In considering the risks detailed in the following sections, those
who hold the Antithesis position would wish readers and researchers
to keep in mind the wise little proverb: "The burdens that
appear easiest to bear are those that are borne by others."
This is particularly important to keep in mind because virtually
all volunteers in phase III HIV vaccine trials will be persons
from groups which may easily be seen by research sponsors as The
Other. The doctors at Buchenwald and Auschwitz, for example, had
little trouble distancing themselves from the pain that they inflicted
on subjects in their medical experiments because the subjects
were all Other: they were Jews or Poles or homosexuals or Gypsies
or Slavs or mental patients, and especially important, they were
all prisoners, they all had tatoos, and their heads had all been
shaved. They did not look like "Us," and they did not
act like "Us". It was easy, though of course not morally
justified, for doctors to perceive the prisoner-subjects as The
Other.
I do not wish at all to hint, not even indirectly, that today's
research sponsors of HIV vaccine trials are somehow like the Nazi
doctors. Today's vaccine researchers are highly compassionate
and are not racially prejudiced as were the doctors of the Third
Reich who worked in Auschwitz and Buchenwald and Birkenau. No
one who has seen the effects of the pandemic in Uganda or Rwanda
or any of the other hardest hit nations could fail to be greatly
moved by the deep tragedy of it, and by the powerful sufferings
of whole families and whole regions. What I do wish to underscore,
though, is how easy it is for ordinary human beings to feel differently
toward The Other than we feel toward someone whom we perceive
as Us. Whenever we perceive someone as Other we become less likely
to understand them, and even less likely to make an effort to
understand them. We are less likely to take their sufferings and
their burdens as seriously as we take the sufferings and burdens
of people whom we perceive as Us. I am inclined to think that
this tendency in us weak and ignorant human beings is a rather
prevalent tendency, but it is certainly not a good one. It stems
from a weakness and a narrowness of perception, and we have a
strong moral obligation to strive to overcome it. We must strive
to appreciate the sufferings and burdens of others as much as
we appreciate the sufferings and burdens in our own lives. Research
sponsors particularly should take very seriously the insight of
Mrs Eva Mozes-Kor.
Eva is still alive. She and her twin sister Miriam were human
subjects in Dr Josef Mengele's experiments on twins, at Birkenau.
To look back at my childhood is to remember my experiences as a human guinea pig in the Birkenau laboratory of Dr Josef Mengele. To recount such painful memories is to relive the horrors of human experimentation, where people were used as merely objects or means to a scientific end.
Mrs Mozes-Kor proceeds to describe the horror of these experiments in which she and her sister were subjects, some of which involved studies in genetics and some of which concerned germ warfare, and how they were conducted. Interested readers can find and read (in the book cited below) her moving six page account of what it was like to be one of those twins, but for our purposes here I want to focus on her conclusions.
I hope that what was done to me will never again happen to another human being. This is the reason I have told my painful story. Those who do research must be compelled to obey international law. Scientists should continue to do research. But if a human being is ever used in the experiments, the scientists must make a moral commitment never to violate a person's human rights and human dignity. The scientist must respect the wishes of the subjects. Every time scientists are involved in human experimentation, they should try to put themselves in the place of the subject and see how they would feel. The scientists of the world must remember that the research is being done for the sake of mankind and not for the sake of science; scientists must never detach themselves from the humans they serve. I hope with all my heart that our sad stories will in some special way impel the international community to devise laws and rules to govern human experimentation.
We will examine later in this book
a document, sponsored and published by the Council for International
Organizations of Medical Sciences (CIOMS) and the World Health
Organization, titled International Ethical Guidelines for Biomedical
Research Involving Human Subjects, published in its final form
in late 1993, after long years of consultation and research. We
will be exploring this document in detail, but for now it would
be well to consider Eva's key words: "Every time scientists
are involved in human experimentation, they should try to put
themselves in the place of the subject and see how they would
feel."
I again wish to emphasize that the human experiments performed
by the Nazi doctors in the concentration camps are not here being
compared to today's HIV vaccine trials. These are two entirely
different categories of human experiments. The former were done
with utter disregard for human beings and human suffering, and
the latter are being planned by compassionate researchers with
the greatest concern for the well being of humanity in general,
and the research subjects in particular. The only similarity is
that both involve the participation of human beings as research
subjects, and whenever human beings participate as volunteers
in research protocols, there is some degree of risk that they
will be seen more as a means than as ends, more as an Other than
as an Us. Eva's words are reminders to us to overcome this tendency
to see other human beings as Other, particularly when those others
look and act differently than we do. Eva asks us to "put
ourselves in the place of," particularly when it comes to
medical research involving human subjects.
The unspoken conclusion to Eva's words is a variation on the Golden
Rule (to do unto others as you would have others do unto you).
The variation, sometimes called the Silver Rule, is phrased thus:
Do not do unto others what you would not wish others to do unto
you. This is Eva's main request to researchers: Put yourself in
place of the Other. Anticipate the Other's concerns. Do not do
to them what you would not wish done to you. If ever any principle
should be kept foremost in the minds of those who undertake human
subjects research, this is that principle.
Now let us consider, from the perspective of the Antithesis position, some of the potential hazards, large and small, more probable and less probable, that may have to be borne by those who would choose to volunteer in these vaccine trials.
11.1 No future protocols
The opportunity to participate in a future vaccine research protocol
is, in all likelihood, effectively sacrificed when one volunteers
for these present experiments. Should a more promising candidate
vaccine be developed in the future - and future candidate vaccines
would almost certainly be in some ways superior - today's volunteers
would be excluded from participating in that research. Reasons
for exclusion might vary, but would probably be built around the
notion that these subjects had been "contaminated" by
another significant variable, namely, exposure to a previous vaccine.
Volunteers in today's experiments should know that they will probably
not be able to participate in future vaccine research. This should
be considered a "harm" for them, but (in my opinion)
perhaps not the most important one. That this "harm"
would actually happen to subjects in the present studies is a
virtual certainty.
11.2 Immediate systemic reactions
A usually mild, but still real, systemic reaction sometimes immediately
follows upon a vaccination procedure. Sometimes the reaction is
as mild as a headache, local pain at the site of the injection,
and a fever, but sometimes the reaction can be more severe, including
symptoms as serious as convulsions. Subjects will want to be aware
of these possibilities.
