Table of Contents

Volume 4, Issue 5

  September/October 2008

  Pages 323 - 392

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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 323
http://dx.doi.org/10.4161/hv.4.5.6763
PDF




PORTAIT OF A LEADING VACCINOLOGIST

Open Access Article

The path of discovery

Denise L. Doolan
Pages 324 - 327
http://dx.doi.org/10.4161/hv.4.5.6707
PDF




REVIEWS

Open Access Article

Immunogenicity of a two-component (PT&FHA) acellular pertussis vaccine in various combinations

Emmanuel Vidor and Stanley A. Plotkin
Pages 328 - 340
http://dx.doi.org/10.4161/hv.4.5.6008
Abstract | PDF

Immunogenicity data for the pertussis components of the French diphtheria-tetanus-two component acellular pertussis vaccine (DTaP_2Fr) obtained after primary series of immunizations were compiled from 75 study groups comprising 36 clinical trials or vaccination programs conducted between 1987 and 2006. DTaP_2Fr vaccine was administered either as a standalone vaccine or as the backbone of several combination vaccines that included IPV, HepB, and/or PRP-T antigens. Most of the variability in responses was associated with differences in the schedules, and to a lesser extent the geographical region where the study was performed, suggesting the importance of ethno-ecological factors. However the addition of other vaccine antigens did not affect the immunogenicity of the aP_2Fr antigens. The immune responses to the PT and FHA antigens of the DTaP_2Fr vaccine used in the Senegal efficacy trial, which established its good efficacy relative to a highly effective DTwP vaccine, was in the middle of the range of titers observed during other studies using the 2-4-6 months schedule conducted with the same vaccine. The consistent immunogenicity of the DTaP_2Fr vaccine is accompanied by effectiveness in controlling pertussis disease in the areas where it is used on a large scale with good vaccination coverage.

Open Access Article

Pneumococcal polysaccharide vaccination in Australia: An examination of barriers and arguments in support of the hospital based approach

Craig Motbey
Pages 341 - 343
http://dx.doi.org/10.4161/hv.4.5.6114
Abstract | PDF

Pneumococcal disease is a major cause of morbidity and mortality, arguably responsible worldwide for more deaths than any other single pathogen. Despite the severe impact of pneumococcal disease and the availability of a safe, efficacious and cost-effective vaccine, vaccination rates have generally remained far below targets. Since 2005 a publicly funded program offering free pneumococcal polysaccharide vaccine for at-risk patients has been implemented in Australia, and early data suggest that this change has had a major positive impact on pneumococcal vaccination rates. However, rates still remain far below the ideal. A literature review identified physician related factors as the major impediment to raising vaccination rates and the use of hospital based vaccination strategies as a potentially useful response.




MEETING REPORTS

Open Access Article

Next generation of human vaccines: What does the future hold?

Sita Awasthi
Pages 344 - 346
http://dx.doi.org/10.4161/hv.4.5.6370
Abstract | PDF

The World Vaccine Congress was held in Arlington, VA April 21st -24th, 2008. Tevi Troy, the deputy secretary of the US Department of Health and Human Services, set the tone of the meeting during his keynote address. He discussed the government’s plan to deliver a strategic outlook and follow a road map for vaccine development. He also emphasized the importance of ongoing cooperation between industry and the government’s many departments. In an electrifying keynote address Gregory Poland, Professor of Medicine and Infectious Diseases at the Mayo Clinic in Rochester, MN discussed the role of recent advancements in the fields of Immunology, Genetics, Molecular Biology, Bioinformatics, and the completion of the Human Genome Project. Poland described the recent emergence of the field of Vaccinomics and laid out his vision for an era of personalized medicine. Next-generation vaccine approaches targeting cervical cancer, meningitis, childhood diarrhea, and renal cell carcinoma were presented by leaders in the field. Preclinical and early-stage clinical successes of vaccines against Malaria, TB, and Ebola were discussed along with a road map for HIV, TB, and Malaria vaccine development. The importance of collaborations among government departments, academic institutions, industries, and philanthropic foundations was a common theme stressed throughout the conference.

