Past, Present, and Future:

Vaccine Technologies
Leonard Friedland, MD, FAAP
Vice President and Director, Scientific Affairs and Public Health
GSK Vaccines

National Press Foundation Vaccines Program

Understanding Vaccines and Health

July 31, 2019

 Disclosure

Employed by GSK where I am a vaccine research physician scientist

Presentation at the invitation of Chris Adams, National Press Foundation

Presentation is for educational purposes only; this is not a sales,

marketing or promotional presentation

Content of presentation will not include unapproved or investigational uses

of products or devices
Globally, Many Diseases are Currently Preventable
by Vaccination
“Vaccines are one of the greatest achievements
of biomedical science and public health”3

Global public health1 Regional focus2

Diphtheria H5N1 flu Adenovirus
Haemophilus influenzae type b Pertussis Anthrax
Hepatitis A Poliomyelitis Cholera
Hepatitis B Pneumococcal Dengue
Herpes zoster Rotavirus Japanese encephalitis
Human papillomavirus Smallpox and vaccinia Tick-borne encephalitis
Influenza Tetanus Typhoid fever
Measles Tuberculosis Rabies
Meningococcal A, B, C, W, Y Varicella Yellow fever
Mumps

1. CDC. List of Vaccines Used in United States. https://www.cdc.gov/vaccines/vpd/vaccines-list.html. Accessed Jan 2017.
2. WHO. Vaccines and Diseases. http://www.who.int/immunization/diseases/en/. Accessed Jan 2017. 3
3. CDC Achievements in Public Health, 1900-1999 Impact of Vaccines Universally Recommended for Children – United States, 1990-1998.
https://www.cdc.gov/mmwr/preview/mmwrhtml/00056803.htm. Accessed Jan 2017.
 Health and Human Services
Healthy People 2020

Immunization and Infectious Diseases: goal

“Increase immunization rates and reduce preventable infectious diseases.”

Vaccines are among the most cost-effective clinical

preventive services and are a core component of
any preventive services package.

https://www.healthypeople.gov/2020/topics-objectives/topic/immunization-and-infectious-diseases
Vaccine Science: Two Centuries of Continuous
Research, Improvements, and Achievements

5
R. Thom, ‘Jenner: Smallpox is Stemmed, from "The History of Medicine,”’ Collection of the University of Michigan Health System, Gift of Pfizer.
Bonanni P, et al. Chapter 1 in: Garçon, et al. Understanding Modern Vaccines: Perspectives in Vaccinology. Vol 1. Amsterdam: Elsevier; 2011.
The Science of Immunology Began in the 19th Century

Courtesy of CDC/Janice
Haney Carr/Jeff Hageman
Microorganisms were identified as M.H.S.
the true cause of infectious diseases

Host cells that ingest and destroy

invading microbes were discovered
and called ‘phagocytes’

Passive immunotherapy of diphtheria

with anti-diphtheria toxin antibodies
discovered ‘immune serum’

The antibodies theory was formulated

The concept of ‘natural immunity’

to infection was born

Bonanni P, et al. Chapter 1 in: Garçon, et al. Understanding Modern Vaccines: Perspectives in Vaccinology. Vol 1. Amsterdam: Elsevier; 2011.
New Technologies Make Vaccines Possible
That Were Previously Impossible

1930 1980 1990 2010

Empirical Recombinant Reverse
Glycoconjugation
Approach DNA Vaccinology

Diphtheria, Tetanus, Hepatitis B, MenACWY, MenB, GBS, GAS,

Pertussis, Rabies, Acellular Pertussis, Pneumo, E. coli, S. aureus,
Influenza, Smallpox, Lyme, Human Hib, GBS, S. aureus C. difficile
Polio, BCG papillomavirus

Finco O, Rappuoli R. Front Immunol. 2014;5:1-6.

 1930s–1950s
Growing Viruses

Embryonated eggs (1930s) Cell culture (1950s)

Courtesy of CDC

In the 1930s, Max Theiler at Rockefeller

Foundation used an egg system for the Enders, Weller and Robbins at Harvard
development of an effective yellow fever received the Nobel Prize in Medicine
vaccine, for which he was awarded the in 1954 for demonstrating the ability of
Nobel Prize in Medicine in 1951 polio viruses to grow in cell cultures

Bonanni P, et al. Chapter 1 in: Garçon, et al. Understanding Modern Vaccines: Perspectives in Vaccinology. Vol 1. Amsterdam: Elsevier; 2011.
Whole Pathogen Antigens: Live-attenuated Vaccines

