Results of a randomized, open-label, controlled study evaluating the safety and immunogenicity of a new meningitis vaccine for infants have been published in the January issue of the Journal of the American Medical Association.
Meningitis is the inflammation of the meninges, the thin membrane covering the brain and spinal cord. Although noninfectious meningitis can occur, the majority of meningitis cases are caused by bacterial or viral infections, of which three bacteria Haemophilus influenzae type b, Neisseria meningitidis and Streptococcus pneumoniae are responsible for 80% of bacterial meningitis. Vaccines are available but only work well in adults and children older than 2 years of age, leaving infants a vulnerable population. The current tetravalent meningococcal vaccine (against N. meningitidis serogroups A, C, W-135 and Y) is recommended for all US adolescents 11–18 years of age, and 2–10-year-olds at increased risk of developing meningitis. Infants are given a monovalent meningococcal glycoconjugate vaccine (MenC) that only protects them from the serogroup C.
The newly published clinical trial involved 225 UK and 196 Canadian healthy infants aged 2 months, who received an experimental meningitis vaccine developed by Novartis Vaccines and Diagnostics. Similar to the currently approved vaccine, the new vaccine – MenACWY – also protects against four N. meningitidis serogroups. The vaccine is conjugated to a potent carrier, CRM197 – a modified diphtheria toxin, which would hopefully increase immune responses to the N. meningitidis components.
In this study, Matthew Snape and colleagues from University of Oxford (UK) and other researchers from Italy and Canada followed different immunization schedules using the MenACWY or MenC vaccines. They found that the experimental MenACWY vaccine triggered immune responses to all four serogroups after immunizations at 2–3–4 or 2–4–6 months of age. Minor adverse effects, including pain on leg movement and mild fever, were observed in 2–4% of the vaccinees and were similar in MenACWY and control groups.
‘MenACWY is well tolerated and immunogenic in infancy,’ the authors concluded. ‚This vaccine, therefore, extends the immune protection provided by the monovalent MenC vaccine to serogroups A, W-135 and Y in infancy.’
Lee Harrison of the University of Pittsburgh (PA, USA) commented in an accompanying editorial that the research “provides evidence for a well-tolerated and immunogenic tetravalent (serogroups A, C, W-135 and Y) conjugate vaccine for infants.’ Although the vaccine remains subject to approval and licensing, and other issues, such as the duration of immunity and the necessity of booster doses later in life, need to be addressed, he concluded: “Taken together with other ongoing progress, the outlook for comprehensive global prevention of this devastating disease has never been better.”
Sources: Snape MD, Perrett KP, Ford KJ et al. Immunogenicity of a tetravalent meningococcal glycoconjugate vaccine in infants: a randomized controlled trial. JAMA 299(2), 173–184 (2008); Harrison LH. A multivalent conjugate vaccine for prevention of meningococcal disease in infants. JAMA 299(2), 217–219 (2008).
New epitope of HIV gp41 recognized by a novel broad-spectrum recombinant Fab
The intrinsic high rate of mutation enables HIV to escape immune recognition, which has been the main challenge in HIV vaccine development. Few antibodies can neutralize diverse strains of HIV and escape mutants emerge quickly. The identification of new epitopes (or antigenic determinants) on HIV glycoproteins, such as gp41 and gp120, is important, as is the discovery of new monoclonal antibodies with broad spectrum against different HIV strains.
Using a chimeric HIV-1 protein gp41 and a monoclonal Fab from AbD Serotec (part of MorphoSys AG, Germany), Marius Clore and colleagues at the National Institute of Diabetes and Digestive and Kidney Diseases have identified a new epitope on the gp41 protein.
The monoclonal Fab – Fab 3674 – itself was selected from the MorphoSys HuCAL GOLD antibody library. It is a recombinant, functional fragment of an immunoglobulin that can neutralize diverse laboratory- adapted HIV-1 B strains as well as primary isolates of subtypes A, B and C in an in vitro virus neutralization assay.
The findings have been published in the January issue of the Journal of Virology.
Source: Gustchina E, Louis JM, Lam SN, Bewley CA, Clore GM. A monoclonal Fab derived from a human non-immune phage library reveals a new epitope on gp41 and neutralizes diverse HIV-1 strains. J. Virol. DOI:10.1128/JVI.01260-07 (2008);
AbD Serotec, Germany: www.ab-direct.com
Bioven seeks funding for cancer vaccine clinical trials and commercialization
Bioven (Malaysia) is looking to raise US$16 million to fund clinical trials and fast track the commercialization of its three therapeutic cancer vaccines and a therapeutic hepatitis B vaccine.
