Table of Contents

Volume 1, Issue 1

  January 2005

  Pages 1 - 42

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REVIEWS

Open Access Article

Safety Concerns Regarding Combination Vaccines: Perspective of Select European Countries

Margie C. Andreae, Gary L. Freed and Samuel L. Katz
Pages 1 - 5
http://dx.doi.org/10.4161/hv.1.1.1422
Abstract | PDF

This study explored health officials’ perception of parental concern regarding the safety of combination vaccines and its impact on policy decisions in different European countries. Interviews were conducted with governmental and non-governmental health officials in the United Kingdom, France, Ireland and Sweden over a four-month period. Parental concern regarding the safety of combination vaccines was perceived to be prevalent in the United Kingdom, Ireland and Sweden while no such concern was evident in France. The concern was limited to the combined measles, mumps and rubella vaccine and its alleged causal association with autism and did not carryover to other combined vaccines. Although proposed by certain political groups, no policy changes regarding combination vaccines were made in any study country.

Open Access Article

Medical Burden of Respiratory Syncytial Virus and Parainfluenza Virus Type 3 Infection Among US Children: Implications for Design of Vaccine Trials

Min-Shi Lee, Robert E. Walker and Paul M. Mendelman
Pages 6 - 11
http://dx.doi.org/10.4161/hv.1.1.1424
Abstract | PDF

Respiratory syncytial virus (RSV) and parainfluenza virus type 3 (PIV3) are two leading causes of lower respiratory illness (LRI) in infants. Many efforts have been directed to develop vaccines against these two viruses. Licensure of new vaccines includes three phases of clinical trials to evaluate safety, immunogenicity, and efficacy. To design an efficacy trial, age-specific incidence rates of suitable clinical endpoints need to be available. In this review, historical data are summarized to estimate the age-specific rates of acute respiratory illness (ARI), LRI, and hospitalization caused by RSV and PIV3 among US children <5 years of age. Nation-wide data are available for hospitalization but not ARI and LRI. Age-specific rates of RSV and PIV3-related ARI or LRI can vary 9-fold or 5-fold, respectively, in different studies conducted in different populations using different clinical and laboratory definitions. The annual medical burden for RSV and PIV3 in children <5 was estimated respectively to be about 4.19 and 3.24 million cases of medically-attended ARI, 2.1 and 1.08 million cases of LRI, and 113 and 29 thousand cases of hospitalization, respectively. The impact of three important variables including age at vaccination, clinical endpoints, and laboratory diagnosis in designing efficacy trials are discussed. A RSV vaccine which is safe and effective in the first six months of life is optimal to reduce the severe disease burden of LRI and hospitalization, however, interference of maternal antibody may reduce vaccine efficacy in this age group. LRI occurs more frequently than hospitalization and may be the most feasible clinical endpoint for designing efficacy trials. Since age-specific rates of RSV and PIV3-related LRI can vary significantly in different populations, collecting age-specific LRI rates in phase 1 and 2 trials to further understand this variability appear warranted.

Open Access Article

Free-Riding, Fairness, and the Rights of Minority Groups in Exemption from Mandatory Childhood Vaccination

Thomas May and Ross D. Silverman
Pages 12 - 15
http://dx.doi.org/10.4161/hv.1.1.1425
Abstract | PDF

Abstract not yet available.




RESEARCH PAPERS

Open Access Article

A DNA-Based Vaccine for the Prevention of Human Cytomegalovirus-Associated Diseases

C. Selinsky, C. Luke, M. Wloch, A. Geall, G. Hermanson, D. Kaslow and T. Evans
Pages 16 - 23
http://dx.doi.org/10.4161/hv.1.1.1335
Abstract | PDF

Multiple lines of evidence indicate that in the transplant population human cytomegalovirus (HCMV) infection and its associated diseases are controlled by humoral and cellular immune responses similar to those that arise in asymptomatic, healthy individuals during a naturally-acquired infection. The dominant antibody response to HCMV is to the major surface glycoprotein B (gB) and the dominant cellular immune response is to the tegument phosphoprotein (pp65). We propose that an immunotherapeutic plasmid DNA (pDNA) vaccination approach that induces the requisite responses to major immunological targets of HCMV may provide relief from HCMV-associated diseases in the transplant setting. We have developed gene-based immunotherapeutic products consisting of pDNAs encoding gB and pp65 of HCMV. When tested individually in mice, both pDNAs were highly immunogenic. Relative to vaccination with either gB or pp65 pDNA delivered alone, vaccination with gB and pp65 pDNAs delivered together in phosphate-buffered saline (PBS) elicited reduced antibody and T cell responses to each antigen. Formulating this bivalent vaccine with a poloxamer-based delivery system (VF-P1205-02A), however, significantly increased the antigen-specific immune responses relative to those induced with the bivalent vaccine in PBS, and completely abrogated the decrease in pp65-specific T cell responses observed in mice co-vaccinated with the pDNAs in PBS. Based on these data, and a favorable safety and toxicity profile in pre-clinical studies, the bivalent HCMV vaccine consisting of gB and pp65 pDNAs delivered with VF-P1205-02A has advanced to human clinical trials.

