"VACCINI: NIENTE SARÀ PIÙ COME PRIMA" - SERGIO ABRIGNANI, MD, PHD
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«Vaccini: niente sarà più come
prima»
Sergio Abrignani, MD, PhD
- Istituto Nazionale Genetica Molecolare “Romeo ed Enrica Invernizzi”, Milano
- Dipartimento di Scienze Cliniche, Università degli Studi di Milano
26 gennaio 2022
1
Vaccination, the most effective medical
intervention ever
• In the decade 2011-2020, the 27 vaccines we use
worldwide have prevented 25 million deaths
- 2.5 million/year
- 7000/day
- 300/hour
- 5/min
WHO Global Action Plan
2
Different classes of licensed vaccines
Killed Whole Recombinant Adenoviral
Live-attenuated Purified Protein Glycoconjugate RNA
Microorganism proteins Vectors
18th Smallpox
19th Rabies
Tuberculosis (BCG)
Yellow fever
Influenza
Polio (OPV)
Typhus Diphtheria
Measles
20th Polio (IPV) Tetanus
Mumps HBV
Rabies Acellular Perussis Hib
Rubella
Japanese Encephalitis Anthrax
Thyphoid
Tick-Born Encephalitis Influenza subunit
Varicella
HAV
Rotavirus
Cholera
HPV
21st Cold-adapted Influenza Pneumococcus
MenB EbolaVirus
Rotavirus reassortants Sars-Cov2 MenACWY Sars-Cov2
Sars-Cov2 Sars-Cov2
Zoster
3
Covid ha ridotto l’aspettativa di vita di 1 anno (da 83 a 82)
Niente di nuovo sotto il sole
Source: P. Palese. Influenza: old and new threats.
Spanish Flu (1918)
Nature Medicine 10:S82-S87, 2004
AIDS in Africa (now)
Source: World Bank World Development Indicators,
2004
4
SARS – Beginning to understand a new virus
Stadler K, Masignani V, Eickmann M, Becker S, Abrignani S, Klenk HD
Nat Rev Microbiol. 2003 Dec;1(3):209-18.
5
SARS-Cov2 is the Coronavirus responsible for Covid-19
• It is a beta-coronavirus, moderatly to very highly infectious, R0 is 2.5 – 12
(depending on the variants).
• It causes acute infections in 100% of cases. No chronic cases. About 99% of
symptomatic infected individuals resolve within 2-6 weeks About 1% of
symptomatic patients, the most fragile (98% are over60), die.
• Antiviral drugs, such as neutralising mAbs and direct antiviral molecules (Merck
and Pfizer) are partially (50-80 %) effective in preventing progression to severe
disease in «at risk» patients.
• Five vaccines (two RNA-based, two based on Adenoviral vectors, one based on
recombinant protein and adjuvant) approved by FDA and EMA; dozens in
development.
6
The Two Responses of the Immune System
INNATE ADAPTIVE
Complement
NK
B cells
Phagocytes
T cells
Inflammation
SPECIFICITY
MEMORY
SPEED
7
Storia clinica dell’infezione da SARS-CoV-2
e ruolo duale delle risposte immunitarie
Stage I Stage II Stage III
(Early infection) (Pulmonary Phase) (Hyperinflammation Phase)
IIA IIB
Severity of Illness
Viral response phase
Host inflammatory response phase
Time course
Risposta immunitaria adattativa Risposta immunitaria innata
PROTEGGE DANNEGGIA
(Antivirali, mAbs e pills, effective. (Antivirali inefficaci
AntiInflammatory to be avoided) AntiInfiammatori raccomandati)
8
Le due risposte del sistema immunitario
INNATA
ADATTATIVA
Complemento
NK Linfociti B
Monociti Linfociti T
Infiammazione
SPECIFICITÀ
MEMORIA
VELOCITÀ
I vaccini si basano sulla risposta immunitaria adattativa
9
La risposta immunitaria è protettiva perchè induce:
• Anticorpi neutralizzanti, prodotti da linfociti B
• Linfociti T CD4 pro-infiammatori (the key player)
• Linfociti T CD8 killer
10I VACCINI ANTI-COVID SALVANO LA VITA
11Disruptive points in the vaccine field
• 1) For the first time, genetic vaccines (Adeno and
mRNA) brought to human use.
