# Presentation: 648368

**Recent developments in seasonal influenza epidemiology and prevention**
- Anthony Fiore, MD, MPH
- Influenza Division
- National Center for Immunization and Respiratory Diseases
- CDC
- Clinician Outreach and Communication Activity (COCA) Teleconference
- May 27, 2008_ _

## Continuing Education Credits DISCLAIMER:In compliance with continuing education requirements, all presenters must disclose any financial or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters as well as any use of unlabeled product(s) or product(s) under investigational use. CDC, our planners, and the presenters for this seminar do not have financial or other relationships with the manufacturers of commercial products, suppliers of commercial services, or commercial supporters. This presentation does not involve the unlabeled use of a product or product under investigational use. 

## Overview

**Brief review of clinical presentation and epidemiology of influenza **
**Review of the 2007-8 US influenza season**
**Seasonal influenza vaccine effectiveness**
**New and updated recommendations from the Advisory Committee on Immunization Practices (ACIP)**
**Recent influenza vaccine coverage data, United States**

## Human Influenza

**Highly transmissible respiratory illness caused by influenza viruses**
**Yearly winter epidemics (seasonal or interpandemic influenza)**
**Sporadic, unpredictable pandemics**

## Annual Interpandemic Influenza Impact

- 2.5-20% of population ill
- Highest rates in children
- Attack rates over 30% in children reported
- Average of >36,000 deaths (wide range)
- >90% in those >64 years
- Average of >200,000 hospitalizations (wide range)
- About 50% in those >64 years
- Risk of hospitalization for children <2 years similar to elderly
- Substantial economic impact
- Burden of annual epidemics estimated at $87.1 billion annually

## Influenza Virus Type A

- Subtyped based on surface glycoproteins
- 16 hemagglutinin (HA) and 9 neuraminidase (NA)
- Current human subtypes:  H1N1 & H3N2
- Capable of epidemics and pandemics
- Infects multiple other species and can jump between them
- Birds, pigs, horses, dogs...
- Birds are the reservoir for new subtypes: H1-16

## Influenza A: Antigenic Drift and Shift

- Antigenic _drift_
- Point mutations in viral genes
- Continual process
- Diminished immune response among previously infected or immunized persons to “drifted” strains
- Results in yearly epidemics
- Requires that vaccine updated yearly
- Antigenic _shift_
- Replacement of HA or HA + NA (i.e., new subtype) from an animal influenza A
- Sporadic, unpredictable event
- No immunity within the population
- Can result in a pandemic
- However: Many reports of transmission of animal influenza viruses to humans that do not result in pandemic
- H5N1, H7N2, H7N9, swine influenza viruses

## Influenza A(H5N1)

**Numerous outbreaks among among wild birds in Asia, Africa, Europe, Middle East**
**Highly lethal to domestic poultry (numerous ongoing outbreaks in multiple countries)**
**382 human cases, including 241 deaths since 2003***
- Close contact with infected domestic birds established in nearly all cases
**No efficient human-to-human transmission**
**H5N1 is the influenza virus with pandemic potential of greatest concern, but other influenza A viruses in animals also of concern**

- *As of May 20, 2008

## Influenza Virus Types B and C

- Influenza B
- Humans only reservoir
- Less mortality in most years c/w type A
- Associated with epidemics, not pandemics
- One influenza B strain in the annual seasonal influenza vaccine
- Influenza C
- Causes mild disease, sporadic cases
- Not included in vaccine

## Influenza Clinical Diagnosis

***Clinical symptoms are non-specific***
**Symptoms overlap with many pathogens**
**Laboratory data needed to verify diagnosis **
- Rapid tests most often used but some have poor sensitivity in adults
- Culture, PCR available but typically not timely
**Even at peak influenza season, about 25-35% of specimens from persons with symptoms of acute respiratory infection test positive for influenza**

