out there, because I was once a teen girl, so I'm going to say teen girls.

[Kristin] (58:41 - 59:14)
Yeah, it's teenage girls, yes. And I'm not trying to malign teenage girls. I have a teenage girl.

She's super hardy, by the way. But that is the group where this most commonly occurs. And guess what?

That's exactly the same group that we are vaccinating against HPV. Regina, did you know the Salem witch trials are believed to be an example of mass psychogenic illness?

[Regina]
Oh, fascinating.

What symptoms did they have?

[Kristin]
They had things like seizures, twitching, convulsions, nausea, vomiting, headache. And you can imagine people seeing other people twitching, right?

[Regina] (59:15 - 59:28)
This reminds me of TikTok. It's like an early TikTok. This is what young people do.

They copy each other. They bond. Yeah.

And it sometimes looks like witchcraft.

[Kristin] (59:29 - 1:00:11)
Yes, exactly, yeah.

All right, so let's talk about a few case studies from the literature. There was one in 1998 in Jordan. The kids were being vaccinated at school against tetanus and diphtheria.

And a few kids didn't feel so well after the vaccine. So I think that started the fear. But the next morning, a boy collapsed at school in front of everybody and was taken to the hospital.

And then within an hour, another 20 students were reporting symptoms.

[Regina]
Ooh, power of suggestion.

[Kristin]
Absolutely.

But of course, at that point, the teachers didn't know, and they thought it was some kind of outbreak. And pretty quickly, they started to think, maybe it's a bad batch of the vaccine. It got widely covered on the media.

The health minister got on TV and told schools to stop vaccinating and encouraged anyone with symptoms to go to the hospital out of precaution.

[Regina] (1:00:12 - 1:00:16)
And I bet that just made everything spiral.

[Kristin] (1:00:16 - 1:01:21)
By the end of the next day, about 800 kids from schools all over the area had reported symptoms, and 122 had been hospitalized.

[Regina]
Wow, big numbers.

[Kristin]
Yeah, so they, of course, followed up with a major outbreak investigation, but they determined there was no organic cause of the illness.

It turned out that that same batch of the vaccine was being used in two other countries around the same time. So they were able to rule out it being a bad batch.

[Regina]
Group panic attack.

[Kristin]
Yes, but I want to emphasize that these are real symptoms. It's not in your head. You're not faking it.

If you've ever had a panic attack, and I have, your heart races. I get like a little tingling above my lip, actually. You might have shortness of breath.

You may feel faint. It's just that those physical symptoms are caused by fear rather than an actual organic cause. And I can totally understand how this happens.

Imagine you're smelling something really weird and you start to think it's a toxin. You get afraid. That fear causes you to have physiologic symptoms.

But then those symptoms tell your brain, oh, I have been exposed to a toxin because now I'm having symptoms, so it must be a toxin. And maybe I'm going to die. And now I have more symptoms.

[Regina] (1:01:21 - 1:01:26)
It really spirals in that way. Yeah, that mind-body link. It's powerful.

[Kristin] (1:01:26 - 1:03:14)
It's amazingly powerful. You want to hear another example?

[Regina]
Yes.

[Kristin]
Also from 1998, this was in Tennessee in the US. It started with a high school teacher noticing a funny smell and she started to feel dizzy, nauseous, short of breath. And then pretty quickly, students in her classroom started having the same symptoms.

[Regina]
What happened?

[Kristin]
They evacuated the school. Emergency responders showed up in droves.

[Regina]
Heightening the fear.

[Kristin]
Oh, yeah. So by the end of the day, about 100 students and teachers had gone to the ER and 38 were hospitalized.

[Regina]
And they found nothing?

[Kristin]
They did a huge investigation. They actually shut down the school for five days, but there was no toxic gas, no chemical leak, nothing.

But of course, during this time, it was widely covered in the media. And so when they reopened the school five days later, they actually had a second wave of cases. Another 71 people ended up in the ER and they evacuated the school a second time.

[Regina]
Oh, this kept spreading. No end to this.

[Kristin]
Yep, but in the end, it was well-documented.

It was mass psychogenic illness. All right, let's bring this back now to the HPV vaccine because there've been several documented cases of this following HPV vaccinations at school. The first was back in 2007 in Australia.

There was a girls' school. Everybody got vaccinated. And within a few hours, 26 girls reported symptoms like dizziness, headaches, palpitations, tingling, numbness, and some fainting.

