Human Vaccines & Immunotherapeutics: News

Abstract

GBM vaccine study: 50% of patients alive after five years

Vaccines prevented 100 million cases of disease in the US during the past 100 years 

Phase 1 data for anti-MUC1 vaccine targeting various cancers 

Bexsero offered to students after meningitis outbreak at Princeton 

Novavax and Novartis announce Phase 1 results for their H7N9 vaccines 

Tuberculosis vaccine helps prevent multiple sclerosis 

Mass vaccination campaign using oral cholera vaccine in Africa

Two doses of Cervarix work as well as three doses in young girls

GBM vaccine study: 50% of patients alive after five years

Researchers from Cedars-Sinai (CA, USA) recently presented promising long-term follow-up results from a Phase 1 clinical study of the brain cancer vaccine ICT-107. Five years after diagnosis of glioblastoma multiforme (GBM) and treatment with the vaccine, 50% of patients were still alive.

The original clinical trial inlcuded 16 patients with GBM, enrolled between May 2007 and January 2010. They received three doses of the vaccine at two-week intervals after standard radiation and chemotherapy. Results published in January 2013 showed a median overall survival (OS) of 38.4 months, a great improvement compared to 15 months median OS with standard of care (SOC), that is tumor-removal surgery followed by radiation and chemotherapy. Median progression-free survival (PFS), the time from treatment to tumor recurrence, was 16.9 months at study‘s end. With standard care, median PFS is about seven months.

At the recent Fourth Quadrennial Meeting of the World Federation of Neuro-Oncology in San Francisco, the research team led by Dr Surasak Phuphanich presented additional new results from their Phase 1 trial. Eight of 16 patients participating in the study survived longer than five years, and seven of them still are living, with length of survival ranging from 61 to 83 months after diagnosis. Six of the patients also were “progression-free” for more than five years, meaning that the tumors did not return or require more treatment during that time. Four participants still remain free of disease with good quality of life. One patient who remained free of brain cancer for five years died of leukemia. Interestingly, all eight long-term survivors had tumors with at least five antigens (targeted by the vaccine), 75% had tumors with all six antigens associated with cancer stem cells—cancer-originating cells that appear to enable tumors to resist radiation and chemotherapy and even regenerate after treatment.

“Our findings suggest that targeting antigens that are highly expressed by cancer stem cells may be a viable strategy for treating patients who have glioblastomas. Long-term remission of disease in this group of patients was correlated with the expression of cancer stem cell tumor-associated antigens,“ said Dr Surasak Phuphanich, professor of neurology at Cedars-Sinai.

The dendritic cell (DC)-based vaccine ICT-107, a product of the biotechnology company ImmunoCellular Therapeutics, is designed to alert the immune system to the existence of cancer cells and activate a tumor-killing response. DCs are isolated from patient’s blood, then cultured in the laboratory with synthetic peptides of six antigens involved in the development of glioblastoma cells. These activated DCs, trained to recognize the tumor antigens as targets, are injected under the patient’s skin and can then seek and destroy lingering tumor cells. ICT-107 is being evaluated in a Phase 2 multicenter, randomized, placebo-controlled trial.

Vaccines prevented 100 million cases of disease in the US during the past 100 years

Over the past century, public health programs—especially vaccination programs —have led to dramatic declines in the incidence of contagious diseases in the United States and most other parts of the world. In fact, vaccination added approxiamtely ten years to the average human lifespan during the 20th century. Scientists at the University of Pittsburgh have recently presented data to further support this view.

Looking at health records going back more than 100 years, the researchers estimated that US childhood vaccine programs have prevented over 100 million cases of disease. They examined reports of seven major infectious diseases (polio, measles, rubella, mumps, hepatitis A, diphtheria, and pertussis) before and after the introduction of the respective vaccines. Introduction of a vaccine was accompanied with a reduction of disease incidence in all cases. Almost two-fifths of the prevented cases were accounted for by the vaccine for diphtheria, which can be explained in part by its longer duration of use compared to the other vaccines included in the study. Before introduction of the diphtheria vaccine, this disease was very common with 237 cases per 100 000 people annually. The study, recently published in The New England Journal of Medicine, makes a very strong case for the importance of vaccines and could help inform the (anti)vaccine debate.

Moreover, more than 100 years of weekly reports on the incidence of notifiable diseases have been digitized in the frame of this research project. These data are available in an open-access database that other researchers can mine.

