UN LUNGO (E ACCIDENTATO) VIAGGIO IN VACCINOLOGIA - GIUSEPPE DEL GIUDICE, MD PHD ROMA, 25 MAGGIO 2021
←
→
Page content transcription
If your browser does not render page correctly, please read the page content below
Un lungo (e accidentato) viaggio
in vaccinologia
Giuseppe Del Giudice, MD PhD
Roma, 25 Maggio 2021
G. Del Giudice, 27 January 2018
Leishmania major
Plasmodium falciparum
sporozoites
2
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021
Le opportunità in un contesto
multidisciplinare come l’OMS…
Reality check Meet people
– Immunologists
– Epidemiologists
– Public health experts
– Pharmacologists
– Parasitologists
– Microbiologists
– Virologists
– Vaccine manufacturers
–…
3
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021
…e quindi in un contesto di ricerca e
sviluppo industriale
E. coli enterotoxin
& mucosal adjuvants Adjuvants Influenza
Helicobacter pylori
Pertussis
Glycoconjugates
Antimicrobial Vaccination of
Resistance older adults
4
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021
Changing demographics require new
vaccination strategies1,2
1925 1950 1975 2000–2020
Vaccines were developed to
control infectious diseases
and to protect the most
vulnerable
In early 1900s, countries had
a relatively high proportion 1. Rappuoli R et al. Nat Rev Immunol.
2011;11:865-72.
of children and a life 2. Global Coalition on Aging. Life-course
immunization: a driver of healthy aging.2013.
expectancy of 60–65 years1 http://www.globalcoalitiononaging.com/v2/data/
uploads/documents/life-course-
immunization_gcoa-for-web.pdf (Accessed Nov
2016).
Childhood immunization has traditionally been the focus of vaccination initiatives1
5
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021
Changing demographics require new
vaccination strategies1,2
1925 1950 1975 2000–2020
The role of vaccination is evolving from saving
lives to improving the health and well-being of
modern societies1
In the 21st century, in developed countries and
1. Rappuoli R et al. Nat Rev Immunol.
2011;11:865-72.
countries in development, societies have a
2. Global Coalition on Aging. Life-course
immunization: a driver of healthy aging.2013.
high proportion of older people and
http://www.globalcoalitiononaging.com/v2/data/
uploads/documents/life-course-
a life expectancy of ~80 years1
immunization_gcoa-for-web.pdf (Accessed Nov
2016).
There is a need for life-course immunization to address the challenges of
an aging population2
6
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021
Influenza has a greater impact in infants/young
children and older adults1
Influenza attack rate is higher in children and mortality is higher in older adults1
0,250 Attack rate Mortality rate 0,012
(probability of death per
case of flu infection)
[N]/total population [N])
0,010
Mortality rate
0,200
(new cases per year
Attack rate
0,008
0,150
0,006
0,100
0,004
0,050 0,002
0,000 0,000
0–4 5–17 18–49 50–64 ≥65
Age group (years)
1. Molinari NA et al. Vaccine. 2007;25:5086-96
7
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021
Incidence of shingles and risk of PHN
increases with age
PHN: post-herpetic neuralgia
1. Harpaz L et al. Incidence of pediatric and adult herpes zoster in an era of varicella and herpes zoster vaccines. IDWeek. (Abs 1052). Oct 7-11, 2015. San Diego, CA.
2. Harpaz L et al. MMWR Recomm Rep. 2008;57(RR-5):1-30; quiz CE2-4.
8
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021
Incidence of infections in various age groups in
Norway
Invasive pneumococcal disease Pertussis
Campylobacter Salmonellosis
MRSA infections Vancomycin-resistant enterococci
Invasive GBS infection Tuberculosis
Adapted from Steens
A et al, BMC Infect
Dis 14:54, 2014
10
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021
Vaccination: the most effective and cost-effective
medical intervention ever introduced
• So far saved >3.0 billion disease In the USA 1994-2013
cases
>500 million deaths • Vaccines prevented
• 2011-2020 vaccines will save • 322 million illnesses
• 25 million deaths • 21 million hospitalizations
- 2.5 million/year • 732,000 deaths
- 7000/day
- 300/hour
- 5/min • Vaccines generated net
savings of
• 295 Billion direct costs
• 1.38 Trillion in total
societal costs
WHO Global Action Plan
http://www.who.int/immunization/global_vaccine_action_plan/G
VAP_doc_2011_2020/en/index.html)
11
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Vaccination of older adults with pneumococcal and influenza vaccines
