Excerpt from research paper - vaccinating older women - Discussion - National Cervical Cancer and HPV Coalition Support Community

The attached is from a research study entitled, "Prevaccination Distribution of Human PapillomavirusTypes in Women Attending at Cervical Cancer Screening in Belgium." You can google to find the abstract and if you e-mail the contact highlighted in the abstract, that person will send you a complete text copy of the study.

In this paper, there's a discussion about vaccination of older women which essentially says that if a woman is seropositive (has antibodies to HPV indicating prior infection), but is HPV DNA negative (meaning that they're testing negative for an active infection), that, theoretically, the vaccine might protect against future exposure. This indicates to me that the question about whether the vaccine can prevent reinfection from the same virus type after clearance is an open issue.

We know that the vaccine has not been effective in clearing an active infection (clearing the virus from cells that are already infected). But, in my view, it seems like, theoretically, the vaccine could prevent infection in new spots, such as orally, where it's possible a person isn't yet exposed. That's not discussed here, and I haven't seen that discussion anywhere.

But here's the quote from this study on vaccination of previously exposed women:

"Wide consensus exists among vaccinologists and immunologists that HPV DNA negativity in sexually inexperienced girls or young women corresponds with a high probability of protection offered by HPV vaccination. Seropositive but HPV DNA–negative women seem to be protected as well, but observations are based on too small sample sizes to be conclusive. No data are available on the risk of HPV-induced disease in women that havecleared a prior infection. It would be interesting to assess
differences in risk and protective effect of vaccination in HPV DNA–negative women who were previously HPV DNA positive and those who were previously HPV DNA negative. This could be done by HPV DNA testing on archived smears from cytology biobanks. For instance, one could look for previous smears stored in laboratories taken from women who were DNA negative and seronegative for the vaccine types at enrollment in the trials. Then, one could distinguish HPV16/18 experienced (archived smear positive for HPV16/18) from inexperienced women (archived smear negative for HPV16/18). If this could not be done for women enrolled in a phase III trial, a new prospective study could be set up. If such a study would reveal no difference in risk and protection, an argument for vaccinating older women would be provided. In the absence of this, we cannot reject the hypothesis that HPV DNA–negative women having cleared the virus have sufficient cellular immunity and do not need vaccination anymore."

By Pirkar
Posted April 1, 2009 at 3:59 pm
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Thanks a lot. I will try to get the article also. FYI, in Estonia, lots of social adds, recommendations by resoected gyns in magazines and internet, and even during personal appointment in clinics, do highly recommend vacciantion for HPV DNA negative older women, who have definitely been infected before. All this social campaing to propagate the vaccine to women over 26 is made publicly, with the approval of our gyn unions, medical administrations etc. So my question is - if there is so little info on the positive effect of the vaccine for HVP DNA negative, HPV seropositive women, and moreover, if it is not known if the vaccine is safe for them as this study says, how can all these respected gyns in my country highly recommend vaccination? I wonder if they know some other reserach results which we are not aware of, or if they will just get nice bonus from the drug companies selling the vaccine..

By corellin
Posted April 1, 2009 at 8:26 pm
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Good question, Pirkar! I wonder who pays for the vaccine in your country and whether it's as expensive as it is in our country? But, in a way, it's great that there's such widespread advertising, because I'm sure it leads to better overall vaccination of the population. Have they been vaccinating men or boys yet?

By chocoholic
Posted April 2, 2009 at 11:09 am
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Hi Corellin and Pirkar,

I wish in the UK there were any recognition of HPV. No one knows about it, no one talks about it. Our healtcare system does not want to fund it. According to the NHS website, research on the topic (whether or not testing is financially viable and could save more lives - can you believe they are even asking this) was due to be published autumn 2008, but currently there is only silence. When I asked my consultant if I am HPV positive and which strain, I received the answer that as I have cancer I am likely to be HPV positive, but it's not something that is tested for. And was told the HPV vaccine would not be beneficial, as I'm already infected. But surely it might suppress other variations of HPV (there are over 100) - and as Corellin mention, could protect from types of cancer not contracted (oral cancers). And blimey, what about our men? Conclusive HPV testing for men does not exist - and awareness is zero.
Thanks for this post. Good to know many of you are asking the same questions. What can we do?