Open Access Article

Vaccine adjuvants: The dream becomes real

Aldo Tagliabue and Rino Rappuoli
Pages 347 - 349
http://dx.doi.org/10.4161/hv.4.5.6438
Abstract | PDF

After about 70 years two new adjuvants have been approved for human vaccines. The first is MF59 developed by the ex-Chiron now Novartis Vaccines and it consists in an oil-in-water emulsion, comprising a low content of biodegradable squalene oil (4.3%) as the dispersed phase, which is stabilized by two non-ionic surfactants (Tween 80 and Span 85), and a low ionic strength citrate buffer as the continuous phase. The second defined as AS04 it has been developed by GSK Biologics it consists in 3-0-descyl-4’-monophosporyl lipid A (MPL) that comes from the cell wall LPS of Gram-negative Salmonella minnesota R595 and is detoxified by mild hydrolytic treatment and purification. It is absorbed on aluminum hydroxide or aluminum phosphate. Thus, new molecules are available to improve the immune response to vaccine also in humans: this is the beginning of a new era in vaccinology.




RESEARCH PAPERS

Open Access Article

Stabilization of measles virus for vaccine formulation

Julian Kissmann, Salvador F. Ausar, Angela Rudolph, Chad Braun, Stephen P. Cape, Robert E. Sievers, Mark J. Federspiel, Sangeeta B. Joshi and C. Russell Middaugh
Pages 350 - 359
http://dx.doi.org/10.4161/hv.4.5.5863
Abstract | PDF

An attenuated live measles virus (MV) was characterized by several biophysical methods as a function of temperature and pH. Following a method developed previously, the resultant light scattering and spectroscopic data were synthesized into an empirical phase diagram that visually and simultaneously represents the entire data set. Using this empirically-based phase diagram, screening assays were developed to identify potential vaccine stabilizers. Various compounds are shown by these assays to inhibit the temperature-induced aggregation of viral particles, and also to protect the integrity of the viral envelope. Accelerated stability assays show that, upon thermal challenge, MV formulated with these excipients retains its infectivity to a significant extent. Thus, the enhanced physical stability produced by this method is shown to protect the biological activity of this important but labile vaccine.

Open Access Article

An intranasal heat shock protein based vaccination strategy confers protection against mucosal challenge with herpes simplex virus

Christopher D. Pack, Malgorzata Gierynska and Barry T. Rouse
Pages 360 - 364
http://dx.doi.org/10.4161/hv.4.5.5978
Abstract | PDF

Herpes simplex virus-1 (HSV-1) represents a significant obstacle for vaccine designers, despite decades of investigation. The virus primarily infects the host at vulnerable mucosal surfaces that progresses to lesion development, latency in nervous tissue, and possible reactivation. Therefore, protection at the site of infection is crucial. Mucosal adjuvants are critical for the development of an effective vaccine approach, and heat-shock protein 70 (Hsp70) represents an attractive candidate for this purpose. This study demonstrates that Hsp70 coupled to gB498-505 from HSV-1 induced mucosal and systemic priming of CD8⁺ T cells capable of protecting C57BL/6 mice against a lethal vaginal challenge. Elevated gB-specific cytotoxicity was observed in the spleen of mice immunized with conjugated Hsp70 and gB498-505. In addition, both vaginal IFN-γ levels and viral clearance were enhanced in mice mucosally immunized with Hsp70 and gB peptide versus peptide only control mice or mice receiving Hsp70 and a control peptide. These studies demonstrate that Hsp70 can be used as an effective mucosal adjuvant capable of generating a protective cell-mediated immune response against HSV-1.

Open Access Article

Protecting Indian schoolchildren against rabies: Pre-exposure vaccination with purified chick embryo cell vaccine (PCECV) or purified verocell rabies vaccine (PVRV)

Preeti Shanbag, Nitin Shah, Madhuri Kulkarni, Manisha Juvekar, Shampur N. Madhusudana, Hoshang B. Vakil and Claudius Malerczyk
Pages 365 - 369
http://dx.doi.org/10.4161/hv.4.5.5987
Abstract | PDF

