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103 Issue 19 Franco Transcript

Zach Rathner: Hello, and welcome to the Journal of the National Cancer Institute’s audio interviews. In each issue we invite an important figure in cancer research to sit down and talk with us about specific cancer issues and in a brief but informative Q and A segment. HPV infection is the main cause of cervical cancer; however, most women infected with HPV do not have cervical pathology, and most HPV infections in women under the age of 25 go away. A JNCI study recently examined the effectiveness of the HPV vaccine in its prevention of cervical cancer. I recently spoke with Eduardo Franco, a professor in the departments of Oncology and Epidemiology and Biostatistics at McGill University and the Faculty of Medicine in Montreal, Canada. Professor Franco, first off, can you explain the relationship between HPV and cervical cancer?

Eduardo Franco: Well, HPV infection is a very common virus, but in the past 20 years or so there has been tremendous amount of research that has conclusively shown that infection by this virus and certain genotypes, as we call it, of HPV are the root cause and central cause of cervical cancer, and as we keep on discovering now as a community of more additional types of cancer that are HPV-related, but cervical cancer is the one that in which HPV seems to be so important to the point of being a necessary cause. We have gotten to the point where we can conclusively say that a woman would not develop cervical cancer if it were not for a pathway initiated by HPV infection.

Zach Rathner: So what can you tell me about the new findings in this vaccine? How effective is it?

Eduardo Franco: There are two available vaccines. There are more or less many similarities in terms of how they were developed. They essentially-- they cast the envelope of the virus without the DNA content. HPV is what you call a DNA virus. It cannot be grown in culture, so the traditional method that-- used in the past with other vaccines cannot be used with HPV, so the whole casting of the virus has to be engineered via very sophisticated techniques of molecular recombination, so officially the two vaccines that are available. They’re produced-- there are two different manufacturers. One is Merck pharmaceutical company as produced in a vaccine that’s quadrivalent as immunogenic properties against four types of HPV, two of them the most important ones as cause of cervical cancer, [inaudible] 16 and 18, most types, but that vaccines also includes immunogens for two HPV types, HPV 6 and 11, which cause benign lesions such as genital warts, also respiratory [ph?] [inaudible], which is the latitude that they are responsible for a great deal of suffering in terms of disease, and these are STIs in the case of [inaudible] genital warts and causes [inaudible] inconvenience and suffering [inaudible] to those affected, but again it’s certainly not the same extent as cervical cancer itself, which is far more serious.

Eduardo Franco: There’s also another manufacturer that’s GlaxoSmithKline, which has gone through the motions producing their bivalent [ph?] vaccine that focuses primarily on HPV 16 and 18, the 2 genotypes that responsible for vast majority of cervical cancers, so it’s actually these are-- the similarities are both capsule-based vaccines. We call them VLP vaccines or virus-like particles, and then there are some differences among them in addition to the valency that Merck having a quadrivalent vaccine and GSK having a bivalent vaccine. They’re both very, very potent, and they do what they’re supposed to do in inducing very strong antiviral response against the types that are in the vaccine, and eventually it protective in response, prevent infections against these types, and ultimately, which is the most important thing, you also prevent the lesions that are developed in consequence of these infections.

Zach Rathner: And how were the researchers able to determine that one or two doses of the vaccine were just as effective as the usual amount of three doses?

Eduardo Franco: Originally women came, and they did not know which vaccine they were receiving, but they knew that they were going to receive three doses, but for a variety of reasons, many failed to return for a second dose and third doses, and some failed to come for the third dose, and they had only two doses, so altogether as Dr. Cramer [ph?] and Pauley [ph?] found out that when they looked at the data they had from the nearly 7,500 women who were randomized, they had about 3,000 women per group per arm with placebos [ph?], both of these HPV vaccines and of the placebo vaccine. Interestingly enough there were really 500 of them only had two doses. They failed to come for the third dose, and some nearly 300 women, additional 300 women only came for the first dose, but failed to come for the second and third dose, so they only have one dose of these vaccines. Interestingly enough and luckily enough there was balance because the study was blinded, and there was concealment about intervention [ph?], so the women who failed to come for second or third doses, they did not know which vaccines we were doing, and this at the end assured that the number of non-compliance per group was about the same, so they had more or less well-balanced groups, which allowed them to have validity in the final comparison that they did.

