New Shingles Vaccine on the horizon after successful Phase 3 Trial
GlaxoSmithKline (GSK) has completed an initial Phase 3 clinical trial of a new shingles vaccine known as HZ/su with a 97% reduction in the rate of shingles in individuals aged 50 years and older. The study, called ZOE-50, started in 2010 and enrolled 16,000 people from 18 countries. They received two intramuscular injections two months apart.
Shingles is caused by the varicella-zoster virus, the same that causes chickenpox in children. The virus stays dormant in nervous tissues of the body after a chickenpox attack, then reappears in an older age as a painful skin rash with complications such as vision impairment and secondary infections. In the U.S. alone, around a million people are affected every year.
There is only one shingles vaccine on the market, Merck's Zostavax. It was approved in 2006 but only minority of elderly people have been vaccinated. Unlike Zostavax, which is a live attenuated vaccine, HZ/su consists of viral protein gE administered with adjuvant AS01B,1 manufactured by the U.S.-based company Agenus.
“It's great news that the ZOE-50 trial has met its primary endpoint.” said Alain Brecx, Vaccine Development Leader at GSK in a press release. “If approved, this candidate vaccine may offer an important option for the prevention of shingles, a painful disease that negatively impacts peoples’ health and quality of life.”
The ZOE-50 trial was a part of yet a larger study involving 37,000 people with additional focus on immunocompromized people, including solid and haematological cancer patients, haematopoietic stem cell and renal transplant recipients and HIV-infected people. The full Phase 3 results will be announced in the upcoming months.
Breast Cancer Vaccine passes early clinical Trial
A breast cancer vaccine developed at the Washington University School of Medicine in St. Louis proved safe in a Phase 1 trial. Results published in Clinical Cancer Research also suggest that the vaccine might be effective in slowing down cancer progression.
14 patients with metastatic breast cancer reported few side effects after vaccination, and notably around half showed no tumor progression after one year, compared to around 20% in a 12-member unvaccinated control group. These patients had undergone extensive therapy, and their immune systems were weakened as a result. Therefore, researchers plan to conduct a larger trial with patients at the beginning of the treatment whose immune systems are stronger.
The vaccine targets mammaglobin-A, a protein of unknown function found almost exclusively in breast tissue. “Being able to target mammaglobin is exciting because it is expressed broadly in up to 80 percent of breast cancers, but not at meaningful levels in other tissues,” said senior author William Gillanders in a statement. “In theory, this means we could treat a large number of breast cancer patients with potentially fewer side effects.” The vaccine will be ineffective in breast tumors that do not overexpress mammaglobin-A.
Breast cancer is the most common type of invasive cancer in women, accounting for more than one in five cases. Half a million people are estimated to die annually, and the survival rate varies from 80% in high-income countries to 40% in less developed countries, according to WHO.
FDA approved 9‑valent HPV Vaccine for preventing infection that can progress to Cancer
The U.S. Food and Drug Administration approved Merck's Gardasil 9, a recombinant vaccine effective against nine strains of Human Papillomavirus. The vaccine has the potential to prevent ∼90% of cervical, vulvar, vaginal and anal cancers.
Gardasil 9 is administered in a three-dose regimen at months 0, 2 and 6. It is approved for use in females aged 9-26 and males of 9-15 years, and it covers five more strains than its predecessor Gardasil. These five strains cause ∼20% of cervical cancers.
The vaccine's safety was tested on a sample of 13,000 people. The most common adverse reactions were injection-site pain, swelling, redness and headaches.
Efficiency of Gardasil 9 was tested in two age cohorts separately. 14,000 HPV-negative females aged 16-26 were given either Gardasil or Gardasil 9. Both vaccines were equally effective against infections caused by the shared target strains, while Gardasil 9 was 97% effective in preventing cervical, vulvar and vaginal cancers caused by the five additional HPV strains. Efficacy in a younger population was tested in a group of 1,200 males and 2,800 females aged 9-15. Based on immune responses similar to those in older participants, the vaccine is expected to be similarly efficacious in this age group.
There are at least 13 HPV strains that cause cancer, according to WHO. Infection in women frequently leads to the development of cervical cancer that kills almost 300,000 women every year, mostly in low-income countries.
Two PD-1 Inhibitors investigated for treatment of Classical Hodgkin Lymphoma
Two Phase 1 studies of novel immunotherapy of Classical Hodgkin Lymphoma (CHL) were presented at the 56th Annual Meeting of the American Society of Hematology. Use of Pembrolizumab and nivolumab, both PD‑1 inhibitors, gave very promising results in CHL patients who had failed to respond to prior treatment and had relapsed after autologous stem cell transplantation.
PD‑1 inhibitors are immunotherapeutics of growing interest. PD‑1, a T‑cell surface protein, inhibits T‑cell activation. Some cancers exploit this pathway to shut down an immune response that might otherwise prevent tumor growth. PD‑1 inhibitors block PD-1 function and thereby reinforce the T‑cell-mediated immune response.
