In this section of the coronavirus pandemic series, we discuss the need for an effective COVID-19 vaccine to return to full normalcy. The slides would give a brief overview on how our immune systems work, and how a vaccine would train our immune system to recognize and fight the infection. Current vaccine platform technologies will be compared, and upcoming candidates will be highlighted for newer-generation vaccines. We'll also discuss in-depth on factors involving vaccine manufacturing, hesitancy & acceptance, and contingencies. The market capitalization of pharma companies involved in the development of the coronavirus vaccine will also be compared.

1. Vaccine Platforms, Ensuring Coverage & Challenges
For more info, contact us: xeraya@xeraya.com
Follow us: @xerayacapital
www.xeraya.com
Coronavirus Pandemic
Part III (C): Vaccines

2. Coronavirus Pandemic Series
Part III (C): Vaccines
• Call to global cooperation
• Past outbreaks compared
• Vaccines for long term
• How vaccines work
• Production & distribution
• Platforms compared
• Market capitalization for
pharma companies
compared

3. Part III (B) Recap: Therapeutic Options
As healthcare systems across the
globe reach critical capacity,
potential treatments such as RNA
drugs, monoclonal antibodies
(mAbs) & convalescent plasma
are being tested at a fast pace.
Improved clinical outcomes for
critical-stage patients have been
observed when antiviral therapies
are used in combination with
immunomodulatory agents.
Source: Worldometers.info, UN, Medium.com
Almost 2.7m Active
Cases Worldwide
>1.14m active cases
in the US &
>221k in Russia
117 Therapeutics
in R&D Pipeline
Including RNA (8),
mAbs (28) and
antibodies (13)

4. Significance of Vaccines
Source: https://www.cdc.gov/vaccines/vac-gen/whatifstop.htm
https://www.discovermagazine.com/health/the-deadly-polio-epidemic-and-why-it-matters-for-coronavirus
1952, polio cases in the
U.S. peaked at 57,879,
resulting in 3,145
deaths. Polio vaccines
reduced the number of
cases reported each
year from an estimated
350,000 in 1988 to 33 in
2018.
Polio
In 1964-65, German
measles infected 12.5
million Americans, killed
2,000 babies and
caused 11,000
miscarriages. A vaccine
was first licensed in
1969. Since 2012, 15
cases of rubella were
reported to the CDC.
Rubella
More than 15,000
Americans died from
diphtheria in 1921,
before a vaccine was
developed in 1923. Only
2 cases of diphtheria
have been reported to
the CDC between 2004
and 2014.
Diphtheria

5. Vaccines for The Long Term
Source: Evaluate Vantage COVID-19 Report, National Law Review
It’s impossible to declare the
pandemic ‘truly over’ until an
effective vaccine exists.
Therapeutics to treat COVID-19
illness is a nearer-term hope.
For the long term, an effective
vaccine needs to be developed,
manufactured & distributed
globally. Pharma giants are racing
to own patent rights to a COVID-19
vaccine.
Several pharmaceutical companies in US,
Europe, & China believe that producing a
successful COVID-19 vaccine is within reach.

6. Therapeutics vs. Vaccines
Source: Evaluate Vantage COVID-19 Report, National Law Review
THERAPEUTICS (Rx) VACCINES (Vx)
Target Group Patients diagnosed with COVID-19 Administered to all
Longevity Short-term, remedial Long-term, preventive measure
Price per Dose Potentially high Low to ensure max. coverage
Implications
Old people & other risk groups require
additional attention
Little to no side-effects
Effectiveness
Diagnosed asymptomatic or awaiting
treatment are still carriers of the virus
Effective coverage can ensure the
prevention of future outbreaks

7. Call to Global Cooperation to Develop Vaccines
Source: https://www.france24.com/en/20200416-un-chief-calls-for-global-cooperation-to-speed-up-covid-19-vaccine
A COVID-19
vaccine may be
the only thing that
can bring back
"normalcy".
- United Nations
Secretary-General
Antonio Guterres
April 16th, 2020

