BETHESDA, MdBuoyed 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 well 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
NCIs 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.
Theres 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
Well 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 vaccines 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.