Current Drug Targets - Infectious Disorders, Volume 5, No. 2, 2005
Contents
HIV Vaccine Discovery and
Development
Guest Editor: Julia L.
Hurwitz
Editorial Pp.81-83
Julia L. Hurwitz
The HIV Pandemic: A Forgotten Crisis? Pp.85-86
Maxwell Madzikanga,
Abigail Kangwende, John Pfumojena, Karen S. Slobod and Julia L. Hurwitz
Fundamental Immunology and What it Can Teach
us About HIV Vaccine Development Pp.87-93
N. Avrion Mitchison
and Quentin Sattentau
Antibodies: Can They Protect Against HIV
Infection? Pp.95-111
C.M. Mc Cann, R.J.
Song and R.M. Ruprecht
CD8+ T-cells: Are they Sufficient to Prevent,
Contain or Eradicate HIV-1 Infection? Pp.113-119
Scott A. Brown, Julia
L. Hurwitz, Xiaoyan Zhan, Peter C. Doherty and Karen S. Slobod
Differentiation of CD8 T Cells in Response to
Acute and Chronic Viral Infections: Implications for HIV Vaccine Development Pp.121-129
J.D. Miller, D.
Masopust, E.J. Wherry, S. Kaech, G. Silvestri and R. Ahmed
Inactivated- or Killed-Virus HIV/AIDS
Vaccines Pp.131-141
Haynes W. Sheppard
Application of the Polyvalent Approach to
HIV-1 Vaccine Development
Pp.143-156
Julia L. Hurwitz, Karen S. Slobod, Tim D. Lockey, Shixia Wang, Te-Hui W. Chou, Shan Lu
HIV-1: The Confounding Variables of Virus
Neutralization Pp.157-170
Peter L. Nara and George Lin
HIV-1 Envelope Evolution and Vaccine Efficacy Pp.171-177
D. E. Mosier
Predicting the Potential Public Health Impact
of Disease-Modifying HIV Vaccines in South Africa: The Problem of Subtypes Pp.179-192
Sally M. Blower, Erin N. Bodine, Kathie Grovit-Ferbas
Non-Human Primate Models for AIDS Vaccine
Research Pp.193-201
Shiu-Lok Hu
Abstracts
[Back to top] Editorial
Julia L. Hurwitz
HIV Vaccine Discovery and Development
The HIV pandemic rages unabated; approximately five million people are newly infected and another three million die of HIV/AIDS each year. Unfortunately, despite decades of research, no HIV-1 vaccine has yet shown evidence of a protective effect in clinical trial [1,2]. Although the development of an effective HIV-1 vaccine is surely achievable, a number of concerns have been raised which dampen optimism among HIV-1 researchers. It is important to remember that each of these concerns has been surmounted in other vaccine fields, and it may be constructive to review them in that light:
HIV-1 establishes a chronic infection: Numerous viruses establish chronic infections by residing in immune-privileged sites (e.g. brain) that are inaccessible to B and T cells. VZV is one such virus for which an effective, licensed vaccine has recently been produced [3].
HIV-1 is diverse: Diversity is not unique to HIV-1. When faced with the diversity of pneumococcus, vaccine developers created a cocktail vaccine representing more than 20 pneumococcal serotypes [4]. The vaccine is licensed and effective.
The disease is unique: This point is undeniable, yet it was similarly made during the polio pandemic. In 1945, Dr. Frank McFarlane Burnet, an eventual Nobel Prize winner, stated “The practical problem of preventing infantile paralysis has not been solved. It is even doubtful whether it ever will be solved.” [8]. Shortly thereafter, the success of the Salk polio vaccine was demonstrated. The power of vaccination has since been underscored by the near-complete eradication of polio.
