# Presentation: 600442

## Influenza Vaccine Effectiveness:  Considerations for Prioritization of Pandemic Influenza Vaccine

**Carolyn B. Bridges, MD **
**National immunization Program, CDC**
**for**
**NVAC/ACIP Influenza Vaccine Working Group**
**April 20, 2005**

## Influenza Vaccine Effectiveness (VE)

- Reviewed by ACIP Influenza Working Group January 2005 meeting on inter-pandemic prioritization
- Kristin Nichol
- John Treanor
- Wendy Keitel
- Lone Simonsen
- Litjen Tan
- Niranjan Bhat
- Guillermo Herrera
- Raymond Strikas

## Outline

- VE TIV during inter-pandemic years
- By age group and chronic condition
- VE LAIV
- 1 versus 2 doses in immunologically naïve populations
- TIV in children
- LAIV in children
- Swine flu and “Russian flu” H1N1 vaccines
- Studies of H5 vaccines

## Vaccine Effectiveness

- Varies by age group, risk group, and antigenic match
- Variety of outcomes/methods in literature
- Influenza-like illness
- Laboratory-confirmed influenza
- Influenza-related hospitalization and death largely based on modeling
- Herd immunity effects may also be considered

## Healthy Adults < 65 Yrs

- Key literature reviewed
- US military trials
- Cochrane review (updated 2004)
- 8 clinical trial papers published since 1988

## Efficacy of Influenza Vaccine in Healthy Young Adults

*** Adapted from Davenport, Med J Aust 1973 (suppl): 33-8.**
**+ Adapted from Meiklejohn. J Infect Dis 1983; 148: 775-84.**

-     US Army Field Trials*		     US Air Force Field Trials+

## VE Healthy Adults

- VE estimates (Cochrane review for IV)
- Lab-C illness	70% (56% - 80%)
- Clinical ILI	25% (13% - 35%)
- Work loss reduction:
- 0.16 days per person vaccinated (0.04 – 0.29)
- Other studies generally similar
- Vaccination also associated with reductions in health care provider visits & antibiotic use due to URI / ILI
- Insufficient data on serious complications

## VE During Pregnancy  (1 cohort study)

- Black SB, Am J Perinatology 2004
- Subjects: 49,585 women with live births Nov thru Feb 97-98 thru 00-01 (KPNC)
- Results
- Hospitalizations: very rare
- Outpt visits for resp illness: HR 1.15 (p = .09)
- Note: vaccination rates low (4.7% - 11.9%)

## Community Dwelling Elderly	

- 4 clinical trials published from 1994 on
- Numerous observational studies
- 1 meta analysis

## VE in Community Dwelling Elderly Persons (meta analysis)

| Outcomes (All Cause Outcomes) | Effectiveness |
| --- | --- |
| Clinical ILI | 35% (19% - 47%) |
| Hospitalizations for |  |
|      Respiratory Conditions | 30%   (25% - 35%) |
|      Pneumonia & Influenza | 33%   (27% - 38%) |
| Mortality |  |
|      Pneumonia & Influenza | 47%   (25% - 62%) |
|      All Cause | 50%   (45% - 56%) |

- Vu T, et al. Vaccine 2002; 20: 1831.

**Notes:**
Data are from a Meta-analysis.  Most of included studies were observational & from North America or Europe.

## VE by Risk Status

| Nichol, Arch Intern Med 1998 | Cohort study, 1990-91 thru 1995-96 | HPI
  low risk
  intermediate
  high risk
Death
  low risk
  intermediate
  high risk | 
49% (29-69)
32% (-8-71)
29% (11-47)

55% (45-69)
64% (52-73)
49% (41-57) |
| --- | --- | --- | --- |
| Hak, CID 2002 | Cohort study, 1996-97 

1997-98 | Death or HPI
  low risk
  high risk
  low risk
  high risk | 
46% (34-56)
47% (40-53)
42% (28-52)
29% (22-35) |