By corellin
Posted April 2, 2009 at 3:11 pm
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Hi chocoholic,
Wow! So, no HPV testing is available at all in the UK? I understand your frustration.
I think we can start by being vocal about our experience -- sharing with the people we know and expressing our thoughts, feelings & needs to our health care providers in the hopes of influencing protocol & policy.

By Pirkar
Posted April 25, 2009 at 8:31 am
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Hi, there is no free access to this research article, but according to the abstract, the efficacy of HPV vaccine has been proved up till age 45. This is the first time I came across a claim that there is a proof for vaccination of older women.

Human Papillomavirus
Vaccines for Biodefense and Emerging and Neglected Diseases, 2009, Pages 469-496
William Bonnez

Summary

Abstract
Human papillomaviruses (HPVs) include over 100 different genotypes that infect the stratified squamous epithelia and may cause proliferative lesions. Some of the HPVs are responsible for cutaneous warts, while one subset of HPVs is found in the skin lesions of epidermodysplasia verruciformis, a condition that leads to the development of cutaneous squamous cell carcinomas. A third subset of HPVs is associated with infections that can cause benign, premalignant, and malignant lesions not only of the genital tract, the anus, but also of the oropharynx. These lesions include external genital warts, intraepithelial neoplasias of the penis (PIN), anus (AIN), vulva (VIN), vagina (VAIN), and cervix (CIN), as well as cancer of the cervix. Cervical cancer is the second most commonly acquired cancer in women worldwide. This significant disease burden explains the great importance of genital (or mucosal) HPVs. The availability since 2006 of highly effective vaccines to prevent a large fraction of these morbidities has been a major advance whose promises are growing. The two vaccines available, Gardasil and Cervarix, are based on the expression of the major viral capsid protein in yeast or insect cells, and the spontaneous assembly of this protein into a noninfectious capsid called a virus-like particle (VLP), because it retains the appearance, size, and immunologic properties of the native, infectious viral particle.

Gardasil is made of the VLPs of HPV types 6 and 11 that account for 90 of external genital warts, and of HPV types 16 and 18 that account for over 70% of cervical cancers worldwide. Cervarix is a bivalent vaccine that includes only HPV VLP of types 16 and 18. Trials have shown that these vaccines protect virtually 100% of the subjects against the immediate precursor to cancer, high-grade CIN, caused by the vaccine HPV types the subjects are naive to. Gardasil has received indications in the United States not only for the prevention in 9–26-year-old women of cervical cancer and CIN of all grades, but also for the prevention of VIN and VAIN grades 2 and 3, as well as of external genital warts. The most effective use of the vaccine is when administered before sexual debut, at a time the subject is naive for the infections caused by the HPV types included in the vaccine. The efficacy of the HPV vaccine has now been demonstrated up to the age of 45 years in women. Trials in men for the prevention of external genital warts are in progress, and could serve as a basis for the immunization of both males and females. The HPV vaccine, especially when it covers a broad range of viral types, holds the promise of not only affecting cervical cancer and its screening, but also of reducing the burden of the other cancers attributable to HPV, such as those of the vulva, vagina, penis, and anus, as well as a majority of oropharyngeal cancers. To attain these goals, maintenance of safety, favorable cost–benefit ratios, and broad delivery and accessibility of the vaccine will need to be achieved.

By corellin
Posted April 25, 2009 at 11:37 am
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Thanks, Pirkar! Also, Merck's study on Gardasil in women over 26 should be completed sometime this year and a new application made to the FDA to approve the vaccine for older women. I hope they release data along with their recommendations.

By rj_4320116
Posted September 16, 2009 at 6:34 pm
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Hi Corellin,

I've been reading your posts regarding HPV's natural history and clearance tendencies for a while now. Very helpful and thought-provoking stuff.

