# Evolution of anti-filovirus B cell responses and mechanisms of protection

> **NIH NIH R01** · INTEGRATED BIOTHERAPEUTICS, INC. · 2020 · $738,574

## Abstract

The 2014 outbreak in West Africa, cause by Ebola virus (EBOV), has highlighted the global threat of filoviruses.
Major progress has been made recently towards vaccines and monoclonal antibody (MAb) therapeutics specific
for EBOV including development of ZMapp, a cocktail of three mAbs, and two vaccine platforms that advanced
to clinical trials. The success of ZMapp has highlighted the critical role of antibodies in protecting against filovirus
hemorrhagic fever. However, cross reactive MAbs and vaccines that would also protect against other members
of Filoviridae such as Marburg, Sudan, and Bundibugyo viruses are lagging behind. Little is known about the key
features of broadly protective responses including cross-species neutralizing epitopes within filovirus surface
glycoprotein (GP), the mechanisms by which antibodies against different epitopes synergize for effective
neutralization, features that determine the evolution of cross protective versus species specific B cell responses,
and the extent to which neutralizing and cross-reactive antibodies are elicited after vaccination or natural
exposure. This proposal aims to address these important questions.
Using a soluble HIV envelope glycoprotein as model antigen and a combination of B cell cloning and deep
sequencing we have extensively characterized the features of broadly neutralizing HIV antibodies including the
VH/VL usage and the degree of somatic hypermutations (SHM) in rhesus macaques. Here we intend to use a
similar approach to understand the evolution of B cell responses to filovirus antigens in macaques. Cynomolgus
and rhesus macaques are highly relevant models for filovirus vaccine development and, given the high homology
between the human and monkey immunoglobulin VH loci (91.7±2.2%), also for the study of the B cell evolution
or identification of therapeutic filovirus MAbs. We have recently performed two immunization studies using
filovirus antigens in cynomolgus and rhesus macaques and generated a large collection of peripheral blood
mononuclear cells (PBMC), bone marrow, and splenocytes that will be used in this proposal for in depth
characterization of broadly protective B cell responses and identification of novel therapeutic MAbs. Using the
PBMC from the first cynomolgus study we have already identified several pan-ebolavirus and pan-filovirus
antibodies including MAbs that cross-neutralize and protect against SUDV and EBOV in mice and guinea pigs.
This is the first report of antibodies protective against these two most divergent ebolavirus species. We have
also discovered a novel mechanism of cooperative neutralization by certain pan-ebolavirus MAbs, a
phenomenon that builds a rational basis for design of effective MAb cocktails as well as broadly protective
vaccines. This proposal is designed in three specific Aims. In Aim 1, we will define the genetic elements of
cynomolgus naïve Ig repertoire to complement the knowledge that already exists on rhesus. Novel cross-reactive
...

## Key facts

- **NIH application ID:** 9890991
- **Project number:** 5R01AI126587-04
- **Recipient organization:** INTEGRATED BIOTHERAPEUTICS, INC.
- **Principal Investigator:** M Javad Aman
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $738,574
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9890991

## Citation

> US National Institutes of Health, RePORTER application 9890991, Evolution of anti-filovirus B cell responses and mechanisms of protection (5R01AI126587-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9890991. Licensed CC0.

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