Eduardo Franco: Essentially, when they looked at the doses they looked at the efficacy, but those with the pure intervention among those with two doses, a minimum dose of one dose, that of course does not allow for a lot of statistical precision, but still they were able to conclude, and they were quite striking. They ended up with a serendipitous arrangement here which allowed them to examine the question of whether fewer than three doses would provide protection, and this is what the office set out to do, to take advantage of the fact that there were quite a few women paid to get three doses. They found that the models who had three doses the way they were supposed to be, they had about 6,000 women who did the full set of procedures, and they were looking for something that would be indicative of whether the vaccine was working or not, which was to prevent something that we know is a good intermediate biological end point for cervical cancer, which is HPV persistence, so when they looked at the proportion of women who developed a new HPV 16 or HPV 18 infection that’s persistent or at least eight-- 12 months, they found that among those who took all three doses of HPV vaccine, there were about 3,000; 55 women developed such infection.

Eduardo Franco: Now, in the control group there were 133 women. For the number of women, there were 3,000 women, but 133 developed-- so when you take into account these proportions and rates of women in both groups, and you calculate what proportion that the vaccine-- proportion of these persistent infections the vaccine prevented, it turns out to be about 81 percent, and the other group, the control group, there’s 17 of them. If you calculate again same differences in rates here and establish that as a percentage for efficacy, the result of the investigated drug was 84 percent. When you look at the context [ph?] boundaries here for statistical precision, they overlap. It should indicate that there’s a statistical tie here between what they found with three doses, which is the way it should have been done, and as good as those with two doses, and then they looked at the group that received only one dose of the vaccine. These are women who failed to come for the second and third doses. There were about 200 of these women, and there were 0, no women at all in the one with the vaccinated the single dose of vaccine, and there were 10 of those in the group that did the control vaccine, so altogether that indicated that whether the women used three doses or one dose, the protection given by the vaccine was just about the same.

Zach Rathner: What are the challenges of introducing these vaccines in developing countries?

Eduardo Franco: One of the [inaudible] for developing countries is that bringing the vaccine to the people, to the women who need it the most is always a change. Eventually science would be strong enough to show that fewer than three doses would be sufficient. The problems of [inaudible] often the vaccinations [inaudible] instead of doing zero, two, and six months they have often where zero, six months, and five years. In other words they delay the second dose to six months, and eventually they delay the third dose to five years, and they began vaccination a little earlier. Instead of vaccinating 13 and 14-year-olds, they’re vaccinating 9 to 11-year-olds hoping that by the time these 9 and 11-year-olds receive the second dose they’ll be fully protected. By the time they’re ready to be vaccinated with the third dose five years later the scientific knowledge will be such that they perhaps will be able to buy that and skip that third dose, reserve for them for five years. The important price is for countries who have trouble-- I mean Mexico is middle resource country that of course struggles with disparity and reaching remote areas and underprivileged populations, and this would also be true for many countries in Southeast Asia, Sub-Saharan Africa, all the countries that are severely affected by cervical cancer.

Zach Rathner: So it’s a very important need because we spend a whole lot of money to prevent it, so with the HPV vaccine we do better because we can actually prevent the root cause of the [inaudible] with just perhaps even fewer than three doses that [inaudible] indicate and eventually go for decades of protection without having to repeat pap smears every year.


Zach Rathner: That was Professor Eduardo Franco, a professor in the Department of Oncology and Epidemiology and Biostatistics at McGill University’s Faculty in Medicine in Montreal, Canada as well as the director at the Division of Cancer Epidemiology and acting Chair of the Department of Oncology at the university. For a transcript of this podcast or to listen to other JNCI podcasts, please visit us at our website at I’m Zach Rathner. Thanks for listening.

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