Table of Contents

Volume 3, Issue 6

  November/December 2007

  Pages 231 - 296

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 Issue Catalogue (MARC XML)

RESEARCH PAPERS

Open Access Article

Effectiveness and Efficiency of Imperfect Therapeutic HSV-2 Vaccines

Elissa J. Schwartz, Erin N. Bodine and Sally Blower
Pages 231 - 238
Abstract | PDF

BACKGROUND: Efforts are currently underway to develop therapeutic vaccines for Herpes Simplex Virus type 2 (HSV-2). Methods: We use a mathematical model to predict the potential public health impact of imperfect, therapeutic HSV-2 vaccines. We evaluate vaccine effectiveness and efficiency for the general population in the United States where HSV-2 prevalence is currently 22%. We assume that therapeutic vaccines will produce two therapeutic benefits in vaccinated infected-individuals: (i) the rate of viral reactivation will decrease (hence infected-individuals will experience fewer viral shedding episodes), and (ii) the average length of the viral shedding episodes will be shortened. In addition, we assume that therapeutic vaccines will benefit uninfected individuals by reducing viral shedding in (and hence transmission from) vaccinated infected-individuals.

RESULTS: Our predictions show that therapeutic vaccines could substantially reduce HSV-2 epidemics by reducing new infections by 77% and preventing 0.84 new infections for each vaccinated individual. These vaccines could prevent 212,600 (median; IQR, 156,064-288,558) new infections after only one year. We show that increased effectiveness and efficiency are more strongly correlated with a vaccine-induced reduction in transmission probability than with either of the two therapeutic benefits that accrue directly to the infected individuals (specifically, the reduction in episode length and number of episodes).

CONCLUSIONS: We suggest that current vaccine development efforts target mechanisms that reduce viral shedding (thereby reducing transmission) thus providing both a beneficial therapeutic and a beneficial epidemic-level impact. Our results also demonstrate that therapeutic vaccines would be substantially more useful than prophylactic vaccines for epidemic control.

Open Access Article

The Changing Epidemiology of Severe Cytomegalovirus Disease in Australia

Holly Seale, C. Raina MacIntyre, Dominic E. Dwyer and Han Wang
Pages 239 - 244
Abstract | PDF

Few studies have reported the epidemiological characteristics and burden of severe cytomegalovirus (CMV) in the hospital setting. This study used data compiled by the Australian Institute of Health and Wealthfare 1 to examine the trends in hospital admissions due to CMV in different patient groups. As CMV disease mainly occurs in high-risk populations and almost always results in hospitalisation, hospital data are an appropriate source of information on the epidemiology of clinically relevant disease. The study found that between 1993 and 2001 the average annual rate of hospital admissions where CMV was identified as the principal reason for admission amounted to 14.2 cases per 100,000 populations. This rate varied between 21.6 (1993/94) and 2.0 (2000/01) per 100,000 per year, and was always somewhat higher for men compared to women. The average annual incidence of children admitted to hospital with congenital CMV (principal and secondary diagnosis) in children aged 0-4, 5-9 and 10-14 years was 1.4, 1.3 and 0.4 per 100,000 respectively. Correlations with Human Immunodeficiency Virus (HIV), organ transplantation and other causes of immuno-suppression were also examined. The burden of severe CMV disease in Australia was found to be significant and comparable to other diseases for which national vaccination programs exist. As new vaccines for CMV may soon be available, understanding the pre-vaccination burden of CMV disease is useful for planning a vaccination program should a suitable vaccine be developed.

Open Access Article

Smallpox Vaccination: Comparison of Self-Reported and Electronic Vaccine Records in the Millennium Cohort Study

Cynthia A. LeardMann, Besa Smith, Tyler C. Smith, Timothy S. Wells and Margaret A.K. Ryan
Pages 245 - 251
Abstract | PDF