Given all this (and despite all the uncertainties), if there is no known HARM from older women getting the vaccine, which I think is a fair assumption because if Merck/GSK are testing in women up to 45 - (for whom it is safe to assume 90+% would have been exposed to some HPV at some point in their life) - then I think it is safe to say getting vaccinated despite having been previously infected is at least NOT HARMFUL. So then, no harm in getting it, once we are able to clear an existing infection, right? (besides any out of pocket costs incurred)

I am 31 and recently got infected - I know it is hard to tell when exactly, but I had vaginal sex for the first time in my life 10 months ago (have had a very conservative sexual upbringing), with my current bf. I've also been getting paps since 25 and have never had an abnormal one until last month, so its very likely my infection is 8-10 months old. Also, my recent exam revealed I have warts, VIN-III and LGSIL on my last pap. Very upsetting

So now I am scheduled for painful surgery on my vulva (local excision and laser), and will either have LEEP done at the same time or take a "watch and wait" approach based on biopsy results I am awaiting (i.e. whether my LGSIL pap is confirmed as CIN-I or is actually something more serious).

After all my treatments, praying that I don't have any recurrences (my readings suggest that VIN tends to recur more often than CIN) and if I somehow manage to clear my current infection (for which I lose hope at times), I'm at this point leaning towards vaccination to aid my body in preventing a potential reinfection. I recognize that cells already infected - whether dormantly or actively - can't be helped but if it can prevent spread to other areas (anal, oral, even other cells in my cervix or vulva), isn't that helpful?

By rj_4320116
Posted September 16, 2009 at 7:02 pm
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Also just came across another research paper that concludes that 15% of the women enrolled in Gardasil's Phase III trail actually were seropositive but DNA negative for one or more of the strains covered by the vaccine, and results appeared to help protect them against reinfection.

Conclusion from the study abstract states:

"These results suggest that natural HPV infection-elicited antibodies may not provide complete protection over time, however the immune response to the HPV 6/11/16/18 vaccine appears to prevent reinfection or reactivation of disease with vaccine HPV types. Vaccine-related adverse experiences were higher among subjects receiving vaccine, mostly due to increased injection site adverse experiences. "

I didn't, but you can purchase the full paper for $19 here: http://www.landesbioscience.com/journals/vaccines/article/9515

-RJ

By rj_4320116
Posted September 16, 2009 at 7:13 pm
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And one more, from the CDC (when you start digging, there's a lot of research out there :))

Efficacy in Females with Current or Previous Vaccine HPV-Type Infection

"Because participants were enrolled into the clinical trials even if they were HPV DNA or antibody positive, evaluating efficacy in females infected with a vaccine HPV type at the time of vaccination was possible. Overall, 27% of the study population had evidence of previous exposure to or infection with a vaccine HPV type. Among these participants, 74% were positive to only one vaccine HPV type and did not have evidence of infection with the other three types. Among participants positive to one or more vaccine HPV types, the vaccine had high efficacy for prevention of disease caused by the remaining vaccine HPV types (112).

The vaccine's impact on the course of infection present at the time of infection was evaluated using data from four clinical studies (protocols 005, 007, 013, and 015). Three different groups were analyzed on the basis of antibody and HPV DNA detection at the time of vaccination (Table 5). Among persons seropositive to the relevant HPV type but HPV DNA negative, efficacy against CIN 2/3 or AIS caused by that type was 100% (CI = -63.6%--100%). Among women who were HPV DNA positive but seronegative, efficacy was 31.2% (CI = -4.5--54.9). Among women who were both seropostive and HPV DNA positive, efficacy against CIN 2/3 caused by that type was -25.8% (CI = -76.4%--10.1%). Because of the small numbers and wide confidence intervals around efficacy estimates, limited conclusions can be drawn from these estimates."

