Human Vaccines & Immunotherapeutics

Abstract

Efficacy and safety of first-ever Dengue vaccine candidate in Phase 3

Agenus‘ brain cancer vaccine doubles survival rate in GBM patients

New study: Rotavirus vaccines dramatically cut hospitalization rates in US children

Therapeutic vaccines – from heart disease to cancer

Agenus‘ genital herpes vaccine significantly reduces viral burden in Phase 2

The latest on PaxVax‘ and Gotovax AB’s cholera vaccine candidates

ACIP ponders recommendation for Prevnar use in seniors

Efficacy and safety of first-ever Dengue vaccine candidate in Phase 3

Sanofi Pasteur, the vaccine division of Sanofi, recently announced positive efficacy data from the first Phase 3 trial of of any Dengue vaccine. Detailed results, published in the journal The Lancet,¹ showed overall efficacy against symptomatic dengue of 56.5% in children aged 2–14 y, with an 88.5% reduction in hemorrhagic fever, a severe form of the disease.

Dengue is caused by four distinct virus serotypes transmitted by mosquitoes. Nearly half of the world's population is at risk of contracting dengue. The World Health Organization (WHO) estimates up to 100 million infections per year. However, dengue is probably underreported, often being misdiagnosed due to a large spectrum of clinical symptoms from mild non-specific illness to life threatening complications and due to the limitations of surveillance systems. There is no specific treatment. Sanofi has been working on a dengue vaccine for > 20 y. While other companies like GlaxoSmithKline and Merck are also developing dengue vaccines, Sanofi`s candidate is the only one in Phase 3.

The randomized, observer-blind, placebo-controlled multicenter Phase 3 clinical trial included 10,275 children aged 2–14 y from dengue-endemic areas of Indonesia, Malaysia, Philippines, Thailand and Vietnam. They were randomized to receive three injections of vaccine or placebo at 0–6-12 mo. The primary endpoint was measured by the number of symptomatic virologically-confirmed dengue cases caused by any serotype. Long-term follow-up of the study population is planned until 2017.

The vaccine showed an overall efficacy against symptomatic dengue of 56.5%. Hemorrhagic fever, the severe form of dengue, was reduced by 88.5%. The risk of hospitalization due to dengue was reduced by 67% during the study. Moreover, the vaccine was found to be safe, confirming the findings of previous clinical studies. On a closer look, the measured efficacy of the vaccine seems to vary by dengue serotype and by age. While the vaccine performed well against variants 1, 3 and 4, it was only 35% efficacious against serotype 2. Vaccine efficacy increased with age, with the youngest subjects gaining the least benefit.

Sanofi expects the results of a second Phase 3 trial in Latin America and the Caribbean, including > 200.000 children and adolescents, later this year, likely to be followed by filing for regulatory approval.

“These pivotal Phase 3 vaccine efficacy study results take us closer to our ambition to bring the first vaccine against dengue to the world,” said Dr John Shiver, Senior Vice President, R&D at Sanofi Pasteur. “After more than 20 years of commitment in collaboration with the scientific community, we are on course to make dengue the next vaccine-preventable disease. The public-health implications of a future dengue vaccine are significant and these findings are an important stride towards meeting the WHO's strategic goals of reducing dengue mortality by half and morbidity by at least 25% by 2020.”

Agenus‘ brain cancer vaccine doubles survival rate in GBM patients

Agenus Inc. recently announced promising results from a Phase 2 study of its autologous cancer vaccine Prophage. Given together with the standard of care (SOC) treatment, Prophage nearly doubled the expected lifespan of newly diagnosed glioblastoma multiforme (GBM) patients. 50% of patients lived for two years, which is an encouraging result for a cancer that usually kills patients within one year. Median overall survival (OS) of Prophage patients was ~24 mo, and 33% of patients were alive at two years and continue to be followed for survival.

The autologous cancer vaccine Prophage is prepared individually for each patient from their own surgically resected tumor. Since most cancers result from an accumulation of random mutations, which produce different mutant proteins in each patient, this approach is intended to individually tailor each patient's vaccine to optimally target the immune attack to that patient's actual tumor. Moreover, the design of Prophage should cause fewer side effects than conventional therapies such as chemotherapy or radiation therapy. Prophage Series vaccines are based on Agenus' heat shock protein platform technology.