• 2) Vaccine development accelerated from 8 years to
8 months.
• 3) Worldwide Vaccine production doubled (from
5B to 11B) in 10 months.
• 4) Mass vaccination campaign of unprecedented
dimension (several billions/Y)
• 5) Vaccination during pandemic time. Thus, more
effector needed than memory
12Disruptive points in the vaccine field
• 1) For the first time, genetic vaccines (Adeno
and mRNA) brought to human use.
• 2) Vaccine development accelerated from 8 years to
8 months.
• 3) Worldwide Vaccine production doubled (from
5B to 11B) in 10 months.
• 4) Mass vaccination campaign of unprecedented
dimension (several billions/Y)
• 5) Vaccination during pandemic time. Thus, more
effector needed than memory
13Piattaforme vaccinali
Classic vaccines: Ags are produced in labs and then injected
Inactivated virus Subunit protein
Examples: Sinovac, Sinopharm Examples: Novavax
Genetic vaccines: Genetic informations are injected and Ags are made by our own cells
Viral Vectors mRNA
Examples: Moderna, BioNTech,
Examples: Oxford, J&J, CanSino CureVac
14Suppression of RNA Recognition by Toll-like
receptors: the impact of nucleoside Modification
and the evolutionary origin of RNA
K Karikò, D Weissman et al
Showed how to modify mRNA without triggering key
inflammatory pathways, overcoming a key hurdle and
paving the way for current vaccines
Immunity, August 1, 2005
15Generating an immune response with mRNA vaccines
1. Recruitment of immune cells to 2. Migration of LNPs and APC 3. LNP uptake and antigen expression
the site of administration to the draining lymph note in cells at the injection site and in draining
lymph nodes
LNP
Antigen
presenting
cell (APC)
Antigen presenting cell (APC)
Draining
Lymph node
16Unique features of mRNA technology
o Highly precise: mRNA-coded instructions are translated in the
cells into proteins with native-like structure;
o Non-infectious: mRNA is not transmitted from one cell to
another, duplicate itself or generate infective virus;
o Transient: mRNA is rapidly degraded after delivery into cells and
translation into protein;
o Non-mutational: mRNA does not integrate into the human
genome.
17Disruptive points in the vaccine field
• 1) For the first time, genetic vaccines (Adeno and
mRNA) brought to human use.
• 2) Vaccine development accelerated from 8
years to 8 months.
• 3) Worldwide Vaccine production doubled (from
5B to 11B) in 10 months.
• 4) Mass vaccination campaign of unprecedented
dimension (several billions/Y)
• 5) Vaccination during pandemic time. Thus, more
effector needed than memory
18Standard vaccines, indicative development timeline till 2020
Sequential development : Average development time 7-10 years
19The pandemic stress test has shortened vaccine development
timelines to 7-10 months
Public money has neutralised the risks of failure at every step.
Covid vaccines, for the first time in history, have been
developed with parallel phases rather then sequential ones
20COVID-19 Vaccines
• Efficacy in clinical trials
• Impact of SARS-CoV-2 variant
21We do not have a clear correlate of immune/protection
How to compare the three main types of vaccines for Covid-19?
Rec Spike + Adjuvant (Novavax) 90% efficacy
Neutralizing tites
in convalescence patients
in vaccinees
Neutralizing titers
mRNA (Moderna and Pfizer) 95% efficacy
AdenoViral Vectors 70% efficacy
(AstraZeneca and J&J)
22La risposta immunitaria è protettiva perchè induce:
• Anticorpi neutralizzanti, prodotti da linfociti B
• Linfociti T CD4 pro-infiammatori (the key player)
• Linfociti T CD8 killer
L’efficacia del vaccino Novavax, a base di proteine ricombinanti e
quindi inducente ”solo” Ab e CD4, è la prova che la risposta
protettiva minima anti-Covid è mediate da linfociti B e linfociti T
CD4 specifici per la Spike e che non sono necessari i T CD8
23In caso di infezione, la risposta immunitaria
precedentemente indotta da un vaccino può:
1) Prevenire l’infezione (immunità da infezione o
sterilizzante): nessun segno di infezione. Si
blocca la trasmissione
2) Impedire la progressione verso la malattia
permettendo un’infezione asintomatica o
paucisintomatica (immunità da malattia). Non
si blocca la trasmissione.
