Current
Volume 3, Number 3, 2003
Contents
HIV Vaccines
Executive Editor: Melissa
Pope
HIV Vaccines: A Global Perspective Pp.183-193
J.
Esparza and S. Osmanov
Cellular Immunity for Prevention and
Clearance of HIV Infection
Pp.195-208
Spyros
A. Kalams
Defining the Protective Antibody Response for
HIV-1 Pp.209-216
John
R. Mascola
The Role of Mucosal Immunity in Prevention of
HIV Transmission Pp.217-228
Pamela
A. Kozlowski and Marian R. Neutra
Dendritic Cells as A Conduit to Improve HIV
Vaccines Pp.229-242
Melissa
Pope
Subunit Protein Vaccines: Theoretical and
Practical Considerations for HIV-1 Pp.243-263
Michael
W. Cho
Sites, Mechanism of Action and Lack of
Reversibility of Primate Lentivirus Inactivation by Preferential Covalent
Modification of Virion Internal Proteins Pp.265-272
Elena Chertova, Bruce J. Crise, David R. Morcock, Julian W. Bess, Jr., Louis E. Henderson and Jeffrey D. Lifson
Live Recombinant Vectors for AIDS Vaccine
Development Pp.273-284
Rebecca Voltan and Marjorie Robert-Guroff
Cytokine, Chemokine, and Costimulatory
Molecule Modulation to Enhance Efficacy of HIV Vaccines Pp.285-301
Jeffrey D. Ahlers, Igor M. Belyakov and Jay A. Berzofsky
HIV Vaccines in Infants and Children: Past
Trials, Present Plans and Future Perspectives Pp.303-312
Jeffrey T. Safrit
Abstracts
[Back to top] HIV Vaccines: A Global Perspective
J.
Esparza and S. Osmanov
Twenty years after
its recognition, HIV/AIDS has become the most important infectious disease globally
and the leading cause of death in
[Back to top] Cellular Immunity for Prevention and
Clearance of HIV Infection
Spyros
A. Kalams
Despite the major
strides that have been made in HIV therapy with the advent of potent
antiretroviral drugs, these medications are quite expensive and are still not
readily available for the vast majority of infected individuals worldwide. Even
when available, the long-term toxicities associated with anti-retroviral
medications and the frequent emergence of drug-resistance mutations can
complicate therapy, making the formulation of effective vaccines imperative.
This chapter will review the current state of understanding regarding
cell-mediated immune responses that are associated with control of HIV
replication. This knowledge has generated sound hypotheses regarding the
prospects for augmenting cell-mediated immunity through immune-based therapies.
With regard to prophylactic vaccines, it is presently unclear which
vaccine-induced immune responses will protect against infection. While much
progress has been made in formulating vaccine constructs designed to elicit
cell-mediated immune responses, sterilizing immunity is unlikely to be achieved
with the current vaccines. However, the ability to control viremia and prevent
disease progression in animal infection models looks promising. The ability to
measure immune responses has also advanced markedly over the past few years and
will allow investigators to more accurately measure the immunogenicity of
vaccine constructs, and correlate the magnitude and breadth of these responses
with protection.
[Back to top] Defining the Protective Antibody Response for
HIV-1
John
R. Mascola
The development of
an effective HIV-1 vaccine would be greatly facilitated by knowledge regarding
the type and quantity of antibodies that are protective. Since definitive
immune correlates are established only after a vaccine has been shown to be
effective in humans, animal models are often used to guide vaccine development.
Experimental lentivirus infection of non-human primates has shown that
neutralizing antibodies can protect against infection. Most specifically,
studies of passive antibody transfer in the chimeric SIV/HIV-1 immunodeficiency
virus (SHIV) model have provided quantitative data on the level of protective
antibody required. While direct extrapolation to humans is difficult, these
data likely provide important insights into the protection afforded by
antibodies against HIV-1. When used alone, high levels of neutralizing
antibodies are required to completely block infection. However, even modest
levels of antibody can provide partial protection and affect disease course.
Understanding the exact level of protective antibody becomes even more complex
in the setting of active immunization and coexisting cellular immunity. Despite
this uncertainty, recent findings from lentiviral animal models strongly
suggest that neutralizing antibodies will contribute to protection against
HIV-1. Based on these data, a major goal of HIV-1 vaccine strategies is the
induction of neutralizing antibodies against circulating primary HIV-1 strains.
