Two new combination pediatric vaccines advancing to use in infants
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GlaxoSmithKline's MenHibrix vaccine against *Neisseria meningitidis* (meningococcal disease) serogroups C and Y and *Haemophilus influenzae* type b (Hib) has been approved by the US Food and Drug Administration (FDA) for use in infants and toddlers.

MenHibrix will be used against *N. meningitidis* serogroups C and Y and *H. influenzae*type *b*, both of which can cause life threatening complications like sepsis if they infect the bloodstream and meningitis if they infect the lining of the brain. The vaccine will be administered as a four-dose series every other month from two to six months and sometime between 12 to 18 months of age. According to Dr Karen Midthun, director of the FDA's Center for Biologics Evaluation and Research, MenHibrix vaccine is the first of its kind that can be given to infants as young as six weeks old. It also is the first vaccine to target menigitis caused by two different types of bacteria.

The safety of MenHibrix was evaluated in 7,500 infants and toddlers in the US, Mexico and Australia. Adverse reactions included pain, redness and swelling at the injection site, irritability and fever, according to the FDA statement.

The next important step for MenHibrix will come in October this year, when the Centers for Disease Control's advisory committee on immunization practices (ACIP) is expected to vote on whether to recommend the vaccine for routine pediatric use.

Also recently, another pediatric vaccine, Sanofi Pasteur's Hexaxim (DTaP-IPV-Hib-HepB vaccine) has received a positive scientific opinion from the European Medicines Agency (EMA), as part of a procedure designed to evaluate medicinal products intended for markets outside the European Union.

Hexaxim is the only fully liquid, ready to use 6-in-1 vaccine to protect infants against diphtheria, tetanus, pertussis (whooping cough), Hepatitis B, poliomyelitis and invasive infections caused by *Haemophilus influenzae*type*b*.

"A 6-in-1 pediatric vaccine reduces the number of vaccination visits for infants. It is more convenient for parents to complete the recommended vaccination schedule and thus better protect their children against 6 major childhood diseases," said Dr Pio Lopez, Pediatrician, Infectologist and principal investigator for a clinical study of the vaccine in Colombia. "Hexaxim also includes inactivated poliovirus vaccine, which is an important step to ensure communities remain polio-free."

The EMA assessment was conducted with the participation of experts from the World Health Organization (WHO) according to the same quality, safety and efficacy criteria as vaccines authorized for the European Union. Many countries in Latin America, Africa, the Middle East and Asia grant market authorization based on the EMA scientific opinion.

The EMA positive opinion is supported by results of multi-center clinical studies involving approximately 4,000 infants in Argentina, Peru, Mexico, South Africa, and Thailand. Phase 3 clinical studies comparing Hexaxim to licensed combination vaccines demonstrated that Hexaxim is safe and induces a robust immune response against the six targeted diseases.

"Our goal is to provide access to children throughout the world to the same standard of care for childhood immunization. Availability of Hexaxim ready to use 6-in-1 pediatric vaccine will raise the standard of care of vaccination for millions of children," said Dr. Olivier Charmeil, President and CEO of Sanofi Pasteur. "Upon licensure we intend to introduce Hexaxim in countries looking for improved and effective solutions in particular for public immunization programs."

Oncolytic viruses successfully delivered intravenously
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Oncolytic viruses, which preferentially lyse cancer cells and stimulate an antitumor immune response, represent a promising approach to the treatment of cancer. A new clinical study sheds light on how they evade the antiviral immune response and their selective delivery to, and replication in, tumor tissue.

Reovirus has been demonstrated to have oncolytic properties; this has encouraged the development of reovirus-based therapies for cancer treatment. The virus attacks the disease on two fronts; not only does the virus kill cancer cells directly, but it also triggers an immune response---like a vaccine---that helps eliminate residual cancer cells. Until now, experts have not been sure about the best way to deliver the experimental treatment. The virus can be injected directly into tumors, but this is a relatively complicated procedure requiring significant technical expertise and makes it difficult to treat tumors deep within the body, such as in liver, lungs, pancreas and stomach. Intravenous delivery has been believed to be problematic; researchers had been concerned that antibodies in the blood would neutralize the reovirus before it could reach the tumor. But a new study in a small group of patients has shown that this is not the case, as recently published in the journal *Science Translational Medicine*.^1^

Researchers from the University of Leeds (Leeds, UK) and The Institute of Cancer Resarch (ICR; London, UK) treated 10 patients with up to five doses of intravenous reovirus before planned surgery to resect colorectal cancer metastases in the liver. Blood tests carried out shortly after treatment found the active virus associated with blood cells. Samples taken later showed that the hitch-hiking virus did not overstay its welcome with the cells and was cleared from the system quickly. When researchers looked at pieces of tissue removed during surgery up to four weeks later, they found "viral factories" and active virus in the tumor, but not normal liver. These results suggest that the reovirus had been delivered specifically to the cancer after being injected into the bloodstream.

