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Social values and scientific evidence: the case of the HPV
vaccines
Kristen Intemann and
Montana State University, Bozeman, MT, USA
Inmaculada de Melo-Martín
Weill Cornell Medical College, New York, NY, USA
Kristen Intemann: intemann@montana.edu
Abstract
Several have argued that the aims of scientific research are not always independent of social and
ethical values. Yet this is often assumed only to have implications for decisions about what is studied,
or which research projects are funded, and not for methodological decisions or standards of evidence.
Using the case of the recently developed HPV vaccines, we argue that the social aims of research
can also play important roles in justifying decisions about (1) how research problems are defined in
drug development, (2) evidentiary standards used in testing drug “success”, and (3) clinical trial
methodology. As a result, attending to the social aims at stake in particular research contexts will
produce more rational methodological decisions as well as more socially relevant science.
Keywords
HPV vaccine; Values in science; Evidence for use
Introduction
There is growing consensus that the aims of science often depend on social aims (Kitcher
2001; Solomon 2001; Longino 2002; Kourany 2003). Kitcher has argued that the main goal
of science is not merely to discover truths about the world, but particularly significant truths,
which are determined by human values and interests (Kitcher 2001, 44). Yet some assume that
this only has implications for which research programs to pursue or prioritize and does not
affect scientific methodology or standards of evidence. For example, Kitcher (2001) focuses
only on how to democratize decisions about research priorities. Similarly, Solomon (2001) is
concerned with promoting a fairer distribution of research resources and effort among
empirically adequate research programs that are driven by different values and interests. This
assumption reinforces the position that values may play a legitimate role in the context of
discovery, but not in the context of justification.
We argue that when the aims of research depend on social values, such values not only have
implications for research priorities but also help justify methodological decisions and standards
of evidence. Using the case of the recently developed human papillomavirus (HPV) vaccines,
we show that social, as well as epistemic, aims of the research play an important role in
methodological decision-making during basic research and in the design and execution of
© Springer Science+Business Media B.V. 2010
Correspondence to: Kristen Intemann, intemann@montana.edu.
NIH Public Access
Author Manuscript
Biol Philos. Author manuscript; available in PMC 2011 January 6.
Published in final edited form as:
Biol Philos. 2010 January 6; 25(2): 203–213. doi:10.1007/s10539-009-9191-9.
NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author Manuscript
clinical trials. In examining the development of HPV vaccines, we show that the justification
for a variety of methodological and evidentiary decisions depends partly on the extent to which
they promote the social aims of the research. In the final section, we draw out the normative
implications this has for research practices.
The case of the HPV vaccine
HPV, estimated to be the most common sexually transmitted infection worldwide, affects
approximately 20 million people in the United States and 6.2 million are newly infected each
year (Dunne and Markowitz 2006). Worldwide, genital HPV infection affects 440 million
people (WHO 2008).
There are over 100 HPV types, which are classified as “high-risk” and “low-risk” according
to the likelihood of developing cancer after infection (WHO 2008). Although in most cases
HPV infection is transient, persistent infection with high-risk HPV types is the major cause of
cervical intraepithelial neoplasia (CIN) and cervical cancer (Bosch et al. 2002). The most
common high-risk HPV types are 16, 18, 45 and 31, with HPV 16 and 18 accounting for about
70% of all genital cancers (WHO 2008).
Cervical cancer is the second most common cancer among women worldwide. Nearly 500,000
women are diagnosed with it each year, and over 250,000 die of the disease (WHO 2008;Parkin
et al. 2005). 83% of these cancers occur in developing countries, with Latin America, sub-
Saharan Africa, and South and Southeast Asia having the highest incidence (Parkin et al.
2005). In the US, in 2004, genital HPV infection resulted in nearly 12,000 new cases of cervical
cancer and 3,850 women died from the disease (U.S. Cancer Statistics Working Group
2007).
Two prophylactic vaccines, Gardasil® and Cervarix®, have recently been approved to protect
women against persistent infection from the most prevalent high risk HPV types, HPV 16 and
18 and CIN. Both vaccines are composed of noninfectious, recombinant HPV virus-like
particles (VLPs) of the major capsid protein, L1. L1 has the intrinsic capacity to self-assemble
into VLPs when expressed in eukaryotic cells. The advantage of these VLPs is that they are
morphologically indistinguishable from authentic virions but they lack the viral genome.
