A vaccine against HPV has been in use since 2007, and in countries that have a national HPV vaccination program, incidence of the virus is declining. Significant reductions in cancer incidence are expected to follow some years later.
Let's look at the science that led to the reduction in HPV, and is expected to lead to a reduction in cancer. What follows is a somewhat arbitrary selection of scientific and news articles along the timeline from theory to vaccine to public health effects.
The subsequent review by Goldberg and Gravell (8) stresses the possible role of HSV-21 infections in human cervical cancer. Although seroepidemiological studies do suggest an association of HSV-2 with this type of cancer (12, 14), repeated attempts, with 1 exception (6), have failed to demonstrate viral DNA by nucleic acid hybridizations in cervical cancer cells ...It is the intention of this note to draw attention to a virus- induced and virus particle-containing tumor revealing a similar epidemiological pattern, as does cervical cancer: the genital warts or condylomata acuminata. Condylomata acuminata have been shown to contain a papilloma virus (5, 13), which appears to differ from human wart virus when tested biochemically (20) or immunologically (1). These particles can be detected by electron microscopy in about 50% of all condylomas examined (13). ...
Genital warts seem to be transmitted primarily by sexual contact and are predominant in populations of high sexual promiscuity. In contrast to common warts, condylomata may become malignant (although rarely), and there exist a number of clinical observations on malignant transition of this tumor (3, 4, 7, 9-11, 15, 17). ...
The condyloma agent has been entirely neglected thus far in all epidemiological and serological studies relating not only to cervical and penile, but also to vulvar and perianal, carcinomas. This is particularly unusual in view of the localization of genital warts, their mode of venereal transmission, the number of reports on malignant transition, and the presence of an agent belonging to a well- characterized group of oncogenic DNA viruses.
All Caucasian women in a large Eastern city who developed pathologically confirmed cervical cancer between 1950 and 1969 are being prospectively followed in an epidemiological test of the venereal hypothesis of cervical carcinogenesis. We are attempting to identify all men who were married to these probands at any time prior to the date of their cancer diagnosis. ... To date, a total of 1,087 other wives and 659 control wives has been fully traced. Cervical cancer or carcinoma in situ was detected in 29 (2.7%) of the other wives and in seven (1.1%) of the control wives. A total of 14.0% of the other wives had either cervical cancer or a cervical cytological specimen which was other than normal. The corresponding statistic for the control wives was 8.0%. These differences in the prevalence of cervical cancer and of non-normal cervical cytology are statistically significant.This supported the viral theory of cervical cancer.
The finding of virus particles by transmission electron microscopy (TEM) in fixed cervical and vaginal scrape material and their identification as papilloma viruses by negative staining is described.
A polymerase chain reaction DNA amplification method for the detection of HPV was used to investigate the determinants of genital HPV infection in a cross-sectional sample of 467 women attending a university health service. In contrast to studies using less accurate detection methods, the risk factors for HPV infection found here were consistent with those for cervical neoplasia. The risk of HPV infection was strongly and independently associated with increasing numbers of sexual partners in a lifetime, use of oral contraceptives, younger age, and black race. Age at first intercourse, smoking, and history of a prior sexually transmitted disease were correlated with, but not independently predictive of, HPV infection. These results demonstrate that the key risk factors for cervical carcinoma are strongly associated with genital HPV infection. This correlation suggests that HPV has an etiologic role in cervical neoplasia and reaffirms the sexual route of HPV transmission.
Ian Frazer at the University of Queensland succeeded in March 1991, filed for a patent on the technique three months later, then published "Expression of vaccinia recombinant HPV 16 L1 and L2 ORF proteins in epithelial cells is sufficient for assembly of HPV virion-like particles" (Zhou J, Sun XY, Stenzel DJ, Frazer IH; Princess Alexandra Hospital, Brisbane, Queensland). 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" (F Breitburd, R Kirnbauer, N L Hubbert, B Nonnenmacher, C Trin-Dinh-Desmarquet, G Orth, J T Schiller, and D R Lowy; Institut Pasteur, Paris; National Cancer Institute, Bethesda; University of Vienna, Austria), 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.
