Table of Contents

Volume 7, Issue 6

  June 2011

  Pages 593 - 711

Special Focus: Viral Hemorrhagic Fevers – Vaccine Development

View covers archive

 Issue Catalogue (MARC XML)

EDITOR'S CORNER

Open Access Article

Letter from the Editor

Ronald W. Ellis and Eva M. Riedmann
Page 593
http://dx.doi.org/10.4161/hv.7.6.16768
PDF




NEWS, POLICY AND PROFILES

Open Access Article

News

Eva M. Riedmann
Pages 594 - 596
http://dx.doi.org/10.4161/hv.7.6.16769
Abstract | PDF

First approval of meningitis vaccine for infants
New vaccines fights cancer early
Merck and sanofi pasteur initiate Phase III study of pediatric combination vaccine
New promising vaccine candidate against norovirus
GeoVax expands its HIV/AIDS vaccine program
Vaccine against ricin toxin enters clinical trials

Open Access Article

Parents’ vaccination concerns are about more than risk and benefit

Anna K. Mikulak
Pages 597 - 599
http://dx.doi.org/10.4161/hv.7.6.16770
PDF




PORTRAIT OF A LEADING VACCINOLOGIST

Open Access Article

A passion for global vaccines

Seth Berkley
Pages 600 - 603
http://dx.doi.org/10.4161/hv.7.6.16841
PDF




MEETING REPORTS

Open Access Article

Correlates of immune protection: Standardized and automated assays to interrogate correlates of immunity--Phacilitate Vaccine Forum Washington 2011

Wade Bolton
Pages 604 - 606
http://dx.doi.org/10.4161/hv.7.6.16275
Abstract | PDF

The utility of functional cell mediated immune assays in the assessment of immune response or immunogenicity is increasing significantly as we search for surrogates to determine vaccine efficacy or therapeutic response. No definitive reports to date have demonstrated that CMI assays in human clinical trials correlate with clinical outcome, although animal and non human primate studies have reported surrogacy in varying degrees. This report discusses the approaches identified, their advantages and disadvantages, and their justification for inclusion in the clinical trial setting.

Open Access Article

How will diagnostics create new opportunities for prophylactic and therapeutic vaccines?

Niranjan Y. Sardesai
Pages 607 - 609
http://dx.doi.org/10.4161/hv.7.6.16257
Abstract | PDF

The Phacilitate Vaccine Forum in Washington DC (Jan 24-26, 2011) brought together vaccine stakeholders from industry, government and non-government organizations to discuss broad current issues covering the spectrum of vaccine policy, funding, research and clinical development, manufacturing, regulatory, and post marketing safety and surveillance. While the conference is held annually and the topics generally discussed reflect the emerging trends, case studies, and best practices of current interest to the vaccine industry, this year’s meeting had a new plenary session focusing on the intersection of diagnostics and vaccine development. The session was chaired by Dr. Una Ryan (President and CEO, Diagnostics for All) with the provocative title “How will diagnostics create new opportunitites for prophylactic and therapeutic vaccines?” and was followed by a panel discussion amongst industry leaders discussing the key diagnostic applications gaining interest in the vaccine industry. A common theme running through the session was the increasingly significant role of companion diagnostics and immune monitoring to facilitate and accelerate vaccine development. Indeed the recent examples from pneumococcal and meningococcal vaccine development where the developers and regulatory agencies have considered the use of diagnostic assays and immune markers to assess efficacy of the candidate vaccines in regards to licensure strategies for expanding the serotypes covered, can be considered as breakthrough events for the diagnostics developers. As such the meeting and the session was timely in presenting current progress and for soliciting a convergence of opinions amongst the vaccine industry and the regulatory agencies.