Senior study author Dr Alan Melcher from the University of Leeds said: "It seems that reovirus is even more clever than we had thought. By piggybacking on blood cells, the virus is managing to hide from the body's natural immune response and reach its target intact. This could be hugely significant for the uptake of viral therapies like this in clinical practice."

And Dr Kevin Harrington from the ICR, who jointly led the study with Dr Melcher, stated: "Viral treatments like reovirus are showing real promise in patient trials. This study gives us the very good news that it should be possible to deliver these treatments with a simple injection into the bloodstream. It would have been a significant barrier to their widespread use if they could only have been injected into the tumor, but the finding that they can hitch a ride on blood cells will potentially make them relevant to a broad range of cancers. We also confirmed that reovirus was specifically targeting cancer cells and leaving normal cells alone, which we hope should mean fewer side-effects for patients."

### Reference

1\. Adair RA , et al. Sci Transl Med 2012; 4:138ra77.

Cuba eliminates hepatitis B among minors under 15
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According to recent reports in Cuba's state media, the country has eliminated viral hepatitis B in people under 15 years of age thanks to a massive immunization campaign with the locally developed vaccine Herberbiovac HB.

The vaccine was produced by the Center of Genetic Engineering and Biotechnology in Havana. Since 1992 every Cuban newborn has been immunized with Herberbiovac HB. Students, health staff and dialysis patients deemed vulnerable to the virus were also vaccinated. According to Maria Fonte Reyes, an expert in hygiene and epidemiology at the Health Ministry, the country has not reported any cases of hepatitis B disease in people under 15 years of age for the last 23 years. Compared to 1989, the number of hepatitis B cases in the country has dropped by 99% to only 21 cases by the end of 2011. Those infected are all aged 30 and above.

Hepatitis B virus is spread through contact with human fluids such as blood and semen and is one of the five identified viruses that causes liver inflammation and may lead to chronic hepatic diseases, including cirrhosis and cancer.

The biotech center in Havana exports the hepatitis B vaccine to many countries. In recent years, Cuba's immunization programs have successfully produced a number of vaccines against infectious diseases such as pneumonia, meningitis, diphtheria, pertussis and dengue. Some deem the greatest achievement in the country's medical biotech development to be the CimaVax-EGF vaccine for lung cancer, which is said to be the only one of its kind in the world and has been exported to over 40 countries.

Alzheimer's vaccine trial a success
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A new study led by researchers from the Karolinska Institute (Sweden) reports for the first time the positive effects of an active vaccine against Alzheimer's disease (AD). The new vaccine CAD106 was tested in a Phase 1 clinical trial, results of which were recently published in the journal *Lancet Neurology*.^1^

AD is a complex neurological dementia disease that causes much human suffering and great cost to society. According to the World Health Organisation (WHO), dementia is the fastest growing global health epidemic of our age. The disease is believed to be caused by amyloid precursor protein (APP), which resides in the outer membrane of nerve cells. Instead of being broken down, APP forms a harmful substance called beta-amyloid (Aβ), which accumulates as plaques and kills brain cells.

Current drugs can only mitigate the symptoms. In the hunt for a cure, scientists are following several tracks, of which vaccination may be the most popular. The first human vaccination study, performed almost a decade ago, had to be discontinued due to too many severe adverse reactions. The vaccine used in that study activated a certain type of T-cells that started to attack the body's own brain tissue. In contrast, the new treatment involves active immunization using a type of vaccine designed to trigger the body's immune defense against Aβ . The vaccine was modified to affect only the harmful Aβ .

The double-blind, placebo-controlled Phase 1 study was performed in two centers in Sweden and included 58 participants aged 50 to 80 years with mild-to-moderate AD. Patients received three subcutaneous injections of CAD106 (50 µg or 150 µg) or placebo. Primary objectives were to assess the safety and tolerability of CAD106 and to identify the Aβ-specific antibody response. The researchers found that 80% of the patients involved in the trials developed their own antibodies against Aβ without suffering any side-effects over the three years of the study. These results suggest that the CAD106 vaccine is a tolerable treatment for patients with mild to moderate AD. Larger trials need to be conducted to confirm the CAD106 vaccine's efficacy.

### Reference

1\. Winblad B, et al. Lancet Neurol 2012; 11:597-604.

