# Presentation: 566740

## Introduction to Pandemic Influenza Vaccine and Antiviral Decision Issues  

- Ben Schwartz, MD
- National Vaccine Program Office, DHHS

- “The pandemic influenza clock is ticking.
-   We just don’t know what time it is.”
- 				*Ed Marcuse, ACIP Member*

## Pandemic Response Actions:

- Time

- Impact

- Pandemic influenza disease

- Timing and Potential Impacts

- Vaccination

## Key Vaccine and Antiviral Issues

- Approach to vaccine purchase and distribution (role of the public and private sectors)
- Priority groups for receipt of pandemic vaccine
- Priority groups for antiviral drugs and drug use strategy (chemoprophylaxis & therapy)

## Pandemic Influenza Vaccine Production Timelines

- Development of reference strain
- Use of reverse genetics allows HA and NA from pandemic strain to be combined with other genes from a strain well adapted to growth in eggs
- Vaccine production (monovalent)
- Master seed developed from reference strain
- Growth in eggs and purification
- Formulation and filling
- Regulatory process
- Optimal timing ~3 months (if reference strain and potency testing reagents already developed)

## Pandemic Spread and Seasonality

- Spread of a pandemic
- Months before U.S. community outbreaks for prior pandemic strains
- 1918 – 0; 1957 – 4-5; 1968 – 2-3; 1977 – 3-4
- Spread of the next pandemic
- More rapid because of increased international travel
- More warning because of better surveillance
-  Seasonality
- Fall – Spring seasonality generally preserved
- Multiple pandemic waves occur – potentially in the same season

## Asian Influenza in the U.S., July 1957

- Ref: Trotter, Am J Hyg, 1959

## Percentage of counties

- per State reporting
- influenza outbreaks,
- July – October, 1957

- Ref: Trotter, Am J Hyg, 1959

## Influenza by Week of Onset in U.S. Counties, Fall 1957

- Ref: Trotter, Am J Hyg, 1959

## Timeline of First and Second Pandemic Waves, 1957-58

- Ref: Trotter, Am J Hyg, 1959

## Pandemic Vaccine Availability in Prior Pandemics

| Year | Vaccine status |
| --- | --- |
| 1957 |  6 US based manufacturers
 60 m vaccine doses produced
 Peak of disease and vaccination in October
 PHS recommended priority for HCWs and high-risk but recommendations largely ignored   |
| 1968 |  New strain identified in June
 Limited pandemic vaccine production & availability
 Recommendations and use? |

## Vaccine Availability for the Swine Influenza Program 

| Year | Vaccine status |
| --- | --- |
| 1976 |  4 US based manufacturers
 New strain identified in February
 150 m vaccine doses produced under federal contract
 Vaccine distributed to states for mass vaccination (no defined priority groups)
 Vaccination begun in October
 40 m doses administered before program halted due to occurrence of GBS |

## Pandemic Influenza Vaccine Supply Estimates: Current Status

- Pandemic vaccine supply assumptions
- Only US produced vaccine will be available (1 mfr)
- 15 ug antigen/dose and 2 doses/person will be needed for protection
- Monovalent vaccine production capacity will be 3-fold that of annual vaccine (e.g., similar Ag yield/egg)
- Current Sanofi production is sufficient to deliver ~250 M monovalent doses/year (~5 million/week)
- Implication – about 1% of the population can be protected per week

## Pandemic Vaccine Purchase and Distribution

- Should vaccine purchase and distribution in the next pandemic be...
- Similar to 1957 and annual influenza vaccination with most doses distributed in the private sector; or
- Similar to 1976 Swine influenza program when vaccine was purchased and distributed by the public sector; or
- Some other model?

## Pandemic Vaccine Purchase & Distribution: Stakeholder Meetings, 2002

- Series of individual discussions and meetings with stakeholders, coordinated by CDC
- Objective to make recommendations on vaccine purchase and distribution to help state health departments in planning
- Issues considered included ability to target supply, equity, cost, feasibility of implementation, and others

## Pandemic Vaccine Purchase & Distribution: Stakeholder Meetings, 2002

- Options considered
- Primarily private sector program similar to inter-pandemic influenza seasons
- Federal purchase for “traditional” public health care recipients (uninsured, military, children eligible for VFC) – est. 40-50 M
- Federal purchase for above, HCWs, essential workers, and persons at high risk – est. 130-140 M
- Federal purchase of all pandemic influenza vaccine

## Pandemic Vaccine Purchase & Distribution: Stakeholder Meetings, 2002

- Most stakeholders preferred the federal purchase option
- Greatest equity; avoids price inflation; best targeting
- This option was recommended for the first pandemic year only
- Recommended negotiating a fair price and providing liability protection to manufacturers and those administering vaccine

## Vaccine Purchase and Distribution: Potential for Changes Over Time

**First wave**

**Second wave**

**Vaccine available**

**All public**

**Current**

**Increased public**

**Timeline and waves of pandemic disease**

## Reconsideration of Vaccine Purchase and Distribution Recommendations

- Experience since 2002
- Release of draft HHS pandemic plan and progress in State pandemic planning
- Experience with influenza and other vaccine shortages
- Expansion of influenza vaccine recommendations for inter-pandemic seasons
- Potential alternate approaches to consider