Prophage was tested in a Phase 2 single-arm, multi-institutional, open-label trial in 46 patients with newly diagnosed GBM. Patients were treated with surgical resection, radiation and temozolomide as the SOC in addition to Prophage vaccination. Analyses of data collected to date showed that > 50% of vaccinated patients were alive at two years, compared with 26% of patients treated with SOC only. Median OS was 24 mo and remained durable in Prophage patients. Median OS survival rate for SOC alone was 15 mo. In addition to the long-term survival data, vaccinated patients had a median progression-free survival (PFS) of ~18 mo, which is ~2–3X longer than patients treated with SOC. Nearly 22% of patients were alive without and without progression at 24 mo and continue to be followed for survival.

“These data suggest that Prophage is generating an effective immune response which is translating into an extension in survival far beyond what is historically seen in patients with GBM. These data provide the impetus for a definitive, randomized clinical trial,” said Dr Andrew Parsa from the Feinberg School of Medicine at Northwestern University, Principal Investigator of the study. “Glioblastoma tumors are often resistant to standard therapies and the extended progression-free survival and proportion of long-term survivors is very encouraging.”

Interestingly, the response to Prophage seems to be more pronounced in those patients with less expression of the checkpoint ligand PDL-1 on the white blood cells, suggesting that combinations of Prophage with checkpoint modulators like PD-1 antagonists might make Prophage even more effective in a greater percentage of patients with GBM.

“We believe that Prophage may play an important role in changing the treatment paradigm for patients with GBM,” said Garo Armen PhD, CEO and chairman of Agenus Inc. “We are exploring partnerships for Phase 3 studies of Prophage in GBM. Additionally, we are excited about the potential combinations of Prophage with PD-1 antagonists and other checkpoint modulators in GBM.”

GBM is the most common primary malignant brain tumor and accounts for the majority of diagnoses. It has been associated with a particularly poor prognosis, with survival rates at one and five years of 34% and 5% respectively. Current treatment options for recurrent GBM include surgery, chemotherapy, bevacizumab and radiotherapy. These treatments can prolong survival are not curativ, and the vast majority of GBM patients experience recurrent disease with a median time to recurrence of 7 mo.

New study: Rotavirus vaccines dramatically cut hospitalization rates in US children

According to a new study in the journal Pediatrics,² the implementation of rotavirus (RV) vaccines RotaTeq (RV5; Merck) and Rotarix (RV1; GSK) has substantially reduced diarrhea health care utilization in US children. Since the US Advisory Committee on Immunization Practices (ACIP) recommended RV vaccination for all children in 2006, the number of children hospitalized for RV-related diarrhea has plunged.

The study authors set out to examine reductions in diarrhea-associated health care utilization after rotavirus vaccine implementation and to assess direct and indirect effectiveness of RV vaccination. To this end, they performed a retrospective cohort analysis of claims data of commercially-insured US children under age five. RV vaccine coverage was examined, and rates of diarrhea-associated health care utilization in prevaccine (2001–6) vs. postvaccine introduction (2007–11) years were compared.The researchers also compared rates of diarrhea-associated health care utilization in vaccinated vs. unvaccinated children and compared rates in unvaccinated children in post- vs. pre-vaccine years.

The authors found that among 400,000 children from 37 states, 64% of those less than one year old had been vaccinated in 2007, and the number rose to 78% by 2010. Looking at all children under age five, RV5 and RV1 coverage rates reached 58% and 5%, respectively, by the end of 2010. Compared with pre-vaccine years, RV hospitalization rates were reduced by 75% in 2007–8, 60% in 2008–9, 94% in 2009–10, and 80% in 2010–1. Compared with unvaccinated children in 2010–1, the rate of RV-coded hospitalizations was reduced by 92% among RV5 recipients and 96% among RV1 recipients. In other words, RV5 and RV1 helped avoid 177.000 hospitalizations, 242.000 visits to the ER, and > 1 million outpatient visits for diarrhea amoung children younger than 5 y. The authors estimate that RV vaccination saved $924 million saved for the US healthcare system. Compared with prevaccine rates in 2001–2006, RV-coded hospitalization rates among unvaccinated children decreased by 50% in 2007–2008, 77% in 2009–2010, and 25% in 2010–2011. These results clearly suggest a herd-immunity effect.

