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Structural and biochemical characterization of phenotypically distinct classes of HCV E1E2 glycoproteins critical for vaccine development

Award Number: R01AI198503
ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2026
PERIOD OF PERFORMANCE END DATE: 06/30/2031

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Structural and biochemical characterization of phenotypically distinct classes of HCV E1E2 glycoproteins critical for vaccine development - PROJECT SUMMARY The global burden of Hepatitis C virus (HCV) infection is at least 58 million with an annual rate of 1-2 million new infections. While major advances have been made in the development of direct acting antivirals, a preventive vaccine is needed to control infection rates. The natural target of the protective antibody response in HCV- infected individuals is the membrane-anchored heterodimeric E1E2 surface glycoprotein. E1E2 exhibits an extraordinary degree of sequence diversity, which has complicated vaccine efforts. Large differences have also been observed in the susceptibility of different HCV strains to neutralization by E1E2-specific monoclonal antibodies and patient polyclonal sera, but these differences cannot be explained by simple sequence variations between viral strains, and an understanding of how E1E2 strain neutralization susceptibility correlates with its efficacy as a vaccine antigen is currently unknown. The possibility of dynamic conformational states of E1E2 has been suggested to play a role in antibody resistance, but the limited structural information that is available on the native E1E2 heterodimer has hindered an understanding of its key conformations and epitopes that are accessible in neutralization sensitive and resistant viruses. Moreover, recovery of monoclonal antibodies (mAbs) specific to the native E1E2 heterodimeric state has been difficult due to lack of available native soluble mimics of the E1E2 ectodomain for use as probes in antigen specific memory B cell sorting. Our team has recently developed a secreted E1E2 heterodimer (sE1E2) that closely mimics and retains antigenic features of the native glycoprotein heterodimer. This platform is compatible with production of native E1E2 from multiple genotypes and is highly amenable not only to structural analysis by single particle cryo-electron microscopy (cryo-EM) but also for use as a probe in isolation of E1E2-specific mAbs. Here, we use the sE1E2 heterodimer platform to study a panel of recombinant sE1E2 proteins from diverse HCV strains that span the spectrum of neutralization susceptibility. In Aim 1, we will biophysically characterize 30 sE1E2 variants from phenotypically diverse tiers of viruses to assess molecular features that define their neutralization susceptibility and resistance, including antigenic integrity and host receptor recognition. To further understand the antigenic differences between phenotypically diverse sE1E2s, in Aim 2 we will apply an immunological approach by using diverse sE1E2s as probes for B cell sorting and recovery of new E1E2-specific mAb panels from HCV infection and NHP immunizations, which will subsequently define antigenic differences between neutralization sensitive and resistant viruses. In Aim 3, we will leverage sE1E2s amenable to structural studies and undertake cryo-EM analysis of phenotypically diverse sE1E2s from our panel and define their recognition by new mAbs from Aim 2. Finally, in Aim 4 we examine the immune response to sE1E2 immunogens spanning the range of neutralization sensitivity, culminating with polyvalent immunization with combinations of sensitive and/or resistant sE1E2s. Overall, successful completion of this work will facilitate the development of a broadly neutralizing HCV vaccine.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $1,575,599 )
2026	2026	UNIVERSITY OF MARYLAND, COLLEGE PARK	3112 LEE BUILDING	COLLEGE PARK	MD	20742	PRINCE GEORGES	USA	Allergy and Infectious Diseases Research	000	1	6/26/2026	NEW	$1,575,599
														Subtotal = $1,575,599

Grand Total All Awards = $1,575,599

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Structural and biochemical characterization of phenotypically distinct classes of HCV E1E2 glycoproteins critical for vaccine development

Award Number: R01AI198503

ORGANIZATION: NATIONAL INSTITUTE OF ALLERGY & INFECTIOUS DISEASES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/01/2026

PERIOD OF PERFORMANCE END DATE: 06/30/2031

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