Seasonal influenza - current perspective with special reference to India - aug 2011

Influenza Disease & Vaccination: Current Perspective with special

reference to India

Dr. Gaurav Gupta, Practising Pediatrician

Member AAP, IAP Charak Clinics, Mohali, Punjab

Influenza: An overview!

General introduction to influenza viruses and infection

Influenza outbreaks and pandemics

Analysis of pandemic H1N1

Defining at-risk populations

Influenza Vaccine – Data from Chandigarh

Influenza Vaccines Recommendations 2010-11 season


Influenza Vaccines









Influenza Vaccines

Influenza virus has several subtypes!

HA, hemagglutinin; NA, neuraminidase

Different influenza A subtypes result from differentcombinations of the HA and NA proteins

Influenza is a member of the Orthomyxoviridae family of viruses

Influenza A and B cause seasonal epidemics, C mainly causes mild respiratory illness

Influenza A is divided into subtypes based on the HA and NA proteins

HA and NA genes can be reassorted (switched) between strains generating novel subtypes

H1N1

H1N2

H2N1

H2N2

Orthomyxoviridae family

A 16 HA proteins

9 NA proteins

B

C

H1

H2

N1

N2

Influenza infection has a variety of symptoms!

Clinical symptoms Influenza infections are asymptomatic in

30–50% of cases

Common symptoms include abrupt onset of fever (38–40°C), sore throat, unproductive cough, runny or stuffy nose, headache, myalgia, chills, anorexia and extreme fatigue

Uncommon symptoms include photophobia, abdominal pain and diarrhea

Illness improves in under 7 days, cough and malaise may persist for weeks

Children may experience high fevers that can lead to febrile seizures

Fever may be absent in the elderly; presenting signs may include anorexia, lassitude or confusion

Influenza virus particles (brown) invade cilia (blue) in the airways

Virus shedding Adults: from the day before symptoms appear

until 5 days after illness onset

Young children: several days before illness onset until >10 days afterwards

Severely immunocompromised patients: weeks to months

Symptoms associated with seasonal influenza are well defined and can vary between individuals

Zambon MC. J Antimicrob Chemother 1999; 44 (Suppl. B):3-9; CDC, Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR Recomm Rep 2007; 56:1-54.

Clinical Differentiation Between the Common Cold

and the Flu

The following symptoms are more commonly seen in influenza rather than the common cold:• High fever lasting 3 to 4 days

• Headache

• Myalgia

• Fatigue and weakness

• Extreme exhaustion

• Severe chest discomfort and cough

The following symptoms are more commonly seen in the common cold rather than influenza:• Stuffy nose is common

• Sneezing is common

• Cough is generally mild to moderate

• Symptoms such as fever, headache, aches and pains and exhaustion are rare in those with colds.

Influenza viruses are spread by virus-laden aerosols!

How influenza viruses are spread: From person to person primarily through

large-particle respiratory droplet transmission

• Requires close contact betweensource and recipient as droplets only travel <1m

By contact with surfaces contaminated with respiratory droplets

By airborne transmission of evaporated droplets that may remain in the air for long periods of time (data are limited)

Virus transmission may be slowed by social distancing

CDC, Epidemiology and prevention of vaccine-preventable diseases. Atkinson W, Hamborsky J, McIntyre L, Wolfe S, eds. 10th ed. Washington DC: Public Health Foundation; 2007:235-56; Rust MJ, et al. Nat Struct Mol Biol 2004; 11:567-573; CDC, Prevention and control of influenza: recommendations of the Advisory Committee on Immunization Practices (ACIP), 2007. MMWR Recomm Rep 2007; 56:1-54.









Influenza Vaccines

Influenza virus changes due to antigenic drift or shift!

Antigenic drift occurs when there are small changes in the virus

Antigenic drift produces new virus clades that may not be recognized by the immune system, meaning reinfection can occur

Drifted strains may be mismatched with seasonal influenza vaccine

Antigenic shift is a major change in the influenza A virus, altering the HA and/or NA proteins

Antigenic shift leads to the emergence of a new influenza A subtype

Most people have little or no protection against the new virus

Antigenic drift

NAHA

A/H1N1

Antigenic shift

A/H3N2

A/H1N2

Geneticressortment

Antigenic drift can lead to epidemics; antigenic shift can lead to pandemic influenza

Geneticmutations

Cox NJ, Subbarao K. Annu Rev Med 2000; 51:407-421; Zambon MC. J Antimicrob Chemother 1999; 44 (Suppl. B):3-9; Koelle K, et al. Science 2006; 314:1898-1903.