Open Access Article

Exercise-Induced Serum Enzyme Elevations Confounding the Evaluation of Investigational Drug Toxicity: Report of Two Cases in a Vaccine Trial

Casey Johnson, Thomas P. Monath, Niranjan Kanesa-Thasan, Danell Mathis, Chuck Miller, Seth Shapiro, Richard Nichols, Karen McCarthy, Alison Deary and Philip Bedford
Pages 24 - 29
http://dx.doi.org/10.4161/hv.1.1.1324
Abstract | PDF

Two subjects developed marked elevations in creatine kinase and other serum enzymes associated with mild myalgia during a randomized, double-blind, controlled Phase 1 clinical trial of an investigational live, attenuated vaccine against West Nile virus (ChimeriVax™-WN02). One subject had received ChimeriVax™-WN02 while the other subject was enrolled in an active control group and received licensed yellow fever 17D vaccine (YF-VAX®). Subsequently, the clinical trial was interrupted, and an investigation was begun to evaluate the enzyme abnormalities. As daily serum samples were collected for determination of quantitative viremia, it was possible to define the enzyme elevations with precision, and to relate these elevations to physical activity of the subjects, symptoms, and virological and serological measurements. Evaluation of both subjects clearly showed that skeletal muscle injury, and not cardiac or hepatic dysfunction, was responsible for the biochemical abnormalities. This investigation also implicated strenuous exercise as the cause of the apparent muscle injury rather than the study vaccines. As a result of this experience, subjects engaged in future early-stage trials of these live, attenuated viral vaccines will be advised not to engage in contact sports or new or enhanced exercise regimens for which they are not trained or conditioned. The inclusion of placebo control arm (in lieu of or addition to an active vaccine control) will also be useful in differentiating causally related serum enzyme elevations.

Open Access Article

A Meta-Analysis of Studies Comparing the Respiratory Route with the Subcutaneous Route of Measles Vaccine Administration

Girish S. Hiremath and Saad B. Omer
Pages 30 - 36
http://dx.doi.org/10.4161/hv.1.1.1423
Abstract | PDF

The respiratory tract has been suggested as an optimal alternative site to target measles vaccine delivery. We performed a meta-analysis to evaluate the efficacy of measles vaccine administered through the respiratory route compared to the subcutaneous route. We analyzed 20 reported results from sixteen eligible studies. Seroresponse was 4% higher amongst vaccinees in the respiratory group compared to the subcutaneous group (M-H pooled RR = 1.04; 95% CI = 0.98–1.10). For vaccinees over 9 months of age, seroresponse was 15% higher in the respiratory group (M-H pooled RR = 1.15; 95% CI = 1.08 to 1.17). When Edmonston Zagreb (EZ) strain was used, the vaccine was found to be neither more nor less efficacious when administered through respiratory route (M-H pooled RR=1.00; 95% CI = 0.94 to 1.08). Seroresponse in the vaccinees receiving aerosol measles vaccine was 10% higher (M-H pooled RR = 1.10, 95% CI = 1.04–1.17) compared to those who received measles vaccine through the subcutaneous route. Seroresponse due to aerosolized EZ vaccine was 9% higher than subcutaneous EZ vaccine (M-H pooled RR = 1.09; 95% CI = 1.02–1.16). The seroresponse among seropositive vaccinees was 60 % higher (M-H RR = 1.60; 95 % CI = 1.40 to 1.80). The results suggest that the respiratory route of delivery of measles vaccine is at least as efficacious as measles vaccine administered through the subcutaneous route. However, more research is required on standardization of dosage, administration equipments, efficacy, and safety of respiratory (aerosol) route of administration of measles vaccine.

Open Access Article

A Phase I, Randomized, Controlled Trial to Study the Reactogenicity and Immunogenicity of a Nasal, Inactivated Trivalent Influenza Virus Vaccine in Healthy Adults

Scott A. Halperin, Bruce Smith, Kevin Clarke, John Treanor, Taoufik Mabrouk and Marc Germain
Pages 37 - 42
http://dx.doi.org/10.4161/hv.1.1.1553
Abstract | PDF

We performed a randomized, placebo-controlled, dose-escalating clinical trial to evaluate the safety and immunogenicity of an inactivated, split virion, trivalent, nasal influenza vaccine using lipid/polysaccharide molecules as carriers. A total of 64 adults (mean age 29; range 19-69 years) were randomly allocated to receive a mixture of lipid/polysaccharide carrier molecules and 7.5, 15, or 30 µg hemagglutinin antigen of each of the three influenza strains (A/Johannesburg/82/96 [H1N1], A/Nanchang/933/95 [H3N2], B/Harbin/07/94) or placebo via nasal spray on two occasions separated by 28 days. Adverse events were assessed immediately after immunization and for 14 days after each dose. Nasal and serum antibodies were measured before and two weeks after each dose. All but three participants completed the study; no withdrawals were because of adverse events. Adverse events were similar immediately after immunization except for anterior nasal dripping after the first dose which was more common in the combined vaccine groups (64.4%) than in the placebo group (31.3%; p<0.05). A similar trend was observed after the second dose. Nasal dripping was also more common in the first two days after immunization in the vaccine groups than the placebo group (31.3%-50% vs. 0%) with no difference with increasing vaccine dose. The vaccine elicited a modest serum antibody response against all three viruses, with the highest dose eliciting the highest serum antibody levels. In contrast, significant nasal antibody rises were observed for all three viruses; again, the 30 µg group achieved the highest mucosal antibody levels at the earliest time points. We conclude that this trivalent, split virion, inactivated nasal influenza vaccine formulated with lipid/polysaccharide molecule carriers is well tolerated and modestly immunogenic in healthy adults.