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August 20, 2008 — 因为许多重要的问题仍然没有答案，因此须对进行大范围的人类乳突病毒(HPV)疫苗计划提出警告；这是Charlotte Haug博士在Norwegian医学协会期刊中提出的研究结论，也登载在8月21日的新英格兰医学期刊的编辑评论中。
Haug博士建议，HPV疫苗对于子宫颈癌之实际影响的观察还不到几十年，但是饱受全球政策制定者将HPV疫苗导入全国疫苗计划的压力。
目前全球有两种HPV疫苗上市— 美国和澳洲使用Gardasil (Merck & Co药厂)，英国最近宣布使用Cervarix (GlaxoSmithKline药厂)，这些疫苗计划的主要目标族群是12至13岁的女孩，因为疫苗在发生性行为之前最有效。
不过，Haug博士质疑，政策制定者何以在没有充分证据下，认为导入医疗介入在未来会有助益，特别是我们都还不清楚此一方法是否有效或者造成伤害时？
【数学模型中的花费-效益估计】
登载在同篇期刊上的编辑评论中，哈佛公共卫生学院的Jane Kim博士与Sue Goldie医师论及HPV疫苗对于美国的健康与经济影响，他们使用数学模式计算疫苗在已建立子宫颈癌筛检计划国家的花费与效益关系。
该研究结论认为，如果可以高度普及到12岁女孩、如果疫苗的免疫力是终身的话，疫苗预期有经济上的吸引力，但是，年长女孩和妇女的补充计划则没有经济效益。
Haug博士认为，这些结论是根据有许多假设的数学模式，而且太过乐观；她表示，实际上还需要有试验来检视这些假设是否合理，并进行追踪研究。
Haug博士根据一些细节讨论该模式中的许多假设，指出在许多案例中的资料相当有限。
主要假设之一是，疫苗的效果是终身的(即不需要追加)；但是疫苗效果可以持续多久的问题，仍没有答案；研究者本身指出，如果保护力在10年后衰退，疫苗变得比较没有经济效益，而筛检会比补充计划更有效。参与HPV疫苗临床试验的主要研究者之一，Dartmouth医学院的Diane Harper医师表示，目前的证据显示，保护力在施打疫苗后持续5年，但是没有长期资料，一如之前 Medscape Oncology期刊中所报导的。
另一个假设是，疫苗对于青春期前的女孩和年长妇女的效果一样；不过，Haug博士指出，一些针对青春期前女孩进行的试验，只有测量免疫效果，而该试验的临床终点设定在16至24岁。
Haug博士指出，在他们的模式中，研究者也假设不是疫苗目标的其他HPV病毒株不会发作，不过，已经有证据指出这会发生；已经出版的试验显示，疫苗目标(HPV-16和HPV-18)之外的HPV血清型引起的癌症前期子宫颈病灶有增加的趋势。目前为止，此结果尚无统计上的显著意义，而研究对象也少。她表示，如果继续临床试验，未来几年持续累积资料，将可证明这是否是真正的趋势。
此外，Haug博士指出，该模式假设施打疫苗的女性会继续接受子宫颈癌筛检计划，而该疫苗不会影响对于HPV的自然免疫力；而这些都只是假设，还得看看它们是否真正正确。
回顾所有有待解答的问题时，Haug医师表示需要更多有关HPV疫苗的研究，她结论表示，我们应专注于透过研究寻找更有力的答案，而非根据间接、未经证实的假设，做出一些代价昂贵的决定。
该项研究没有相关利益冲突。
Caution Urged Over Large-Scale HPV Vaccination Programs
By Zosia Chustecka
Medscape Medical News
August 20, 2008 — "There is good reason to be cautious about introducing large-scale vaccination programs" with the human papillomavirus (HPV) vaccines, because many essential questions are still unanswered. This is the conclusion of Charlotte Haug, MD, PhD, from the Journal of the Norwegian Medical Association, in Oslo, writing in an editorial in the August 21 issue of the New England Journal of Medicine.
"The real impact of HPV vaccination on cervical cancer will not be observable for decades," Dr. Haug comments, but there has been pressure on policy makers worldwide to introduce the HPV vaccine in national or statewide vaccination programs.
Two HPV vaccines are marketed worldwide — the United States and Australia use Gardasil (Merck & Co), while the United Kingdom recently announced that it has chosen Cervarix (GlaxoSmithKline). A major target of these vaccination programs is girls between 12 and 13 years old, as the vaccine is most effective before the onset of sexual activity.
However, Dr. Haug questions how policy makers can make "rational choices about the introduction of medical interventions that might do good in the future but for which evidence is insufficient, especially since we will not know for many years whether the intervention will work or — in the worst case — do harm?"
Cost-Effectiveness Estimated in a Mathematical Model
The editorial accompanies a study published in the same issue of the journal on the health and economic implications of HPV vaccination in the United States by Jane Kim, PhD, and Sue Goldie, MD, from the Harvard School of Public Health, in Boston, Massachusetts. They use a mathematical model to calculate cost-effectiveness of vaccination in a country where there is already an established cervical cancer–screening program.
The study concludes that vaccination is expected to be economically attractive if high coverage can be achieved in the primary target group of 12-year-old girls and if the vaccine-induced immunity is lifelong. But adding a catch-up program for older girls and women is not cost-effective.
However, these conclusions are based on a mathematical model that makes many assumptions, and these are "quite optimistic," Dr. Haug comments. "Whether these assumptions are reasonable is exactly what needs to be tested in trials and follow-up studies," she maintains.
Dr. Haug discusses several of the assumptions on which the model is based in some detail, pointing out that in many cases there are very little data.
One of the main assumptions is that the effects of vaccination will be lifelong (ie, there will be no need for a booster). But 1 of the main questions still unanswered is how long the protection conferred by the vaccine will last. The researchers themselves point out that if protection wanes after 10 years, vaccination becomes much less cost-effective and screening becomes more effective than catch-up programs. One of the key investigators involved in the HPV-vaccine clinical trials, Diane Harper, MD, from Dartmouth Medical School, in Hanover, New Hampshire, has said that the evidence so far suggest that protection lasts for 5 years after vaccination, but there are no longer-term data, as previously reported by Medscape Oncology.
Another assumption is that the vaccine has the same effect on preadolescent girls as on older women. However, Dr. Haug points out, the only trials that have been carried out on preadolescent girls measured only immune responses, and the trials with clinical end points were conducted in 16- to 24-year olds.
In their model, the researchers also presume that other strains of the HPV virus, which are not targeted by the vaccine, will not take over. However, there is already some evidence suggesting that this may happen, Dr. Haug says. Published reports of trials show an increasing trend of precancerous cervical lesions caused by HPV serotypes other than those targeted by the vaccine (HPV-16 and HPV-18). So far, the results have not been statistically significant, but the numbers involved have been small. If clinical trials continue, data accumulating over the next few years will likely show whether this is a true trend, she says.
In addition, the model presumes that vaccinated women will continue to attend screening programs for cervical cancer and that the vaccine will not affect natural immunity against HPV, Dr. Haug comments. Again, these are assumptions, and it remains to be seen whether they are correct.
In view of all the questions that remain to be answered, Dr. Haug urges more research into HPV vaccination. "We should concentrate on finding more solid answers through research rather than base consequential and costly decisions on yet-unproven assumptions," she concludes.
No conflicts of interests were reported.
N Engl J Med. 2008;359:821-832, 861-862.