Infectious pathogen

Wild virus is replicated in

unfavorable conditions in
cell culture

The process is repeated

several times…

…to produce an attenuated

strain that is unable to Live-attenuated
cause disease vaccine

Plotkin SA, Orenstein WA. Chapter 41: Technologies for Making New Vaccines in Vaccines. 4th Ed. Philadelphia, PA: Elsevier; 2004.
Whole Pathogen Antigens: Killed/inactivated Vaccines

Infectious pathogen

The virus is grown under

suitable conditions
It is purified…

…and treated with

heat or chemicals…

…so that it is inactivated Killed/inactivated

but still immunogenic vaccine

10

Plotkin SA, Orenstein WA. Chapter 41: Technologies for Making New Vaccines in Vaccines. 4th Ed. Philadelphia, PA: Elsevier; 2004.
 1970s Combination Vaccines

Live-attenuated, combined MMR vaccine developed in order to

minimize the total number of injections in infants
Clinical trial data demonstrate a combined antigen vaccine can
be effective and can have an acceptable safety profile
Measles Mumps Rubella

Courtesy of CDC/Cynthia S. Courtesy of CDC/Dr Fred Murphy Courtesy of CDC/Dr Erskine Palmer
Goldsmith, William Bellini, PhD

MMR, measles-mumps-rubella
Bonanni P et al. Chapter 1 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011.
 1970s–1980s
Split Pathogen and Subunit Vaccines

– Antigen choice: provides immune protection & Whole virus vaccine

technologically achievable
– Often reduced immunogenicity versus whole pathogen
– Non-infectious, low reactogenicity, acceptable
tolerability Pathogen
fragmentation
– No or limited availability of innate defensive triggers
Subunit/purified
– For subunit vaccines with lower immunogenicity, Split vaccine
vaccine
adjuvants often needed to compensate
– Facilitate supply via synthetic production versus whole
pathogen
eg, acellular pertussis
components: PT, PRN,
eg, some influenza FHA, FIM; HA in some
vaccines influenza vaccines

12

Strugnell R, et al. Chapter 3 in: Garçon, et al. Understanding Modern Vaccines: Perspectives in Vaccinology. Vol 1. Amsterdam: Elsevier; 2011.
New Technologies Make Previously Impossible Vaccines
a Reality

1930 1980 1990 2010

Empirical Recombinant Reverse
Glycoconjugation
Approach DNA Vaccinology

Diphtheria, Tetanus, Hepatitis B, MenACWY, MenB, GBS, GAS,

Pertussis, Rabies, Acellular Pertussis, Pneumo, E. coli, S. aureus,
Influenza, Smallpox, Lyme, Human Hib, GBS, S. aureus C. difficile
Polio, BCG papillomavirus

13

Finco O, Rappuoli R. Front Immunol. 2014;5:1-6.

 1980s
Recombinant Protein Vaccines: HBV

Hepatitis B Insert gene into yeast Purification of recombinant

surface antigen expression system protein encoding antigen
(natural assembly into spheres)

Sequence gene Protein Administration

encoding HBsAg expression as vaccine

14
HBsAg= hepatitis B surface antigen; HBV= hepatitis B virus.
Strugnell R, et al. Chapter 3 in: Garçon, et al. Understanding Modern Vaccines: Perspectives in Vaccinology. Vol 1. Amsterdam: Elsevier; 2011.
 1990s Recombinant Protein Vaccines: HPV

Self-
assembly
into viral
capsids
(VLPs)
Elicit
Self- immune
HPV viral
assembly response
capsid
into
pentamers

Purification
DNA from
encoding L1 Antigen expression
DNA system

L1 capsid
Yeast DNA proteins
Transcription
HPV, human papillomavirus; VLP, virus-like particle Translation

Strugnell R et al. Chapter 3 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011.
 1980s-1990s Polysaccharide-conjugate
vaccines
B-cell Polysaccharide-

B-cell + antibody
conjugate vaccine

quantity
Antibody, Polysaccharide
Polysaccharide no memory vaccine
vaccine
Polysaccharide-
conjugate vaccine

T-cell quantity
Conjugated
protein

Polysaccharide-
Antibody
conjugate and No T-cell response to
T-cell memory
vaccine polysaccharide alone

Strugnell R et al. Chapter 3 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011.
 1980s-1990s Reassortant Live-attenuated
Vaccines
Bovine Human
rotavirus rotavirus

Co-infection with wild and attenuated virus

strains, in cell culture, allows ‘swapping’ of
genome segments
– eg, human/bovine reassortant rotavirus vaccine:
human antigens on a bovine virus core

