Re: [asa] NEJM Editorial on HPV Vaccine

From: David Opderbeck <>
Date: Fri May 11 2007 - 22:02:30 EDT

Stewart's letter concerning the jurisprudential issues is lame. The Supreme
Court has held that states may mandate vaccines for schoolchildren -- well,
duh. That says nothing about whether any particular vaccine ought to be
required as a general policy matter. And note the conclusions in Sawaya and
McLune's editorial, which isn't quite so sanguine, given the variety of HPV
types. Personally, I don't think it's wise to consider this a simple
question of whether folks are willing to accept established science or not.

Sawaya and McLune:

Another factor explaining the modest efficacy of the vaccine is the role of
oncogenic HPV types not included in the vaccine. At least 15 oncogenic HPV
types have been
targeting only
2 types may not have had a great effect on overall rates of preinvasive
lesions. Findings from the FUTURE II trial showed that the contribution of
nonvaccine HPV types to overall grade 2 or 3 cervical intraepithelial
neoplasia or adenocarcinoma in situ was sizable. In contrast to a plateau in
the incidence of disease related to HPV types 16 and 18 among vaccinated
women, the overall disease incidence regardless of HPV type continued to
increase, raising the possibility that other oncogenic HPV types eventually
filled the biologic niche left behind after the elimination of HPV types 16
and 18. An interim analysis of vaccine trial data submitted to the
a disproportionate, but
not statistically significant, number of cases of grade 2 or 3 cervical
intraepithelial neoplasia related to nonvaccine HPV types among vaccinated
women. Updated analyses of data from these ongoing trials will be important
to determine the effect of vaccination on rates of preinvasive lesions
caused by nonvaccine HPV types.

What can be inferred from these data about the potential effect of
vaccination among girls 11 and 12 years of age? The FUTURE trials did not
enroll subjects in this age group. Within both trials, subgroups of subjects
with no evidence of previous exposure to relevant vaccine HPV types were
evaluated separately for vaccine efficacy. In these subgroups, efficacy of
nearly 100% against all grades of cervical intraepithelial neoplasia
and adenocarcinoma
in situ related to vaccine HPV types was reported in both trials. However,
it would be important to know the overall rates of grade 2 or 3 cervical
intraepithelial neoplasia or adenocarcinoma in situ regardless of HPV types.
Without these data, it is difficult to infer both the effectiveness of
vaccination and the role of nonvaccine HPV types in overall rates of
preinvasive lesions.