You can read the full report here: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5602a1.htm

By rj_4320116
Posted September 16, 2009 at 7:26 pm
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Lastly, a site indicating that perhaps the potential risk from vaccination if already previously infected is higher than we think (which is potentially very scary, and would be a BIG problem if they approve this vaccine for women upto 45, without mandating testing of seropositivity):

FDA documents reveal HPV vaccine may increase your risk of cancer if you already have HPV. In trials, Gardasil increased risk by 44.6% of developing high-grade precancerous lesions in women who are already sero-positive and PCR-positive for vaccine-relevant genotypes of HPV. However, pre-screening for HPV infections has not been included in the vaccination program.
See:
“VRAN HPV Vaccine Analysis” by Susan Fletcher, 2008-07-31, PDF 62kb
“Gardasil—my error is the smoking gun” by Cynthia A. Janak, RenewAmerica.us, 2007-12-11
FDA Reclassification Petition “07p-0210-ccp0001-01-vol1″, PDF

http://vran.org/in-the-news/hpv-human-papilloma-virus-cervical-cancer-vacci ne-mercks-gardasil%C2%AE/

By corellin
Posted September 16, 2009 at 8:15 pm
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Hi rj 4320116, I feel just sick and sad about your situation. So very not fair that you waited all that time to have sex and then almost immediately developed disease from HPV. I'm so sorry to hear about your situation.

I actually called the head of the Merck vaccine program and talked to him about the above study. The participants weren't randomized and were not equal in the degree of CIN they had when entering the trial. The group that showed 44.6% higher risk actually started with higher grades of CIN at the beginning of the trial. Another group that was more equal in their beginning status showed more equal results. There was another trial that matched women who had CIN and who received the vaccine against those who didn't and there was virtually no difference in outcomes.

There was some talk at the International Papillomavirus conference that for recurrent types of HPV disease -- like VIN or venereal warts or even the respiratory papillomas that kids can get from moms who have HPV's 6 or 11 -- that maybe Gardasil could actually act as a therapeutic vaccine by preventing infection from spreading to new places. That was speculation by some clinicians. There haven't been any trials that I know of to support that.

But...there was a study of young men who took Gardasil and the results were really interesting. Unlike the women, who demonstrated almost no positive HPV tests, the men actually had a surprisingly high percentage test positive for a vaccine type after taking the vaccine, but the vaccine prevented "persistent" infection and development of disease. That's just so surprising. The study authors suggested that perhaps the positive HPV test represented "contamination" rather than a true infection or perhaps the participants actually had been infected prior to receiving the vaccine -- but what's amazing to me is that they still test positive, but then didn't develop persistent disease which almost suggests that there's a stage where a person may be testing positive, but HPV isn't established yet. And that would suggest that some of those 80% of women supposedly infected with HPV at least once in their lifetime perhaps didn't get a true infection or got an infection that didn't permanently establish itself in the basal cell layer meaning there may be such a thing as true clearance (complete clearance) or perhaps there's such a thing as not a real infection. And, I wonder what that says about infectiousness. Were those young men who briefly tested positive for HPV contagious at that time? It will be interesting to see what future studies say and whether the results are similar or whether the results of that study were just an anomaly.

If I were you, given VIN, I would just get the vaccine, though. It may stimulate an immune response that might prevent infection in new places or might even cause spontaneous remission of the existing VIN -- who knows. The other studies where Gardasil didn't help were on CIN, which is different, because it infects a different type of cells and maybe HPV acts differently in those cells.

Here's a study I found on VIN where one person had spontaneous regression of VIN after developing an immune response. But it's interesting because it describes the immune response in some detail. The difficulty with HPV is targeting the immune response at the right spot in the right cells because sometimes an immune response is generated but it doesn't go to the right place and so it doesn't do any good. (OK -- that's my basic stab at trying to recap what I thought I heard at the papillomavirus conference, but a lot of it was way, way, way technical and over my head and I may have misunderstood.)

http://cancerres.aacrjournals.org/cgi/reprint/64/23/8761
spontaneous regression VIN

Thanks for posting all those links. I just love the amount of work people are doing on this site to research and share information. Sure, we may not have gone to school for this stuff, but we sure are personally motivated to find answers (plus we have personal, real world experience) and I think that might actually give us a bit of an edge in some respects.

Good luck to you!

By corellin
Posted September 16, 2009 at 8:32 pm
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Oh my goodness, check this out!! I decided to google "cervarix clerance VIN":

http://content.karger.com/ProdukteDB/produkte.asp?Aktion=ShowFulltext&Artik elNr=214922&Ausgabe=248740&ProduktNr=224224

Am I reading this correctly that the vaccines could potentially prevent infection in new places? I just wrote the author and I'm hoping she will clarify or perhaps clarification will be in the full text of the article, which I've requested from her.

