# Presentation: 744832

## VRBPAC Topic #2:Clinical Development of Influenza Vaccines for Pre-pandemic Use

**Joseph G. Toerner, MD, MPH**
**VCTB/DVRPA/OVRR/CBER/FDA**
**February 27, 2007**

## Introduction

**The current situation with Influenza A/H****5****N****1**** highlights the need for vaccine development**
** ****Host: expanded outside avian species**
** ****Human infection: 278 cases reported**
** ****Case fatality 63%**

- 2

## Introduction

**Use During Pandemic or Situations of Potential High Risk of Exposure **
** ****Draft Guidance for Industry, March 2006**
**  ****Immune response reasonably likely to predict clinical benefit**
** ****HI antibody 4-fold increase: 40% ****(lower bound 95% CI) ****[and/or]**
** ****HI antibody % ****≥ 1:40: 70% ****(l****ower bound 95% CI) **
** ****Safety database requirements**
** ****Different scenarios based on seasonal manufacturing experiences**
_**Use Prior to a Pandemic**_**: Different strategies**
** “****Prime-boost”  or “Cross-protection”**
** ****VRBPAC Discussion**
** ****Clinical study designs, endpoints, and duration**
** ****Safety database**

- 3

## Pre-pandemic Vaccination

**“****Priming” vaccination**
** ****Pediatric population: influenza “naïve”**
** ****Administration of two doses 1 mo. apart**
** ****Two doses widely separated in time: ****Englund et al. Pediatrics 2005;115:1039-1047**
** ****Two different strains widely separated in time: ****Walter et al.  Pediatrics 2006;118:570-578**
** ****Remote administration of H****5 ****antigen**
** ****Immune response following single “boost” widely separated in time: ****Treanor et al.  IDSA 2006**

- 4

## Pre-pandemic Vaccination

** ****Prior antigenic experiences protect or ameliorate influenza illness: ****Couch and Kasel, Ann Rev Microbiol 1983;37:529-549**
** ****Homologous immunity**
** ****Heterologous immunity**
** ****Influenza vaccine and cross-protection against antigenically drifted influenza strains**
** ****Greater than 70% efficacy noted in culture-confirmation studies:**
** ****Ohmit et al. NEJM 2006;355:2513-2522**
** ****Meiklejohn et al.  J Infect Dis 1978;138:618-624**

- 5

## Pre-pandemic Vaccination: Risk versus Benefit

** ****Risks and benefits of seasonal trivalent influenza vaccine are known****	**
** ****IOM: data do not support association between seasonal influenza vaccine and GBS**
** ****ACIP: 1 additional case GBS per 1 million persons vaccinated, if assoc. exists**
** “****Swine Flu Vaccine” experience in 1976**
** ****GBS 1 case per 100,000 persons vaccinated**
** ****Rare serious adverse events during pre-pandemic use: unknown benefit**

- 6

## VRBPAC DiscussionHypothetical Clinical Development

** ***During ***Pandemic/High Risk Indication**

| Cohort
 | Day 1 | Day 28 |   |  |  |
| --- | --- | --- | --- | --- | --- |
| A | A/Vietnam |  |  |  |  |
| B | A/Vietnam | A/Vietnam |  |  |  |
|  |  |  |  |  |  |
|  |  |  |  |  |  |
|  |  |  |  |  |  |

- 7

## VRBPAC DiscussionHypothetical Clinical Development

** ****Pre-pandemic Use Indication: homologous**

| Cohort | Day 1 | Day 28 | Month 6 | Mo. 12 | > Mo. 12 |
| --- | --- | --- | --- | --- | --- |
| A | A/Vietnam |  |  |  |  |
| B | A/Vietnam | A/Vietnam |  |  |  |
| C | A/Vietnam |  | A/Vietnam |  |  |
| D | A/Vietnam |  |  | A/Vietnam |  |
| E | A/Vietnam |  |  |  | A/Vietnam |

- 8

## VRBPAC DiscussionHypothetical Clinical Development

** ****Pre-pandemic Use Indication: heterologous**

| Cohort | Day 1 | Day 28 | Month 6 | Mo. 12 | > Mo. 12 |
| --- | --- | --- | --- | --- | --- |
| A | A/Vietnam |  |  |  |  |
| B | A/Vietnam | A/Vietnam |  |  |  |
| F | A/Vietnam |  | A/Indonesia |  |  |
| G | A/Vietnam |  |  | A/Indonesia |  |
| H | A/Vietnam |  |  |  | A/Indonesia |

- 9

## Committee DiscussionEfficacy

** ****Please discuss the use of immune responses to determine evidence of efficacy for pre-pandemic use or “priming”**
** ****Immune response assay following “prime”**
** ****Immune response assay following “boost” at future time points**
** ****HI Antibody vs. other immune response assays**
** ****Microneutralization**

- 10

## Committee DiscussionClinical Trial Design

** ****Please discuss the feasibility of longer-term clinical studies of “prime” and “boost” pandemic influenza vaccine**
** ****Duration of study: 6 months, 1 year, > 1 year**
** ****Collaboration among different sponsors**

- 11

## Committee DiscussionSafety

** ****Please discuss safety considerations for licensure of vaccines for pre-pandemic use**
** ****Pre-licensure safety database**
** ****Rare serious adverse events (i.e. 1 per 100,000) not likely to be detected in a typical pre-licensure database**
** ****Novel manufacturing processes or adjuvants**
** ****Pre-licensure safety data collection and duration of follow-up**

- 12