“One of the interesting findings we had was in one of the later years we saw a 94% decrease in hospitalization; rotavirus had practically disappeared in 2010,” lead author Dr Eyal Leshem, of the CDC, told Reuters. “This is attributed to good vaccine effectiveness and high coverage.”

Therapeutic vaccines – from heart disease to cancer

In recent years, vaccine R&D has extended well beyond the prevention of infectious diseases. Immunotherapeutic approaches for cancer, autoimmunity, inflammation, allergy, Alzheimer and addiction are being extensively studied.

One example is the world`s first vaccine for heart disease, which is being developed at the La Jolla Institute for Allergy and Immunology. About 600,000 US Americans die of heart disease every year. Besides cholesterol, inflammation is an important contributing factor to arterial plaque building, which eventually leads to heart disease. Researchers led by Dr Klaus Ley demonstrated that their candidate vaccine significantly reduced arterial plaque buildup in a mouse model of disease.

Dr Ley had found that CD4⁺ T cells orchestrate the inflammatory attack on the artery wall by receiving antigen-specific signals from other inflammatory cells in the vessel wall. These immune cells behaved as if they had seen the antigen that causes them to launch the attack. This discovery suggested that the immune cells had „memory“ of the molecule brought forth by the antigen-presenting cells.

“Immune memory is the underlying basis of successful vaccines,” he explained. “This meant that conceptually it was possible to consider the development of a vaccine for heart disease.”

The vaccine against heart disease is based on two peptides derived from apolipoprotein B, which prompt the arterial attack in mice – the byproduct of which is inflammation. The idea is that gradual exposure to the vaccine can teach the body to tolerate rather than attack those proteins. Mice treated with the peptide based vaccine had ~40% less arterial plaque than mice that did not receive the vaccine. Study results were published in a recent issue of the journal Frontiers in Immunology.³

If successful, the vaccine could be given to aid in preventing recurring heart disease and to stop or reduce disease progression. In addition to heart disease, the vaccine could target strokes, which are also fueled by plaque buildup in the arteries. Nevertheless, immunization with this self-antigen will necessitate rigorous observations of the safety of this candidate vaccine.

Another very active field of research is the development of therapeutic vaccines for the treatment of various cancers. Madison Vaccines Inc. (MVI) recently announced the expansion of a Phase 2 trial of its lead product candidate MVI-816, a DNA-based vaccine for treating prostate cancer. The original cohort included 56 non-metastatic prostate cancer patients who had rising levels of prostate-specific antigen (PSA) after their primary treatment (surgery or radiation), but before patients required androgen deprivation therapy (castration therapy). Now another 50 patients will be added to obtain more robust results. The aim of the study is seeking clinical evidence that MVI-816 can delay the onset of metastatic disease

“Our goal is to help men with recurrent prostate cancer live longer with a better quality of life,” said Dr Richard Lesniewski, President of MVI. “The expansion of this Phase 2 trial represents a significant step forward for our young company and advances our efforts to establish clinical proof of concept toward a safe and approvable immune activation therapy for men with prostate cancer at this crucial stage of their disease.”

MVI-816 targets prostatic acid phosphatase (PAP), a well-defined prostate antigen. The plasmid DNA vaccine can be delivered to patients by simple intradermal injection, is readily manufactured and highly stable.

PsiOxus Therapeutics, another biotech company working on new treatments for cancer, recently initiated a Phase 1/2 clinical trial to assess the safety and efficacy of its oncolytic vaccine enadenotucirev in platinum-resistant ovarian cancer patients (OCTAVE study).

Enadenotucirev, originally developed using a directed evolution process with the aim of generating an entirely novel virus with optimised cancer-lytic properties, has been shown to have little or no activity in normal cells while keeping a very high level of anti-cancer potency. Besides assessing how effective intraperitoneal enadenotucirev is for treating ovarian cancer, PsiOxus is also carrying out clinical studies evaluating its safety and efficacy via intravenous injection in patients with colorectal cancer.

In the OCTAVE study, the vaccine will be administered directly into the abdomen (intra-peritoneally) of cancer patients, where ovarian cancer tends to recur. The Phase 1 component of the trial will determine the dose of enadenotucirev to be used alone or in combination with paclitaxel. The Phase 2 component will be an open-label dose expansion of the combination regimen of enadenotucirev and paclitaxel to determine whether this combination has a risk benefit profile that supports further investigation in the treatment of patients with platinum-resistant epithelial ovarian cancer.

