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Principal Investigator: SEAN D SULLIVAN
Organization: UNIVERSITY OF WASHINGTON
Fiscal Year: 2021
Award: $499,999
Funding agency: NIH Office of the Director
PROJECT SUMMARY
The deployment of efficacious SARS-CoV-2 vaccines has prevented the death of millions of people. New SARS-
CoV-2 variants that are more transmissible exhibit increased resistance to neutralizing antibodies elicited by
either the current vaccine or by prior infection with the original strain. To address this, we have developed a 2nd
generation COVID19 vaccine that employs a self-amplifying replicon RNA (repRNA) and is delivered using a
novel nanolipid carrier formulation (LION) that can be rapidly scaled up and is more stable at warmer
temperatures to support effective worldwide distribution. Our repRNA vaccine expresses a structurally intact
receptor binding domain (RBD) immunogen (called SHARP) that matches variants exhibiting resistance to
neutralization by current vaccines. Second generation vaccines like this one will be administered to people that
are already pre-immune to earlier variants of SARS-CoV-2 due to prior immunization or infection but, to date,
the impact of pre-immunity to the original variants on these new vaccines is not known. Pre-immunity may enable
the new vaccines to induce even broader antibody responses against different variants. On the other hand,
original antigenic sin (OAS), wherein the immune response to an infection preferentially recalls memory cells
primed by the first antigenic exposure, could dampen efficacy of 2nd generation vaccines if upon exposure to the
new variant, B cell responses primed by the original variant are preferentially recalled. To gain a better
understanding of the impact of pre-existing immunity on 2nd generation COVID-19 vaccines, we propose a pilot
study using a repRNA vaccine expressing SHARP to immunize macaques with pre-existing immunity to the
original D614G variant due to prior immunization. Our goal is to determine if pre-immunity improves or,
alternatively, dampens the immunogenicity and/or protective efficacy of 2nd generation vaccines designed to
protect against new variants. These questions are best addressed in NHPs that closely model the repertoire of
innate and adaptive immune responses in humans and can be challenged with SARS-CoV-2 to investigate the
impact on protective efficacy and recall responses. Our Aims are: 1) Characterize the magnitude, specificity and
type of immune responses induced in macaques pre-immune to the original D614G variant and boosted with a
a repRNA vaccine expressing the B.1351 variant immunogen. 2) Investigate pathogenesis of B.1351 infection
in pigtail macaques, protective efficacy of the repRNA B.1351 SHARP vaccine in pre-immune macaques, and
immune correlates of protection. 3) Determine the impact of prior immunization with the original D614G variant
on innate immune responses and their role in the immunogenicity and efficacy of the 2nd generation repRNA
B.1351 SHARP vaccine. Knowledge gained on the impact of pre-immunity from this study will have broader
implications for the development of this and other 2nd generation vaccines. If successful, this study will also
support further development and evaluation of a trivalent repRNA SHARP vaccine that is more amenable for
worldwide distribution than current mRNA vaccines and could provide broad protection against multiple variants.
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