INFLUENZA STAGIONALE E
INFLUENZA PANDEMICA: PERCHE’
E COME PREVENIRLE
Susanna Esposito
Dipartimento di Scienze Materno-Infantili Università degli Studi di Milano
Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico
Milano
0 5 10 15 20 25 30
45 46 47 48 49 50 51 52 1 2 3 4 5 6 7 8 9 10 11 12 13 14
Influenza RSV hMPV Coronaviruses Rhinovirus Adenovirus
Weeks
% cases
DISTRIBUTION OF RESPIRATORY VIRUSES DURING THE WINTER SEASON 2003-2004
(Children enrolled = 2,060)
Esposito S et al. J Med Virol 2006
2003 2004
HOSPITALIZATION DURING INFLUENZA SEASON ACCORDING TO AGE
(Da Neuzil KM et al. NEJM 2000)
Neuzil KM et al. , N Engl J Med 2000
INCREASE IN OUTPATIENT VISITS AND ANTIBIOTIC COURSES DURING
INFLUENZA SEASON
INFLUENZA ASSOCIATED DEATHS AMONG CHILDREN IN THE UNITED STATES
• 153 influenza-related deaths
• Median age of died children was 3 years (63% aged <5 yrs)
• 31% died outside hospital setting
• 29% died within three days after the onset of the illness
• 47% had previously been healthy
Bhat et al., N Engl J Med 2005
MMWR September 4th, 2009
Fattori di rischio per influenza stagionale o pandemica grave in bambini ricoverati in Canada
(Da O’Riordan S et al. CMAJ 2009)
From MMWR, August 28, 2009
October 6, 2009 — On the second day of nationwide vaccination for the influenza A
(H1N1) virus, the director of the US Centers for
Disease Control and Prevention (CDC) reiterated
that the vaccine is safe in an effort to assuage
public misgivings.
Ordinanza
30 sett 2009
Ordinanza
30 sett 2009
Requirements for a pediatric influenza vaccine
• Children have immature immune systems that can limit their responses to vaccination
• The efficacy (prevention of confirmed influenza) of inactivated influenza vaccines in children (1–18 years of age) is approximately 60% 1
• For children <24 months of age, some studies have reported that the efficacy of inactivated vaccines is similar to placebo (37%) 1,2
• To overcome these limitations, pediatric influenza vaccines should offer the following:
– Robust immune responses – A favorable tolerability profile
• Adjuvants may be able to overcome these limitations and offer effective and safe pediatric vaccines
1. ECDC. Technical Report of the Scientific Panel on Vaccines and Immunisation. 2007;
2. Jefferson T, et al., Cochrane Database Syst Rev 2008; 2:CD004879.
15
Adjuvants: What role do they play in vaccination?
O’Hagan D, De Gregorio E. Drug Discov Today 2009; 14:541–51.
Extend the duration of the immune response by increasing antibody persistence and enhancing the cellular response
Increase the breadth of the immune response, providing heterologous activity
Reduce the antigen dose required in the vaccine to induce an immune response
Overcome the limited immune response in populations
such as young children
IMMUNOGENICITY OF TWO DIFFERENT INFLUENZA VACCINES IN CHILDREN AGED
6 MONTHS – 5 YEARS
(Kanra, Marchisio et al., Pediatr Infect Dis J 2004)
EFFICACY OF VIROSOMAL-ADJUVANTED INFLUENZA VACCINE IN OTHERWISE
HEALTHY CHILDREN AGED 2-5 YEARS
(Esposito et al., Vaccine 2006)
IMPACT OF VIROSOMAL-ADJUVANTED
INFLUENZA VACCINE IN CHILDREN AGED 2-5 YEARS ON HOUSEHOLDS
(Esposto et al. Vaccine 2006)
COST-EFFECTIVENESS OF ADJUVANTED INFLUENZA VACCINATION
Marchetti et al., Hum Vaccine 2007
FLUAD: Study to evaluate the immunogenicity, safety, and tolerability in healthy children 6–35 months of age*
* Not previously vaccinated against influenza Vesikari T, et al. Ped Infect Dis J 2009; 28:563–571.
FLUAD is not licensed in US. FLUAD is recommended for active prophylaxis of influenza in the elderly.
