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A successful vaccine to prevent cervical cancer could make a huge dent in the disease's death toll. Here are the exciting results from an important trial of an experimental HPV 16 vaccine, in which participants gained immunity from the most common strain of the virus.
A vaccine that prevents persistent human papillomavirus (HPV) could dramatically reduce the 200,000 annual cervical cancer-related deaths worldwide4,000 of which occur in the United States. The encouraging news from an important recent clinical trial is that an HPV vaccine is definitely on the horizon, although its approval and implementation are some years away.
One of the most common sexually transmitted diseases, genital human papillomavirus (HPV) chiefly infects those between ages 18 and 25. The infections are usually asymptomatic and transient (detectable for a median time of less than 1 year). However, when the infection persists, it's more likely to be associated with cervical neoplasia. Of the more than 100 different types of HPV, roughly 38 types preferentially infect the anogenital epithelium and may cause genital warts or cervical neoplasia, as well as vaginal, vulvar, anal, or penile neoplasia.
There are "low-risk or nononcogenic" types of HPV and "high-risk or oncogenic" types. Types 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 68, 73, 82, and probably 26, 53, and 66 are considered oncogenic.1 Virtually all cervical cancers are positive for oncogenic HPV strains, with about 70% of cases worldwide positive for HPV 16 or HPV 18.2
Our goal here is to sum up the aims and results of our recently reported Phase II, proof-of-principle trial of a monovalent HPV 16 vaccine. We'll also look at future implications for the practicing gynecologist of a prophylactic HPV vaccine.
The good news is that in developed countries, the incidence and mortality rates of cervical cancer have fallen dramatically in the last 50 years, largely due to Pap smear screening. However, because most women live in developing countries that lack effective Pap smear screening programs, cervical cancer remains the second most common cancer among women globally, with about 500,000 new cases per year worldwide and at least 200,000 related deaths.3 In the US alone, there are 13,000 new cases per year and 4,000 related deaths.4
Cervical cytology does have limitations, however. Three factors appear to account for its failures in controlling cervical cancer: (1) the absence of regular screening; (2) the poor reproducibility of cytologic diagnosis5-7; and (3) the high rate of false-negatives.8,9 Roughly 50% of women in the US who develop cervical cancer say they've never had a Pap test, and 30% say they've had only "normal" results.10,11
Because of these limitations and the evidence linking HPV with cervical neoplasia, several investigators set out to explore the usefulness of HPV DNA testing as an adjunctive or primary screening test. One of the goals of the multicenter, NCI-sponsored, randomized ASCUS/LSIL Triage Study (ALTS) was to determine the efficacy of HPV DNA testing of women with atypical squamous cells of undetermined significance (ASCUS) Pap smears. Results from this study and others showed that HPV testing of women with ASCUS (with referral to colposcopy of those positive for oncogenic HPV DNA) was more sensitive for detection of cervical intraepithelial neoplasia 3 (CIN 3) or above than referral of those with a repeat Pap smear showing ASCUS or above.12,13 Both approaches, however, provided similar estimates of specificity.14 The new 2001 Consensus Guidelines for Management of Cervical Cytologic Abnormalities incorporate HPV testing into the management algorithm. Now patients with ASCUS are tested for the presence of oncogenic HPV DNA, and if positive, are sent directly to colposcopy.15
Both animal and human studies illustrate the importance of host immunity in controlling HPV infections. Animal studies have shown that serum can passively transfer immunity to infection, suggesting that antibodies protect against reinfection with the same type of papillomavirus.16 In addition, vaccination studies done in animals revealed that antibodies develop when subjects are exposed to the intact L1 capsid proteins or inactivated virions.16-18
Natural history studies in humans have now clarified the length of time from the detection of HPV DNA until the development of serum antibodies to the specific type of HPV.19,20 The development of a vaccine has relied upon the fact that the HPV genome is not prone to mutation and that the L1 capsid protein (an immunogenic portion of the virus) is capable of self-assembling into particles that are indistinguishable from native virions.21,22
The Phase II proof-of-concept trial of a monovalent HPV 16 vaccine had three specific aims: (1) to determine whether HPV 16 vaccine prevents persistent HPV 16 infection among HPV 16-naïve women; (2) to estimate the vaccine's potential impact on the incidence of HPV 16-related CIN; and (3) to assess its immunogenicity and tolerability.23
The vaccine itself was designed using protein from the L1 gene of the HPV Type 16 virus. When the L1 gene is inserted into the genome of yeast, L1 protein (which is produced as the yeast replicates) self-assembles into empty viral capsids. These empty capsidscalled virus-like particles (VLPs)lack the infectious portion of the virus. Earlier, in Phase I trials, this HPV 16 VLP-based vaccine had produced an excellent immune response in the host.