Human

Human/bovine
reassortment

Bonanni P et al. Chapter 1 in: Garçon et al. Understanding Modern Vaccines, Perspectives in Vaccinology, Vol 1, Amsterdam, Elsevier, 2011.
Classical Vaccinology

Growing Pathogens
Reverse Vaccinology
design from information

18
Rino Rappuoli, Matthew Bottomley, Ugo D’Oro, Oretta Finco, Ennio De Gregorio J Exp Med 2016:213;469-481
Rappuoli R, et al. J Exp Med. 2016;213:469-481.
 2000s
Reverse Vaccinology: Human Immunology Instructs
Vaccine Antigen Design

Classical Vaccinology Reverse Vaccinology

growing pathogens design from information

B-cell

19

Rappuoli R, et al. J Exp Med. 2016;213:469-481.

Reverse Vaccinology: A Genomic Approach for a
Meningococcus B Vaccine1,2
In silico vaccine
candidates
Express
recombinant
proteins
600 potential vaccine candidates identified

350 proteins successfully expressed

in E. coli

91 novel surface-exposed
proteins identified

28 novel proteins
have bactericidal
activity

Vaccine Candidates
20
1. Ulmer JB, et al. Nat Biotechnol. 2006;24:1377-1383.
2. Serruto D, et al. J Biotechnol. 2004;113:15-32.
 Vaccines Today: An Explosion of New Technologies

1930 1980 1990 2010 2015

Empirical Recombinant Reverse Next Generation
Glycoconjugation
Approach DNA Vaccinology Technologies

Diphtheria, Hepatitis B, MenACWY, MenB, GBS, GAS, Structural

Tetanus, Pertussis, Acellular Pertussis, Pneumo, E. coli, S. aureus, Vaccinology
Rabies, Influenza, Lyme, Human Hib, GBS, C. difficile
Smallpox, Polio, papillomavirus S. aureus Adjuvants
BCG
Synthetic Biology/
RNA Vaccines

Systems
Vaccinology

21

Finco O, Rappuoli R. Front Immunol. 2014;5:1-6.

Current Challenges for Vaccines1

Challenging Need for booster Recombinant Pathogens Need for antigen

populations vaccinations antigens that require broad sparing
due to impaired generally less and complex immune potential supply
immune system immunogenic than response problems
(eg, elderly, children, live or attenuated (eg, pandemic flu)
immunocompromised) organism vaccine2

Increase Prolong Overcome Induce Reduce

the level of the the duration of the a weakened the generation of a the amount of
immune response immune response, immunogenicity high and broad antigen needed
improve immune immune response (dose-sparing)
memory, and
protection

22
1. Garçon N, et al. Understanding Modern Vaccines: Perspectives in Vaccinology. Vol 1. Amsterdam: Elsevier; 2011; Chapter 4: 89-113.
2. Petrovsky N, Aguilar JC. Immunol Cell Biol. 2004;82:488-496.
Examples of Novel Approaches to Vaccine Design

DNA1 Live vectors1 Reverse Self-amplifying Novel adjuvants

vaccinology1 RNA2 and adjuvant
combinations3
• Pathogen-derived • Targeted antigens • Computer analysis of • Synthetic virus • Substances included
genetic material encoded by gene(s) the pathogen’s entire particles include in a vaccine
coding for the incorporated into the genome is antigen proteins formulation to
antigens contained in vector’s genetic conducted to find • Once inside host cell enhance the quality
a non-replicating material genes that may be cytoplasm, these and strength of the
DNA plasmid • Antigens expressed antigenic self-amplify in large immune response
• Antigen is expressed by a vector (like virus • Vaccine candidate amounts, express induced by the
by the cells of the or bacterium) that is identified based on antigen proteins and vaccine antigen(s)
vaccine recipient non-pathogenic prediction of protein interact with the host
sequences similar to immune system
pathogen’s genome
sequences

1. Stanberry L, Strugnell R. Understanding Modern Vaccines: Perspectives in Vaccinology. Vol 1. Amsterdam: Elsevier; 2011; Chapter 6: 155-199. 23
2. Geall A, et al. Semin Immunol. 2013;25:152-159.
3. Garçon N, et al. Understanding Modern Vaccines: Perspectives in Vaccinology. Vol 1. Amsterdam: Elsevier; 2011; Chapter 3: 61-88.
Adjuvant1,2

– From Latin, adiuvare: to aid

– Substance included in a vaccine to enhance and modulate the quality and/or strength of
the immune response induced by the antigen
– Old technology, made new