## Influenza Surveillance in the United States, 2007-08 Influenza Season

## National Influenza Surveillance System

**CDC**

**Laboratories**

**Sentinel Providers**

**State and Territorial **
**Epidemiologists**

**Vital Statistics**
**Registrars**

**Public Health**
**Officials**

**Physicians**

**Media**

**Public**

**Health Departments**

**Population-based **
**Hospitalization**

**Pediatric Mortality**

**Novel influenza A**

## Seasonal Influenza

**Seasonal Influenza**

**Geographic Spread**
**Virus Monitoring**
**Mortality**
**Outpatient Illness**
**Hospitalizations**
**Antiviral Resistance**

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## Slide 18

## Slide 19

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## Slide 24

## Seasonal Influenza

**Seasonal Influenza**

**Geographic Spread**
**Virus Monitoring**
**Mortality**
**Outpatient Illness**
**Hospitalizations**
**Antiviral Resistance**

## U.S. WHO/NREVSS Collaborating LaboratoriesNational Summary, 2007-08

**U.S. WHO/NREVSS Collaborating Laboratories****National Summary, 2007-08**

## Strain Characterization, 2007-8 Season

**CDC has characterized 881 viruses**
**A (H1) [n=381]:  **
- 69% - A/Solomon Islands/3/2006-like viruses (similar to vaccine virus)
**A (H3) [n=280]**
- 21% - A/Wisconsin/67/2005-like viruses (similar to vaccine virus)
**B [n=220]**
- 3% in B/Victoria lineage that are B/Ohio/01/2005-like viruses similar to vaccine virus

## Seasonal Influenza

**Seasonal Influenza**

**Geographic Spread**
**Virus Monitoring**
**Mortality**
**Outpatient Illness**
**Hospitalizations**
**Antiviral Resistance**

## Pneumonia and Influenza Mortalityfor 122 U.S. CitiesWeek Ending 05/10/2008

- Epidemic Threshold

- Seasonal Baseline

**Pneumonia and Influenza Mortality****for 122 U.S. Cities****Week Ending 05/10/2008**

- 2005

- 2006

-  50     10      20      30     40       50      10       20      30     40      50     10     20     30     40      50      10      20      30       40       50      10

- 2007

- 2004

- 2008

## Influenza-Associated Pediatric Mortality

**71 influenza-associated deaths reported (as of May 14, 2008)**
- Median age: 4.5 years
- Vaccine status (n=62)
- 5 of 55 children eligible for vaccination were fully vaccinated
- Bacterial co-infections (n=53)** **
- 23 (43%) children had *Staphylococcus aureus* co-infection
- 12 methicillin resistant *S. aureus* (MRSA)
- 9 methicillin sensitive *S. aureus* (MSSA)
- 2 no sensitivities done

## Seasonal Influenza

**Seasonal Influenza**

**Geographic Spread**
**Virus Monitoring**
**Mortality**
**Outpatient Illness**
**Hospitalizations**
**Antiviral Resistance**

## Percentage of Visits for ILI & ARI Reportedby Sentinel Providers and BioSense Outpatient FacilitiesWeek 18 (April 27- May 3, 2008)

## Seasonal Influenza

**Seasonal Influenza**

**Geographic Spread**
**Virus Monitoring**
**Mortality**
**Outpatient Illness**
**Hospitalizations**
**Antiviral Resistance**

## NVSN Influenza Laboratory-Confirmed Cumulative Hospitalization, Children 0 - 4 Years, 2007- 08 and Previous 4 Seasons

## Seasonal Influenza

**Geographic Spread**
**Virus Monitoring**
**Mortality**
**Outpatient Illness**
**Hospitalizations**
**Antiviral Resistance**

## Antiviral Resistance (as of May 10, 2008)

**Neuraminidase Inhibitor Resistance (1,591 samples tested):**
-  106 (11%) of 969 influenza A (H1N1) viruses resistant to oseltamivir
- All of the resistant viruses have H274Y mutation
- 2006-7 season:** **4 (0.7%) of 588 influenza A (H1N1) viruses isolated in U.S. were resistant
-  0 of 332 influenza A (H3N2) viruses resistant to oseltamivir
-  0 of 290 influenza B viruses resistant to oseltamivir
-  All tested viruses remain sensitive to zanamivir
-  Given type/subtype prevalence in the United States, low rate of overall resistance (~2%)
**Adamantane Resistance**
-  136 (99%) of 137 influenza A (H3N2) viruses tested were resistant
- 79 (14%) of 565 influenza A (H1N1) viruses tested were resistant