Because L1 VLPs mimic the natural virus structurally they are able to elicit high titres of virus-
neutralizing-antibodies in animals and humans (Frazer 2004; Schiller and Lowy 1996).
Gardasil® is a quadrivalent vaccine, produced in yeast. It includes VLPs of HPV types 6, 11,
16, and 18 (Garland et al. 2007). Cervarix®, is a bivalent VLP vaccine for HPV types 16 and
18 that is manufactured in an insect-cell system (Harper 2008). Research is also being
conducted on therapeutic vaccines for women who have already contracted an HPV, but we
discuss only prophylactic vaccines.
Though evidence indicates these vaccines are efficacious in preventing CIN, we show that the
extent to which this is evidence of drug success depends on the social aims of the research. If,
for example, one takes the goal of the research to be a reduction in cervical cancer morbidity
and mortality among vulnerable populations, alternative evidentiary standards and
methodological decisions would been more useful in helping to achieve that aim. We thus
argue that the extent to which methodological and evidentiary decisions are justified depends
partly on the degree to which they promote the social aims of the research. In particular, we
examine how the social aims of the research help justify (1) framing of research problems and
parameters for solutions, (2) evidentiary standards used in evaluating vaccine success and
safety, and (3) clinical trial methodology.
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Framing of the research problem and parameters for solution in vaccine development
One potential social aim of HPV research was to decrease cervical cancer morbidity and
mortality. How might this aim be relevant to adopting parameters for vaccine development?
As mentioned, the greatest incidence of cervical cancer occurs in developing countries. Since
the introduction of routine screening programs with Papanicolaou tests in the 1960s and 1970s
the incidence of cervical cancer has decreased in most industrialized countries, where it
accounts for only 7% of all female malignancies (Safaeian et al. 2007; Parkin et al. 2005). In
developing countries, however, where screening programs are less prevalent, cervical cancer
accounts for 24% of all female cancers (Safaeian et al. 2007; Suba et al. 2006). In these
countries, fewer than 50% of women affected by the disease survive longer than 5 years, while
about 66% do so in industrialized nations (Franco and Harper 2005). Thus, if the aim of HPV
research is to significantly decrease cervical cancer morbidity and mortality, then developing
a vaccine that will work in developing countries is crucial to this goal.
In investigating possible solutions to this problem however, researchers fail to attend to the
very different methodological criteria of testing efficacy or testing effectiveness of the possible
vaccines. Evidence about efficacy is not sufficient to establish that the medical procedures in
question will be effective, i.e., will work in real world conditions. Efficacy studies evaluate
whether the experimental procedure generates specific therapeutic effects and thus they
establish the extent to which a particular procedure is causally efficacious in treating or
preventing the studied condition, under the controlled circumstances of the laboratory. But in
practical contexts, like the ones usually present with developing medical intervention, a
solution to the question of efficacy, what vaccine can be developed that will under some ideal
protocol of use prevent HPV infection and cervical cancer, is adequate only if one does not
take into account the social goals of the research. This is so because efficacy studies, despite
their high internal validity, might not be very useful in guiding clinical care (Nallamothu et al.
2008; Cartwright 2007; Grossman and Mackenzie 2005). Such internal validity might tell us
little about how medical interventions perform in different real-world settings. If, on the other
hand, the social goals of the investigation are taken to be relevant in guiding research, then the
question of effectiveness, that is whether given the actual real world circumstances particular
vaccine strategies will have the desired effect, becomes relevant.
The two vaccines now on the market present significant challenges to be useful in developing
countries. First, these vaccines are expensive to manufacture because they are produced in
eukaryotic cell cultures and need extensive purification. Second, they require refrigeration and
thus are expensive to distribute, as they need a cold chain for storage. Third, three doses, over
a six month period, are delivered by intramuscular injection, which increases the costs of
production and distribution. Women in resource-poor countries, particularly those in rural
areas, will lack access to medical facilities, decreasing the likelihood they will be able to receive
all three doses. Fourth, they are most effective when given to females in early adolescence, but
in many developing countries, cultural barriers make this a difficult group to enroll in
vaccination programs. Finally, the vaccines are of little use to women who are already HPV-
infected or who have already developed neoplasia (Hildesheim et al. 2007; Schiller and
Nardelli-Haefliger 2006).
