The presentation given by Professor Susanna Esposito at ECCMID 2019. A view on vaccines recommendations, combined vaccinations and impact of vaccination practices in the eradication of major infectious diseases. To learn more, please visit www.waidid.org

1. DESIGNING VACCINES FOR
SPECIFIC POPULATIONS AND
GERMS
Susanna Esposito
Pietro Barilla Children’s Hospital
University of Parma, Parma, Italy

2. Disclosures
Research Grants: Abbott, DMG, GSK, Janssen,
Sanofi-Pasteur, Vifor
Advisory Board Membership: GSK, Janssen, MSD,
Sanofi-Pasteur, Pfizer, Vifor

3. 3
How many lives are saved by vaccines?
2.5 million per year
7,000 per day
300 per hour
5 per minute
WHO – 2011-2020

4. DDF 4
THE RISE OF LIFE EXPECTANCY

5. Facultad de Medicina
Universidad de Chile
Berkeley, 17 maggio 1749 – Berkeley, 26 gennaio 1823

6. Smallpox Eradication Timeline
Year Milestone
1959 WHA adopts goal to eradicate smallpox
-reliance on compulsory vaccination and revaccination of 80%
of the population through campaigns using freeze-dried vaccine
1966 Inadequate supplies in a West African outbreak facilitated use
of the surveillance/containment approach, after scale up in
other countries in the region smallpox disappears in 3.5 years
1967 Global Smallpox Eradication Program officially launched by
WHO
-44 countries (31 had endemic smallpox) reported 217,218
cases
1968 WHO Scientific Group promotes both mass vaccination and
surveillance/containment as “co-strategies”. India adopts
surveillance/containment.
1974 Bihar, India identifies 1500 new cases of smallpox every day
1977 Last case of naturally-acquired smallpox occurred in Merca
District of Somalia
1980 WH0 certified the world free of naturally-occurring smallpox,
routine vaccination ceased

7. Over 200 years of Vaccine Development!!

8. Perugia 2017

10. Poliovirus Vaccine
• 1955 Inactivated vaccine
• 1961 Types 1 and 2 monovalent OPV
• 1962 Type 3 monovalent OPV
• 1963 Trivalent OPV
• 1987 Enhanced IPV (IPV)

11. Polio Vaccination Recommendations
• Sequential schedule with 2 IPV and
2 OPV in 1999-2001
• Exclusive use of IPV recommended
in 2002
• VAPP eliminated

13. … at least 19
recommended UMV!
Rationale of combined vaccines in infants and toddlers - Knuf 13

14. A: universal recommendation; B: recommendation for specific cohorts; N: catch-up
Europäisches Zentrum für Krankheitskontrolle und Prävention (ECDC). Vaccine schedule. http://vaccine-schedule.ecdc.europa.eu/Pages/Scheduler.aspx (Abgerufen im April 2017)
Vaccination calendar for infants and toddlers in five
european countries
France
Germany
Italy
Spain
UK
France
Germany
Italy
Spain
UK
F
D
I
E
UK
France
Germany
Italy
Spain
UK
France
Germany
Italy
Spain
UK
France
Germany
Italy
Spain
UK
PertussisHib
Hepatitis
B
Diphtherae
Polio-
myelitisTetanus
B
B
B
A
B
A
A A
A
A
A
A
A
A
A
A
A
A
N
N
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
N
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
N
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
N
N
N
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
A
up to 3 years
up to 3 years
up to 16 yeras
up to 18 years
up to 3 years
up to 7 years
up to 3 years
birth
Rationale of combined vaccines in infants and toddlers - Knuf 14

15. Perception of ‘too many’ shots may affect
vaccine coverage
• Vacc schedules require more than one shot in each
visit1
– Parents anxiety may drive them to postpone or avoid some
vaccines2
• Vaccine delay:
– Driver to receive less vaccines, especially in small infants3
– Increase infections and diseases2,3
✘
1. Centers for Disease Control and Prevention (CDC). Recommended immunization schedule for children and adolescents aged 18 years or younger,
2. United States, 2017. https://www.cdc.gov/vaccines/schedules/downloads/child/0-18yrs-child-combined-schedule.pdf Accessed May 21, 2017.
3. Bielicki JA, et al. Vaccine. 2013;31(46):5375–5380.
4. Luman ET, et al. JAMA. 2005;293(10):1204–1211.