Adjuvant

24
1. Bonanni P, et al. Chapter 5 in: Garçon, et al. Understanding Modern Vaccines: Perspectives in Vaccinology. Vol 1. Amsterdam: Elsevier; 2011.
2. Garçon N, et al. Chapter 4 in: Garçon, et al. Understanding Modern Vaccines: Perspectives in Vaccinology. Vol 1. Amsterdam: Elsevier; 2011.
Adjuvants have a long history in the fight
against infectious diseases
No adjuvant Varicella Hepatitis B
Adjuvanted Diphtheria, tetanus, Zoster
pertussis-based combinations Malaria
Pertussis Influenza
Hib Meningococcus B

Adjuvant discovery
Pandemic influenza
Meningococcus ACWY
Influenza Zoster
Rubella HPV
Mumps Meningococcus ACWY
Measles
Rotavirus
Polio, live
Influenza
Polio, inactivated* Influenza
Pneumococcus Pneumococcus
Influenza Meningococcus
Yellow fever Typhoid
Diphtheria Typhoid
Plague
Cholera Tuberculosis Hepatitis A
Typhoid Tetanus Hib
Smallpox Rabies Pertussis Hepatitis B

1750 1800 1850 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010

Hib=Haemophilus influenzae type b; HPV=human papillomavirus; IPV=inactivated polio vaccine; OPV=oral polio vaccine (live).
*IPV is adjuvanted when formulated in combination with diphtheria, tetanus, pertussis-based vaccines but is not adjuvanted when formulated as a stand-alone vaccine. 25

1. Figure adapted from Di Pasquale A, et al. Vaccines. 2015;3:320-343. 2. CDC Pink Book 2018. https://www.cdc.gov/vaccines/pubs/pinkbook/appendix/appdx-b.html. Accesed September 2018.
Antigens May Need Help: The Role of Adjuvants

High Adjuvants
Native virus
Purified antigens/
Adjuvants combination
Immunogenicity

Replicating
(live attenuated) Non-replicating
(inactivated)
Subunit
(eg, split virus)
Purified antigens
(eg, recombinant protein)

Low Tolerability High

26

Figure adapted from Di Pasquale A, et al. Vaccines. 2015;3:320-343.

Expected Impact of Adjuvants on Vaccine Immune
Response Immune response

Stronger/broader Adjuvanted formulation

immune response

Longer-term
immune response

Non-adjuvanted formulation

Earlier Time
immune response

27

Garçon N, et al. Chapter 4 in: Garçon, et al. Understanding Modern Vaccines: Perspectives in Vaccinology. Vol 1. Amsterdam: Elsevier; 2011.
Adjuvants–Few Approved, Many in Development
Adjuvants in Licensed Products Adjuvants in Development
Mechanism or Licensed Mechanism or Clinical
Adjuvant Adjuvant
Receptor product receptor phase
Numerous (eg, ISCOMs (Matrix-M) Unknown 2
Nalp3, ITAM,
Aluminum salts pertussis, hepatitis,
antigen delivery dsRNA analogues TLR3 1
pneumococcal)
Flagellin TLR5 1
AS04 TLR4 HPV
C-type lectin ligands Mincle, Nalp3 1
Immune cell
Emulsions CD1d ligands CD1d 1
recruitment, Influenza
(MF59, AS03)
antigen uptake GLA-SE TLR4 1
TLR4, Zoster IC31 TLR9 1
AS01
inflammasome
Mincle, antigen
CAF01 1
CpG ODN TLR9 Hepatitis B delivery

28

Adapted from Reed SG, et al. Nature Med. 2014;19:1597-1608.

Some potential advantages of game-changing technology
New wave of technologies may address unmet needs in vaccine development

Enhanced Rapid Accelerated Simplified Cost

vaccine vaccine antigen manufacturing reductions
efficacy development discovery
Bioconjugation1

Viral vectors (adenovirus)2

Synthetic biology (SAM)3–5

Structural vaccinology6

GMMA7

Adjuvant Systems8

GMMA, generalised modules for membrane antigens; SAM, self-amplifying mRNA

1. LimmaTech Biologics, 2017. http://www.lmtbio.com/technology/bioconjugates-as-vaccines (accessed November 2017; 2. Colloca S et al. Sci Transl Med 2012;4:115ra2; 29
3. Kindsmüller K, Wagner R. Hum Vacc 2011;7:658–662; 4. Ulmer JB et al. Expert Opin Drug Discov 2015;10:101–106; 5. Geall AJ et al. Proc Natl Acad Sci USA 2012;109:14604–14609;
6. Dormitzer PR et al. Trends Biotechnol 2008;26:659–667; 7. Berlanda Scorza F et al. PLoS ONE 2012;7:e35616; 8. Di Pasquale A et al. Vaccines 2015;3:320–343
Platform technologies can act as ‘on-demand’ solutions
to produce vaccines against multiple diseases
Traditional vaccinology1 Platform-based vaccine development2