24I vaccinati sono molto, molto più protetti dei non vaccinati
(I vaccinati sono il 75% circa)
Il confronto Incidenza non vaccinati per
100.000
Incidenza vaccinati completi per
100.000
Positivi Ricoverati in ospedale
(24/09/2021 – 24/10/2021) (17/09/2021 – 17/10/2021)
450 404,28 180 160,28
387,72
400 354,33 160
350 300,19 140
300 120
250 100
200 80 64,72
150 89,49 95,43 60
100 70,81 77,3 40 28,52
13,44 21,16
50 20 0,67 1,35 5,48
0 0
Età 12-39 40-59 60-79 80+ Età 12-39 40-59 60-79 80+
Ricoveri in terapia intensiva Decessi
(17/09/2021 – 17/10/2021) (03/09/2021 – 03/10/2021)
14 100 93,53
12,07
12
80
10 8,24
8 60
6 40
4 3,21
15,86
1,07 20 7,98
2 0,75 0,56 1,65 0,07 0,95
0 0,11 0,1 0,01
0 0
Età 12-39 40-59 60-79 80+ Età 12-39 40-59 60-79 80+
Fonte: Istituto Superiore di Sanità
25COVID-19 Vaccines
• Efficacy in clinical trials
• Impact of SARS-CoV-2 variant
26COVID-19 Vaccines
• Efficacy in clinical trials
• Impact of SARS-CoV-2 variant:
• 1) Diffusività, 2) Patogenicità, 3) Efficacia dei vaccini
In 12 mesi abbiamo avuto almeno 3 varianti che ci hanno
preoccupato (VOC):
Autunno 2020: Alfa
Primavera 2021: Delta
Autunno 2021: Omicron
Ne arriveranno altre. Ma noi abbiamo i vaccini
27Variant waves
Although SARS-CoV-2 sequences captured within a country might not be representative of the overall disease burden,
they do help to show how different variants have become dominant.
Source: Nature, Vol. 600, Dec 2021
28Aprile 2021 (protezione verso variante Alpha)
Estimated Effectiveness of 2 Doses of Pfizer/BioNTech COVID-19
Vaccine Against 5 Outcomes, Israel
• Alpha variant accounted for ~95% of SARS-CoV-2 infections
Estimated adjusted effectiveness, ≥7 days
after the second dose, Jan 24 to April 3, 2021
SARS-CoV-2 infection 95.3%
Symptomatic COVID-19 97%
COVID-19 related hospitalization 97.2%
Severe or critical COVID-19 related hospitalization 97.5%
COVID-19 related death 96.7%
29Omicron Variant
Transmissibility, Patogenicity, Vaccine efficacy
• Transmissibility greater than Delta variant – 2x
greater (R0 = 12).
• Disease severity is reduced of about 50%
compared to Delta, because it tends to stop in the
upper airways
• Vaccine efficacy similar to Delta, i.e., people
vaccinated with three doses are partially protected
(65-70%) from infection and are higly protected
(>95%) from severe disease.
30Estate 2021: variante Delta
Effectiveness of 2 Doses of Pfizer mRNA Vaccine Against
Alpha and Delta Variants – UK, Canada, Israel
England/Scotland Canada Israel
100 96 100
90 93
88 87
80 79
70
64 64
60
50
40
30
20 Confirmed Symptomatic Hospitalization Symptomatic Hospitalization Confirmed Symptomatic Hospitalization
10 infection Disease Disease or death infection Disease or death
0
Alpha Delta
Sources: Sheikh et al. Lancet, June 2021; Bernal et al. NEJM, June 2021; Stowe et al. PHE, June; Nasreen et al. medRxiv, July 2021; Israel MOH, July 2021
31Stima dell’efficacia nei soggetti vaccinati con ciclo completo da oltre di sei mesi e da meno
di 6 mesi rispetto ai non vaccinati per diagnosi e malattia severa, nella popolazione italiana
di età > 12 anni, per classe d’età (periodo 05 luglio – 21 novembre 2021)
NB. I soggetti che risultano vaccinati da oltre sei mesi
appartengono principalmente alle categorie maggiormente a
rischio di infezione/ricovero/morte (operatori sanitari,
residenti nelle RSA, ultraottantenni e persone estremamente
vulnerabili). L’efficacia dei vaccinati con ciclo completo da >6
mesi risulta quindi verosimilmente sottostimata.
