Table of Contents

Volume 2, Issue 4

  July/August 2006

  Pages 147 - 191

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 Issue Catalogue (MARC XML)

RESEARCH PAPERS

Open Access Article

Evaluation of the Thermal Stability of Gardasil®

Mary L. Shank-Retzlaff, Qinjian Zhao, Carrie Anderson, Melissa Hamm, Katrina High, Mai Nguyen, Feng Wang, Ning Wang, Bei Wang, Yang Wang, Michael Washabaugh, Robert Sitrin and Li Shi
Pages 147 - 154
http://dx.doi.org/10.4161/hv.2.4.2989
Abstract | PDF

The thermostability of GARDASIL® (Merck & Co., Inc, Whtehouse Station, NJ, USA), a developmental vaccine against human papillomavirus (HPV), was evaluated using an enzyme immunoassay, referred to as the in vitro relative potency (IVRP) assay and differential scanning calorimetry (DSC). Gardasil samples were stored at temperatures ranging from 4 to 42 °C and tested for IVRP at various time points. Extrapolation of the IVRP results indicates GARDASIL is extremely stable. The half-life of the vaccine is estimated to be 130 months or longer at temperatures up to 25 °C. At 37 ºC, the half-life is predicted to be 18 months and at 42 ºC, the half-life is predicted to be approximately 3 months. Differential scanning calorimetry (DSC) analysis was used to evaluate the process of protein denaturation during a rapid temperature increase (as opposed to longterm storage at a specific temperature). Differences were seen among the DSC profiles of the four HPV types tested. This indicates that small differences in the amino acid structure can have a significant effect on the intermolecular contacts that stabilize the L1 proteins and the VLP assembly. For the Gardasil samples evaluated here, DSC results demonstrated the relative overall structural stability of the VLPs, but were not predictive of the excellent long-term stability observed with the IVRP assay.

Open Access Article

Safety and Immunogenicity of a New Fully Liquid DTPw-HepB-Hib Combination Vaccine in Infants

Güler Kanra, Ates Kara, Okan Demiralp, Mario Contorni, Anne Katrin Hilbert, Christian Spyr and Simonetta Viviani
Pages 155 - 160
http://dx.doi.org/10.4161/hv.2.4.2942
Abstract | PDF

We assessed the safety and immunogenicity of a fully liquid, DTPw-HepB-Hib combination vaccine (Quinvaxem™) in comparison with separately administered DTPw-Hib and hepatitis B vaccines. Infants participating in this open-label, randomized, phase II study received a primary vaccination course using a 2-3-4 month schedule. Blood samples were taken immediately prior to the first and one month after the third vaccination. Adverse events were assessed over a 7-day post-vaccination period using subject diaries. After completion of the primary vaccination course, 94.7% [95%CI: 89.8 – 97.7%] of infants receiving the combination vaccine achieved protective anti-HBs antibody titers (?10 mIU/mL) with a mean 39-fold increase in GMTs in comparison with 99.3% [95%CI: 96.3 – 100%] seroprotection and a mean 29-fold GMT increase in the comparator group. Diphtheria, tetanus, and Haemophilus influenzae type B (Hib) seroprotection rates and pertussis seroconversion rates were also similar between the two groups. There was no statistically significant difference in GMTs for diphtheria between the two groups, but significant differences were shown for tetanus, Hib, and pertussis with higher GMTs for each antigen observed in the comparator group. The combination vaccine was well tolerated, with fever (body temperature 38°C) being the most frequently reported adverse event in both the DTPw-HepB-Hib (12.5% [95%CI: 7.7 – 18.8%]) and comparator (12.6% [95%CI: 7.7 – 19.0%]) groups. This study demonstrated that the fully liquid DTPw-HepB-Hib combination vaccine has safety and immunogenicity profiles similar to the DTPw-Hib and hepatitis B vaccines when administered separately.

Open Access Article

Influenza Vaccination and Risk of Incident Myocardial Infarction

James D. Heffelfinger, Susan R. Heckbert, Bruce M. Psaty, Noel S. Weiss, William W. Thompson, Carolyn B. Bridges and Lisa A. Jackson
Pages 161 - 166
http://dx.doi.org/10.4161/hv.2.4.2943
Abstract | PDF

Background: Several studies suggest that influenza vaccination may be associated with a decreased risk of acute cardiovascular events. We examined the association between influenza vaccination and risk of incident myocardial infarction (MI) in persons at least 65 years of age in a population-based case-control study.
Methods: Case subjects were members of Group Health Cooperative (GHC), a health maintenance organization, with incident MI during 1992-1998. Control subjects were GHC members without a history of MI who were frequency matched to case subjects by age, sex, calendar year, and presence of treated hypertension. The medical records of 750 case subjects with MI and 1735 controls were reviewed.
Results: Receipt of influenza vaccine was not associated with risk of incident MI during the months of November through March (odds ratio [OR]: 0.97, 95% confidence interval [CI]: 0.75-1.27) or April through September (OR: 0.97, 95% CI 0.75-1.26).
Conclusions: This study does not provide evidence supporting an association of influenza vaccination and reduction in risk of myocardial infarction.
The findings and conclusions in this paper are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

Open Access Article

The Live Attenuated Dengue Serotype 1 Vaccine rDEN1Δ30 is Safe and Highly Immunogenic in Healthy Adult Volunteers

Anna P. Durbin, Julie McArthur, Jennifer A. Marron, Joseph E. Blaney, Jr., Bhavin Thumar, Kim Wanionek, Brian R. Murphy and Stephen S. Whitehead
Pages 167 - 173
http://dx.doi.org/10.4161/hv.2.4.2944
Abstract | PDF