We performed a population-based case-control study [of] 436 cases of histologically confirmed invasive cervical cancer and 387 randomly selected population controls.... The presence of HPV-DNA and detection of types 16, 18, 31, 33 and 35 were strongly associated with cervical cancer in each country regardless of the assay used. Our results indicate that there is a very strong association between HPV 16, 18, 31, 33 and 35 and invasive cervical cancer and that this association is probably causal.
In 1997, MedImmune licensed their HPV vaccine patents to SmithKline Beecham, later GlaxoSmithKline.
In 2005, Merck and GlaxoSmithKline cross-licensed their HPV vaccine patents.
1999: HPV found in nearly all cervical cancer
In 1999, the paper "Human papillomavirus is
a necessary cause of invasive cervical cancer worldwide"
(Walboomers JM, Jacobs MV, Manos MM, Bosch FX, Kummer JA, Shah KV, Snijders
PJ, Peto J, Meijer CJ, Munoz N;
University Hospital Vrije Universiteit, Amsterdam;
Johns Hopkins University;
Institute Catala d'Oncologia;
Institute of Cancer Research, Belmont, Surrey, UK;
IARC, Lyon, France) said
The worldwide HPV prevalence in cervical carcinomas is 99.7 per cent. The presence of HPV in virtually all cervical cancers implies the highest worldwide attributable fraction so far reported for a specific cause of any major human cancer. The extreme rarity of HPV-negative cancers reinforces the rationale for HPV testing in addition to, or even instead of, cervical cytology in routine cervical screening.
This paper was cited over 5000 times, an indication of extreme interest.
2001: a VLP-based vaccine has successful phase I human trial
The study "Safety and
immunogenicity trial in adult volunteers of a human papillomavirus 16 L1
virus-like particle vaccine"
( C. D. Harro, M. J. Reynolds, T. C. Mast, R. A. Karron, R. B. S. Roden
Johns Hopkins University;
Y.-Y. S. Pang, J. T. Schiller, D. R. Lowy, A. Hildesheim, National Cancer Institute, Bethesda, MD;
Z. Wang, J. Dillner, Karolinska Institute, Stockholm, Sweden;
R. Robinson, Novavax, Inc.;
B. R. Murphy, National Institute of Allergy and Infectious Diseases, NIH, Bethesda;
supported by the NIH and National Cancer Institute)
described a phase I safety and immunogenicity trial of an HPV-16
VLP vaccine in 58 females and 14 males, and concluded
The HPV16 L1 VLP vaccine is well tolerated and is highly immunogenic even without adjuvant
The causal role of human papillomavirus infections in cervical cancer has been documented beyond reasonable doubt. The association is present in virtually all cervical cancer cases worldwide. It is the right time for medical societies and public health regulators to consider this evidence and to define its preventive and clinical implications. A comprehensive review of key studies and results is presented.
This paper was cited over 2500 times, an indication of great interest.
2003: Incidence of HPV associated with new sex partner is high
The paper
"Genital Human Papillomavirus Infection: Incidence and Risk Factors in a Cohort of Female University Students"
(full
text; R Winer, S Lee, J Hughes, D Adam, N Kiviat, and L Koutsky;
University of Washington, Seattle; supported by NIH)
found
The authors followed 603 female university students in Washington State at 4-month intervals between 1990 and 2000. Incidences calculated from time of new-partner acquisition were comparable for enrolled virgins and nonvirgins. Smoking, oral contraceptive use, and report of a new male sex partner - in particular, one known for less than 8 months before sex occurred or one reporting other partners - were predictive of incident infection. At 24 months, the cumulative incidence of first-time infection was 32.3% (95% confidence interval: 28.0, 37.1). Always using male condoms with a new partner was not protective. Infection in virgins was rare, but any type of nonpenetrative sexual contact was associated with an increased risk. ... The data show that the incidence of HPV associated with acquisition of a new sex partner is high and that nonpenetrative sexual contact is a plausible route of transmission in virgins.
"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."
