Abstract
GSK`s Synflorix: Highly effective at preventing invasive pneumococcal disease
Positive phase 1 interim results for killed whole-virus HIV vaccine
Therapeutic HBV vaccine drives immune responses in liver
New tuberculosis vaccine candidate to enter the clinic
Novartis receives positive CHMP opinion for MenB vaccine Bexsero
New research points way to faster flu vaccines
New Meth vaccine shows promise in animals
RTS,S malaria vaccine reduces malaria by approximately one-third in African infants
GSK`s Synflorix: Highly effective at preventing invasive pneumococcal disease
Glaxo SmithKline (GSK) recently announced positive results from the first randomized controlled European clinical trial of its pneumococcal conjugate vaccine (PCV) Synflorix. The vaccine was shown to be highly effective at preventing invasive pneumococcal disease (IPD) in infants younger than two years of age, who are the age group most vulnerable to infection.
The Finnish Invasive Pneumococcal Disease Vaccine Trial (FinIP) was conducted nationwide and tracked Synflorix effectiveness over a two-year period on average. More than 47,300 children were enrolled, making this the largest IPD effectiveness trial of PCVs in children. Infants received two or three dose in their first year and a booster at two years of age. No safety concerns were noted during the study. Vaccination with Synflorix was found to be highly effective at either the three-dose (2+1) or the four-dose (3+1) schedule. In particular, Synflorix effectiveness agaist IPD caused by vaccine serotypes was 92% in the 2+1 schedule and 100% in the 3+1 schedule. Synflorix effectiveness against overall IPD regardless of pneumococcal serotypes was 93%. Furthermore, a high level of effectiveness was observed in different catch-up schedules for older children. The results were recently published in the journal The Lancet.1
Dr William Hausdorff, Vice President and Vaccine Development Leader for Pneumococcal Vaccines, GSK Vaccines said: “IPD causes illness, hospitalization and even death in Finnish children and across the world. These significant data show that Synflorix is an important public health tool in helping to reduce the burden of the disease.”
Pneumococcal bacteria can cause life-threatening diseases such as meningitis, pneumonia and sepsis. Streptococcus pneumoniae infections are estimated to kill up to half a million children under five years of age, mostly in developing countries. In addition, S. pneumoniae also causes less severe, but considerably more common diseases of the respiratory tract such as middle ear infections, sinusitis and bronchitis.
The pediatric PCV Synflorix aims to protect against IPDs, such as meningitis, bacteraemic pneumonia and sepsis. Synflorix also provides protection against pneumococcal middle ear infection, otherwise known as acute otitis media (AOM). The vaccine is available in over 90 countries. Synflorix was the first PCV eligible under the Advanced Market Commitment (AMC) to receive WHO prequalification.
Reference
1. Palmu AA, et al. Lancet 2012; S0140–6736:1854–6
Positive Phase 1 interim results for killed whole-virus HIV vaccine
The first and only preventive human immunodeficiency virus (HIV) vaccine based on a genetically-modified killed whole-virus is being studied in a Phase 1 trial by Sumagen Canada, a subsidiary of the Korean-based pharmaceutical venture company Sumagen Co. Ltd. Recently, the company announced positive interim results from the Phase 1 study.
The vaccine SAV001-H was developed by Dr Chil-Yong Kang and his team at Western University’s Schulich School of Medicine and Dentistry. It is the only HIV vaccine currently under development in Canada. Since HIV was identified in 1983, there have been numerous clinical trials by pharmaceutical companies and academic institutions around the world to develop vaccines. HIV vaccine candidates previously studied in humans included vaccines consisting of one specific component of HIV as an antigen, genetic vaccines using recombinant DNA, or recombinant viruses carrying HIV genes. In contrast, SAV001-H uses a killed whole HIV-1, much like the killed whole-virus vaccines for polio, influenza, rabies and hepatitis A. The HIV-1 strain is genetically engineered so it is non-pathogenic and can be produced in large quantities.
The randomized, observer-blinded, placebo-controlled Phase 1 study evaluates the safety and tolerability of SAV001-H following intramuscular administration. The study includes HIV-infected individuals between18 and 50 y of age, randomized into two treatment groups to receive the vaccine SAV001-H or placebo. Interim analysis of the trial showed that SAV001-H is safe and well tolerated in humans. Significant increases in HIV-1 antibody levels were observed after vaccination. Even though this study is blinded until completion, these results are encouraging in regard to the possibility of the prophylactic potency of SAV001-H.
Dr Dong Joon Kim, a spokesperson for Sumagen Co. Ltd, says, “We have proven that there is no safety concern of SAV001-H in human administration, and we are now prepared to take the next steps towards Phase 2 and Phase 3 clinical trials.”