11.3 Potential immune tolerance
The possibility exists, though it may be a relatively small one,
that a subject who receives this present candidate vaccine could
become immune to the effects of any future HIV vaccines. This
circumstance, if it were to come about, would be called "immune
tolerance" and would have the effect of rendering a person
immunologically unresponsive to the original antigen [HIV], i.e., viral protein(s) capable of inducing immune responses. Immune tolerance may prevent the immune system from mounting any response upon "seeing" this antigen again.
No one presently knows how likely
or unlikely this occurrence might be, nor will they know until
phase III trials are well under way, but it is within the realm
of possibility.
If this were to occur it would have two serious consequences:
1) It would mean that this person's immune system would no longer
mount any response at all against HIV. It would mean that if this
person were to become infected with HIV, the immune system would
not fight the virus at all, so progression to disease would likely
be more rapid than normal. 2) Immune tolerance would also mean
that if an effective vaccine against HIV were to be developed
and proven successful at some time in the future, this volunteer
would not be able to use it because they would not respond to
it at all. It would do them no good. They would probably not even
be offered a future successful vaccine, especially if it is a
vaccine of the whole attenuated virus type, for fear that it would
simply infect the person and cause them to develop AIDS.
This risk, though perhaps small, may be a significant one in the
minds of some potential volunteers.
11.4 Enhanced infectivity
A more important hazard for volunteers is the uncertain possibility
of "antibody enhanced infectivity".
It has been shown by a number of investigators that some HIV antibodies actually help HIV enter host cells, primarily monocyte cells. This phenomenon is called antibody enhanced infectivity. Antibodies that enhance HIV infectivity have been identified in the serum of HIV-infected patients and in HIV infected and immunized animals.
This potential hazard would mean
that subjects inoculated with the candidate vaccine could actually
be at greater risk for disease than non-vaccinated persons. It
would mean that persons who have developed antibodies to HIV (which
is what most vaccines stimulate the body to do), and who then
subsequently became exposed to HIV through one of the usual routes
of infection (which is what phase III subjects will be doing),
would then be
1) more likely to become infected (that is, more easily infected)
with the virus,
2) more likely to progress to disease,
3) more likely to progress to disease faster, and/or
4) perhaps more likely to develop a more serious form of disease
than non-vaccinated persons.
Antibody-enhanced infectivity in candidate viral vaccines is not,
unfortunately, either unknown or unprecedented. According to studies
cited below, the phenomenon has been shown to exist in at least
three or four candidate vaccines for various viral diseases. This
hazard became enough of a danger that it blocked research into
a vaccine against respiratory syncytial virus (RSV, the major
cause of infantile pneumonia) thirty years ago. When an RSV vaccine
was undergoing testing in infants in the 1960s "researchers
found to their surprise that a strong immune response against
the virus can, for unknown reasons, actually enhance the disease".
Research was stopped because the hazard was considered too great
a risk for the subjects in the trials. This candidate RSV vaccine
had already been through phase I and II trials and had been "shown
to be nontoxic and antigenic in adult volunteers and nontoxic
in infants and children before the larger efficacy study was initiated.
The apparent sensitizing effect of the vaccine was entirely unexpected."
The problem of antibody enhanced infectivity has also "been
shown to be important in other viral diseases such as dengue fever
and rabies". It was a problem in some earlier measles vaccines
as well.
I believe this risk, if it is indeed as real as the literature
suggests, is a significant one. Subjects in phase III trials may
have the experience of the subjects in phase I and II trials to
give them some estimate of the likelihood of this occurrence,
but perhaps not (as we have just seen with the RSV experimental
vaccine). The number of subjects in phase I and II trials may
simply be too small to demonstrate the risk, or the length of
the trials too short (only one or two years) to establish just
how serious or likely this risk actually is. Or the subjects in
phase I and II trials may simply be at too low a risk to demonstrate
the enhancement that would occur only in the presence of encounter
with wild virus. In any case, subjects in phase III trials will
probably have no more information on what level of risk to expect
for antibody-enhanced infectivity than we have right now. (The
problem of enhanced infectivity with the measles vaccine mentioned
above was not discovered to be a significant problem until long
after phase I and II trials had been completed, and the vaccine
had already been administered to "hundreds of thousands of
recipients". ) In sum, the risk for antibody-enhanced infectivity
in HIV vaccines may be fairly high or not very high. We simply
do not yet know. And unfortunately we cannot know until we test
the candidate vaccines in human populations.
I imagine that some volunteers will see this risk as important
enough to decline participation in the trials. When it is made
clear to them that "antibody-dependent enhancement of HIV
is [truly] a genuine concern," they may conclude that this
risk alone offsets the potential (perhaps small potential) for
protection against HIV infection offered by the vaccine. All potential
volunteers should be made to fully understand this potential hazard.
11.5 Discrimination
11.5.1 The problem
Social discrimination due to the volunteers' new HIV antibody
status should be expected. Probably for the rest of their lives
these volunteers will be HIV antibody positive (HIVAb+) as a result
of being given an HIV vaccine. They may find that when they wish
to donate blood or other organs or tissues, or enlist in military
service, or apply for health or life insurance, or travel internationally,
or even be treated by certain health care or dental practitioners,
that they are subjected to unfair discrimination. They may be
treated with hostility by neighbors, friends, or work associates.
They may have difficulties finding a marriage partner.
The potential for harm to one's personal reputation also comes with trial participation. The peers of potential participants may view cooperating with government researchers as evidence of gullibility or foolhardy complicity with authority. Participants should know that such social discrimination could seriously affect their everyday lives and may not be compensable.
Moreover, the degree of social discrimination
faced by volunteers in phase III trials is liable to be significantly
higher than the risk of discrimination faced by those in phase
I and II trials, since most of the subjects in phase I and II
trials will probably be from the middle classes of a society and
will also be from groups at lower risk of infection.
Already, even before trials begin, the social discrimination suffered
by persons who are HIV+ is severe. In Thailand, for example, it
is reported that one of the biggest problems facing HIV+ persons
is the social discrimination leveled against them. "Disclosure
of a positive status," says one account, "usually leads
to the loss of employment, isolation from the community, and problems
within the family". It may lead to numerous other problems
as well. And we can be sure that the fear of HIV+ persons is not
unique to Thailand.