A/H1N1A/H3N1

NAHA

Influenza pandemics & emerging new pandemic threats exist since 1900!

The emergence of H1N1 has demonstrated the difficulty in predicting pandemicsNicholson KG, Wood JM, Zambon M. Lancet 2003; 362:1733-1745; WHO, Cumulative number of confirmed human cases of avian influenza A/(H5N1), available at: http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_09_10/en/index.html (accessed 5 November 2008); CDC, Avian Influenza, available at: http://www.cdc.gov/flu/avian/outbreak.htm (accessed 5 November 2008).

Pandemic outbreaks Recent outbreaks of influenza

1918 1957 1977 2000 2008

>50 million deaths

H1N1

1918Spanish

1957Asian

~2 million deaths

H2N2

1968Hong Kong

~1 million deaths

H3N2

<1 million deaths

H1N1

1977Russian

H9N2

1999Hong Kong

2 cases

H5N1

1997Hong Kong

18 cases

Six

deaths

H7N7

82 cases

One death

H5N1

2003-2008

Global

387 cases

245 deaths

2003Dutch

1968

H1N1

2009Global

~30,000 cases

145 deaths

2009

Pandemic

The circulation of H5N1 in poultry and its high fatality rate have raised concerns over an H5N1 pandemic if this virus acquires the capacity for sustained human-to-human transmission

Transmission dynamics are described using the reproductive number (R0) and case fatality ratio, which may vary depending on country and season

http://www.who.int/csr/disease/avian_influenza/country/cases_table_2008_09_10/en/index.html

http://www.cdc.gov/flu/avian/outbreak.htm









Influenza Vaccines

Emergence of Swine Flu Virus

Human virusHuman virus

Avian virusAvian virusAvian

ReservoirAvian Reservoir

New ReassortedvirusNew Reassortedvirus

SwineSwine

Other mammals?Other mammals?

START

March 2009

1-10

11-50

51-500

>500

Cumulative cases

April 2009

Pandemic H1N1 rapidly spread worldwide: April 2009

The H1N1 pandemic was first reported by the US and Mexico on 26 April 2009 Phase 4 of pandemic alert was declared on 27 April, and Phase 5 on 29 April By 30 April, 257 cases including eight deaths had been reported in 11 countries

WHO, H1N1 number of laboratory confirmed cases, available at http://gamapserver.who.int/h1n1/atlas.html (accessed 30 April 2009); WHO, H1N1 cases, situation update 6, available at http://www.who.int/csr/don/2009_04_30_a/en/index.html (accessed July 2009).

http://gamapserver.who.int/h1n1/atlas.html

http://www.cdc.gov/flu/avian/gen-info/flu-viruses.htm

http://www.who.int/csr/don/2009_04_30_a/en/index.html

START

March 2009

April 2009

May 2009

Pandemic H1N1 rapidly spread worldwide: May 2009

* Date of last report for May 2009. WHO, H1N1 number of laboratory confirmed cases, available at: http://gamapserver.who.int/h1n1/atlas.html (accessed 29 May 2009); WHO, H1N1 cases situation update 41, available at http://www.who.int/csr/don/2009_05_29/en/index.html (accessed July 2009).