8. Herd Immunity: Vaccine Is the Best Chance
Source: https://hub.jhu.edu/2020/04/30/herd-immunity-covid-19-coronavirus/
https://www.discovermagazine.com/health/is-herd-immunity-our-best-weapon-against-covid-19
Herd immunity happens when a
large percentage of a population
becomes immune to an infectious
disease. It stops the disease from
spreading.
Experts agree that a COVID-19 vaccine is
our best chance to safely achieve herd
immunity and minimize infections.
According to John Hopkins Bloomberg
School of Public Health, at least 70% of
the population needs to be immunized to
prevent future outbreaks of COVID-19.
Credit: The Arizona Daily Wildcat

9. No Vaccine: The 1918 H1N1 Pandemic
Source: https://www.cdc.gov/flu/pandemic-resources/1918-pandemic-h1n1.html
The 1918 ‘Spanish Flu’ was the
most severe pandemic in
recent history caused by an
H1N1 virus with genes of avian
origin.
There was no vaccine to protect
against the infection and no
antibiotics to treat secondary
associated bacterial infections.
One-third of the population was
infected, 50 million died.
The 1918 H1N1 virus infected 500m people
worldwide, killed an estimated 50m (675k in
the US). Control efforts were limited to
isolation, quarantine, personal hygiene,
disinfectants, limit public gatherings, etc.

10. Key R&D Sectors To Address COVID-19
Source: WHO R&D
A:Diagnostics
• IDENTIFICATION
• It’s critical that
local healthcare
systems can
diagnose
patients quickly &
effectively
• Asymptomatic
patients
represent a
considerable
portion of cases
B:Therapeutics
• TREATMENT
• With almost 2.8
million active
cases worldwide
(and rising),
healthcare
providers are in
desperate need
of effective
treatment
options
C:Vaccines
• PREVENTION
• Development,
production &
coverage of
vaccines is
crucial to prevent
future outbreaks
of COVID-19

11. Our Immune System
Innate vs. Adaptive & How Vaccines Leverage

12. Our Immune System: Lymphocytes
B-CELLS
• Key player in our immune system,
there are 10 billion B-cells circulating
in the human body, each carrying 10k
copies of a unique antibody.
• Produce antibodies specific to each
pathogen and can lock onto the
surface of an invading cell/virus,
marking it for destruction.
• Activated B-cells divide rapidly to
either become antibody factories or
migrate to the bone marrow,
harboring the ‘memory’ of the
pathogen.
T-CELLS
• Helper T-cells stimulate B-cells
to make antibodies and help
killer cells develop.
• Killer T-cells directly kill infected
host cells marked by B-cell
antibodies.
• Activated T-cells form a colony
of ‘memory’ cells that can
destroy host cells if they're
infected by the same pathogen
in the future.
Source: https://lubrizolcdmo.com/blog/the-guide-to-vaccine-development/
https://www.cancercenter.com/community/blog/2017/05/whats-the-difference-b-cells-and-t-cells

13. Innate Vs Acquired/Adaptive Immunity
Source: https://ib.bioninja.com.au/standard-level/topic-6-human-physiology/63-defence-against-infectio/lymphocytes.html
Credit: BioNinja

14. Understanding How Vaccines Work
Source: Understanding How Vaccines Work by the CDC
Vaccines leverage the
adaptive immune system,
‘training’ it to recognize the
virus.
Vaccines ‘mimic’ an infection,
triggering the body to produce
'memory' white cells (macrophages,
B-cell & T-cell lymphocytes).
After vaccination, these cells will
‘remember’ how to fight the disease
in the future.
Credit: MLive.com

15. Vaccine Candidates
Types of Vaccines, Platforms Compared & Highlights

16. Types of Antiviral Vaccines
Source: https://www.publichealth.org/public-awareness/understanding-vaccines/vaccines-work/
Subunit
(protein or
peptide)
Inactivated
(‘dead’)
Live
Attenuated
(weakened)
DNA/mRNA
Recombinant
Vector

17. Examples of Vaccines
Source: https://lubrizolcdmo.com/blog/the-guide-to-vaccine-development/
Credit: Lubrizol Life Science

18. Comparing Vaccine Platforms: DNA vs mRNA
Plasmid DNA
• Needs to cross nuclear
membrane within cells, lower
efficacy
• Produces mRNA molecules
• Stable & can produce encoded
proteins longer
• Manufactured by growth in cells
(like bacteria)
• Stability increases when
supercoiled
mRNA
• Only needs to be present within
the cell cytosol
• Quantitative advantage for self-
replicating mRNA
• Unstable, temporary nature
• Synthetic manufacturing without
animal/cellular components
• Induces T-cell mediated immune
response
• Manufactured mRNA is stable in
liquid or lyophilized form
Source: A Comparison of Plasmid DNA and mRNA as Vaccine Technologies by Margaret A. Liu
An mRNA vaccine
gives our immune
system the ability to
detect and attack
all strains of a virus,
in addition to
triggering antibody
reactions to
specific strains.
– Lothar Stitz,
CureVac 2012