Researchers will probably provide each volunteer with official
documentation certifying that their HIVAb+ status is due to their
participation in a vaccine trial, and will probably also provide
a toll-free phone line for doubters to call and confirm. Researchers
will probably also make pre-arrangements with insurance companies
and other agencies so they will accept such documents, unless
there are extenuating circumstances. But there may be good reason
to doubt that these documents would ever be taken seriously. In
the first place, documents can be forged and phone numbers can
be bogus, so an effective method of insuring authenticity would
need to be devised. But more importantly, the persons to whom
you would present such documents might not accept them because
they may be secretly thinking, "Of course I see that you
were in a vaccine experiment a few years ago, and that caused
you to become HIVAb+, even though you were not infected with the
virus. But perhaps you have also become infected with the real
virus in the interval since that vaccine experiment, and I have
no simple and quick way of testing for that. Also, I wonder if
the researchers might have chosen you to participate in their
vaccine trials because you are a person who is at higher than
normal risk for HIV infection. So I think I'll just play it safe
and not hire you, not let you join the army, not let you donate
blood, not sell you our insurance, not etc etc."
This hypothetical person's thinking is not illogical, since the
volunteer could very well have become really infected with the
virus since participation in the vaccine experiment. In fact,
it would be a safe bet that the volunteer probably has engaged
in some risky behaviors. As we will see below, most volunteers
would not have been chosen as subjects in the vaccine trials if
the researchers did not have good reason to believe that they
would in some manner expose themselves to the virus now and then.
Phase III vaccine trials must, after all, be done with subjects
who are at some significant risk of exposure to the virus, otherwise
the research would be pointless. Thus, our hypothetical secret
thinker is correct in reasoning that this candidate is probably
a person who is, or who was at some fairly high risk of becoming
HIV infected. In any event, whether we consider this thinking
to be correct or not, it is very likely that this sort of thinking
will occur, namely, thinking which leads to discrimination against
volunteers.
It is indeed reasonable to assume that such real discrimination
will occur at some times in that volunteer's future life. In fact
any interested reader can peruse some first person accounts of
real discrimination against HIV+ persons who live in developing
nations. Richardson and Bolle have collected a wide variety of
such personal interviews in their book titled Wise Before Their
Time. Some persons have even been socially stigmatized by their
mere association with an "AIDS" trial, and the potential
for such discrimination is unlikely to diminish.
In order to help minimize such social discrimination, research
sponsors should provide volunteers with all the protections they
can offer, including certificates, toll free phone numbers for
confirmation, and free ELISA and Western Blot tests for HIV antibodies
for as many years as necessary. Unfortunately, according to one
study, in up to 40 per cent of vaccine trial volunteers, even
the more specific Western Blot test will be unable to distinguish
between a positive test that is due to receiving a vaccine, and
a positive test that is due to being actually infected with HIV.
This means that, even with the tests presently used to determine
whether a subject is actually HIV+, or just appears to be HIV+
because of having received a vaccine, up to 40 per cent of volunteers
could be mis-identified as actually infected with HIV, using both
of today's standard HIV tests, the ELISA and the Western Blot.
More complex candidate vaccines are already being proposed for
new studies this year, vaccines in which it will be even more
difficult to distinguish apparent HIV infection from actual HIV
infection.
There are viral detection methods, such as antigen capture assay,
viral culture and the PCR test, however, which test for the presence
of the actual virus, rather than just for the presence of antibodies
to the virus. These methods are able to distinguish between a
vaccine-induced positive response, and an infection-induced positive
response. Unfortunately, these methods are more expensive and
require some degree of laboratory sophistication and may, therefore,
not be as readily available in developing nations. If possible,
however, some sort of free viral detection method should also
be made available to volunteers for as long as necessary. Free
intervention services and/or legal services in the event of discrimination
should also be provided to all subjects.
These are some of the precautions that trial sponsors will probably
provide to their volunteers. But volunteers should also be made
aware of the very real likelihood that in their future lives they
will probably suffer some forms of discrimination, and that some
of these acts of discrimination (for example, in hiring or firing,
in housing, in blood and organ donations, in application for military
service, in application for some kinds of jobs, in application
for insurance, for travel visas, and so on) will not be resolved
in the volunteer's favor. Persons seeking travel visas to Russia,
for example, may at some point be required to be tested for HIV.
Any applicants who test positive would simply not be granted entry
visas.
Volunteers who live in developing
nations face additional struggles. In many cultures a right to
privacy and to confidentiality about personal medical information
has not been as strongly established as in some industrial nations.
(Although not typical, in some regions of China, for example,
there is sometimes public posting in medical clinics of "highly
personal information about individuals' health status, inoculations,
women's menstrual cycles, and other data". )
In addition, it will probably be commonly known in many communities
who the people are who are participating in these vaccine trials;
or at least it may be easily discovered who they are. Some community
members might easily make uncomplimentary assumptions about persons
who volunteer for HIV trials: people might assume that these volunteers
had been "dirtied" by the vaccine, or that they had
been infected by it, or that they had been chosen as a volunteer
because they were at high risk for infection, and so on. And additionally
for those subjects who do become infected with the virus during
the course of the trials, it may be (in some close-knit communities)
very easily discovered who got infected and who did not. Those
infected persons can expect potentially serious discrimination.
Nor is HIV serostatus the only information that is potentially sensitive for subjects. Drug use practices, types and frequency of sexual practices, and identity and/or number of sexual partners are all equally sensitive information, and if volunteers are not confident that such information will be kept private, they may be reluctant to participate in a trial which will require them to disclose such information to researchers.
11.5.2 Confidentiality: relativism
vs essentialism
Furthermore, it may be that confidentiality and privacy are not
values at all in some communities. In those communities, then,
researchers and public health officials would be faced with a
serious meta-ethical issue: should they impose strict confidentiality
standards on the community in order to protect the welfare of
the volunteers, even though confidentiality and privacy do not
have a place in the values of that community? Or should sponsors
simply accept the prevalent standards of the community and not
act to protect the privacy of individual volunteers? Should a
value such as "the right to privacy," which might be
perceived in that community as a "western world" value,
be simply imposed on the community in order to protect individual
subjects, or should the privacy of the individuals be ignored
in order to respect the ethos of the community? How should this
question be resolved?
This question is sometimes referred to as the thorny question
of "medical-ethical imperialism". If you answer the
question in one way, and say "Yes, the value of protecting
individual volunteers is so important that it must be provided
for even though the prevailing standards of that community do
not endorse the value of the individual's right to privacy,"
then you risk being labeled a medical-ethical imperialist. If
on the other hand you say "No, the value of respecting the
local community standards is so important that we will not impose
the value of privacy and confidentiality, even though in many
parts of the world (and in the WHO/CIOMS Guidelines) privacy is
seen as a significant human right," then you run the risk
of simply running rough-shod over the personal safety of the individual
volunteers in that community.