can reduce disease-associated complications, reducing healthcare
burden and mortality1
1. Hung IFN et al. Clin Infect Dis. 2010;51:1007-16.
13
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Vaccination can help address the problem
of antibiotic resistance1
1. Laxminarayan R et al. Lancet. 2016;387:168-75.
15
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Antibiotics are proportionally “short-lived” in
comparison to vaccines1
1. Tagliabue A and Rappuoli, Front Immunol. 2018;9:1068.
Black X symbols indicate insurgence of resistance, with lines starting at product introduction (yellow stars; except for smallpox vaccination that began much earlier;
16
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Vaccines currently recommended
for the older adults
DEPENDING ON OFFICIAL VACCINE RECOMMENDATIONS AT COUNTRY LEVEL
Lang PO & Aspinall R, Drugs Aging 31: 581 (2014)
17
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Vaccination Coverage Among Elderly
Populations (≥ 65 YoA) - United States 2014
Factors contributing to low coverage:
• Racial/ethnic differences
• Lack of awareness (public/HCP)
• Lack of recommendation by HCP
• Lack of systematic assessment of vaccination
status at each visit
• Reimbursement system (Medicare part D)
• Lack of vaccine requirement
• No stocking of vaccines at HCP’s level
MMWR Surveillance Summaries / February 5, 2016 / 65(1);1–36
19
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Immunosenescence affects several different
immune cell types1
1. Aw D et al. Immunology. 2007;120:435-46. 5. Franceschi C et al. Mech Ageing Dev. 2007;128:92-105.
2. Kumar R et al. Expert Rev Vaccines. 2008;7:467-79. 6. Maggi S et al. Expert Rev Vaccines. 2010;9(3 Suppl.):3-6.
3. High K. J Am Geriatr Soc. 2010;58:765-76. 7. Naylor K et al. J Immunol. 2005;174:7446-52.
4. Camous X et al. J Biomed Biotechnol. 2012:195956. 8. Tu W & Rao S. Front Microbiol. 2016;7:2111.
21
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021What to do?
• Vaccinate more with existing vaccines: increase the coverage: e.g.
improved flu vaccines (adjuvanted, high dose, etc), conjugated
pneumococcus vaccines
• Vaccinate people when they are young with vaccines inducing long-
lasting memory
• Use existing vaccines against targets not considered as needs for the
elderly: e.g. pertussis
• Develop more efficacious vaccines: e.g. herpes zoster, influenza
• Develop novel vaccines: e.g. RSV, CMV, S. aureus, C. difficile
• Intervene on mechanisms leading to immunosenescence: e.g. CMV,
mTOR inhibitors, and take control of negative effect of other drugs
• Accelerate testing of novel vaccines in the elderly; more translational
studies
• How to translate vaccines into vaccination
22
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021What to do?
• Vaccinate more with existing vaccines: increase the coverage: e.g.
improved flu vaccines (adjuvanted, high dose, etc), conjugated
pneumococcus vaccines
• Vaccinate people when they are young with vaccines inducing long-
lasting memory
• Use existing vaccines against targets not considered as needs for the
elderly: e.g. pertussis
• Develop more efficacious vaccines: e.g. herpes zoster, influenza
• Develop novel vaccines: e.g. RSV, CMV, S. aureus, C. difficile
• Intervene on mechanisms leading to immunosenescence: e.g. CMV,
mTOR inhibitors, and take control of negative effect of other drugs
• Accelerate testing of novel vaccines in the elderly; more translational
studies
• How to translate vaccines into vaccination
23
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021More efficacious vaccines: the examples of influenza and Zoster
24
2 | Vaccini | G.
