Table of Contents

Volume 4, Issue 6

  November/December 2008

  Pages 395 - 457

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 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Open Access Article

Letter from the Editor

Ronald W. Ellis and Eva Maria Riedmann
Page 395
http://dx.doi.org/10.4161/hv.4.6.7074
PDF




PORTAIT OF A LEADING VACCINOLOGIST

Open Access Article

Mucosal immunization for bacterial respiratory infections

Allan W. Cripps
Pages 396 - 399
http://dx.doi.org/10.4161/hv.4.6.7057
PDF




REVIEW

Open Access Article

MHC and MHC‑like molecules: Structural perspectives on the design of molecular vaccines

Vasso Apostolopoulos, Elizabeth Yuriev, Eliada Lazoura, Minmin Yu and Paul A. Ramsland
Pages 400 - 409
http://dx.doi.org/10.4161/hv.4.6.6690
Abstract | PDF

Major histocompatibility complex (MHC) molecules bind and present short antigenic peptide fragments on the surface of antigen presenting cells (APCs) to T‑cell receptors. Recognition of peptide‑MHC complexes by T‑cells initiates a cascade of signals in T‑cells and activated cells either destroy or help to destroy the APC. The MHCs are divided into three subgroups: MHC class I, MHC class II and MHC class III. In addition, nonclassical MHC molecules and MHC‑like molecules play a pivotal role in shaping our understanding of the immune response. In the design of molecular vaccines for the treatment of diseases, an understanding of the three‑dimensional structure of MHC, its interaction with peptide ligands and its interaction with the T‑cell receptor are important prerequisites, all of which are discussed herein.




RESEARCH PAPERS

Open Access Article

Novel linear DNA vaccines induce protective immune responses against lethal infection with influenza virus type A/H5N1

Frédéric Kendirgi, Nadezda E. Yun, Nathaniel S. Linde, Michele A. Zacks, Jeanon N. Smith, Jennifer K. Smith, Harilyn McMicken, Yin Chen and Slobodan Paessler
Pages 410 - 419
http://dx.doi.org/10.4161/hv.4.6.6177
Abstract | PDF

Vaccine development for possible influenza pandemics has been challenging. Conventional vaccines such as inactivated and live attenuated virus preparations are limited in terms of production speed and capacity. DNA vaccination has emerged as a potential alternative to conventional vaccines against influenza pandemics. In this study, we use a novel, cell-free DNA manufacturing process (synDNA™) to produce prototype linear DNA vaccines against the influenza virus type A/H5N1. This synDNA™ process does not require bacterial fermentation, so it avoids the use of antibiotic resistance genes and other nucleic acid sequences unrelated to the antigen gene expression in the actual therapeutic DNA construct. The efficacy of various vaccines expressing the hemagglutinin and neuraminidase proteins (H5N1 synDNA™), hemagglutinin alone (H5 synDNA™) or neuraminidase alone (N1 synDNA™) was evaluated in mice. Two of the constructs (H5 synDNA™ and H5N1 synDNA™) induced a robust protective immune response with up to 93% of treated mice surviving a lethal challenge of a virulent influenza A/Vietnam/1203/04 H5N1 isolate. In combination with a potent biological activity and simplified production footprint, these characteristics make DNA vaccines prepared with our synDNA™ process highly suitable as alternatives to other vaccine preparations.

Open Access Article

Recombinant Influenza B virus HA and NA antigens administered in equivalent amounts are immunogenically equivalent and induce equivalent homotypic and broader heterovariant protection in mice than conventional and live influenza vaccines

Bert E. Johansson and Ian C. Brett
Pages 420 - 424
http://dx.doi.org/10.4161/hv.4.6.6201
Abstract | PDF

Influenza B virus is an important cause of acute upper respiratory disease in humans. Vaccination is the primary method of control of influenza related disease, yet vaccine methodology and production technology have not changed in over 40 years. In this study, we compare the efficacy of recombinant baculovirus produced protein based neuraminidase containing influenza B vaccines with conventional inactivated influenza vaccine (CIV) and live-attenuated influenza vaccine (LAIV) in a murine model. All HA containing vaccines stimulated antibody and protected against an infectious challenge with homotypic virus (B/Harbin/7/94), only recombinant protein based (rHA+rNA and rNA) vaccines containing immunogenic amounts of influenza neuraminidase (NA) protected against challenge with a significantly antigenically different heterovariant virus (B/Beijing/243/1997), as measured by a reduction in mean pulmonary virus titers. This report demonstrates with influenza B virus, in a side-by-side comparison with CIV and LAIV in a murine model system the superiority of vaccines containing immunogenic NA over currently approved CIV and LAIV vaccines.

