CHICAGO (FRONTLINE MEDICAL NEWS) – The 9-valent human papillomavirus (HPV) vaccine recently approved by the Food and Drug Administration has high efficacy for preventing disease caused by the vaccine-covered viral types and is well tolerated, according to end-of study data from a randomized trial.

The vaccine was on par with the quadrivalent vaccine when it came to protection against infection with the four original viral types covered by both vaccines. Additionally, for the five new viral types, it was associated with a 97% reduction in all cervical, vaginal, and vulvar intraepithelial neoplasia, a 100% reduction in cervical intraepithelial neoplasia 3, and a more than 90% reduction in related procedures and treatments, investigators reported at the Annual meeting of Society of Gynecologic Oncology. Meanwhile, it had a good safety profile.

“The consistency of the data is very reassuring,” said Dr. Elmar A. Joura of the Medical University of Vienna, General Hospital, and Comprehensive Cancer Center, also in Vienna.

Dr. Marcela delCarmen , session comoderator and a gynecologic oncologist at the Massachusetts General Hospital in Boston, asked, “You’ve presented data on the efficacy of the vaccine in the study population, but do you have any data on the effectiveness or the impact that the vaccine will have on the public health atmosphere of the general population?”

“First of all, we saw that the vaccine was doing exactly what was expected. These vaccines don’t have any therapeutic effect, so those women who have been infected at the time of vaccination, we did not observe a benefit during the course of the study. But from the previous study of the quadrivalent vaccine, we know [that] over the course of time, they also will get some benefit,” Dr. Joura replied.

“The second thing is, the vaccine really has the potential with this high effectiveness to change the screening practice in the long term. But what’s definitely needed is good coverage. And in many countries and also in this country, the coverage rates are far from optimal. Once you achieve a rate like in Australia or the United Kingdom, then the next step definitely is a change of screening algorithm,” such as a switch to primary HPV screening, he added.

There is a persistent medical need to develop new HPV vaccines, even though two highly effective vaccines have been on the market for some time, Dr. Joura maintained. “With HPV 16 and 18, you cover about 70% of invasive cervical cancer and about 50% of cervical precancer. Adding the next five most common most oncogenic HPV strains would give a coverage of 90% for both invasive and precancer, giving an additional benefit of 20% for invasive cancer and 35% for cervical precancer,” he elaborated.

In the Merck-sponsored phase IIb/III trial , the investigators randomized 14,215 women aged 16-26 to double-blind receipt of the quadrivalent vaccine (Gardasil, which covers viral types 6, 11, 16, and 18) or the 9-valent vaccine (Gardasil 9, which additionally covers viral types 31, 33, 45, 52, and 58). “It was not possible to have this trial placebo-controlled since two effective vaccines were available, so the controls were vaccinated with the quadrivalent HPV vaccine,” Dr. Joura explained. The women had follow-up with sample collection for up to 54 months.

Initial results showed that antibody titers for the original four viral types in the group given the 9-valent vaccine were noninferior to those in the group given the quadrivalent vaccine, and when compared against the historical placebo arm of the quadrivalent vaccine trial, there was dramatic and near full protection against type 16- and 18-related cervical, vaginal, and vulvar neoplasia. These findings led to approval of the vaccine late last year and a recent publication ( N. Engl. J. Med. 2015;372:711-23 ).

The new, end-of-study data, capturing roughly an additional year of observation, showed that relative to the quadrivalent vaccine, the 9-valent vaccine provided good protection for the five new viral types among women negative for these types at baseline: Efficacy was 97.7% for protection against any neoplasia of the cervix, vagina, or vulva; 97.4% for protection against high-grade neoplasia; and 96.0% for protection against 6-month persistent infection.

“What is important for public health decisions is what is the effect on procedures and treatments,” Dr. Joura said. In fact, the 9-valent vaccine was highly efficacious for reducing external genital biopsies (92.3% risk reduction), cervical biopsy (97.7%), and loop electrosurgical excision procedure/conization (90.2%) related to the five new viral types covered.

The rate of vaccine-related adverse events was 92.2% with the 9-valent vaccine and 87.6% with the quadrivalent vaccine, with the difference mainly due to more injection site reactions with the former. There was two vaccine-related serious adverse events in the 9-valent group and one in the quadrivalent group.

In a related study, investigators led by Dr. Warner K. Huh , a professor in the department of obstetrics and gynecology at the University of Alabama at Birmingham, determined the relative prevalence of HPV genotypes in the U.S. population.

“We are going to see a transition from the quadrivalent vaccine to the 9-valent vaccine, so information regarding genotypes in this country becomes extremely important,” he said. “There is very limited information in terms of the HPV prevalence for genotypes across the U.S. and more importantly, we almost have zero information on what that prevalence is in a low-risk population. To understand changes in the prevalence in this country, particularly with vaccination and then ultimately as it relates to screening, you are going to need to understand what that baseline data is.”

The investigators analyzed data from 46,751 women aged 21 years or older in the ATHENA study (Evaluation of the Cobas 4800 HPV Test for the Detection of High-Grade Cervical Disease), the largest HPV screening cohort nationally. The Roche-funded study was used to gain Food and Drug Administration approval for primary HPV screening in the United States. Less than 3% of enrolled women had received an HPV vaccine.

The women had HPV testing, in addition to liquid-based Pap testing and colposcopy, with follow-up out to 3 years in a subset. Genotyping was used to detect 16 high-risk types of HPV (16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 59, 66, 68, 73, and 82), and the prevalence of each was benchmarked to that of HPV 16.

“We benchmarked to HPV 16 for a couple of reasons,” Dr. Huh explained. “One of which is that we now have two vaccines – the quadrivalent and the 9-valent vaccines – and we thought it would be interesting to see what happens to that ratio as we have had one for essentially 10 years and the other one transitions in. The other reason, of course, is that it’s a highly prevalent type and a type that’s seen in both vaccines.”

Results showed that the absolute prevalence of all 16 types combined was 11.5% in the entire cohort and 10.0% in the low-risk subset with normal Pap results. In age-stratified analyses, it was higher among women aged 21-24 years than among older women.

The prevalence ratio relative to HPV 16 for the most common viral types among those assessed ranged from 0.12 for HPV 33 to 0.57 for HPV 52.

“The ratios may not be relevant to you today, but they may become highly relevant 10, 20, or 30 years from now,” Dr. Huh commented, discussing HPV type 31, which had a ratio of 0.43, as an example. As coverage by the quadrivalent vaccine and hence protection against type 16 rises, “what we would expect over the next 10 years is that ratio to increase substantially, some theorize as much as fourfold. Then as you roll out the 9-valent vaccine, theoretically, that ratio should normalize back to 0.43, assuming again that the efficacy is equivalent for [type 31] and for type 16,” he explained. “So this is where it becomes very interesting, because if it doesn’t, there is something else going on in the population.”

The new data additionally allow good ability to track the phenomenon of viral type replacement, Dr. Huh said.

“But most importantly, what it allows us to do is to look at screening and the impact of the nonavalent vaccine on screening in the United States. If you all buy into primary HPV screening, the current algorithm uses type 16 and type 18. Well, if type 16 and type 18 go away and these ratios change, then we need to seriously revisit how we do primary HPV screening because the current algorithm is probably not the right algorithm to use,” he maintained.


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