19. Source: Evaluate Vantage COVID-19 Report
https://www.nytimes.com/2020/05/18/health/coronavirus-vaccine-moderna.html
Moderna, Inc. claims that mRNA
vaccines are better at mimicking
infection. The manufacturing
system is also agile.
Recent Phase I clinical study of the
mRNA-1273 vaccine reports the first 8
healthy volunteers who each received
two doses found it to be safe and
provoked a strong immune response.
It is on an accelerated timetable to
begin larger human trials soon.
Vaccine Highlight: mrna-1273 by Moderna
Production for a Phase II trial could begin a
few months after Phase I, and ultimately
allow millions of doses to be made.

20. BioNTech and Pfizer are
jointly developing BNT162, an
mRNA vaccine.
In Germany, dosing in the 1st cohort
of Phase I/II clinical trial was
commenced April 23rd and 12
participants have received the
vaccine so far.
Companies intend to conduct trial
BNT162 in the US following
regulatory approval.
BNT162 comprises 4 vaccine candidates: 2
nucleoside-modified mRNA (modRNA), 1 uridine-
containing mRNA (uRNA), and the fourth
candidate utilize self-amplifying mRNA (saRNA).
Source: https://www.clinicaltrialsarena.com/news/biontech-pfizer-covid-19-vaccine-dosing/
Vaccine Highlight: BNT162 (mRNA) by BioNTech

21. Source: http://ir.inovio.com/news-releases/news-releases-details/2020/INOVIOs-COVID-19-DNA-Vaccine-INO-4800-
Demonstrates-Robust-Neutralizing-Antibody-and-T-Cell-Immune-Responses-in-Preclinical-Models/default.aspx
Inovio Pharmaceuticals
leveraged its DNA medicines
platform to create the vaccine
candidate INO-4800 for
COVID-19.
INO-4800 targets the major
surface antigen Spike protein of
the SARS-CoV-2 virus.
Preliminary data from Phase 1
clinical trial expected in June, and
Phase 2/3 efficacy trial planned to
start in July/August pending
regulatory approval.
Vaccine Highlight: INO-4800 (DNA) by Inovio
Recent publication in Nature
Communications demonstrates generation of
robust binding & neutralizing antibodies as
well as T-cell responses against the virus.

22. China's CanSino Biologics is
advancing its Ad5-nCoV
vaccine candidate into Phase
II, putting the company ahead
of others in the race against
the novel coronavirus.
Ad5-nCoV is a genetically
engineered recombinant vaccine
candidate with the replication-
defective adenovirus type 5 as the
vector.
Phase II trial will include 500 healthy
participants, CanSino hopes to see the
presence of COVID-19 antibodies in patients
on day 28 following vaccination.
Source: https://www.biospace.com/article/china-s-cansino-prepares-to-advance-covid-19-vaccine-candidate-into-phase-ii/
Vaccine Highlight: Ad5-nCoV by Cansino

23. Source: https://www.biocentury.com/article/305211
Vaccine Highlight: ChAdOx1 nCoV-19 by Oxford
Developed by the University
of Oxford Jenner Institute,
ChAdOx1 nCoV-19 is a type
of recombinant adenovirus
vector.
A single dose has protected 6
rhesus macaques from
pneumonia caused by the virus.
Preclinical data suggest that it
reduces the severity of symptoms
but does not prevent infection.
The replication-deficient chimpanzee
adenovirus delivers a SARS-CoV-2 protein to
induce a protective immune response.