16. Combined vaccines: History
• Multi antigen
– 1945: Influenza (3 antigens)1,2
– 1947: S. pneumoniae (6 antigens)1,2
– 1955: IPV (3 antigens)1,2
• Multi valent
– 1948: DTPw1,2
– 1960: DTPw IPV1,2
– 1971: MMR1
– 1990: DTPw Hib2
DTPw IPV Hib2
1. Decker. PIDJ 2001;20(Suppl.1):S10–8
2. Decker y cols. 2004. In: Vaccines Ch 29

17. Why combinations?
• Less pain
• Simplicity of administration
• Simplicity of program
• Improved compliance
• Improved effectiveness
• Lower costs
Rationale of combined vaccines in infants and toddlers - Knuf 17

18. Potentially interactions between
vaccine components
Possible adverse consequences:
• reduced immunogenicity
• increased reactogenicity
• shortened shelf life
• complicated manufacture
Antigens
Preservative(s)
Adjuvant(s)
Contaminants
pH
Stabiliser(s) Excipient(s)
Rationale of combined vaccines in infants and toddlers - Knuf 18

19. Hexavalent vaccines
Vaccine Producer Year of Licensure
• (DTaP2-IPV-HepB/Hib) SP-MSD 2000-2005
• DTaP3-IPV-HepB/Hib GSK 2000
• DTaP2-IPV-HepB-Hib SP 2013
• DTaP5-IPV-HepB-Hib MCM (MSD/SP) 2016

20. Reduction of Hib-associated diseases in Europe
due to vaccination programs
Eskola J. Foresight in medicine: current challenges with Haemophilus influenzae type b conjugate vaccines. J Intern Med. 2010;267(3):241-250
UK
Finland
The Netherlands
Ireland
Israel
-1 0 1 2 3 4 5 6
0
20
40
60
80
100
120
Years after introduction of a Hib-combined vaccine
Hib-incidence(in%)afterimplementationof
vaccinationcorrespondingtoinciidencebevor
introductionofHib-vacconation(%)
Annual incidence of Hib-associated infectious diseases after introduction
of a Hib-vaccination program

21. Impatto della varicella in Europa/anno
Impatto della varicella in Europa/anno/età

22. Varicella incidence rates based on mandatory notifications (x
1.000) and hospitalization rates (x100.000) due to varicella in
8 Italian Regions (2003-2012)
• Annual incidence rate
0.8 (2003)  0.2 (2012)
• Hospitalization rate
3.3 (2005) 1.1 (2012)
• Annual incidence rate
1.1 (2003)  0.6 (2012)
• Annual incidence rate
1.0 (2003)  0.1 (2012)
• Hospitalization rate
3.4 (2003)  0.5 (2012)
• Annual incidence rate
3.2 (2004)  0.4 (2012)
• Hospitalization rate
5.3 (2004)  1.2 (2012)
• Annual incidence rate
3.9 (2003)  3.7 (2012)
• Hospitalization rate
2.3 (2003)  2.1 (2012)• Annual incidence rate
3.0 (2003)  0.4 (2012)
• Hospitalization rate
3.2 (2003)  0.8 (2012)
• Annual incidence rate
1.4 (2003)  0.3 (2012)
• Hospitalization rate
1.8 (2003)  0.5 (2012)
• Hospitalization rate
3.8 (2003)  1.8 (2012)
• Annual incidence rate
1.1 (2003)  0.1 (2009)
• Hospitalization rate
4.8 (2003)  0.8 (2012)

24. Fever Seizures

25. Czajka H et al, Vaccine 2009
…… measles antibody titer
after receipt of MMRV was
associated positively with the
rate of fever.
Use of separate MMR and
varicella vaccines averts the
slight increase in risk of
fever and febrile seizures
after MMRV
administration……..

26. MMRV 1

28. Pertussis: Age-related incidence (USA)
Rationale of combined vaccines in infants and toddlers - Knuf 28

29. Complications of Pertussis in Children
 4 Years of Age in the US, 1997‒2000
Age Hospitalization Pneumonia Seizures Encephalopathy Death
No. with
Pertussis
< 6 M 4,543 847 103 15 56 7,203
6‒11 M 301 92 7 1 1 1,073
1‒4 Y 324 168 36 3 1 3,137
CDC. MMWR 2002;51(4):73‒76

30. 30Infect Immun 2001

31. Pertussis prevention strategies throughout life
0 3
months
Adolescents AdultsChildren
Waning
immunity1
Vaccine induced
protection1
Limited natural
immunity1
Transmission2,3
Elderly
1. Adapted from Wendelboe et al. Pediatr Infect Dis J 2005: 24; S58–S61; 2. Sawyer, Chair ACIP Pertussis Vaccine WG, Oct 24, 2012; 3. CDC. MMWR 2011; 60: 13–15;
4. Tan & Gerbie, Obstetrics Gynecol 2013; 122: 370–3; 5. CDC. MMWR 2011; 60: 1117–23; 6. CDC. MMWR 2012; 61; 66–72; 7. CDC. MMWR 2013; 62: 66–72;
8. Healy et al. Clin Infect Dis 2011; 52: 157–62

32. Department of Health Sciences
University of Florence
all adolescents and adults receive the Tdap
vaccine to replace the scheduled tetanus and
diphtheria toxoids vaccine (Td) booster
all people who have or anticipate having
close contact with infants <12 months of age
receive a single dose of Tdap,
all immediately postpartum women who have
not previously received a Tdap vaccine
receive a dose prior to leaving the hospital.
Recommendations have now been
expanded to routinely immunize all
adults 65 years of age and older
with a single dose of Tdap;
administer a booster dose of Tdap
with each pregnancy, regardless
of interval between pregnancies,
ideally after the 20th week of
gestation.