Open Access Article

Improving immunogenicity, efficacy and safety of vaccines through innovation in clinical assay development and trial design: The Phacilitate Vaccine Forum, Washington D.C. 2011

Ioana R. Moldovan and Magdalena Tary-Lehmann
Pages 610 - 612
http://dx.doi.org/10.4161/hv.7.6.15682
Abstract | PDF

The 9th Annual Vaccine Forum organized by Phacilitate in Washington D.C. 2011 brought together 50+ senior level speakers and over 400 participants representing all the key stakeholders concerning vaccines. The main focus of the meeting was to define priorities in the global vaccines sector from funding to manufacturing and evaluation of vaccine efficacy. A special session was devoted to improving immunogenicity, efficacy and safety of vaccines through innovation in clinical assay development and trial design. The current regulatory approach to clinical assay specification, validation and standardization that enable more direct comparisons of efficacy between trials was illustrated by the success in meningococcal vaccine development. The industry approach to validation strategies was exemplified by a new serologic test used on the diagnostic of pneumococcal pneumonia. The application of the Animal Rule to bridge clinical and non-clinical studies in botulism has allowed significant progress in developing one of the first vaccines to seek approval under the FDA Animal Efficacy Rule. An example of pushing the boundaries in the correlation of immunological responses and efficacy points was represented by a recent cell-based influenza vaccine for which the same correlates of protection apply as for the traditional, egg-based flue vaccine. In the field of HIV phase 2b studies are underway, based on promising results obtained with some vaccine candidates. The conclusion of this session was that creativity in vaccine design and evaluation is beneficial and can lead to innovative new vaccine designs as well as to validated assays to assess vaccine efficacy.




SHORT REPORT

Open Access Article

Immunogenicity, safety and tolerability of monovalent 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine in children and adolescents with Williams or Cornelia De Lange syndrome

Susanna Esposito, Angelo Selicorni, Cristina Daleno, Antonia Valzano, Marta Cerutti, Carlotta Galeone, Silvia Consolo, Francesca Menni and Nicola Principi
Pages 613 - 617
http://dx.doi.org/10.4161/hv.7.6.15133
Abstract | PDF

In some subjects with severe neurological diseases, a reduced immune response to seasonal influenza vaccine has been demonstrated. Patients with Williams or Cornelia de Lange syndrome frequently have abnormalities in neurodevelopment. This study has evaluated the immunogenicity, safety and tolerability of a monovalent 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine in these subjects. Eighteen patients with Williams syndrome (ten males; mean age ± standard deviation [SD] 12.74 ± 4.49 years), 11 with Cornelia de Lange syndrome (six males; mean age 12.90 ± 4.85 years) and 30 age- and gender-matched healthy controls (16 males; mean age 12.49 ± 4.55 years), never vaccinated against influenza, received a dose of the vaccine between 1 and 30 November 2009. Four weeks later, the seroconversion rates in the three groups were between 72% and 80% and the seroprotection rates were 100%, with a similar increase in antibody levels. Two months later, most of the subjects remained seroconverted with no statistically significant difference between the groups, and about 94% of the patients with Williams syndrome, all of those with Cornelia de Lange syndrome and all of the healthy controls were still seroprotected. Safety and tolerability were very good, with no difference between the groups. None of the patients developed documented influenza during the study period. These results show that the immunogenicity, safety, and tolerability of a single dose of the monovalent 2009 pandemic influenza A/H1N1 MF59-adjuvanted vaccine in children and adolescents with Williams or Cornelia de Lange syndrome and moderate to severe mental disabilities is very good, and similar to that of healthy subjects.




RESEARCH PAPERS

Open Access Article

Muramyl Dipeptide modulates differentiation, maturity of dendritic cells and anti-tumor effect of DC-mediated T cell in acute leukemia children

Ling-zhen Wang, Xiao-ling Li, Xiu-ying Pang and Li-rong Sun
Pages 618 - 624
http://dx.doi.org/10.4161/hv.7.6.14988
Abstract | PDF