And four went to the hospital.

[Regina]
Wow, and they found nothing?

[Kristin]
Yeah, the doctors did full evaluations, found no physical cause for the symptoms.

Everyone recovered. There was no evidence that this was a bad batch of the vaccine. It was a pretty clear case of mass psychogenic illness.

But this had a good outcome. The government intervened quickly. They emphasized to the public that the vaccine is safe, that there was no biological cause for the symptoms, and they encouraged the vaccine program to continue.

[Regina] (1:03:15 - 1:03:28)
Wow, I think that shows the power of a government communication because earlier you said Australia ended up with some of the highest vaccination coverages. So clearly it did not derail their vaccinations at all.

[Kristin] (1:03:28 - 1:03:37)
That's right, but you can imagine it absolutely could have gone the other way because there's another big incident that happened in Columbia in 2014, and it did go the other way.

[Regina] (1:03:37 - 1:03:38)
Oh no, what happened?

[Kristin] (1:03:39 - 1:03:59)
So in a period of five days, 15 girls from the same school were hospitalized with all sorts of symptoms, shortness of breath, numbness, twitching. It was actually two months after they had gotten the HPV vaccine, but their parents still blamed the vaccine. And videos of these girls fainting, twitching, arriving unconscious at the hospital went viral on social media.

[Regina] (1:04:00 - 1:04:03)
Can you imagine Salem Witch Trials if they had had social media at the time?

[Kristin] (1:04:04 - 1:06:29)
Oh wow, a lot more burning at the stake. Yeah, so the symptoms of course spread with the viral videos. Over 600 cases were reported across Columbia in the next few weeks.

They also did a very thorough investigation. It was again shown to be an example of mass psychogenic illness. Unlike in Australia, there was a lot of public distrust even after the experts cleared the vaccine.

And in Columbia, vaccination coverage completely plummeted. They were at over 80%. It went down to about 14% and it's still under 40%.

[Regina]
Oh wow, long memory.

[Kristin]
Yeah, again, it's that fear is very sticky. All right, Japan experienced something akin to a mass psychogenic illness in the early 2010s.

Though it might be more accurately described as a diffuse national panic because the symptoms didn't emerge all at once and they tended to be more chronic.

[Regina]
Like what?

[Kristin]
So in some girls, a few months after they got the HPV vaccine, they reported symptoms consistent with chronic fatigue syndrome, a particular chronic pain syndrome, and also POTS.

[Regina]
POTS, remind me what POTS is again.

[Kristin]
Right, I actually hadn't heard of this before except that Katie Ledecky recently talked about how she has POTS.

[Regina]
Swimmer, Olympic swimmer.

[Kristin]
That's the Olympic distance swimmer, the miler, yes. Okay, so POTS is postural orthostatic tachycardia syndrome. And basically it's when your heart rate spikes when you stand up and that can lead to dizziness and fainting.

[Regina]
Ah, okay.

[Kristin]
So these girls' stories, of course, were all over the news and that caused the symptoms to spread and it spread even beyond Japan.

[Regina]
Like where?

[Kristin]
Denmark had a similar situation in 2015, a few years after Japan may be influenced by the Japanese cases. A group of Danish doctors ended up publishing a famous case series in the literature. It's often called the Brinth case series because of the lead author, it's Dr. Brinth. And they reported cases of POTS occurring after HPV vaccination. Now they were careful in the paper to say, hey, this doesn't mean there's a causal link there, right? Because it's just case reports.

But of course it got picked up in the media and sensationalized. Oh, no, no. Yeah, there was a 2015 documentary in Denmark called The Vaccinated Girls, Sick and Abandoned.

[Regina]
They were tugging at the heartstrings.

[Kristin] (1:06:29 - 1:06:41)
A little dramatic there, yes.

And Regina, I want to say case reports, case series, they are very important, but they remind me a lot of that VAERS database that we talked about earlier.

[Regina] (1:06:41 - 1:06:45)
Right, the starting point. So did people follow up with rigorous studies like they're supposed to?

[Kristin] (1:06:46 - 1:06:56)
Absolutely. There have been a ton of large, well-done studies. There were several studies published in 2017 and 2020 that used health data from Sweden, Denmark, and Norway.

[Regina] (1:06:57 - 1:07:01)
Hmm, all of which have great national health data.