CONFIDENTIAL Del Giudice –|FOR
INFORMATION Roma, 25 Maggio
INTERNAL 2021
USE ONLYNew approaches towards better vaccines for
the elderly
G. Del Giudice et al, npj Aging & Mechanisms of Disease 4(1) 1-8, 2018
25
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Strategies to improve protection of older adults:
high dose vaccines
1. Robertson CA, et al. Expert Rev Vaccines 2016; 15(12):1495–1505. 2. DiazGranados CA, et al. N Engl J Med 2014; 371:635–645
26
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Strategies to improve protection of older adults:
high dose vaccines
1. Robertson CA, et al. Expert Rev Vaccines 2016; 15(12):1495–1505. 2. DiazGranados CA, et al. N Engl J Med 2014; 371:635–645
27
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Emulsion adjuvants have a long history
MF59: The progenitor of licensed oil-in-water adjuvants
Oil-in-water emulsion adjuvant licensed for use in seasonal influenza
vaccine since 1997
More than 60 million commercial doses distributed
Licensed with pandemic H1N1 vaccine
More than 100 million doses distributed
>120 Clinical studies, >200,000 subjects
No safety signals in either pharmacovigilance database or meta-analysis of clinical
trial database with subject follow-up
Safety shown also in pregnant women
Pediatric studies and efficacy trial in >4,000 subjects
MF59 is a trade mark of Novartis
Del Giudice G and Rappuoli R, Curr Top Microbiol Immunol, 386: 151, 2015
28
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021How does MF59 exert its adjuvant effect?
Strong potentiating activity at local, not at distant level
1. Strong local transcriptome 2. Recruitment of
activation professional cells
and uptake of
antigen
1. Mosca et al, Proc Natl
Acad Sci USA 105 (30),
10501-6, 2008
2. Calabrò et al, Vaccine 29
3. Lack of activation of innate (9), 1812-23, 2011
3. Seubert et al, J Immunol
immunity in the lymph nodes 188 (7), 3088-98, 2012
30
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021In humans, MF59 favors the induction of long-term
Th1-type memory
Seder et al, Nature Rev Immunol 8: 247-258, 2008
Mind the mouse!
These data could not be predicted by studies in mice, in which
MF59 induced a predominant Th2-type response
32
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021… and enhances efficacy as compared
to non adjuvanted vaccines
N= 4,707, 2007 – 2009 Seasons
MF59-
VE (%) compared TIV
to non influenza Relative efficacy of Fluad vs. non-adjuvanted vaccine (TIV)
control vaccine) 80% 68% 91% 75%
1
100% 1
96%
89%
1
81% 1
80% 75%
Fluad
TIV
60% MF59-
TIV
TIV
48%
45%
41% Figure 2 | Target population for vaccines in the twenty-first century. a | The and th
40% most important vaccines for each age group are reported. b | Special target
groups for vaccination in the twenty-first century. The most important vaccines
for each target group are reported. The lists of vaccines reported are indicative
20%
(discussed in more detail below). However, several new medical needs. F
an immunization schedule should be immune system makes them
2% for adults and should include
established able to many infections again
0% Age of
vaccination against emerging strains (months)
were previously immune. Sus
influenza virus and2 periodic boosts to to infections, such as influenz
6 –LIVE – Lombardy Influenza Vaccine Effectiveness: observational
study of pneumonia/influenza hospitalizations in older adults
§ ~175,000 person seasons observation: 2006-07, 07-08, 08-09 seasons
§ 23% fewer “pneumonia/influenza” hospitalizations in MF59-TIV vs TIV
recipients after multiple adjustments for age, disability and other risk factors
The final analysis showed that MF59-TIV
reduced “pneumonia/influenza”
hospitalizations by 23% over TIV
Peak
23%
CI: 1-41%
Influenza incidence
>1 cases/1,000 persons
Cases/1,000 persons
1
Figure 2 | Target population for vaccines in the twenty-first century. a | TheIntermediate
and they are not intended to be exhaustive.
, ; ,
15%
most important vaccines for each age group are reported. b | Special target , ;
CI:-5% – 35%
Influenza , incidence ;
groups for vaccination in the twenty-first century. The most important vaccines , ;
for each target group are reported. The lists of vaccines reported are indicative , ; SARS, severe acute respiratory syndrome.
>0.5 cases/1,000 persons
0.5 (discussed in more detail below). However, several new medical needs. First, the aging efficiently used to boost immune responses
an immunization schedule should be Low
immune system makes them more vulner- in the elderly is the oil-in-water emulsion
9% for adults and should include
established able to many infections against which they MF59 (Novartis), which is licensed for use
CI:vaccination
-5% - 22% against emerging strains of Influenza incidence
were previously immune. Susceptibility as an adjuvanted seasonal influenza vac-
influenza virus and periodic boosts to
maintain immunity to diphtheria, tetanus,
Entire influenza season
to infections, such as influenza virus,
meningococcus, group B streptococcus,
cine in European countries and in several
other countries and has been shown to
pertussis, hepatitis B virus, respiratory syn- pneumococcus, respiratory syncytial virus reduce hospitalization in the elderly 11.