PsiOxus CEO Dr John Beadle commented: “Our enadenotucirev oncolytic vaccine has enormous potential to treat a broad spectrum of solid cancer types and starting this OCTAVE study is a key milestone as we progress towards demonstrating its effectiveness in a second form of cancer with a very significant unmet medical need.”

Agenus‘ genital herpes vaccine significantly reduces viral burden in Phase 2

Agenus Inc. recently announced promising Phase 2 results for HerpV, a vaccine candidate for the treatment of subjects with genital Herpes Simplex Virus-2 (HSV-2). HerpV induced a significant reduction in viral load that correlated with CD8 T-cell activation.

HerpV is a recombinant therapeutic vaccine based on Agenus' Heat Shock Protein (HSP) platform technology and contains the company‘s proprietary plant-derived adjuvant QS-21. HerpV consists of recombinant human HSP-70 complexed with 32 distinct 35-mer synthetic peptides from the HSV-2 proteome. This broad spectrum of HSV antigens is intended to enable more accurate immune targeting and surveillance, reducing the likelihood of immune escape. Furthermore, the diversity of antigens in HerpV increases the chance of providing efficacy for a wide segment of the patient population.

The randomized, double-blind, Phase 2 multi-center trial included 80 subjects with a history of 1–9 herpes recurrences within the prior 12 mo. Three injections of HerpV (70 subjects) or placebo (10 subjects) were administered at 2-wk intervals, and a booster dose was given at Month 6. HSV-2 activity in the genito-urinary tract was monitored by PCR for HSV-2 DNA in genital swabs for 45 d before and after the initial course of three vaccinations. Primary endpoint results reported in November 2013 showed a 15% reduction in viral shedding in the vaccinated group, while viral load was reduced by 34% in the vaccinated group with no reduction in the placebo group. Secondary analysis after the booster dose showed that > 50% of vaccinated subjects developed a robust anti-HSV cytoxic T-cell response, and in those patients there was a statistically significant 75% reduction in viral load. This level of reduction in viral load has the potential to result in reduced incidence and severity of herpetic outbreaks and a reduction in viral transmission. Viral shedding was durably reduced by 14% after the booster injection with HerpV and remained consistent with the reduction in viral shedding observed during the initial treatment period. Reported adverse events were short-lived and included flu-like symptoms and injection-site reactions. Patients continue to be followed for safety and long-term immune response.

“We are pleased that the cellular immune response observed with HerpV vaccination is associated with a significant reduction in viral replication in the genital tract,” said Dr Robert Stein, Chief Scientific Officer of Agenus. “The fact that our vaccine contains multiple HSV-2 antigens may contribute to its desired effects. We look forward to advancing discussions with potential partners to take this program into the next phase of clinical research.”

According to the Centers for Disease Control and Prevention, about one in six Americans between 14 and 49 y is infected with HSV-2. Two-thirds of the population that gets herpes is ≤ 25 y. The lifelong and incurable infection with HSV-2 can cause recurrent and painful genital sores. Herpes is the fastest growing sexually transmitted disease in US.

The latest on PaxVax‘ and Gotovax AB’s cholera vaccine candidates

PaxVax Inc. recently announced positive efficacy results from a Phase 3 cholera challenge study. The single-dose oral cholera vaccine candidate PXVX0200 was highly effective in preventing disease in vaccinated subjects following a challenge with wild-type pathogenic cholera bacteria. On an other note, Hilleman Laboratories announced a strategic collaboration with Gotovax AB to develop a next-generation oral cholera vaccine.

Cholera is an acute intestinal diarrheal infection caused by toxigenic Vibrio cholerae bacteria generally acquired by ingesting contaminated water or food. According to WHO, the global disease burden is estimated to be 3–5 million cases and 100–130,000 deaths per year. Cholera often manifests as explosive epidemics that rapidly move through populations, e.g., the outbreak in Haiti in 2010.

