How Close Are We To An HIV Vaccine?
Michael Sands, M.D.
Michael Sands, MD, MPH&TM is Chief, Infectious and Communicable Disease,
Clinical Associate Professor of Medicine, University of Florida Health
Science Center / Jacksonville and Duval County Health Department.
Since the identification of HIV as the viral etiology of AIDS, enormous progress has
been made in defining transmission modes, molecular biology, and pathogenesis of the
virus. Genetic unraveling of HIV has enabled targeted drug development i.e. the
nucleoside, non-nucleoside and protease inhibitor classes of antiretroviral drugs; the
development of HIV specific diagnostic and prognostic laboratory tests e.g. viral load
measurement by PCR or B-DNA testing; and HIVspecific diagnostic testing by detecting
antibodies to HIV structural proteins. Nucleotide sequencing of two of the virus's genes,
env and gag, has lead to group classification of the HIV-1 virus into a major or M group
and a genetically distinct O group. Among the M group there are at least 9 genetic
subtypes termed clades. Subtype or clade B appears most common in North America and
Europe, while A and D are more common in sub-Saharan Africa and E in south east Asia.
Antigenic variability between clades has become a crucial issue in determining if a
geographically defined target antigen or multivalent antigen vaccine will be necessary.
The HIV virus attaches to it's target locale on the T lymphocyte or macrophage at the
cell's primary receptor site, the CD4 molecule, and a second co-receptor site, the CCR5
and/or the CXCR4 chemokine receptors. The virus attachment protein is the gp120 envelope
protein. GP120 is a conformationally complex protein containing several specific binding
sites, termed "C" or conserved and "V" or variable sequence regions.
The region V3 is a major site for antibody neutralization and is part of the chemokine
receptor binding area. The site C4 is close to the CD4 binding area. Despite the genetic
variability between clades, these attachment relationships occur with all HIV types and
suggest common epitopes (antigenic foci) or conformational protein structures for all HIV
types. If this premise holds true, there would be hope for development of a cross clade
vaccine. Early vaccine trials in non-human primates using gp120 or gp160 from laboratory
adapted HIV strains found that the glycoprotein vaccine produced neutralizing antibody
only against the laboratory strain and not against wild isolates of virus. It is
hypothesized that laboratory culture adapted strains lose the conformational gp120
relationships of wild isolates. More recent trials have demonstrated that immunization
regimens producing high titres of neutralizing antibody induce cross clade immunity. It is
still unclear if these neutralizing antibodies will be active against wild strains of
HIV-1.
Despite a thorough understanding of the epidemiology of HIV transmission with the
defining of high risk groups and targeted education and prevention campaigns, there is
continued active transmission of HIV in all risk groups. Recent trends in HIV infection
reporting indicate increased HIV transmission among inner city minority populations,
particularly heterosexual transmission to young black women and among young homosexual
men. Clearly, although remarkable progress has been made in HIV therapy, public education
to alter risk behavior will not eliminate the spread of infection. HIV care has created an
enormous economic burden on the health resources of developed countries and is not
available in many developing countries. An HIV vaccine remains the only hope of slowing or
eliminating the spread of HIV infection for the majority of the world.
The immunologic responses needed for protection against HIV after exposure or to
produce an abortive infection are unknown and not necessarily predictable from studies of
the immunologic reactions of infected patients. Clues to the necessary immunologic
responses are suggested by several clinical observations. Studies of primary HIV infection
in man have shown that cytotoxic T cell response (CD8 mediated) correlates with a
reduction in the viral load prior to the appearance of neutralizing antibody. Limited
studies in parenterally HIV exposed health care workers, subsequently shown non-infected,
have demonstrated cytotoxic T cell responses to envelope glycoproteins in about 35% of the
workers, suggesting aborted HIV infections. Studies of long term HIV infected
non-progressors cannot differentiate protective immunologic responses from those that are
the result of chronic low-grade viral exposure. Immunologic investigations of high risk,
multiply exposed but HIV uninfected individuals have been inconclusive.