Non-adjuvanted
split virion vaccine (n=139) Dose 1 Dose 2 MF59-adjuvanted vaccine
FLUAD (n=130) Dose 1 Dose 2
Objective: Immunogenicity and tolerability of FLUAD in comparison with
non-adjuvanted split-virion vaccine
Immune responses measured against the vaccine strains:
2006/07 influenza season
T o ta l (N ) = 2 6 9
Blood draws (day) 0 21 42
Proportion of subjects with an HI titer ≥1:40 following two doses of vaccine
* P=0.001 FLUAD vs. split
Vesikari T, et al. Ped Infect Dis J 2009; 28:563–571.
FLUAD is not licensed in US. FLUAD is recommended for active prophylaxis of influenza in the elderly.
FLUAD induced higher rates of seroprotection against all tested strains, including influenza B, than the non-adjuvanted vaccine
FLUAD (n=104) Non-adjuvanted split vaccine (n=118)
CHMP adult
guideline threshold
S u b je c ts ( % ± 9 5 % C I)
H3N2
*
0 20 40 60 80 100
0 28 49
H1N1
*
*
0 28 49
0 20 40 60 80
100 *
0 28 49
0 20 40 60 80 100
Day post-first dose
Influenza B
22
Sw elli ng
Ind ura tion
Ery the ma
Ten der nes s
Fev er ≥≥≥≥ 38 °°°° C Pai n (An alg esi c/
ant ipy reti c u se)
Irrit abi lity
Unu sua l cry ing
*
In c id e n c e o f s e le c te d lo c a l/ s y s te m ic r e a c ti o n s ( % )
Local reactions Systemic reactions FLUAD (n=130)
0 20 40 60 80 100
Overall rates of local and systemic reactions following vaccination
* P=0.033 FLUAD vs. split
Vesikari T, et al. Ped Infect Dis J 2009; 28:563–571.
FLUAD is not licensed in US. FLUAD is recommended for active prophylaxis of influenza in the elderly.
Rates of reactions were comparable between FLUAD and the non-adjuvanted split vaccine
Non-adjuvanted
split vaccine (n=118)
Summary of clinical trial data for FLUAD
• FLUAD was immunogenic in children 6–35 months of age
– Higher seroprotection rates than non-adjuvanted vaccine (P=0.001) – Day 49 seroprotection rate against influenza B was 99% compared
with 33% for non-adjuvanted vaccine
• FLUAD demonstrated a favorable tolerability profile
– Rates of local and systemic reactions were similar to non-adjuvanted vaccine
• Injection site swelling was more common with FLUAD
– Most reactions were mild and of short duration
FLUAD was well tolerated in children and induced greater and broader
immune responses than non-adjuvanted split vaccine
DOUBLE DOSE VS STANDARD DOSE OF VIROSOMAL ADJUVANTED VACCINE
(Esposito S et al., ESPID 2010)
• Healthy children aged 6-35 months who had not been previously vaccinated against influenza
• Children were randomly assigned 1:2 to receive 2 doses 4- week apart of 0.25 mL (standard dose, SD) or 0.50 mL (double dose, DD) of seasonal virosomal-adjuvanted influenza vaccine ( Inflexal V, Crucell), separated by an interval of four weeks
• Blood samples were collected pre-vaccination, 4 weeks after each dose and 6 months after the second dose
• Local and systemic reactions were recorded for the 14 days
after vaccine administration
SEROCONVERSION RATES (%)
(Esposito S et al., ESPID 2010)
0 20 40 60 80 100
double-dose standard-dose double-dose standard-dose double-dose standard-dose
Virus A/H1N1 Virus A/H3N2 Virus B
28 ± 3 days after baseline 57 ± 3 days after baseline 210 ± 3 days after baseline
%
* p <0.05
*
*
*
*
*
SEROPROTECTION RATES (%)
(Esposito S et al., ESPID 2010)
0 20 40 60 80 100
double-dose standard-dose double-dose standard-dose double-dose standard-dose
Virus A/H1N1 Virus A/H3N2 Virus B
* p <0.05
% * * *
*
*
*
Baseline
28 + 3 days after baseline
57 + 3 days after baseline
210 + 3 days after baseline
GEOMETRIC MEAN TITRES
(Esposito S et al., ESPID 2010) (GMTs)
0 10 20 30
double-dose standard-dose double-dose standard-dose double-dose standard-dose
Virus A/H1N1 Virus A/H3N2 Virus B
28 ± 3 days after baseline 57 ± 3 days after baseline 210 ± 3 days after baseline
* p <0.05
G M T s m e an i nc re as e s
*
*
*
*
*
FLU-SPECIFIC IFN-Y-SECRETING CD8+ T CELLS