Study: Shingles vaccine safe for patients on immune-suppressing drugs
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According to a new study, there is no risk for shingles among people with rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis or inflammatory bowel disease who have been treated with biologic medicines and receive the shingles vaccine.

Shingles is a painful but common condition that affects half of Americans by the age of 85 years. The disease is caused by varicella zoster virus---the same virus that causes chickenpox. Anyone who has had chickenpox is susceptible to developing shingles because the virus remains in the body's nerve cells after the chickenpox clears, and can later reactivate as shingles.

The Center for Disease Control's (CDC) Advisory Committee on Immunization Practices (ACIP) recommends that all adults aged 60 years and older should receive a vaccine against shingles, except for people who are being treated with immune suppressing drugs (biologics), which control how the body reacts to inflammation in a variety of conditions such as rheumatoid arthritis and psoriasis. Researchers worried that exposing people with weakened immune systems to a live virus vaccine, like the shingles vaccine, could result in infecting them rather than protecting them from getting sick.

"There is a live virus vaccine that can prevent shingles and its been studied in tens of thousands of people and it works very well, but anybody with an autoimmune disease who is on anti-TNF or other biologic therapies are not supposed to get this vaccine," said study lead author Dr Jeffrey R. Curtis of the University of Alabama at Birmingham (AL, USA).

His new study published in the *Journal of the American Medical Association*­^1^ disproved this theoretical concern. Dr Curtis and his team analyzed data from over 463.500 Medicare beneficiaries over 60 years of age who had rheumatoid arthritis, psoriasis, psoriatic arthritis, ankylosing spondylitis or inflammatory bowel disease. Over 18.600 of them received the shingles vaccine during the four-year study period (January 2006 through December 2009), and out of this population 633 patients had been treated with biologics. None of those 633 patients developed shingles within the 42-day period after vaccination, which is when shingles would be expected to develop. After the 42-day incubation period, 138 of these patients did go on to develop shingles. This is in accordance with the overall effectiveness of the vaccine, which has been shown to be \~40--50%.

While these study results will likely not be practice-changing or change the current recommendations for the shingles vaccine, the findings may prompt future clinical trials that can include prospective, randomized, placebo controlled study of the vaccine within this particular population and perhaps reveal practice-changing results.

### Reference

1\. Zhang J, et al. JAMA 2012; 308:43-9.

Therapeutic cancer vaccine against metastatic renal cell carcinoma enters Phase 3
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The US company Argos Therapeutics recently announced that the US FDA has approved the company's revised Special Protocol Assessment (SPA) for its phase 3 clinical trial of AGS-003, a therapeutic cancer vaccine against metastatic renal cell carcinoma (mRCC).

Argos Therapeutics focuses on the development and commercialization of fully personalized immunotherapies for the treatment of cancer and infectious diseases using its proprietary Arcelis technology platform. This fully personalized active immunotherapy technology captures all antigens including mutated variant antigens that are specific to each patient's disease. It has been shown to overcome immunosuppression by producing a durable memory T-cell response without adjuvants that are sometimes associated with toxicity. The Arcelis process uses a small tumor or blood sample and the patient's own dendritic cells (DCs), which are derived and optimized following a single leukapheresis procedure. RNA isolated from the patient sample is used to program the DCs to target the entire disease-antigen repertoire. The activated, antigen-loaded DCs are then formulated into the patient's plasma and administered as an injection into the skin.

In a previous phase 2 clincial trial, treatment with the cancer vaccine candidate AGS-003 has shown encouraging median and long-term survival for newly diagnosed mRCC patients who presented with intermediate or poor risk ("unfavorable" risk) factors. Adding AGS-003 to standard sunitinib doubled the overall survival rate for these patients compared to historical results for unfavorable risk patients treated with sunitinib alone. Importantly, more than 50% of patients in the study survived longer than 30 months after initiating therapy, which is four times the expected rate for sunitinib, suggesting a pronounced survival benefit for the combination regimen with no added toxicity.

The new phase 3 study (ADAPT) will enroll up to 450 patients at approximately hundred sites in North America and outside the US. The vaccine AGS-003 will be studied in newly diagnosed mRCC patients in a 2:1 randomized, open-label trial in combination with standard targeted therapy (beginning with sunitinib), compared to targeted therapy alone. Primary endpoint of the study is overall survival (OS). Additional endpoints will include overall response, immune response, progression-free survival (PFS) and safety.