Now, one might argue that scientists cannot adopt research parameters in relation to the social
aims of the research because researchers cannot always predict how medical interventions
might work in the “real world.” Even when researchers are able to foresee that a solution will
not be completely effective in helping achieve a social aim, it may still be the “best available,”
given current scientific research. That is, scientists should adopt research parameters solely on
the basis of whether they are the most epistemically promising.
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At the time HPV vaccines were under development, however, researchers had a variety of
options that would have increased the ease of preparation, stability of the components, and
effectiveness of delivery. First, they could have used naked DNA that contained the L1 gene
driven by a strong eukaryotic promoter. Naked DNA is easily prepared in large scale with high
purity, is relatively safe, and can be used for repeat administration. Also, naked DNA vaccines
are highly stable relative to proteins and can sustain high levels of antigen expression in cells.
All of these characteristics make DNA vaccines cheaper in terms of ease of preparation, storage,
and delivery (Moniz et al. 2003; Schiller and Lowy 1996).
A second option was to use live bacterial vectors such as live attenuated Salmonella strains.
These vaccines can induce both mucosal and systemic immune responses and are able to
express foreign antigens (Fraillery et al. 2007). They can be generated inexpensively and are
likely to be potentially effective in a single dose. Moreover they do not require a cold chain
(Fraillery et al. 2007). This type of vaccine would have been easier to distribute and administer
in rural areas.
Another possibility was the oral delivery of VLPs in food, for instance, by generating transgenic
plants that express VLPs (García Carrancá and Galván 2007; Schiller and Lowy 1996).
Contrary to current parenteral vaccines, transgenic plants expressing recombinant vaccine
immunogens are an inexpensive alternative given that edible plants can be grown locally and
distributed easily without special training or equipment (Fernández-San Millán et al. 2008;
Warzecha et al. 2003).
We claim that which of these avenues for vaccine development would have been best, or most
justified, depends partly on the social aims of the research. If the aim of the research were to
significantly decrease cervical cancer morbidity and mortality, it would have been more
rational to use a vaccine technology more likely to be useful in the context of resource poor
countries. If the aim of the research were, say, to produce a profitable vaccine, then this would
justify developing a vaccine more likely to work in industrialized countries. The social aims
of the research help justify the parameters that a successful vaccine must meet (as well as the
decision about which research strategies are most likely to achieve them). Different aims will
help justify different research parameters.
Now, one might argue that no particular social aims of research need to be endorsed, as multiple
aims can be pursued simultaneously through a variety of empirically adequate research
programs. Solomon (2001) advocates this approach. On Solomon’s view, research effort
should be distributed among the development of each type of vaccine to the extent that the
research program is yielding empirical success (Solomon 2001, 32). This way, whether we
value helping the most vulnerable populations or producing profits for drug companies, each
empirically promising avenue of research will be pursued (solely on epistemic grounds).
While research on each of the different vaccine strategies is presently being conducted, it is
unclear that decisions about which strategies to pursue can be made on the basis of empirical
success alone. First, because there are limited resources, pursuing all empirically adequate
possibilities may be difficult. More importantly, pursuing some vaccine development options
may hinder work on others, even if they are empirically successful. The fact that efficacious
prophylactic HPV vaccines already exist might make it more difficult for other vaccines to
reach clinical trials and the market. If the public in industrialized countries perceives that
current vaccines solve the problem of cervical cancer, public funding sources to develop
alternative vaccines may be unavailable. Similarly, because of intellectual property constraints,
competitive commercialization of other VLP-based vaccines might be difficult. Given the
significant investments by Merck and GSK in the current vaccines, it is unlikely that they will
be interested in the development of substantially different and cheaper vaccines (Schiller and
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Nardelli-Haefliger 2006). Thus, not all empirically adequate research avenues can be pursued
simultaneously. Choices must be made about which properties are necessary for a successful
vaccine to have. Making this decision rationally, however, involves endorsing and consulting
particular social aims.