In December 2002, the US Government implemented policy to immunize health workers, first responders, and military personnel against smallpox in preparation for a possible bioterrorist attack. Self-reported vaccination data are commonly used in epidemiologic research and may be used to determine vaccination status in a public health emergency. To establish a measure of reliability, the agreement between self-reported smallpox vaccination and electronic vaccination records was examined using data from the Millennium Cohort Study. Descriptive measures and a kappa statistic were calculated for data from 54,066 Millennium Cohort Study participants. Multivariable modeling adjusting for potential confounders was used to investigate vaccination agreement status and health metrics, as measured by the Short Form 36-Item Health Survey for Veterans (SF-36V) and hospitalization data. Substantial agreement (κ = 0.62) was found between self-report and electronic recording of smallpox vaccination. Of all participants with an electronic record of smallpox vaccination, 90% self-reported being vaccinated; and of all participants with no electronic record of vaccination, 82% self-reported not receiving a vaccination. There was no significant difference in hospitalization experience prior to questionnaire completion between vaccinated and unvaccinated participants. While overall scores on the SF-36V suggested a healthy population, participants whose self-reported vaccination status did not match electronic records had slightly lower adjusted mean scores for some scales. These results indicate strong reliability in self-reported smallpox vaccination and also suggest that discordant reporting of smallpox vaccination is not associated with substantial differences in health among Millennium Cohort participants.

Open Access Article

Can Hexavalent Vaccines Be Simultaneously Administered with Pneumococcal or Meningococcal Conjugate Vaccines?

Alberto E. Tozzi, Chiara Azzari, Giorgio Bartolozzi, Susanna Esposito, Gaetano Maria Fara and Milena Lo Giudice
Pages 252 - 259
Abstract | PDF

Background
Local immunization programs may include hexavalent and conjugate pneumococcal or meningococcal vaccines administered in the same vaccination visit. Information based on evidence is necessary for correctly planning schedules and for parents who often fear the administration of too many vaccines. We reviewed the available literature to assess the effects on immunogenicity and safety of simultaneous administration of hexavalent and conjugate pneumococcal and meningococcal C vaccines in healthy children.

Methods
We searched for papers including a comparison of coadministration and single administration of hexavalent with conjugate pneumococcal or meningococcal C vaccines. Data sources included Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, MEDLINE, and EMBASE. Immunogenicity and safety results were extracted and compared. We calculated the absolute risk increase of being a non responder to any antigen and of experiencing common adverse events.

Results
Four relevant articles were included in the review. Immunogenicity of components included in the hexavalent vaccines was maintained with coadministration of conjugate pneumococcal and meningococcal C vaccines. However individuals who received hexavalent vaccine with conjugate pneumococcal vaccines were 18% more likely to have anti-PRP < 1 μg/mL after the third dose although this difference disappeared after the fourth dose, and titres against meningococcal C antigens were higher when vaccines were administered separately. Children who received simultaneous administration of hexavalent vaccines with conjugate pneumococcal vaccines had a 13-17% additional risk of experiencing fever compared with single administration.

Conclusion
Few studies deal with coadministration of vaccines. Hexavalent and conjugate pneumococcal or meningococcal vaccines may however be administered simultaneously without noteworthy negative effects on immunogenicity or safety profile. Parents of vaccinees should be appropriately informed on the effects of coadministration to improve their compliance. Studies on vaccine coadministration should be promoted and unpublished studies realized for vaccine registration should be made available.

Open Access Article

Influence of IFNγ Co-Expression on the Safety and Antiviral Efficacy of Recombinant Fowlpox Virus HIV Therapeutic Vaccines Following Interruption of Antiretroviral Therapy

S. Emery, A.D. Kelleher, C. Workman, R.L. Puls, M. Bloch, D. Baker, J. Anderson, J. Hoy, S. Ip, K. Nalliah, L.D. Ward, M.G. Law and D.A. Cooper
Pages 260 - 267
Abstract | PDF

Therapeutic immunization to stimulate host immune responses and control human immunodeficiency virus (HIV-1) replication is being investigated as a supplimentary treatment for the management of HIV infection. On completion of an earlier study involving three vaccinations while taking combination antiretroviral therapy (CART), twenty-five subjects with plasma viral load (pVL) <50 copies/mL received a booster vaccination with either placebo (n=7); fowl pox vaccine (rFPV) expressing HIV-1 Gag/Pol; (partial construct- PC (n=8)) or rFPV co-expressing HIV-1 Gag/Pol and human interferon-γ (full construct – FC (n=10)). One week after the booster vaccination, participants stopped ART and were monitored for safety, pVL and immunological parameters for < 20 weeks. The time weighted mean change (SD) from baseline plasma HIV RNA was 1.80 (0.72), 1.78 (0.91) and 0.96 (0.91) log10 copies/mL for placebo, PC and FC recipients respectively (p=0.06; mean differences between placebo and FC). Laboratory evaluations did not reveal differences in anti-HIV specific immune responses between study arms. No difference between treatment arms for host genetic factors known to affect pVL was demonstrated. In conclusion, vaccination with FC was associated with a trend toward lower rates of HIV replication following cessation of ART relative to placebo or PC. The promising antiretrovirological effect supports further study of FC in a larger trial with a broader population of patients with HIV disease.