In the future, the company will be looking for collaboration with multi-national biopharmaceutical companies for globalizing clinical trials and commercialization.
Therapeutic HBV vaccine drives immune responses in liver
A new study published in the journal Cancer Gene Therapy1 showed that a synthetic hepatitis B (HBV) therapeutic vaccine generated strong T cell responses that eliminated targeted liver cells in mice. These results suggest that the vaccine, developed by Inovio Pharmaceuticals Inc., has the potential to clear HBV infection at least partially in humans.
Although an effective preventive vaccine against HBV infection has been available for over three decades, 400 million people are chronically infected with the virus and at risk of developing cirrhosis or liver cancer. Liver cancer is the third most common cancer and among the most deadly, killing most patients within five years of diagnosis. Currently, the only available therapies for chronically infected indviduals are interferon-α and nucleoside analog treatments, which function by controlling viral replication but unfortunately do not clear infection. An effective HBV therapeutic vaccine would be of great value to fight chronic hepatitis B.
Inovio‘s therapeutic vaccine candidate tested in the preclinical study is a synthetic DNA vaccine that encodes an HBV core antigen (HBcAg) and represents a consensus of the unique HBcAg DNA sequences of all major HBV genotypes. Mice that received the DNA vaccine via Inovio’s proprietary electroporation-based delivery technology showed strong peripheral HBcAg-specific T-cell and antibody responses. Immunization also induced antigen-specific CD8+ and CD4+ T cells as well as IFN-γ and TNF-α in the liver, indicating that a strong vaccine-induced T-cell response was also present in the liver. Furthermore, study researchers found that the vaccine-specific T cells exhibited a killing function, and could migrate to and stay in the liver and cause clearance of target cells without any evidence of liver injury. Taken together, this is the first study to provide evidence that intramuscular immunization can induce killer T cells that can migrate to the liver and eliminate target cells.
Inovio’s President and CEO, Dr J. Joseph Kim, said: “Inovio has established a potent immune therapeutics platform. With our recent scientific breakthrough represented by our human data showing the powerful killing effect of T cells generated by our cervical dysplasia therapeutic vaccine, we are encouraged by the published preclinical results generated by our therapeutic vaccine against HBV. Hepatitis B is one of the most important global health problems, and we are excited by the prospect of addressing HBV and other chronic infectious diseases with our vaccines“.
Reference
1. Obeng-Adjei N, et al. Cancer Gene Ther 2012; 19:779–87
New tuberculosis vaccine candidate to enter the clinic
A new vaccine to prevent tuberculosis (TB) has been under development for more than a decade in different laboratories across Europe, and will now undergo clinical evaluation, according to University World News.
The live vaccine called MTBVAC was the first to be based on Mycobacterium tuberculosis, the bacterium that causes TB. It is designed to stimulate the human immune system to recognize and eventually prevent TB infection. Various partners of the Tuberculosis Vaccine Initiative, a consortium set up and part-funded by the European Commission to facilitate TB vaccine research, were involved in the preclinical study of MTBVAC. Swiss-medic, the Swiss regulatory authority for medicine, has recently provided permission to start clinical evaluation of MTBVAC in healthy adult volunteers.
European Commissioner for Research, Innovation and Science Máire Geoghegan-Quinn said: “Tuberculosis is a killer that claims seven victims every hour in Europe alone, with particularly drug-resistant strains emerging. That is why the European Union is investing so much to combat this disease.”
TB is a huge public health problem in many countries, with nearly nine million new cases and 1.4 million deaths worldwide every year. The steady increase in resistance against treatment with the most common antibiotics adds to the problem.
According to Professor Carlos Martin of Zaragoza University (Spain), who took the lead in developing MTBVAC, the only currently available vaccine—BCG—provides limited protection against TB. The researchers hope that the new vaccine will offer lifelong protection against all forms of TB, thereby providing a solution for drug-resistant TB.
Novartis receives positive CHMP opinion for MenB vaccine Bexsero
As recently announced by Novartis, the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency (EMA) has adopted a positive opinion for the meningococcal group B (MenB) vaccine Bexsero for use in individuals from 2 mo of age and older. Upon approval, Bexsero will become the first licensed broad-coverage vaccine to protect all age groups against MenB infections, the leading cause of meningitis in Europe.
“We are proud of the major advance that Bexsero represents within the field of vaccine development against what up until now has been a very challenging disease target,” said Andrin Oswald, Division Head, Novartis Vaccines and Diagnostics. “For over two decades, our researchers and clinicians have been dedicated to finding a solution to prevent MenB disease. Our steadfast determination has been inspired by the testimonies from survivors and families who have lost loved ones to this disease.”
The European Commission generally follows the recommendations of the CHMP and delivers its final decision within three months, which will be applicable to all EU countries. Upon approval, each member state will evaluate Bexsero reimbursement schemes and determine the potential inclusion of the vaccine into National Immunization Programs.