Here's the quote:
"Neither vaccine will inhibit an already HPV-infected basal epithelial cell which continues to transform differentiated epithelial layers into cervical dysplasias. There is a clinical hope, though, already supported by early data, that the vaccines are capable of neutralizing HPV virions in host tissues from both auto-inoculated infections and infections in other organs than the cervix, thereby making it possible for these vaccines to prevent less common HPV-associated cancers of the penis, vagina, vulva, anus, oral cavity and oro-pharynx."

By rj_4320116
Posted September 16, 2009 at 11:26 pm
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Thanks, Corellin!

Since my diagnosis (about a month ago) I've become obsessed with researching this stuff and thought I'd tried just about every search key word permutation for Google possible, but guess not!

Very interesting indeed! It pretty much matches what our own logic led us to speculate on, which is very intresting! I'm curious and anxious to hear what the author has to say to you!

Thanks also for sharing what you found from contacting Merck about the negative study I referenced above. That Canadian website sounded a bit suspect / biased to me based on some of there other bullet-points there, but still a bit unnerving to read such things, if I'm considering taking the vaccine after having been infected (even moreso now based on this latest article you posted).

I understand that they had to get Gardasil out as a prevantative vaccine as soon as it was ready to market, but if this proves to be true, I'm sure we'll see a second wind of advertising from Merck, as Gardasil is also marketed to prevent warts and this is essentially saying it could prevent recurrences of warts in already infected patients, which kind of slips through the cracks in all the current marketing which centers around the (i) "its only preventative" and (ii) "it isn't therapeutic on existing infections" statements, leaving out the middleground of impact on other "not yet infected" cells in the host's body...

As for my personal situation - yes, I really think I drew the short stick on this one, waiting so long to have sex and then getting "rewarded" with this crap. I was very very upset in the days following my diagnosis, but feel as though I'm starting to get over it a bit and able to focus on what I need to do now to treat it.

The one bright spot in all this I guess, is that my bf has been very sweet and supportive, which I think anyone should be but I've seen and heard that to not always be the case, unfortunately. He also feels terrible about his role in this - keeps saying its "his fault" and had he told me about his one wart 18 months ago maybe I would have taken Gardasil before we got together (which is true, but he didn't do it in malice, he was like the millions of others who don't think much of HPV, expect that they've cleared it if they never saw a recurrence and are encouraged in this line of thinking by their docs), so I don't blame him that way and am happy that he's been so supportive.

He is also very nervous right now about PIN (though its very rare), as his warts just recurred about 18 months since his first and last episode, and then the shock of my VIN crap on top of it. So he is getting an appt with a urologist to swab his penis and perform some biopsies.

The question of whether or not he should get Gardasil (once its approved for men) is an interesting one to think about in light of what you posted previously about the way it worked on men, as well as above. Also, he has two autoimmune conditions (psoriasis and psoriatic arthritis) - fairly mild symptoms, but he's had them for years and recently started taking HUMIRA (a TNF-inhibiting drug), which I've wondered if that had something to do with reactivating his older infection(s), which in turn also had an impact on me. He's since stopped taking it, after consulting with his rheumatologist. Since you've done a lot of research on HPV, I'd be curious to hear your opinions on this.

Another place where I got lucky (despite all the overall unluckiness) is that my VIN got diagnosed pretty quickly as my gyn decided to biopsy right off the bat. I have since seen that VIN is often grossly misdiagnosed, with even practicing gyn's so appallingly ignorant about it, and sending women home with yeast infection or rash creams for years. Even my own gyn, though making the right call in choosing to biopsy, was disappointingly unaware of the best way to truly treat it (saying just removing any "bumps" would be sufficient, when in fact VIN can often be asymptomatic and any cells that show up white in the vinegar wash should be treated) and she didn't even refer me to a Gyn-Onc (I referred myself), which I've since learned is best practice for people with VIN.