From October 1998 through November 1999, 2,392 women between 16 and 23 enrolled in a randomized, double-blind fashion were given either placebo vaccine or 40 µg of purified HPV 16 L1 virus-like particle vaccine. The vaccine was administered at enrollment (day 0), month 2, and month 6. Women were examined 1 month after the third dose of vaccine (month 7), 6 months after the last dose (month 12), and subsequently every 6 months through month 48, but no further vaccination was given.
At each study visit, women underwent a full gynecologic examination with cervical specimens collected for Pap smear screening, and cervical swab, external genital swab, and cervicovaginal lavage specimens collected for HPV-16 DNA testing. Clinicians performed colposcopies and cervical biopsies at exit and as indicated for abnormal Pap smear cytology. They also collected immunogenicity data with regular blood draws to evaluate the serum for antibodies to HPV 16.
Of the 2,392 women enrolled, 1,194 received the vaccine and 1,198 were given placebo. The two study groups were similar with regard to age, race, smoking status, lifetime number of sex partners, and Pap smear results. At a median follow-up time of 17.4 months after the third dose of vaccine, the incidence of persistent HPV-16 infection was 3.8 per 100 woman-years in the placebo group and 0 per 100 woman-years in the vaccine group. All 41 women with persistent HPV-16 infection received placebo injections. Of these 41 women, 32 had persistent HPV-16 infection without evidence of cervical intraepithelial neoplasia (CIN), five women had HPV 16-related CIN 1, and four had HPV 16-related CIN 2. In short, the data suggest that this monovalent HPV 16 VLP vaccine is highly effective.
In addition, the seroconversion rate and antibody titers were quite high and, overall, the vaccine was generally well tolerated. Nearly all (99.7%) of the women who received the HPV 16 vaccination seroconverted. At month 7 of the study, women who had received the vaccine showed antibody titers to HPV 16 that were 58.7 times higher than titers among women with serologic evidence of natural HPV-16 infection at enrollment. The vaccine was well tolerated with no serious adverse effects reported. Both groups reported pain at the injection site as the most common adverse effect.
International, multicenter Phase III trials of a tetravalent HPV vaccine are currently under way. This vaccine includes VLPs from HPV 16 and HPV 18, the two HPV types involved in about 70% of cervical cancers worldwide and HPV 6 and 11, the two HPV types involved in about 90% of genital warts.
With the prophylactic HPV vaccine on the horizon, and FDA approval 5 to 7 years away, it is important to understand the future implications to gynecologic practice. Even though the vaccine's effectiveness in HPV-negative women has been shown, we don't yet know how long protection lasts. It is still unclear whether booster shots will be needed. The vaccine should be given to all individuals before they acquire HPV, or before they become sexually active, in order to induce an immune response prior to exposure to HPV. Some evidence from mathematical modeling suggests that young men should also receive the vaccine. Although they are not at risk for cervical cancer, they are at risk for genital warts and for transmitting HPV infections to their partners. Vaccinating males in addition to females may further reduce the prevalence for that specific HPV type.24
Researchers recently reported an approximately ninefold reduction in cervical anti-HPV-16 IgG levels at the time of ovulation in 11 women who received alumfree HPV-16 L1 VLP vaccine synthesized in a baculovirus system.25 The authors hypothesized that the efficacy of prophylactic HPV vaccines may be reduced in women who are not using hormonal contraception. In the proof-of-concept HPV 16 vaccine trial discussed earlier, about half of the women in both vaccine and placebo groups were using hormonal contraceptives. Since vaccine efficacy was 100%, ovulation and potential fluctuations in cervical anti-HPV 16 IgG levels did not appear to substantially affect vaccine efficacy. Larger trials with longer follow-up are required to determine if ovulation has a more subtle impact on vaccine efficacy.
How will we manage women who've already acquired the HPV types included in the vaccine? Whether these patients will benefit from vaccination as well is still an unanswered question. Several groups are working on therapeutic HPV vaccines. Results to date have been mixed. One approach that involves linking mycobacterial heat-shock protein 65 (Hsp65) with E7 protein of HPV appears to be promising. A Phase III trial evaluating this vaccine as treatment for anal intraepithelial neoplasia (AIN) has begun.
Assuming that one day most women will be routinely vaccinated with a prophylactic vaccine that prevents HPV 16 and 18 infections, Pap screening will still continue for many decades. Thousands of women will remain at risk for cervical cancer either because they were infected with HPV 16 or 18 before the vaccine became available or because they're infected with a cancer-associated HPV type that the vaccine cannot prevent. Although Pap screening won't disappear, a smaller percentage of women will develop abnormal Pap smears and fewer women will require colposcopies, biopsies, and treatments for intraepithelial lesions and cancers. Ideally, researchers will develop a screening test that is more accurate than the Pap smear and, over a lifetime, a woman will require fewer screening tests.
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Laura Koutsky, Katherine Van Kessel. The HPV Vaccine: Will it one day wipe out cervical Ca?
Nov. 1, 2003;48:71-78.