September Peak virus and meningococcus April
cytialweeks (groups A, and varicella
Mannino et al, Am J EpidemiolOther
zoster virus, becomes higher 176licensed or experimental
(6), 527-33, 2012adjuvants
B, C, Y and W135). in this age group; as such, they will need are good candidates for novel vaccines for
more-frequent booster vaccinations, in elderly patients in the future 34
(TABLE 1).
Elderly individuals. An important target many cases with vaccines potentiated by The second medical need for the elderly
2 | Vaccini |ofG.new
group for the development Delvac-
Giudice | Roma, 25 Maggio
adjuvants 2021
that are specifically designed is immunity to antibiotic-resistant bacteria
cines will be the elderly, a demographic to stimulate the aging immune system to that are acquired during hospitalization —Latent VZV infection and reactivation
HZ risk correlates with a decline in VZV-specific T-cell levels
Centers for Disease Control and Prevention (CDC). MMWR Early Release 2008; 57:1–30; Johnson R.W. Expert Rev Vaccines, 2010;9(3s):21-26;
Kimberlin DW, Whitley RJ. N Engl J Med 2007;356:1338–43
VZV: varicella zoster virus; HZ: herpes zoster
36
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Age-specific HZ incidence rates1
Mean age of occurrence in adults
(defined as over 22 YOA) is 59.4
YOA1
20 Hope-Simpson (UK) Brisson (UK)
18 Gonzalez (France) Ultsch (Germany) 68% of cases occur in
Insinga (US) Yawn (US)
16 people over 50 YOA1
(per 1,000 person-years)
Stein (Australia) Brisson (Canada)
14 Jih (Taiwan) Choi (South Korea)
Annual incidence
12
10
8
6
4
2
0
0 10 20 30 40 50 60 70 80 90
Age
Several studies have shown that the incidence of
HZ increases substantially with age1,2
HZ, herpes zoster; YOA, years of age
1. Yawn and Gilden. Neurology 2013; 81: 928930; 2. Harpaz et al. MMWR Recomm Rep 2008; 57: 1–30
37
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Incidence of HZ in patients with reduced
USA 2005–2009 immune function
HZ in patients with comorbidities HZ in patients receiving immunosuppressive
that alter immune system function therapy or chemotherapy
50
Incidence per 1,000 person-years
45
40
35
30
25
20
15
10
5
0
n T T IV E A r D S s
tio C SL R ce IB si
l a S SO H
an M ir a HZ incident rate ratio (users vs non-users)
opu BM C
Ps
o
p
le
ho
W
Patients with altered immune function have been shown to have an
increased risk of HZ due to both the underlying condition and the treatment
BMSCT, bone marrow or stem cell transplant; HZ, herpes zoster; IBD: inflammatory bowel disease;
MS, multiple sclerosis; RA, rheumatoid arthritis; SLE, systemic lupus erythematosus; SOT, solid organ transplant
Chen et al. Infection 2014; 42: 325–34
38
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Live attenuated vaccine against herpes zoster
One dose vaccine – high-titer VZV Oka: ≥19,400 pfu/dose
USA: indicated for prevention of HZ in individuals ≥50 YOA
and recommended in individuals ≥60 YOA
SPS and ZEST trials: short term VE VE over time2-4
Age group HZ (%) PHN (%)
(years) Overall (≥60) HZ (%) PHN (%)
Overall (≥60)1 51 671 0–4 years2 51 67
50–592,* 70 NR
4–7 years2 40 60
60–691 64 661
≥701 38 671 7–10 years3,4 21 35
≥801 18 (ns) NR
SPS: N=38,501 subjects ≥60 YOA
Contraindicated in immunosuppressed/immunodeficient individuals
*ZEST trial.
HZ, herpes zoster; NR, nor reported; NS, not significant; PFU, plaque forming units; PHN, post-herpetic neuralgia; SPS, Shingle Prevention Study; VE, vaccine efficacy; YOA, years of age
1. Oxman et al. N Engl J Med 2005; 352: 2271–84; 2. Schmader et al. Clin Infect Dis 20112; 55: 1320–8; 3. Morrison et al. Clin Infect Dis 2014: doi: 10.1093/cid/ciu918; 4. EMA. Zostavax™ summary of
product characteristics, November 2014. Available from: http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000674/WC500053462.pdf [Accessed Dec
2014]
39
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Towards a subunit zoster vaccine
The VZV glycoprotein E (gE)
1-4
Zerboni L et al, Nat Rev Microbiol 12: 197 (2014)
1
Arvin AM et al, J Immunol 137: 1346 (1986). 2 Brunell PA et al, J Infect Dis 156: 430 (1987).