“Rather than have individual groups work on these data depending on restricted data access, that access can now be expanded to the whole world,“ said Dr Willem van Panhuis, lead author of the NEJM paper.¹ Further investigation of these data may improve our understanding of the rise, spread and interaction of epidemics, which in turn may lead to more effective use of vaccines and other medical counteractions.

Phase 1 data for anti-MUC1 vaccine targeting various cancers

The US-based biotech company Oncothyreon recently presented promising data from an ongoing Phase 1 trial of their therapeutic cancer vaccine ONT-10 in patients with advanced, previously treated malignancies of types associated with the expression of MUC1.

The vaccine targets the tumor-associated antigen MUC1, which is found on many types of malignant tumors, including lung, breast, colorectal, prostate and ovarian cancer. It contains a glycosylated antigen designed to mimic the hypoglycosylated state of tumor-associated MUC1 and intended to stimulate both the humoral and cellular arms of the immune response. In preclinical experiments, administration of ONT-10 produced a strong cellular immune response as well as a robust antibody response, and significant anti-tumor activity. ONT-10 also contains the adjuvant component PET-Lipid A, a fully synthetic toll-like receptor 4 agonist, which was shown to have enhanced potency compared to the adjuvant monophosphoryl lipid A that is in other licensed vaccines.

The current Phase 1 study enrolled 33 patients with advanced maligancies, including ovarian (10), pancreatic (5), endometrial (4), colorectal (4), lung (3), and breast (3) cancers, and who had received extensive prior therapies. ONT-10 was administered weekly (250–1000 ∝g) or biweekly (250–2000 ∝g) over an eight week period. Patients with stable disease for at least twelve weeks after starting treatment with ONT-10 were eligible for a separate maintenance protocol in which the same dose of the vaccine was administered every six weeks until tumor progression. By the end of 2013, 19 patients had entered the maintenance protocol.

ONT-10 has been well tolerated without any dose-limiting toxicity. Thus, patients are currently enrolled in a 2000 ∝g weekly cohort. One trial endpoint was to determine whether ONT-10 stimulates the production of MUC1-specific antibodies, and indeed, IgM and IgG anti-MUC1 antibodies were observed in the majority of patients at titers frequently exceeding 50 000. Furthermore, 31 patients were evaluated for anti-tumor activity by RECIST (Response Evaluation Criteria in Solid Tumors). At the time of first tumor assessment at 9 or 10 weeks, twenty patients (65%) were progression-free, while progressive disease occurred in eleven patients (35%). Eight patients have been progression-free for six months or greater (range 6–18 months).

“Our early experience with ONT-10 is encouraging,” said Dr John Nemunaitis, Executive Medical Director at Mary Crowley Cancer Research Centers, Dallas, Texas and Principal Investigator for this study. “The lack of observed toxicity, the immune response to the vaccine, and the delayed time-to-progression of >6 months in advanced-stage patients are all supportive of the expansion of ONT-10 into later stage trials.”

The data were presented at the recent Annual Meeting of the Society for Immunotherapy of Cancer (SITC) in National Harbor, Maryland.

Bexsero offered to students after meningitis outbreak at Princeton

Meningitis outbreaks at Princeton University in New Jersey and the University of California in Santa Barbara (UCSB) have prompted the US Centers for Disease Control and Prevention (CDC) to take unconventional measures. They have agreed to import the Neisseria meningitidis (meningococcus) serogroup B vaccine Bexsero of Novartis Vaccines, which is approved in Europe and Australia but not in the US, for use in the Princeton University community and potentially also at UCSB.

Over the past eight months, a meningococcal meningits outbreak has slowly spread across Princeton University, with eight cases confirmed to date. The CDC filed an investigational new drug (IND) application to import Novartis‘ vaccine Bexsero from Europe or Australia after the fifth meningitis case was confirmed in early October last year. Princeton University provided the first dose of Bexsero in mid-December to 5268 individuals, representing 91% of the ~5800 University community members who were eligible to receive the vaccine. The second dose of the vaccine will be made available in February, and for those who missed the first shot, catch-up vaccination will be offered in January.

Prior to starting the Princeton vaccination campaign, “open forums” were being held to inform staff and students about meningococcus B and Bexsero. Extensive information was also made available on the university‘s website. Anyone receiving the vaccine had to complete an informed consent form, which was explained to students by CDC staff at the vaccination clinics.

Health officials also are considering to expand the vaccination campaign to UCSB, where at least 4 students contracted meningococcal B disease during November 2013. According to a statement on the CDC’s website, they are prepared to make the vaccine available for UCSB students if necessary; however, most outbreaks of serogroup B meningococcal disease stop at 3 or 4 cases. Although they cannot predict how the UCSB outbreak will develop over the coming weeks and months, the CDC is hopeful that the outbreak has concluded.