The immune system, if appropriately harnessed, has an enormous surveillance capacity. Perhaps the most impressive utilization of immune potential was accomplished in the 18th century by Edward Jenner, who without knowledge of B-cell and T-cell mechanisms, designed an effective smallpox vaccine. Today, we in the 21st century are challenged to match Jenner’s achievement. Perhaps solutions simply require an open mind and a memory of immunology lessons from the past. As the pursuit for solutions continues, scientists are testing a number of new vaccine strategies. Table 1 lists examples of vaccines in pre-clinical and clinical stages of development. Details and updates may be found on websites such as <http://www.iavi.org/> and http://chi.ucsf.edu/vaccines.
In this issue, we examine the fundamental concepts of immunology as they relate to vaccine development. The reader may find common themes among the articles, but there are clear differences of opinion as well; these may be the natural result of our field’s struggle to conquer a world tragedy. Madzikanga et. al. lead off this issue with a reminder of the magnitude of human misery caused by the HIV pandemic. Mitchison and Sattentau then review basic immune mechanisms relevant to vaccine efficacy. McCann et. al. and Brown et. al. respectively examine the protective potentials of neutralizing antibodies and T-cell populations. Miller et. al. describe the details of immune memory. Two different vaccine strategies are described by Sheppard and by Hurwitz et. al. Nara and Lin highlight the pros and cons of neutralization assays. Mosier examines the various characteristics of HIV-1 isolates which must be considered during vaccine design. Blower et al. suggest possible outcomes of clinical vaccination programs. Finally, Hu describes the attributes and weaknesses of non-human promate models for HIV/AIDS.
Here’s a special thank-you to all the authors for their contributions, to James Bradac (NIH/NIAID/DAIDS) for Table 1, to Bob Goldman as Editor, to Bentham Science Publishers, and to support from the NIH (P01-AI45142) and the American Lebanese Syrian Associated Charities (ALSAC).
References
[1] Graham, B.S.; Mascola, J.R. J. Infect. Dis., 2005, 191, 647.
[2] Cohen, J. Science, 2004, 305, 1545.
[3] Goldman, G.S. Vaccine, 2003, 21, 4243.
[4] Biagini, R.E.; Schlottmann, S.A.; Sammons, D.L.; Smith, J.P.; Snawder, J.C.; Striley, C.A.; MacKenzie, B.A.; Weissman, D.N. Clin. Diagn. Lab. Immunol., 2003, 10, 744.
[5] Tsui, R.; Herring, B.L.; Barbour, J.D.; Grant, R.M.; Bacchetti, P.; Kral, A.; Edli, B.R.; Delwart, E.L. J. Virol., 2004, 78, 94.
[6] Gonzales, M.J.; Delwart, E.; Rhee, S.Y.; Tsui, R.; Zolopa, A.R.; Taylor, J.; Shafer, R.W. J. Infect. Dis., 2003, 188, 397.
[7] Altfeld, M.; Allen, T.M.; Yu, X.G.; Johnston, M.N.; Agrawal, D.; Korber, B.T.; Montefiori, D.C.; O'Connor, D.H.; Davis, B.T.; Lee, P.K.; Maier, E.L.; Harlow, J.; Goulder, P.J.; Brander, C.; Rosenberg, E.S.; Walker, B.D. Nature, 2002, 420, 434.
[Back to top] The HIV Pandemic:
A Forgotten Crisis?
Maxwell Madzikanga, Abigail Kangwende, John Pfumojena, Karen S. Slobod and Julia L. Hurwitz
The devastation caused by HIV and AIDS has touched virtually every world region. One concern is that the unrelenting nature of the HIV pandemic fosters a disposition, not of fear and determination, but of tolerance and complacency.
