NCI Plans Major Efficacy Trial of HPV Vaccine in Costa Rica

BETHESDA, Md—Buoyed by early findings from a phase I trial, researchers at the National Cancer Institute plan to launch an efficacy trial of an NCI-developed vaccine against human papillo-mavirus-16 (HPV-16), a leading cause of cervical cancer. The study will involve 6,000 women.

In the first trial of the vaccine at the Johns Hopkins University School of Medicine, volunteers injected with the vaccine demonstrated up to 10-fold greater antibody response than occurs with natural infection. The results encouraged further clinical testing of the vaccine, “and we hope that within a year or so we’ll be doing an efficacy trial down in Costa Rica,” John T. Schiller, PhD, told the National Cancer Advisory Board (NCAB).

Although Pap smears have reduced cervical cancer cases considerably in developed countries, the disease is the second leading cause of cancer death worldwide, noted Dr. Schiller, a section chief in NCI’s Laboratory of Cellular Oncology. He developed the vaccine with NCI colleague Douglas R. Lowy, MD.

About 15,000 cases of cervical cancer are diagnosed each year in the United States and “far more cases of high-grade and low-grade dysplasias,” which result in an annual treatment bill of some $6 billion, he said.

“There’s really overwhelming evidence that HPV infections are the principal cause of cervical cancer,” Dr. Schiller said. “More than 95% of cervical cancers contain HPV, and about half of them contain HPV-16. And there is very strong epidemiological evidence.”

The NCI vaccine is one of several now in testing that rely on the discovery that the major HPV capsid protein has the intrinsic capacity to self-assemble into particles that look like the authentic virus but which contain no DNA inside to cause infection. These viruslike particles (VLPs) produce high titers of neutralizing antibodies in animals.

Doses, Adjuvants Compared

The ongoing study at Johns Hopkins, led by Clayton Harrow, MD, is enrolling college men and women with fewer than four lifetime sexual partners into six groups. Each group consists of 12 volunteers, 10 who receive the vaccine and 2 who serve as placebo controls. The initial vaccination injection is followed by shots at 1 month and 4 months. The aim is to compare 10-µg and 50-µg vaccine doses with no adjuvant, alum adjuvant, and MF-59 adjuvant.

The first study findings involve students who received 10- and 50-µg doses with or without alum adjuvant. “The 50-µg dose gives us about a 10-fold elevated antibody response,” Dr. Schiller said. “So we think 50 µg is a good base dose.” The 10-µg dose gave about a fourfold increase over that seen with natural infections.

NCI chose Costa Rica for its planned vaccine trial because the Central American nation is the site of a very large collaborative study of HPV and cervical cancer being carried out by Institute researchers and local scientists and public health officials. The trial will involve 3,000 women vaccinated with the new vaccine and 3,000 controls. The women will be followed for 3 to 4 years.

‘An Incredibly Important Trial’

“We’ll be looking at whether simple parenteral injection of VLPs induces effective immunity against genital mucosal infections in women,” Dr. Schiller said. The researchers will use both virologic and disease endpoints to measure the vaccine’s efficacy.

“This is an incredibly important trial,” NCI director Richard D. Klausner, MD, told NCAB members. “Because we have Pap smears in this country, we are not as aware of the extraordinary burden of cervical cancer around the world.”

Dr. Klausner said that National Institute of Health vaccine experts who have reviewed the animal and human data developed by Drs. Schiller and Lowy “say they have never seen anything so good in predicting that it is going to be a successful intervention.”