MenB disease is easily misdiagnosed, can kill within 24 h, and can cause serious life-long disabilities, such as brain damage, hearing impairment or limb loss. About one in ten of those who contract the disease dies despite appropriate treatment. The highest rates of MenB disease occur in the first year of life. Currently available vaccines do not offer broad protection against MenB, which accounts for up to 90% of all meningococcal disease in Euopean countries.
MenB has been a particularly challenging target because the outer coating of the bacteria is not well recognized as an antigen by the immune system. Novartis was able to overcome this difficulty by using a pioneering approach known as “reverse vaccinology“. This approach involved decoding of the genetic makeup (genome sequence) of MenB and selection of those proteins that are most likely to be broadly-effective vaccine candidates. The resulting vaccine Bexsero (also known as 4CMenB) contains multiple components, which independently are highly immunogenic and, taken together have the potential to protect against a broad range of disease-causing strains. To date, more than 8,000 infants, toddlers, and adults have been enrolled in studies of Bexsero.
With the anticipated approval of the MenB vaccine Bexsero and the 2010 approval of Menveo (protecting against meningococcal bacteria serogroups A, C, W-135 and Y), Novartis strengthens its leadership position in the global fight against meningococcal disease.
New research points way to faster flu vaccines
An experimental vaccine based on RNA was shown to protected animals against influenza and may one day offer a rapid way to develop new vaccines for humans.
The vaccine, developed by Dr Lothar Stitz of Friedrich-Loeffler-Institute (Germany) and the German biotech company CureVac, is made solely of mRNA (mRNA), a single-stranded molecule that directs cells to make a specific protein. Traditional influenza vaccines, which are made in chicken eggs or more recently in animal cell cultures, have the problem of variable yields and production delays. It can take up to 6 mo to produce a flu vaccine in fertilized chicken eggs. For a flu vaccine using cell culture technology, manufacturing time may be reduced by about 8–10 weeks. In contrast, the new RNA-based vaccine could be produced much more quickly, within 6–8 weeks after the genetic code of a influenza virus is published. Another potential advantage of mRNA vaccines is that they might not need to be refrigerated.
“The only thing we need is the sequence of the relevant genes,” Dr Stitz said. “It’s a new option and it does not take long to do.”
Dr Stitz and his team vaccinated mice, ferrets and pigs with an mRNA vaccine and found that the immune response was similar or better than that found with conventional vaccines. Moreover, the new vaccines showed a high level of efficacy in very young and very old animals, which can be a problem for very young and old people with current flu vaccines. The mRNA vaccine elicited B- and T-cell-dependent protection and targeted multiple antigens, including the highly conserved viral nucleoprotein, indicating its usefulness as a cross-protective vaccine. In ferrets and pigs, mRNA vaccine induced levels of antibody that meet immunological correlates of protection and protective effects similar to those of a licensed influenza vaccine in pigs. The results were recently published in the journal Nature Biotechnology.1
Extensive clinical trials will be needed to evaluate safety and efficacy of this new mRNA influenza vaccine. CureVac will take on the job of moving the vaccine forward. CureVac is also developing a mRNA vaccine for lung cancer and one for prostate cancer, the later one is already in human trials. In collaboration with Sanofi, CureVac is working on prophylactic vaccines against several infectious diseases.
Reference
1. Petsch B, et al. Nat Biotechnol 2012; 30:1210–6
New Meth vaccine shows promise in animals
Scientists at The Scripps Research Institute (TSRI) have successfully tested an experimental methamphetamine vaccine in rats. Immunized animals that received the drug were largely protected from typical signs of methamphetamine (Meth) intoxication. The results of the study were recently published in the journal Biological Psychiatry.1
Meth has become one of the most common drugs of abuse around the world, with an estimated 25 million people worldwide suffering from Meth addiction. In the United Stated alone there are said to be more than 400.000 current users. Currently, there are no approved treatments for Meth addiction.
In recent years, innovative approaches of developing vaccines against addictive drugs have been pursued. These vaccines elicit antibody responses against the drug molecules, just like traditional vaccines evoke antibody responses against microbial pathogens. Anti-drug antibodies bind to drug molecules and prevent them from reaching the brain. The drug no longer gives the user a high, such that the incentive for taking the drug is missing. While vaccines against nicotine and cocaine have advanced into clinical trials, Meth vaccine development is more difficult. “The simple structure and long half-life of this drug make it a particularly difficult vaccine target,” said one of the study authors, Dr Kim Janda from TSRI.