On 5/11/07, Rich Blinne <> wrote:
> *Human Papillomavirus Vaccine Opportunity and Challenge*<>
> *Lindsey R. Baden, M.D., Gregory D. Curfman, M.D., Stephen Morrissey, Ph.D.,
> and Jeffrey M. Drazen, M.D. *
> In this issue of the *Journal,* we publish three Original Articles,1<>
> , 2 <>,3<> two
> Perspective articles,4
> <>,5<>two editorials,
> 6 <>, 7<>a letter to the
> editor,8 <> and an
> audio interview 9<>on the subject of human papillomavirus
> (HPV). We bring together this unique body of information in response to
> the enormity of the health problems that stem from HPV and the broad
> interest that has been kindled by the possibility of preventing
> HPV-related cervical cancer and other anogenital conditions through
> vaccination.
> The HPV vaccine is the first vaccine explicitly designed to prevent cancer
> induced by a virus. (The hepatitis B vaccine was not primarily designed to
> prevent cancer.) As noted in the Perspective article by Agosti and Goldie,
> 5 <> the
> consequences of HPV infection are a global health concern that
> disproportionately affects those in developing countries. The potential
> ability to reduce the burden of HPV-related disease by vaccination against certain
> disease-inducing strains of the virus has created a volatile intersection
> between the community's interest in limiting the transmission of
> infectious diseases and promoting health on the one hand and social mores
> on the other, as discussed by Charo in her Perspective article 4<>and related audio interview (podcast
> available at<>However, this volatility should
> not keep us from recognizing the enormous potential for medical progress
> and from addressing the numerous unanswered questions that remain.
> The finding that infection with HPV is a critical factor in the majority
> of cases of cervical cancer allowed the development of strategies to
> prevent this form of oncogenesis. It is important to note that several
> other cancers are also associated with HPV infection, including head and
> neck cancers, as demonstrated by D'Souza and colleagues. 3<>Although there are many HPV serotypes, two
> of them 16 and 18 account for the lion's share of the oncogenesis. The
> data that are presented in reports on the vaccine efficacy trials in this
> issue of the *Journal*1<>
> ,2 <> confirm the
> success in reducing the incidence of precancerous cervical lesions with
> vaccine directed against the HPV-16 and HPV-18 serotypes.
> Although this is a remarkable achievement, the efficacy of the vaccine is
> limited by at least these two factors. First, not all cervical cancer is
> caused by HPV-16 or HPV-18, and second, it appears necessary to vaccinate
> young women before they are infected with these two serotypes. Also,
> whether this approach will extend the paradigm of vaccination to the
> prevention of death and disability from cervical cancer is an unanswered
> question. [emphasis mine]
> It is difficult to show that an intervention prevents cancer, given the
> relatively long induction phase between exposure to an inducing agent and
> development of disease. Thus, key surrogate markers, in this case cervical
> intraepithelial neoplasia grades 2 and 3, were used so that data could be
> gathered in a timely fashion. However, correlation with the ultimate
> outcome cancer prevention will require the long-term observation of a
> large number of treated women. We must also carefully monitor for
> unintended adverse consequences of vaccination. For example, when
> selective immunologic pressure is applied with vaccination, the potential
> exists for nonvaccine-related strains to emerge as important oncogenic
> serotypes. These critical points are clarified in the editorial by Sawaya
> and Smith-McCune. 6<>
> Many other questions are raised by these remarkable data. Should young men
> be vaccinated? What is the durability of immune protection? Could fewer
> than three vaccinations provide adequate protection? Will future HPV
> vaccines extend protection to cover additional pathogenic serotypes? Will
> the economics allow this therapy to reach all who may benefit, such as
> those in the developing world? Might HPV vaccination be beneficial in
> preventing other, noncervical HPV-induced cancers (such as HPV-related
> oropharyngeal cancer 3<>
> )?
> There is no doubt that the findings reported in this issue of the *Journal
> * open a new field at the interface of basic science, clinical medicine,
> public health, and public policy. It is important to keep in mind that
> these new treatments raise many scientific, medical, economic, and
> sociological questions. We have begun an exciting journey; we need to
> continue in the right direction.
> *References*
> 1. The FUTURE II Study Group. Quadrivalent vaccine against human
> papillomavirus to prevent high-grade cervical lesions. N Engl J Med
> 2007;356:1915-1927. [Free Full Text]<>
> 2. Garland SM, Hernandez-Avila M, Wheeler CM, et al. Quadrivalent
> vaccine against the human papillovmavirus to prevent anogenital diseases. N
> Engl J Med 2007;356:1928-1943. [Free Full Text]<>
> 3. D'Souza G, Kreimer AR, Viscidi R, et al. Case-control study of
> human papillomavirus and oropharyngeal cancer. N Engl J Med
> 2007;356:1944-1956. [Free Full Text]<>
> 4. Charo RA. Politics, parents, and prophylaxis -- mandating HPV
> vaccination in the United States. N Engl J Med 2007;356:1905-1908.
> [Free Full Text]<>
> 5. Agosti JM, Goldie SJ. Introducing HPV vaccine in developing
> countries -- key challenges and issues. N Engl J Med 2007;356:1908-1910.
> [Free Full Text]<>
> 6. Sawaya GF, Smith-McCune K. HPV vaccination -- more answers, more
> questions. N Engl J Med 2007;356:1991-1993. [Free Full Text]<>
> 7. Syrjanen S. Human papillovmaviruses in head and neck carcinomas.
> N Engl J Med 2007;356:1993-1995. [Free Full Text]<>
> 8. Stewart S. Mandating HPV vaccination -- private rights, public
> good. N Engl J Med 2007;356:1998-1999. [Free Full Text]<>
> 9. Interview with R. Alta Charo. (Available at

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Received on Fri May 11 22:03:05 2007

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