Research & development

AdVac^® technology involves the use of adenoviral vectors, such as Ad35 and Ad26, in vaccines for diseases caused by viruses, bacteria or parasites. These vectors are harmless adenoviruses that have been disabled so that they cannot replicate. A vector functions as an efficient ‘gene taxi’, delivering into the human body a fragment of DNA that carries the code for a protein of a specific pathogen. Once inside the body, the vectors express (produce) these proteins and present them to the person’s immune system, which augments its protective response. Using this versatile vaccine vector platform in combination with our PER.C6^® manufacturing technology, we are working with our partners to develop vaccines against diseases like tuberculosis, malaria, Ebola and Marburg and HIV.

Tuberculosis (TB) is a major cause of illness and mortality worldwide, responsible for 9.4 million new cases and 1.8 million deaths in 2008¹. The current TB vaccine Baccille Calmette Guérin (BCG), developed more than 85 years ago, is probably the world’s most widely used but least effective vaccine. It does reduce the risk of disseminated TB, a form that spreads from the lungs to other organs, and is especially lethal in children. However, it does not reliably prevent pulmonary TB, the most prevalent form of the disease. The problem is compounded by the emergence of extensively drug-resistant tuberculosis (XDR-TB).

To address this urgent need, Crucell has joined forces with the Aeras Global TB Vaccine Foundation, one of several non-governmental organizations we collaborate with to combat diseases. Together, we are developing the novel TB vaccine candidate AERAS-402/Crucell Ad35. Several Phase I trials have been held with promising results–a South African study found that CD8-cell immune responses were much higher than those seen in humans in any previous TB vaccine studies. In January 2010, a Phase I clinical trial was initiated in Portland, Oregon, to obtain a more detailed analysis of the immune response to AERAS- 402/Crucell Ad35. In October 2008, enrollment for the first Phase II study of this vaccine candidate began in South Africa, conducted by the University of Cape Town Lung Institute in conjunction with the South African Tuberculosis Vaccine Initiative. It has found that CD8-cell immune responses are induced in patients who have completed TB treatment.

“More than 2 billion people, equal to one-third of the world’s population, are infected with TB bacilli, the microbes that cause TB.”
(WHO, 2009 Update, Tuberculosis Facts)

(WHO, 2009, Global tuberculosis control)

“Tuberculosis is a leading killer of people with HIV.”
(WHO, 2009 Update, Tuberculosis Facts)

¹

World Health Organization (WHO) 2009 Update, Tuberculosis Facts.

Malaria is one of the most prevalent infections in tropical and subtropical regions with children and pregnant women most severely affected. According to the World Health Organization (WHO), half of the world’s population is at risk of malaria, and an estimated 243 million cases led to nearly 900,000 deaths in 2008. No licensed vaccine is currently available.

Crucell is collaborating with the US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH), on malaria vaccine research and development. A candidate vaccine arising from this partnership is being tested in a Phase I trial at two US sites: Vanderbilt University in Nashville, Tennessee, and Stanford University in Palo Alto, California. Boost vaccinations for the fourth and final group of volunteers have been completed and preliminary examination of the blinded data indicates that the vaccine is immunogenic.

In July 2009, we announced a new collaboration with the US-based Malaria Vaccine Initiative (MVI) and USAID Malaria Vaccine Development Program (MVDP) to accelerate development of a promising new type of malaria vaccine. Using funding from the USAID MVDP, the partners will conduct studies to determine how effectively Crucell’s proprietary recombinant adenoviruses (a type of virus associated with the common cold and other mild respiratory infections) delivers a malaria antigen to the immune system. Using Crucell’s AdVac^® technology with two different adenovirus vectors–Ad35 and Ad26–as delivery mechanisms, this approach seeks to elicit a protective immune response.

Ebola is one of the world’s most lethal viral diseases and can be found on the US Department of Defense’s Category ‘A’ list of bioterror agents. Both Ebola and Marburg are among the few viruses capable of causing hemorrhagic fever, a severe, often fatal disease in humans. There are currently no vaccines or antiviral therapies available for either disease.

Crucell is developing a multivalent filovirus vaccine against Ebola and Marburg in collaboration with the Vaccine Research Center of the NIH/NIAID. The candidate vaccine is based on Crucell’s proprietary adenoviral vector technology and is produced using Crucell’s PER.C6^® technology.

A Phase I study showed safety and immunogenicity at the doses evaluated. Based on these results, a second Phase I study is anticipated. This will use alternative multivalent adenovirus vectors that are able to bypass pre-existing immunity against the more commonly used adenovirus serotype 5 (Ad5).

Over the past 25 years, HIV infection resulting in AIDS has claimed millions of lives, devastated communities, and enormously frustrated efforts to fight poverty, improve global health and promote economic development. According to the 2009 AIDS Epidemic Update (a joint report by the United Nations Program on HIV/AIDS (UNAIDS) and WHO), 33.4 million people, more than ever before, are living with HIV. There is currently no licensed HIV vaccine available.

