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Live Attenuated Rubella Viral Vectors for Enhanced Vaccine Potency

US Food and Drug Administration, Office of Vaccines, Center for Biologics, Silver Spring, Maryland

Position Description:

The goal of this project is to identify vaccine targets and to enhance vaccine potency by expressing these antigens in a new vaccine platform based on a live rubella viral vector.  The live attenuated rubella vaccine strain RA27/3 has been given to nearly every child in the US as part of the MMR vaccine program.  The vaccine has demonstrated safety and potency in millions of children, as well as durability that persists for decades.  In macaques, these vectors have shown safety, durability, and high antibody titers, as well as the potential to elicit mucosal immunity.  These features are particularly important for vaccines against SARS CoV-2, since mucosal spread and antigenic variation are important features of COVID-19 infection.   

The research project will start with inserting a foreign gene into the structural insertion site of rubella.  The fellow will transfect viral RNA into Vero cells, followed by virus recovery by reverse genetics.  He will expand virus in cell culture and demonstrate stable expression of the vaccine insert. 

When given to rhesus macaques, rubella vectors have elicited antibodies with high titer and broad specificity for the new vaccine insert, as well as antibodies to the rubella proteins.  For example, the insert can be SIV gag protein.  Rubella can accommodate the entire SIV gag protein p27 at the structural insertion site, and the insert is stably expressed for more than 10 passages.  The rubella/SIV vector grows well in rhesus macaques, and it elicits antibodies and T cell immunity against SIV gag that are comparable to natural SIV infection.  These immunogens may one day lead to prevention or treatment of SIV infection in macaques.

Other examples include the CSP protein of malaria and the S1 spike protein of SARS CoV-2 virus.  One quarter of the world's population are exposed to malaria, yet there is no reliable vaccine available. The vaccine insert can be malaria CSP protein.  Antibodies specific for CSP can protect against malaria infection. The rubella/CSP vectors may establish sufficient immunity in young children age 2 to 5 to prevent the severe cerebral form of malaria that occurs in this age group. 

Similarly, we have found that the S1 spike protein of SARS CoV-2 virus can be well expressed in rubella vectors.  We anticipate that the best growing and most stably expressed constructs in cell culture will also be the most immunogenic in vivo.  The vectors will be tested in macaques for eliciting antigen specific T cells, systemic IgG antibodies, and mucosal IgA immunity, as well as neutralizing antibodies against SARS CoV-2.    

Recently, we found that certain host cell proteins can be expressed by rubella vectors.  By immunizing against cell proteins that define a lymphocyte subset, we may knock out selectively the function of an entire cell subset.  For example, antibodies to CD20, CD4, or CD8 could wipe out the effector functions of B cells, helper T cells, or cytolytic T cells if given separately.  But, given together, they could modulate the function of all lymphocytes. 

Methods will include:
  • Molecular biology for generating viral vectors,
  • Virological methods for viral rescue and propagation
  • Immunological methods to analyze the immune response to vaccine and viral challenge.

To Apply:

Directions for submitting an application:

  • CV and one or two recommendation letters and 1 or 2 publications

 Send documents via email to ira.berkower@fda.hhs.gov or via mail to:

Ira Berkower, MD, PhD
Bldg 52/72, Room 1212
FDA White Oak Campus,
10903 New Hampshire Ave.,
Silver Spring, MD 20993
 
Application Deadline: Sept 1, 2022 or when filled
 

This post will be available until August 2, 2022 or until filled.

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