(Esposito S et al., ESPID 2010)
0 50 100 150 200 250
T0 T1 T2 T7
S F U x 1 0
6c el ls ( b ac kg ro un d s ub tr ac te d )
Double dose
Standard dose *
*
* p <0,05
*
*
PERCENTAGES OF IL-2- AND IFN-Y- PRODUCING CD4+ T CELLS
(Esposito S et al., ESPID 2010) lymphocytes
0 1 2 3 4 5 6 7 8
T0 T1 T2 T7
% of Flu-specific IL2-secreting CD4+ T cells
Double dose Standard dose
*
*
*
0 1 2 3 4 5 6 7 8
T0 T1 T2 T7
% of Flu-specific IL2-secreting CD4+ T cells
Double dose Standard dose
*
*
*
* p <0,05
ADVERSE EVENTS
(Esposito S et al., ESPID 2010)
0 5 10 15 20
Ir ri ta bi lit y
de cr ea se a pp et it e vo m iti ng
co ug h
rh in iti s
re dn es s
sw el lin g/ in du ra tio n
at le as t 1 A E
Systemic events Local events
double-dose after 1st dose standard-dose after 1st dose double-dose after 2nd dose standard-dose after 2 nd dose
%
FOCETRIA: Phase IV trial to evaluate immunogenicity and safety in children with chronic disease
Objective: Immunogenicity and safety of one dose of FOCETRIA in children (3–18 years of age) with chronic disease and healthy
controls
Immune responses* measured against the vaccine strain:
Pandemic H1N1 virus A/California/7/2009
* Assays ongoing. Immunogenicity data shown for children with thalassemia and healthy controls Esposito S. et al. Unpublished data.
Healthy
controls (n=28) Vaccination
Children with thalassemia
(n=31) Vaccination
T o ta l (N ) = 1 0 5
Blood draws (day) 0 30 90
Children receiving dialysis treatment (n=11)
Vaccination
Children with
malformative syndromes (n=35)
Vaccination
Immune responses following a single dose of FOCETRIA in children with thalassemia
Children with
thalassemmia (n=31) Healthy controls (n=28) CHMP adult
guideline threshold
Esposito S. et al. Unpublished data.
HI titer ≥ 1:40 Seroconversion GMT
Day post-vaccination
0 20 40 60 80 100
S u b je c ts ( % )
0 20 40 60 80 100
S u b je c ts ( % )
30 90 30 90
10 100 1,000 10,000
G M T ( L o g s c a le ) 1
30 90
A single dose of FOCETRIA induced immune responses in children
with thalassemia which met licensure criteria 30 and 90 days post-vaccination
Local and systemic reactions following a single dose of FOCETRIA in children with thalassemia
Esposito S. et al. Unpublished data.
0 20 40 60 80 100
S u b je c ts ( % )
Redness Swelling /Induration
Dolorability Fever
≥38°C
Rhinitis Irritability Insomnia Decreased appetite
Vomiting Diarrhea
Rates of local and systemic reactions were comparable between groups No serious adverse events were observed for either group
Local reactions Systemic reactions
Children with thalassemia (n=31) Healthy controls (n=28)
34
Local and systemic reactions following a single dose of FOCETRIA in children receiving dialysis treatment
Esposito S. et al. Unpublished data.
0 20 40 60 80 100
S u b je c ts ( % )
Local reactions Systemic reactions
Redness Swelling /Induration
Dolorability Fever
≥38°C
Rhinitis Irritability Insomnia Decreased appetite
Vomiting Diarrhea
Rates of local and systemic reactions were comparable between groups No serious adverse events were observed for either group
Dialysis patients (n=11) Healthy controls (n=28)
Local and systemic reactions following a single dose of FOCETRIA in children with malformative syndromes
0 20 40 60 80 100
S u b je c ts ( % )
Local reactions Systemic reactions
Redness Swelling /Induration
Dolorability Fever
≥38°C
Rhinitis Irritability Insomnia Decreased appetite
Vomiting Diarrhea
* Malformations include Angelman syndrome, Ataxia telangiectasia, Cockayne syndrome, Cornelia de Lange syndrome, Deletion of chromosome 22, Down syndrome, Malformative syndrome, Noonan syndrome, Pallister-Killian syndrome, Polimalformative syndrome, Smith Magenis syndrome, Williams syndrome, Wolf Hirschhorn syndrome, suspected NDD syndrome, suspected Noonan syndrome, suspected noonan syndrome with neurofibromatosis. Further details on notes page.
