Ebola Vaccines development progresses expeditiously
One year after the first cases of Ebola were confirmed, the search for an effective vaccine continues. The World Health Organization (WHO) has given permission to a Phase 2 trial of two vaccine candidates, produced by GSK and Merck, after early-stage trials showed an ‘acceptable safety profile.’
The Phase 2 study is being conducted in the West African countries most severely struck by the Ebola epidemic. It involves 9,000 people from Guinea, 6,000 from Sierra Leone and 27,000 from Liberia. Whereas the two former groups lack placebo control, the latter is split into three sub-groups, each receiving GSK vaccine, Merck vaccine, or placebo.
The third vaccine candidate to enter a clinical trial is produced by J&J and Danish company Bavarian Nordic. The Phase 1 study is being carried out in Britain, United States, Kenya, Uganda and Tanzania and involves around 300 subjects. This vaccine consists of two doses administered several weeks apart. J&J announced they could prepare 2 million doses this year.
Another vaccine candidate is produced by Indian company Zydus Cadila. It is both a preventive and a therapeutic vaccine, currently in preclinical studies carried out in Catania, Italy.
To date, more than 20,000 people have been infected with Ebola, and over 8,000 have died. The worst situation is in Sierra Leone, but Guinea and Liberia are also severely affected. Nevertheless, the situation has stabilized, according to WHO.
Early Vaccination against Rotavirus correlates with lower Disease Burden
Healthcare providers with higher rates of rotavirus vaccination see lower rates of acute gastroenteritis, according to a study published in Pediatrics1.
Researchers from the Baylor College of Medicine and Texas Children's Hospital monitored visits at the Texas Children's emergency center over a two-year period, and associated each patient with a specific provider location. The providers were grouped according to vaccine coverage into low (<40%), medium (40-79%) and high (≥80%).
More than 30% of all rotavirus-positive patients came from low-coverage locations, compared to 13% and <10% from medium- and high-coverage locations, respectively. “This shows that there is an association between not being vaccinated and getting the disease,” Leila Sahni of Texas Children's Hospital said in a statement.
Rotavirus vaccine is a live, oral vaccine. The first dose is given to infants of no more than 15 weeks of age. “It's the only vaccine that is given by mouth, so parents should ask about it during the two-month visit if they notice that their child did not receive it,” said Sahni.
Rotaviruses are the world-leading cause of severe diarrheal disease in young children, according to WHO. More than half a million children aged <5 years die of rotavirus diarrhea annually, especially in low-income countries.
1. Sahni LC, Tate JE, Payne DC, Parashar UD, Boom JA. Variation in Rotavirus Vaccine Coverage by Provider Location and Subsequent Disease Burden. Pediatrics 2015; doi: 10.1542/peds.2014-0208
Vaccine Hesitancy found to be geographically correlated
Opposition to vaccination spreads in communities, according to a study published in Pediatrics1. Analysis of medical records of >150,000 children from Northern California identified five geographical clusters in which children under age 3 years were significantly under-immunized.
“This research confirms anecdotal reports of under-immunization clusters,” Tracy Lieu, director of the Kaiser Permanente Division of Research, said in a statement. “In addition, we found clusters in places we hadn't anticipated.”
The results may help doctors identify areas and communities where raising awareness is of great importance and where the risk of outbreaks is highest. “Our findings raise awareness that there may be communities where parents have more vaccine hesitancy and may be interested in more information or more in-depth conversations with their children's doctors.” said Tracy Lieu.
The U.S. Centers for Disease Control and Prevention (CDC) recommends at least 17 injections in the first two years of life. Under-immunization and vaccine refusal are associated with higher risk of preventable disease and community risk of measles and pertussis.
1. Lieu TA, Ray GT, Klein NP, Chung C, Kulldorff M. Geographic Clusters in Underimmunization and Vaccine Refusal. Pediatrics 2015; doi: 10.1542/peds.2014-2715
WHO approved Meningitis A Vaccination for Infants in sub-Saharan Africa
Routine immunization against meningitis A in infants aged <1 year is now possible in sub-Saharan Africa. WHO approved MenAfriVac, manufactured by Serum Institute of India, after its success in the “meningitis belt” countries.
The region between Senegal and Ethiopia has been regularly struck by meningitis A epidemics and previous vaccines were unable to break the cycle. During the worst outbreak in 1996, >250,000 people were infected and >25,000 died.
Since MenAfriVac was first administered in 2010, over 200 million people aged 1-29 have been vaccinated in 15 countries, resulting in a drop of up to 90% in disease incidence. Unvaccinated groups were also found protected, suggesting that MenAfriVac provided community protection.
“Initial mass vaccination campaigns with MenAfriVac have been highly effective in reducing the number of meningitis A cases,” Marie-Pierre Préziosi of Meningitis Vaccine Project said in a press release. “But epidemics will return when rising numbers of unprotected newborns become a larger proportion of the total population over time. Now, with this decision, health officials will be able to ensure that population-wide protection is sustained by routinely immunizing infants.”
Seven countries are on the way to implementing routine infant vaccination in 2015.
Phase 1 trial started for Combinatorial Immunotherapy of Melanoma
Amgen has initiated clinical trials of its oncolytic immunotherapy talimogene laherparepvec (T-vec) in combination with Merck's Keytruda for treatment of advanced melanoma. The Phase 1 study will look at safety and preliminary efficacy in >100 untreated patients in the U.S., Australia and Europe.
T-vec is based on an oncolytic virus that selectively replicates in tumors and stimulates the immune system. It successfully completed Phase 3 as monotherapy. Keytruda (Pembrolizumab) is a PD-1 inhibitor that prevents tumors from escaping the immune response.
