When one looks at the fight against HIV/AIDS in the third world, there have been very few victories. We were reminded this week about one significant accomplishment in those regions, that being the fight against Mother-to-Child transmission of HIV. The program Prevention of Mother-to-Child Transmission of HIV (PMTCT) provided nevirapine at no cost to infected mothers and newborn babies from 2000 to 2010 as a way to prevent HIV transmission. PMTCT is credited with saving four million babies from HIV infection. Please click here for the final report of the project. I am proud to say that Dr. Riku Rautsola, our President and CEO, was instrumental in launching the Mother-to-Child program when he was with Boehringer Ingleheim. He also co-founded and chaired “Accelerating Access,” which focused on providing low-cost HIV treatments in developing countries. Dr. Rautsola and our team here at VIRxSYS continue the search for breakthrough therapies for the treatment of HIV.
- Gary J. McGarrity, PhD – Executive Vice President of Scientific and Clinical Affairs
Therapeutic HIV vaccines were once considered to be a dead end. However, several recent research studies presented during a special session at the 2010 International AIDS Conference (IAC) show the renewed hope for therapeutic vaccines in the fight against HIV/ AIDS. An article in Nature also discussed the new developments in therapeutic HIV vaccines.
A typical vaccine, which does not yet exist for HIV, is designed to prevent infections, whereas a therapeutic vaccine treats infected people. Therapeutic HIV vaccines aim to boost damaged immune systems. Current HIV drug combination treatments have a high level of toxicity and often cause premature aging. Therapeutic vaccines have the potential to treat HIV without such side effects. Clinical trials on therapeutic HIV vaccines in the 1990’s were not successful and the line of research was marked as a failure. Currently several biotechnology companies are re-examining the potential of therapeutic vaccines for HIV with positive results.
The VIRxSYS Corporation is working to create a therapeutic HIV vaccine (VRX1273) using lentiviral vectors. This unique approach shows tremendous promise in treating those infected with HIV/ AIDS. CEO Riku Rautsola presented updated data from the Company’s HIV vaccine study during the National Association of People with AIDS (NAPWA) and The AIDS Institute’s Community Forum at International AIDS Conference 2010 in Vienna, Austria. VIRxSYS is excited to be a part of the active conversation on the potential of therapeutic HIV vaccines.
Significant strides utilizing gene therapy to create potentially effective HIV treatments continue to be made in our lab and others’. In addition to our work with Lexgenleucel-T (VRX496™) anti-HIV therapy, in which we modify autologous CD4 T cells to prevent HIV replication and is currently being tested in Phase II human clinical studies, we are seeing promising gene therapy reports out of other labs.
Nature Biotechnology has recently published a study conducted at UCLA in which stem cells, genetically modified with zinc finger nucleases to disrupt the viral co-receptor CCR5, were transplanted into humanized mice. After transplant, the mice were infected with HIV, as were control mice who received unmodified stem cells. The genetically modified cells multiplied into immune cells that successfully conferred HIV control. Mice that received the modified cells had higher human T cell counts and lower viral loads compared with animals that received unmodified cells. Although it will be several years before such research can be tested in human clinical trials, the success in humanized mice supports the potential for a successful gene therapy treatment for HIV. Clinical success of this type of approach will depend on several factors, including whether the HIV can mutate around this block as well as the specific tropism of HIV that a patient has. The study also provides further evidence that modifying just a fraction of the immune cells can potentially confer HIV resistance, much as we have observed in our Lexgenleucel-T studies to date.
We just got back from presenting data at the 13th American Society of Gene and Cell Therapy (ASGCT) Annual Meeting. It was a great opportunity to connect with the scientific community and share our work vaccine and treatments through RNA therapies. We presented eight abstracts representing results of the company’s clinical trials for Lexgenleucel-T (VRX496™), an autologous cell and gene therapy product for the treatment of HIV/AIDS; preclinical trials of the company’s prophylactic HIV vaccine VRX1023, now called VRX1273; and work utilizing the company’s spliceosome mediated RNA trans-splicing (SMaRT™) platform technology. VIRxSYS has over 40 publications in top tier journals showing the effectiveness of SMaRT™ in a broad variety of applications. Highlights of the presentations include data from VIRxSYS’s Phase 2 study of Lexgenleucel-T, which continue to show no evidence of long-term safety issues after the cumulative infusion of over 4 x 1012 vector copies in a total of 2 x 1012 modified CD4 T cells. To date, data from the Lexgenleucel-T clinical trial program comprises of the largest safety database of subjects enrolled in a clinical trial using a lentiviral vector. In accordance with FDA guidelines, all subjects will continue to be monitored for safety for up to 15 years. Additional data from the Lexgenleucel-T Phase 2 study demonstrate that the therapeutic efficacy of Lexgenleucel-T treatment is not affected by the development of anti-vector antibodies, nor is the development of these antibodies associated with clinically detectable adverse events, a common concern in gene therapy trials. Although our research has not, as of yet, been proven with human trials, our monkey study data is so compelling that it gives us great encouragement and optimism for its potential as an effective HIV Vaccine.