It has never been clearly demonstrated that an animal model of infection will yield
immunologic correlates for human disease. Further, the correlates of immune protection,
e.g. neutralizing antibody titres, for many of the existing successful non-HIV vaccines
have only been identified after successful human clinical trials. However, several
observations in animal models have been encouraging. Chimpanzees are the only primate
susceptible to HIV. Macaques can be infected with SIV (simian immunodeficiency virus) or
SIV-HIV laboratory hybrid constructs. Low dose vaginal exposure to live virus in both
these primates has led to transient, self limiting viremias without evidence of viral
persistence or seroconversion. This observation in unimmunized primates suggests the
possibility of self limited infection following mucosal exposure and that vaccine induced
immunity may provide the additional needed protection against larger viral innocula.
Chimpanzees vaccinated with gp120 vaccines to achieve high titre neutralizing antibody
have been protected against subsequent HIV challenge.
The general concept behind previous non-HIV vaccines has been to develop vaccines that
protect against the development of disease once primary infection has occurred. The
current successful non-HIV viral vaccines have not been sterilizing (i.e. prevented
primary infection) and none has achieved 100% effectiveness in all populations tested. For
example, influenza vaccination prevents clinical illness in 60 - 90% of those vaccinated,
however it is estimated at between 70 - 90% effective in preventing deaths from severe
influenza disease. For most of the existing viral vaccines, prevention of disease has been
the goal with the public health advantages of reducing mortality from infection and
reducing transmission or secondary spread of infection.
An HIV vaccine would ideally generate an immune response enabling the body to abort
infection following a high dose mucosal or parenteral innocula. The immune response would
assumedly involve both humoral (antibody production) and cellular (cytotoxic lymphocytes)
arms of the immune system. It is recognized that carbohydrate antigens or glycoproteins,
eg. Hepatitis B vaccine, are not very effective antigens. They stimulate predominantly
humoral immunity and require multiple dosing and boosting to obtain and maintain immunity.
In contrast, live attenuated virus vaccines, e.g. Rubella vaccine, or virus vectored
vaccines are efficient at producing durable cellular and often humoral immunity. It is
unlikely that a live attenuated HIV vaccine will ever be trialed in man due to the long
period needed to demonstrate safety from such a vaccine; e.g. would it produce AIDS
illness 15 years after vaccination? This apprehension was amplified following the finding
in a macaque SIV infection model that a nef gene deleted, attenuated SIV virus vaccine
strain after innoculation was able to mutate and repair it's gene deletion, producing a
fatal AIDS like illness in macaques.
The ideal vaccine would: 1) produce durable, cross clade protection against exposure at
all potential sites; 2) have short and long term safety; 3) be stable to store and easy to
deliver, perhaps orally, requiring only one dose for full immunity; 4) be inexpensive and
easy to produce in large quantities; and 5) have an easy serologic marker for immune
effectiveness.
Vaccine development is a laborious process entailing a coordinated effort between the
basic sciences, animal and human clinical trials. There is ongoing controversy in the HIV
vaccine community regarding whether the immunology of HIV should be clearly defined,
animal models well established and candidate vaccines tested in those animal models prior
to any human clinical trials being conducted. The molecular biologist, immunologists and
animal laboratorians argue for a pure science approach to HIV vaccine testing. Given the
human impact of the HIV epidemic, with an estimated 16,000 new infections occurring daily
and 30 million people currently infected worldwide, the practical approach is to conduct
well designed clinical trials of safe, immunologically active candidate vaccines in
parallel with continued basic science investigation. The knowledge gained from both arms
of investigation should be coordinated for development of subsequent generations of
vaccine.