## Oseltamivir Resistance in Influenza A(H1N1) 2007-08*

**http://www.who.int/csr/disease/influenza/h1n1_table/en/index.html**

**Oseltamivir Resistance in Influenza A(H1N1) 2007-08***

## Determinants of Antibody Response to Influenza Vaccines

**Age**
- Elderly, infants and chronically ill generally lower antibody response
**Prior exposure to virus strains similar to those in vaccine (infection or previous vaccination)**
**Immune competence of person being vaccinated**
**Amount of antigen in vaccine**
**Virus – strains can vary as to how robust immune responses will be**

**Notes:**
How effective vaccination is going to be in preventing influenza is often predicted by using the antibody response to vaccination as an indicator. For example, the very young and the elderly generally have lower antibody responses. Persons with previous exposure to virus strains similar to those in the vaccine (either because of previous infection or previous vaccination) will usually have a better antibody response. 
The immune competence of the person being vaccinated will affect response.
A larger amount of antigen in the vaccine can produce a better response, although a point of diminishing returns is often reached as antigen amounts are increased.
Finally, the type of vaccine affects the immune response. Live attenuated vaccines might provide a better immune response, but this response is more difficult to measure because it requires measuring types of immune responses beyond those that can be measured using serologic samples. Whole virus inactivated vaccines can be more immunogenic, but are also more likely to cause adverse reactions to the vaccine.

## Seasonal Influenza Vaccine Effectiveness

## Measuring Seasonal Influenza Vaccine Effectiveness

**Effectiveness varies by **
- Age group
- Risk group
- Timing and intensity of season
- Degree of antigenic match between vaccine strains and circulating strains
**Variety of outcomes/methods in literature make comparisons difficult**
- “Influenza-like illness” (e.g., fever and cough or sore throat) – non-specific but relatively easy to ascertain
- Laboratory-confirmed influenza -- most specific but requires clinical specimens and lab

**Notes:**
Clearly effectiveness, by any measure, varies according to the age group, influenza risk group, and the degree that the vaccine strains match the circulating strains. 
One of the challenges of determining the effectiveness of seasonal influenza vaccination is how to choose an outcome to measure effectiveness. The variety of different outcomes used in the influenza literature to assess effectiveness has made comparison across studies and time very difficult. Some outcomes often used to assess effectiveness is quite non-specific, such as influenza-like illness or ILI, which is usually defined as acute onset of fever and either cough or sore throat. This syndrome can be caused by a variety of respiratory pathogens or even non-infectious etiologies. However, influenza vaccine is only going to prevent ILI caused by influenza virus. Therefore effectiveness estimates that use ILI as an outcome typically find the vaccine to have a relatively low effectiveness in preventing ILI. Effectiveness of influenza vaccine in preventing laboratory-confirmed influenza is typically much higher, but requires more expensive and carefully designed studies. Effectiveness estimates using severe outcomes such as hospitalization or death are usually done retrospectively, and typically require modeling techniques. These studies can substantially overestimate the effectiveness of vaccination in preventing these outcomes if generally healthier persons tend to be preferentially vaccinated. 