The most developed product is the epidermal growth factor (EGF) cancer vaccine, which has entered Phase II/III clinical trials in terminally ill, late-stage NSCLC patients. The vaccine is injected once a month as a complement to standard chemotherapy/radiotherapy. According to the head of the project, Gisela Gonzalez Marinello, the vaccine has shown efficacy in earlier trials in Cuba, Canada and the UK, where it extended patients’ lives up to 2 years compared with 6 months using standard treatments.
“We are looking for investors to come into the project,” said Bioven’s chairman Mukhriz Mahathir. The new funds will be used for Phase II/III clinical trials of the EGF and hepatitis B therapeutic vaccines in Asian and European sites.treatments.
Phase III clinical trials of the EGF vaccine in terminally ill, late-stage NSCLC patients have already been started in Cuba. “We hope to register the product in Cuba for use on patients by mid 2008,” said Gonzalez Marinello.
In Malaysia, 12 hospitals are recruiting late-stage cancer patients and the company aims to enroll 230 patients for its clinical trials. Bioven has also identified European sites, including London, where some trials will take place.
“The outcome of these clinical trials will have global implications by bringing new hope to cancer patients. The clinical trials in Malaysia and Europe are designed to demonstrate the cancer vaccine’s ability to extend the lives of cancer patients and fast tracking global approval for the products,” said Mukhriz.
Source: Bioven, Malaysia: www.bioven.com.my
New immunization schedules for US children and adolescents
In the January issue of the journal Pediatrics, the American Academy of Pediatrics, the Advisory Committee on Immunization Practices of the US CDC, and the American Academy of Family Physicians published the updated immunization schedules for children aged 0–6 years, 7–18 years and those with late or incomplete immunizations.
The following changes are included in the 2008 schedules compared with the 2007 ones:
| • | Single dose of pneumoccoal conjugate vaccine for healthy children aged 24–59 months who are incompletely immunized; | ||||
| • | Extending the age recommendation for live-attenuated influenza vaccine to healthy children from 5 to 2 years of age; | ||||
| • | Reducing time interval for the second dose (when required) of live attenuated nasal influenza vaccine from 6 to 4 weeks after the first dose; | ||||
| • | Single dose of quadrivalent meningococcal conjugate vaccine for all adolescents aged 11–18 years who has not been vaccinated previously, and for at-risk children 2–10 years of age. | ||||
The new schedules reflect current recommendations for use of vaccines licensed by the US FDA. Immunization- related adverse events should be reported to the Vaccine Adverse Event Reporting System.
Source: The Committee on Infectious Diseases. Recommended immunization schedules for children and adolescents – United States, 2008. Pediatrics 121(1), 219–220 (2008); The American Academy of Pediatrics: www.aap.org
Trial watch
Emergent BioSolutions receives recommendation to continue Phase II trial of its hepatitis B vaccine
An independent Safety Monitoring Committee (SMC) has recommended that Emergent BioSolutions (MD, USA) continue the Phase II clinical trial of its therapeutic vaccine against HBV.
According to the WHO, approximately a third of the world’s population is infected by HBV at one point in life. Adults can recover from HBV infection, while infants usually become chronic carriers. There are between 350 and 400 million chronically infected individuals worldwide and chronic HBV is the leading cause of liver cancer.
Emergent BioSolutions has developed a therapeutic vaccine using a Salmonella-based bacterial vector that carries the hepatitis B core antigen (HBcAg). The company’s proprietary vector – spi- VEC – is administered orally and delivers HBcAg to the gut’s macrophages, which will trigger immune responses including HBcAg-specific T-cell-mediated immunity. This will, hopefully, help the patients clear HBV and reduce liver damage.
In this clinical trial, 45 patients with chronic HBV infection will be randomized into three groups receiving either the vaccine or placebo. The SMC’s recommendation followed the safety data review from the first group of patients who have completed day 70 of the study. The study can now proceed with the two remaining groups of patients.
“We are pleased by the SMC’s recommendation and look forward to advancing this critical study of our hepatitis B candidate. Hepatitis B is the tenth leading cause of death worldwide and our commitment to the development of this therapeutic vaccine is squarely in line with our mission – to protect life,” said Daniel Abdun-Nabi, president of Emergent BioSolutions Inc.
Emergent BioSolutions anticipates that results from this trial will be available in the first half of 2009, with preliminary safety and efficacy data available in the last quarter of 2008.
Source: Emergent BioSolutions Inc., MD, USA: www.emergentbiosolutions.com
Promising Phase IIb data of a non-small cell lung cancer vaccine
Preliminary results of a Phase IIb clinical trial evaluating a cancer vaccine for advanced non-small cell lung cancer (NSCLC) have been released by Transgene (France). The vaccine appears safe and well tolerated.