24. An inactivated vaccine
developed by China National
Pharmaceutical Group Corp.
(Sinopharm) has entered the
2nd phase of human trials.
Phase II clinical trials are critical,
as they can evaluate whether
antibodies are produced after
vaccines are injected, as well as
measuring the effectiveness of
the said antibodies.
Vaccine Highlight: Inactivated Vaccine by Sinopharm
Given the ongoing pandemic, it might take
more than 6 months to assess how much of
an immune response the vaccine generates.
Source: https://www.caixinglobal.com/2020-04-25/another-chinese-coronavirus-
vaccine-candidate-enters-phase-two-human-trials-101547174.html

25. Source: https://www.news-medical.net/news/20200421/PiCoVacc-vaccine-candidate-for-COVID-19-effective-in-animal-trials.aspx
Inactivated Vaccine Highlight: PiCoVacc by Sinovac
Pilot-scale production of this
purified inactivated virus
vaccine ‘PiCoVacc’ has shown
to induce specific neutralizing
antibodies in rats, mice, &
non-human primates.
The vaccine candidate potently
neutralized 10 representative SARS-
CoV-2 strains, indicating a broad
neutralizing ability.
Sinovac Biotech Ltd. used a 50-liter culture
of Vero cells to produce a pilot-scale
PiCoVacc for animal studies.

26. Vaccine Industry
Market Challenges, Production Constraints
& Contingencies

27. Source: https://www.who.int/immunization/programmes_systems/procurement/market/en/
Challenges with The Vaccine market
Highly Regulated Market with
Controlled Prices
Low Profit
per dose
Production
Constraints
Hesitancy
from
Certain
Groups
With the outbreak of
COVID-19 and the
emergence of new
technology platforms,
investors are re-
evaluating to explore
the vaccine market,
which has the potential
for significant growth.
Manufacturing Capacity
Cost per dose

28. Source: https://pediatrics.aappublications.org/content/early/2016/08/25/peds.2016-2146#sec-5
Tackling Vaccine Hesitancy
CAUSE OF HESITANCY WAYS TO INCREASE INTENTION
Fear of vaccine causing autism in
children
Assurance that there is no connection between vaccines &
autism.
Animal-derivatives (eggs, bovine,
porcine) used in vaccine manufacturing
Newer generation processes are becoming less dependent on
live-cell systems or animal-derived components. DNA & RNA
vaccines can be produced synthetically.
Vaccine safety, not enough testing
Assurance that vaccine has been clinically tested, approved &
safe to administer in all ages
Vaccines overwhelming immune system
Number of immunogenic proteins and polysaccharides
contained in current vaccines is significantly smaller than the
number of antigens contained in earlier vaccines
Presence of mercury (thimerosal) in
vaccines for infants
Assurance that none of the current single-dose vaccine
preparations given to infants contain any mercury

29. Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5518734/
https://www.prnewswire.com/news-releases/ginkgo-bioworks-provides-support-on-process-optimization-
to-moderna-for-covid-19-response-301040876.html
Production Constraints vs High Demand
Vaccine manufacture is one of
the most challenging
industries. During times of a
pandemic (like COVID-19),
production capacity and
speed is a critical constraint.
New manufacturing premises
should be robust to cater to the
production of other vaccines when
the need arises.
Ginkgo Bioworks is providing support to
Moderna in the manufacturing of its mRNA
vaccines. Ginkgo invested USD400m in the
last 5 years to build a 100,000 square-foot
bioengineering facility, supporting partners
like Roche and Bayer for biotech R&D.

30. Source: https://techcrunch.com/2020/05/12/greenlight-biosciences-raises-17m-to-ramp-mrna-production-for-covid-19-vaccine-candidate-trials/
GreenLight is developing several
different versions of its mRNA-
based vaccine candidates.
With the recent funding, GreenLight
will expand its mRNA production
capacity in order to support the
creation of billions of doses of
potential COVID-19 vaccines for use in
trials and eventual deployment.
Currently in the pre-clinical
development stage, the vaccine
candidates will undergo laboratory
evaluation of their immunogenicity.
Vaccine Highlight: mRNA by GreenLight Biosciences
GreenLight is accelerating work on their
proprietary cGMP mRNA production
platform, allowing scalable manufacturing
capacity to meet vaccine demands.