“T-vec is designed to promote tumor antigen release and presentation to initiate an anti-tumor immune response, which may be complementary to Keytruda's role in releasing PD-1 pathway-mediated inhibition of anti-tumor immune responses,” Stephen Hodi of Dana-Farber Cancer Institute said in a statement. “Antigen release and presentation is a fundamental step required for mounting a systemic effect against melanoma, and we think there is a strong rationale for combining the oncolytic immunotherapy T-vec with the immune checkpoint inhibitor.”
Melanoma, the most aggressive form of skin cancer, affects more than 130,000 people every year.
Influenza Vaccine was less effective during this season
This year's seasonal influenza vaccine reduced the risk of getting the disease by 23%, according to CDC. The effectiveness thus decreased from previous years, during which it was ∼50%. The vaccine against H3N2 was most effective in young people aged ≤17 years (26%).
Nevertheless, CDC is recommending vaccination, since it can decrease severity of disease as well as prevent influenza caused by other strains that can circulate later in the season.
Since influenza vaccine efficacy was first monitored in the 2004-5 season, efficacy has ranged between 10% (2004-5) and 60% (2010-1). Influenza virus is highly variable, and this year's drop in efficacy is caused by a mismatch between the virus used in vaccine production and the virus in circulation. Manufacturers must commit to the choice of strains for the vaccine at least 8 months before the influenza season, which can result in mismatch if a new strain emerges during this time interval.
Two Checkpoint Inhibitors seek FDA approval for treatment of Lung Cancer
Merck's Keytruda and Bristol-Myers Squibb's Opdivo might soon be used in lung-cancer patients. These monoclonal antibodies are inhibitors of the PD-1 pathway, which is commonly hijacked by tumors to suppress immune response. Both immunotherapeutics are approved for advanced melanoma.
Opdivo was successful in Phase 3 study known as Checkmate-017, in which it was compared to standard chemotherapy. It showed extended survival in non-small cell lung cancer patients to such extent that independent monitors halted the trial. It is the first time that a PD-1 inhibitor prolonged survival in comparison with another drug rather than placebo.
Merck plans to file an application for Keytruda in mid-2015, and the FDA could decide on approval within a few months.
Additional trials are carried out by Roche. Their PD-1 inhibitor is tested in lung- and bladder-cancer patients. Results and potential application for approval are expected in second half of 2015.
Lung tumors account for most cancer-related deaths worldwide. 1.5 million people die each year, according to WHO.
Chikungunya Fever Vaccine candidate passes Phase 1 Trial
In a sample of 42 subjects, the new Chikungunya fever vaccine proved safe and well-tolerated, and it induced production of neutralizing antibodies. The candidate is a collaborative effort of Thermis Bioscience and Insitut Pasteur.
Chikungunya is a debilitating disease of viral origin transmitted by mosquitoes. It is accompanied by headaches, fatigue, vomiting and joint pains. Chikungunya fever affects hundreds of thousands of people in endemic countries in Africa and Asia, and the first outbreaks in Europe and the Americas have been reported.
The vaccine utilizes a unique technology, in which a Chikungunya gene is inserted into the genome of a well-established measles vaccine, which delivers the antigen into the cells. Thermis and Institut Pasteur now want to extend this technology to developing vaccines against other infectious diseases. A Dengue vaccine candidate of similar design is already in the making.
Vaccine against ‘Bad Cholesterol’ might soon enter Clinical Trials
Pfizer is developing a vaccine against PCSK9, a protein that plays a crucial role in cholesterol homeostasis. PCSK9 induces degradation of the low-density lipoprotein (LDL) receptor, which can result in reduced LDL-cholesterol metabolism promoting hypercholesterolemia. This can eventually lead to coronary heart disease or atherosclerosis. Blocking PCSK9 was shown to cause a decrease in levels of LDL-cholesterol.
In addition to the vaccine, which could enter human trials in 2016, Pfizer is developing a whole PCSK9 ‘franchise.’ This includes the injectable monoclonal antibody bococizumab, which was able to decrease ‘bad’ cholesterol by 60%, and a small-molecule drug which has also reduced cholesterol levels substantially in animal models.
According to Pfizer's R&D chief Mikael Dolsten, the pill could be used for people with moderate to high cholesterol, while the antibody might be suitable for patients with very high cholesterol that failed other treatments.
Personalized Cancer treatment enters Clinical Trial
Researchers at University of Connecticut have developed a novel personalized cancer treatment. According to a report published in Journal of Experimental Medicine1, they were able to deep-sequence RNA from mouse sarcoma and identify mutations in immunologically relevant epitopes. This allowed them to selectively immunize mice with mutant peptides, which resulted in CD8-dependent immunity.
“This has the potential to dramatically change how we treat cancer,” Pramod Srivastava, director of the Carole and Ray Neag Comprehensive Cancer Center, said in a press release. “This research will serve as the basis for the first ever genomics-driven personalized medicine clinical trial in immunotherapy of ovarian cancer.”
The trial is underway at University of Connecticut Health Center, enrolling 15-20 women with ovarian cancer. The reason for choosing ovarian cancer is that it responds well to treatment in the short term but frequently reappears after a year or two. This gives the researchers time to prepare and administer the new personalized vaccine. If the pipeline proves safe, Phase 2 will look at its capacity to prolong patients’ lives.
1. Duan F, Duitama J, Al Seesi S, Ayres CM, Corcelli SA, Pawashe AP, Blanchard T, McMahon D, Sidney J, Sette A, Baker BM, Mandoiu II, Srivastava PK. Genomic and bioinformatic profiling of mutational neoepitopes reveals new rules to predict anticancer immunogenicity. J Exp Med 211:2231-48