At the root of this issue is an even more basic philosophical
question about the universalizability of ethical norms. I call
it the conflict between ethical relativism and ethical essentialism.
The position of ethical relativism holds that no values are universal
and hence that no values hold true absolutely, always and everywhere.
Ethical relativism sees that different communities do empirically
have different ethical norms, and it concludes from this observation
that therefore these communities also ethically have the moral
right to have whatever norms they choose.
Ethical essentialism, on the other hand, holds that not all values
or actions are equally valid or worthy. Ethical essentialism holds
that some acts are wrong, even if there is a whole community that
endorses them. Ethical essentialism would hold, for example, that
torture is wrong, that slavery is wrong, and that genocide is
wrong, even though whole communities might endorse those practices
and live by them. Ethical essentialism holds that some acts are
essentially, in themselves, in their essence, wrong, and should
not be endorsed by anyone or any community.
This issue is most complex and multifaceted. Some philosophers
argue that the tension between these two positions is the defining
ethical issue in any modern pluralistic democracy; others have
even claimed that this tension is the key philosophic issue that
defines what modernity means. The issue is indeed a thorny one,
and much too complicated to deal with inside the scope of this
small book. And yet, as is the case with many philosophical questions,
the way the issue gets decided will have tremendous practical
consequences.
In the case we are discussing here, for example, the practical
consequence will be either that regulations protecting the confidentiality
and privacy of volunteers will be enacted and enforced, or they
will not be. What position does the WHO/CIOMS International Ethical
Guidelines take on the question?
The Council for International Organizations of Medical Sciences,
in collaboration with the World Health Organization, which drafted
the International Ethical Guidelines for Biomedical Research Involving
Human Subjects, was sensitive to the issue of medical-ethical
imperialism and took steps to insure that they would respect the
values of the world's wide variety of cultures. The committee
which prepared the document - over more than a decade of research
and consultation - was composed of nearly 150 participants from
thirty-five diverse countries. Participants came from both developed
and developing countries, "including representatives of ministries
of health and medical and other health-related disciplines, health
policy-makers, ethicists, philosophers and lawyers". Representatives
attended from all over the world, including some from sub-Saharan
Africa, from Asia and from South America (including one representative
each from Thailand and Brazil, two of the countries in which WHO
plans to initiate phase III HIV vaccine trials; Uganda was not
represented, nor was Rwanda nor Tanzania, but Kenya was.) After
the last conference ended in February of 1992, the Guidelines
were then revised using all the research, discussions and position
papers that had been presented by participants. It was then sent
out to the 150 participants for final comments. Dr Bankowski,
chair of the committee, explains the process:
The draft guidelines were revised to reflect the consensus of the conference, but with due regard to minority points of view. The revised draft was then sent for comment to the conference participants, to international associations, and to medical research councils and other interested bodies and institutions in both developed and developing countries. The final text duly reflects the comments received. It has been endorsed by the WHO Global Advisory Committee on Health Research and the Executive Committee of CIOMS, which have recommended its publication and wide distribution.
I mention all this to make it clear
that the WHO/CIOMS Committee which drafted these Guidelines and
published them in 1993 did not act hastily. Committee members
made every attempt to face the complex issue of medical-ethical
imperialism and to deal with its difficulties as fairly as they
could. In the end, however, they had to come down on one side
or the other of the question of privacy and confidentiality for
research volunteers.
The document they finally published, International Ethical Guidelines
for Biomedical Research Involving Human Subjects, comes out clearly
in favor of supporting and even requiring the protection of confidentiality.
It insists that all research subjects have the right to confidentiality
concerning their serostatus, their medical records, and even confidentiality
as to whether they are participants in the study or not. This
message is stated very clearly in the CIOMS Guidelines.
11.5.3 Weak protections for confidentiality
However, although this document clearly supports the policy of
protecting confidentiality, it also recognizes that there are
very real de facto limitations on that policy, and that these
limitations could severely weaken any significant implementation
of the policy. Guideline 12 of that document, which addresses
the issue of safeguarding confidentiality, states:
The investigator must establish secure safeguards of the confidentiality of research data. [However,] subjects should be told of the limits to the investigators' ability to safeguard confidentiality and of the anticipated consequences of breaches of confidentiality.
This general principle is indeed
important, but it should also be made clear to prospective subjects
that the "limits to the investigator's ability to safeguard
confidentiality" may be very grave, and they should not be
minimized. Some jurisdictions, for example, will probably require
mandatory reporting of HIVAb+ persons. Trial sponsors, of course,
will seek exemptions from such reporting requirements, but if
they are not able to acquire such exemptions, prospective volunteers
will need to be aware that their confidentiality would probably
be seriously compromised if they chose to join the trial.
Even in jurisdictions which do not require mandatory HIVAb+ reporting,
protections for confidentiality are often not very strong. One
serious instance, to mention only one, of having ineffective safeguards
for the protection of subjects' confidentiality, concerns the
usual manner of protecting confidential medical records. The usual
method of protecting the privacy of these personal documents is
to require that the individual subject sign a consent form before
releasing any confidential medical information. This method, though
valuable in many circumstances, does have serious limitations:
1) One limitation is that the policy makes it clear to everyone
that such records do already exist, and it specifies where they
exist and who is the custodian of the records. Clever people with
strong motivation will perhaps be able to obtain some of the information
they want without getting anyone's formal consent. 2) Another
limitation on this method of protecting privacy is that great
social and personal pressure can be brought to bear on an individual
volunteer to sign a release form. 3) A third serious limitation
on this method of protection is that refusal by a volunteer to
give consent for release of information may well be considered
damning in itself, much as invocation of Fifth Amendment rights
by someone testifying in a trial in the US makes people suspicious
that the testifier probably has something to hide. This suspicion
alone could lead to acts that would discriminate against the volunteer.
This is all to say that protecting volunteers from discrimination
by protecting the privacy of their medical records might be only
partially effective.
Another method of protecting against discrimination is to enact
laws that proscribe discrimination. Such laws, as everyone knows,
can sometimes be extremely difficult to enact and even more difficult
to enforce. Witness, for example, the difficulty of enacting and
enforcing civil rights legislation in the southern states in the
US during the early 1960s, and the violently heated confrontations
that have accompanied attempts at gay rights legislation in the
US in recent years. Laws protecting civil liberties are sometimes
difficult to enact even in the best circumstances of relative
civil order, but they can be especially difficult to enact in
situations of unstable social order, or if the proposed laws do
not really represent the community's actual standards and beliefs.