Esposito S. et al. Unpublished data.
Rates of local and systemic reactions were comparable between groups No serious adverse events were observed for either group
Children with malformative
syndromes* (n=35) Healthy controls (n=28)
FOCETRIA: Phase III randomized trial, use of FOCETRIA
± seasonal vaccine in mmunocompromised children
Objective: Immunogenicity* and safety of one dose of FOCETRIA ± virosomal-adjuvanted seasonal vaccine † in immunocompromised and healthy children
(7–18 years of age)
Impact of vaccination on HIV RNA and CD4+ cells in children with HIV, or creatinine and urea in kidney transplant recipients, one month post-
vaccination
* Assays ongoing, data not shown. †Inflexal V®(Crucell).
Esposito S. et al. Unpublished data.
T o ta l (N ) = 8 9
Blood draws (day) 0 30
FOCETRIA (n=19) FOCETRIA
+ seasonal (n=17) FOCETRIA
(n=14) FOCETRIA
+ seasonal (n=15) FOCETRIA
(n=12) FOCETRIA
+ seasonal (n=12)
Healthy controls (n=24)
Kidney transplant recipients (n=29) Children with HIV (n=36)
Vaccination
Vaccination Vaccination
Vaccination
Vaccination
Vaccination
Local and systemic reactions following a single dose of FOCETRIA in children with HIV
Children with HIV FOCETRIA alone
Children with HIV FOCETRIA + seasonal*
191712 1917 19171212 19 12 1917 19 12 19 1917 12 19 1917
0 20 40 60 80 100
S u b je c ts ( % )
Local reactions Systemic reactions
Redness Swelling /Induration
Dolorability Fever
≥38°C
Rhinitis Irritability Insomnia Decreased appetite
Vomiting Diarrhea
Healthy controls FOCETRIA alone
Healthy controls
FOCETRIA + seasonal*
* Inflexal V®(Crucell).
Esposito S. et al. Unpublished data.
FOCETRIA was well tolerated in children with HIV
No serious adverse events were observed for any group
Local and systemic reactions following a single dose of FOCETRIA in children who received a kidney transplant
* Inflexal V®(Crucell).
Esposito S. et al. Unpublished data.
14 14 14
15 15 15 15 15
0 20 40 60 80 100
S u b je c ts ( % )
Local reactions Systemic reactions
Transplant recipients FOCETRIA alone
Transplant recipients FOCETRIA + seasonal*
Healthy controls FOCETRIA alone
Healthy controls
FOCETRIA + seasonal*
Redness Swelling /Induration
Dolorability Fever
≥38°C
Rhinitis Irritability Insomnia Decreased appetite
Vomiting Diarrhea
12 1212 12 12 12
FOCETRIA was well tolerated in children who received a kidney transplant
No serious adverse events were observed for any group
HIV biomarkers following vaccination with FOCETRIA in children with HIV
* Inflexal V®(Crucell).
Esposito S. et al. Unpublished data.
19 17 19 17
0 20 40 60 80 100
S u b je c ts ( % )
HIV-RNA (<40 copies /mL)
0 30
19 17 19 17
CD4+ cell count
200 400 600 800 1,000
0 30
M e a n C D 4 + c e ll s ( n )
No significant differences were observed in HIV biomarkers
between subjects receiving FOCETRIA and FOCETRIA + a seasonal vaccine FOCETRIA alone FOCETRIA + seasonal vaccine*
Days post-vaccination
Kidney function following vaccination with FOCETRIA in children who received a kidney transplant
* Inflexal V®(Crucell).
Esposito S. et al. Unpublished data.
14 15 14 15
0 0.4 0.8 1.2 1.6 2.0
M e a n c re a ti n in e ( m g /d L )
0 30
Days post-vaccination
14 15 14 15