## VE: Elderly in Nursing Homes

- 1 meta analysis
- Several observational studies

## VE Nursing Home Residents

| Gross, AIM 1995  | Meta analysis of 20 cohort studies, 1960s to 1980s | Resp illness
Pneumonia
Hosp
Death | 56% (39-68)
53% (35-66)
48% (28-65)
68% (56-76) |
| --- | --- | --- | --- |
| Ohmit, JAGS 1999 | CC study, 1989-90 | ILI | 42% (21-58)
 |
| Monto, Am J Epi 2001 | Cohort study, 1991-92 | ILI or pneumonia
Pneumonia
Death within 3 mos of resp illness | 33% (17-46)
43% (11-64)
32% (-18-86) |
| Loeb, Arch Intern Med 1999 | Cohort study of pneumonia | Pneumonia
Lower resp tract illness | 60% (50-70)
70% (60-80) |

## VE: Poor Match Yrs

| CDC, MMWR 1998 | Cohort studies 1997-98
CT

NY

VA | 

ILI
Death from flu
ILI
Death from flu
ILI
Death from flu
Death (all resp) | 

-5% (-87-41)
35% (-417-92)
-34% (-714-78)
91% (30-99)
25% (-20-54)
-20% (-434-73)
33% (-102%-78%) |
| --- | --- | --- | --- |
| Health Canada, CCDR 2004 | Cohort study 2003-04 | ILI
Pneumonia
Death from pneumonia | 8% (-18-28)
48% (-11-75)
39% (-147-86) |

## Summary of VE in Adults

- Healthy adults
- Vaccination reduces illness / work loss
- Elderly
- Vaccination reduces illness & serious complications of influenza
- Vaccination provides benefits for healthy & high risk elderly & for community dwelling & NH residents
- VE with mismatch is variably reduced
- Even with lower VE, NNT must be considered

## Influenza VE Studies in Children

- Data more limited compared with adults
- Hoberman, et al JAMA 2003
- 2 dose TIV vs placebo among children 6-24 months
- 66% VE in year 1 and 0% in year 2 with low incidence influenza
- No VE versus otitis media
- Good immune responses to vaccine

## Pediatric VE Summary TIV

- Influenza vaccine is efficacious in children
- 21-76% for ILI
- 30-95% for lab-confirmed influenza
- 32-36% for otitis media
- Generally similar results for healthy and high risk

## Pediatric VE Summary, cont

- Vaccine efficacy in children increases with age
- Limited data in children aged 6-23 months

## LAIV vs. TIV

## Live and inactivated vaccines

- Theoretical considerations
- Live vaccines must replicate
- Level of replication depends on the host
- Children > adults > elderly
- Live vaccine stimulate mucosal immunity
- May be more effective at limiting shedding
- No well standardized immune correlates

## Live and inactivated vaccines

- Theoretical considerations
- Inactivated vaccines do not replicate
- Level of immunity depends on host priming
- Adults > children > elderly
- Inactivated vaccines stimulate serum antibody
- Well standardized immune correlate

## Live and inactivated vaccines

- There are few direct comparisons
- Indirect comparisons can be difficult to interpret
- Randomized direct comparisons
- Pediatric
- Adult
- Elderly
- More definitive comparisons in adult and pediatric populations are underway

## Pooled results of experimental infection studies in adults Vaccine 18:899 (2000)

- TIV

- CAIV

- 0

- 1

- 0

- 1

- 0

- 1

- 0.36

- 0.64

- 0.14

- 0.35

- 0.18

- 0.10

**Pooled Odds Ratio (95% CI) compared to placebo**

- Virus shedding

- Infection

- Influenza illness

## Natural infection in adults

- Edwards (1994) J Infect Dis 169:68-76
- Multiple years, subjects remain in group
- Control vaccines monovalent B/allantoic fluid
- Children did _**not**_** **receive 2-dose schedule
- LAIV given by drops
- Outcomes included ILI, serologic and culture-confirmed illness

## Evaluation of the protective efficacy of LAIV in adults

**H1N1**

**H3N2**

- Rate per 1,000 subjects

## Pediatric subgroup analysisNeuzil (2001) Pediatr Infect Dis J 20:733

- Analysis restricted to children younger than 16 at the time of immunization
- 474 age 1 to 5
- 744 age 6 to 10
- 591 age 11 to 15
- Two outcomes
- Culture positive illness
- Seroconversion