31. Source: https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-020-0626-6
http://www.ncirs.org.au/sites/default/files/2018-12/vaccine-components-fact-sheet.pdf
Vaccine Manufacturing: Old Vs New
Conventional vaccine
manufacturing processes
can between 6 to 36
months to produce a
single batch.
Newer generations of vaccines such as recombinant
vectors utilize innovative techniques to shorten
production time. DNA & RNA platforms will likely follow
suit with increased capacity & reduced production
time.
Credit: ResearchGate

32. Source: https://www.precisionnanosystems.com/areas-of-interest/payloads/mrna
mRNA Vaccine Manufacturing: Lipid Delivery Systems
RNA vaccines contain a mixture
of lipids that encapsulate the
RNA into nanoparticles during
manufacture. The choice of lipids
is critical to efficacy.
They also require specialized
manufacturing equipment that
combines the RNA with the lipids to
form nanoparticles.
While RNA-based vaccines offer the
potential for rapid development,
formulation & encapsulation expertise
are required to maximize their effect.

33. Source: https://www.who.int/influenza/vaccines/David_Mackay_EMEA.pdf
In principle, the option of
using veterinary vaccine
facilities to produce vaccines
for human use is technically
feasible. Additional
investments might be needed,
e.g. for purification facilities.
Regarding GMP, some veterinary
facilities already have the same
standards as human vaccine
production facilities.
Boosting Production: A WHO Contingency
A technology transfer would still be needed
as the production processes are different.

34. Source: https://www.fortunebusinessinsights.com/industry-reports/vaccines-market-101769
Vaccine Market: Key Figures
Global Vaccine
Market Size:
USD 41.7 Billion
(2019)
Expected to reach
USD 58.4 billion by
2024 with CAGR of
7% during forecast
period
- Markets and
Markets
Jan 2020
Highest CAGR in
Asian Markets
Driven by healthcare
expenditure & large
patient population.
North America
Dominates Vaccine
Market
USD 22.03 billion in
2018 due to increasing
investments.
Recombinant,
Subjugate & Subunit
Most Dominant Type
Biggest market share
(57.7%) followed by
inactivated.

35. Ongoing R&D Projects
Source: Various Online Research as of Mid-April 2020
Diagnostics
112
Therapeutics
117
mRNA, 8
Others, 42
Adenovirus, 5
DNA, 6 Vaccines
To date, 21% of
ongoing R&D projects
are focused on
developing vaccines
for large scale
immunization.
Vaccines
61

36. Source: BioCentury Inc. - End of the beginning for COVID-19 vaccines
Timeline of COVID-19 Vaccines
Credit: BioCentury

37. Source: BioCentury Inc. - End of the beginning for COVID-19 vaccines
Timeline of COVID-19 Vaccines
Credit: BioCentury

38. Vaccine technologies Comparison
Source: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6156540/
Current
Platforms
Recombinant
vector vaccines
DNA vaccines RNA vaccines
Speed of production
(- means more time)
- ± + +
Cost of production
(- means higher cost)
- ± + ++
Economies of scale - - + ++
Formulation stability + + + ±
Quality of immune response ++ + ± ±
Synthetic production - - ± +
Vaccine hesitancy
(- means high)
- - - +
Vaccine safety ++ ± + ++

39. 0
100
200
300
400
500
600
Gilead Regeneron
Pharma
Quidel Arcturus
Therapeutics
Vir Biotech Moderna Inovio
Pharmaceuticals
22.1
46.9
80.5
107.9
160.9 161.6
545.5
%GROWTH
Increased Market Capitalization (Dec 2019 – Apr 2020)
Source: Evaluate Vantage COVID-19 Report
Significant increase in market capitalization for
companies with new technology platforms.

40. • The best approach to address the global pandemic is to
immunize (vaccinate) at least 70% of the global population to
ensure herd immunity and prevent reoccurrence of a
coronavirus outbreak.
• This translates to an estimated 5.5 billion doses of vaccines,
which is not a trivial task.
• Joint partnerships with existing manufacturers are necessary
to ensure sufficient supply to meet global needs (perhaps
even involving those in veterinary vaccines).
Conclusion (1 of 2)

41. • Given that the generally accepted price for a vaccine is only
USD25-50 per dose, the industry will need to work with tight
cost structures to make this economically viable.
• Companies with new technology platforms have witnessed a
significant increase in their market capitalization.
• These new technologies show a lot of promise in speed, scale,
safety, increasing vaccine acceptance, and ease of
production but will still need to demonstrate quality in the
overall immune response through clinical development and
robust processes.
Conclusion (2 of 2)

42. By xeraya capital
For more info, contact us: xeraya@xeraya.com
Follow us: @xerayacapital
www.xeraya.com