33. Countries with cocooning recommendations
1. Australian Immunisation Handbook 9th edition 2008; Part 2.3.2, available from: http://www.health.gov.au/internet/immunise/publishing.nsf/Content/Handbook-
specialgroups (accessed June 2011); 2. Kinkhoest (pertussis) – vaccinatie. Available from: http://www.zorg-en-gezondheid.be/Ziektes/Vaccinaties/Vaccins-A-Z/Kinkhoest-
%28pertussis%29---vaccinatie/ (accessed June 2011; 3. Haut conseil de la santé publique. Bulletin Épidémiologique Hebdomadaire 2009;16–17:46–76; 4.
Impfempfehlungen der Ständigen Impfkommission am Robert Koch-Institut/Stand: Juli 2010. Epidem Bull 2010;30:279–98; 5. New Zealand Ministry of Health
Immunisation Handbook 2011; Ch 6; 6. CDC. MMWR 2011;60:13–5; 7. http://www.cdc.gov/vaccines/recs/provisional/default.htm (accessed August 2011); 8. WHO
vaccination schedule, available from: http://apps.who.int/immunization_monitoring/en/globalsummary /ScheduleSelect.cfm (accessed June 2011)
Country with
cocooning
recommendatio
n
Country without
cocooning
recommendation

34. Department of Health Sciences
University of Florence
Hasala,2008  the results of neonatal
vaccination with DTaP vaccine in 50 infants
between 2 to 14 days of age. The
administration of an additional dose at birth
was safe and well tolerated, but was
associated with lower geometric mean
antibody concentration for toxin and pertactin
fimbrae, diphtheria
efficacia del vaccino della
vaccinati alla nascita [n: 45]
età anti-PT anti-FHA anti-PRN
3 mesi 8.7 4.3 13.0
5 mesi 41.2 29.4 70.6
6 mesi 60.9 39.5 82.6
12 mesi 87.5 42.5 85.0
Belloni C et al. Pediatrics 2003; 111: 1042-1045
pertosse somministrato alla nascita
Vaccination in the neonates

35. Lancet 2014

36. VACCINE EFFECTIVENESS ACCORDING TO TRIMESTER OF
PREGNANCY
(Winter et al., Clin Infect Dis 2017)

37. Immune Responses and Antibody Decay after
Immunization of Postpartum Women with Tetanus
and diphtheria toxoids and acellular pertussis
vaccines (Tdap)
Fortner KB1, Hunter DL2, McDonald WL2,
Rock MT2, Edwards KM2
1Division Maternal-Fetal Medicine, Vanderbilt University
2Division Pediatric Infectious Disease, Vanderbilt University
Are Tdap Vaccines Needed with Each Pregnancy?

38. Department of Health Sciences
University of Florence
total of 21 studies were included in this review.
OR 0.47 to 1.50 for preterm birth (less than 37 weeks of gestation)
0.65-1.00 for small for gestational age (birth weight less than the 10th percentile)
0.36-0.85 for stillbirth
0.16-1.00 for neonatal death
0.76-1.20 for low birth weight (less than 2,500 g)
0.20-0.91 for congenital anomalies
All lower 95% confidence intervals (CIs) were less than 1.0.
Of three retrospective studies assessing chorioamnionitis after vaccination, one showed a
small but statistically significant increase.
Safety of Tetanus, Diphtheria, and Pertussis Vaccination
During Pregnancy: A Systematic Review.
McMillan M. Obstetrics & Gynecology 2017; 129:560-73

39. The risk groups by age of seasonal influenza
ESPID 2013 *Based on 3930 US cases from 2007-2008. Soucres: WHO, CDC; American Journal of Hygiene

40. Effect of Age on Healthcare Burden
<6 months 6–12 months 1–<3 years 3 –<5 years 5 –<15 years
Excesseventsper100children
Outpatient visits16
14
12
10
8
6
4
2
0
Courses of antibiotics
Excess treatment events in otherwise healthy children under 15 years of
age; data over 19 consecutive seasons (US)
Neuzil KM, et al. N Engl J Med 2000;342:225–31.
Age

41. Subjects(%)
0
5
10
15
20
25
30
35
40
45
Acute otitis
media
Pneumonia Sinusitis Antibiotics
<3 years 3–6 years 7–13 years
Complications of influenza in different age groups, prospective cohort study, Turku, Finland, 2000–2002
Children Under 3 Years of Age are Most Likely to Develop Acute
Otitis Media and Require Antibiotics
Heikkinen T, et al. J Infect Dis 2004;190:1369–73.