[Back to top] Fundamental Immunology and What it Can Teach
us About HIV Vaccine Development
N. Avrion Mitchison
and Quentin Sattentau
This survey covers the immunological background to development of an HIV vaccine, starting from an overview of present understanding of the mechanisms of immunoregulation. It follows the uptake, processing and presentation of an antigen, from its initial uptake by a dendritic cell and its deposit on the dendrites of follicular dendritic cells. It pursues the antigen through uptake by B cells, presentation of epitopes to helper T cells and the eventual production of antibody. In the second arm of the immune response it follows synapse formation between dendritic cell and CD4/CD8 cells leading to production of CTL. It identifies epitope linkage as a key element in directing these pathways. It identifies the principal functions of the various types of cell cooperation. Continuing, it focuses on topics relevant to vaccine development: Th1/Th2 balance: new adjuvants based on ligands of TLRs and other activators of innate immunity, as well as new forms of intervention in antigen processing. We urge that the new vaccine fusion constructs be evaluated against a fusion gold standard rather than against antigen alone. These considerations open new strategies of HIV vaccine development. . Finally we urge that vaccine trials should include storage of individual DNA samples, in order to gain better understanding of the genetic parameters of vaccine efficacy.
[Back to top] Antibodies: Can They Protect Against HIV
Infection?
C.M. Mc Cann, R.J.
Song and R.M. Ruprecht
More than 20 million people have died since the discovery of human immunodeficiency virus (HIV), yet a broadly reactive AIDS vaccine remains elusive. Neutralizing antibody (nAb) response-based vaccine strategies were the first to be tested; however, when the difficulty in neutralizing primary HIV isolates was recognized, vaccine development focused instead on generating cytotoxic T-lymphocyte (CTL) responses. Recently, interest in anti-HIV nAbs has been revived by the impressive protection achieved in primates given passive immunization with neutralizing monoclonal antibodies (nmAbs) isolated from HIV clade B-infected individuals. The nmAbs used in these studies target conserved, functionally important epitopes in HIV gp120 and gp41. Regimens involving combinations of such human nmAbs or high-dose single-agent nmAb protected monkeys against intravenous (iv) and mucosal challenges with simian-human immunodeficiency virus (SHIV) strains encoding X4, X4R5 or R5 HIV env genes. In several such studies, sterilizing immunity was achieved, thus providing proof-of-concept that nAbs targeting conserved epitopes can be fully protective. The existence of these broadly reactive nmAbs suggests that it may be possible to design immunogens capable of inducing similar nAb responses by active vaccination. Unraveling the three-dimensional structures involved in the nmAb-HIV Env epitope interactions may facilitate the future development of a potent AIDS vaccine.
This review is focused on the importance of nAbs in protecting against HIV infection or in containing viral spread, with particular emphasis on the successful use of nmAbs in passive immunization studies. The implications of the data from these studies on AIDS vaccine design in general are also discussed.
[Back to
top]
CD8+ T-cells: Are they Sufficient to Prevent, Contain or Eradicate HIV-1
Infection?
Scott A. Brown,
Julia L. Hurwitz, Xiaoyan Zhan, Peter C. Doherty and Karen S. Slobod
The prevention of HIV-1 by vaccination has proven to be a formidable task. In an ongoing endeavor to end the HIV-1 pandemic, scientists seek vaccines that will elicit quantitatively and qualitatively robust B-cell and T-cell activities. Given that cytotoxic T-lymphocytes (CTL) play a substantial role in the immunological control of immunodeficiency virus infections, this review will focus on vaccines designed to elicit HIV-1-specific CTL. Vaccine approaches using various HIV-1 proteins or specific CTL determinants, partnered with diverse delivery systems and adjuvants will be discussed. Lessons from studies with other virus models (e.g. gamma herpes virus and influenza virus) will also be examined. Since CTL contribute to the success of vaccines in other model systems, an understanding of the strengths and possible limitations of these cells may be critical to future successes in the HIV-1 vaccine field.
[Back to top] Differentiation of CD8 T Cells in Response
to Acute and Chronic Viral Infections: Implications for HIV Vaccine Development
J.D. Miller, D.