29 May *, 15,510 cases including 99 deaths reported by 53 countries

1-10

11-50

51–500

500-5,000

Cumulative cases

>5,000

http://gamapserver.who.int/h1n1/atlas.html

http://www.who.int/csr/don/2009_05_29/en/index.html

Pandemic Influenza : Status in 2010


Influenza virological Surveillance (ILI) from 1st week Dec 2010 till now

http://gamapserver.who.int/GlobalAtlas/sharedFunction/sharedFunctionInterface.asp?displayType=map

Influenza : % positive cases & virus subtypes





Analysis of current pandemic H1N1





Influenza Vaccines

In hospitalized children:

• Febrile seizures reported by 6-20%1

• Intensive care required by 4-11%1

• 80% were <5 years of age; 27% were <6 months of age1

Exacerbation of underlying chronic pulmonary and cardiovascular diseases3

Complication rate higher for subjects with chronicheart disease (46.9%) vs. those without (22.8%)4

Infection rates for seasonal influenza are highest among children1

Elderly are at high risk of complications from seasonal influenza

Cumulative hospitalization rates for laboratory-confirmed influenza among children 0-4 and 5-17 years of age, by season, US2

Annual rates of influenza-associated cardiorespiratory hospitalizations in those ≥50 years of age, US5

Age (years)

Ho

sp

ita

liza

tio

n r

ate

pe

r 1

0,0

00

pe

rso

n-y

ea

rs

50-64 65-69 70-74 75-79 80-840

200

400

600

800

1,000

Po

pu

lati

on

-ba

se

d r

ate

40 42 44 46 48 50 52 2 4 6 8 10 12 14 16 18

Week

1

2

3

4

5

2004-05 0-4

2005-06 0-4

2006-07 0-4

2007-08 0-4

2004-05 5-17

2005-06 5-17

2006-07 5-17

2007-08 5-17

0

1. CDC, 2010 Yellow Book, available at http://wwwn.cdc.gov/travel/yellowbook/2010/chapter-2/influenza-seasonal-avian-pandemic.aspx (accessed August 2009). 2. CDC, Mortality and Morbidity Weekly Report 2009; 58:369-374. 3. Bridges CB, et al. Inactivated influenza vaccines. In: Plotkin SA, Orenstein WA, Offit PA, eds. Vaccines. 5th ed. Philadelphia: Saunders; 2008. 4. Irwin DE, et al. BMC Health Serv Res 2001; 1:8. 4. Thompson WW, et al. JAMA 2004; 292:1333-1340.

Season Age range (years)

Seasonal Influenza : elevated risk for complications is associated with both age extremes!

http://wwwn.cdc.gov/travel/yellowbook/2010/chapter-2/influenza-seasonal-avian-pandemic.aspx

The majority of pandemic H1N1 cases have occurred in subjects <20 years of age!

1. Molinari NA, et al. Vaccine 2007; 25:5086-5096. 2. ECDC Surveillance Report, Analysis of Influenza A(H1N1)v individual case reports in EU and EEA countries, Update 9 July 2009. 3. WHO, Current WHO phase of pandemic alert, available at http://www.who.int/csr/disease/avian_influenza/phase/en/ (accessed July 2009).

Age distribution and travel status of pandemic H1N1 2009 cases in EU and EEA countries2

H1N1 pandemic influenza is predominantly found in patients <20 years of age; in contrast, the very young and the elderly are most at risk from seasonal influenza

The high level of domestic cases indicates community-level spread of the virus, meeting the WHO criteria for Phase 6 pandemic alert3

Seasonal influenza attack rates and proportionof population at high risk of serious complications, by age (US)1

N=7,681 cases reported by 28 EU/EEA countries as of 6 July 2009

0

10

20

30

40

50

60

0-4 5-17 18-49 50-64 65+

Age group

Pro

po

rtio

n o

f p

op

ula

tio

n (

%)

Gross attack rate

At high risk ofserious complications

Higher incidence of pandemic H1N1 than seasonal influenzain age group 10-19 years

≥6050-5940-4930-3920-2910-190-9

Domestic Travel related

2,500

2,000

1,500

1,000

500

0

Nu

mb

er o

f ca

ses

Age group

http://www.who.int/csr/disease/avian_influenza/phase/en/

Age sex pattern of H1N1 cases in India

http://mohfw-h1n1.nic.in/documents/PDF/EpidemiologicalTrendsInIndia.pdf

Win – Win Situation vaccinating Pregnant Women

ACIP/ CDC/ ACOG recommend Flu vaccination during pregnancy

Can be done at any gestational age, earlier the better.

Benefits mothers by reducing serious respiratory infections during pregnancy

Benefits fetus – Better weight gain & decreased incidence of SGA

Benefits infant – the most effective way to prevent influenza in the first 6 months of life.