Open Access Article

Correlation between direct ELISA, single epitope-based inhibition ELISA and Pseudovirion-based neutralization assay for measuring anti-HPV-16 and anti-HPV-18 antibody response after vaccination with the AS04-adjuvanted HPV-16/18 cervical cancer vaccine

Francis J. Dessy, Sandra L. Giannini, Catherine A. Bougelet, Troy J. Kemp, Marie-Pierre M. David, Sylviane M. Poncelet, Ligia A. Pinto and Martine A. Wettendorff
Pages 425 - 434
http://dx.doi.org/10.4161/hv.4.6.6912
Abstract | PDF

To monitor immune status during clinical trials and after vaccine registration, several assays have been developed to measure type-specific human papillomavirus (HPV) serum antibody levels. These include neutralization assays, single epitope-based inhibition immunoassays, and direct enzyme-linked immunosorbent assays (ELISAs). Neutralization assays based on multiple epitopes and independent of vaccine material are considered the ‘gold standard’ for unbiased assessment of the protective potential of vaccine-induced antibodies. However, their use in large clinical trials is challenging. Here, we compare both the direct ELISA and the single epitope-based inhibition ELISA with the pseudovirion-based neutralization assay (PBNA) for HPV-16/18 antibody responses in vaccinated women enrolled in trials of Cervarix™, GSK's cervical cancer vaccine. The direct ELISA, which is based on multiple epitopes, was shown to have a higher degree of sensitivity and correlation with the PBNA when compared with the single epitope-based inhibition ELISA. Among double-positive results, high correlations were observed between the PBNA and the direct ELISA (0.70-0.88 for HPV-16 and 0.82-0.94 for HPV-18) and also with the single epitope-based inhibition ELISA (0.60-0.89 for HPV-16 and 0.57-0.96 for HPV-18) in women aged 15-25 years. The correlation persisted up to 6.4 years after primary vaccination. Similar levels of correlation were observed for adolescents aged 10-14 years and women aged 46-55 years. Therefore, the direct ELISA appears to be an excellent surrogate for neutralizing activity and can be used to evaluate antibody response induced by L1 VLP-based cervical cancer vaccines, regardless of time elapsed after vaccination (up to 6.4 years) and the age of the vaccine recipient.

Open Access Article

Neither antibody to a group B streptococcal conjugate vaccine nor the vaccine itself is teratogenic in rabbits

Lawrence C. Paoletti, Hilde-Kari Guttormsen, Mildred S. Christian, Alan M. Hoberman and Pamela McInnes
Pages 435 - 443
http://dx.doi.org/10.4161/hv.4.6.6178
Abstract | PDF

Group B Streptococcus (GBS) is a leading cause of human neonatal bacterial disease, resulting in pneumonia, sepsis, meningitis, and sometimes, death. Supportive preclinical studies of GBS capsular polysaccharide (CPS)-protein conjugate vaccines have led to several phase 1 and phase 2 trials in healthy, non-pregnant adults, which demonstrated that the vaccines, produced at the Channing Laboratory, were safe and immunogenic. However, evaluation of the safety and immunogenicity of a GBS conjugate vaccine administered to pregnant women demanded that it be manufactured under current good manufacturing practices (cGMP) and that it undergo developmental toxicity evaluation. In this report, we describe a GBS type III CPS-tetanus toxoid (III-TT) vaccine lot 3-1-96 manufactured and vialed under cGMP and our evaluation of the effect of this vaccine and of GBS type III CPS-specific antibody on conception and early- and late-stage fetal development in rabbits. III-TT lot 3-1-96 was compositionally similar to prototype III-TT lot 91-1, produced under non-GMP, and was potent in a mouse maternal vaccination-neonatal pup challenge model of GBS disease. Four groups of 30 female rabbits each were randomized to receive III-TT lot 3-1-96 vaccine, saline-alum, or combinations of these treatments before and after insemination. The dose of conjugated CPS on a weight basis was 1 µg/kg, mimicking the anticipated actual human dose. Based on the weight of the rabbits, this was 20- to 100-fold greater than the expected human dose. Does were pre-assigned to deliver litters naturally or have their kits delivered by Caesarean-section at gestation day 29, to assess late fetal development. Sera from does and kits were collected, and the presence of type III CPS-specific IgG was confirmed by quantitative ELISA. Based on all assessments, GBS type III-TT lot 3-1-96, nor antibody to it did not affect embryo-fetal viability, sex ratio, growth or cause malformations (i.e., it was non-teratogenic). In addition, that III-TT lot 3-1-96 was found to be safe and immunogenic in two clinical studies involving healthy non-pregnant adults supports a clinical evaluation of this vaccine in pregnant women.