"FDA acceptance of our revised SPA is an important step forward for our continued clinical development of AGS-003 in newly diagnosed mRCC patients," said Dr Jeff Abbey, CEO of Argos Therapeutics. "Based on the highly encouraging long-term survival we observed in our phase 2 combination study of AGS-003 plus sunitinib, we amended our Phase 3 protocol to focus on a primary endpoint of improving overall survival for patients randomized to receive AGS-003 plus sunitinib versus sunitinib alone. With our revised SPA, the FDA has agreed that the pivotal ADAPT study could support a future Biologics License Application (BLA) submission if the study objectives are met."

Pfizer's Men B vaccine shows promise in phase 2
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A new vaccine candidate for the prevention of meningococcal B disease has been successfully tested in a phase 2 clinical trial. The study, recently published in the journal *Lancet Infectious Diseases*,^1^ found the bivalent recombinant factor H-binding protein vaccine (recombinant lipoprotein 2086, developed by Pfizer) to be immunogenic and safe.

*Neisseria meningitidis* serogroup B (MenB) is a major cause of invasive meningococcal disease; in some areas like North America, Europe and Australia, MenB is actually the most prevalent serogroup strain. There is no broadly protective vaccine against MenB that is licensed. However, it should be noted that Novartis' 4CMenB vaccine is close to licensure.

The randomized, placebo-controlled phase 2 trial enrolled 539 healthy adolescents from 25 sites across Australia, Poland and Spain to test the safety and immune response of the lipoprotein 2086 vaccine. Participants were randomized to receive ascending doses of the vaccine (60, 120 or 200 µg) or placebo at 0, 2 and 6 months. Immunogenicity was measured by serum bactericidal assays using human complement (hSBA) against eight diverse MenB strains. The co-primary endpoints were seroconversion for the two indicator strains (PMB1745 and PMB17) analysed by the Clopper-Pearson method.

The trial data showed that the potential vaccine produced protective antibodies against 90% of the invasive MenB strains tested. The vaccine was well-tolerated with mild-to-moderate injection site pain being the most common local reaction.

"Meningococcal B can cause meningitis and blood poisoning and can progress very quickly with devastating effects," said study lead author Dr. Peter Richmond, who heads the Vaccine Trials Group, a collaboration between the University of Western Australia affiliated Telethon Institute for Child Health Research and Princess Margaret Hospital (WA, Australia). "This is the last major cause of meningitis for which we do not have a vaccine, so we are very excited about the progress towards developing a safe and effective vaccine."

The groups most at risk of contracting MenB are children between one month and one year and teenagers, and Pfizer is targeting adolescents in the research for this vaccine. The next stage of development will involve larger trials in a wider range of age groups.

### Reference

1\. Richmond PC, et al. Lancet Infect Dis 2012; 12:597-607.

Biovest initiates formal regulatory approval process for BiovaxID in Europe
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Biovest International (Tampa, FL, USA) recently submitted formal notification to the EMA informing of its intent to file a Marketing Authorization Application (MAA) seeking approval in the EU for its personalized cancer vaccine BiovaxID. The therapeutic vaccine BiovaxID has been developed for the treatment of follicular non-Hodgkin's lymphoma, an incurable cancer of the immune system. Upon approval, BiovaxID would be the first cancer vaccine available in Europe for lymphoma patients.

Dr Carlos F. Santos, Biovest's Senior Vice President, Product Development and Regulatory Affairs said: "This formal notice submitted to the EMA marks a significant milestone in our BiovaxID global regulatory strategy, as this is the initial step required by the EMA in the process leading up to our planned MAA submission."

Under the EMA centralized procedure, Biovest's application will be assessed by the EMA's Committee for Medicinal Products for Human Use (CHMP). An approval under this centralized procedure is valid in all EU-member countries.

Biovest develops active immunotherapies (cancer vaccines) that treat and diminish the aggressiveness of B-cell non-Hodgkin's lymphoma. The company's lead product, BiovaxID, has been evaluated in three clinical trials conducted in collaboration with the US National Cancer Institute (NCI) demonstrating that BiovaxID increases the duration of cancer remission following chemotherapy and induces immune responses which correlate highly with long-term survival. Biovest is currently in the process of seeking US and international marketing approvals for this product.

Dr J.H. Veelken, Professor of Internal Medicine (Hematology) and Head of the Department of Hematology at Leiden University Medical Center, (Leiden, Netherlands) recently was called to Biovest's Scientific Advisory Board. The internationally-recognized authority in cancer immunotherapy said: "BiovaxID will meet an important need in the management of lymphoma in the European clinic as an active immunotherapy that can extend duration of tumor remission and offer patients a non-immunosuppressive post-induction therapy."

Previously published online: [www.landesbioscience.com/journals/vaccines/article/21700](http://www.landesbioscience.com/journals/vaccines/article/21700/)