www.iss.it/presidenza
32“Booster” shots for
SARS-CoV-2 Vaccines
33Key points about memory and booster dose(s) for Covid vaccines
facing the Delta variant
• Covid vaccines were developed with two-doses schedule because
of time constraint
• In the absence of a correlate of immunity, the key question was
whether the decline in clinical efficacy, 5-8 months after second
dose, was due to a decline of memory responses (that
could be corrected by a «Wuhan spike » third dose), or whether
it was an immune escape of the Delta variants (that would
have required a Delta Spike vaccine)
• Is a third dose the end of the story as it is for most vaccines that
only require additional boosters after many years, if any?
34Some examples of vaccines with three-doses schedule:
• Hepatitis B
• Haemophilus influenza type B
• Inactivated poliovirus (IPV)
• Pneumococcal conjugate (PCV13)
• Diptheria
• Tetanus
• Pertussis
• MenB
With the exception of Vaccines based on attenuated viruses,
the 3-dose schedule is the general vaccination rule
in immunologically naive persons
35Schedula vaccinale
1) Le migliori risposte immunitarie si ottengono quanto più si spaziano le dosi
(idealmente 3 dosi: 0, 1 e 6-12 mesi).
2) Dosi ravvicinate tengono ad indurre più risposte effettrici che risposte
memoria. Quindi si favoriscono più dosi ravvicinate quando si è in fase di
esplosione pandemica.
3) È falso che spaziare di più le dosi favorisca lo sviluppo di varianti più
aggressive, infatti è vero l’opposto. Tutte le varianti si sono sviluppate in
popolazioni ancora non vaccinate e spesso in individui immunodepressi.
36A third dose of the Wuhan vaccine, 6-8 months after the
first one, restores efficacy against Delta variant.
Thus decline was due to a waning of memory responses
149,144 subjects 675,630 subjects
Received 3rd shot booster Received only 2 shots
37 infections 1,064 infections
86% effective
A fourth dose vaccine dose not change this picture!!
37“Booster” shots for SARS-CoV-2 vaccines.
Time will tell whether:
the booster shot is a boost for a vaccine
with short lived memory and waning efficacy
(to be repeated every 8-12 months)
OR
the booster shot is actually part of the
original vaccine regimen (0, 1, 8 months)
(to be recalled after 5-10 years)
38Grande è la confusione sotto il cielo
• 1) Non abbiamo mai provato a vaccinare
tutto il mondo in 2-3 anni (20Miliardi di
dosi)
• 2) Non Abbiamo mai fatto vaccinazione di
massa durante una pandemia
• 3) Le varianti ci dimostrano che stiamo
inseguendo il virus
39L’unica certezza che abbiamo è che
I VACCINI ANTI-COVID SALVANO LA VITA
4041
La variante Omicron preoccupa ma non troppo,
serve un grande progetto vaccinale PanCoronavirus
Dobbiamo sviluppare un vaccino contro tutti i coronavirus passati, presenti e
futuri (vaccino Pan-Coronavirus), per essere pronti ad un prossimo probabile
salto di specie di un nuovo Coronavirus nei prossimi anni.
Il vaccino Pan-Coronavirus dovrà indurre una memoria immunitaria contro
le sequenze conservate fra tutti i Coronavirus.
Una poco rassicurante sequenza numerica nel 21° secolo:
2002 2012 2019 2021 2030
SARS-CoV-3
?