Novavax and Novartis announce Phase 1 results for their H7N9 vaccines

The US-based biotech company Novavax became the first group to announce positive Phase 1 clinical data for their virus-like particle (VLP) vaccine candidate against H7N9 influenza virus. Novartis is close behind, presenting recently positive interim results from a Phase 1 trial of its novel cell-culture-based H7N9 vaccine.

Avian-origin influenza H7N9 emerged during March 2013 as a potential pandemic concern, with the first cases reported in China. Since then, many scientists have worked on developing surveillance, diagnostics, and vaccines in the event that the H7N9 virus becomes transmissible among humans. Molecular genetic changes have occurred, suggesting adaptation of the virus to humans. After a quiescent period during the summer months, four new cases of human H7N9 disease were reported in Fall 2013, prompting concerns and expectations over the virus reemerging in human populations in the coming winter season. To date, H7N9 has caused 137 confirmed cases and 45 deaths, which is a very high lethality rate for an influenza virus.

Novavax’ Phase 1 study included 284 adults who received two injections of H7N9 VLP vaccine or placebo on Days 0 and 21. The vaccine was tested in different doses and formulations: 15 or 45 µg of vaccine alone, or 5 or 15 µg of vaccine with either 30 or 60 ISCO units of the saponin-based ICOMATRIX adjuvant, developed by CSL Limited in Australia. Serology was assessed at Days 0, 21, and 35 post-immunization. The safety profile of the vaccine was acceptable across all doses and formulations. The vaccine induced hemagglutination-inhibition (HI) antibody titers of >1:40 (generally equated with seroprotection) and a 4-fold HI antibody rise (seroconversion) against H7N9 in 81% of subjects at the 5∝g dose of antigen with 60 ISCO units of adjuvant. The vaccine also elicited anti-neuraminidase (NA) antibodies against N9 in 92–97% of subjects receiving 5 ∝g with either adjuvant dose level. The study data were published in a letter to The New England Journal of Medicine.²

Novavax obtained the genetic sequence of the H7N9 strain and commenced production of a recombinant vaccine less than 10 days after Chinese health authorities announced an outbreak of this novel influenza virus. Clinical trial material was manufactured and released in late June 2013 with the first doses injected in humans in early July.

“The production and testing of a vaccine for a novel, lethal influenza virus in such a short time period validates the agility of Novavax‘ technology in addressing pandemic threats,“ said Dr Lou Fries, the company‘s Vice President of Clinical and Medical Affairs.

Only slightly behind Novavax, Novartis recently announced positive interim results from a Phase 1 clinical trial in 400 healthy adults for its cell culture vaccine for H7N9. Two doses of 15 ∝g MF59-adjuvanted vaccine elicited a protective immune response in 85% of study subjects, compared to only 6% in those who received 15 µg vaccine without the adjuvant.

The vaccine was produced utilizing full-scale cell-culture manufacturing technology, an alternative technology that can significantly accelerate vaccine production compared to traditional egg-based methods. Along with partners from the Craig Venter Institute, Novartis first synthesized the viral strain several days after it was shared with global researchers by the Chinese Centers for Disease Control. They began producing clinical lots, started trials in August, and initiated large-scale production in October last year.

“This rapid response underscores our leadership position in pandemic preparedness,“ said Dr Andrin Oswald, Division Head, Novartis Vaccines. “Thanks to our investments into innovative production technologies and adjuvants, we are now able to offer a protective solution for a potentially deadly pandemic virus within a few months after the emergence of the H7N9 virus.”

Tuberculosis vaccine helps prevent multiple sclerosis

A lack of exposure to infections early in life has been proposed as one possible factor contributing to the development of multiple sclerosis (MS). If this was true, giving the immune system a light workout could help delay the autoimmune disorder. This idea is supported by a new study from Italy, recently published in the journal Neurology.³

The double-blind, placebo-controlled trial included 73 subjects with early signs of MS, such as imbalance, numbness and vision problems. One dose of the tuberculosis vaccine Bacille Calmette-Guérin (BCG) was administered to 33 subjects, while the rest of the subjects received a placebo. Following vaccination, participants were monitored monthly with brain magnetic resonance imaging (MRI) for 6 months. During these 6 months, the number of cumulative lesions was significantly lower in vaccinated subjects. After 60 months, 58% of vaccinees had not developed MS, compared to 30% in the placebo group. Looking at the typical course of disease, within 2 years of showing symptoms 50% of patients develop clinically definite MS, while 10% remain unchanged.