We used a novel HPV whole-genome sequencing technique to evaluate an exceptionally large collection of 5,570 HPV16-infected case-control samples to determine whether viral genetic variation influences risk of cervical precancer and cancer. We observed thousands of unique HPV16 genomes; very few women shared the identical HPV16 sequence... In case-control analyses, HPV16 in the controls had significantly more amino acid changing variants throughout the genome. Strikingly, E7 was devoid of variants in precancers/cancers compared to higher levels in the controls; we confirmed this in cancers from around the world. Strict conservation of the 98 amino acids of E7, which disrupts Rb function, is critical for HPV16 carcinogenesis, presenting a highly specific target for etiologic and therapeutic research.
"Modeling the impact of quadrivalent HPV vaccination on the incidence of Pap test abnormalities in the United States" (Chesson HW, Flagg EW, Koutsky L, Hsu K, Unger ER, Shlay JC, Kerndt P, Ghanem KG, Zenilman JM, Hagensee M, Weinstock H, Datta SD; CDC) says
Estimated reductions in abnormal Pap results among women in the 21- to 29-year age group were 0.8%, 10.2%, and 11.3% in years 5, 15, and 25 of the vaccine program respectively, in the lower vaccine coverage scenario, and 7.4%, 21.4%, and 22.2%, respectively, in the higher coverage scenario."Estimates of the timing of reductions in genital warts and high grade cervical intraepithelial neoplasia after onset of human papillomavirus (HPV) vaccination in the United States" (Chesson HW, Ekwueme DU, Saraiya M, Dunne EF, Markowitz LE; CDC) says
Using different coverage scenarios, the lowest being consistent with current 3-dose coverage in the United States, we estimated the number of years before reductions of 10%, 25%, and 50% would be observed after onset of an HPV vaccination program for ages 12-26 years.
RESULTS:
The model suggested female-only HPV vaccination in the intermediate coverage scenario will result in a 10% reduction in genital warts within 2-4 years for females aged 15-19 years and a 10% reduction in CIN 2/3 among females aged 20-29 years within 7-11 years. Coverage had a major impact on when reductions would be observed. For example, in the higher coverage scenario a 25% reduction in CIN2/3 would be observed with 8 years compared with 15 years in the lower coverage scenario.
CONCLUSIONS:
Our model provides estimates of the potential timing and magnitude of the impact of HPV vaccination on genital warts and CIN 2/3 at the population level in the United States. Notable, population-level impacts of HPV vaccination on genital warts and CIN 2/3 can occur within a few years after onset of vaccination, particularly among younger age groups. Our results are generally consistent with early reports of declines in genital warts among youth.
Here is a (short) list of countries with national vaccination programs and good statistics that might shed light on their effects. (See also similar info on genital warts.)
In August 2014, "Assessment of herd immunity and cross-protection after a human papillomavirus vaccination programme in Australia: a repeat cross-sectional study" said
"... we recruited women aged 18-24 years who attended Pap screening between October, 2005, and July, 2007, in three major metropolitan areas of Australia to form our prevaccine-implementation sample. For our postvaccine-implementation sample, we recruited women aged 18-24 years who attended Pap screening in the same three metropolitan areas from August, 2010, to November, 2012...Compared with the prevaccine-implementation sample, adjusted prevalence ratios for vaccine-targeted HPV genotypes were 0.07 (95% CI 0.04-0.14; p<0.0001) in fully vaccinated women and 0.65 (0.43-0.96; p=0.03) in unvaccinated women, which suggests herd immunity. No significant declines were noted for non-vaccine-targeted HPV genotypes...
within the postvaccine-implementation sample, adjusted vaccine effectiveness against vaccine-targeted HPV types for fully vaccinated women compared with unvaccinated women was 86% (95% CI 71-93), and was 58% (26-76) against non-vaccine-targeted but related genotypes (HPV 31, 33, and 45)."