If laws protecting individual rights are enacted in such circumstances,
they will probably be exceedingly difficult to enforce. Nevertheless,
it is probably better to have such laws on the books than to not
have them at all.
A third method of dealing with discrimination is to in some way
compensate its victims. (Cf chapter 13 below, Compensating Volunteers
for Injury.) This of course does not prevent discrimination, nor
can any compensation ever replace the individual's actual loss.
Furthermore, it might be questionable whether it is even realistic
to expect that compensation will actually be given in most cases.
To sum up this section: a person's participation in HIV vaccine trials carries "significant... risk of social discrimination or harm". Volunteers should be "apprised in advance of those situations in which trial sponsors might be required to disclose confidential information," and should be fully informed about the extent and implications of this risk.
11.6 Whole virus vaccines
Vaccines come in three basic forms: killed virus vaccines, live,
attentuated virus vaccines, and subunit vaccines. Each type of
vaccine uses a slightly different method of stimulating an immune
response. The first two types, if used against HIV, would carry
significantly more risk than subunit vaccines.
11.6.1 Inactivated virus vaccines
A killed or inactivated virus vaccine uses the whole virus, minus
the genetic material in its core, to stimulate a successful immune
response. (Pseudovirion vaccines are genetically engineered virus-like
particles which closely resemble a live three dimensional virus,
but also have no genetic material in their core.) Inactivated
virus vaccines have been used successfully against hepatitis B,
rabies, influenza, and polio (Salk vaccine). These vaccines do
stimulate an immune response, but the risk is that the process
used to inactivate the viruses may have been imperfect and not
all viruses got killed. If this happened while using a killed
virus vaccine for HIV, then some persons in the vaccine trials
would be accidentally injected with an active virus, and hence
may become infected with HIV and progress to AIDS. That, of course,
would be an important risk.
Such a tragedy did actually occur at one point with the Salk polio
vaccine, an inactivated virus vaccine, shortly after the conclusion
of the efficacy trials for that vaccine, in 1954.
Of the 400,000 people inoculated with certain preparations, 79 contracted polio. Another 125 individuals became infected through contact with those vaccinated. Three-quarters of these cases involved paralysis and 11 cases were fatal.
This tragic event, widely known as the Cutter incident, gave warning to all vaccine researchers of the possible consequences that could result if not all viruses had been completely inactivated.
11.6.2 Live, attenuated virus vaccines
A live, attenuated virus vaccine uses active viruses, but viruses
which have been in some way weakened. Many of the vaccines currently
in use against viral diseases are of the live, attenuated form,
including the Sabin oral polio vaccine, and the vaccines for measles,
yellow fever and mumps . The advantage of using attenuated virus
vaccines is that the virus continues to exist in the vaccinee's
body, continues to replicate, and therefore continues to stimulate
an immune response as long as the person lives.
Attenuated viruses continue to reproduce, thereby acting as a
constant source of antigenic stimulus to the immune system. Thus
attenuated vaccines appear to provide lifelong immunity without
requiring periodic boosters.
Thus, the advantage of attenuated
virus vaccines is that they could theoretically continue to protect
persons against disease for the remainder of their lives. For
this reason alone an attenuated virus vaccine for HIV would be
extremely desirable.
The risks, however, of using an attenuated virus vaccine for HIV
are very high. One of the risks of vaccinating people with a weakened
form of HIV is that, since HIV replicates and mutates so rapidly,
it would simply eventually mutate back into a highly virulent
form. It would, after all, have the rest of the person's life
to so mutate. Then all we would have done is infect volunteers
with real HIV. (With this form of vaccination, the attenuated
virus particles could also be transmissible to others via blood
and body fluids, which may be beneficial, if the vaccine is safe,
but may be deadly if it is not.)
Such mutations that revert to virulence are by no means unknown.
The Sabin oral polio vaccine, for example, is an attenuated virus
vaccine and it does happen, even with that extremely safe vaccine,
that in very rare cases (one in every two or three million vaccinations)
the attenuated virus will mutate back to its virulent form within
the body of the vaccinated person and cause a case of active paralytic
poliomyelitis. Also, in present SIV vaccine studies, a recent
study in the UK using an attenuated SIV vaccine in rhesus macaque
monkeys, resulted in the attenuated virus actually reverting,
over a rather short time, back to a virulent form and causing
one monkey to come down with simian AIDS.
With HIV, which is so highly and rapidly mutable, this risk is
serious; so serious, in fact, that I know of only one candidate
HIV vaccine in development now that is of the attenuated form,
and it has not reached even phase I trials. Many doubt that it
ever will. Researchers recognize that one of HIV's most successful
attributes is its ability to replicate rapidly and mutate often.
Whether it would mutate toward greater virulence or toward lesser
virulence is anybody's guess. Evidence so far, however, seems
to overwhelmingly indicate that, in an environment with relatively
mild selective pressures, HIV generally mutates toward increased
virulence.
Another problem with attenuated virus vaccines is that they pose
additional risks to persons who are in any way immunocompromised.
Such persons, because of their suppressed immune systems, may
be overwhelmed even by a weakened form of the pathogen against
which they are being vaccinated. In some lesser developed communities,
of course, malnutrition may contribute to some cases of immunosuppression.
Undetected HIV disease may also put persons at risk for immunosuppression.
Any persons or groups who may be immunosuppressed for any of these
reasons would probably need to be tested for immunocompetence
before administering a live virus vaccine to them. This would
require screening those populations for various markers of immunosuppression
before administering a live virus vaccine that might put them
at serious risk. Such large scale screening would add one more
enormous logistical challenge to an already complex set of logistical
difficulties, when it came time to actually deploy a successful
HIV vaccine.
11.6.3 Subunit vaccines
Subunit vaccines are not made from whole live viruses, nor from
killed viruses, but from certain key fragments of the virus, often
surface proteins. In these first generation HIV-1 vaccines, the
subunit that has been most often used is the glycoprotein gp120
(or its precursor, gp160), which is the portion of the viral surface
that actually binds to the CD4 molecule on the surface of human
cells. Sometimes a viral core protein, such as p17, may be used
instead. Often, chemical or biological adjuvants are injected
(or ingested) along with the vaccine in order to help the immune
system detect the subunit, "thereby producing a more potent
immune response".