Masopust, E.J. Wherry, S. Kaech, G. Silvestri and R. Ahmed
[Back to top] Inactivated- or Killed-Virus HIV/AIDS Vaccines
Haynes W. Sheppard
Inactivated or “killed” virus (KV) is a “classical” approach that has produced safe and effective human and veterinary vaccines but has received relatively little attention in the effort to develop an HIV/AIDS vaccine. Initially, KV and rgp120 subunit vaccines were the two most obvious approaches but, unfortunately, rgp120 has not been efficacious and the KV approach has been limited by a variety of scientific, technical, and sociological factors. For example, when responses to cellular antigens, present on SIV grown in human cells, proved to be largely responsible for efficacy, the KV approach was widely discounted. Similarly, when lab-adapted HIV-1 appeared to lose envelope glycoprotein during preparation (not the case for primary isolates), this was viewed as a fundamental barrier to the KV concept. Also, a preference for “safer”, genetically-engineered vaccines, and emphasis on cellular immunity, have left KV low on the priority list for funding agencies and investigators. The recent suggestion that “native” trimeric gp120 displays conserved conformational neutralization epitopes, along with the failure of rgp120, and difficulties in raising strong cellular responses with DNA or vectored vaccines, has restored some interest in the KV concept. In the past 15 years, several groups have initiated pre-clinical development of KV candidates for SIV or HIV and promising, albeit limited, information has been produced. In this chapter we discuss the rationale (including pros and cons) for producing and testing killed-HIV vaccines, the prospects for success, the nature and scope of research needed to test the KV concept, what has been learned to date, and what remains undone.
[Back to top] Application of the Polyvalent Approach to
HIV-1 Vaccine Development
Julia L. Hurwitz, Karen S. Slobod, Tim D. Lockey, Shixia Wang, Te-Hui W. Chou, Shan Lu
One major obstacle to the design of a global HIV-1 vaccine is viral diversity. Presently, data suggest that a single antigen will not suffice to generate broadly reactive neutralizing antibodies to protect all individuals against all subtypes of HIV-1 infection. While some of the neutralizing epitopes are identified in the constant regions of the HIV-1 envelope (Env) glycoprotein, many are localized to variable regions and differ conformationally from one virus to the next. The successes of polyvalent vaccine approaches against other antigenically variable pathogens encourage adoption of the same approach for HIV-1 vaccine design. The critical question is which envelope antigens should be combined in a vaccine cocktail to provide maximum protection against HIV-1. A review of the existing human vaccines based on the polyvalent principle is included here to provide a historical perspective for the current effort of developing a polyvalent HIV-1 vaccine. Data generated from several groups actively working on candidate polyvalent HIV-1 vaccines are summarized. Information presented in this review highlights the potential and importance of the polyvalent vaccine approach for the future development of an effective HIV-1 vaccine.
[Back to top] HIV-1: The Confounding Variables of Virus
Neutralization
Peter L. Nara and George Lin
The development of an effective vaccine against HIV-1 would be greatly facilitated by the ability to elicit potent, high affinity antibodies that are capable of broad neutralization, viral inactivation and protection against infection and/or disease. New insights into the structure and function of the HIV-1 envelope glycoprotein (Env) that mediates viral fusion and entry may ultimately lead to strategies successful in eliciting these protective antibody responses. Insights have been gained regarding HIV-1 Env attachment and receptor engagement, the fusion process and kinetics, and the structural/functional attributes of Env that allow humoral immune evasion. In addition, studies of a limited number of broadly neutralizing human monoclonal antibodies have shed some light as to how antibodies may penetrate the immune evading armor that HIV-1 has evolved. As the elusive goal of generating these types of antibodies emerge and are developed in the context of generating new candidate HIV-1 vaccines, a relevant in vitro measurement of neutralization by these types of antibodies becomes a complex task. This is in part due to a list of confounding variables which include: the physical and genomic nature (amino acid variation) of the infecting virion, the type of target cells, the concentration and clonality of the reactants, assay format and design, the affinity and kinetics of the reaction, receptors/coreceptors and attachment factors, and soluble host factors. This review will focus on the past, current, and future knowledge required to advance the field of HIV-1 humoral immunity as it impacts future HIV-1 vaccine development.
