HPV and Genital Warts



Although HPV is most famous recently for causing cervical and throat cancer, it was originally discovered as the cause of warts.

Perhaps the nastiest form of warts are genital warts, also called anal warts, ano-genital warts, condylomata acuminata, genital verruca, or venereal warts. They affect somewhere between 0.2% and 5.1% of the population, and the numbers are increasing. In a study of four Nordic countries, those born between 1979 and 1986 were 1.5 to 5 times (depending on country) as likely to have ever had genital warts by age 25 as those born between 1958 and 1963. When transmitted to newborns, this can result in a rare disease called juvenile-onset recurrent respiratory papillomatosis.

The annual economic burden from treating genital warts was estimated to be about $220 million/year in the US in 2004, 50 million Euro/year in Germany in 2005, $27 million/year in the UK in 2008, and $10 million/year in Denmark.

Happily, Gardasil not only protects against the two strains of HPV that cause most cervical cancer, it also protects against the two strains that cause most genital warts. Countries with national vaccination programs for HPV are successfully reducing rates of genital warts.

Let's fire up the wayback machine and take a look at the science related to this public health victory.

1823-1958: Observations of Wart Transmission in Humans

Scientific inquiries into to the cause of warts began perhaps in 1823, when Sir Astley Cooper wrote in "On Warts":
"I must observe, that they frequently secrete a matter which is able to produce a similar disease in others: I have known two instances of this..."
(quoted in 'Warts and all'--the history and folklore of warts: a review., pubmed 1548655)

In 1896, Jadassohn showed that warts were transmissible by inducing warts in six volunteers via innoculation with material from a wart. He described the incubation time as 7 to 12 weeks. ("Sind die Verrucae vulgares uebertragbar?", Verhandl Deutsch Dermat Gesellsch 1896;5:497)

In 1907 and 1908, Ciuffo showed and Serra confirmed that warts could be induced using a wart extract passed through a Berkefeld filter - and thus were transmitted by something smaller than a bacterium. (summarized in "Infectious Oral Papillomatosis of Dogs", DeMonbreun and Goodpasture, pubmed 19969997)

In 1958, Goldschmidt showed that warts can be induced by innoculating a volunteer with material from a genital wart ("Experimental inoculation of humans with ectodermotropic viruses", pubmed 13575891)

1983: 90% of Genital Warts Contain HPV6 or HPV11

"Human papillomavirus types 6 and 11 DNA sequences in genital and laryngeal papillomas and in some cervical cancers" said
Condylomata acuminata mainly contained HPV 6 DNA. From 63 biopsy specimens, 41 clearly harbored HPV 6 DNA and 13 harbored HPV 11 DNA.

1991: First virus-like particle synthesized

In the past, producing vaccines against a virus required growing it in the lab, but that's really hard to do with HPV. So virologists at Georgetown University, University of Rochester, University of Queensland, and the US National Cancer Institute went looking for ways around this problem.

Ian Frazer at the University of Queensland succeeded in March 1991, and filed for a patent on the technique three months later. Researchers from the other institutions also filed patents slightly later on their contributions to the technique.

Major research findings paving the way for a functional VLP vaccine continued through the period 1991 to 1993; see e.g. "The story behind the world's first cancer vaccine" at io9.com and "Who Invented the VLP Cervical Cancer Vaccine?" in Journal of the National Cancer Institude.

The technique was verified independently, for instance in the 1995 paper "Immunization with viruslike particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection", which said

We tested the ability of vaccination with virus-like particles (VLPs) to protect domestic rabbits against papillomas induced by the cottontail rabbit papillomavirus (CRPV). A recombinant baculovirus system that expressed only the L1 major papillomavirus structural protein or L1 plus the minor L2 protein was used in insect cells as the source of VLPs. Groups of 10 rabbits were immunized with native or denatured VLPs from CRPV or type 1 bovine papillomavirus by using Freund's adjuvant. ... Animals inoculated with native CRPV VLPs composed of L1 alone or L1-L2 developed many fewer lesions... We conclude that native VLPs can induce antibody-mediated, type-specific protection against experimental papillomavirus infection.

1995: Commercial development of HPV vaccine begins

According to a timeline published in Nature Biotechnology, MedImmune, Merck, and CSL licensed the VLP technique from the University of Rochester and the Univerisity of Queensland in 1995.

In 2005, Merck and GlaxoSmithKline cross-licensed their patents.

2006: VLP-based HPV Vaccine Approved

In June, 2006, the FDA licensed the Gardasil HPV vaccine for use in girls and young women for the prevention of cervical cancer and genital warts.

2007: Meta-analysis of clinical trials

"Prophylactic vaccination against human papillomavirus infection and disease in women: a systematic review of randomized controlled trials" (pubmed 17671238) found
"We conducted a systematic search of the literature to identify all randomized controlled trials of prophylactic HPV vaccination [up to June 2007]... Of 456 screened reports, 9 were included in the review (6 were reports of randomized controlled trials and 3 were follow-up reports of initial trials). Findings from the meta-analysis showed that prophylactic HPV vaccination ... [was] highly efficacious in preventing other HPV-related infection and disease outcomes, including persistent HPV infection, low-grade lesions and genital warts."

2007-2013: Large scale vaccination campaigns and incidence of genital warts

Let's look at the four national HPV vaccination campaigns for which there is data on genital warts trends since vaccination started.


Sweden began vaccinating girls in 2006. Between 2006 and 2010, 30% of girls were vaccinated.

"Incidence of genital warts in Sweden before and after quadrivalent human papillomavirus vaccine availability" said

"Between 2008 and 2010, the overall incidence appeared to increase among males, and the incidence among females declined. Females aged 17 and 18 years had a >25% decline in GW rates between 2006 and 2010, with significant decreases through the age of 25 years."
So a 30% vaccination rate was associated with a 7% annual decline in new cases of genital warts (25% total decline over four years) in the core age group.