Once candidate vaccines are identified, they are brought through a series of phased
clinical trials under close scrutiny by the FDA. Phase 1 trials evaluate the safety,
immunogenicity and adverse events of the vaccine in a limited group of healthy adult
volunteers at low risk of HIV acquisition. Phase 2 trials expand on Phase 1 to attempt to
determine optimal formulation, dosage and dosing regimen in a randomized controlled
fashion in a population at higher risk of HIV acquisition. Phase 3 trials are large scale,
randomized, controlled trials to further knowledge of safety and determine the efficacy of
the vaccine in the target risk population. During the phase 3 trials period, interim
analyses are regularly performed to determine if statistical evidence of efficacy has been
demonstrated or issues of safety have appeared. The clinical trials period to determine
the safety and efficacy of a vaccine may take in excess of 5 years. This timeframe is too
long to do sequential trials, necessitating the conducting of concurrent trials for
reasonably timely vaccine development.
A number of strategies and innovative means of antigen delivery are being developed in
an attempt to design a safe vaccine that would stimulate both arms of the immune system.
The two vaccine types farthest in development and trial at this time are 1) gp120
glycoprotein with alum adjuvant vaccines and 2) combination prime/boost vaccine
strategies. The gp120 vaccines are recombinant glycoproteins produced in non-human tissue
cell culture systems and are analogous to current Hepatitis B vaccines. They contain pure
glycoprotein with adjuvant, have no live virus component and are thus safe from any
infection risk, but require multiple doses to induce neutralizing antibody. A recombinant
produced gp120 vaccine is currently in Phase 3 trial in the United States and Thailand.
Prime/boost strategies are new to human vaccination. The primer vaccine uses a
genetically engineered, non-HIV virus, either modified vaccinia (Ankara strain) or
canarypox virus (ALVAC strain) as the vector, into which one or more genes of HIV have
been inserted. The HIV gene insertions into the vectoring virus have encoded gp120 or 160,
gag, nef, tat or pol genes. The vectoring virus, once inoculated, undergoes limited
intracellular replications in the vaccine recipient during which the HIV gene protein
product is expressed and antigen sensitization occurs. In animal models and in limited
human trials, these vectored vaccines have produced varying degrees of cellular immunity
(cytotoxic T cell or CD8 cells) to the gene protein products. Subsequent dosing with a
glycoprotein vaccine (the boost component of the strategy) produces neutralizing antibody.
This unique vaccine strategy of prime/boost is currently in phase 1 and early phase 2
trials.
Two other vaccine strategies are currently in preclinical or phase 1 trials. These are
aimed at producing both humoral and cellular immunity with vaccines that do not contain
replicating HIV.
- Peptide vaccines: synthetic peptide constructs to proposed target sites such as V3 loop
regions combined with an adjuvant or coupled to a second substance e.g. PPD for enhanced
immunogenicity;
- Naked DNA vaccines: immunization is done with HIV-DNA genes that have been incorporated
into a carrier plasmid. The genes are taken up by host cells and the HIV DNA encoded
protein antigens produced and presented on the cell surface for host immune processing.
This may induce both humoral and cellular immunity to the targeted antigen.
Summary
Finding an effective HIV vaccine is a possibility. It is unlikely that any vaccine will
be 100% protective. However, even a 50% effective vaccine combined with continued
infection prevention education will result in a significant number of lives saved.
Continued parallel, well controlled trials of safe candidate vaccines should be
encouraged.
References
This article is a digest of multiple articles. Further and supporting
information can be found in the following sources:
- AIDS Research and Human Retroviruses. October 1998; 14 (Suppl 3).
- Esparanza J, Heyward WL, Osmanov S. HIV Vaccine Development: from basic research
to human trials. AIDS. 1996; 10
(suppl A):S123-S132.
- NIAID Division of AIDS Vaccine Site at http://www.niaid.nih.gov/daids/vaccine
- International Aids Vaccine Initiative at http://www.iavi.org
- AIDS Vaccine Evaluation Group at http://camelot.emmes.com/avctn
August, 1999/ Jacksonville Medicine |