# Presentation: 138322

## Session 2:  Introduction

- Peter A. Patriarca, M.D.
- Director, Division of Viral Products
- OVRR/CBER/FDA
**VRBPAC meeting, 26 July 01**

## FluMistTM

**Live**

**Attenuated**

**Cold-adapted**

**Temperature-Sensitive**

**Trivalent**

**Influenza virus vaccine**

**Active viral replication**

## FluMistTM

**Live**

**Attenuated**

**Cold-adapted**

**Temperature-Sensitive**

**Trivalent**

**Influenza virus vaccine**

**Active viral replication**

**“****Mild” illness**

## FluMistTM

**Live**

**Attenuated**

**Cold-adapted**

**Temperature-**
**sensitive**

**Trivalent**

**Influenza virus vaccine**

**Active viral replication**

**“****Mild” illness**

**Replication restricted**
**mainly to nasopharynx**

## FluMistTM

**Live**

**Attenuated**

**Cold-adapted**

**Temperature-**
**sensitive**

**Trivalent**

**Influenza virus vaccine**

**Active viral replication**

**“****Mild” illness**

**Replication restricted**
**mainly to nasopharynx**

**A (H3N2, H1N1), B**

## FluMistTM

- PB2

- PB1

- PA

- NP

- M

- NS

- PB2

- PB1

- PA

- NP

- M

- NS

- PB2

- PB1

- PA

- NP

- M

- NS

**FluMist****TM**

**Trivalent +**
**Allantoic Fluid**

**Master**
**Donor**

**Wild-**
**type**

**“****6:2”**
**Reassortant**

## Purpose

- 	Orient the Committee/audience
-    Review November ’98 VRBPAC

**Review risk-benefit considerations**

- 3.

- 2.

- 1.

## Potential benefits

- Influenza = most common cause of medically attended acute respiratory illness
- High risk of mortality and other severe complications
- Recent “rediscovery” of clinical and public health impact in children, esp. 0-4 years
- High-risk: 500 excess hospitalizations/100,000
- Healthy: 100 excess hospitalizations/100,000

## Special Challenges

- Administration of a live (replicating) agent
- Large target population
- Annual vaccination required
- Annual reformulation likely
- Licensed product (inactivated vaccine) available x 50 years

## Benefit

***Benefit***

***Risk***

**vaccine strains**
**cell substrate**

**manufacturing**
**process &**
**consistency**

**host response**

**transmission**
**to contacts**

## Benefit

***Benefit***

***Risk***

**Seed strains**
**Cell substrate**

**Manufacturing**
**process**

**Host response**

**Transmission**
**to contacts**

**Antigenicity**
**Immunogenicity**
**(homologous,**
**  ****heterologous)**

**Reactogenicity**
**Exogenous &**
**  ****endogenous**
**  ****adventitious**
**  ****agents**

## Benefit

***Benefit***

***Risk***

**Seed strains**
**Cell substrate**

**Manufacturing**
**process**

**Host response**

**Transmission**
**to contacts**

**Antigenicity**
**Immunogen.**
**(homologous,**
**  ****heterologous)**

**Reactogen.**
**Exogen &**
**  ****endogen**
**  ****advent.**
**  ****agents**

**Purity**
**Potency**
**Consistency**

**Contamination**
**Genetic Instability**
**  ******** ****Attenutation**
**  ******** ****Antigenicity**
**Residual cellular**
**   ****DNA, proteins**

## Benefit

***Benefit***

***Risk***

**Seed strains**
**Cell substrate**

**Manufacturing**
**process**

**Host response**

**Transmission**
**to contacts**

**Antigenicity**
**Immunogen.**
**(homologous,**
**  ****heterologous)**

**Reactogen.**
**Exogen &**
**  ****endogen**
**  ****advent.**
**  ****agents**

**Purity**
**Potency**
**Consistency**

**Contamination**
**Genetic Instab**
**  ****Attenuation**
**  ****Antigenicity**
**Resid cellular**
**   ****DNA, prot**

_**Reduction in:**_
**Infection (wt)**
**Shedding (wt)**
**Illness**
**Complications**
**Mortality**

**Acute/delayed ADRs**
**Reversion**
**Immune selection**
**Immune interference**
**Allergic reactions**

## Benefit

***Benefit***

***Risk***

**Seed strains**
**Cell substrate**

**Manufacturing**
**process**

**Host response**

**Transmission**
**to contacts**

**Antigenicity**
**Immunogen.**
**(homologous,**
**  ****heterologous)**

**Reactogen.**
**Exogen &**
**  ****endogen**
**  ****advent.**
**  ****agents**

**Purity**
**Potency**
**Consistency**

**Contamination**
**Genetic Instab**
**   ****Attenuation**
**   ****Antigenicity**
**Resid cellular**
**   ****DNA, prot**

_**Reduction in:**_
**Infection (wt)**
**Shedding (wt)**
**Illness**
**Complic.**
**Mortality**

**ADRs**
**Reversion**
**Immune selec**
**Immune interf**
**Allergic rxns**

**Indirect**
**Immunization**

**Reversion**
**Reassort-**
**  ****ment with**
**   ****wt virus**

## November 1998 VRBPAC

- Virus containment
- Maintenance of attenuation
- Potential for reassortment with wt
- Risk of allergic rxns (egg protein) and/or bacterial superinfection

## 1.  Containment

- Issues:
- Release of H2N2 or B master donor virus
- Manufacture of LAIV with novel HA and/or NA (pre-pandemic)
- Opinion:
- Not considered problematic
- Use of wt with novel HA and/or NA would require high-level of biosafety

## Hypersensitivity rxns &bacterial superinfection

- Issues:
- Repeated admin egg protein intranasally
- Active replication: de-epithelialization, cilliary dysfunction, PMN dysfunction
- Opinion:
- Egg protein cleared prior to virus replic (?)
- Bacterial infections more likely to be prevented than caused

## 3.  Introduction of new viruses in the form of LAIV

- Issues:
- Purposeful introduction of genetically modified influenza viruses into the general population
- Potential for reassortment with wt viruses to create more virulent human strains
- Opinion:
- Transmission very limited; progeny likely to be attenuated
- No circulation of genes derived from A/Leningrad LAIV
- Genetic modifications cannot be ruled out

## 4.  [Conservation of] Attenuation

- Issues:
- Maintenance of attenuated phenotype in different (annual) 6:2 reassortant strains
- Animal models (ferret) less than ideal
- Genetic basis of attenuation generally unknown
- Opinion:
- Annual human testing desirable ... approach and logistics not determined

## Other issues

- Difficulties in assessing reactogenicity (“placebo” = allantoic fluid)
- Rare/uncommon adverse events
- Repeated (annual) dosing:
- Potential adv immunological consequences?
- Replicates poorly (or not at all) in seropositives
- Lack of co-admin data with other vaccines
- Limited experience in high-risk groups

## Summary

- FluMistTM poses complex benefit-risk considerations
- Principal focus of today’s discussion = clinical considerations
- Other issues:
**Manufacturing**
**Attenuation/reversion**
**Transmission**
**Use in medically high-risk populations**