Background:Targeted therapy is a potentially useful approach for antileukemic therapy, in particular eliminating minimal residual disease(MRD) to prevent tumor relapse. This study was aimed to find out an effective, nontoxic dendritic cell (DC) maturating agent for the immunotherapy of acute leukemia. Results: MDP-matured DCs(M-DCs) expressed higher level of phenotypic markers and secreted higher cytokine level, while lower than TNF-α-matured DCs (T-DCs) and co-administration of MDP and TNF-α-matured DCs (MT-DCs). MT-DCs promoted significantly allogeneic T-cells reaction. As a result, allogeneic T-cell proliferated significantly and secreted higher amount of IFN-γ. HL60-derived antigens were presented more effectively by MT-DCs to cytotoxic T lymphocytes (CTLs) to induce more beneficial anti-tumor effects in a dose-dependent manner. Methods: Purified mononuclear cells (MNCs) from bone marrow of acute leukemia children were differentiated by granulocyte-macrophage colony stimulating factor (GM-CSF) and recombinant human interleukin-4 (rhIL-4) and further matured by either Muramyl Dipeptide（MDP), tumor necrosis factor-alpha (TNF-α) or co-administration of MDP and TNF-α. Conclusions: These results demonstrate MDP can be used as a candidate clinical agent for antigen specific cancer immunotherapy.

Open Access Article

Five-year post vaccination efficacy of hepatitis B vaccine in rural Nigeria

Olumuyiwa. O. Odusanya, Ewan Alufohai, François P. Meurice and Vincent. I. Ahonkhai
Pages 625 - 629
http://dx.doi.org/10.4161/hv.7.6.14990
Abstract | PDF

Hepatitis B (HB) is an important public health problem affecting millions of people globally and is endemic in Nigeria. The objective of this study was to determine the effectiveness of the HB vaccine five to seven years post-introduction within a rural community in Nigeria.
The study design was cross-sectional. Eligible children were either vaccinated subjects who had received at least two doses of HB vaccine or unvaccinated subjects (controls) who had not received HB vaccine. Following informed consent obtained from mothers/care givers, data was obtained using an interviewer-administered questionnaire. Venous blood was obtained to measure HB markers including hepatitis B surface antigen (HBsAg), and antibodies to the core (anti-HBc) and antibody to the hepatitis B surface (anti-HBs) antigens.
Eight hundred and twenty-two subjects were eligible for analysis consisting of 449 vaccinated and 373 controls. The prevalence of anti-HBc was 43.2% in unvaccinated children compared to 10.5% in vaccinated children (p < 0.001). The rate of HBsAg was 11.8% in the unvaccinated group and 2% in the vaccinated group (p < 0.001). The vaccine effectiveness against anti-HBc was 84.6% (95% confidence interval 77.8, 89.3%) and the effectiveness against infection was 84.7% (95% confidence interval 68.2, 92.6%). Sixty-one percent of vaccinated subjects had protective antibodies ≥10 EIU/ml compared to 18% of controls (p < 0.001) and the geometric mean titers (GMT) were 19.96 and 7.28 EIU/ml respectively (p < 0.001). Vaccinated subjects were protected at least for five to seven years following HB vaccination.

Open Access Article

Development of a rat central venous catheter model for evaluation of vaccines to prevent Staphylococcus epidermidis and Staphylococcus aureus early biofilms

Tim Ebert, Sharon Smith, Greg Pancari, Xiaoqing Wu, Julie Zorman, Desmond Clark, Jim Cook, Carol Burns, Joseph M. Antonello, Leslie Cope, Eszter Nagy, Andreas Meinke and Tessie McNeely
Pages 630 - 638
http://dx.doi.org/10.4161/hv.7.6.15407
Abstract | PDF

Indwelling central venous catheters are a common and important source of nosocomial Staphylococcus epidermidis and S. aureus infections, causing increased morbidity and mortality during hospitalization. A model was developed to reflect the clinical situation of catheter colonization by transient hematogeneously spread staphylococci, in order to investigate potential vaccine candidates. Rats were cannulated in the right jugular vein, followed by challenge through the tail vein with either S. epidermidis RP62a, or S. aureus Becker. At 24 hr post challenge, colonizing bacteria were found to be present on the catheter in an early biofilm, as evidenced by the presence of polysaccharide intercellular adhesin (PIA). For vaccination studies, rats were first immunized, surgically cannulated, and then challenged via the tail vein. At 24 hr post challenge, the catheters were harvested and cultured on mannitol salt agar plates. The catheters were scored as positive if there was outgrowth of bacterial colonies, and negative if no colonies were observed. A S. epidermidis antigen (SERP0630, MenD), and a S. aureus antigen (SACOL1138, iron regulated surface determinant B, IsdB) were found to have significant protective activity in this model, compared to mock immunized controls. Using SERP0630 as the test immunogen, it was also determined that a single vaccination of rats after cannulation was sufficient for significant catheter protection. This model may be used to evaluate antigens for protective activity against transient hematogenous spread of staphylococci resulting in catheter colonization and early biofilm formation.