In December 2014, Statistical Report 2013, Victorian Cervical Cytology Registry said
"Notable in these data are the year-on-year declines in the rate for the youngest women (aged 20 to 24 years), corresponding to the implementation of the HPV vaccination program between 2007 and 2009. Historically this age group had the highest rates of abnormalities but from 2009 the rate has been higher amongst 25 to 29 year olds. Since 2008, the rate in 20 to 24 year olds has fallen ..." (2008=21.1; 2009=18.7; 2010=17.9; 2011=15.8; 2012=15.3; 2013=13.5 per 1000)..."Interestingly, following an underlying trend of increases in incidence, the high-grade detection rate for 25 to 29 year old women for 2013 is slightly lower than in previous years (2008=18.4, 2009=18.9, 2010=18.1, 2011=18.8, 2012=18.8, 2013=17.7)"
In May 2014, Statistical Report 2012, Victorian Cervical Cytology Registry said
"Figure 5.2 shows the rate of histologically-confirmed high-grade cervical abnormalities by year since 2000, for young women (<20, 20-24, 25-29) and those 30+ years of age. [32] The previously noted decline, following the National HPV Vaccination Program, in women under 20 years of age is continuing, with a near halving of the rate of 11 cases per 1,000 women screened in 2006 down to 6 cases per 1,000 in 2012 (p<0.001). Rates in women 20 to 24 years have been declining since 2010; however there has been a steady rise in detection rates for 25 to 29 year old women over the last 10 years."
In May 2014, "Cervical screening in Australia 2011-2012" reported
"in contrast with the overall trend of increasing detection over time, there has been a steady decline in high-grade abnormality detection in women under 20. Highest at 13.2 in 2005, this decreased to 6.4 women with high-grade histology per 1,000 women screened in 2012 (Table 4.4; Figure 4.5). ...Looking in more detail at the change in the high-grade detection rate by age, using the 3 years 2004-2006 as the pre-vaccination comparator, the decrease in women aged under 20 was small but perceptible from 2007, the first year of the National HPV Vaccination Program..., becoming larger with each passing year to reach a decrease of 6.8 by 2012, the latest data available (Table 4.5). For women aged 20-24, this decrease begins in 2011, falling further in 2012 to reach a decrease of 3.7 (Table 4.5). Older age groups are unaffected, as sufficient time has not yet passed for girls vaccinated from 2007 to have moved into age groups beyond 20-24..."
In March 2014, "Effectiveness of quadrivalent human papillomavirus vaccine for the prevention of cervical abnormalities: case-control study nested within a population based screening programme in Australia" found
"Participants [were] Women eligible for free vaccination (aged 12-26 years in 2007) and attending for their first cervical smear test between April 2007 and March 2011... vaccine effectiveness [was] 46% (95% confidence interval 33% to 57%).For girls 15-18 at vaccination, vaccine effectiveness was higher, 57% (CI 38% to 69%). There were not yet enough girls aged 11-14 at vaccination to give statistically significant results.
In October 2013, "Impact of a population-based HPV vaccination program on cervical abnormalities: a data linkage study" found
"The study included 14,085 unvaccinated and 24,871 vaccinated women attending screening who were eligible for vaccination at school, 85.0% of whom had received three doses... VE adjusted a priori for age at first screening, area level socioeconomic status and remoteness index, for women who were completely vaccinated, was greatest for CIN3+/AIS at 47.5% (95% CI 22.7 to 64.4)..."(Figure 3a in that paper shows that the vaccine cut risk of high-grade abnormalities in pap smears by about 75% in women who got all three shots on schedule. Getting less than the recommended number of shots provided less protection.)
See also "The Australian Experience With the Human Papillomavirus Vaccine".
[A laboratory serving 28 gynecologists provided data... on 24 vaccinated women with CIN1+. 4 of the cases had HPV 16 or 18; these patients were 33-34 years old therefore it is supposed that these patients were vaccinated too late. ... The most frequent HPV types in the different combinations were hrHPV 52 (11 cases), hrHPV 39 (10), hrHPV 31 (9 cases), hrHPV 45 (6 cases), and hrHPV 51 (6 cases).]
"Early Impact of Human Papillomavirus Vaccination on Cervical Neoplasia -- Nationwide Follow-up of Young Danish Women" (full text) reports on results in the catch-up group (vaccinated at ages 15 though 18):
"we identified all girls and women born in Denmark in the period from 1989 to 1999 and obtained information on individual HPV vaccination status in the period from 2006 to 2012 from nationwide registries... Risk of atypia or worse (atypia+) and of cervical intraepithelial neoplasia grade 2 or 3 (CIN2/3) were statistically significantly reduced among vaccinated women in birth cohorts 1991 to 1994.In particular, of the 72,544 girls born in 1993-1994, 88% were vaccinated at ages 15-16, and the risk of CIN3 was 80% lower (confidence interval 29%-94%) in those girls.