Today is HIV Vaccine Awareness Day, and we at VIRxSYS would like to recognize the thousands of volunteers, community leaders, health professionals, and scientists that work to develop a safe and effective preventive HIV vaccine. Existing HIV drugs are limited to merely treating symptoms and are facing serious obstacles to availability, even in wealthy nations. VIRxSYS is honored to be a part of the movement toward a solution to global HIV prevention and treatment with our research on vaccine therapies. A wealth of data from our research is being presented at the 13th American Society of Gene and Cell Therapy (ASGCT) Annual Meeting this week, illustrating the potential of RNA therapies in developing a HIV vaccine as well as answers to other medical issues. HIV Vaccine Awareness Day calls attention to the need for an effective method of HIV prevention—VIRxSYS is committed to this goal and is optimistic that our research will contribute to a victory in the fight against global HIV/AIDS.
In a new paper published in the February issue of Vaccine, my VIRxSYS colleagues discuss the benefits of lentiviral vector-based vaccine candidates for HIV and provide additional details on our HIV-based lentiviral vector vaccine candidate for HIV, VRX1023, now called VRX1273.
As the paper, “An HIV-based lentiviral vector as HIV vaccine candidate: Immunogenic characterization,” points out, in contrast to vectors used in many previous HIV vaccine trials, lentiviral vectors have been shown to be less sensitive to anti-vector neutralizing activity, while displaying desirable characteristics, such as transduction of non-dividing cells (including antigen-presenting cells) and long-term transgene expression. At VIRxSYS, we have seen these benefits in our preclinical studies of VRX1023. As described in the new paper, this lentiviral vector-based HIV vaccine candidate induced significant mucosal and systemic cellular and humoral responses against HIV after sub-cutaneous injection in mice. We have also successfully used this candidate with a DNA prime (e.g. a prime-boost vaccine strategy) in mice, where it elicited as high as 21% HIV Gag-specific CD8 responses as measured by intracellular cytokine staining. Moreover, anti-vector immunity has not been an obstacle to repeated lentiviral vector-based vaccine administrations, as shown by improved anti-vector immune responses compared with repeat vaccine administrations compared to one-time administration. In addition, in head to head comparisons with adenoviral (Ad5) vectors expressing the same vaccine payload in mice, VRX1023 elicited higher and more persistent cellular and antibody responses to HIV than its adenoviral counterpart.
Adding to the preclinical data on VRX1023, in February we presented data from our non-human primate studies at the Conference on Retroviruses and Opportunistic Infections, showing that VRX1023, used as a prophylactic vaccine, is capable of achieving significant control of viral load and improving immune response following a large challenge with a highly pathogenic simian immunodeficiency virus (SIV), a virus found in non-human primates and similar to HIV. VIRxSYS is currently preparing for a Pre-IND Meeting followed by an Investigational New Drug Application for the therapeutic use of this HIV vaccine candidate in HIV infected patients.
VRX1023, our HIV-1-based lentiviral vector vaccine candidate for HIV, is the topic of a new paper authored by three of my VIRxSYS colleagues and published in the January issue of Vaccine. VRX1023 has been engineered to deliver HIV-1 Gag, Pol and Rev antigens.
In the new paper, “Heterologous HIV-based lentiviral/adenoviral vectors immunizations result in enhanced HIV-specific immunity,” our scientists report on the vaccination of mice with VRX1023 and an adenovirus serotype 5-based vector, using a “prime-boost” approach (an immunization strategy in which one vaccination is given, followed by a second vaccination at another time).
Compared to homologous prime-boost regimens (i.e. using only one type of vaccine, such as only the adenoviral-based candidate), the heterologous immunization regimen using both the lentiviral and adenoviral vector candidates dramatically improved immunogenicity, increasing the number of CD4+ and CD8+ immune cells that were specific to HIV. In addition, this combined approach did not induce high levels of anti- vector-neutralizing antibodies, whereas a high level of anti-vector neutralization was observed in mice who received homologous prime-boost regimens using the adenoviral vaccine.
