How did discoveries made with bovine papillomavirus help scientists develop the human papillomavirus vaccine? Doug Lowy discusses his journey that began with basic research and led to the production of the HPV vaccine.
Julie's Biggest Takeaways
In the early 1950s, the U.S. was a high-incidence country for cervical cancer. Through application of screens using the Pap smear, doctors have been able to catch and excise suspicious tissue, leading to a significant drop in incidence. Cervical cancer remains high-incidence in low- and middle-income countries; in high-incidence countries, cervical cancer is the most common form of HPV-associated cancer. In the U.S., cervical cancer represents around 50% of the HPV-associated cancers, with others like penile, anal, and oropharyngeal cancers also represented.
Henrietta Lacks, the woman from whom HeLa cells were derived, had a cervical adenocarcenoma caused by HPV-16. The viral DNA had integrated near the myc oncogene to generate high expression of this oncogene. The cell lines have been growing for decades but the epigenetic changes from HPV infection have led to a dependence of the cells on E6 and E7; if they are blocked or removed, the HeLa cells undergo apoptosis.
Lowy's work on bovine papilloma virus (BPV) played a key role in development of the HPV vaccine. Other researchers attempting to generate a neutralizing response to the HPV capsid failed, but Lowy and his colleague Reinhard Kirnbauer had successfully achieved neutralization using BPV. By comparing HPV and BPV sequences, Lowy realized there was a single amino acid change in the HPV-16 strain that was being used as a lab standard strain; fixing this restored capsid self-assembly, led to immunogenicity and provided the basis for the HPV vaccine.
HPV L1 capsid protein has a repeating structure that induces a very high level of immune protection. Protection is so high that it is sterilizing, meaning that exposed individuals prevent any infection, not just disease. This may serve as the basis for a new strategy, using repeating structures such as ferretin in vaccine development.
The incubation between infection and development of cancer can take decades, and the vaccine has not been on the market long enough to assess a difference in cancer incidence. It has resulted in a decrease in cervical dysplasia, the endpoints used in cervical cancer screening via pap smear, but no cancer reduction has been observed yet.
"It was really the discovery that the HPV types that cause genital infection are actually distinct from HPV that cause nongenital infection, and then the discovery of HPV-16 and HPV-18, by Harold Zur Hausen and his colleagues that led to the linkage between HPV and cervical cancer."
"Usually the interval between the infection and the development of cancer is many years. We think it's uncommon to occur in less than 10 years and not uncommonly it may take 20 or 30 years."
"If you initiate vaccination after you become sexually active, you're going to end up with a lot of prevalent infection, that is established infection, and [the vaccine] is not going to do anything for that even though it will have an impact on preventing new infection."
"The HPV vaccine has been given to more than 100 million people around the world. When you give something to a large number of people, well, bad things happen to people all the time. It's important to differentiate between coincidence and causality. The HPV vaccine has been scrutinized very carefully, not just in the United States, but in many other countries. There just doesn't seem to be any clear, very serious adverse events….that doesn't mean that one shouldn't be vigilant."
"The important research I've done has been in close collaboration with John Schiller. One of the hallmarks of our research is that we have not been afraid to try new things. For example, we had initially studied the viral oncogenes, but then moved into studying the viral capsid proteins. We had no background in working on the structural viral proteins. We had no background in vaccines. We had no background in immunology. But we weren't afraid to try and to learn as we went along, and to ask people who were more knowledgeable than we were in those areas."
Links for This Episode
- Take the MTM listener survey (thanks!)
- Harold zur Hausen Nobel Prize for association between HPV and cancer
- Lowy D. HPV Vaccination to Prevent Cervical Cancer and Other HPV-Associated Disease: From Basic Science to Effective Interventions. Journal of Clinical Investigation. Jan 2016.
- Schiller J. and Lowy D. Explanations for the High Potency of HPV Prophylactic Vaccines. Vaccine. August 6 2018.
- VAERS Vaccine Adverse Event Reporting System
- ASM Article: A Brief History of Cancer Virology
- JHU Press: Vaccines Did Not Cause Rachel's Autism
History of Microbiology Tidbit
The story I want to cover in today's history of microbiology tidbit is also related to vaccines, however: it's the history of the antivaccine movement.
I think most of you are aware that there are pockets of communities who don't want to vaccinate their children for one reason or another. We discussed this a bit when I spoke to vaccine advocate Peter Hotez, whose new book Vaccines Did Not Cause Rachel's Autism directly addresses the myth that vaccines and autism are somehow related. This myth is tied to the infamous Andrew Wakefield report, long retracted from the Lancet, where it was published in 1999. But anti-vaccination movements existed before the retracted Lancet report—way before that.
This may surprise you, as it did me, when I first saw some historical documents on exhibit at Microbe last year. Every year at Microbe, Jeff Karr, the archivist at the Center for History of Microbiology Archives, puts together an exhibit with materials around a particular theme. Last year, that theme was antivaccination and the documents dated back into the 17 and 1800s. For example, there was a political cartoon from Thomas Gilray titled "The Cow-Pock-or-the wonderful effects of the new inoculation," published in 1802. The cartoon shows a number of people lined up, waiting to receive their inoculation against small pox. Several people who have passed the doctor doing the inoculations and already received it are quite upset, shouting and raising their arms. The cartoon is captioned "A scene in a vaccine institution; poor patients crowd in through a doorway on the left; in the room are those whose treatment has had dire consequences," where Gilray is obviously referring to the melee on the vaccinated side of the picture.
A century later and not much had changed. Another exhibit featured several books railing against the practice of vaccination, including JM Pebbles' "Vaccination: A Curse and a Menace to Personal Liberty with Statistics Showing Its Dangers and Criminality," published in 1900, and HB Anderson's "The Facts Against Compulsory Vaccination," published in 1929.
My favorite was probably a list of questions published in 1856 by CGG Nittinger in the book "Evils of Vaccination," in which CC Schieferdecker lays out some of the questions he believes would-be vaccinators could not answer, with answers in parentheses. "1. Do you know the nature of the smallpox poison? (No!) 2. Do you know the nature of the vaccine poison? (No!) 3. Do you know how, in vaccination, both work upon and against each other? (No!)" And so on. There are 12 questions, the last of which is "Can you deny that absurdity reigns without logic?" so it's safe to say Nittinger did not have a positive opinion of either vaccination or the government — a view shared by some who choose not to vaccinate today.
In Anderson's book, the Milwaukee Wisconsin Commissioner of Health in 1925 gives a quote that rings true today. He says "Since people cannot be vaccinated against their will, the biggest job of a health department has always been, and always will be, to persuade the unprotected people to get vaccinated. This we attempted to do in 3 ways: first, by education, second, by fright, and third by pressure. We dislike very much to mention fright and pressure, yet they accomplish more than education, because they work faster than education, which is normally a slow process." Although this quote was used in the context of highlighting the negative tactics, fright and pressure, used by the Health Department, the Commissioner is correct in that fear works faster than education — we've seen this with the tactics used by antivaccination campaigns (even some quoted here!). He was also correct that education is a slow process, but the best weapon against ignorance.
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