"Incidence of cervical lesions in Danish women before and after implementation of a national HPV vaccination program" looked at incidence in all Danish women regardless of vaccination status, and found
"After introduction of the quadrivalent HPV vaccine into the vaccination program, the ... incidence of CIN2+ ... decreased significantly in 18-20-year-old women (EAPC (estimated annual percentage change) -14.8 %; 95 % CI -21.6;-7.5) in 2010-2013, but no significant decrease was seen in older age groups.(I've only read the abstract, but a 14.8% annual decline in CIN2+ would mean a 38% total decrease in CIN2+ since introduction.)The incidence of cervical lesions decreased significantly in age groups with high HPV vaccine coverage, indicating an early effect of HPV vaccination."
"Reduction in HPV 16/18 prevalence in sexually active young women following the introduction of HPV immunisation in England" surveyed HPV prevalence in 2008 and again in 2010-2012 in women visiting clinics for chlamydia tests, and found
"The prevalence of HPV 16 and/or 18 in the post-immunisation survey was lowest in 16-18 year olds, at 6.5% (95% CI: 5.2-8.0%) ... In contrast in 2008, the prevalence was highest in 16-18 year olds (19.1%, 95% CI: 16.6-21.8%)."
Since 2007, all females in Germany aged 12-17 years have been eligible for vaccination free of charge... Between 2010 and 2012 we conducted a population-based cross-sectional study in Germany to determine HPV prevalence... in women aged 20-25 years... In 223 vaccinated women, prevalence of HPV 16/18 was significantly lower compared to non-vaccinated women (13.9% vs. 22.5%, p = 0.007). When stratifying by age groups, this difference was only significant in women aged 20-21 years..."
In 2008, a national human papillomavirus (HPV) immunisation programme began in Scotland for 12-13 year old females with a three-year catch-up campaign for those under the age of 18. Since 2008, three-dose uptake of bivalent vaccine in the routine cohort aged 12-13 has exceeded 90% annually, while in the catch-up cohort overall uptake is 66%.... three doses (n=1100) of bivalent vaccine are associated with a significant reduction in prevalence of HPV 16 and 18 from 29.8% (95% confidence interval 28.3, 31.3%) to 13.6% (95% confidence interval 11.7, 15.8%). The data also suggest cross-protection against HPV 31, 33 and 45. HPV 51 and 56 emerged as the most prevalent (10.5% and 9.6%, respectively) non-vaccine high-risk types in those vaccinated, but at lower rates than HPV 16 (25.9%) in those unvaccinated.
From 2008 to 2012, prevalence of HPV 16/18 in CIN2+ lesions statistically significantly decreased from 53.6% to 28.4% among women who received at least one dose (Ptrend<.001) but not among unvaccinated women (57.1% vs 52.5%; Ptrend=.08) or women with unknown vaccination status (55.0% vs 50.5%; Ptrend=.71). Estimated vaccine effectiveness for prevention of HPV 16/18-attributable CIN2+ was 21% (95% CI: 1-37), 49% (95% CI: 28-64), and 72% (95% CI: 45-86) in women who initiated vaccination 25-36 months, 37-48 months, and >48 months prior to the screening test that led to CIN2+ diagnosis.
"Impact of human papillomavirus (HPV) vaccination on HPV 16/18-related prevalence in precancerous cervical lesions" (2012) says
"Among women who initiated vaccination >24 months before their trigger Pap, there was a significantly lower proportion of CIN2+ lesions due to 16/18 compared to women who were not vaccinated (aPR=.67, 95% CI: .48-.94)."
"Reduction in Human Papillomavirus (HPV) Prevalence Among Young Women Following HPV Vaccine Introduction in the United States, National Health and Nutrition Examination Surveys, 2003-2010" (full text; Markowitz LE, Hariri S, Lin C, Dunne EF, Steinau M, McQuillan G, Unger ER; CDC) says
Among females aged 14-19 years, the vaccine-type HPV prevalence (HPV-6, -11, -16, or -18) decreased from 11.5% (95% confidence interval [CI], 9.2-14.4) in 2003-2006 to 5.1% (95% CI, 3.8-6.6) in 2007-2010, a decline of 56% (95% CI, 38-69).