SARS CoV-1 MERS-CoV SARS-CoV-2Istituto Nazionale Genetica Molecolare – INGM
“Romeo and Enrica Invernizzi”
INGM:
Funding: Cristina Manara Ospedale Niguarda
Renata Grifantini
Samuele Notarbartolo Elisa Pesce Salvatore Siena
Francesca Granucci Eugenia Galeota Ospedale Pini
Andrea Favalli Roberto Caporali
Valeria Bevilacqua
AdG Marilena Mancino
Serena Curti Antonio Lanzavecchia
Anna Putignano
Andrea Gobbini IRCCS Policlinico,
Mauro Bombaci Milano:
Tanya Fabbris Blood bank
Maria Lucia Sarnicola Daniele Prati
Infectious diseases
Paola Gruarin
A. Gori
Riccardo Rossi A. Bandera
Valeria Ranzani
Jens Geginat
42 Maria Cristina Crosti43
The immune response induced by vaccines is protective because of:
• Neutralizing antibodies, produced by B cells
Induced by all vaccines
• CD4 T lymphocytes (help IR to develop)
Induced only by vaccines that
• CD8 T lymphocytes (kill infected cells) carry the genetic information
to make viral proteins
All anti-covid vaccines aim at inducing CD4 T
lymphocytes specific for the Spike protein, which in turn
help production by B cells of anti-Spike antibodies
capable of neutralizing binding of the virus to the ACE2
receptor on human cells.
44SARS-Cov2 is the Coronavirus responsible for Covid-19
• It is a beta-coronavirus, moderatly to highly infectious, R0 is 2.5 - 6 (depending
on the variants)
• It causes acute infections in 100% of cases. No chronic cases. About 99% of
symptomatic infected individuals resolve within 2-6 weeks About 1% of
symptomatic patients, the most fragile (98% are over60), die
• Partially (50-60%) effective antiviral drugs are neutralising mAbs, anti-IL1
(Anakinra) and direct antiviral molecules (Merck)
• Four vaccines (two RNA-based and two based on Adenoviral vectors) approved
by FDA and EMA; dozens in development.
45Resolution and Severe form of disease are both related to
Immune Responses
Infezione da
SARS-CoV-2
Fase Virus-dipendente Risoluzione
60% 40% Risposta immunitaria
asintomatici sintomatici ADATTATIVA
Risoluzione (entro 2-3 settimane)
Fase Virus-indipendente
Buona efficacia degli
Risposta immunitaria
anticorpi monoclonali e antivirali
INNATA
diretti
1. Tempesta citochinica
2. CID
3. Insufficienza multiorgano
4. Complicanze sistemiche
Discreta efficacia di
antinfiammatori quali
steroidi e anti-IL1
46Three types of Covid vaccines in Europe,
all having the same goal
January 10th, 2020
Virus sequencing Vaccines Clinical trials
2 weeks (3 months)
mRNA
All candidate vaccines
4 weeks (4 months)
Viral vectors progressed to clinical trials
after 3-8 months
4 months Recombinant (6 months)
proteins
Adenoviral vector vaccines will soon be replaced by mRNA and recombinant
protein based vaccines, due to the need of a recall.
47Dicembre 2020 (protezione vaccinale verso il ceppo Wuhan)
Pfizer/BioNTech Vaccine Moderna Vaccine
The The
New England New England
Journal of Medicine Journal of Medicine
Published online December 10, 2020 Published online December 30, 2020
Safety and Efficacy Efficacy and Safety
of the BNT162b2 of the mRNA-1273
mRNA COVID-19 SARS-CoV-2
vaccine Vaccine
FP Polack et al. for the LR Baden et al. for the COVE Study
C4591001 Clinical Trial Group Group
Efficacy: 95% Efficacy: 94,1%
48World vaccination status
October 1st, 2021
Number of people (in millions)
5000
4500 4290
3910
4000
3499
3500
3000 2567 2678
2500 2308
1861
2000 1641
1399
1500
952 1021
1000 821 706
650
380 454
500
15 8
0
World High-income countries Upper-middle income Lower-middle income Low-income countries Developing worild
countries countries
Unvaccinated Vaccinated ≤1 dose Fully vaccinated
Please note: The classifications above are based on World Bank income classifications for each country. The Developing World includes
upper-middle income countries, lower-middle income countries, and low-income countries. Source: the graphic is based on the latest
available data from Our World in Data and is compiled by Pandem-ic.