Influenza Vaccines

Methodology-Clinical Effectiveness Study

• Prospective Observational Cohort Study• Vaccinated cohort (n=170) vs. Unvaccinated

cohort (n=330)Study Design

• Healthy child, of either sex, above 6 months of

age up to 18 years of age

• No chronic illness except asthma

Inclusion criteria

• H/O hypersensitivity to eggs and chicken proteinsExclusion criteria

25


• Private outpatient pediatric setting(Charak Care

Clinics, Mohali)Study site

• September, 2010 to May, 2011Study period

• Poisson regression analysis and Unpaired t-test for Risk ratio & statistical significance.

Statistical Analysis

26

Continued…..


• First call after 45 days of first dose of vaccine

then every month

Follow up Protocol

• Standard Predefined Data Form used. • Parameters measured –

ILI, Absenteeism, ARI, Unscheduled Physician visits

Data Collection

27

Continued…..

Overall Results

Vaccinated (198) vs Unvaccinated Cohort (397)

# Parameter RR CIp value

VE (%)

1 ILI0.65 0.49-0.84 0.001 35

2 ARI0.98 0.96-1.01 0.88

3 Unsch. Visit0.75 0.52-0.99 0.003 25

4Absenteeis

m0.97 0.70-1.32 0.86

Clinical Effectiveness of Influenza vaccine-1

Sr.No

Parameters Odds Ratio CI VE % P-value

1 Influenza like illness

0.58 0.24-0.92 42 0.009

2 Visits to Physician 0.71 0.33-1.09 29 0.039

Fully vaccinated cohort (n=154) vs. Unvaccinated cohort (n=330)*

Conclusion: Influenza vaccine is effective in reducing the ILI and visits to physician for ARI in fully vaccinated Indian children as compared to unvaccinated children.

*Renuka R, Gupta G, Tiwari P. Clinical effectiveness of the 2010-2011 seasonal influenza vaccine among healthy Indian children. WSPID-2011, Melbourne.


Sr.No Parameters Odds Ratio CI P-value

1 Influenza like illness 0.69 0.39-0.99 0.20

2 Visits to Physician 0.64 0.29-1.01 0.64

Partially vaccinated cohort (n=16) vs. Unvaccinated cohort (n=330)*

Conclusion: Partially vaccinated children had no significant protection against ILI and visits to physician as compared to unvaccinated children.



Sr.No

Age group (no.) Odds Ratio

CI P-value VE %

1 6 m – 3 y (78) 0.57 0.46-1.31 0.55

2 3 y – 9 y (64) 0.48 0.17-0.72 0.002 52 %

3 9 y – 18 y (28) 0.69 0.39-1.03 0.06

Age-wise efficacy for prevent of ILI*

Conclusion: Children aged 3-9 year had the best protection rates against ILI as compared to unvaccinated children.


Comparative Vaccine Effectiveness

Fully vaccinated (154) vs Unvaccinated Cohort (330) (2010-11)

# Parameter RR CI p value VE (%)

1 ILI 0.65 0.48-0.86 0.003 35

2 Unsch. Visit 0.74 0.51-0.99 0.007 26

Fully vaccinated (101) vs Unvaccinated Cohort (141) * (2009-10)

# Parameter RR CI p value VE (%)

1 ILI 0.57 0.32-0.09 0.05 43

2 Unsch. Visit 0.43 0.22-0.09 0.007 57

* Singh H, Gupta G, Tiwari P. Clinical effectiveness of the 2009-2010 seasonal influenza vaccine among healthy Indian children. ISPOR 4th Asia Pacific Conference, Phuket, Thailand.

Safety and Tolerability of Influenza vaccine-1

Inj. s

ite te

nderness

Fever

Cough/ cold

Runny nose

Sore th

roat

Vomitin

g

Irrita

bility

Diarrh

ea

Abdomin

al pain

Absente

eism

Unschedule

d visi

ts

Serious

side e

ffect

02468

101214161820 18

11.3

8

5.5

2.2 2.6

5.5

2.91.1

4.7

10.2

0

Percentage

Primary and secondary parameters(N=272)

Percentage

Singh H, Gupta G, Tiwari P. Safety and tolerability of trivalent inactivated influenza (TIV) vaccine in healthy Indian children. 62nd Indian Pharmaceutical Congress, 2010. Manipal, India. (Poster No. L-6).