[Back to top] The Role of Mucosal Immunity in Prevention
of HIV Transmission
Pamela
A. Kozlowski and Marian R. Neutra
Vaccines designed
to prevent mucosal transmission of HIV should establish multiple immune
effectors in vaccine recipients, including antibodies which are capable of
blocking HIV entry at mucosal epithelial barriers and of preventing initial
infection of target cells in the mucosa. Immunological analyses of
HIV-resistant humans and data obtained in nonhuman primate vaccine studies indicate
that both secretory and serum antibodies may play an important role in
protection against mucosal transmission of HIV or SIV, whereas cytotoxic T
cells are required for clearance of mucosal infection and prevention of
systemic spread. This review summarizes the roles of IgA and IgG antibodies in
preventing mucosal infection by other viral and bacterial pathogens, and then
discusses the various mechanisms by which antibodies might contribute to
protection against HIV at mucosal surfaces. These include prevention of mucosal
contact, blocking attachment of virus or infected cells to epithelial cells,
interception of virus during transepithelial transport, neutralization of virus
in the mucosa, and elimination of locally infected cells through antibody-dependent
cell-mediated cytotoxic reactions. The regional nature of mucosal immune
responses is reviewed in light of its relevance to HIV vaccine development. We
conclude that mucosal immunization should be considered a component of vaccine
strategies against HIV.
[Back to top] Dendritic Cells as A Conduit to Improve HIV Vaccines
Melissa Pope
Many potential HIV
vaccine strategies are being explored in both animal model and human settings.
The success of any vaccine relies on relevant antigenic determinants being
presented to the immune system for the activation of broad and long-lasting
immunity. Effective immunity against HIV infection will likely require both the
cellular and humoral arms of the immune system, where HIVspecific killer cells
eradicate infected targets and neutralizing antibody responses contribute by
preventing the initial infection of host cells. As the most potent antigen
presenting cell of the immune system, the dendritic cell (DC) orchestrates the
activation of adaptive immune responses as well as contributing to the early
innate responses to a pathogen, which may also aid in the initial control of
infection. It follows therefore, that the efficiency of a vaccine antigen would
be greatly enhanced if targeted to the appropriate DCs to ensure optimal
presentation to and subsequently activation of the immune system. This review
will discuss (i) the current status of DC biology, covering distinct DC subsets
and stages of activation and how these influence the types of immune responses
that are induced, (ii) how DCs can be exploited to improve the efficacy of HIV
vaccine strategies currently under investigation, (iii) what has been learned
from in vivo model systems using DCs, and (iv) future considerations to advance
HIV vaccinology.
[Back to top] Subunit Protein Vaccines: Theoretical and Practical Considerations for
HIV-1
Michael
W. Cho
With the spread of
AIDS still rampant in many parts of the world, there is a global urgency to
develop a vaccine against HIV-1. Without a doubt, developing an effective
vaccine against the virus has been a monumental scientific challenge. Although
advances in molecular biology and biotechnology over the years have enabled us
to generate “designer antigens,” our ability to transform them into
successful vaccine candidates has been limiting. This review will be divided
into three sections: First, the theoretical benefits and limitations of subunit
protein vaccine strategy will be presented. Secondly, recent progress in our
understanding of immune responses against AIDS vaccine candidates that
incorporate recombinant proteins or peptides will be reviewed, mainly those
that are designed to elicit humoral immune responses. Finally, some of the
factors that must be considered in designing and evaluating future vaccine
candidates will be discussed.
[Back to top] Sites, Mechanism of Action and Lack of
Reversibility of Primate Lentivirus Inactivation by Preferential Covalent Modification
of Virion Internal Proteins
Elena
Chertova, Bruce J. Crise, David R. Morcock, Julian W. Bess, Jr., Louis E.
Henderson and Jeffrey D. Lifson
By exploiting the
intrinsic chemistry of retroviruses, we have developed a novel method for
generating whole inactivated virion vaccine immunogens with functional envelope
glycoproteins. The method takes advantage of the fact that the internal
proteins of retroviruses are adapted to the intracellular (reducing)
environment, and have cysteine residues present in thiol-form (S-H), while the
surface proteins of retroviruses (the envelope glycoproteins SU and TM) are
adapted to the (oxidizing) environment of the extracellular milieu, and have
their cysteines present as disulfides (S-S). Treatment of retroviral virions
with appropriate mild oxidizing agents thus results in preferential covalent
modification and functional inactivation of key S-H-containing internal viral
proteins, such as the nucleocapsid (NC) protein, that are required for
infectivity, while the envelope glycoproteins with their disulfide bonded
cysteines remain unaffected. This treatment thus results in virions that do not
retain detectable infectivity, but preserves the conformational and functional
integrity of the envelope glycoproteins. We have extensively used the disulfide
reagent 2,2’-dithiodipyridine (aldrithiol-2, AT-2) to inactivate HIV and
SIV via this mechanism and such inactivated virions appear to be a promising
vaccine immunogen based on macaque studies. We have biochemically characterized
the targets and mechanisms of inactivation involved in AT-2 treatment of
virions, and investigated the kinetics of inactivation. Although extremely
unlikely under physiological conditions, reversibility of this type of
inactivation is a theoretical concern. We have therefore conducted a series of
in vitro experiments, in cell free systems and in cell culture, to evaluate
this possibility. The results indicate that as judged by both biochemical and
biological (infectivity) criteria, inactivation by AT-2 does not appear to be
reversible under conditions likely to obtain in vivo.
