Over the past 6 years, Dr. Peter Barry’s lab at the Center for Comparative Medicine has been collaborating with Dr. Louis Picker and colleagues at the Oregon Health Science University (OHSU) to optimize a novel HIV vaccine. The vaccine stems directly from research in Dr. Barry’s lab that has focused on the rhesus macaque model of human cytomegalovirus (HCMV) persistence and pathogenesis. HCMV is a common virus in humans, infecting between 50-100% of adults around the globe. Most infections in people with a functioning immune system with HCMV are asymptomatic, indicating that the infected individuals immune response to viral infection protects that individual from disease. However, HCMV is a significant cause of disease in those without fully functional immune systems, notably immunosuppressed transplant recipients, AIDS patients not on antiretroviral drugs, and fetuses who acquire the virus from their mother across the placenta. Despite over 4 decades of efforts, there is still no FDA-approved vaccine that protects those most susceptible to the often devastating consequences of HCMV infection. Dr. Barry’s lab developed the rhesus macaque model of HCMV using infection of macaques with rhesus cytomegalovirus (RhCMV) to address possible vaccine strategies that could be translated to HCMV vaccine clinical trials.
There are many aspects of HCMV natural history that indicate that it could be an effective viral vaccine vector to express foreign proteins to induce immune responses against those foreign proteins, as has been done for other viruses such as vaccinia and adenovirus. Particular attributes of HCMV that suggested its use as a viral vaccine vector include its (1) large viral genome, (2) the relatively low disease potential in immune competent hosts, (3) the ability of HCMV to reinfect those with preexisting immunity to HCMV, and (4) the tractable RhCMV model in a highly relevant primate host (rhesus macaques).
Recognizing this, Dr. William Chang, in Dr. Barry’s laboratory, molecularly engineered the genetic backbone of RhCMV to enable rapid and efficient insertion of non-RhCMV genes that could be expressed as proteins during the course of RhCMV infection. Dr. Barry began his collaboration with Louis Picker by supplying him with the engineered RhCMV. Dr. Picker further manipulated the RhCMV genetic backbone into a vaccine vector by cloning into Dr. Chang’s modified version of the RhCMV genome portions of the simian immunodeficiency virus (SIV). Dr. Picker and colleagues immunized rhesus macaques with the chimeric RhCMV/SIV viral vector. Macaques immunized with Dr. Picker’s vaccine and then exposed to the virus were remarkably protected against SIV infection – more than 50-60 percent were protected. No other SIV vaccine has had that kind of success, either in monkeys or in human trials of HIV vaccines. Dr. Picker also demonstrated that this novel vaccine mechanism eradicates SIV from the body. Instead of using antibodies to fight the virus, the RhCMV/SIV vaccine stimulates T cells to control and ultimately eradicate SIV infection. Through a mechanism by which no one could have predicted, RhCMV expressing SIV proteins naturally arms CD8+ T cells to be on alert against subsequent SIV. Thus, vaccinating with strains of cytomegalovirus into the body that have been engineered to express particular SIV genes trains the body to attack SIV after exposure.
Dr. Picker and his colleagues are keenly interested in translating the extremely promising results in rhesus macaques to human clinical trials, hopefully beginning in 2017 or 2018. Dr. Picker’s group wants to use versions of HCMV for the human clinical vaccine trials based on the results in the rhesus macaque model. To accomplish this, Dr. Picker is making versions of RhCMV that are further weakened for the ability to cause any disease. Notably, although HCMV is considered a virus with low disease potential, there are some risks associated with primary HCMV infection. Accordingly, Dr. Picker is working with CNPRC and CCM scientists to critically evaluate these new versions for (1) the ability to stimulate immune responses against SIV infection, while (2) exhibiting significantly reduced disease potential.
Drs. Barry and Alice Tarantal, CNPRC, together with Dr. Yujuan Yue in Dr. Barry’s lab, are actively collaborating with Dr. Picker’s group on safety testing of the weakened versions of RhCMV at the CNPRC in the fetal CMV pathogenesis proof-of-concept model, where the results of these critical safety studies are directly informing Dr. Picker’s group on which vectors to use in the human clinical trials.