[Kristin] (1:07:01 - 1:07:21)
Right, so it's actually easy to track both vaccination status and disease status. And they looked at millions of girls. They found no difference between vaccinated and unvaccinated in the rate of POTS, chronic fatigue syndrome, complex regional pain syndrome, and also another thing that had popped up in some case reports, premature ovarian failure.

[Regina] (1:07:21 - 1:07:27)
Because all of these things, unfortunately, do happen in the background, even without a vaccine.

[Kristin] (1:07:27 - 1:07:37)
They do. For example, POTS affects a few million Americans. And Regina, do you want to guess what group has the highest incidence of POTS in the US?

And I'm just going to give you one guess.

[Regina] (1:07:38 - 1:07:44)
Oh no, not again. Okay, teenage girls, we love you, but things happen.

[Kristin] (1:07:44 - 1:08:18)
Yeah, it just happens to be that POTS strikes teenage girls with the highest incidence. So of course, that means that sometimes these kinds of diseases, like POTS, are going to occur coincidentally after an HPV shot. Actually, an interesting study in 2016, they followed up in Denmark with some of the girls who had been complaining of these symptoms after an HPV shot.

They compared those cases to controls who were similar in age, but weren't having these symptoms. And interestingly, Regina, they found that the cases, compared with the controls, had spent more time at doctor's offices before they got the HPV shot.

[Regina] (1:08:19 - 1:08:32)
So that hints that maybe they already had health problems before the vaccine. What about Japan and Denmark? How did they respond to these, what did you call them, diffuse national panics?

[Kristin] (1:08:32 - 1:08:56)
They responded very differently, actually. In 2013, Japan's Ministry of Health stopped recommending the HPV vaccine. So vaccination coverage dropped.

It was over at 70%. It dropped to less than 1%. And it remained under 1% for years because Japan did not start recommending the vaccine again until 2022.

Vaccination rates are still only around 20%.

[Regina] (1:08:56 - 1:08:56)
Wow.

[Kristin] (1:08:57 - 1:09:09)
And we're talking about modeling studies today, Regina. There was a modeling study that estimated that those missed vaccines since 2013 are going to eventually lead to over 5,000 cervical cancer deaths in Japan.

[Regina] (1:09:09 - 1:09:15)
So it is not hyperbolic to say vaccine hesitancy actually kills.

[Kristin] (1:09:15 - 1:10:12)
Yeah, I mean, actually we're seeing that now, right? In the United States, children dying of measles.

[Regina]
What about Denmark?

[Kristin]
So in Denmark, there was a quick plummet after that documentary aired, but the government there came back, launched a national information campaign, got vaccination rates back up. There were about 25,000, they estimate, girls that missed out on vaccination, but still not nearly as bad as Japan. Regina, the last thing I want to mention here is there was a recent wave of HPV vaccine lawsuits that were dismissed.

You might've heard about it in the news.

[Regina]
I have.

[Kristin]
There were about 200 cases that were consolidated in federal court.

The plaintiffs alleged that Merck, this is the maker of the vaccine Gardasil, failed to warn about risks like POTS and premature ovarian failure. But the judge threw this out of court. He said, no scientist could reasonably conclude there is a causal association between POTS and premature ovarian failure and Gardasil based on this paucity of evidence.

[Regina] (1:10:12 - 1:10:22)
Ooh, paucity of evidence. I love that phrase. Apparently he was unimpressed.

[Kristin]
And with good reason. Yeah.

[Regina] (1:10:22 - 1:10:37)
Was this the one that Bobby Kennedy Jr. was involved with?

[Kristin]
Yes. Before becoming secretary of health and human services, he helped organize these lawsuits.

And Regina, he made close to a million dollars referring clients to law firms for these lawsuits.

[Regina] (1:10:37 - 1:10:44)
You are kidding. People are making money off of vaccine hesitancy.

[Kristin] (1:10:44 - 1:10:58)
They are. And you don't think about that, right? But that is a great incentive to bend the truth.

Regina, I actually went ahead and read one of the lawsuits out of curiosity. I'm going to share a few of their arguments because let's just say they were thinner than the plot of a bad porn movie.

[Regina] (1:11:02 - 1:11:05)
A bad porn movie? Kristin, how would you know?

[Kristin] (1:11:05 - 1:11:18)
Actually, I don't. Okay, little confession here. You're funnier than me. So I was trying to find a joke. So I went to Chat GPT and asked for a joke. That's what I got, which I thought wasn't bad.

And along the lines of the theme of our podcast.