Although rabies can be effectively prevented by means of pre-exposure or post-exposure prophylaxis, in India, an estimated 17,000 to 20,000 human rabies deaths occur annually. Tragically, 50% of these victims are children under the age of 15. In addition to immediate post-exposure prophylaxis measures, including active and passive immunization, pre-exposure vaccination using tissue culture vaccines is a safe and effective but highly underutilized method of preventing rabies in humans living or working in areas at risk. This study assessed the safety and immunogenicity of Purified Chick Embryo Cell Vaccine (PCECV) and Purified Verocell Rabies Vaccine (PVRV), administered as a three-dose intramuscular pre-exposure regimen on days 0, 7 and 28 in 175 healthy schoolchildren. PCECV was administered after reconstitution using either 1.0 mL or 0.5 mL (half the diluent volume) and PVRV was given after reconstitution with 0.5 mL. Vaccine safety was assessed observer-blind, including pain assessment with a validated visual analogue scale for children. Rabies virus neutralizing antibody (RVNA) concentrations were measured on day 49 by RFFIT. All children developed adequate RVNA concentrations above 0.5 IU/mL. Solicited local and systemic reactions were within the range expected, pain after vaccination was reported in 2 to 12% of study subjects, fever was reported in 2 to 5%. There was no statistical difference in the vaccination group or vaccination day. No unexpected or serious adverse event was reported during the study. In conclusion, PCECV and PVRV are safe and immunogenic when administered intramuscularly for pre-exposure prophylaxis of rabies in children. A 1.0 mL dilution volume for PCECV was as well tolerated as PVRV or PCECV reconstituted in half the volume.

Open Access Article

Functional activity of antisera to group B streptococcal conjugate vaccines measured with an opsonophagocytosis assay and HL-60 effector cells

Hilde-Kari Guttormsen, Yongdong Liu and Lawrence C. Paoletti
Pages 370 - 374
http://dx.doi.org/10.4161/hv.4.5.5988
Abstract | PDF

Conjugate vaccines against group B Streptococcus (GBS), which is a leading cause of bacterial disease among newborns and the elderly with underlying illnesses, have progressed from animal studies to phase 1 and 2 clinical trials in healthy adults. Due to the wide-spread use of antibiotics to treat at-risk deliveries, a phase 3 efficacy trial of a GBS vaccine to prevent neonatal disease in the United States is unlikely. A viable approach to assess a vaccine’s efficacy is to use a surrogate of protection which in the case of GBS is the opsonizing activity of serum antibody. The opsonophagocytosis assay (OPA) measures the ability of serum antibody to opsonize GBS for killing by effector cells in the presence of complement. In this report we demonstrate that differentiated HL-60 cells can substitute for human peripheral blood leukocytes (hPMNLs) in the OPA. Antisera to GBS type Ia CPS and type III CPS conjugate vaccines opsonized homologous GBS for killing at effector cells to GBS ratios of 2-4:1 regardless of whether HL-60 or hPMNLs were used. These results represent the first important step in developing a standardized, high-throughput OPA that could be used to assess the functional activity of vaccine-induced antibody and potentially serve as a surrogate of efficacy.

Open Access Article

Development of a sandwich enzyme-linked immunosorbent assay (ELISA) for determining of bovine serum albumin (BSA) in trivalent measles-mump-rubella (MMR) vaccines

Sedigheh Khamehchian, Rasool Madani, Fariba Golchinfar and Mohammad Taghavian
Pages 375 - 378
http://dx.doi.org/10.4161/hv.4.5.6009
Abstract | PDF

A sandwich enzyme-linked immunosorbent assay (ELISA), using polyclonal antibody, was developed and compared with the commercial kit for detecting and estimating of BSA content in Measles-Mump-Rubella (MMR) vaccine samples in detection limit of nanogram level. The test depends on the capturing and detecting of BSA antigen by the polyclonal antibody. Initially, a detection range of 0-64 ng/ml was established, could be used for estimation of BSA content according to WHO requirement (50 ng/ml) in MMR vaccines. Comparative analysis of the test results for 85 MMR vaccine samples obtained with the commercial kit gave a sensitivity of 58.8% and a specificity of 97%. A high correlation (r=0.94) was observed between BSA sandwich ELISA and commercial kit for BSA content in MMR samples. However, variations in values also were observed for the two assays. These variations may have been due to difference of upper limit of detection range of BSA content in commercial kit (32 ng/ml) and new sandwich ELISA (64 ng/ml) as well as the use of a different polyclonal antibody. In concerning the cutoff value for the WHO requirement and employment of standard solution of 64 ng/ml in developing assay, it would be adequate to use this test for assessing BSA content in viral vaccines same as MMR vaccines.

Open Access Article

Predicting response to HBV vaccination in people with positive anti-HBc but negative HBsAg and anti-HBs

Ali Kabir, Seyed-Moayed Alavian, Amir Hossein Faghihi Kashani and Maryam Keshvari
Pages 379 - 383
http://dx.doi.org/10.4161/hv.4.5.6010
Abstract | PDF

Objective: There are 5.1-6.5% of people with positive anti-HBc in Iran. The aim of this study was to assess the predicting factors of response to hepatitis B vaccination in anti-HBc positive subjects.