Subunit vaccines can be developed in three different forms. In
one form, a) the subunits themselves are simply grown in vitro
(for example, in ovarian cells of Chinese hamsters), collected,
and then injected directly into the vaccinee. In another form,
b) a peptide of the subunit - that is, a subunit of the subunit
- is developed and injected into the vaccinee. And in a third
form, c) the gene that encodes for that particular subunit is
taken from the DNA stage of HIV replication and spliced into the
DNA of another virus, a vector virus such as vaccinia or canary
pox virus. Then the newly engineered vector is injected into the
vaccinee, and when that vector virus replicates in his or her
cells, it will express the selected viral subunit for which the
gene encodes. The presence of that subunit will then (it is hoped)
stimulate an immune response against any wild virus that displays
the same subunit. These are called recombinant vector subunit
vaccines, and they do actually use a live virus, though it is
not the virus which is responsible for the infection that is being
vaccinated against.
The advantage of the a) and b) forms of subunit vaccines (the
subunit and the peptides) is that they are not whole viruses,
so have absolutely no capacity to infect the vaccinee or anyone
else the vaccinee may contact. Their primary disadvantage, however,
is that they seem to produce an immune response that is specific
to only those subtypes and strains of HIV that have the exact
same form of the subunit as is in the vaccine (that is, homologous
strains), and the response seems to be relatively short-lived.
These would be significant disadvantages. The advantage of the
c) form using a vector virus would be that the immune response
would probably last much longer, since the vector would continue
to replicate inside the vaccinee, would continue to express the
desired HIV surface subunit, and hence would continue to stimulate
an immune response in the vaccinee as long as it continued to
replicate. This would be a significant advantage.
The disadvantage of the c) form, however, is that it requires
the introduction of a live, albeit usually harmless, virus into
persons who may be immunocompromised already and not in good enough
condition to fight off yet another virus. There have purportedly
been deaths from fulminant vaccinia disease caused by the vaccinia
vector virus in some recombinant vaccines for other diseases.
Furthermore, besides this risk to the vaccinated individual, there
is the additional risk that the process of immunization itself
will probably produce purulent sores that could put other nearby
immunosuppressed third parties at risk of infection with a disease
that they are not capable of fighting off. Deaths from fulminant
vaccinia disease, while rare, did sometimes even occur during
the years that vaccinia virus was being used as a vaccine against
smallpox. As recently as 1968, for example, two decades after
the US had seen its last case of smallpox, "15 million persons
were vaccinated that year [against smallpox], and because of vaccine
complications, 240 required hospitalization, 9 died, and 4 were
permanently disabled". Vaccinia virus, then, while a generally
safe vector virus, is still potentially a disease-causing agent,
and its use in immunocompromised communities may be problematic.
These latter risks, however, seem to be more of a problem for
those recombinant vaccines in which vaccinia virus is the vector
used for carrying in the subunit gene, and vaccinia is indeed
the vector being used in some of the recombinant subunit vaccines
presently in phase I and II testing. Vaccinia, after all, is the
agent originally responsible for the disease of cowpox. Cowpox
is normally quite a mild disease in humans, but we do not yet
know the full effects cowpox might have if it were to be introduced
into persons who are already immunocompromised. Because of this
potential risk, other viruses are also being explored as potential
vectors. Avipox virus (canary pox) vector vaccines are just beginning
phase I testing. This virus has the peculiar trait of replicating
only one time in human host cells, so the infection is actually
aborted before it can develop into anything that would cause disease.
As Seattle researchers Julie McElrath and Larry Corey point out,
the canary pox virus
can infect avian fibroblasts but induces [only] one round of replication in the human host. Because it causes an abortive infection, the risk of transmission to immunocompromised patients is minimized.
Other vectors that are presently being investigated for potential
HIV vaccine use include adenovirus, rhinovirus, BCG (presently
used as a tuberculosis vaccine in many parts of the world), salmonella,
and hepatitis B.
To sum up, then: the advantage of
subunit vaccines is that they are almost certainly lower risk
vaccines, and in fact are probably the safest of the three kinds
of vaccines.
They are also probably the least effective of the vaccine types,
because (as we have seen) each vaccine seems to protect against
only a very few variants of HIV, namely, those variants that have
a gp120 (or 160) molecule which is virtually identical to the
gp120 that was used for the vaccine. Furthermore, the immune response
stimulated by these subunit vaccines seems to last only several
months to two years at the most. This means that revaccination
would be necessary quite often. That would be a significant logistical
challenge for already overburdened public health services in any
community, whether developed or not.
Each of these three types of vaccines, then, has its own virtues and dangers. Volunteers should be made fully aware of the risks involved with the vaccine type they are using. If there is any meaningful risk at all of becoming infected with HIV and developing AIDS, participants will have to weigh that risk against the potential benefits of the vaccine. Becoming infected with HIV and developing AIDS is a harm for which it would be almost impossible to compensate a person.
11.7 Being monitored
Another of the "inconveniences and hazards reasonably to
be expected" by vaccine trial participants, particularly
in phase III studies, is that they will need to be monitored by
researchers for a number of years, perhaps for many years, perhaps
for the rest of their lives. In addition to preliminary screening,
educating and counseling prior to vaccination, subjects will also
need to be tested regularly after vaccination, and be given checkups
and counseling regularly, perhaps as often as once every two or
three months, or even more often. Checkups, testing and counseling
will need to continue for some years, during the entire course
of the trial.
How long might phase III trials last? The answer to that question,
about when the endpoint of the study would be, depends entirely
on the "criterion of effectiveness" in that study. If
the criterion of effectiveness in phase III trials is only a)
the emergence of certain immune system markers, then that could
be achieved in a matter of months, so the trial would be short.
This criterion (immunogenicity), however, is applicable in phase
II trials only, and would not be an adequate criterion of efficacy
for phase III trials by anyone's account. So immune system markers
would not be used as a criterion, at least not in these first
generation vaccine trials.
If the criterion of effectiveness is prevention of infection,
then trials lasting three to five years may be adequate. But if
the one of the criteria of effectiveness is prevention of disease
(or postponement or amelioration of disease), which is the traditional
criterion of effectiveness in most vaccines - and this doubtless
will be one of the criteria, especially in the early trials -
then phase III trials will need to last much longer. How long
will subjects need to be followed before we know they will not
get AIDS? Ten or fifteen years? Twenty years? For life?
If participants will need to be followed for that long, that means
they will need to be checking in with researchers for that number
of years, or for the rest of their lives. This may amount to only
an inconvenience for many participants, but it may amount to a
genuine hardship for others. Some may find their lives restricted
in some significant ways due to this requirement that they be
available. Volunteers should be made aware of this requirement
and its possible attendant inconveniences and hardships.
