Developmental Projects

DP002 Johnson

Hantaviruses are carried by many different rodents worldwide and can infect humans in the form of aerosols derived from rodent urine or faeces.  These viruses cause two related human diseases involving hemorrhagic fever.  Hemorrhagic fever with renal syndrome (HFRS) is caused by hantaviruses endemic to Europe and Asia, with over 200,000 cases requiring hospitalization annually and mortality rates ranging from 0.1% to 15%.  In the Americas, hantavirus pulmonary syndrome (HPS) presents as pneumonia and progresses to severe respiratory collapse and cardiovascular distress.  HPS is less frequent, compared with HFRS, but often much more severe, with mortality rates that range as high as 30-50%.  Sin nombre virus was first recognized in 1993 after outbreak of acute respiratory distress syndrome in the southwestern United States.  Andes Virus (ANDV) was identified in 1995 as the agent causing a series of HPS outbreaks in Argentina and Chile, where there was evidence for person-to-person transmission.  Given their ubiquitous nature, the rapid onset of disease, capacity to infect in the form of aerosols and high rates of mortality with few therapeutic options, hantaviruses represent a substantial threat to public health, to military personnel, and as potential biologic weapons. No safe effective vaccines are currently available and vaccines are urgently needed.  A lethal disease model of HPS involving ANDV-infected Syrian hamsters was described in 2001.  However, to date, no experimental vaccines have successfully protected hamsters from ANDV.  We constructed non-replicating adenovirus (Ad) vectors expressing the ANDV N, GN, and GC proteins.  Ad vectors are especially well suited for delivering these proteins into the respiratory tract and are known to be safe and effective.  Hamsters vaccinated with any of these Ad vectors were all completely protected from a lethal challenge with ANDV.  Moreover, animals vaccinated with both the GN and GC proteins resisted ANDV very effectively because ANDV RNA was not detected in the hamsters.  In our ongoing studies, we will perform detailed analyses of the immune responses in these animals to determine whether antibodies or cellular immunity (T cells) are important for this protection.  Other Ad vectors will be produced to simplify vaccination, express SNV proteins, and deal with the problem of pre-existing immunity to Ad in humans.  Other studies will involve adoptive transfer of T lymphocyte lines or clones into hamsters to characterize immunopathology. Together, these studies should produce a much better picture of the protective immunity produced in Ad vector vaccinated hamsters and substantially advance efforts to produce human vaccines.