COMMENTARIES

Open Access Article

Group B streptococcal conjugate vaccine: A timely concept for which the time has come

Morven S. Edwards
Pages 444 - 448
http://dx.doi.org/10.4161/hv.4.6.6507
Abstract | PDF

Invasive disease due to group B Streptococcus (GBS) has been recognized as a threat to the health of pregnant women and their infants for almost half a century. Development of GBS vaccine candidates has progressed at an exemplary pace given lack of manufacturer development, but efficacy testing of candidate GBS conjugate vaccines has been mired in economic and regulatory concerns for longer than a decade. A trivalent or pentavalent vaccine will be required, and decisions must be made as to the criteria by which efficacy will be determined and the population in whom efficacy will be assessed. Concerns regarding durability of conjugate vaccine-derived immunity, pregnant women as a possible target group and regulatory issues required for licensing must be resolved if the prospect of impacting GBS disease burden through immunization is to become a reality.

Open Access Article

Immunogenicity of DNA vaccines in humans: It takes two to tango

Shan Lu
Pages 449 - 452
http://dx.doi.org/10.4161/hv.4.6.6179
Abstract | PDF

Two recently completed phase I clinical trials with candidate HIV-1 vaccines demonstrated that DNA vaccines are, indeed, immunogenic in humans, even when administered through routine needle injections. However, the best use of this evolving technology lies in its potential to prime the host’s immune system. Since the discovery of DNA immunization as a new method of vaccination in the early 1990s, the real value of this technology for human vaccine development was questioned due to the apparent poor immunogenicity in repeated early phase clinical studies when DNA plasmids were injected into humans by conventional needle injections. New results indicate that DNA vaccination can provide excellent priming effects to the human immune system, and high level, antigen-specific antibody and T cell immune responses are elicited upon further stimulation through the employment of a different form of vaccine which contains antigens that match those included in the original priming DNA vaccine formulation. These findings in no way will reduce the value of DNA vaccines, instead, the roles of DNA vaccines should be redefined. It is very likely that DNA vaccine can be most useful by providing an antigen-specific immunologic help to other types of vaccines that are known to have low immunogenicity, including inactivated or recombinant protein-based subunit vaccines.

Open Access Article

Molecular and cellular mechanisms of DNA vaccines

Cevayir Coban, Shohei Koyama, Fumihiko Takeshita, Shizuo Akira and Ken J. Ishii
Pages 453 - 457
http://dx.doi.org/10.4161/hv.4.6.6200
Abstract | PDF

Although DNA vaccines are already in use for treatment of some animal diseases, they suffer from lower immunogenicity in humans which limits their effectiveness. Thus, recent studies have been focused on strategies to improve the immunogenicity of DNA vaccines. However, there is little known about the molecular and immunological mechanisms by which DNA vaccines work. It has long been the central dogma that DNA vaccine immunogenicity can be attributed to its immunostimulatory CpG motifs acting as ‘a built-in adjuvant’, which is recognized by Toll-like receptor (TLR) 9, the sole receptor for CpG motifs. Recent research, however, has provided evidence for a new mechanism of action for DNA vaccines. It was reported that the adjuvant effect of plasmid DNA is mediated by its double-stranded structure, which activates TBK1-dependent innate immune signaling pathways in the absence of TLRs. Moreover, TBK1-signaling may delineate direct or indirect (cross) antigen presentation through distinct types of cells in vivo, critical for the induction of antigen-specific CD4+ or CD8+ T cells, respectively. This additional information about the mechanism of action of DNA vaccines will lead to improvements in their efficacy and safety.