Two years ago Dr Janda and coworkers developed six candidate Meth vaccines. The main active ingredient was a chemical cognate of the methamphetamine molecule linked to a larger, antibody-provoking carrier molecule. Three of the six candiates evoked strong antibody responses to Meth in mice and were taken further to be studied in rats. The candidate that worked best, designated MH6, was able to block two typical effects of Meth: an increase in physical activity and a loss of the usual ability to regulate body temperature.
In this new study, members of Michael Taffe’s laboratory at TSRI investigated the MH6 vaccine in more depth. Using a different experimental setup, the researchers confirmed previous findings. Immunized animals showed a robust antibody response, and more of the drug was kept in the bloodstream and out of the nervous system, compared with control rats. Looking at behavioral measures, immunization prevented a rise in body temperature and burst of wheel-running hyperactivity that otherwise occur after meth exposure.
“These are encouraging results that we’d like to follow up with further animal tests, and, we hope, with clinical tests in humans some day,” said study lead author Michelle Miller.
A seperate group of researchers recently reported promising results for an antibody-based treatment of Meth addiction. Anti-Meth antibodies were isolated from cultured cells using standard biotechnology methods and then injected into animals in a concentrated dose, preventing a Meth high. One problem with this approach is that antibody-based therapies are typically expensive and the effects are short-lived. A Meth treatment probably would have to be much more cost-effective to be widely useful, since addicts frequently have little money and no health insurance and receive their treatments from government health services.
In principle, an active vaccine would be cheap to make and administer and would confer protection for months per dose, rather than weeks with conventional monoclonal antibody therapy. The MH6 vaccine candidate in the current study was given in four doses over 12 weeks, but Drs Janda and Taffe believe that with further adjustment an active Meth vaccine could sustain an anti-Meth antibody response for a much longer period.
Reference
1. Miller ML, et al. Biol Psychiatry 2012; S0006–3223:00803–7
RTS,S malaria vaccine reduces malaria by approximately one-third in African infants
Results from an ongoing pivotal, large-scale Phase 3 trial show that the RTS,S malaria vaccine candidate, developed by GlaxoSmithKline (GSK), can provide modest protection for African infants against malaria. In this trial, RTS,S demonstrated an acceptable safety and tolerability profile. Infants vaccinated with RTS,S had one-third fewer episodes of both clinical and severe malaria, compared with infants who received a control vaccine.
Eleven African research centers in seven African countries conducted the Phase 3 trial, together with GSK and the PATH Malaria Vaccine Initiative (MVI), with funding from the Bill and Melinda Gates Foundation to MVI.
RTS,S aims to trigger the immune system to defend against Plasmodium falciparum malaria parasite when it first enters the human host’s bloodstream and/or when the parasite infects liver cells. The vaccine is designed to prevent the parasite from infecting, maturing, and multiplying in the liver, after which time the parastie would re-enter the bloodstream and infect red blood cells, leading to disease symptoms.
In the Phase 3 trial, RTS,S was administered in three monthly doses, followed by a booster dose given 18 mo after the third dose. When administered in combination with standard childhood vaccines, the efficacy of RTS,S in infants aged 6–12 weeks (at first vaccination) against clinical and severe malaria was 31% and 37% respectively over 12 mo of follow-up after the third dose. Insecticide-treated bed nets were used by 86% of the trial participants, which demonstrated that RTS,S provided protection beyond existing malaria control interventions. No increase in overall reporting of serious adverse events between infants receiveing the RTS,S vaccine and infants in the control group was observed. The study results were recently published in the New England Journal of Medicine.1 (http://www.ncbi.nlm.nih.gov/pubmed/23136909). Previous data obtained in children aged 5–17 mo had shown an efficacy of RTS,S against clinical and severe malaria of 55% and 47%, respectively. These data were published last year in the same journal.2
Dr Salim Abdulla, a principal investigator for the trial from the Ifakara Health Institute, Tanzania, said: “The efficacy is lower than what we saw last year with the older 5–17 month age category, which surprised some of us scientists at the African trial sites. It makes us even more eager to gather and analyze more data from the trial to determine what factors might influence efficacy against malaria and to better understand the potential of RTS,S in our battle against this devastating disease. We were also glad to see that the study indicated that RTS,S could be administered to young infants along with standard childhood vaccines and that side effects were similar to what we would see with those vaccines.”
“This is an important scientific milestone and needs more study,” said Bill Gates, co-founder of the Bill and Melinda Gates Foundation. “The efficacy came back lower than we had hoped, but developing a vaccine against a parasite is a very hard thing to do. The trial is continuing and we look forward to getting more data to help determine whether and how to deploy this vaccine.”
References
1. RTS,S Clinical Trials Partnership, et al. N Engl J Med. 2012; 367:2284–95
2. Agnandji ST, et al. N Engl J Med 2011;365:1863–75
Footnotes
Previously published online: www.landesbioscience.com/journals/vaccines/article/23607