Open Access Article

Prevalence of specific neutralizing antibodies against Sendai virus in populations from different geographic areas: Implications for AIDS vaccine development using Sendai virus vectors

Hiroto Hara and 21 others
Pages 639 - 645
http://dx.doi.org/10.4161/hv.7.6.15408
Abstract | PDF

A Sendai virus (SeV) vector is being developed for delivery of an HIV immunogen. SeV is not known to cause disease in humans. Because it is genetically and antigenically related to human parainfluenza virus type 1 (hPIV-1), it is important to determine whether pre-existing hPIV-1 antibodies will affect immune responses elicited by a SeV vector-based vaccine. To quantify SeV neutralizing antibodies (NAb) in human serum, a sensitive virus neutralization assay was developed using a SeV vector encoding green fluorescent protein. Samples from 255 HIV-uninfected subjects from Africa, Europe, United States, and Japan, as well as from 12 confirmed hPIV-1-infected patients, were analyzed. SeV NAb titers did not vary significantly after serum was treated with receptor-destroying enzyme, indicating that non-specific hemagglutination inhibitors did not affect the assay sensitivity. A significant correlation was observed between hPIV-1 ELISA and SeV NAb titers. SeV NAb were detected in 92.5% subjects with a median titer of 60.6 and values ranging from 5.9- 11,324. The majority had titers <1000 with 71.7% <100 (<5 considered negative). There was no significant difference in titer or prevalence by gender, age range or geographic origin. However, African males had a lower titer than non-Africans of either gender (p=0.007). Overall, the prevalence of SeV NAb is high and likely due to neutralization by cross-reactive hPIV-1 antibodies. Clinical trials will be needed to assess the influence of pre-existing SeV NAb on HIV-specific immune responses elicited by a SeV vaccine vector expressing HIV.

Open Access Article

The first use of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB) in humans

Daniela Toneatto, Shevqet Ismaili, Ellen Ypma, Kay Vienken, Philipp Oster and Peter Dull
Pages 646 - 653
http://dx.doi.org/10.4161/hv.7.6.15482
Abstract | PDF

Background: Neisseria meningitidis serogroup B is a well-recognized cause of bacterial meningitis and sepsis for which no broadly protective vaccine exists. Whole genome sequencing was used to identify three antigens: factor H binding protein (fHbp), Neisserial adhesin A (NadA), and Neisseria heparin binding antigen (NHBA) for an investigational vaccine candidate (rMenB). This was the first trial of an investigational multicomponent meningococcal serogroup B vaccine (4CMenB), containing rMenB and outer membrane vesicles (OMV) from the New Zealand epidemic strain in humans. Results: Seventy adults enrolled and received study vaccine. All vaccines were generally well tolerated. Immune responses were observed to multiple serogroup B strains following all investigational vaccines, suggesting the potential for broad coverage against this serogroup. Immunogenicity was enhanced by the addition of OMV; the 4CMenB displayed the optimal profile for further investigation. Methods: In a phase I, observer blind, randomized trial, healthy adults (18-40 years of age) were randomized 2:2:1 to receive 3 doses of 4CMenB, rMenB with OMV from the Norwegian outbreak strain, or rMenB alone. Pre- and postvaccination sera were evaluated in a serum bactericidal assay using human complement (hSBA) against a panel of 15 serogroup B strains, with titers ≥4 considered protective. Solicited injection site and systemic reactions were evaluated for 7 days following each vaccination and adverse events were reported throughout the study. Conclusion: In this trial, 4CMenB displayed a favorable profile for further clinical development. 4CMenB demonstrated immunogenicity against multiple heterologous serogroup B strains. All vaccines were generally well tolerated in this study.




COMMENTARIES

Open Access Article

Hepatitis B vaccination strategy in vaccine low and non-responders: A matter of quantity of quality?