11.8 Feeling safe
One of the biggest risks for participants in vaccine trials is
the danger that they will now feel more secure and protected,
as a result of having been "vaccinated," and will thus
feel freer to engage in risky behaviors. This is no small risk,
especially since it operates below the level of conscious motivations.
Researchers must be particularly emphatic when they counsel trial
participants to avoid risky behaviors. They must make it clear
that the candidate vaccine being tested is not a proven protection
against anything, and that in fact participants may be at greater
risk of infection than if they had not chosen to participate in
the study (due to possible factors such as antibody enhanced infectivity).
Counselors must also make it abundantly clear that the study is
double-blinded and placebo controlled, which means that a substantial
percentage of the volunteers will be receiving a completely inert
substance that provides absolutely no protection of any kind.
Counseling that makes these facts clear must be thorough and forceful.
(Such counseling must also, of course, be culturally and linguistically
appropriate.)
In spite of such counseling, however, some subjects may choose
to secretly get tested for HIV antibodies in some other testing
facility in order to determine whether they were one of the subjects
who was lucky enough to get the candidate vaccine. That is, they
might choose to "unblind" themselves in the study. This
unblinding could have two unfortunate consequences, one for the
individuals and one for the study itself: a) the unfortunate consequence
for the individual subject is that they may now feel even safer
than when they first joined the study and may therefore feel much
freer to engage in risky sexual or needle-sharing behaviors. Such
behavior change could put that subject at even higher risk of
HIV infection than the risk with which they had lived before joining
the study. Such increased risk behavior on the part of those who
had unblinded themselves might also b) have an unfortunate effect
on the statistical structure of the study itself, as explained
by one group of researchers:
If volunteers who discover that they have received the vaccine are falsely reassured and then engage in high-risk behavior at a greater rate than do placebo recipients, a less-than-optimal vaccine candidate (one with an efficacy of 50% to 60%) may be judged completely ineffective because of selective high-risk behavior among decoded vaccine recipients.... The unblinding of a few vaccine trial participants has already occurred in phase I trials.
Those who design these trials will want to devise ways of dealing
with the problem of unblinding. They will want to be able to a)
identify those who are most likely to try to unblind themselves
(for example, by noticing, during pre-trial counseling, that these
prospective subjects' main motivation for wanting to join the
trial is to be protected by the "vaccine"), so that
these persons might not be selected to participate in the trial;
b) somehow motivate persons who do join the trial to not want
to unblind themselves; c) somehow identify - probably by self-report
- those who do unblind themselves, either deliberately or inadvertently;
d) provide regular blinded HIV testing for those subjects who
are worried that they may have exposed themselves to infection,
so that they can be notified if their test is positive for the
virus (not just for antibodies to the virus); and e) have open
and frank discussion about some of the consequences of unblinding.
In addition, some trial subgroups, such as commercial sex workers
and injection drug users, may be more likely than most to be arrested,
charged with a crime, and incarcerated. It is not unusual for
penal systems to require mandatory HIV screening for all inmates,
so it is not unlikely that the problem of unblinding will be a
very real one in these trials, even if it only happens inadvertently.
Possible consequences for the statistical significance of the
trials will need to be determined.
Probably the best way to minimize the likelihood of such untoward
consequences is to insure that counseling about the risks of the
study is thorough and clear, that subjects are made fully aware
that this candidate vaccine is only possibly effective, that even
if it is effective in some persons it may be completely ineffective
in others, and that it must not be relied on at all for protection
against anything. In fact, in some cases,
even vaccines that produce very good immunity may be overwhelmed by vast numbers of invading organisms and a "breakthrough" infection may result. This is not uncommonly seen, for example, with measles vaccination in developing countries where "breakthrough" infections occur quite frequently in the overcrowded conditions of socio-economically deprived communities, even though the vaccine itself usually provides excellent immunity.
Counseling that makes subjects aware
of these realities may be effective in discouraging the feeling
that volunteers in the study are somehow safer and can engage
in risky behaviors.
Furthermore, in addition to the verbal counseling, condoms should
probably also be provided free of charge to all participants,
and depending on the setting of the study and the populations
being studied, clean needles for drug injection should perhaps
be provided as well.
Research sponsors must be particularly
cognizant of their obligation to observe one of the most basic
principles of medical ethics: "first do no harm" (primum
non nocere). This means: at least don't make things worse. In
vaccine trials that use killed virus vaccines or attenuated virus
vaccines, there could be, as we saw above, some additional risk
that participants may accidentally receive a vaccine with virus
in it that is capable of causing disease. If this were to happen,
then the vaccine trial would have made things worse for those
particular subjects. Furthermore, if this tragic accident were
to come to pass, and these trial participants continued to engage
in risky behaviors (unprotected sex, sharing needles, and so on),
then they would be putting not only themselves at risk, but they
would be spreading to others the virus with which they had been
accidentally infected. Vaccine trial participants would, in that
case, be worsening the spread of the epidemic, and trial sponsors
would bear some of the responsibility for that.
For all these reasons, there is a strong duty to provide clear,
thorough and effective counseling to all participants. (See chapter
12 below for the ethical problem of counseling with dual intent.)
11.9 Immunosuppression
Another danger, even of the safer gp 120 subunit vaccines, is
that the vaccine itself could have a compromising effect on the
immune system of the vaccinated person. Two mechanisms for such
immunocompromise may occur, syncytia and decrease in CD4 availability.
a) Syncytia is the pathological bunching together of a cluster
of individual T4 cells into one big clump. All the T4 cells in
the clump are disabled, and therefore become ineffective in their
role as chief directing cell in the overall immune system response.
The causes of syncytia (from the Greek: syn = together, and cyt
= cell) are not entirely clear, but seem to be related to the
function of gp120 and its ability to bind to the CD4 molecule
on T4 cells. Whatever the mechanism of the pathology, the result
is a compromise in the overall functioning of the person's immune
system.
b) A second possible mechanism of immunosuppression could be a
decrease in the number of CD4 molecules available on the surface
of T4 cells for performing their normal functions. Dr Barry Shoub,
Director of the National Institute of Virology at the University
of Witwatersrand in Johannesburg, explains:
Another difficulty with the use of gp120 as an antigen in a vaccine is the fact that its attachment to the CD4 receptor may compete with the physiological function where the macrophage attaches to the CD4 receptor of the [T4 ] lymphocyte to present new antigens to the immune system. An additional fear is the fact that the antibodies elicited by gp120 could attach to the surface proteins of the macrophage involved in this interaction with the CD4 antigen.