## Vaccine Effectiveness when Vaccine Strains and Circulating Strains are not Well-matched

**Studies conducted in “drift” years (predominant circulating virus is significantly drifted from vaccine strain) show lower vaccine effectiveness in preventing laboratory-confirmed influenza**
- 95% confidence interval for VE estimate against drifted strains might include 0 (i.e., no effectiveness)
**Some studies in these years still show significant protection for more severe outcomes (hospitalization or need to seek medical care)**
- Presumed due to partial protection

**Suggested reading: Herrera Vaccine 2007; Ritzwoller N Engl J Med 2006**

## Inactivated Vaccine Effectiveness by Age and Risk Group 

| Age/Risk group | Outcome | Effectiveness* |
| --- | --- | --- |
| 6m-16 years, healthy | Influenza | 50-90% |
| 18-64 years, healthy | Influenza  | 50-90% |
| >65 years, community | Influenza | 30-70% |
| Elderly, nursing home | Influenza  | 30-40% |
| Elderly, nursing home | Hospitalization | 30-60% |

**Inactivated Vaccine Effectiveness by Age and Risk Group **

- *Overall range from studies conducted when good antigenic match between vaccine and circulating strains with lab-confirmed influenza.  Effectiveness may be lower when vaccine and circulating strains antigenically different.

## Interim Within-Season Estimate of the Effectiveness of Trivalent Inactivated Influenza Vaccine – Marshfield, Wisconsin, 2007-08 Influenza Season

**MMWR 2008;57:393-8.**
**DK Shay (CDC), E Belongia (Marshfield Clinic), et al**

## Objectives

**Estimate vaccine effectiveness (VE) for preventing medically attended acute respiratory illness (MAARI) which is lab-confirmed as influenza**
**Provide interim and final estimates of vaccine effectiveness (VE) for the 2007-08 influenza season**

## Interim Within-Season Estimate of VE: Marshfield, Wisconsin, 2007-08 Influenza Season

**Estimate VE for preventing medically attended acute respiratory illness (MAARI) which is lab-confirmed as influenza**
**Patients living in a 14 postal-code area surrounding the Marshfield Clinic eligible for the study**
**Enrollment began on 21 Jan 2008, and interim data through 8 Feb reported **
**Enrolled subjects:**
- Cases: MAARI with influenza infection diagnosed by RT-PCR
- Controls: MAARI negative by RT-PCR

## Vaccine Effectiveness:  Conclusions

** ****Despite a suboptimal match (based on antigenic characterization) between 2 of 3 vaccine strains and viruses isolated from study participants, interim VE was 44%**
** ****VE for influenza A(H3N2) medically attended infections was 58%, vs. no VE for influenza B**
** ****Must interpret antigenic characterization data with clinical effectiveness data**
** ****Feasible to produce within-season estimates of VE in the United States**
**Final end-of-season estimate will be available this summer**

- MMWR 2008;57:393-8

## Summary: 2007-08 Influenza Season, United States

- Moderately severe season with Feb-March peak
- Mixed viral types with influenza A(H3N2) predominating
- Oseltamivir resistance emerged
- Increased global surveillance underway to monitor trends
- Studies to evaluate clinical importance of resistance
- Vaccine effectiveness likely moderate despite antigenic differences between the circulating influenza H3N2 and B strains and those in the** **vaccine

## New and Updated Recommendations from the Advisory Committee on Immunization Practices (ACIP)

## Universal Vaccination against Influenza: Increasing Interest

- Better understanding of health and economic impact of influenza among older children and adults
- Recognition of suboptimal vaccine effectiveness among groups at highest risk for influenza complications (e.g., elderly, persons with chronic illness)
- Potential for reducing community transmission though vaccinating school children and healthy adults if high coverage can be achieved
- Lessened concerns about vaccine supply
- Belief that current low coverage for most recommended groups might be improved by a simple universal recommendation
- Increased concern about an influenza pandemic – need to learn how to vaccinate an entire population against influenza

## Rationale for Expanding Vaccination Recommendations to Include all School-age Children and Adolescents*

- _Rationale_
- Evidence that influenza has _substantial adverse impacts_ among school age children and their contacts (e.g., increased school absenteeism, antibiotic use, medical care visits, and parental work loss)
- Evidence that influenza vaccine is _effective and safe_ for school-age children
- The expectation that a simple age-based influenza vaccine recommendation _will improve current low vaccine coverage levels_ among the approximately 50% of school-age children who already had a risk- or contact-based indication for annual influenza vaccination
- _Also noted_
- The potential for the indirect effect of reducing influenza among persons who have close contact with children, and reducing overall transmission within communities, _if sufficient vaccination coverage_ among children can be achieved