Results: Total response rate to vaccination was 79.8% (75 cases) and 67.9% (38 cases) in cases and controls, respectively. Nineteen persons (20.2%) in cases and 18 persons (32.1%) of controls had negative anti-HBs even after three doses of HB vaccination. Factor associated with decreased response to vaccination was prior history of being HBsAg positive (OR = 1.3, p = 0.01).

Conclusion: The rate of response to hepatitis B vaccination is nearly like other studies but somewhat different. Higher percent of married cases together with higher percent of positive HBsAg in spouses may explain the slight difference in the response to vaccination in cases in comparison with controls as a result of booster like effect that seldom happens because of recurrent contacts between the subjects and the HBsAg positive spouses spontaneously.

Methods: In a quasi-experimental study, 94 people with negative HBsAg, negative anti-HBs and positive anti-HBc (cases) and 56 persons with negative HBsAg, anti-HBs and anti-HBc (controls) were vaccinated at zero, one and six months with recombinant hepatitis B vaccine. Successful immunization was defined by anti-HBs antibody titer >= 10 mIU/mL.




COMMENTARIES

Open Access Article

Custom designing therapeutic cancer vaccines: Delivery of immunostimulatory molecule adjuvants by protein transfer

Periasamy Selvaraj, Archana Yerra, Linda Tien and Rangaiah Shashidharamurthy
Pages 384 - 388
http://dx.doi.org/10.4161/hv.4.5.5866
Abstract | PDF

Attempts to create vaccines for humans against invading pathogens such as viruses and bacteria have met with tremendous success. The process of developing vaccines against these pathogens is greatly aided by the fact that they contain antigens that are entirely foreign to humans. Although the knowledge and strategies developed for designing vaccines against these microbes may be of use in developing cancer vaccines, the poor antigenicity and immunosuppressive ability of cancers pose major hurdles to vaccine development. Established tumors have not only withstood immune screening and selection pressure, making them poor stimulators of an immune response, but have also adapted mechanisms to continue evading immune surveillance by creating an immunosuppressive environment. Also, genetic differences in immune responses to an antigen among individuals result in an antigenic profile that varies from patient to patient. Cancers bear such great similarities to normal cells in the body that, on a molecular level, the differences between cancerous and non-cancerous cells are minor. Therefore, developing vaccines which use the host's own tumor tissues carries the risk of breaking tolerance to self-antigens that are present in the tumor tissue. Vaccination strategies that will optimally stimulate the immune system against tumor specific antigens under immunosuppressive conditions need to be developed. In practical terms, this calls for a method by which therapeutic vaccines may be custom-designed to treat cancers case by case. Ex vivo manipulation of dendritic cells and gene transfer of immunostimulatory molecules in ex vivo expanded tumors are being tested in both experimental models and also in human clinical trials. Some of them have met with limited success. Emerging technologies such as protein transfer, which make it possible to express immunostimulatory molecules on tumor cell membranes, offer the means to develop efficient tumor vaccines that are simple and fast, while being easy to store and administer in human patients. Progress in these techniques will move the cancer vaccine field a step closer towards realizing custom designed cancer vaccines in human clinical settings.

Open Access Article

Monitoring circulating tumor cells in cancer vaccine trials

J.D. Gates, L.C. Benavides, A. Stojadinovic, E.A. Mittendorf, J.P. Holmes, M.G. Carmichael, S. McCall, A.L. Milford, G.A. Merrill, S. Ponniah and G.E. Peoples
Pages 389 - 392
http://dx.doi.org/10.4161/hv.4.5.6115
Abstract | PDF

The presence of circulating tumor cells (CTC) from various cancers has provided a wealth of information and possibilities. As the role of CTC detection in the treatment assessment of metastatic breast cancer becomes standard, there is interest in applying this tool in cancer vaccine development and clinical trial monitoring. Since we lack a proven immunologic assay that correlates with clinical response, CTC detection, quantification, and phenotypic characterization may be a useful surrogate for clinical outcome. The Cancer Vaccine Development Program is involved in the development of HER2/neu peptide based vaccine development for the prevention of recurrence in HER2/neu expressing cancers like breast cancer. The CellSearch System (Veridex, LLC Warren, NJ) has been used by our lab in conjunction with in vivo and/or in vitro immunologic measurements to define a monitoring tool that could predict clinical response. Once validated, this assay could significantly shorten clinical trials and lead to more efficient assessment of potentially promising cancer vaccines.