Our data on the VRX1023 lentiviral vaccine in macaque monkeys in a prophylactic setting was presented at the Conference on Retroviral Opportunistic Infections (CROI) in San Francisco this February.
It’s been a busy day for us at CROI: We are pleased to announce that researchers from the University of Pennsylvania School of Medicine presented a poster today detailing the results from an ongoing Phase I/II open-label clinical trial of our VRX496™ (Lexgenleucel-T) RNA therapy for the treatment of HIV/AIDS.
This Phase I/II, NIH funded clinical trial evaluated whether multiple infusions (6 infusions or 3 infusions) of VRX496™ will allow patients with undetectable viral loads on antiretroviral treatment (HAART) to stop taking HAART (treatment interruption) and still control their viral load.
Interim results of the study showed that seven of eight evaluable subjects experienced a decrease in viral load set point (HIV RNA value specific for each infected individual in absence of anti-retroviral drug control) – and one subject experienced prolonged, complete control of HIV viremia for more than 14 weeks in the absence of HAART.
Current therapies for HIV-infected patients require daily drug regimens and have well documented side effects. It is anticipated that VRX496™ will require only a minimal number of infusions. To date VRX496™ has been infused in 65 patients, which represent an accumulative safety time period of 211 therapy years. VRX496™ also is different from previous gene therapies because it uses a lentiviral vector derived from HIV-1 itself. Unlike other viral vectors, lentiviral vectors appear to sustain expression of the delivered genes of interest for a longer period of time and do not appear to elicit an inflammatory immune response.
We’ve just presented the data from our prophylactic HIV vaccine (VRX1023) study in Rhesus Macaque monkeys at CROI, and are proud to report that it was well received.
Franck Lemiale, Ph.D., my colleague and Director of Immunobiology at VIRxSYS, presented the findings. We are extremely encouraged by the results, which demonstrated that this vaccine candidate achieved a 95% reduction of viral load in Rhesus monkeys which received lentiviral vaccination, as compared to non-vaccinated control animals, as well as a strong and durable immune response and major CD4+ T cell preservation.
Our candidate differs from other HIV vaccine candidates in that it employs an engineered HIV-based lentiviral (LV) vector to deliver the vaccinating antigens. In a mouse study recently published in Vaccine, our lentiviral vector has demonstrated benefits over adenovirus serotype 5 (Ad5)-based vectors (the current industry standard, utilized in the Merck STEP Study, for example) in terms of:
- Anti-vector immunity – Unlike Ad5, LV are not sensitive to anti-LV neutralization by the immune system. This allows the vaccine to be successfully re-administered.
- Anti-HIV immunogenicity – LV either outperformed or induced similar magnitude of T-cell responses compared to two Ad5 vectors, and LV-induced responses persisted for a much longer period than the responses triggered by Ad5, which achieved only short term immunogenicity.
We are currently developing the vaccine for use in the therapeutic setting, but also intend to discuss developing the product for prophylactic use with regulatory agencies, based on the risk/benefits for this population. A successful therapeutic vaccine could significantly delay or even prevent progression to AIDS. Such a therapy could also significantly reduce or eliminate the need for HIV patients to take costly and dangerous medications, and may also reduce the risk of HIV transmission.
This is an exciting milestone for us, and we currently are pursuing an Investigational New Drug (IND) submission to the U.S. Food and Drug Administration (FDA). We hope to begin testing this vaccine candidate in human clinical trials in 2011.
A recent issue of Time featured an article of Dr. David Ho regarding his newest scientific endeavors against HIV and AIDS and his team’s attempts to develop a new generation of antibodies that would block HIV entry into CD4 T cells. The referred antibody, ibalizumab or TNX355, has already been tested in the clinic with decent results (Jacobson et al. Antimicrobial Agents and Chemotherapy. 53(2):450-457, 2009). The authors did find, however, that HIV could mutate and by-pass the blockade of the CD4 receptor. This therapeutic approach is not what we would consider a traditional “vaccine” since it would require a constant re-infusion of the antibody to exercise its therapeutic effects. The data in the literature seem to indicate this product will never be a stand alone therapy as a more formal vaccine would be, but could be another interesting biological against HIV when combined with other anti-HIV products for HIV infected subjects who are already resistant to several classes of anti-HIV drugs. Only future clinical trials beyond Phase 1 will tell.