Also, here'a an excerpt from a summary of the more recent study "Association of varying number of doses of quadrivalent human papillomavirus vaccine with incidence of condyloma":

"The researchers behind the current study have taken advantage of the Swedish health care registers to study all girls and young women (between 10 and 24 years of age) in Sweden between 2006 and 2010, in more than a million individuals. ... 'When it comes to the vaccine's ability to protect against genital warts in girls between 10 and 16 years of age we can see that two doses provide good protection, up to 71 per cent, but that three doses is better, up to 82 per cent'..."


Germany began vaccinating its girls in March 2007; the percentage of girls vaccinated rose from 0% in March 2007 to 38% in March 2008.

"Changes in incidence of anogenital warts diagnoses after the introduction of human papillomavirus vaccination in Germany-an ecologic study." said

In a large health insurance database in Germany, incidence of anogenital warts among 15- to 19-year-old females decreased from 316/100,000 person-years in 2007 to 242 in 2008 (23% reduction, P = 0.0001). The decrease started between the first and second quarter of 2007...
So a 38% vaccination rate was associated with a 23% annual decline in new cases of genital warts (23% total decline over one year) in the core age group.


"Significant decrease in the incidence of genital warts in young Danish women after implementation of a national human papillomavirus vaccination program." said
Denmark has provided the quadrivalent HPV vaccine to all 12-year-old girls since 2009 and catch-up vaccination to girls up to 15 years since 2008, with up to 80% to 85% vaccine coverage. We determined the incidence of GWs in Denmark since 1996, focusing on the period after licensing of HPV vaccination (October 2006)... The overall incidence of GWs in women increased significantly until 2007, followed by an average yearly decline of 3.1% (95% confidence interval [CI], -5.5 to -0.7). In men, the incidence increased by 6.2% per year from 2004 (95% CI, 4.6-7.8). Stratifying on age, a significant decline was seen only for young women, particularly those aged 16 to 17 years, in whom GWs were virtually eliminated (average annual percentage change, -45.3%; 95% CI, -55.8 to -33.3). The incidences of genital Chlamydia, syphilis, and gonorrhea were stable or increased during the study period.
So an 85% vaccination rate was associated with 45% annual reduction in new cases of genital warts in vaccinated girls (or a 95% total reduction over four years) in the core age group.


"Genital warts in young Australians five years into national human papillomavirus vaccination programme: national surveillance data." said
Objective: To measure the effect on genital warts of the national human papillomavirus vaccination programme in Australia, which started in mid-2007....

Results: Large declines occurred in the proportions of under 21 year old (92.6%) and 21-30 year old (72.6%) women diagnosed as having genital warts in the vaccination period-from 11.5% in 2007 to 0.85% in 2011 (P<0.001) and from 11.3% in 2007 to 3.1% in 2011 (P<0.001), respectively. No significant decline in wart diagnoses was seen in women over 30 years of age. ... In 2010 the vaccination coverage rates in the school based programme were reported to be 83% for the first dose, 80% for the second dose, and 73% for the third dose in 12-13 year olds.

So an 83% vaccination rate was associated with a total 93% decline in new cases of genital warts over five years (or an annual decline of 40%) in the core age group.

See also "Fall in Genital Warts Diagnoses in the General and Indigenous Australian Population Following Implementation of a National Human Papillomavirus Vaccination Program: Analysis of Routinely Collected National Hospital Data" and "Decreased Management of Genital Warts in Young Women in Australian General Practice Post Introduction of National HPV Vaccination Program: Results from a Nationally Representative Cross-Sectional General Practice Study".


Surprisingly, Cervarix seems to be decreasing genital warts in the field, though not as much as Gardasil, which was designed to do so.

"Efficacy of the HPV-16/18 AS04-Adjuvanted Vaccine Against Low-Risk HPV Types (PATRICIA Randomized Trial): An Unexpected Observation. says

"Public Health England has reported a decrease of up to 20.8% in new diagnoses of external genital warts (GWs) among women aged <19 years since the national vaccination program with the human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine began in 2008. A post hoc analysis of the phase III PATRICIA (PApilloma TRIal against Cancer In young Adults) trial (NCT00122681) was performed to ascertain whether protection against low-risk HPV types was apparent.

Methods. Vaccine efficacy (VE) at 48 months was assessed against 6-month persistent infection (6MPI) with low-risk HPV types in the total vaccinated cohort (TVC) and in the TVC naive (for 25 HPV types tested) populations.

Results. In the TVC naive cohort, VE against 6MPI (95% confidence interval) was 34.5% (11.3 to 51.8) for HPV-6/11, 34.9% (9.1 to 53.7) for HPV-6, 30.3% (-45.0 to 67.5) for HPV-11, and 49.5% (21.0 to 68.3) for HPV-74.

Conclusions. The HPV-16/18 AS04-adjuvanted vaccine appears to have moderate efficacy against persistent infections with a number of low-risk HPV types (HPV-6/11/74), which are responsible for the majority of external GWs, and recently, antibody and cell-mediated immune response to HPV-6/11 have been observed. These findings may help to explain the decrease in external GW diagnoses seen in England."

Summing it up: a low Gardasil vaccination rate of about 40% in girls alone was associated with about a 25% total decline in new cases of genital warts over three to four years, but a high vaccination rate of 80% was associated with a 90%-95% total decline in new cases over four to five years.

Presumably also vaccinating boys with Gardasil would make it possible to achieve the kind of results seen in Denmark and Australia without requiring really good (80%) coverage.

Copyright 2013, Dan Kegel
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