Project: Disarming the stealth properties of the HIV-envelope for AIDS vaccination by rational design of non-immunosuppressive VLPs

The ultimate objective of HIVAC is to develop the first preventive HIV vaccine based on a modified HIV-1 envelope (Patent application filed August 2008 on HIV-1 envelope polypeptides for HIV vaccine), where we aim to reach phase-I trials 12 months post-project. The vaccine will be capable of eliciting both neutralizing antibodies and cellular immunity with enough breadth to protect against primary HIV isolates of great variations._x000D__x000D_Background – The problem_x000D_The latest research on the HIV virus has contributed to new knowledge of the fundamental biology leading to new antiviral drugs and strategies for vaccine design. However, despite an effort of more than €3.9 Bn since the millennium no effective vaccine has been developed yet, thus the devastating virus is responsible for an increasing number of deaths every day. Worldwide, AIDS has killed more than 25 million people since 1981._x000D__x000D_HIV is according to WHO one of the most serious health crises the world faces today. There are an estimated number of 33 million people infected with HIV virus globally, and more than 3 million became infected in 2008 alone. Sub-Saharan Africa reCOs the most heavily affected region in the world; however the rapid growth of the epidemic in Eastern Asia and neighboring Central Asia is of increasing concern. At the current rate of progression of the epidemic, 40 million additional new infections are feared by 2015 and a total of 70 million deaths by 2020._x000D__x000D_The importance of arresting the uncontrolled pandemic is obvious. However, developing a preventive HIV vaccine – the only effective solution – is one of today’s greatest scientific challenges. _x000D__x000D_During the recent years of HIV vaccine development, where numerous different strategies have been evaluated in primate studies, superior immunity has been achieved by using a vaccination strategy based on attenuated (i.e. live but weakened) virus. However, this strategy entails a serious safety risk since the attenuated HIV strain is able to regenerate the virus and thus become pathogenic. An efficient HIV-vaccine must be able to generate a strong cellular as well as humoral immune response as a result of cross-priming between these two arms of the immune system. Antigens presented on virus-like particles (VLPs) are known to mediate both types of responses. Based on this knowledge and observations in patient cohorts we have chosen to focus on a VLP-method for delivery of antigens. _x000D__x000D_The solution_x000D_The consortium wants to develop a novel vaccine concept that disarms important viral immune evasive properties. In the proposed research only the envelope protein needed for the generation of a specific immune response will be derived from HIV. The HIV envelope entails natural immunosuppressive properties that render this crucial antigen a poor target for vaccine purposes. SKAU has designed and provided the initial evidence that these natural immunosuppressive properties can be modified in order to significantly enhance the immunogenicity of the envelope. Moreover, the vaccine design enables different HIV-1 envelope variants to be included and administered simultaneously in a vaccine dosage, thus overcoming the antigenic diversity problems faced by other vaccine strategies. Consequently, we expect that the HIVAC project will result in development of the first HIV vaccine that combines superior safety with an immune protection level that meets regulatory and market requirements._x000D__x000D_The consortium_x000D_The consortium consists of Ps that, among them, possess the expertise and extensive experience in multifarious aspects of HIV research that are required in order to overcome the many challenges related to developing a successful HIV vaccine._x000D__x000D_SKAU Vaccines (SKAU)_x000D_Project coordinator and holder of the original idea and concept. Spin-out from the Department of Infectious Diseases at Aarhus University Hospital as well as the Department of Molecular Biology at Aarhus University. The company has fostered a strong cooperation between clinical researchers in infectious diseases, vaccine specialists, and molecular biologists specialising in retroviruses. _x000D__x000D_Karolinska University Hospital (KUH)_x000D_KUH is recognized for excellence – in Sweden as a teaching hospital and internationally as a center for clinical research. The Vecura GMP facility at KUH is a renowned GMP/GLP manufacturer of viral particles for clinical applications. Over the past ten years Vecura has provided gene therapy vectors for more than 20 clinical trials in different countries. _x000D__x000D_Ruhr-Universität Bochum (RUB)_x000D_RUB is one of the strongest research universities in Germany and has treatment and prevention of HIV/AIDS as one of its CO research focuses. RUB has an established track record of HIV vaccine studies in non-human primates with the well characterized SHIV viral variant. This will provide the foundation for studying vaccine efficacy and possibly immune correlates of protection._x000D_

Acronym	HIVAC (Reference Number: 5242)
Duration	01/05/2010 - 30/04/2014
Project Topic	HIVAC aims to develop a preventive HIV vaccine via a novel approach of unmasking the immunosuppressive properties of the HIV envelope by introduction of rationally designed mutations. Virus-like-particles displaying such disarmed envelopes will be used for superior stimulation of the immune system
Project Results (after finalisation)	We tested several mutations in the immune suppressive doCO of HIV gp160 and identified three that show impaired immune suppressive activity in vitro. IPR was protected for these findings. We have also produced trimeric gp140 (truncated extracellular portion of the gp160) containing the mutations, but these did not go through animal testing because of the complications we encountered with extending the program time line (please see below).
Network	Eurostars
Call	Eurostars Cut-Off 3

Project partner

Number	Name	Role	Country
3	Karolinska University Hospital	Partner	Sweden
3	Ruhr-Universität Bochum	Partner	Germany
3	SKAU Vaccines	Coordinator	Denmark