In the first trial, 29 CHL patients were given pembrolizumab; these subjects had undergone unsuccessful brentuximab + vedotin treatment, and thus had very few remaining treatment options. After twelve weeks, 21% had complete remissions and 45% had partial remissions. One patient discontinued therapy due to side effects, but no serious adverse events were observed.
“These results are quite extraordinary given the dire circumstances these patients were facing,” said Craig Moskowitz of Memorial Sloan Kettering Cancer Center who led the study. “Pembrolizumab has already been approved for patients with advanced melanoma and we are excited that the drug is producing responses in other cancer types.”
In the second trial, 23 CHL patients were treated with nivolumab. 17% had complete responses and 70% partial remissions after 24 weeks. Three serious adverse events were reported. Based on the results, nivolumab was given Breakthrough Therapy Designation by the FDA for relapsed CHL and a Phase 2 study is underway.
Clinical trial shows moderate success of PD-1 Immunotherapy for Triple‑Negative Breast Cancer
New opportunities might soon arise for triple-negative breast cancer (TNBC) patients, according to results of a Phase 1 trial presented at San Antonio Breast Cancer Conference. TNBC accounts for up to 20% of all breast cancers, and is notoriously difficult to treat in that it does not respond to hormonal therapy.
32 patients who entered the trial had advanced TNBC and failed extensive prior treatment. Five subjects (18%) responded with partial (4) or complete (1) remissions to administration of the PD‑1 inhibitor pembrolizumab (Keytruda, Merck), which is approved for advanced melanoma.
“Three of the five responders remained on therapy for 48 weeks or longer,” said Rita Nanda of the University of Chicago, School of Medicine who led the study. “The median progression-free survival was just under two months, and the PFS rate at six months was 23%.”
“Pembrolizumab showed an acceptable safety and tolerability profile,” she added. “While 56% of patients did experience a therapy-related adverse event, the vast majority of these toxicities were easily managed, well tolerated, and did not require treatment discontinuation.” The side effects included fatigue, joint and muscle pain.
Screening for suitable probands, the researchers found that 58% of TNBC patients were positive for PD‑1, suggesting rather broad applicability of pembrolizumab in TNBC treatment. A Phase 2 trial is planned for 2015.
Introduction of 13‑valent Pneumococcal Vaccine correlates with Decrease in Disease
A conjugate vaccine against 13 strains of Streptococcus pneumoniae (PCV13) was introduced in 2010, and the first surveys conducted in the U.S. show that its use is correlated with a drop in pneumococcal diseases. A nationwide study examined antibiotic-resistant invasive pneumococcal disease in children under age five, and found a decline of 62% from 2009 to 2013.The U.S. government's goal to reduce such severe cases to 6 per 100,000 children by 2020 has been met earlier thanks to PCV13—the rate is now only 3.5 cases per 100,000 children.
Researchers at Vanderbilt University analyzed the Tennessee Hospital Discharge Data System and showed that the introduction of PCV13 correlates with a 27% decrease of pneumonia admissions in local hospitals in children under age two. The annual rate is now ∼4 admissions per 1,000 children under age two.
PCV13 replaced the 7‑valent vaccine (PCV7) introduced in 2000, which was itself a big success in causing a 43% improvement in the Tennessee statistic. “We had such a dramatic decline from the first vaccine that we really didn't know how much more effect you would get by adding six more serotypes to the vaccine. So it was very gratifying to see that there was another major drop in pneumonia hospitalizations—a pretty dramatic additional decline,” said Marie Griffin of Health Policy and Medicine at Vanderbilt in a press release.
In the U.S., PCV13 is administered in four doses at 2, 4, 6 and 12‑15 months of age. Three doses are scheduled in European countries. Vaccination is also recommended for adults older than age 65.
S. pneumoniae is the most common vaccine-preventable cause of death in children. Most severe infections occur in children under age two, but also in the elderly. Growing resistance of the bacterium to antibiotics complicates treatment and highlights the need for an effective vaccine to be available worldwide.
HPV Vaccination does not lead to riskier Sexual Behavior
Sexual behavior of teenage girls is not influenced by HPV vaccination, according to a study conducted at McGill and Queen's Universities in Canada. Researchers examined Ontario's administrative health databases to track >260,000 adolescent girls, with half being eligible for Ontario's publicly funded HPV vaccination program at schools. 6% scored positive for clinical indicators of sexual behavior, i.e., pregnancy or non-HPV sexually transmitted infection, but no significant link to receiving the vaccine was observed.
The 4‑valent HPV vaccine, available in almost 100 countries since 2006, prevents infections that can develop into cervical cancer and anogenital warts. In some regions, vaccination utilization is suboptimal due to concerns that it would give young girls a false sense of security. “These findings suggest fears of increased risky sexual behavior following HPV vaccination are unwarranted and should not be a barrier to vaccinating at a young age,” said Leah Smith of McGill University, the corresponding author of the study published in Canadian Medical Association Journal.