3 Grose C, Annu Rev Microbiol 44: 59 (1990). 4 Herper DR et al, J Med Virol 30: 61 (1990)
40
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021The recombinant zoster vaccine
gE protein plus AS01 adjuvant
Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1,
Amsterdam: Elsevier; 2011; chapter 4: p89–113
Didierlaurent et al, J Immunol 193: 1920 (2014)
41
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021AS01-adjuvanted gE induces strong gE-specific
CD4+ cells and antibodies in older adults
Adapted from Chlibek R, et al. Vaccine. 2014;32(2014):1745-1753.
42
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Strong efficacy against herpes zoster in all
age groups, including >70 year-old elderly
Zoster vaccine group
Lal et al, New Engl J Med 372: 2087 (2015)
43
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Intervene on mechanisms leading to immunosenescence?
47
2 | Vaccini | G.
CONFIDENTIAL Del Giudice –|FOR
INFORMATION Roma, 25 Maggio
INTERNAL 2021
USE ONLYVaccinate against CMV to slow down immunosenescence?
gB + MF59 adjuvant efficacious in seronegative mothers
The n e w e ng l a n d j o u r na l of m e dic i n e
P = 0.01). The rate of myalgias was greater in the
1.0
Vaccine vaccine group than in the placebo group after the
0.9 first dose (36 of 228 subjects [16%] vs. 13 of 225
0.8 subjects [6%], P = 0.007) and after the third dose
Placebo
0.7
(28 of 176 subjects [16%] vs. 5 of 159 subjects [3%],
0.6
50% efficacy over P = 0.001). The – Could
majoritythese findingsreactions
of all systemic be
0.5
a 42-month period were mild. The only systemic reaction for which
0.4 extended to other groups
there was a significant difference in the duration
0.3
of subjects?
of symptoms was headache, which was of longer
0.2
0.1 duration in the – Vaccinate
placebo groupatthan
childhood?
in the vaccine
0.0 group after the secondlasting
– Long dose. The median duration
immunity?
0 3 6 9 12 15 18 21 24 27 30 33 36 39 42
for most reactions was less than 1 day.
– Antibodies enough?
Local reactions at the site of injection within
7 days after – Improvement
immunization of more often
occurred
Vaccine 225 213 211 204 195 178 160 154 145 136 127 116 112 98 88
Placebo 216 193 185 178 169 153 141 128 121 114 108 104 97 87 75 “healthspan”?
in the vaccine group (Table 3). After the third dose
of vaccine, 3% of subjects in the vaccine group
Figure 2. Kaplan–Meier Estimates of Probability of Remaining Free of CMV reported severe pain, and 2% reported severe ery-
Infection. AUTHOR: Pass Pass RF et al, NEJM 360: 11911st
RETAKE (2009)
ICM
2nd
thema; for all other injection-site reactions, the
FIGURE: 2 of 2
Up to 42 months after study enrollment, subjects in the vaccine 3rdgroup
REG F
proportion of subjects in the vaccine group who
were more likely
CASEto remain free of CMV infection than Revised
were subjects in the
reported having severe symptoms was 1% or less.
(P = 0.02). In the vaccineLine
placebo groupEMail 4-C subjects were found to
group, 18
have CMV infection,
Enon
ARTIST: ts
as compared withH/T31 in theH/T 22p3
placebo group. In the placebo group, only one subject reported
Combo
severe pain after the first dose, and there were
no other severe local reactions. The majority of48all
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021
Table 2. Outcome of Pregnancy during the Study Period.* local reactions lasted less than 1 day, and thereCan we intervene on pathways regulating aging?