The study authors led by Dr Marco Salvetti from the Sapienza University of Rome (Italy) concluded that early BCG may benefit clinically isolated syndrome (potential initial stage of MS) and affect its long-term course. The trial is only small and far from conclusive, but it has caught the attention of MS researchers.

Dr Susan Kohlhaas, MS Society‘s head of biomedical research, told the BBC: “Ultimately, the chance to take a safe and effective preventative treatment after a first MS-like attack would be a huge step forward.“ Larger studies are needed to show whether BCG vaccine (or other well-tolerated vaccines) can indeed help prevent or delay the switch from early signs of MS to full-blown disease.

Mass vaccination campaign using oral cholera vaccine in Africa

A recent study published in PLoS Neglected Tropical Diseases⁴ looked at vaccination coverage, acceptibility and surveillance of adverse events in the first mass vaccination campaign using two doses of the oral cholera vaccine (OCV) Shanchol as an additional control measure to respond to the ongoing nationwide epidemic in Guinea. Past concerns about the acceptibility, potential diversion of resources, as well as cost and feasibility of implementing timely vaccination campaigns have discouraged the use of two safe and effective OCVs, both of which were prequalified by the World Health Organization (WHO).

The mass vaccination campaign in Guinea, organized in 2012 by the Ministry of Health of Guinea with the support of Médecins Sans Frontières, included individuals older than 12 months, eligible for vaccination, and residing in the areas targeted for vaccination (Forécariah and Boffa, Guinea). Overall, 316 250 vaccine doses were delivered. The international team of researchers performed a cross-sectional cluster survey and implemented adverse event surveillance. Data sources were household interviews with verification by vaccination card and notifications of adverse events from surveillance at vaccination posts and health centres. In total, 5248 people were included in the survey (3.993 in Boffa and 1255 in Forécariah). In Boffa, 89% and 80% were vaccinated during the first and second round, respectively. In Forécariah, the corresponding numbers were 88% and 83%. The two-dose vaccine coverage (including card and oral reporting) was ~76% in both Boffa and Forécariah. Vaccination coverage was found to be higher in children, and the main reason for non-vaccination was absence. No severe adverse events were reported.

Shanchol was used for the first time in a mass vaccination campaign on the African continent. The study shows that the campaign was well-accepted and reached a high level of coverage in a remote area with a mobile population. The authors concluded that although OCVs should not be foreseen as the long-term solution for global cholera control, they should be integrated as an additional tool into the outbreak response strategies.

Two doses of Cervarix work as well as three doses in young girls

GlaxoSmithKline (GSK) recently reported results of a Phase 3 study of its human papilloma virus (HPV) vaccine Cervarix, showing that two doses of the vaccine in girls aged 9–14 years provide a level of immunogenicity matching the currently licensed three-dose schedule in 15–25-year-olds. The simplified dosing regimen could make it easier to implement national immunization programmes against HPV infection.

The randomized Phase 3 study included 1447 girls between 9 and 25 years of age in five countries. A group of girls aged 9–14 years received Cervarix in a two-dose schedule, which was compared to another group of 15–25-year-olds who received three doses. Immune responses to and safety profile of the vaccine were found to be comparable in these groups. Study results were presented at the recent EUROGIN conference in Florence (Italy).

In the US and the EU, Cervarix is approved for females 9 years and older for the prevention of premalignant genital (cervical, vulvar, and vaginal) lesions and cervical cancer causally related to certain oncogenic HPV types. The vaccine is administered according to a three-dose schedule (0, 1, and 6 months). In August 2013, a variation to the current Marketing Authorization was submitted to the European Medicines Agency (EMA), suggesting use of a two-dose schedule (0 and 6 months) in girls aged 9–14 years. Several countries have adopted the two-dose schedule for this age group, including Guatemala, Honduras, El Salvador, Haiti, Suriname, Chile, Guyana, Nigeria, and Ghana.

Thomas Breuer, senior vice president and lead physician at GSK’s vaccines unit, called the endorsement by the Committee for Medicinal Products for Human Use (CHMP) “another major milestone in our commitment to reducing the global burden of cervical cancer, which remains high”. He added that many countries are unable to implement national immunization programs in young adults with high coverage, so having access to a simpler regimen could help expand the population that will benefit from protection.

Merck & Co also reported data last year suggesting that two-doses of its own HPV vaccine Gardasil could be effective in younger females.