# Presentation: 912859

## Pandemic Influenza Vaccine Supply IssuesApril 20, 2005

- Raymond A. Strikas, M.D.
- National Immunization Program, Centers for Disease Control and Prevention

**Notes:**
I’m going to talk about Effective Immunization Interventions, and will focus mainly on adults. The findings I will be  discussing are based mainly on a review of the literature that was conducted as part of the Guide to Community Preventive Services vaccine chapter.

## Presentation Outline

- Pandemic Vaccine Supply and Timelines (some reminders from yesterday’s and today’s discussions)
- Current status of vaccine supply
- Potential expansion of vaccine supply
- Capacity increase
- Antigen-sparing approaches

## 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** ~3-4 months (if reference strain and potency testing reagents already developed)

## Slide 4

## Pandemic Spread and Seasonality

- Spread of a pandemic/”shifted” virus
- 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

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

- Ref: Trotter, Am J Hyg, 1959

## Asian Influenza, 1957-58

- No national or state plans in place
- 6 US based manufacturers
- States formed advisory committees on influenza control in August-September
- Voluntary vaccine allocation recommended by PHS and ASTHO; no large public purchase of vaccine.  60 million doses produced, but only 35 million available by October 26 (outbreak 1st wave ending)
- PHS considered priority for HCWs, essential personnel, and high-risk (those with heart disease, TB, and “other chronic ailments [including pregnancy]”)
- Recommendations were not made from PHS, but left to state health departments; some added children <1 year, and all persons _>_50 years.

## “Avenues for Exploration in the Inter-pandemic Period”

- “Work should be done with attenuated live vaccines... Mineral
-  oil adjuvant vaccines offer another promising line of attack.
- More work can be done in the inter-pandemic years on potency,
- dosage, route of introduction, number of doses, interval between
- doses, rapid diagnostic techniques.  Some suggest ...working
- toward two separate vaccines in the future, one for children and
- one for adults.  The challenge is unlimited.”

- U.S. Public Health Service, “Influenza 1957,” 1958, unpublished

## Hong Kong Influenza, 1968

- Ad hoc response (again)
- No national or state plans
- ACIP recommendations: same as for that year’s polyvalent vaccine
- Chronically ill persons
- Older age groups (beginning at >45 years)
- 21 million persons vaccinated  (40 million doses produced)

## Swine Influenza Program, 1976

| 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
 45 m doses administered before program halted due to occurrence of GBS (85% in public clinics) |

## 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 Influenza Vaccine Supply: Possible Additional Options

- If 7.5ug/dose is immunogenic, vaccine supply is doubled
- If whole virus vaccine were used, production may be increased 50%
- One to two additional manufacturers may have U.S. licensed vaccine soon, may offer additional pandemic supply

## New Technologies and Antigen-sparing Concepts

## Potential Antigen-SparingApproaches to Influenza Vaccination

- Vaccine delivery strategies
- Partial doses (1/2 dose or other)
- Alternate route of injection (e.g., intradermal)
- Immune enhancement strategies
- Adjuvanted vaccine (e.g., alum, MF59)
- Alternative delivery technologies
- Immunostimulant patch, dose-sparing needles, syringes, jet injectors

## Influenza Vaccine Partial Doses 

- Treanor et al, Vaccine 2002, documented small differences in healthy adults 18-49 yrs, between 7.5ug and 15ug doses:
- <20% in achieving hemagglutinin inhibition titer of 1:40
- <1.5 in ratios for GMTs between doses for all 3 antigens
- Authors concluded that vaccinating N healthy adults with half dose will protect more persons than vaccinating 1⁄2 N with full dose
- DoD conducting study with 2004 vaccine; data to be available spring, 2005

## Alternate route of injection for Influenza Vaccine

- Options include intradermal, subcutaneous, intranasal, oral
- Antigens delivered to nasal, other mucosal surfaces, dermis may increase immunogenicity (more immune receptors)
- Belshe et al, Kenney et al, NEJM, 2004  intradermal studies suggest ID delivery may allow dose sparing, but small studies.  Not as immunogenic in adults >59 years
- Need larger studies, proper controls

## Immune enhancement strategies:Adjuvanted vaccine

- No licensed U.S. influenza vaccine contains an adjuvant
- MF59, ISCOMS (immunostimulating reconstituted influenza virosomes) licensed in Europe
- Adding an adjuvant may provide greater immunogenicity with less antigen
- Alum, MF59 may be most likely choices; do increase local reactions
- Studies with U.S. licensed vaccines necessary

## Alternative Delivery Technologies

- Immunostimulant patches (e.g., with E. coli heat stable enterotoxin)
- Jet injectors for intradermal vaccination
- Dose-sparing needle/syringe combinations (may add 1⁄2 to 1 dose to  a 10 dose vial)

## Potential Timeline of Interventions to Expand Pandemic Vaccine Supply

- 0	1	2	3	4	5	6	7	8

- Partial dose

- Alternate route of administration

- Expanded U.S. egg-based production

- U.S. cell-culture production

- Adjuvanted vaccine

- Number of years until licensure or possible recommendation

## 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?