[Back to top] HIV-1 Envelope Evolution and Vaccine Efficacy
D. E. Mosier
Transmission of human immunodeficiency virus type 1 (HIV-1) selects for envelope variants with a number of defined properties, including use of CCR5 as the preferred coreceptor, binding to CCR5 in a distinct manner compared to HIV-1 isolated later in infection, shorter variable (V) regions, and fewer N-linked glycosylation sites. These features define the ideal target for an envelope-containing vaccine designed to elicit neutralizing antibody. If a candidate vaccine were sufficiently potent to elicit sterilizing immunity, virus evolution would not be an issue. However, all results to date suggest that an envelope-containing vaccine will have a lesser impact, and that virus evolution will contribute to escape from the vaccine-induced antibody response. The key question is whether or not the early selection pressure imposed by neutralizing antibody will have a long term impact on HIV disease progression. Several recent reports suggest that HIV-1 will evolve to rapidly escape antibody selection, and that the cost to the virus in terms of entry fitness will be small. Durable effects of vaccination are predicted to be associated with a reduction in peak viremia and viral set point at the time of primary infection.
[Back to top] Predicting the Potential Public Health Impact
of Disease-Modifying HIV Vaccines in South Africa: The Problem of Subtypes
Sally M. Blower, Erin N. Bodine, Kathie Grovit-Ferbas
Current HIV vaccines in development appear unlikely to prevent infection, but could provide benefits by increasing survival; such vaccines are described as disease-modifying vaccines. We review the current status of vaccines and modeling vaccines. We also predict the impact that disease-modifying vaccines could have in South Africa, where multiple subtypes are co-circulating. We model transmissibility/fitness differences among subtypes. We used uncertainty analyses to model vaccines with four characteristics: (i) take, (ii) duration of immunity, (iii) reduction in transmissibility/fitness, and (iv) increase in survival. We reconstructed, and forecasted, the South African epidemic from 1940 to 2140 (assuming no vaccination). We predict that: (i) incidence will peak in 2014, decline, and stabilize, (ii) prevalence will continue to rise, and (iii) the AIDS death rate curve will peak in 2022. Our predictions show that (over the next 135 years) the epidemic in South Africa will switch from a predominantly Subtype C epidemic to an epidemic driven by other subtypes. We predict that the epidemic could remain unchanged, even with mass vaccination with a vaccine that is equally effective against all co-circulating subtypes. However, if the non-C subtypes are less (or equally) transmissible as Subtype C then disease-modifying vaccines could result in eradication. Thus, in countries where multiple-subtypes are co-circulating it is critical to realize that small biological differences among subtypes will have dramatic consequences for the effectiveness of HIV vaccination campaigns. A slight difference in fitness will determine whether a disease-modifying vaccine has almost no impact on the epidemic or can achieve eradication.
[Back to top] Non-Human Primate Models for AIDS Vaccine
Research
Shiu-Lok Hu
Since the discovery of simian immunodeficiency viruses (SIV) causing AIDS-like diseases in Asian macaques, non-human primates (NHP) have played an important role in AIDS vaccine research. A multitude of vaccines and immunization approaches have been evaluated, including live attenuated viruses, DNA vaccines, viral and bacterial vectors, subunit proteins, and combinations thereof. Depending on the particular vaccine and model used, varying degrees of protection have been achieved, including prevention of infection, reduction of viral load, and amelioration of disease. In a few instances, potential safety concerns and vaccine-enhanced pathogenicity have also been noted. In the past decade, sophisticated methodologies have been developed to define the mechanisms of protective immunity. However, a clear road map for HIV vaccine development has yet to emerge. This is in part because of the intrinsic nature of the surrogate model and in part because of the improbability of any single model to fully capture the complex interactions of natural HIV infection in humans. The lack of standardization, the limited models available, and the incomplete understanding of the immunobiology of NHP contribute to the difficulty to extrapolate findings from such models to HIV vaccine development. Until efficacy data become available from studies of parallel vaccine concepts in humans and macaques, the predictive value of any NHP model remains unknown. Towards this end, greater appreciation of the utility and limitations of the NHP model and further developments to better mimic HIV infection in humans will likely help inform future AIDS vaccine efforts.