49Efficacia vaccinale nella popolazione italiana sopra 12 anni
nei casi di COVID-19 diagnosticati nel periodo 5 aprile – 3 ottobre 2021
Efficacia vaccinale Efficacia vaccinale
Gruppo Fascia di età (vaccinati ciclo incompleto (vaccinati ciclo completo vs
vs non vaccinati) non vaccinati)
12-39 50,8 [50,2-51,3] 74,1 [73,8-74,4]
40-59 67 [66,6-67,5] 75,2 [75-75,5]
Diagnosi di
60-79 77,2 [76,9-77,6] 81,4 [81,2-81,7]
Sars-CoV-2
80+ 59,8 [58,5-61] 85,7 [85,4-86]
Totale 63,56 [63,28-63,84] 77,58 [77,42-77,73]
12-39 82,6 [80,4-84,5] 90,3 [89,1-91,5]
40-59 89 [88,1-90] 93,7 [93,2-94,2]
Ospedalizzazioni 60-79 87,4 [86,7-88] 93,1 [92,7-93,4]
80+ 71,8 [70,1-73,4] 92 [91,7-92,3]
Totale 83,92 [83,39-84,44] 92,53 [92,32-92,74]
12-39 91,6 [81,2-96,2] 95 [88,9-97,8]
40-59 93,2 [90,5-95,1] 95,9 [94,6-96,9]
Ricoveri in Terapia
60-79 91,6 [90,2-92,7] 95,1 [94,4-95,7]
Intensiva
80+ 78,5 [71,3-83,9] 92,2 [90,5-93,6]
Totale 90,83 [89,66-91,87] 94,77 [94,21-95,27]
12-39 58,4 [58,3-58,6] 82,1 [82-82,2]
40-59 88 [82,5-91,8] 93,3 [90,4-95,3]
Decessi 60-79 89,6 [88,3-90,8] Source: World Health Organization
94,7 [94-95,3]
80+ 77,5 [75,3-79,4] 94,9 [94,5-95,2]
Totale 83,49 [82,3-84,59] 94,56 [94,21-94,89]
Source: ISS - Data di ultimo aggiornamento: 6 ottobre 2021
50Pfizer booster increases antibody titers against Delta variant
Post dose 3 titers vs. the DELTA variant are >5-fold post dose 2 titers
in 18-55 y/o & > 11-fold post dose 2 titers in 65-85 y/o
51Riduzione efficacia vaccinale infezione da completamento ciclo vaccinale
(2 dosi o dose unica) (solo fase Delta)
www.iss.it/presidenza
52Rriduzione efficacia vaccinale malattia severa da completamento ciclo vaccinale
(2 dosi o dose unica) (solo fase Delta)
www.iss.it/presidenza
53Key points about memory and booster dose(s) for Covid vaccines
facing the Delta variant
• Covid vaccines were developed with two-doses schedule because
of time constraint
• In the absence of a correlate of immunity, the key questions was
whether the decline in clinical efficacy, 5-8 months after second
dose, was due to a decline of memory responses (that could be
corrected by a «Wuhan spike » third dose), or whether it was an
immune escape of the Delta variants (that would have required a
Delta Spike vaccine)
• Is a third dose the end of the story as it is for most vaccines that
only require additional boosters after many years, if any?
54The Clear side of SARS-Cov2: Accelerated vaccine development
(two doses Vs three doses)
55Efficacy vs Effectiveness
56Consigliereste a nessuno di vivere senza vaccinarsi?
Infezione Efficacia vaccinale (%)
Poliomelite orale 100 %
Difterite 99.90 %
Morbillo 99.90 %
Rosolia 99.70 %
Parotite 99.80 %
Pertosse 98.20 %
H. influenzae 98.80 %
Men B/ Men C 90.40 %
HBV 98.00 %
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