Open Access Article

Safety and Immunogenicity of CVD 1208S, a Live, Oral ΔguaBA Δsen Δset Shigella flexneri 2a Vaccine Grown on Animal-Free Media

Karen L. Kotloff, Jakub K. Simon, Marcela Pasetti, Marcelo B. Sztein, Stacey L. Wooden, Sofie Livio, James P. Nataro, William C. Blackwelder, Eileen M. Barry, Wendy Picking and Myron M. Levine
Pages 268 - 275
Abstract | PDF

A previous Phase 1 trial demonstrated that Shigella flexneri 2a deleted in guaBA, sen and set (strain CVD 1208) is well-tolerated and immunogenic after a single oral dose of 108 or 109 CFU. To facilitate further clinical development, the strain was reconstructed using animal-free media to conform to regulatory guidelines, and designated CVD1208S. Healthy inpatient volunteers were randomized (double-blind) to receive a single oral dose of either CVD 1208S (108 [n = 7] or 109 [n = 7] CFU) or placebo (n = 2). Both vaccine dosage levels were generally well-tolerated. Anti-lipopolysaccharide responses, measured as IgA antibody secreting cells, serum IgG, or fecal IgA levels, occurred in 7 (100%), 3 (43%) and 2 (29%) subjects, respectively, following inoculation with 109 CFU. Interferon gamma production in response to Shigella antigens was observed in 1 of 4 (25%) and 4 of 7 (57%) subjects, respectively, following inoculation with 108 and 109 CFU. We conclude that CVD 1208S retains a favorable safety and immunogenicity profile after reconstruction on animal-free media, comparable to that seen with CVD 1208, which was constructed on media containing animal products, and shows promise as a live, oral Shigella vaccine.

Open Access Article

Buren of Hospital Admissions for Cervical Cancer in Spain During 1999-2002

Angel Gil, María San-Martín, Ruth Gil-Prieto , Hernández Valentín, Josepa Ribes and Antonio González
Pages 276 - 280
Abstract | PDF

Population-based retrospective epidemiological study to estimate the burden of hospitalizations by cervical cancer in Spain. It was conducted by using hospital discharge data from the national surveillance system for hospital data, Conjunto Mínimo Básico de Datos (CMBD). Records of all patients admitted to hospital with a diagnosis of malignant neoplasm of the cervix (ICD-9-MC codes 180.0-180.9) or carcinoma in situ of cervix (ICD-9-MC code 233.1) during a 4-year period (1999-2002), were selected. An annual average of 4,151 hospitalizations with a primary or secondary diagnosis of cervical cancer and 2,761 hospitalizations due to carcinoma in situ were identified. Annually there were 25.5 and 17.0 hospitalizations by cervical cancer and carcinoma in situ per 100,000 women ≥20 years of age, respectively. Hospitalization rate by cervical cancer and carcinoma in situ peaks in women between 45 and 59 years of age (39.4 admissions per 100,000 women) and 30 to 44 years of age (32.2 per 100,000 women), respectively. The mean cost of a hospitalization by cervical cancer and carcinoma in situ was 3,098€ and 2,192€, respectively. The estimated annual cost of hospitalizations for cervical cancer and carcinoma in situ in Spain was 19 million €.