With the support of a $19.2 million grant from the NIH, Crucell is collaborating with Harvard Medical School and its teaching hospital Beth Israel Deaconess Medical Center to develop a recombinant AdVac^®-based vaccine against HIV. Adenovirus serotype 26 (Ad26) is being used as the vaccine vector, in order to avoid the problem of pre-existing immunity to Ad5. Preliminary results of a Phase I study at the Brigham and Women’s Hospital in Boston, USA, show that the HIV candidate vaccine is safe and immunogenic.

Antibodies are proteins made naturally by cells of the body’s immune system. They function as one of the body’s principal defense mechanisms against pathogens – disease-causing agents such as parasites, viruses or bacteria. As antibodies recognize and bind to invading pathogens, ultimately eliminating them, they play a crucial role in protecting humans against disease.

Rabies is widespread across the globe. More than 55,000 people die of rabies each year, with around 95% of those deaths occurring in Asia and Africa–usually following a bite from an infected dog.

“Rabies causes more than 55,000 deaths each year in endemic countries.”
(WHO, rabies factsheet, December 2008)

This highlights the significant unmet medical need for a safe, effective and affordable rabies treatment. The treatment currently used when someone is exposed to the virus combines immunoglobulins (antibodies prepared from human or equine blood) with the vaccine. This is usually successful if administered within 24-48 hours following exposure. However, concerns about the safety and availability of blood-derived rabies antibodies have inspired a search for alternatives.

Using MAbstract^® and PER.C6^® technology, Crucell scientists–in collaboration with the Thomas Jefferson University in Philadelphia and the US Centers for Disease Control and Prevention in Atlanta–have discovered a combination of human monoclonal antibodies (mAbs) for the post-exposure treatment of rabies. Clinical testing of this mAb combination made good progress during 2008, leading to the presentation in October of very promising efficacy and safety data from a Phase II trial in the US. In order to test the mAb combination in different populations and settings, an additional Phase II trial was held among children in the Philippines, which showed that neutralizing activity levels were similar to those achieved by administering human immunoglobulin (HRIG). A third Phase II study, at Lotus Laboratories in Bangalore, India, is due to begin in the coming months. Since January 2008, the route towards global availability of this next-generation, life-saving rabies biological has been facilitated by Crucell’s strategic partnership with sanofi pasteur, a world leader in rabies immunization. The US Food and Drug Administration (FDA) has granted Crucell’s mAb combination Fast Track status, paving the way for priority handling of the regulatory dossier.

(WHO, Rabnet/CDC, 2008)

In December 2008, Crucell announced the discovery of a new class of human monoclonal antibodies (mAbs) with the unprecedented ability to combat a broad range of influenza virus strains.

The broadly neutralizing CR6261 antibody binds in the HA stem, distant from other strain-specific antibodies, by using only its heavy chain.

In a pre-clinical study, Crucell’s mAb CR6261 was compared with the anti-influenza drug oseltamivir (Tamiflu) in terms of its value for flu prevention and treatment; the monoclonal antibody strongly outperformed oseltamivir.

The flu strains tested included the ‘bird flu’ strain H5N1, which experts fear has the potential to cause a pandemic, and H1N1 (including the recent pandemic H1N1 2009 virus), which is similar to a descendant of the flu virus that caused the devastating pandemic in 1918. Importantly, the study showed that CR6261 provides immediate protection against the influenza virus, suggesting that it will be able to prevent disease spread. In contrast, oseltamivir was less efficacious and, in some cases, not effective at all.

In August 2009, Crucell received an award from the US National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health (NIH) for the development of our monoclonal antibodies for the treatment of seasonal and pandemic influenza. A month later, Crucell entered into an exciting strategic collaboration with Johnson & Johnson, through its subsidiary Ortho-McNeil-Janssen Pharmaceuticals, Inc. The immediate focus of the collaboration will be the development and commercialization of a universal monoclonal antibody product (flu-mAb) for the treatment and prevention of influenza. One of the key focus areas of the long-term innovation collaboration will be new discovery programs leading to the development and commercialization of a universal influenza vaccine.

“Worldwide, annual influenza epidemics result in about three to five million cases of severe illness, and about 250,000 to 500,000 deaths.”
(WHO, Influenza (seasonal) fact sheet, April 2009)

In August 2009, Crucell obtained an exclusive license from Stanford University (Palo Alto, California) for the development of an antibody combination against the hepatitis C virus (HCV). A large panel of fully human monoclonal antibodies against HCV is being evaluated by Crucell in a proof of concept phase. The monoclonal antibodies have been found to neutralize the virus across all genotypes tested and each recognizes a different part of the HCV surface protein.