# Presentation: 461042

## Lab of Immunoregulation

**Berkower Lab**                            **Weiss Lab**
-    -- Angelo Spadaccini		         -- Russell Vassell
-    -- Yisheng Ni                                    -- Yong He
- Hong Chen        	                    -- Wei Wang
- Students: Chiraag Patel               -- Nidhi Gupta
-                    Megan Raymond
-                    Ton Pinar                        NIH
- 			   Rebecca Lynch              -- Paul Wingfield
- 			   Sumitra Paul
- LVBVD
- -- Jacqueline Muller, EM
-     VRC
-     -- Sanjay Phogat

## Lab of Immunoregulation

**Regulatory Areas**
**Licensed vaccines:  **
-       approved Hep A/Hep B vaccine * *
**Clinical trials of new vaccines: **
-       reviewed >250 IND documents
**Therapeutic vaccines for HIV infection: **
**   **completed review of first phase 3 trial (3000 subjects)
**Vaccine Policy: **
**     **Guidance for peptides
-      Eliminating BSE risk in vaccines
-      Interagency committee on select agents of
-      bioterrorism

## Research Focus:  Factors affecting vaccine potency and efficacy, including biology of the virus and immune response of the host

**    ****Our goals:*** **	**	**	**	**	**	**	*
- -- To advance the science of AIDS vaccines
- To improve our expertise and add value at each step of the regulatory process

## Weiss Lab Research Focus

**HIV Vaccines**
***Defining conserved neutralizing determinants in Env ***
***Characterizing Env structures as immunogens for eliciting broadly neutralizing antibodies***
***Elucidating the mechanism of antibody neutralization ***
***Assessing neutralization assays***
**Smallpox Vaccines**
***Dissecting neutralizing antibodies elicited by Dryvax***
***Evaluating role of those antibodies in protection  ***

## HIV Vaccines: Major Research Findings 

**Showed that two highly conserved sites in Env fusion intermediate can be targeted for inhibition**
**Designed structure-based strategy for raising antibodies to these conserved sites **
**Evaluated the antibodies for neutralizing activity and studied potential barriers to antibody access**
**Identified Env mutations and potential resistance mechanisms for escaping inhibition at these sites **

## HIV Vaccines: Research Relevance

**New strategies for developing vaccines that induce broadly neutralizing antibodies**
**New methods for characterizing Env immunogens**
**Mechanisms of Env escape from inhibitors (resistance)**
**Expertise in neutralizing assays and potential correlates of protection**

## Smallpox Vaccines: Major Research Findings

**Demonstrated that a recombinant vaccinia protein (A27) elicits potent neutralizing and protective antibodies that**
***Passively protect immunocompromised animals***
***Augment vaccinia immune globulin (VIG)***
**Showed that A27 antibodies are a minor component of antibodies induced by Dryvax**

## Smallpox Vaccines: Research Relevance

**Understanding the protective response to Dryvax will aid in development of new vaccines**
**Identifying viral antigens that induce protective antibodies that may be maximized in new vaccines**
**Providing ways to improve therapeutic immunoglobulins (to augment or replace VIG)**

## Berkower Lab Research Focus

-    Can we enhance HIV vaccine potency by incorporating
-    gp120 or gp41into virus-like particles?
**2. HIV envelope has conserved and variable antigenic**
**   ****determinants, and it migrates between two forms, **
**   ****which can be described as open and closed.**
-    Can we modify envelope to keep it in the open form?
-    This would expose conserved sites and favor the
-    induction of broadly crossreactive antibodies.

## Particle Formation

- <date/time>

**Particle Formation**

-            env

- 226/42

- 125/205

- HBsAg

- 503

- NH2

## Summary of Results

- <date/time>

- _Summary of Results_

- gp120 Particles
- Hybrid proteins assemble efficiently into 20-30 nm particles rich in gp120.
- gp120 is in the native conformation, which changes in response to CD4 receptor binding. It functions like gp120 on the virus.
- Immunogenicity:  elicits neutralizing antibodies earlier than native gp120, but these are still limited to the immunizing strain.
- Progress since the site visit
- gp120 exists in two conformations: unliganded (closed form) or bound to CD4 (open form).  All gp120 vaccines so far have been in the closed form.
- We have identified five structural loops that change position as gp120 changes to the open form.  Removing one of the loops favors the open form and exposes the CD4 binding site for antibody binding.
- This mutant will allow us to immunize with the open form and may lead to vaccines that elicit antibodies to conserved neutralizing sites that are normally hidden.

## Relevance of Antibody Research for Immunity to HIV

- HIV-infected patients make broadly crossreactive neutralizing antibodies
- Monoclonal antibodies derived from these patients target shared neutralizing determinants on gp120 and gp41
- A cocktail of monoclonals gave the most potent protection ever seen in the macaque challenge model, with sterilizing immunity in most cases.
- A vaccine that exposes the functional sites targeted by these antibodies would have the best chance of inducing protective immunity.

## Impact of Research

- 1. A successful AIDS vaccine most likely will elicit
- 	both neutralizing antibodies and effector T cells.
- 2. Antibodies that target essential viral functions, such
-     as receptor binding or viral membrane fusion, can
-     crossreact broadly.
- 3. Successfully modified forms of gp120, with exposed
-     neutralizing determinants, can lead to immunogens
-     with enhanced vaccine potency.  ** **
- 4.** **Studies of viral neutralization will help us to evaluate
-     new vaccine candidates and define the correlates
-     of immunity.