The vaccine, TG4010 (MVA-MUC1-IL2), contains the modified vaccinia Ankara (MVA) virus vector, a highly attenuated poxvirus that has been used extensively in human smallpox vaccines and are safe and immunogenic. The MVA vector carries the cancer antigen, mucin (MUC)1, and cytokine IL-2 gene sequences. MUC1 is a tumor-associated antigen that has been studied extensively in various cancer vaccine candidates. IL-2 can stimulate T-helper cells and has been used in immunotherapy for kidney and lung cancers.
In this randomized, open-label, controlled Phase IIb clinical trial, 148 patients were enrolled in 27 centers in France, Poland, Germany and Hungary. The patients have MUC1-expressing NSCLC (either stage IIIB with effusion or stage IV) and have not received systemic treatment prior to the study. A combination of TG4010 vaccine plus chemotherapy is administered to half of the patients, while the other half only received chemotherapy
Preliminary data revealed that most adverse events so far were associated with the chemotherapy or patients’ underlying disease. Hematological toxicity was comparable in both groups. TG4010-related adverse events included injection-site reactions and asthenia, which are common with other injectable vaccines.
“We report today encouraging trends on the preliminary results of our Phase IIb trial with TG4010 in NSCLC” said Philippe Archinard, Transgene’s chief executive officer. “We expect to present data during the second quarter of this year and final data by the fourth quarter of 2008.”
Although preliminary data showed promising and favorable safety profile for TG4010, these results are subject to further analyses while the study is ongoing.
Source: Transgene, France: www.transgene.fr
New typhoid vaccine moves on to Phase IIb clinical trial
Emergent BioSolutions Inc. (MD, USA) has released the final results of the Phase II clinical trial of its new single-dose, oral typhoid vaccine. The vaccine is safe and immunogenic, and the company will start the Phase IIb clinical trial soon.
Typhoid fever, or enteric fever, is caused by the bacterium Salmonella enterica serovar Typhi. The bacteria are usually transmitted via contaminated water and it does not require a high dose to cause infection. The bacteria primarily affect the gastrointestinal tract, causing fever, stomachache, constipation and anorexia, although in serious cases other organs, such as liver, kidney and brain, are also invaded. The incubation period is between 1 and 4 weeks and diagnosis is based on patients’ history and symptoms, although confirmative bacterial isolation from feces or blood culture is usually necessary. There are approximately 20 million cases of typhoid fever worldwide each year, mainly in developing countries with poor sanitation, and the mortality rate is approximately 3%. Preventive oral vaccines are available and are highly recommended for those traveling to endemic areas.
The new typhoid vaccine developed by Emergent BioSolutions is a live-attenuated S. enterica Typhi strain carrying deletion of two virulence genes. Only one oral dose of the vaccine is needed to give protection, which makes the vaccine more advantageous than currently approved typhoid vaccines.
In this randomized, placebo-controlled, blinded Phase II clinical trial, 101 Vietnamese children aged between 5 and 14 years received a single dose of the vaccine orally, while 50 other children received placebo. Immune responses were observed in 97% of vaccinated children who showed increase in Salmonella lipopolysaccharide-specific IgG or IgA in blood. Side effects were similar between vaccinated and placebo groups, and there were no serious adverse events.
“We are pleased that the full analysis of the data from this Phase II study reaffirms that our typhoid vaccine candidate met the pre-established clinical endpoints. These data are encouraging and indicate great promise regarding both the safety and efficacy of what would be the first single-dose, drinkable typhoid vaccine,” said Fuad El-Hibri, chairman and chief executive officer of Emergent Bio-Solutions. “Typhoid is often endemic in developing countries and claims 200,000 lives annually. A Phase II trial in the USA and a Phase IIb trial in an endemic population are both slated to begin by the end of 2008. Both of these trials will use clinical material produced using a scaled-up commercial manufacturing process.”
The vaccine was safe and well tolerated in a number of previous studies carried out in the UK, USA and Vietnam. Funded by the Wellcome Trust, this Phase II trial is the first study in a pediatric population and was performed in collaboration with the Wellcome Trust (Oxford University, UK) and the Hospital for Tropical Diseases (Ho Chi Minh City, Vietnam).
“We are delighted to have partnered with Emergent BioSolutions to support this trial in Vietnam,” said Ted Bianco, director of technology transfer at the Wellcome Trust. “The trial will advance the development of a sorely needed vaccine for typhoid fever. The ease of administration of the product is one of its chief attractions from a public health perspective.”
Source: Emergent BioSolutions Inc., MD, USA: www.emergentbiosolutions.com