## Evaluation of the protective efficacy of LAIV in kids

**Cx positive**

**Ab positive**

- Rate per 1,000 or per 100
-  subjects

- Per 1,000

- Per 100

## Elderly

- LAIV is not infectious – less than 10% have detectable shedding by culture
- Low antibody response rates, even in subjects with low prevaccination antibody
- Combined vaccine may provide additional protection
- Nursing home – yes
- COPD - no

## One Versus 2 Doses In Naïve Populations

## 1976 Swine Flu and 1977 “Russian” Flu Vaccine Trials

- For persons born before H1N1 viruses last circulated (circa 1957)
- 2 doses needed for best antibody response
- 7 μg + doses gave comparable responses with 2 doses
- “Shallow” doses response with 1 dose with >50 μg needed
- Whole virus vaccine more immunogenic, but more reactogenic at high doses

## VE of LAIV in children 15-71 monthsBelshe RB, et al.  JAMA 1998;338:1405-12

- Trivalent LAIV versus placebo
- N=532 received placebo
- N=1070 received 1 or 2 doses
- VE against culture-confirmed influenza
- 89% with 1 dose
- 94% with 2 doses

## VE of TIV with 1 versus 2 dosesRitzwoller DR.  Pediatrics 2005 (in press)

- Retrospective cohort study children 6-23 months enrolled Kaiser Colorado
- 2003-04 when suboptimal antigenic match
- >5000 in cohort
- Controlled for high risk conditions using administrative data
- No laboratory confirmation
- VE NS with 1 dose, 25% for ILI and 49% for P&I with 2 doses

## LAIV vs Inactivated Vaccine

- One dose alone of inactivated vaccine in immunologically naïve persons
- Less likely to provide protective immune response unless use high doses
- Not protective in young children
-  2 doses inactivated vaccine likely to provide ‘protective’ immune response at lower antigenic content
- LAIV may provide better protection with 1 dose
- Immune-correlate less well defined, so assessment of probable efficacy based on immune response difficult

## H5 vaccines

## Response to Recombinant H5 VaccineTreanor JJ, et al Vaccine 2001;19:1732-7.

- Placebo-controlled trial
- 2 doses at 21, 28 or 42 day intervals
- 25, 45, or 90μg x 2 doses or 90 then 10μg
- Serum collected days 0, 14 days after 1st dose, dose 2 day 0, the 1,2,3,4 weeks after dose 2
- 21%-45% with ELISA immune response
- 17%-52% with micro-neutralization response
- Dose-response, highest at 90 μg x 2
- No significant effect by dosing interval

## Use of adjuvant MF59-H5N3 vaccineStephenson I, et al JID 2005;191:1201-5and Stephenson I, et al Vaccine 2003;21:1687-93

- Adults 18-45 yrs given 7.5, 15 or 30μg A/duck/Singapore/97 (H5N3)
-  IM injection with and without MF-59
- 2 doses, 21 days apart
- 7-14% with MF-59 versus 0-9% without
- 3rd dose 16 months later to subset
- Serum tested by micro-neutralization against HPAI H5N1 1997-2004 strains
- No dose response detected
- Seroconversion 43%-100% with MF-59 and 0%-27% without
- No 3rd dose booster effect with non-MF-59
- Conclusions
- 3 doses and adjuvant needed to improve response
- No difference among doses used, but small numbers

## Overall Summary

- Responses to inter-pandemic influenza vaccines
- Varies by age and chronic condition
- Within an age group, generally higher VE against complications than influenza illness
- LAIV and TIV options for children and adults <65
- Immunologically naïve persons need 2 doses to reach “protective” immune response for inactivated vaccines
- May be able to achieve with high single dose
- May need only 1 dose for live attenuated vaccines?
- Testing of H5 needed to assess safety and immunogenicity
- Clinical studies H5 vaccines to date suggest lower immunogenicity without adjuvant
- Further trials pending