Anna H. Roukens and Leo G. Visser
Pages 654 - 657
http://dx.doi.org/10.4161/hv.7.6.14986
Abstract | PDF

Hepatitis B virus infection can lead to chronic infection and liver failure. Transmission of the virus is preventable though vaccination. Unfortunately, 5-10% of healthy individuals and 40-50% of haemodialysis patients do not develop an adequate immune response against the vaccine. In this commentary we focus on the possible biological mechanisms of hepatitis B vaccine unresponsiveness, and give practical advice to overcome this unresponsiveness.

Open Access Article

Synthetic biology: Impact on the design of innovative vaccines

Kathrin Kindsmüller and Ralf Wagner
Pages 658 - 662
http://dx.doi.org/10.4161/hv.7.6.14987
Abstract | PDF

Conventional vaccine design strategies mainly focus on live-attenuated vaccines, inactivated microorganisms, and subunits thereof comprising purified components or recombinantly expressed proteins, mostly formulated with adjuvants. Although generally very efficient, these approaches are suboptimal or unfeasible for some infectious diseases. Over the past years new technologies to vaccine development have evolved, often utilizing design principles and construction technologies of synthetic biology. The contribution of synthetic biology to vaccine development comprises algorithms for accelerated in silico identification of relevant protein candidates, in silico design of novel immunogens with improved expression, safety and immunogenicity profiles as well as in silico design of (1) nucleic acid based, (2) vectored and (3) live-attenuated vaccines. Furthermore, synthetic biology enables economic and rapid chemical synthesis of DNA encoding the immunogens designed in silico, and their efficient assembly with delivery systems to obtain vectored vaccines. Altogether, synthetic biology can help to develop improved vaccine candidates in considerably less time compared to conventional approaches.

Open Access Article

Increasing pandemic vaccination rates with effective communication

Natalie J. Henrich
Pages 663 - 666
http://dx.doi.org/10.4161/hv.7.6.15007
Abstract | PDF

Communicating effectively with the public about the importance of vaccination during a pandemic poses a challenge to health communicators. The public’s concerns about the safety, effectiveness and necessity of vaccines lead many people to refuse vaccination and the current communication strategies are often unsuccessful at overcoming the public’s resistance to vaccinate. Convincing the public to receive a vaccination, especially during a pandemic when there can be so much uncertainty about the vaccine and the disease, requires a revised communication approach. This revised approach should integrate into messages information that the public identifies as important, as well as presenting messages in a way that is consistent with our evolved social learning biases. These biases will impact both the content of the message and who delivers the message to different target populations. Additionally, an improved understanding between media and health communicators about the role each plays during a crisis may increase the effectiveness of messages disseminated to the public. Lastly, given that the public is increasingly seeking health information from on-line and other electronic sources, health communication needs to continue to find ways to integrate new technologies into communication strategies.




SPECIAL FOCUS REVIEWS

Open Access Article

Vaccines against viral hemorrhagic fevers: Non-human primate models

Ricardo Carrion Jr. and Jean L. Patterson
Pages 667 - 673
http://dx.doi.org/10.4161/hv.7.6.14981
Abstract | PDF

Viral hemorrhagic fevers are a group of disease syndromes caused by infection with certain RNA viruses. The disease is marked by a febrile response, malaise, coagulopathy and vascular permeability culminating in death. Case fatality rates can reach 90% depending on the etiologic agent. Currently, there is no approved antiviral treatment. Because of the high case fatality, risk of importation and the potential to use these agents as biological weapons, development of countermeasures to these agents is a high priority. The sporadic nature of disease outbreaks and the ethical issues associated with conducting a human trial for such diseases make human studies impractical; therefore, development of countermeasures must occur in relevant animal models. Non-human primates are superior models to study infectious disease because their immune system is similar to humans and they are good predictors of efficacy in vaccine development and other intervention strategies. This review article summarizes viral hemorrhagic fever non-human primate models.