The mTOR pathway
Yeast
Anti-aging effects of
mTOR inhibition:
C. elegans
- Altered protein
EXTENDED
D. melanogaster
translation
LIFESPAN AND
- Increased HEALTHSPAN
mitochondrial
biogenesis
- Increased autophagy
- Decreased cellular
Mouse senescence
Adapted from Lamming DW et al, J Clin Invest 123: 980 (2013); Johnson SC et al, Nature 493: 338 (2013)
49
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Enhanced immune response to and efficacy
of vaccines in old mice receiving rapamycin
Influenza
Chen C et al, Sci Signal 2: ra75 (2009)
Tuberculosis (BCG)
Jagannath C & Bakhru P, Methods Mol Biol
821: 295 (2012)
2 | Elderly | G. Del Giudice | 12
February 2020 | Vaccinology Course,
Antwerpen | Business Use Only
50
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Any effect on immunosenescence in humans?
Proof-of principle
Tiziano, Self-portrait,
1562 (77 yrs-old)
Improved
mTOR inhibitor Influenza vaccination antibody
response?
Flu Serum
vaccine Ab titers
– RAD001, 0.5 mg /day
Post-
– RAD001, 5 mg/week
No vaccination
– RAD001 20 mg/week
drug follow-up
– Placebo
6 weeks 2 4 weeks
weeks
RAD001: mTOR inhibitor
51
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Increase in Ab titers to flu antigens in RAD001-
treated vs. placebo 4 wks post-vaccination
All subjects Subjects with baseline titers < 1:40
Mannick JB et al, Science Transl Med 6: 268ra179 (2014)
53
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Treatment with mTOR inhibitors induces activation
of IFN gene families and reduces the rates of
infections in older adults
Mannick J et al, Sci Transl Med 10(449),
eaaq1564, 2018
55
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Not all old people are equally immunologically old
Which role for “extrinsic” factors?
G. Del Giudice et al, npj Aging & Mechanisms of Disease 4(1) 1-8, 2018
60
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021BioAge of the immune system
Furatis et al. Pre-vaccination inflammation and B-cell signalling predict age-related hyporesponse to hepatitis B vaccination.
Nat Commun. 2016 Jan 8;7:10369
61
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021BioAge of the immune system
Transcriptional Transcriptional
modules involved in modules involved in
B cell signaling, the inflammatory
T-cell receptor response, cell
signaling and motility and type II
antiviral response interferon
Furatis et al. Nat Commun. 2016 Jan 8;7:10369
62
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021In conclusion
• The world is changing and the vaccine world needs to change accordingly
• The technology is there, both to develop novel vaccine constructs and to
understand mechanistically how vaccines work in the elderly
• In the past few years we have seen impressive progress in the field of
vaccines for the elderly:
– Efficacy of pneumococcal conjugated vaccine [Bonten MJ et al, NEJM 372: 1114 (2015)]
– Efficacy of high dose influenza vaccine [DiazGranados CA et al, NEJM 371: 635 (2014)]
– Efficacy of recombinant subunit adjuvanted herpes zoster [Lal H et al, NEJM 372: 2087 (2015); Cunningham
AL et al, NEJM 375: 1019 (2016)]
– Enhancement of immune responsiveness with drug treatment (mTOR inhibitors)
[Mannick JB et al, Sci Transl Med 6: 268ra179 (2014)]
• Some areas still need more work
– Move faster to test vaccines in the elderly
– Take into right account not only chronological age, but also the biological age
and the extrinsic factors (co-morbidities, drug treatment, nutrition, etc)
contributing to it
– Give the right value to the vaccines to favor their development and their
introduction into the public health usage
69
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021Alcune vostre domande
• Quali sono i parametri/dati necessari per decidere che tipo di vaccino
usare/realizzare contro un nuovo virus?
• Che preparazione è richiesta per lavorare nelle industrie produttrici di
vaccini o nella farmacovigilanza?
• Le pressioni economico-politiche hanno influenzato la distribuzione dei
vaccini?
• Il Covid-19 ha portato a domandarsi se i piani pandemici non debbano
essere rivisti o migliorati?
• Come e da chi viene gestito il flusso dei dati statistici durante i trial clinici e
da cosa dipende la scelta della popolazione campione?
• Quali e quanti dati sono richiesti, e più importanti, per approvare un
vaccino?
• Il genoma di una popolazione/etnia influenza gli effetti del Covid-19?
• Chi li detiene e come sono stati gestiti i brevetti per i vaccini per SARS-CoV2?
• Quali sono le materie prime necessarie per la produzione di un vaccino
(specialmente quelli per SARS-CoV2)?
70
2 | Vaccini | G. Del Giudice | Roma, 25 Maggio 2021You can also read
