Antibody Fab‐Fc properties outperform titer in predictive models of SIV vaccine‐induced protection

Abstract

Characterizing the antigen‐binding and innate immune‐recruiting properties of the humoral response offers the chance to obtain deeper insights into mechanisms of protection than revealed by measuring only overall antibody titer. Here, a high‐throughput, multiplexed Fab‐Fc Array was employed to profile rhesus macaques vaccinated with a gp120‐ CD 4 fusion protein in combination with different genetically encoded adjuvants, and subsequently subjected to multiple heterologous simian immunodeficiency virus ( SIV ) challenges. Systems analyses modeling protection and adjuvant differences using Fab‐Fc Array measurements revealed a set of correlates yielding strong and robust predictive performance, while models based on measurements of response magnitude alone exhibited significantly inferior performance. At the same time, rendering Fab‐Fc measurements mathematically independent of titer had relatively little impact on predictive performance. Similar analyses for a distinct SIV vaccine study also showed that Fab‐Fc measurements performed significantly better than titer. These results suggest that predictive modeling with measurements of antibody properties can provide detailed correlates with robust predictive power, suggest directions for vaccine improvement, and potentially enable discovery of mechanistic associations.

Distinct Early Serological Signatures Track with SARS-CoV-2 Survival

“…The models were built using a backward feature elimination for selection and then classified using the minimal set of features which maximize accuracy ( Guyon and Elisseeff, 2003 ; Pittala et al., 2019 ). Models were trained and tested in a fivefold cross-validation framework using random stratified sampling to ensure that both groups are represented in each group.…”

Co-immunization of DNA and Protein in the Same Anatomical Sites Induces Superior Protective Immune Responses against SHIV Challenge

“…A role for Env Abs in decreased transmission risk was supported by univariate analyses showing direct correlation (or trend) of early CH505 bAb (binding Ab) responses (after third and fourth vaccinations) and delayed virus acquisition including all vaccinees (Figures 3A and 3B). To identify potential immune mechanisms mediating decreased transmission risk, we analyzed the functional properties and characteristics of Env Ab responses (Tables S2 and S3), including Ab effector functions, previously associated with protection (Ackerman et al, 2018;Barouch et al, 2015;Bradley et al, 2017;Florese et al, 2009;Haynes et al, 2012;Hidajat et al, 2009;Neidich et al, 2019;Pittala et al, 2019;Xiao et al, 2010). We performed an extensive functional analysis of the Env Abs, including NAbs (Montefiori, 2009), recognition of Env on infected cells (Ferrari et al, 2011) and a series of Ab-dependent innate immune functions (Barouch et al, 2015;Lai et al, 2012;Pollara et al, 2011;Vaccari et al, 2016).…”

“…Because several univariate measurements (Env-specific humoral and cellular immunity) showed statistically significant differences between the vaccine groups over time (Figures 2 and 3), we sought to define how accurately immunogenicity data could distinguish between the co-administration and separate administration groups using a multivariate approach (Pittala et al, 2019) including all the immunological parameters outlined in Tables S2 and S3, using data collected after each vaccination, when available. Regularized binomial logistic regression (Cox, 1958) models were used to discriminate between animals in the two vaccine groups at each of the different time points.…”

Mumps Outbreaks in Vaccinated Populations—Is It Time to Re-assess the Clinical Efficacy of Vaccines?

“…It has been suggested that vaccinated individuals have modified B-cell responses to MuV that allow for the rapid generation of IgG antibodies and a blunted or absent IgM response ( 207 , 208 ). In addition, emerging data in Simian Immunodeficiency Virus studies suggests that not all antibody responses are equal, and qualitative features of antibodies may be key to defining protective immune profiles ( 209 ).…”

“…Ensuring the use of a reference sample that had similar replication rate and composition as the virus to be tested will allow accurate determination of the quantity of virus present per lot of vaccine. Investigating novel vaccine candidates shown to induce a similar quantity but qualitatively different antibodies will help segregate and reveal potential correlates of protection ( 209 ). Incorporating more modern technologies such as microarray technology or antibody pattern/profiling (rather than single antibody measures) to investigate biomarkers of neutralizing antibody response and/or correlates of protective immunity, in addition to incorporating what has been accomplished in Finland will allow further understanding of mumps immunity ( 123 , 124 , 173 , 195 , 196 , 295 ).…”