Background: The live attenuated DEN1 vaccine candidate virus rDEN1Δ30 has been evaluated in preclinical animal models and found to be attenuated and immunogenic. These promising preclinical studies have identified rDEN1Δ30 as a candidate DEN1 vaccine virus for further testing in a human Phase I clinical trial. Methods: rDEN1Δ30 at a dose of 103 pfu was administered as a single inoculation to twenty healthy adult volunteers. Eight additional volunteers received placebo. Volunteers were monitored closely for adverse events and serum was collected on study days 0, 28, 42, and 180 for determination of neutralizing antibody titer. Results: The vaccine was well tolerated by the vaccinees. The most common adverse events observed were a transient asymptomatic rash in 40% of vaccinees and a mild neutropenia in 45% of vaccinees. No vaccinee developed a dengue-like illness. The vaccine was highly infectious and immunogenic with 95% of vaccinees developing a ? 4-fold rise in serum neutralizing antibody titer against DEN1 that persisted throughout the six month duration of the trial. Conclusions: The rDEN1Δ30 vaccine is safe and induced a potent and durable antibody response against DEN1. It is a promising vaccine candidate for inclusion in a tetravalent dengue vaccine formulation.

Open Access Article

Maturation of Recombinant Hepatitis B Virus Surface Antigen Particles

Qinjian Zhao, Yang Wanga, Daniel Freedb, Tong-Ming Fub, Juan A. Gimeneza, Robert D. Sitrina and Michael W. Washabaugh
Pages 174 - 180
http://dx.doi.org/10.4161/hv.2.4.3015
Abstract | PDF

The major surface antigen of Hepatitis B virus (HBsAg) is a cysteine-rich, lipid-bound protein with 226 amino acids. Recombinant HBsAg (rHBsAg) with associated lipids can self-assemble into 22-nm immunogenic spherical particles, which are used in licensed Hepatitis B vaccines. Little is known about the structural evolvement or maturation upon assembly beyond an elevated level of disulfide formation. In this paper, we further characterized the maturation of HBsAg particles with respect to their degree of cross-linking, morphological changes, and changes in conformational flexibility. The lipid-containing rHBsAg particles undergo KSCN- and heat-induced maturation by formation of additional intra- and inter-molecular disulfide bonds. Direct measurements with atomic force microscopy (AFM) revealed morphological changes upon maturation through KSCN-induced and heat-/storage-incurred oxidative refolding. Particle uniformity and regularity was greatly improved, and protrusions formed by the protein subunits were more prominent on the surface of the mature particles. Decreased conformational flexibility in the mature rHBsAg particles was demonstrated by millisecond-scale unfolding kinetics in the presence of an environment-sensitive conformation probe. Both the accessible hydrophobic cavities under native conditions and the changeable hydrophobic cavities upon denaturant-induced unfolding showed substantial decrease upon maturation of the rHBsAg particles. These changes in the structural properties may be critical for the antigenicity and immunogenicity of this widely-used vaccine component.

Open Access Article

Hospitalization by Pneumonia and Influenza in the 50-64 Year Old Population in Spain (1999-2002)

Angel Gil, Ruth Gil, Itziar Oyagüez, Pilar Carrasco and Antonio González
Pages 181 - 184
http://dx.doi.org/10.4161/hv.2.4.3104
Abstract | PDF

This epidemiological survey was undertaken to estimate the burden of hospital admissions for pneumonia and influenza in 50-64 years old persons in Spain during a four-year period (1999-2002). Data were obtained from the national surveillance system for hospital data maintained by the Ministry of Health and covering more than 95% of Spanish hospitals. There were 35,620 hospital admissions for pneumonia and influenza (ICD 9 CM 480-487; first listed diagnosis) during the study period. Annual incidence was 143 cases per 100,000 population. Rate of death and case-fatality rate were 8 per 100,000 population and 5.6%, respectively. The average length of hospitalization was 10.4 days. Men and older age groups showed a higher incidence, rate of death and case-fatality rate. These hospitalizations of 50-64 years old persons impose an annual direct cost of 12 to 24 millions euros. Preventive measures, such as vaccination will reduce pneumonia-related morbidity and could result in large cost savings to the Health Care System.




COMMENTARY

Open Access Article

Active Specific Immunotherapy with Autologous Tumor cell vaccines for Stage II Colon Cancer: Logistics, Efficacy, Safety and Immunological Pharmacodynamics

Michael G. Hanna, Jr., Herbert C. Hoover, Jr., H. M. Pinedo and Mitchell Finer
Pages 185 - 191
http://dx.doi.org/10.4161/hv.2.4.3196
Abstract | PDF

In the area of cancer treatment, immunotherapy with vaccines has suffered in the last 5 years, due to many clinical trial failures. One must keep in mind however, that many of the clinical trials conducted in the past decade were performed without the benefit of sound regulatory guidance or validated and compliant manufacturing processes. This has clearly been the case for patient specific, tumor cell vaccine therapy. The safety concerns that emanated within the regulatory agencies from the Somatic Cell Therapy concepts, translated to active specific immunotherapy with vaccines. Fortunately, in the past 5 years advances in understanding the immune system, improved design of clinical trials, improvement and compliance of manufacturing processes provided opportunities to significantly improve efficacy and safety. Clearly, the vaccine research establishment has learned the importance of not just selecting antigens but the requirement of tumor associated immunogens that can stimulate a functional immune response. Also, it has become clear that immunotherapy works best in situations of minimal residual disease. Finally, more realistic endpoints in clinical trials have been recognized and accepted by oversight review committees. This commentary describes the “trials and tribulations” of developing a patient specific, autologous tumor cell vaccine for therapy of Stage II colon cancer.