Open Access Article

Vaccines for the prevention of dengue: Development update

Stephen J. Thomas and Timothy P. Endy
Pages 674 - 684
http://dx.doi.org/10.4161/hv.7.6.14985
Abstract | PDF

The dengue viruses (DENV) are mosquito-borne flaviviruses which cause a spectrum of clinical disease known as “dengue,” and have emerged and re-emerged as a significant global health problem. It is estimated more than 120 countries currently have endemic DENV transmission, 55% of the world’s population is at risk of infection, and there are between 70-500 million infections of which 2.1 million are clinically severe resulting in 21,000 deaths annually. By all estimates the global dengue problem will continue to worsen due to the increasing mobility of the population, ecological changes, and the inability to effectively sustain vector control. There are no licensed antivirals or vaccines to treat or prevent dengue. The development and widespread use of a safe and efficacious dengue vaccine is required to significantly reduce the global dengue burden. In this review the authors discuss dengue vaccines currently in the pre-clinical and clinical development pipeline.

Open Access Article

Human pathogenic hantaviruses and prevention of infection

Detlev H. Krüger, Günther Schönrich and Boris Klempa
Pages 685 - 693
http://dx.doi.org/10.4161/hv.7.6.15197
Abstract | PDF

Hantaviruses are emerging viruses which are hosted by small mammals. When transmitted to humans, they can cause two clinical syndromes, hemorrhagic fever with renal syndrome or hantavirus cardiopulmonary syndrome. The review compiles the current list of hantaviruses which are thought to be pathogenic in humans on the basis of molecular or at least serological evidence. Whereas induction of a neutralizing humoral immune response is considered to be protective against infection, the dual role of cellular immunity (protection versus immunopathogenicity) is discussed. For active immunisation, inactivated virus vaccines are licensed in certain Asian countries. Moreover, several classical and molecular vaccine approaches are in pre-clinical stages of development. The development of hantavirus vaccines is hampered by the lack of adequate animal models of hantavirus-associated disease. In addition to active immunization strategies, the review summarizes other ways of infection prevention, as passive immunization, chemoprophylaxis, and exposition prophylaxis.

Open Access Article

Argentine hemorrhagic fever vaccines

Ana Ambrosio, Maria Saavedra, Mauricio Mariani, Graciela Gamboa and Andrea Maiza
Pages 694 - 700
http://dx.doi.org/10.4161/hv.7.6.15198
Abstract | PDF

Argentine hemorrhagic fever (AHF), an acute disease caused by Junin virus (JUNV, Arenaviridae), has been an important issue to public health in Argentina since the early 1950s. The field rodent Calomys musculinus is JUNV natural reservoir and human disease is a consequence of contact with infected rodents. A steady extention of AHF endemic area is being observed since the first reports of the disease. Important achievements have been made in: (a) improvement of methods for the etiological diagnosis; (b) implementation and validation of therapeutical measures; (c) development of vaccines to protect against AHF. Reference is made to different research strategies used to obtain anti-AHF vaccines in the past and anti-arenaviral diseases in the present. Information is updated on features and field performance of Candid #1 vaccine, a live attenuted vaccine currently used to prevent AHF. This vaccine was developed through a joint international effort that envisioned it as an orphan drug. With transferred technology, Argentine government was committed to be Candid #1 manufacturer and to register this vaccine as a novel medical product under the Argentine regulatory authority. Candid #1 vaccine is the first one used to control an arenaviral hemorrhagic fever, the first live viral vaccine to be manufactured and registered in Argentina, reaching its target population through governmental effort.

Open Access Article

Filovirius vaccines

Steven B. Bradfute, John M. Dye, Jr. and Sina Bavari
Pages 701 - 711
http://dx.doi.org/10.4161/hv.7.6.15398
Abstract | PDF

Filoviruses can cause severe and often fatal hemorrhagic fever in humans and non-human primates (NHPs). Although there are currently no clinically proven treatments for filovirus disease, much progress has been made in recent years in the discovery of therapeutics and vaccines against these viruses. A variety of vaccine platforms have been shown to be effective against filovirus infection. This review summarizes the literature in this field, focusing on vaccines that have been shown to protect NHPs from infection. Furthermore, the uses of rodent models in vaccine development, as well as correlates of immunity, are discussed.