The authors would like to see physicians and policy-makers take the results into account when addressing public and parental fears that HPV vaccination may lead to increased promiscuity.
Birch Allergy Vaccine AllerT will enter Phase 3
Swiss biotechnological company Anergis will continue the development of a birch allergy vaccine AllerT after a successful Phase 2 trial. The findings of the study, announced in September, suggested that AllerT has a potential to relieve symptoms of seasonal allergy and create long-term immune memory. As a result, Anergis was able to raise €12 million from existing as well as new investors. The funds will also be used to bring the AllerR ragweed allergy program closer to clinical testing.
“Since the company's COP platform will allow developing products for additional allergy indications, we believe that Anergis’ portfolio has great potential for establishing a new generation of allergy treatments,” Robert Donohue, CEO of one of the investors, said in a statement. The COP (Contiguous Overlapping Peptide) technology imitates the allergen in separate synthetic peptides of up to 80 amino acids. The peptides should elicit immunogenicity without eliciting IgE antibodies responsible for allergic hypersensitivity. Therefore, desensitization to the allergen can be achieved with high doses in a few months as opposed to 3-5 years of conventional therapy.
Anergis will have some competition. The French company Stallergenes and Britain's Circassia are in the process of developing both birch and ragweed vaccines.
PaxVax will seek FDA approval for its Cholera Vaccine
California-based PaxVax will submit a Biologics License Application for Vaxchora, a single-dose cholera vaccine, in mid-2015. The announcement came after a Phase 3 trial, which enrolled 3,000 participants in the U.S. and Australia, met its immunological and safety endpoints.
No vaccine is available for U.S. tourists traveling to high-risk countries. In Europe, J&J's Dukoral and Sanofi's Shanchol are on the market. Both of these vaccines are administered in two doses, and Vaxchora would become the first single-dose vaccine.
“U.S. travelers currently have limited options to protect themselves against cholera, and we are pleased with the progress we are making in bringing an effective single-dose cholera vaccine to travelers and potentially those suffering endemic disease in developing countries in the future,” PaxVax’ CEO Kenneth Kelley said in a press release.
Caused by the Gram-negative bacterium Vibrio cholerae, cholera is an acute diarrheal dehydrating disease that can kill within hours if untreated. Up to 5 million people are infected and >100,000 die annually from cholera. The most important preventive measures are clean-water and sanitation.
Vaxchora is a live attenuated vaccine that consists of a strain already approved and marketed in several countries under the name Orochol. In the course of clinical testing, it proved effective with some side effects, such as physical weakness, abdominal pain and headaches.
Inovio initiating Phase 1 trial for hTERT Cancer Immunotherapy
DNA immunotherapy for breast, lung and pancreatic cancer patients passed preclinical studies and is ready for Phase I, Inovio announced. The hTERT immunotherapeutic INO-1400 is delivered intramuscularly by electroporation and targets the ribonucleoprotein Telomerase, which is aberrantly expressed in 85% of cancers. It elicited strong and broad immune responses in mice and non-human primates, with the potential to eliminate tumor cells and prolonging overall survival.
The study will enroll patients after surgery, chemotherapy or radiation with a high risk of relapse, and divide them into six groups on a dose-escalation basis. The experimental groups will receive either INO-1400 alone or in combination with an adjuvant. The objectives are to assess safety and tolerability, cellular and humoral immune responses and to evaluate the effect on tumor progression.
In the U.S., lung, breast and pancreatic cancers are ranked first, third and fourth, respectively, in mortality rates among cancer types with a combined 230,000 deaths annually. Despite advances in detection and treatment, the majority of patients relapse.
“We are enthusiastic about the potential use of INO-1400 cancer immunotherapy in multiple major cancers, given that hTERT is expressed in the vast majority of cancer types yet is rare in normal cells,” Inovio's CEO Joseph Kim said in a press release.
Powdered Measles Vaccine advances to Phase 2
Measles remains one of the leading causes of death in children according to WHO, with almost 150,000 deaths in 2013. Despite the availability of an effective injectable vaccine, only 84% of infants are immunized in their first year.
A powdered measles vaccine, delivered with a puff of air, successfully completed a Phase 1 study led by Gates Foundation-backed researchers at the Centers for Disease Control and Prevention. The vaccine elicited immune responses with no adverse effects in a sample of 60 healthy measles-immune men, as reported in Vaccine.
A powdered vaccine could be a cheap option for the developing world. “Delivering vaccines in the conventional way, with needle injections, poses some serious challenges, especially in resource-poor parts of the world,” Robert Sievers, a co-author of the study, said in a statement. “[With powdered vaccine,] you don't need to worry about needles; you don't need to worry about reconstituting vaccines with clean water; you don't need to worry about disposal of sharps waste or other vaccine wastage issues; and dry delivery is cheaper.”
The next step will be to evaluate vaccine's effectiveness in people not yet immune to measles as well as in women and children.