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Principal Investigator: Duane R. Wesemann
Organization: BRIGHAM AND WOMEN'S HOSPITAL
Fiscal Year: 2021
Award: $11,809,995
Funding agency: National Institute of Allergy and Infectious Diseases
OVERALL SUMMARY
Severe Acute Respiratory Syndrome (SARS) Coronavirus (CoV)-2 is a devastating human threat. While
successful vaccine programs are underway, genetic drift and immune escape have already begun to subvert
immunity, with more variants likely to continue to emerge. Moreover, the rates of zoonotic CoV transmission
have increased over the past two decades—indicating that it may not be long before another CoV breaches
host-species barriers into humans. Next generation vaccine design strategies that are able to provide robust
protection against evolving SARS-CoV-2 strains in addition to other CoVs are urgently needed. The overall
goal of this program is to produce critical information necessary for the design and testing of next generation
vaccine strategies that provide protective efficacy with the greatest possible breadth across the CoV
family. The overall Program hypothesis is that immunological discernment of heterogeneity in human
responses to SARS-CoV-2 infection and vaccination will illuminate factors that can impact efficacy and breadth
of CoV vaccine strategies. This hypothesis is supported by recent publications and preliminary data from our
team. In this regard, although hundreds of vaccines are under development, the targets most relevant for pan-
CoV immunity may defy the simple need for the induction of neutralizing antibody responses, which largely
bind to non-conserved areas in the S1 region of the viral Spike (S) protein—susceptible to viral escape.
Emerging evidence from our team points to the importance of the S2 region, which is more conserved across
CoVs. Our team has found that rapid induction of anti-S2 antibodies is connected to less death in severe
disease, more cross-reactive memory B cell responses, swift healing in mild disease, and improved antibody
durability after disease resolution. The factors underlying why some people develop better-clinical-outcome-
associated crossreactive anti-S2 immune responses remains to be fully defined. We have assembled a
multidisciplinary team with expertise in immunology, virology, genetics, medicine, biochemistry, structural
biology and mathematics to achieve the overall Program goal. The complementary and integrative expertise of
the team will come together to: 1) finely map the humoral and cellular responses to SARS-CoV-2 variants and
coronaviral relatives that emerge after natural infection or vaccination, 2) define the mechanism(s) by which
these responses confer protection, and 3) utilize these mechanistic correlates of immunity to inspire cutting
edge, structurally stable native-like S antigens that will be used in a step-wise improvement approach in
vaccination and protection studies. Collectively, the data generated by this team will (a) identify immunological
correlates of anti-CoV breadth expected to inform vaccine design; (b) define the most conserved targets on
CoV S accessible to the human adaptive immune system and mechanistic insights into their recognition; (c)
generate novel immunogens incorporating B and T cell strategies informed by (a-c) above; and (d) test them in
the context of Program-optimized delivery methods to maximize breadth of protective, durable CoV immunity.
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