Efficacy of a Bivalent L1 Virus-Like Particle Vaccine in Prevention of Infection with Human Papillomavirus Types 16 and 18 in Young Women
Abstract & Commentary
Synopsis: The bivalent HPV vaccine was efficacious in prevention of incident and persistent cervical infections with HPV-16 and HPV-18, and associated cytological abnormalities and lesions. Vaccination against such infections could substantially reduce incidence of cervical cancer.
Source: Harper D, et al. Lancet. 2004;364:1757-1765.
The most important clinical manifestation of persistent human papillomavirus (HPV) infection is development of uterine cervix cancer. Worldwide this preventable cancer continues to be a dominant killer and a significant contributor to years of life lost in women. Two years ago efficacy of a monovalent vaccination program was demonstrated against the most common oncogenic HPV type, HPV-16. In the current report, Harper and colleagues report efficacy, safety, and immunogenicity of a bivalent HPV-16/18 L1 virus-like particle (VLP) vaccine. Outcome measures were the prevention of incident and persistent infection with these 2 virus types, associated cervical cytological abnormalities, and development of precancerous lesions. In this study, 1113 women between 15 and 25 years of age participated in this randomized, double-blind, placebo-controlled trial. All were required to be negative for HPV infection at enrollment.
The primary outcome measure was HPV-16/18 infection between 6 and 18 months after enrollment. Participants received 3 doses of either the vaccine formulated with AS04 adjuvant or placebo on a 0 month, 1 month, and 6 month schedule in North America and Brazil. Women were assessed for HPV infection by cervical cytology and self-obtained cervicovaginal samples for up to 27 months. Vaccine safety and immunogenicity were also evaluated. Among women who received all 3 doses, vaccine was 92% effective against incident infection and 100% effective against persistent infection with HPV-16/18. In the intention-to-treat analyses, vaccine efficacy was 95% against persistent cervical infection with HPV-16/18 and 93% against cytological abnormalities associated with HPV-16/18 infection. The vaccine was safe, generally well tolerated, and highly immunogenic. Harper et al concluded that the bivalent HPV vaccine can prevent incident and persistent cervical infections with HPV-16 and HPV-18, and their associated cytological abnormalities and lesions. Widespread vaccination programs against these infections could substantially reduce incidence of cervical cancer.
Comment by Robert L. Coleman, MD
The causal link between HPV infection and development of uterine cervix cancer is now well established and represents an important association underlying developmental therapeutics directed at reducing incident disease. In countries with well-established screening programs for HPV and its associated cervical precancerous pathologies, impressive reductions in disease-specific mortality are the fruit of these initiatives. However, most of the world’s incident cancers are located in countries with little capacity for national screening efforts and affected women experience greater reductions in life expectancy from cervix cancer than complications associated with HIV, pregnancy, and tuberculosis. Even in countries where limited screening does exist, follow-up care, whether it be for treatment or repeat cytology, is even more limited and efforts to gain greater compliance are unlikely to make a measurable difference in incident disease. Clearly the cliché, "An ounce of prevention is worth a pound of cure. . ." is relevant and such an effort would be particularly life saving.
In a 2002 landmark article in the New England Journal of Medicine, Koutsky and colleagues demonstrated the merits of a vaccination program against HPV-16 with a monovalent L1 virus-like particle vaccine.1 Given the association of this viral subtype in more than 60% of cervical cancers, this target was valid. The highly anticipated results demonstrated a clear benefit for 768 vaccinated women against persistent infection and associated cervical dysplasia. In the current well-conducted trial, a bivalent vaccine was used in a similar manner, targeting both HPV-16 and HPV-18. While the addition of HPV-18 represents only about an additional 10-15% of cancers, it is an important addition, as this viral subtype is associated with adenocarcinoma and its precursor lesions. Typically, these are more difficult to screen by Pap smear and represent and important increasingly recognized cohort.
The efficacy of the vaccine in preventing incident disease, reducing persistence of HPV infection (a recognized necessary component in the pathogenesis of cancer) and preventing cytological abnormalities is proof-of-principle and a critically important advance in this regard. Indeed, the one cytological abnormality identified in the vaccinated cohort was judged a result of a viral subtype (HPV-51) not vaccinated against. The measured acute immunogenicity brought about by the vaccine was hundreds of fold higher than that produced by a native infection and persisted as several folds higher for the duration of the trial.2,3
These latter 2 points represent some of the important questions that must be addressed as these products undergo further development. For instance, how many different HPV subtypes should be included? What effect will HPV infections with subtypes not immunized against have on clinical outcomes? How long will the immunity last? When should a booster be given? Will vaccination be efficacious in the treatment of known disease? When should first immunization be undertaken? Should both men and women be vaccinated? How do you roll out a national vaccination program? Answers to these questions will likely be answered in the years to come. Our distinct hope is that a global effort will be extended in eradicating this "preventable" cancer.
Dr. Coleman is Associate Professor, University of Texas; M.D. Anderson Cancer Center, Houston Texas.
1. Koutsky LA, et al. N Engl J Med. 2002;347:1645-1651.
2. Pinto L, et al. J Infect Dis. 2003;188:327-338
3. Munoz N, et al. Int J Cancer. 2004;111:278-285.