Diversity of neutralizing antibody responses in human smallpox vaccinees

Abstract

The smallpox vaccine (vaccinia virus, VACV) is the prototypic vaccine, yet the key antibody targets in humans remain unclear. We set out to identify a stereotypic, dominant, mature virion (MV) neutralizing antibody target in humans; but we have instead found that diversity is a defining characteristic of the human antibody response to VACV. We show H3 is the most immunodominant VACV neutralizing antibody target in humans, as determined by correlation analysis of MV neutralizing antibody titers to IgG of individual viral protein specificities. However, using multiple experimental approaches it was determined that while human anti‐H3 IgG is sufficient for neutralization of vaccinia, anti‐H3 antibodies are not required in vaccinated humans (or mice) for neutralization of VACV. We also detected positive correlations between D8, A27, D13, A14, and L1 IgG and virus neutralization activity in vaccinees. Importantly, no single one of these responses was consistently observed in all individuals. For example, L1, which is an immunodominant target in mice, is infrequently observed in immunized humans, but some individuals do have strong anti‐L1 IgG responses, and those antibodies possess virus neutralization activity. Our results suggest that VACV succeeds in driving strong neutralizing antibody responses to multiple viral proteins in vaccinees. We propose this is a fundamental attribute of the smallpox vaccine.