***Approved at February 27, 2008 ACIP meeting.**
** ****Begins in 2008-09 influenza season**

## New from the ACIP: Influenza Vaccination Recommendations for Children

***All children aged 6 months through 18 years should receive annual influenza vaccination, beginning in 2008 if feasible, and beginning no later than during the 2009-2010 influenza season***

## Timeline of ACIP Recommendation Changes for use of Influenza Vaccine

**Before 2000: **
**	****	**Persons aged 65 or older
- 		Persons with chronic medical conditions that make them 				more likely to have complications of influenza
- 		Pregnant women in the second or third trimester
- 		Contacts (household and out of home caregivers) of the above groups
- 		Healthcare workers
**2000**: 	Adults 50 and older
**2004**: 	Children aged 6--23 months
- 		Contacts (household and out of home caregivers) of 					children aged 0--23 months
- 		Women who will be pregnant during influenza season
**2006**: 	Children aged 6--59 months
- 		Contacts (household and out of home caregivers) of 					children aged 0-59 months
**2008: ****	****All children aged 6 months—18 years**

## Recent Influenza Vaccine Coverage Data, United States

## Coverage levels slow to no

- Source: CDC. MMWR 2007;56:963-5

-  increase over 3 years
- Other recently introduced
- vaccines (varicella, hepatitis B,
- PCV7) have had better
- coverage (43-73%) 3 years
- after initial recommendation

**Notes:**
This bar chart shows vaccination coverage levels among children 6 thru 23 months of age for the 2004-05, 2005-06, and the most recent season – 2006-07, based on data from Immunization Information System (or IIS) sentinel sites. 

Looking at the top graph, among children who received at least 1 dose, vaccination coverage increased during 2006--07 by more than five percentage points at only two sites (Michigan and Montana) compared with the 2005--06 season.  Coverage with at least 1 dose during 2006--07 was either similar to coverage during 2005--06 or decreased at the other four sites.

Looking at the bottom graph, results indicate that fewer than one third of children aged 6--23 months were fully vaccinated at all of the sites during the 2006--07 season. The percentage of fully vaccinated children either was similar or decreased at five of the six sites compared to the previous season.

Every time I show this people ask, what's going on in Montana, why is coverage there so low. I think its because they realize the need to get the legend inside the box. Or maybe its supposed to represent Big Sky country.

## Self-Reported Influenza Vaccination Coverage Levels Among Selected Priority U.S. Adult Populations, 1989-2006, National Health Interview Survey

**Self-Reported Influenza Vaccination Coverage Levels Among Selected Priority U.S. Adult Populations, ****1989-2006, National Health Interview Survey**

- Vaccine shortage: 2004-05 season

- Source: CDC.
- http://www.cdc.gov/flu/professionals/vaccination/pdf/vaccinetrend.pdf

**Notes:**
This slow rate of increase in coverage is not just among 6-23 month olds, and not just for newly recommended age or risk groups. We have minimal increases or even decreases in coverage in each of the priority groups shown here.

## Other Key Updates in the 2008 ACIP Influenza Vaccine Recommendations

- Either TIV or LAIV should be used when vaccinating healthy persons aged _**2**_--49 years
- _2 doses_ separated by _>_4 weeks for children aged 6 months—8 years receiving vaccination for the first time
- Children 2—4 years old should be screened for reactive airways disease before receiving LAIV (MMWR Nov 23 2007)
- “Healthy” means no underlying chronic illness that confers increased risk for influenza complications
- All new 2008–2009 trivalent vaccine virus strains
- A/Brisbane/59/2007 (H1N1)-like
- A/Brisbane/10/2007 (H3N2)-like
- B/Florida/4/2006-like
- Neuraminidase inhibitors (oseltamivir or zanamivir) remain drugs of choice in prevention or treatment
- High levels of resistance among adamantane class drugs

## Thank you

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