If either of these two developments did occur then the vaccinees' normal immune response would be compromised to some degree. This means that trial subjects would thus be more susceptible to opportunistic infections which would take advantage of their weakened immune response.
11.10 Autoimmunity
Autoimmune disorders are those in which the immune system has
lost some of its ability to distinguish between self and non-self
cells, and consequently begins to attack some of the host's own
self cells.
Shoub and others believe that there is some risk that vaccinees
could develop autoimmune disorders. If the CD4 function is compromised
(as explained just above), or if the antibodies elicited by the
vaccine were to attach to the surface proteins of the macrophages
that come to dock with the CD4 molecule on the surface of the
T4 cells, then there is a risk that the immune system could begin
to target the host's own body. Autoimmune disorders can be quite
serious, so if this risk is a probable one, potential volunteers
will want to be aware of it.
11.11 Malignancies
HIV unfortunately belongs to the family of viruses (Retroviridae)
which have been associated with the development of malignancies.
Because of this, if vaccines are made from whole inactivated viruses,
or from whole attenuated viruses (but not if they are made from
subunits of the virus), there could be some risk of cells developing
malignancies. Shoub explains:
This...would make the use of the virus itself unsuitable to develop as an attenuated vaccine..., or as a "killed" or inactivated whole virus vaccine (because the nucleic acid would still be present and the genetic information could hold a theoretical danger of being able to transform cells into malignancy).
Shoub seems to indicate that this outcome has not been empirically seen in any work with retroviruses, but that from his knowledge of retroviruses and malignancy, the risk does theoretically exist. What form such a malignancy might take, or what the likelihood is that it would actually develop, is not presently understood.
11.12 Neurological disease of unknown
origin
"The most feared situation in any vaccine trial is that cases
of severe neurological disease of unknown etiology will be reported
among the participants in the first weeks after an injection."
A few vaccines currently in use do , though rarely, seem to cause
such neurological disorders. A sheep-brain-derived rabies vaccine
sometimes (about one per 400 vaccinations) results in myeloencephalitis,
and a live attenuated poliovirus vaccine very rarely (about one
per one million vaccinations) results in "vaccine paralysis."
In addition, Guillain-Barré syndrome is a well known serious
neurologic disorder that very infrequently follows an influenza
immunization procedure. A close friend recently suffered a relatively
severe attack of the syndrome shortly after receiving his annual
influenza vaccine (flu vaccines are made from inactivated viruses).
This disease is a demyelinating neuropathy which results in loss
of sensation and muscle strength throughout much of the body,
particularly the limbs. It has a one to eight percent fatality
rate, but those who do survive it generally recover most of their
sensation and muscle strength within six months to a year.
Neuropathies of unknown etiology are an uncommon consequence of
some immunization procedures, and the frequency with which they
could follow from an HIV vaccine procedure is completely unknown.
To date, there are no tests for determining whether a given vaccine
does or does not carry a risk of neuropathy; furthermore, our
understanding of the mechanisms by which these neuropathies occur
is fairly rudimentary.
11.13 Learning your antibody status
Some have considered the knowledge of their positive antibody
status to be a "burdensome knowledge that should not be imposed".
A certain number of subjects in these trials (in either a vaccine
or placebo arm) will probably become HIV infected in the course
of their usual risky behaviors, and when they do, then for them
"the necessary surveillance of HIV antibody status might...ultimately
result in knowledge of HIV infection that the subjects would otherwise
have avoided". For some this might not be considered a burden
at all, and may even be considered a benefit. But others may consider
it a burden imposed on them by their participation in the trial.
11.14 Unknown and unanticipated
risks
In addition to the above risks, some of which may perhaps be known
(from phase I and II trials) to have some given degree of likelihood,
great or small, there is also the theoretical possibility of completely
unanticipated hazards. Birth defects that were the tragic consequence
of using Thalidomide were completely unanticipated by researchers
and clinicians, and did not show up until years afterwards when
some Thalidomide recipients became pregnant and gave birth to
severely deformed children.
It is possible that such unanticipated hazards could have shown
up earlier in subjects who participated in phase I and phase II
trials, but they may not have. Phase I and II trials are typically
only one to three years in duration, and typically have only a
few hundred subjects, so long term consequences may not come to
pass in that shorter time span, in that smaller number of subjects.
It may be that some hazards will emerge only in phase III trials,
with their larger number of participants and the longer duration
of the trials.
There is also the possibility that some unanticipated risks could
even affect the regular sex partners of some subjects, thereby
putting third parties at risk. This would be ethically analogous
to Thalidomide having severe deforming effects on the fetuses
of some users, but having no ill effect on the users themselves.
This eventuality could potentially increase the number of persons
who are at some degree of risk in these trials, and would (if
such risks were to actually come to pass) have the consequence
of potential increased liabilities for sponsors. This is the problem
of endangerment of third parties who have not been informed that
they were even at risk, and hence have not been asked for nor
given consent to accept such risk. Because of this possibility,
research sponsors may want to provide counseling to family and
regular partners of subjects who are participating in the trials.
These are some of the risks potentially
to be encountered by human subjects in HIV vaccine trials, particularly
in developing nations. These risks are real and some are probable.
Some of these harms, of course, are clearly more likely to occur
than others. For example, not being allowed to participate in
future HIV vaccine protocols is very likely to happen; developing
immune suppression as a result of a surface subunit vaccine is
probably much less likely to occur. Besides the degree of likelihood
that a given harm will occur, some of these harms are also clearly
more grievous than others. For example, some forms of social discrimination
to which subjects may be vulnerable (loss of jobs, housing, insurance,
and so on) would be much more grievous harms for most people than
learning their antibody status.
These are the two dimensions of any potential harm: its likelihood
of occurring, and its experienced grievousness if it does occur.
Potential harms will probably need to be evaluated in both dimensions.
ERCs will probably want to see potential harms evaluated in terms
of each of these dimensions, and some subjects may wish to be
made aware of such information. (I have proposed the use of some
new application forms for detailing the potential harms that prospective
subjects may wish to be aware of, and that Ethics Review Committees
will definitely want to be aware of when they perform their ethical
review of proposed vaccine protocols; these application forms
are included as Appendix V in this book.)
Those who hold the Antithesis position
insist that volunteers must be made fully aware of all these risks
(and perhaps others) before they are asked for their consent to
participate in the trials.
* To see the citations associated with material in this chapter, see a published printed copy of the book, or contact the author directly.
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