Evidentiary standards in vaccine testing
The social aims of research also play an important role in helping to justify evidentiary
standards in vaccine testing. Randomized clinical trials, the main method for testing and
evaluating medical procedures, are considered the gold standard (Sackett et al. 2000). Because
such trials are carried out in highly controlled laboratory conditions, when designed and
conducted appropriately, they give us evidence for the efficacy of such procedures. Indeed,
results from major Phase II and III trials of the two HPV vaccines show they are highly
immunogenic and efficacious against CIN2/3 lesions and adenocarcinoma in situ (AIS). These
lesions are the obligate and immediate precursors to invasive cancer. Evidence also indicates
that the vaccines offer some protection against persistent HPV16 and/or18 infections to HPV
naïve women. (Harper et al. 2006; Garland et al. 2007; Paavonen et al. 2007; The Future II
Study Group 2007a, b).
But as we indicated earlier, evidence about efficacy is not sufficient to establish the
effectiveness of medical interventions. Hence, clinical trials might be alternatively designed
to obtain evidence of effectiveness. That is, they could be conducted under circumstances more
closely simulating conditions that normally obtain for patients. This, too, would have potential
drawbacks. Obtaining evidence of effectiveness involves allowing a host of complex variables
to influence clinical trial experiments. This makes it far more difficult to isolate and identify
causal relationships. As a result, the effectiveness measured can be due to other factors such
as placebo effect, concomitant therapies, or social factors.
One option would be to require Phase IV clinical trials for drug approval in addition to Phase
II and III trials. Phase IV trials would obtain evidence of longer-term effectiveness in real world
conditions in addition to evidence of efficacy. Such a requirement before drugs are approved,
however, could delay potentially helpful medical interventions.
Thus, researchers have a choice about the kind of evidence that is important to collect for drug
“success.” There are limitations to designing clinical trials that only test for efficacy, as well
as drawbacks to only testing for effectiveness. Our claim is that the grounds for making this
choice include the extent to which various evidentiary standards promote the social aims of
the research. If the aim of the research is to have a vaccine that will be effective in certain real
world conditions, then evidence of efficacy alone will be insufficient. Even if this social aim
is ultimately outweighed by other epistemic or social values, such as the need to isolate causal
relationships or get medical interventions into the market quickly, the justification for adopting
particular evidentiary standards will rest on weighing these competing values. In the next
section we show that the social aims of the research also play a role in justifying specific
methodology adopted in the design of HPV clinical trials.
Methodological decisions in clinical trial design
The social aims of the research also help justify specific methodological choices in clinical
trials. First, they have implications for the appropriate duration of clinical trials. The follow
up for HPV vaccine studies have been relatively short (about 5 years). This is somewhat
problematic insofar as part of the aim of the research is to create vaccines with long term
protection against HPV. Of course, the value of having evidence of long-term HPV protection
must be weighed against the value of getting the vaccine quickly on the market. Balancing
these interests, however, involves weighing the social aims at stake in the research. The extent
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to which methodological decisions about the duration of clinical trials are justified involves
social values.
Second, the social aims of research help justify inclusion and exclusion criteria. Like typical
efficacy studies, clinical trials for HPV vaccines used narrow enrollment criteria such as healthy
women aged 15–26 years, with a particular number of lifetime sexual partners before study
enrollment, adequate contraception over the vaccination period, cytologically negative, and
seronegative for HPV-16 and HPV-18 antibodies. With narrow eligibility criteria, we cannot
determine whether the seroconversion rates, antibody titres, and efficacy rates will be as high
in unselected populations of women (Kahn and Burk 2007). When taking into account women
representative of those in real world settings, such as women who did not follow the protocol
adequately or did not complete the planned vaccination regimen, some studies have reported
only a 17% overall reduction in CIN after administration of the quadrivalent vaccine (The
Future II Study Group 2007a, b). How narrow the selection criteria ought to be depends on
weighing the social, as well as epistemic, consequences of adopting such criteria.