42. Mortalityrate
per1,000people
0
0.02
0.04
0.06
0.08
0.10
6–23
months
2–4
years
5–9
years
10–19
years
20–49
years
50–64
years
≥ 65
years
< 6
months
Age group
Age-associated rates of influenza-related deaths; data from British Columbia, Canada, 1998–2004 influenza seasons
Mortality Rates due to Influenza and Pneumonia
Sebastian R, et al. Vaccine 2008;26:1397–1403.
Provincial and national influenza surveillance reports from the British Columbia Centre for Disease Control, the Public Health
Agency of Canada’s FluWatch Program, and the Canada Communicable Disease Report (CCDR) were analysed from 1 Sep 1998
to 31 Aug 2004, to determine influenza-related deaths in British Columbia, Canada.

43. Season
2007/2008
Seasonal
A/H1N1
(n=126)
Season
2008/2009
Seasonal
A/H3N2
(n=486)
Season
2009/2010
Pandemic
A/H1N1
(n=389)
CLINICAL OUTCOME
Hospitalisation rate, n (%)
Duration of hospitalisation, mean days ± SD
Absence from school, mean days ± SD
4 (3.1)°*
5.1 ± 3.5°*
5.9 ± 4.7°*
79 (16.3)
7.5 ± 4.4*
7.5 ± 3.4*
51 (13.1)
9.1 ± 7.5
8.9 ± 5.3
DRUG USE, n (%)
Antibiotics
Antivirals
Antipyretics
Aerosol therapy
Steroids
99 (78.6)°
0 (0.0)*
100 (79.4)°*
30 (23.8)°*
6 (4.8)
466 (95.9)
0 (0.0)*
460 (94.6)
203 (41.8)
36 (7.4)
297 (76.3)°
16 (4.1)
383 (98.5)
157 (40.4)
23 (5.9)
°p<0.01 vs seasonal A/H3N2 influenza; *p<0.01 vs pandemic A/H1N1 influenza
Clinical Outcomes and Drug Use by Influenza A Subtypes
Esposito S, et al. J Infect 2011;63:300−7.

44. 0
20
40
60
80
100
Clinical presentation in children with
influenza A and B infection is similar
Esposito S, et al. BMC Infect Dis 2011; 11: 271.
LRTI, lower respiratory tract infection.
Influenza A/H1N1 (n = 143)
Influenza A/H3N2 (n = 519)
Influenza B (n = 239)
Children with influenza A/H3N2
had an higher number of LRTI,
wheezing and pneumonia than
those with influenza A/H1N1 o B
(all p < 0.05)
Percentage

45. Influenza vaccination recommendations
WHO/Europe
Recommend that member states vaccinate all individuals ≥6 months1
EU
Member states currently recommend paediatric vaccination;2,3,4
recommendations vary by country:
• 6 months to <18 years of age: Austria, Estonia and Slovakia
• 6–35 months: Finland
• 6–24 months: Slovenia, Latvia
• 24 months-10 yrs: UK
USA, Canada and PAHO countries
• US: All individuals ≥6 months of age5
• Canada: Children 6–24 months of age, and encourages all individuals ≥6
months of age to be vaccinated6
• Currently, 27 PAHO countries and territories recommend paediatric seasonal
influenza vaccination7*

46. Age group and costs (€)
Without
vaccination
With
vaccination
Total
savings
6 months to <3 years (N=140 000)
Medical costs 3 473 091 694 521 2 778 571
Vaccination program costs 0 1 057 916 -1 057 916
Health care costs 3 473 091 1 752 437 1 720 654
Travel costs 247 972 889 016 -641 043
Total direct costs 3 721 064 2 641 453 1 079 611
Productivity costs 3 355 692 1 631 008 1 724 684
Societal costs 7 076 756 4 272 461 2 804 295
Assumed vaccine efficacy 60%.
Vaccination of young children is cost-saving, investing €1 million
will save an estimated €2.8 million in societal costs
Influenza vaccination in young children is
cost effective
Salo et al. Vaccine 2006
The Finnish experience (assumed vaccine efficacy 60%)

47. MICROBIOTA and EPIGENETIC
PROGRAMMING
Heredity deals
the cards;
environment
plays them

48. Messieurs,
c'est les
microbes qui
auront le
dernier mot.
Louis Pasteur
1822-1895

49. I AM VACCINATED. WHAT ABOUT
YOU?