While current cholera vaccines are given in two doses, PXVX0200 has been developed as a single-dose vaccine. It utilizes the same attenuated vaccine strain (CVD103-HgR) that was previously marketed under the brand name Orochol. The current randomized double-blind placebo-controlled Phase 3 challenge study included healthy adults. They received one oral dose of PXVX0200 or placebo, who then ingested V. cholerae O1 El Tor. Subjects were divided in two groups – the first was challenged 10 d following vaccination, and the second 90 d following vaccination to evaluate duration of protection. Trial investigators compared the rate of diarrhea in vaccinated subjects to the rate in the placebo group.

Efficacy in the 10-d group was ~90%: 2 of 35 vaccinees developed diarrhea compared with 39 of 66 placebo recipients. Efficacy in the 90-d group was almost 80%, with 4 of 33 vaccinees experiencing diarrhea compared with 39 of 66 placebo recipients.

Study Investigator Dr Beth Kirkpatrick (University of Vermont) commented: “The 90-day challenge results are very encouraging and provide important new data that further support the efficacy of PXVX0200 in protecting people exposed to cholera. If approved, PXVX0200 has the potential to provide an effective new single-dose option for people living in and travelling to areas where cholera is endemic.”

In addition to the 10- and 90-d cholera challenge studies, immunogenicity, safety, and lot-to-lot consistency of the PXVX0200 cholera vaccine are being evaluated in a broader population (~3,000 subjects) at study sites in Australia, Canada, and US.

Another cholera vaccine candidate is being developed by Gotovax in collaboration with Hilleman Laboratories. Gotovax AB and partners developed an internationally widely licensed oral vaccine against V. cholerae and enterotoxigenic Escherichia coli (ETEC)-induced diarrhea (Dukoral).

Prof Jan Holmgren, CEO of Gotovax and Director of the University of Gothenburg Vaccine Research Institute, explained “Cholera is caused from enteric infection with the bacterium V. cholerae primarily (~99%) of the O1 serotype. By transferring a functional wbeT methyl transferase gene into the genome of an O1 Inaba strain we have created a resulting ‚Hikojima‘ strain that stably expresses both the Ogawa and Inaba serotype antigens on its surface; thus improving the stability and efficacy of the vaccine candidate as well as significantly reducing the cost of production.”

Hilleman Laboratories gains world-wide exclusive rights to the vaccine candidate under the agreement with Gotovax. The not-for profit Hilleman Laboratories (a joint venture partnership between Merck and Co and the Wellcome Trust) will develop the vaccine and be responsible for conducting clinical studies toward successful licensure and commercialization. Hilleman Laboratories aim to deliver the vaccine at a more affordable price than currently vaccines. Moreover, it will be easy to administer, with cross protection against ETEC diarrhea and enhanced with a longer shelf life, making this vaccine candidate most suited for geographies with the highest cholera burden like Africa and South Asia.

ACIP ponders recommendation for Prevnar use in seniors

The Advisory Committee on Immunization Practices (ACIP) recently convened to discuss the use of Pfizer’s pneumococcal polysaccharide conjugate vaccine Prevnar 13 in adults ≥ 65 y. The committee came to the conclusion that immunizing seniors with Prevnar 13 is cost-effective in the short-term, but maybe not in the long-term. The final decision and potential recommendation is expected for ACIP’s October meeting.

Prevnar is the top-selling vaccine in the world, and used primarily in children. Earlier this year, data from the CAPiTA trial showed that the vaccine is also efficacious in adults ≥ 65 y, leading to the licensing of Prevnar 13 for this age group. But ACIP recommendation is key for expansion in the 65⁺ age group – without it, physicians generally will not use vaccines and many payers will not cover them.

Because Prevnar 13 is recommended for all children, fewer adults suffer from infections with the 13 serotypes contained in the vaccine,. This herd immunity effect is the reason that ACIP is hesitant to recommend Prevnar 13 for use in older adults. Over the next years, the effect will expand to protect more and more adults.

ISI group analyst Mark Schoenbaum explained: “This vaccine clearly works. Any person who gets it will have a lower chance of getting the infection. But if the chance of getting the infection at baseline without the vaccine is very, very, very low, as it appears it may be after herd immunity fully kicks in, the cost effectiveness of giving Prevnar to all adults over 65 years old isn't there, according to this committee [ACIP].”

One possible solution would be to recommend the vaccine for older adults at least for the near term. “Given ACIP's opinion that the vaccine is clearly cost effective over the short term, it's hard for me to understand how the committee could not recommend universal use at least over the next few years,” Schoenbaum noted.