Safety and Tolerability of Influenza vaccine-2

*Singh H, Gupta G, Tiwari P. Safety and tolerability of trivalent inactivated influenza (TIV) vaccine in healthy Indian children. 62nd Indian Pharmaceutical Congress, 2010. Manipal, India. (Poster No. L-6).

MIL

D

MO

DE

RA

TE

SE

VE

RE

MIL

D

MO

DE

RA

TE

SE

VE

RE

Local reactions (Inj. site tenderness) Systemic reactions

05

101520253035404550

5.92.2

0

16.4

8.9

0

19.5

41.6

8.94.8 4

46.6

0 0

6.6

0

6.6

> 6 to 35 Months

3Y to 9Y

> 9Y

Grading of the reactions after vaccinationN=272

Percentage

Pandemic influenza: An overview!







Influenza Vaccines

Influenza Vaccines are representative of virus strains circulating in India as well

WHO Influenza Global Surveillance Networko The network was established in

1952

o Currently, WHO have 128 institutions from 99 countries as recognized National Influenza centers

Objectives:

Surveillance enables to recommend twice the content of Influenza vaccine for the season

Serves as a global alert mechanism for the emergence of Influenza virus with Pandemic potential

1 Laboratory

≥ 2 Laboratory

No Laboratory

AIIMS

NICED Kolkata

Chennai

RMRC Dibrugarh

PuneMumbai

V P Chest

New Delhi

IGGMCNagpur

CMCVellore

Regional CentersNew CentersReferral Center

Haffkine Inst

NIV

KIPM

Pandemic Flu protection added to Seasonal flu vaccine

WHO Influenza strain for Northern Hemisphere 2010 – 2011 season:

• an A/California/7/09 (H1N1)-like virus; *

• an A/Perth /16/2009 (H3N2)-like virus; **

• a B/Brisbane/60/2008-like virus.***

*A/California/7/09 (H1N1)-like virus is the pandemic (H1N1) 2009 influenza virus. A monovalent vaccine containing this strain was made available to the United States in the fall of 2009.

**A/Perth/16/2009 (H3N2)-like virus is a change from the 2009-2010 influenza vaccine formulation.

***and B/Brisbane /60/2008-like virus is a current vaccine virus.

http://www.who.int/csr/disease/influenza/recommendations201010north/en/

ACIP Recommendations for seasonal Influenza vaccination 2010-11

1. A recommendation that annual vaccination be be administered to every individual aged ≥6 months for the 2010-11 influenza season

2. Children and adolescents at higher risk for influenza complications

• ! Are aged 6 months–4 years (59 months);

• ! Have chronic pulmonary, cardiovascular, renal, hepatic, cognitive, neurologic/neuromuscular,

• hematological or metabolic disorders (including diabetes mellitus)

• ! Are immunosuppressed (Caused by medications or by HIV)

• ! Are receiving long-term aspirin therapy and therefore might be at risk for experiencing Reye syndrome after influenza vaccination

• ! Are residents of long-term care facilities; and

• ! Will be pregnant during the influenza season.

Source: CDC recommendation available at http://www.cdc.gov/flu








Influenza Vaccines

WHO Recommended strains 2011 -12 season

It is recommended that vaccines for use in the 2011-2012 influenza season (northern hemisphere) contain the following:

an A/California/7/2009 (H1N1)-like virus;

an A/Perth/16/2009 (H3N2)-like virus;

a B/Brisbane/60/2008-like virus.

2011-12 season WHO recommended strain are similar to 2010-11 season northern hemisphere strains

2009

-10

2010

-11

2011

- 12

Brisbane

Brisbane

Brisbane

BA/H3N2

A/H1N1

California

Perth

Brisbane

1. www.who.int; 2. http://www.fda.gov/cber/flu/flu2008.htm.