Oh well, I guess life is about rolling with the punches. For now, I think the best plan of action for me should be to go ahead with my VIN surgery (scheduled for next Monday - not looking forward to it at all, I hear recovery is quite painful) to treat my existing bad cells, and then perhaps ask for the Gardasil vaccine after I've healed.

I did ask my Gyn-Onc if she'd heard of any potential benefit in getting vaccinated even if already infected, but she stuck with the standard rhetoric, "no, it has no therapeutic effect on previously infected people."

As you said (and I agree), I think we actually know more than most docs on this issue - I certainly feel like I do. My doc is a Gyn-Onc surgeon and is great at her skill of performing surgeries on women with cancer and precancer, but that doesn't mean she's up to date on every single piece of research out there on HPV - I have a greater incentive to scour the web for that, so I have no problems printing this and other studies out to show her and discuss a potential case for letting me have Gardasil.

Thanks again, Corellin. That study was one of the most hope-inspiring ones I've come across in a while! Without getting ahead of myself, I look forward to hearing how the author responds to you.

-RJ

PS - I've also created a table with the 5-6 therapeutic vaccines in development now, what they're called, what stage of clinical trials they're in, etc. You prob know of all of them already as well, but let me know if you're interested in a tabular summary nonetheless and I'd be happy to email it to you.

By rj_4320116
Posted September 17, 2009 at 1:02 am
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Okay, last one before I turn in for the night :)

Here's a paper from Dr. Ian Frazer (one of the scientists behind Gardasil) in the International Journal of OBGYN, 2006.

It explains the same old thing about how the preventative vaccines induce a humoral immune response against the L1 proteins that the free virions have, but does not have any impact once the virus has begun binding into host cells and now has capsid E6/E7 proteins, thus requiring natural clearance of HPV infection to be initiated at the cellular level. (This is why most therapeutic vaccines in development are trying to figure out how to induce a cell-mediated immune response specifically against E6/E7 proteins).

But, what was interesting, is his take on what we've been asking for months - would it not potentially protect against "spreading" (autoinoculation) to new areas in the body, via the free virons? I'm starting to be more and more convinced the answer could be yes (obviously acknowledging that I'm not a professional microbiologist (although at this point prob an amateur one :)).

The question I still have is, how often does that really occur? Or, once the virus has lodged itself into your basal epithelial cells, it only "spreads" through some unknown mechanism from cell-to-cell, always coated with the E6/E7 proteins and never again travels as a free virion coated with L1/L2 proteins?

Anywhere, here's the interesting quote:

"As virus-infected cells do not display conformationally correct viral capsid proteins, it is likely that the current vaccines will have little effect on existing HPV infection. It may be, however, that the
induced antibodies may reduce the infectiousness
of lesions already shedding HPV virions, either for
other anatomical sites in the infected individual or
for recipients of the infection."

That's all for tonight from me, good night friends!

-RJ

By corellin
Posted September 17, 2009 at 1:12 am
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Yes -- very interested (in the table) - and, no, I'm really not that up on the therapeutic vaccines!! I love your attitude toward all of this -- seems like you're approaching it with a good amount of common sense and a positive, take charge attitude. I'm so glad to hear your boyfriend is supportive. I also really appreciate the way you're taking an organized approach to your research.

So, I'm just really surprised that the HPV infection progressed to VIN3 in such a short period of time. I just posted something on VIN3 in response to another person where sometimes an LGSIL pap is really just VIN3 cells that migrated up and contaminated the cervix, so maybe they'll find the cervix is OK.

Are they sure it's VIN3 and could that arise from venereal warts, or do they think there's high risk HPV as well? I'm wondering what's the benefit to treating so quickly rather than giving time for your immune response to kick in. I know you've done a lot of research on this, so I'm wondering what you've found.
Thanks!

By corellin
Posted September 17, 2009 at 1:53 am
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Oh -- I just now read your other two posts above -- & thanks so much for that link from Ian Frazer. It's interesting how he talked about the vaccine possibly limiting the action of the virus itself rather than the antibody response of the woman protecting her from infection in new places. I think I'm missing something... (in terms of how the vaccine works).

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Excerpt from research paper - vaccinating older women

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