To the extent that the aim is to measure whether the vaccine will work for the most vulnerable
populations, wider inclusion criteria may be more justified. After all, women in non-
industrialized countries who are most likely to develop and die from cervical cancer are also
likely to fail to meet one or more of the narrow inclusion criteria for the vaccine trials. These
women are more likely to be infected with the human immunodeficiency virus (HIV) and
evidence indicates that HIV positive women are at an increased risk of developing CIN and
cervical cancer (Adam et al. 2008). They are also more likely to have endemic infections, such
as hepatitis B or malaria that chronically alter the immune system and may modify the patterns
of immunogenicity or affect the safety profile of HPV vaccine. Additionally, there may be
significant differences in HPV vaccine immune responses among malnourished, compared
with better-nourished, populations (Pagliusi and Teresa Aguado 2004).
Thus, clinical trials that have “healthy” as an inclusion criterion fail to collect relevant data on
populations of women most at risk for cervical cancer. Again, this is a problem insofar as the
aim of the research is to decrease cervical cancer morbidity and mortality in those populations.
Third, the social aims of the research have implications for what will count as a representative
group of subjects included in clinical trials. For example, to what extent should a pool of
subjects be heterogeneous or ethnically diverse and what sort of diversity is necessary? In HPV
vaccine clinical trials, the proportion of subjects who reported they were black or Hispanic in
these studies was small (Kahn and Burk 2007). This could be problematic given the fact that
Hispanic women are diagnosed with cervical cancer almost twice as often, and African
American women more than 1.5 times as often as non-Hispanic white women (Downs et al.
2008). If the aim is to reduce cervical cancer in the most vulnerable populations, then their
representation in clinical trials is crucial to ensure that ethnicity does not affect the
efficaciousness of the vaccine.
Fourth, the social aims of the research help justify which endpoints or surrogate endpoints
should be adopted in clinical trials. HPV vaccine trials use CIN 2+ as a surrogate endpoint,
given that for both practical and ethical reasons, researchers cannot and ought not to wait to
see if subjects actually develop cancer (Kahn and Burk 2007). This decision is justified insofar
as these are accurate predictors of cervical cancer and insofar as the aim of the research is to
reduce cervical cancer morbidity and mortality. If the social aim of the research were, for
example, reducing the incidence of genital warts, then this would be reason to adopt a different
endpoint. Thus, whether a particular endpoint or surrogate endpoint is justified depends partly
on the social aims of research.
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Finally, the social aims of the research can help justify clinical trial locations. Both the bivalent
and the quadrivalent vaccine have undergone phase III clinical trials in North America, Latin
America, Europe and the Asian Pacific region. Despite the fact that age-standardised HPV
prevalence is significantly higher in sub-Saharan Africa than in other world regions, vaccine
studies were not done in these countries. This is particularly significant given evidence that
suggests heterogeneity in HPV type distribution among women from different populations
(Blossom et al. 2007; Clifford et al. 2005). Studies indicate that HPV-positive women in sub-
Saharan Africa are significantly more likely to be infected with high-risk types of HPV other
than HPV16 than were women in Europe. HPV35, HPV45, HPV52, HPV56, and HPV58 are
all more common in HPV-positive women in sub-Saharan Africa than in Europe. Indeed,
HPV35 is as prevalent as HPV16 in sub-Saharan Africa, but four to five times less prevalent
than HPV16 in other regions (Clifford et al. 2005). Regional differences, although somewhat
weaker, exist not only in cases of HPV infection but also in cases of cervical cancer. A smaller
proportion of cases in sub-Saharan Africa and Asia are associated with HPV16 compared with
those in Europe or North America (Clifford et al. 2005). Hence, HPV vaccines for types 16/18
might have different efficacy measures in clinical trials conducted in different countries
(Muñoz et al. 2004). Thus, the decision about where best to conduct clinical trials depends
partly on the social aims of the research (e.g., which populations are being targeted).
We have shown that methodological decisions about the duration of the study, subject selection
criteria, diversity of subjects, choice of surrogate endpoints, and location of clinical trial sites
are justified partly by the social aims of the research. Some methodological choices will
promote specific social aims better than alternatives. Making good methodological decisions
in the design of clinical trials thus depends on social, in addition to epistemic, values.