One
One technological
technological
development
platform

Repurpose existing tools

Multiple
rounds of Accelerated
refinement development

One vaccine Several vaccine candidates

candidate

1. Strugnell R et al. Perspect Vaccinol 2011;1:61–88; 2. Gilbert SC, Warimwe GM. Vaccine 2017;35:4461–4464 30
Platform technologies allow for the modularisation of
vaccine development

Existing platform Specific antigenic Modular

ingredients module vaccine
Pathogen Antigen

– v

Carrier
Virus

Platform technologies allow for elements of vaccine development to be standardized

Images are for illustrative purposes only

Charlton Hume HK et al. Vaccine 2017;35:4480–4485 31

Platform technologies can provide many practical
benefits for vaccine development (1)

Improved outbreak Increased outbreak Opportunities for vaccine

preparedness1 responsiveness1 component stockpiling1

Lower costs Reduced development

of development1,2 and production times1,2

1. Gilbert SC, Warimwe GM. Vaccine 2017;35:4461–4464; 2. Charlton Hume HK et al. Vaccine 2017;35:4480–4485 32
Platform technologies can provide many practical
benefits for vaccine development (2)

Acquired technological
Improved vaccine expertise reduces uncertainty
tolerability1,2 in vaccine development2

Incremental scientific Increased use of

development leverages previously evaluated
acquired expertise (clinical components1,2
development and licensure)2

1. Gilbert SC, Warimwe GM. Vaccine 2017;35:4461-4464; 2. Charlton Hume HK et al. Vaccine 2017;35:4480–4485 33
How Can These Technologies Help Our Society?

Empirical Recombinant Reverse Next Generation

Glycoconjugation
Approach DNA Vaccinology Technologies

Diphtheria, Hepatitis B, MenACWY, MenB, GBS, GAS, Structural Vaccinology

Tetanus, Pertussis, Acellular Pertussis, Pneumo, E. coli, S. aureus,
Rabies, Influenza, Lyme, Human Hib, GBS, C. difficile Adjuvants/Human
Smallpox, Polio, papillomavirus S. aureus Immune Response
BCG
Synthetic Biology/
RNA vaccines

34

Finco O, Rappuoli R. Front Immunol. 2014;5:1-6.

Vaccines For Every Age

MONTHS YEARS
-3 0 8 18 55 90
Pregnancy Infants & Adolescents Adults Elderly
CMV Children CMV Diphtheria Flu
Flu Diphtheria DTaP boost Flu GBS
GBS Flu EBV HBV Meningococcal
HBV GAS Flu Meningococcal Pneumococcal
Meningococcal HAV HSV Pertussis RSV
Pertussis HBV HPV RSV Zoster
RSV Hib Meningococcal Tetanus Candida
Tetanus IPV C. difficile
Meningococcal E. coli
Pertussis Klebsiella
Pneumococcal P. aeruginosa
Rotavirus Staph
RSV
Tetanus Breast Cancer
Varicella Colorectal Cancer
Measles Prostate Cancer
35
Rappuoli R, et al. Nature Rev Immunol. 2011;11:865-872.
Vaccines For Today’s Society

Poverty Emerging Travelers Patients with Immunotherapy/

Cholera Infections Cholera Chronic Diseases Therapeutic
Dengue AIDS Dengue CMV Vaccines?
ETEC Anthrax ETEC Flu Cancer
HAV Avian influenza Flu Fungal infections
HBV HAV Autoimmune
Cholera P. aeruginosa
HEV HBV diseases
Diphtheria Parainfluenza
Flu Dengue JEV RSV Alzheimer’s
JEV Ebola Malaria Staph Chronic infections
Malaria EV71 Meningococcal TB (HCV, HBV, HPV, HIV…)
MenB Malaria Paratyphoid Metabolic diseases
Parasitic infections SARS Rabies Allergy
Paratyphoid TB Shigella
Drug addiction
Rabies Smallpox TB
Rotavirus West Nile Typhoid Fever
Salmonella Yersinia Yellow Fever
S. enterica
S. typhimurium
Shigella
TB 36
Typhoid fever
Rappuoli R. Vaccine. 2015;33S:B1–B2.
 Discussion
Past, Present, and Future:
Vaccine Technologies

Leonard Friedland, MD, FAAP

Vice President and Director, Scientific Affairs and Public Health
GSK Vaccines