[Back to top] Live Recombinant Vectors for AIDS Vaccine Development
Rebecca
Voltan and Marjorie Robert-Guroff
Live recombinant
vectors entered the AIDS vaccine field with the realization that live
attenuated HIV vaccines posed too great a safety risk, and that subunit
vaccines elicited antibodies which lacked the breadth or potency needed to
induce sterilizing immunity. Vectored vaccines provided a means to bring the
cellular arm of the immune system into play by mimicking natural viral
infection. By delivering antigens within host cells, processing and
presentation could occur for induction of cellular immune responses. This
recombinant vector approach, either alone or combined with other strategies,
has produced impressive results. Recombinants have been generated from DNA and
RNA viruses and bacteria. With few exceptions, each vector poses some risk, yet
each possesses unique features that make it attractive. In addition to safety,
key considerations in vector selection have included previous success as a
vaccine against the wild-type agent or other pathogens; ability to induce
potent, persistent immune responses; ability to target mucosal inductive sites
and antigen presenting cells; lack of integration into the host genome;
presence of pre-existing immunity in people; ease of mucosal administration;
cloning capacity; ease of engineering and production; and stability of the
final product. Here we up-date the status of several live recombinant vectors
that have shown good potential in pre-clinical studies. Some have progressed to
human clinical trials, and others will shortly. The abundance of vectors,
coupled with the complexity arising from use of combination regimens with other
vaccine types and heterologous vectors, will necessitate selection of the most
promising candidates for large-scale efficacy trials in people. The sooner
comparative studies can be designed and implemented in which live recombinant
vectors containing the same inserted genes are evaluated head-to-head, the
closer we will be to an eventual vaccine.
[Back to top] Cytokine, Chemokine, and Costimulatory Molecule Modulation to Enhance
Efficacy of HIV Vaccines
Jeffrey
D. Ahlers, Igor M. Belyakov and Jay A. Berzofsky
Understanding key
intervention points in developing immune responses may allow the rational
inclusion of biological adjuvants into vaccines that could potentiate the
immune response both quantitatively and qualitatively and enhance effective
memory responses. Cytokine and chemokine combinations can potentially help
target antigen to the appropriate antigen presenting cell and initiate
maturation of these presenting cells, attract cells expressing different
chemokine receptors, steer cellular immune responses toward Th1 and CD8 CTL,
and enhance systemic and mucosal IgG and secretory IgA antibodies and determine
their isotype balance. Animal protection studies suggest that synergistic combinations
of cytokines and immunomodulating molecules may be required to protect from a
viral challenge. For example, GM-CSF has been shown to be synergistic with
IL-12 or CD40 ligand for induction of CTL and for antiviral protection, and the
triple combination of GM-CSF, IL-12, and TNF alpha appears to induce the most
effective protection in some mouse models. Chemokineantigen fusions have also
been shown to enhance immunogenicity of the antigen. Combinations of
costimulatory molecules have been found to be synergistic when incorporated in
a vaccine. Combined use of newer more potent vaccine constructs, containing
codon optimized epitopes, relevant CpG motifs, cytokines, costimulatory
molecules and chemokines, used in heterologous prime-boost strategies with
viral vector vaccines or recombinant proteins, might afford the most potent
vaccine approaches yet developed. In this review we will discuss the
application and delivery of cytokines, costimulatory molecules, and chemokines
toward improving current vaccine strategies.
[Back to top] HIV Vaccines in Infants and Children: Past Trials, Present Plans and
Future Perspectives
Jeffrey
T. Safrit
This review will
address the recent history in HIV vaccine trials in the pediatric population
while giving due respect to the pediatric vaccine successes achieved over the
past decades. Success and failure seen when utilizing the neonatal macaque
model of SIV infection and the ramifications of these studies will be
discussed. The short list of pediatric HIV vaccine trials currently in progress
and those in early planning stages will be reviewed. Finally, future
perspectives on the impact of a vaccine that could be used to potentially avert
mother-to-child transmission of HIV and lead ultimately to the establishment of
immunity throughout adolescence and beyond will be presented.