Influenza Season (year)

Drift has led to 15 changes in recommended strains since 1997-19981,2

1997

-98

2007

-08

1999

-00

1998

-99

2000

-01

2001

-02

2002

-03

2003

-04

2004

-05

2005

-06

2006

-07

2008

-09

Bayern

Wuhan

Beijing New Caledonia SolomonIslands

Sydney Moscow FujianCalifornia Wisconsin

Beijing Sichuan Hong Kong Shanghai Malaysia

Brisbane

Brisbane

Florida

BA/H3N2A/H1N1

WHO monitors strain drifts and recommends strains for vaccine inclusion

For the Northern hemisphere, the recommended strains have changed 12 times since 1997-1998

Key Questions

Question 1

Is annual vaccination reqd. if the strain remains the same for consecutive years?

Yes, we require annual Influenza Vaccination if vaccine strains remain the same which is well supported by:

• Local guidance

• International guidance

• Guidance from a standard textbook

Key Questions

Question 2

What is the best time to give the Influenza vaccine in India?

Northern hemisphere

Southern hemisphere

Tropics

Influenza activity peak: November-March2,3

1. Bridges et al. 2008; 2. EISS 2004; 2. Cox and Subbarao 2000; 4. CHP 2008; 5. Yohannes et al. 2003.

Globe image: www.phimap.com

Influenza activity peak: April-September4,5

Year-round activity3,4

0

2

4

6

8

10

1 3 5 7 9 11 13 15 40 42 44 46 48 50 52Week

0

10

20

30

40

50

J F M A M J J A S O N D

Month

ILI/1

000

Po

pu

lati

on

ILI/1

000

Po

pu

lati

on

20

0

4

8

12

1618

2

6

10

14

1 5 9 13 17 21 25 29 33 37 41 49Week

45

ILI C

on

sult

atio

ns/

1000

Po

pu

lati

on

Influenza spread occurs inseasonal patterns

ILI = influenza-like illness.

E.g. India








Influenza Vaccines

How Influenza vaccines are made

o The network was established in 1952

o Currently, WHO have 128 institutions from 99 countries as recognized National Influenza centers

Objectives:

Surveillance enables to recommend twice the content of Influenza vaccine for the season

Serves as a global alert mechanism for the emergence of Influenza virus with Pandemic potential

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

WHO Influenza Global Surveillance Network

1 Laboratory

≥ 2 Laboratory

No Laboratory

Seasonal influenza vaccines are trivalent vaccines derived from the three viral types that are currently in global circulation

http://images.google.co.in/imgres?imgurl=http://www.leb.emro.who.int/search/who%20logo%20final%207.bmp&imgrefurl=http://www.leb.emro.who.int/search/&usg=___yMID_OHaiy1vxooQH52kqMPac8=&h=312&w=383&sz=352&hl=en&start=2&tbnid=BbUlvnx6EW5MHM:&tbnh=100&tbnw=123&prev=/images?q=WHO+LOGO&hl=en

Types of Influenza Vaccines

A) whole-virus, B) split-virion, C) subunit, D) virosomal, E) adjuvanted.

Amorij JP, Huckriede A, Wilschut J, Frijlink HW, Hinrichs WL. Development of stable influenza vaccine powder formulations:

Challenges and possibilities. Pharm Res. 2008;25(6):1256-1273.

Live Attenuated Influenza Vaccine

Inactivated Influenza Vaccine Whole virus vaccines Split-virion Vaccine Subunit vaccine Adjuvanted vaccines Virosomal vaccines Cell culture derived vaccines

Comparison of Influenza Vaccines

Vaccine type Composition Immunogenicity Reactogenecity

Whole-virus (no longer used)

Whole virus +++ +++

Split-virion Surface proteins, nucleocapsid and matrix proteins

++ ++

Subunit Surface proteins ++ +

Virosomal Surface proteins plus virosomes

++ +

Adjuvanted Surface proteins plus adjuvant

+++ ++

Intradermal (subunit)

Surface proteins +++ ++

+Low; ++ Medium; +++ High.

Live vs Inactivated Influenza Vaccine

http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5213a1.htm

Thank You

Health & Medicine

Seasonal influenza - current perspective with special reference to India - aug 2011