title: Redundancy and plasticity of neutralizing antibody responses are cornerstone attributes of the human immune response to the smallpox vaccine.
abstract: The smallpox vaccine is widely considered the gold standard for human vaccines, yet the key antibody targets in humans remain unclear. We endeavored to identify a stereotypic, dominant, mature virion (MV) neutralizing antibody target in humans which could be used as a diagnostic serological marker of protective humoral immunity induced by the smallpox vaccine (vaccinia virus [VACV]). We have instead found that diversity is a defining characteristic of the human antibody response to the smallpox vaccine. We show that H3 is the most immunodominant VACV neutralizing antibody target, as determined by correlation analysis of immunoglobulin G (IgG) specificities to MV neutralizing antibody titers. It was determined that purified human anti-H3 IgG is sufficient for neutralization of VACV; however, depletion or blockade of anti-H3 antibodies revealed no significant reduction in neutralization activity, showing anti-H3 IgG is not required in vaccinated humans (or mice) for neutralization of MV. Comparable results were obtained for human (and mouse) anti-L1 IgG and even for anti-H3 and anti-L1 IgG in combination. In addition to H3 and L1, human antibody responses to D8, A27, D13, and A14 exhibited statistically significant correlations with virus neutralization. Altogether, these data indicate the smallpox vaccine succeeds in generating strong neutralizing antibody responses not by eliciting a stereotypic response to a single key antigen but instead by driving development of neutralizing antibodies to multiple viral proteins, resulting in a "safety net" of highly redundant neutralizing antibody responses, the specificities of which can vary from individual to individual. We propose that this is a fundamental attribute of the smallpox vaccine.
authors.affiliation: La Jolla Institute for Allergy and Immunology, Division of Vaccine Discovery, 9420 Athena Circle, La Jolla, CA 92037, USA.
authors.forename: Mohammed Rafii-El-Idrissi
authors.initials: MR
authors.lastname: Benhnia
authors.forename: Megan M
authors.initials: MM
authors.lastname: McCausland
authors.forename: Hua-Poo
authors.initials: HP
authors.lastname: Su
authors.forename: Kavita
authors.initials: K
authors.lastname: Singh
authors.forename: Julia
authors.initials: J
authors.lastname: Hoffmann
authors.forename: D Huw
authors.initials: DH
authors.lastname: Davies
authors.forename: Philip L
authors.initials: PL
authors.lastname: Felgner
authors.forename: Steven
authors.initials: S
authors.lastname: Head
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sette
authors.forename: David N
authors.initials: DN
authors.lastname: Garboczi
authors.forename: Shane
authors.initials: S
authors.lastname: Crotty
mesh_terms: D000914:Antibodies, Viral / Q000097:blood*; D002352:Carrier Proteins / Q000276:immunology; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood; D009500:Neutralization Tests; D012900:Smallpox Vaccine / Q000276:immunology*; D014616:Vaccinia virus / Q000276:immunology*; D014759:Viral Envelope Proteins / Q000276:immunology; D014764:Viral Proteins / Q000276:immunology; D014771:Virion / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D002352:Carrier Proteins; D007074:Immunoglobulin G; C087715:L1R protein, Vaccinia virus; D012900:Smallpox Vaccine; D014759:Viral Envelope Proteins; D014764:Viral Proteins; C406065:envelope H3L protein, Vaccinia virus