Normative implications and conclusions
The case of the HPV vaccines shows that the specific social aims of biomedical research play
a role in justifying research decisions in both drug development and testing. Such aims can be
relevant to the choice of research strategies, evidentiary standards, and methodologies. If these
decisions are made in relation to social aims, researchers will be more likely to produce medical
interventions that are more socially relevant and effective.
In these ways, social values can play important and appropriate roles that go beyond merely
determining what ought to be studied or funded. That is, they are sometimes necessary to
making fully grounded methodological decisions. Thus, we join those philosophers of science
who argue that ethical and social values can play inescapable and necessary roles in science,
at least in those research contexts that are related to public policy (Longino 2002; Douglas
2007; Kourany 2003). This is not to say that social values stand as evidence for the truth of,
for example, claims about the causal mechanisms of HPV or the efficacy of a particular drug.
They can, however, provide us with reasons to take certain research strategies or methodologies
to be better than alternatives. Thus, our arguments are also consistent with the position, taken
by several philosophers of science, that social value judgments need not undermine the
objectivity or rationality of science (Longino 2002; Dupré 2007). Indeed, we are claiming that
they can increase the rationality of some standards of evidence and methodological decisions.
If we are correct that the social aims of research affect decision-making, this raises the question
of which social values and aims should be endorsed and who, exactly, should be making such
decisions. Clearly, if social values are at stake, we must strive to appeal to values that are well
supported. But, given the existence of multiple competing social values, how is this best
accomplished? While we cannot develop or defend here complete answers to these questions,
we draw some tentative normative lessons from the HPV case.
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Obviously, scientists have an important role in helping to endorse particular social aims of a
research program and making judgments about how best to promote those aims. Biomedical
researchers have the scientific expertise relevant to determining how social aims might be best
conceived in relation to particular health problems, and how those can be promoted given the
current state of biomedical research. For example, biomedical researchers would be in the best
position to know which current vaccine types are possible and most promising, or which
surrogate endpoints are appropriate.
Yet although scientists need to be involved in identifying, endorsing, and promoting the social
aims of research, it is not clear that they can or should be making such judgments alone. As
Kitcher (2001) points out, the social aims of research (in order to be justified) should represent
the interests of all stakeholders. Scientists may be unaware of all the interests at stake, and they
may lack important information relevant to how they could best promote social goals.
Biomedical researchers working on the HPV vaccine may know little about the social
conditions in rural Africa that impose limitations on successful vaccine delivery. Thus, in order
to promote more socially relevant science, there need to be mechanisms for scientists, social
scientists, ethicists and policymakers to collaboratively reflect on the social aims of research
and how best to promote them.
One mechanism for such collaboration is in the writing and evaluation of grant proposals. When
applicable, principal investigators should be required to identify the social aims of their
research, and their proposed methodology should be justified in relation to not only to epistemic
goals, but also to social ones. Grant reviewing teams should include diverse individuals with
relevant expertise. In the HPV case, insofar as the aim of the research is to significantly reduce
cervical cancer among vulnerable populations, this might include microbiologists,
immunologists, sociologists, epidemiologists, public health professionals, and ethicists. In
evaluating the intellectual merit of research programs, reviewers need to consider the extent
to which the social aims of the research are justified, as well as the extent to which the proposed
research strategies, standards of evidence, and other methodological choices promote those
aims better than alternatives. The interests and expertise that will need to be represented in the
review process will depend partly on the nature and content of the particular research project.
While we cannot provide a full account of how the social aims of research might be endorsed
or promoted here, it is clear that a discussion about which social aims should be endorsed in
particular research contexts and who should make those decisions is a conversation that is
appropriate and necessary. It is a discussion that will not take place if scientists continue to
assume that values have no business in science.
Acknowledgments
This publication was made possible by Grant Number P20 RR-16455-06 from the National Center for Research
Resources (NCRR), a component of the National Institutes of Health (NIH). Its contents are solely the responsibility
of the authors and do not necessarily represent the official view of NCRR or NIH.
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