## Inter-Pandemic and Pandemic Vaccine Target Groups

- Inter-pandemic vaccine recommendations
- Persons at high risk of severe influenza & complications
- Persons who can transmit disease to those at high risk (HCWs and family members of high risk)
- Pandemic considerations
- Pandemic impacts may extend beyond health of infected persons
- Need to maintain quality health care system
- Need to maintain essential community services
- Vaccine supply will be more limited relative to need

## Potential Vaccine Target Groups and Population

| Group | Population | Percent  |
| --- | --- | --- |
| Health care workers
  Hospital HCW
  Outpatient | 11 M
  5 M
  6 M |   3.8%
  1.7%
  2.1% |
| Public safety workers |      2.3 M |   0.8% |
| High risk outpatients | 83 M | 28.9% |
| LTCF residents |      3.1 M |   1.1% |
| Essential community service |   ? |   ? |

## Questions in Defining Pandemic Vaccine Priority Groups 

- How should response goals be balanced?
- Can strata be identified within priority groups?
- How does one define essential workers?
- Should priority groups differ in more and less severe pandemics?
- How should direct vs indirect vaccine effects be considered?
- How should ethical issues and public preferences be considered?

- Influenza Antiviral Drug Issues:
- Strategy and Priority Groups

## Goals and Principles of Influenza Antiviral Drug Use

- Goals of antiviral drug use
- Decrease health, economic & social impacts
- (Prevent a pandemic through intensive intervention in a cluster of a less efficiently transmitted strain)
- (Slow disease spread early in a pandemic)
- “Overarching principles”
- Target drug to priority groups
- Maintain flexibility and responsiveness to local needs
- Consider efficiency in drug use strategies
- Use drugs appropriately to limit wastage & resistance

## Influenza Antivirals

- Adamantanes – amantadine & rimantadine
- Effective as prophylaxis; treatment shortens illness
- H5N1 isolates from human cases in Asia resistant; resistance develops rapidly if used as therapy
- Adverse events (neurological and GI) common
- Produced by proprietary & generic manufacturers
- Neuraminidase inhibitors – oseltamivir & zanamivir
- Effective as prophylaxis; treatment shortens illness and reduces complications
- Resistance uncommon
- Few adverse events
- Produced by proprietary manufacturers

## Advantages of NIs for Antiviral Interventions in a Pandemic 

- Documented effectiveness in decreasing influenza complications
- Low rate of antiviral resistance and less risk of resistance spreading with widespread therapy
- Low incidence of adverse events
- Oseltamivir - orally administered, simple dosing, few contraindications (infants <1 year old)

## Pandemic Antiviral Supply

- Global NI production capacity insufficient to meet pandemic needs – requirement for stockpiling
- Antivirals in the Strategic National Stockpile
- Oseltamivir (~2 million courses)
- Rimantadine (~4 million courses)
- Antivirals in the private sector
- ~1-1.5 million oseltamivir courses pre-influenza season

## Critical Factors in Defining Drug Use Strategy: Prophylaxis vs Treatment

- Effectiveness – impact on health outcomes and social & economic function
- Efficiency – optimal use of a limited antiviral supply
- Feasibility – can the recommended approach be implemented?
- Acceptability – is the approach ethical and acceptable to the public?

## Number of Antiviral Drug Courses for Prophylaxis vs Treatment

| Group | Population | Number of courses |  |
| --- | --- | --- | --- |
|  |  | Prophylaxis* | Therapy** |
| HCWs | 11 m | 61.6 m | 3.9 m |
| “Frontline” hosp | 2.5 m | 14.0 m | 0.9 m |
| Public safety | 2.3 m | 12.9 m | 0.8 m |

-   *Assumes 8-week prophylaxis
- **Assumes 35% attack rate

## Prophylaxis vs Therapy In Occupational Settings: Critical Unknowns

- Need for prevention (vs therapy) to avoid absenteeism
- From illness
- From fear of infection
- Risk of transmission in occupational settings
- E.g., from HCWs to co-workers and patients
- Implementation factors
- Ability to implement early therapy
- Ability to assure availability of therapy

## Target Groups for Antiviral Drug Interventions

- Priority groups are not defined in the draft pandemic plan
- Establish priorities based on pandemic response goals
- Draft report developed by an HHS/DoD/VA working group proposes priority groups for antiviral drugs
- Represents conclusions from the working group and not HHS or its agencies

## Cumulative Antiviral Courses for Proposed Groups by Pandemic Severity

## Questions in Defining Pandemic Antiviral Priority Groups

- Similar questions as for vaccines (balancing goals; stratifying within groups; defining essential workers; ethical issues and public preferences; differences based on pandemic severity)
- Will treatment be adequate to maintain health care and community services or will prophylaxis be needed?
- How do implementation issues affect definition of target groups?
- What drugs should be stockpiled and how does this affect definition of target groups?

## Conclusions: Products of the Working Group & Subgroups

- Recommendations on approach to vaccine purchase and distribution, and on vaccine and antiviral strategies and priority groups are important for effective planning
- Analysis of these issues by the PIWG and recommendations through NVAC and ACIP will facilitate decision-making and an effective pandemic response