HIV vaccine pragmatism
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Source:
http://www.thelancet.com/journal/vol357/iss9251/full/llan.357.9251.editorial_and_review.14930.1
What can be achieved with an HIV vaccine?
Jay A Levy
Lancet 2001; 357: 223-24
Division of Haematology/Oncology
Department of Medicine
University of California, San Francisco, CA 94143, USA
mailto:jalevy@itsa.ucst.edu
With HIV spreading throughout the world at an alarming rate, the need
for a preventive vaccine is more urgent than ever before. All at-
tempts thus far to show efficacy of a vaccine in animals have not in-
dicated any clear-cut correlate of protection; in most laboratory
animals, prevention of infection was not recorded.[1]
Is prevention of infection achievable or even feasible by the use of
HIV vaccines? Although some researchers speak about sterilising immu-
nity -- i.e., the absence of any infection of a host cell by the
agent -- one replicative cycle of the virus is highly likely to have
taken place before an appropriate immune response is initiated. Be-
fore the emergence of HIV infection with its severe pathogenic conse-
quences, scientists did not expect that a previous infection or vac-
cination would provide absolute protective immunity against reinfec-
tion.[2,3] Intermittent subclinical reinfections happen and they
maintain immunological memory.[4] By these continual exposures to the
pathogen, or by booster vaccinations, long-term immunity is achieved.
Essentially, sterilising immunity has rarely been seen with any vac-
cine and seems unattainable with HIV. Instead, a reasonable vaccine
should be directed not at prevention of HIV infection but at control
of the spread of infection and at the development of clinically ap-
parent disease.
Whether prevention of HIV infection in a vaccine recipient is attain-
able needs to be assessed in the context of achievements with other
antiviral vaccines. For example, evidence from the poliomyelitis,
measles, rubella, mumps, and influenza virus vaccine trials indicates
that neither killed nor live-attenuated (non-pathogenic) viruses have
prevented infection of immunised hosts by wild-type virus. In some
recipients, subclinical infection can be detected by virus shedding
or an increase in production of antibodies to the infectious
agent.[3-10] Low level replication of virus seems to take place, but
is gradually eliminated through both a direct immunological host re-
sponse and the self-limiting replicative nature of the agent. These
viruses destroy the cells they infect.
For HIV, these findings with other viral vaccines define the chal-
lenge of an effective vaccine. HIV is an agent that on infection in-
corporates its genetic material into the chromosome of the cell. This
infection can then lead to high-level or to low-level virus replica-
tion, or the virus can remain latent within the infected cell.11 No-
tably, by contrast with most other viruses for which we have a vac-
cine, HIV does not necessarily kill the cell it infects. Subse-
quently, unless a strong immunological response, particularly cellu-
lar, eliminates the infected cell, this cell will continue seeding
HIV particles that can spread to various tissues in the host. More-
over, by contrast with other viruses for which there is a vaccine,
the HIV-infected cell can be the source of transmission and must be
recognised by the immune system. Thus, since current vaccine ap-
proaches for other viruses are almost always associated with some
replication of the agent, HIV (as a free virus or infected cell)
would probably also find a way to easily establish itself in cells of
the vaccinated host. Hopefully, a vaccine will stimulate the immune
system sufficiently to maintain control of this virus, as is seen in
HIV-infected individuals living for more than 20 years without symp-
toms and treatment.[11,12] In some, the virus could eventually emerge
to cause disease, but only late in life when the immune system ages.
Thus, pathogenesis but not infection could be prevented or at least
delayed a long time by vaccine.
Importantly, if a vaccine could prevent virus replication suffi-
ciently in the host, the presence of HIV in genital fluids and blood
could be greatly reduced so that transmission is curtailed. Low
plasma virus concentrations do correlate with reduced risk of HIV
transmission to a newborn child or via sexual contact.[13,14] In such
cases, the vaccine would be successful, not at the individual level
but at the population level. Over time, with HIV transmission re-
duced, the virus could become well controlled throughout the world.
And, eventually, HIV prevalence could return to a level similar to
that seen many years ago when it had not reached the required thresh-
old to be widely transmitted.
Complete prevention of an established HIV infection should certainly
remain the primary goal of vaccine research. Perhaps the existence of
highly exposed but uninfected individuals indicates that such a vac-
cine is possible.[15-17] Moreover, evidence from some hepatitis B vi-
rus trials suggest that protection from infection occurs when high
concentrations of antibodies are present; when these antibodies wane,
however, subclinical infection by the agent can take place.[18] It
seems more reasonable, therefore, to accept prevention of infection
at the population, and not the individual, level as an important ob-
jective for HIV vaccine development. Strategies would have to be
aimed at finding approaches that would limit the spread of HIV after
entering the host and curtail its presence in body fluids.
All the lessons learned in vaccine development suggest that this al-
ternative objective is the most reasonable, and one that could be ex-
pected for an HIV vaccine. If other viral infections were not usually
self-limiting or were as pathogenic as HIV, then approval of their
vaccine could also have required evidence of sterilising immunity.
The present vaccines do not usually block infection but prevent
spread of the agent and its pathogenesis. Now, with such a highly
pathogenic agent as HIV, we seem to be expecting more from a vaccine
than can be achieved with present knowledge and technologies. As with
other viruses, a successful HIV vaccine, even if it does not protect
the host from infection, could protect the infected individual from
disease development--perhaps even for a lifetime. This vaccine would
assure that the spread of the virus, which is taking place at such a
rapid rate worldwide, would be suppressed and the epidemic contained.
This direction for achievement of a successful HIV vaccine should be
considered in discussions on the future of vaccine development for
prevention and control of HIV infection and AIDS.
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