[Regina] (1:11:19 - 1:11:28)
Yeah, it is. And Chat GPT is funny. I am laughing.

All right, thinner than the plot of a bad porn movie. Take it away.

[Kristin] (1:11:28 - 1:11:40)
Okay, so here's just a few of the arguments. One argument was that we shouldn't be vaccinating teenagers because cervical cancer deaths, the median age in the U.S. is not until 58 years old.

[Regina] (1:11:41 - 1:11:43)
Are they missing the biology here at the end?

[Kristin] (1:11:43 - 1:11:44)
Oh, biology. Who needs biology?

[Regina] (1:11:44 - 1:11:55)
Okay, you need to vaccinate before the infection, which means before you start having sex, not after the person is already old and infected and dead.

[Kristin] (1:11:56 - 1:12:18)
That's right, yeah. Remember there was that one modeling study I talked about. They estimated that half of the infections that cause cancer are actually acquired before age 21.

So you cannot wait until age 58 to vaccinate. So that's a very specious argument. Another argument they make, they cite the mass psychogenic illness outbreak in Columbia as evidence of a vaccine defect.

[Regina] (1:12:19 - 1:12:29)
Oh, wait a minute. One where they had the girls and it was on social media and the videos of them twitching, they called that evidence?

[Kristin]
They cite that as evidence, yeah.

[Regina]
Okay, ridiculous.

[Kristin] (1:12:29 - 1:12:39)
The lawsuits were kind of ridiculous. Throwing everything at the wall, hoping something would stick.

Fortunately, the judge was savvy enough to recognize the, quote, paucity of evidence.

[Regina] (1:12:39 - 1:13:15)
Kristin, I think we are now ready to wrap things up and rate our claim. Claim today is that cervical cancer will be eradicated in most of the world by the end of this century. And we are going to evaluate this claim, rate it with our very scientific smooch rating scale.

One to five smooches. One smooch means little to no evidence. Five means a lot of strong evidence for this claim.

So, Kristin, kiss it or diss it. What do you say?

[Kristin] (1:13:15 - 1:13:41)
Regina, I'm gonna go with four smooches on this one. I really want this one to be true, so I may be biased. But, I mean, the modeling studies we looked at did project that if we can scale up vaccination, big if, I realize, that in a lot of the world, we could eradicate cervical cancer by the end of the century.

Of course, vaccine hesitancy is a really sticky, hard problem. So, maybe I am overestimating humans here. Regina, how about you?

[Regina] (1:13:41 - 1:14:24)
You know what? I think I am going to go with 3.67 smooches. Three and two-thirds.

[Kristin]
Very precise.

[Regina]
It makes it seem like I calculated it, doesn't it? Instead of just pulling it out of my butt.

Yes, three and two-thirds smooches. I'm not quite as optimistic as you are, and that's just because people. I think that people, once you get people and sex together, they're gonna mess it up somehow.

So, I think eventually, though, I can picture cervical cancer being one of these old-fashioned diseases that people read about in a history textbook.

[Kristin] (1:14:24 - 1:14:45)
We'll see how it plays out. The good thing about my claim also, Regina, is that nobody can say that we're wrong for a really long time.

[Regina]
And what about methodological morals?

[Kristin]
All right, here's mine, Regina. Case reports are medicine's equivalent to see something, say something. They call for hard data, not hysteria.

[Regina] (1:14:45 - 1:15:17)
Ooh, I love that, actually. I decided to go after the Markov model.

[Kristin]
Oh, good.

[Regina]
Angle, yeah. So, how about this one? When reality is too complex to test, let micro-stimulations do the rest.

[Kristin]
Oh, I love that. I think you should get a bonus point for rhyming. We haven't been trying to rhyme these, but what a challenge.

[Regina]
It's not going to win any poetry prizes, but, you know, it has micro-stimulation in there, which just automatically makes it cooler.

[Kristin] (1:15:17 - 1:15:25)
Somebody should write a poem about micro-stimulations. I'm gonna throw it out there as a listener challenge. Send us a poem about micro-stimulations.

[Regina] (1:15:25 - 1:15:46)
Very nice. And remember, we love comments. Go to normalcurves.com.

Let us know if you have any questions, comments, feedback, normalcurves.com. Kristin, this has been fascinating and quite a journey because we have gone all over the world and traveled in time. So, thank you again, and thank you listeners.

[Kristin] (1:15:47 - 1:15:48)
Yeah, thanks everyone, and thank you, Regina.