Two doses of vaccine – and possibly a single dose – may offer as much protection against infection with cancer-causing forms of human papillomavirus as the standard three-dose series, according to results from a large study in Costa Rica published online Sept. 9 in the Journal of the National Cancer Institute .
The finding, the first clinical evidence suggesting that two doses or even one dose may be as effective as three, is a very hopeful one for women in resource-poor countries and may have important implications for women in relatively rich countries, such has the United States, where vaccine uptake has proven difficult to achieve, and where fewer than a third of girls receiving HPV vaccine are estimated to get a full three doses (MMWR 2011;60:1117-23).
Cervical cancer affects an estimated 530,000 women and causes 275,000 deaths annually, according to the International Agency for Research on Cancer, with more than 85% of the burden in less-developed regions of Africa, Asia, and Latin America. Certain types of HPV are the major cause of cervical cancer.
In the Costa Rican study, 7,466 women aged 18-25 years, most of them sexually active, were randomized to receive three doses of the HPV16/18 vaccine Cervarix (GlaxoSmithKline), or a hepatitis A control vaccine, as part of an ongoing phase III randomized controlled trial (J. Natl. Cancer Inst. 2011 [doi: 10.1093/jnci/djr319]).
All women in the study were supposed to receive three doses of either HPV vaccine or control; however, some of the women received fewer doses, largely because of pregnancy and referral to colposcopy.
The fact that many women did not complete the series allowed researchers, led by epidemiologist Aimée R. Kreimer, Ph.D., of the U.S. National Cancer Institute, to conduct an analysis comparing the efficacy of fewer than three doses of this HPV vaccine with the standard regimen in preventing newly detected persistent HPV16 and HPV18 infections.
Persistent infections were defined as evident in visits 10 or more months apart; all women in the study were seen annually during 4 years of follow-up.
After excluding women who had no follow-up or who were HPV16 and HPV18 positive at enrollment, 5,967 women who received three doses of HPV or hepatitis vaccine (2,957 received HPV vaccine or 50%), 802 who received two doses (422 HPV or 53%), and 384 who received one dose (196 HPV or 51%) were entered into analysis, for a total of 7,153.
Vaccine efficacy was 80.9% for three doses of HPV vaccine (25 and 133 1-year persistent HPV16/18 HPV infections in the HPV and control arms, respectively), 84.1% for two doses (3 and 17 infections), and 100% for one dose (0 and 10 infections). Persistent HPV16 or HPV18 infections were found to be unrelated to dosage of the control vaccine.
Dr. Kreimer and colleagues noted that although the study used data from a large randomized trial, their analysis was not randomized. However, they wrote, "the attack rates of new infections were essentially equal among women who received one, two, and three doses of the control vaccine. Equal attack rates in the control arm suggested that risks of infection were the same regardless of number of doses received. Furthermore, pregnancy, the most common reason that women received a reduced number of doses, was unrelated to vaccine assignment," and therefore unlikely to bias the findings.
They also acknowledged that while the benefit appeared to be the same for two and three doses, the duration of that benefit beyond 4 years was uncertain and would have to be established through further research.
Additionally, Dr. Kreimer and colleagues cautioned that their findings from the bivalent vaccine trial could not be extrapolated to the widely used quadrivalent HPV vaccine Gardasil, which is also administered in a three-dose series. Nor could they be considered relevant to populations with a greater incidence of comorbidities, particularly diseases affecting the immune system.
In an editorial comment accompanying Dr. Kreimer and colleagues’ study (J. Natl. Cancer Inst. 2011 [doi: 10.1093/jnci/djr354]), epidemiologist Cosette Marie Wheeler, Ph.D., of the University of New Mexico Health Sciences Center in Albuquerque, praised the study as having important public health implications.
If two doses of vaccine are indeed as effective as three, she wrote, this could be "an important step on the road to more effective and sustainable cervical cancer prevention programs," as more women could be vaccinated for the same cost.
However, Dr. Wheeler also cautioned that longer-term evidence was needed to determine whether clinically meaningful protection was achievable with two doses, noting also that there was biological evidence to suggest that three doses would provide greater cross-protection against heterologous HPV types. The finding of protection with a single dose, Dr. Wheeler wrote, was "unexpected" and should be viewed with caution.