Open Access Article

An Octavalent Lyme Disease Vaccine Induces Antibodies That Recognize All Incorporated ospC Type-Specific Sequences

Christopher G. Earnhart and Richard T. Marconi
Pages 281 - 289
Abstract | PDF

Lyme disease is the most common vector-borne disease in North America and Europe and, if untreated, has significant arthritic, cardiac, dermatological and neurological sequelae. There is no currently available human Lyme disease vaccine. Outer surface protein C, because of its antigenicity, protective ability, and expression characteristics has emerged as a promising second generation vaccine candidate; however, significant sequence heterogeneity has impeded its development. Analyses of OspC sequences have revealed the existence of stable phylogenetic clusters or types, and the type-defining sequence variation within OspC occurs in defined domains of the protein. Recent data indicating that immunodominant, and potentially protective OspC epitopes are located in these hypervariable regions has allowed development of a tetravalent, epitope-based, chimeric vaccine. In this report, we have extended that previously described tetravalent construct to include four additional OspC types. We demonstrate that the construct is highly immunogenic, and elicits type-specific antibodies that recognize each of the eight incorporated OspC type-specific epitopes. Antibody raised to the octavalent construct readily binds to the surface of strains expressing each component OspC type, indicating that the incorporated epitopes are presented on the surface of intact cells. In addition, the construct elicits antibody isotypes associated with complement-dependent bactericidal activity. These results represent an important step forward in the design of a broadly protective polyvalent OspC-based Lyme disease vaccine.




COMMENTARIES

Open Access Article

Strategies for Development of Universal Vaccines Against Meningococcal Serogroup B Disease

Johan Holst
Pages 290 - 294
Abstract | PDF

A vaccine inducing protection against most of the circulating variants of serogroup B meningococcal strains is not yet available. A number of plausible options are currently under investigation. A conjugate vaccine based on a modified capsular polysaccharide might well work, but has safety concerns from molecular mimicry between group B sialic acid and human tissue. Recently, however, the group B capsule has been shown to contain de-N-acetyl sialic acid residues that do not cross-react with normal host tissues and can then be the target of bactericidal antibodies. Potentially, this polysaccharide structure could form the basis of a safe and protective group B vaccine. Outer membrane vesicles (OMVs) from Neisseria lactamica avoid the immunodominant and highly strain specific immune response against the PorA protein, and are reported to elicit cross-reactive protection in mice against lethality from challenge with meningococcal group B bacteria. However, the serum antibody responses lack bactericidal activity, and the mechanisms of protection are unknown. A number of universal, cross-reactive antigens have been identified through “genomic mining” and successfully tested as recombinant protein vaccines. Promising results have also been demonstrated using OMV vaccines prepared from strains engineered for up-regulation of conserved, cross-reactive antigens. This approach takes advantage of experience gained with conventional wild-type OMV vaccines and the large number of new antigens identified through sequencing the genome of N. meningitidis. Initial studies show that the traditional use of detergents to decrease toxicity by extraction of lipopolysaccharides (LPS) should, if possible, be omitted in order to avoid extraction of important lipoproteins. In the absence of detergent extraction, clinical OMV formulations with acceptable toxicity may still be achieved by constructing vaccine production strains with genetically detoxified LPS. Thus, a MenB vaccine might be designed based on non-cross-reactive capsular antigens, OMV vaccines from genetically modified strains, recombinant proteins, or a combination of these approaches. Given all of the recent data available and experience gained, the possibility for development of a universal vaccine for prevention of group B meningococcal disease looks promising. For evaluation of vaccine formulations that relay on cross-reactive proteins, selection of strains for representation of the global epidemiological situation will be of outmost importance. Defining criteria for establishing and revising such strain collections is currently ongoing and will be a key element in developing and evaluating new protein based vaccines in the time to come.

Open Access Article

HPV Vaccine Facts: Can't See the Forest Through the Trees

Janine T. Bryan
Pages 295 - 296
Abstract | PDF

The English language and many other languages, I imagine, are filled with hundreds of colorful clichés that sometimes work their way into our thinking and are treated almost like fact. As a basic scientist developing vaccines, the thought that a mere metaphor or expression, characterized by overuse, could be considered on equal footing as that which has undergone scientific rigor and is therefore proven fact, is hard to stomach. Although I am a bit hesitant to open a can of worms, it does seem worthwhile point out a few clichés which have been passed around in reference to the HPV vaccines which, let's call a spade a spade, are not necessarily fact. It is often difficult to discuss science in a way that is clear to the lay population and thus literary imagery is a powerful tool used to level the playing field.