Vaccines for a moresustainable futureClimate change is upon us, and we don’t
have to look far to find its fallout. Summers
are warmer, sea levels are rising and it’s almost
impossible to look at the news without encounteringa new case of severe weather damage. Heatwaves, storms, floods, and wildfires are occurring
more often - and with greater intensity. Global
temperatures have steadily been climbing and are
up to 1.2°C higher than at the end of the 19th
century. In fact, 2022 was the hottest summer andsecond warmest year ever1.

Clearly, we can’t look away. We
must act, but how?
The challenge of protecting ourplanet goes beyond the climate tonature. Recently, G7 leadersannounced that “our world must not
only become net zero, but also
nature positive, for the benefit ofboth people and the planet.2” Anature positive approach enriches
the resilience of our planet andsocieties. This disruptive idea forces
us to think differently about ourplace in the world.
Nature is the backbone of ouruniversal well-being and has
inextricable ties to our economic
foundation3. When we continually
tap into these resources in anunsustainable
way,
we
will
inevitably run out. This will have direconsequences for the systems
we’ve built that depend on them. We
need collective action and dual
focus to stabilise the climate andpreserve our natural resources forour common future, particularly as
our global demographics continue
to shift due to population ageing andoverall growth.
Ten percent of our growing global
population is over 60 years old4.
This worldwide trend presents animportantopportunity
forSmart science to improve lives™

www.crodapharma.com

sustainable
development.
Thechanging landscape of our society
relies on active participation fromolder generations. We must prepare
for the social and economictransformations associated withageing, developing the necessary
conditions
toenablethesegenerations to lead self-determined,
healthy lives. For this, we rely on
fundamental shifts in policy anduniversal attitudes to older persons
and their part in society. Luckily, theglobal community is reacting.
Recognising the need for dramaticchange to slow this trajectory, theUnitedNations
adopted17
Sustainable Development Goals(SDGs) in 2015, as a universal callto protect the planet, end poverty
and ensure that all humans enjoy
peace and prosperity by 20305. The
17
SDGs
are
interlinked,
emphasising the importance ofaddressing them all.
The third UN SDG describes how
good health is pivotal to sustainable
development. As
theglobalpopulation continues to rise, and as
we’re all living longer, it’s important
to ensure good health continues in
our later years. Preventative care is
one of the best ways to support thisreality. A continual threat is theburden of infectious diseases:
millions of lives are lost to diseases
that are largely preventable. Global
immunisation is the key. That’s
where vaccines get to work.
Vaccines are not only protecting us
from direct pathogens, but alsopaving the way for a moresustainable future.
How vaccines promote planetary
health and sustainability
Major historical events haveevidenced the criticality
andimportance of vaccines for global
health. Vaccines have helped
prevent cervical cancer in women,
as well as reduce pneumococcal
and meningococcal diseases inchildren, and edge us closer toeradicating polio. Since 1988, thenumber of children affected by polio
has reduced by 99 percent6. Thanks
to the measles vaccine alone, 23
milliondeathswere
avertedbetween2010
and20187.
Meanwhile, more recently, thesignificance of vaccines wascrystallised during the COVID-19

mart science to improve lives™
Smart science to improve lives™

pandemic,
wherebyvaccines
averted 20 million deaths, saved theglobal economy trillions, and helped
restore free movement in society8.
Vaccination has enabled us toprevent over 20 life-threatening
diseases. This means more people
are living longer, healthier lives.
However, political, economic, andcultural hurdles have meant thatmany
arelosingout
onvaccinations. In 2020, 22.7 million
children missed basic vaccines –almost 4 million more than the year
before9. Much of this is attributed to
the repercussions of the pandemic,
with countries falling backwards onother vaccinations. Not only does
this widen the inequalities in vaccine
access, but it also leaves certain
populations more vulnerable tofuture threats. For instance, WHOreported that only 82% are now fully
vaccinated against DTP (diphtheria,
tetanus, and pertussis) in theAmericas, down from 91% in201610.
The types of vaccines we use are
equally important as our access tothem.
Sustainablevaccinedevelopment relies on access to adiverse,strongrange
oftechnologies
suchas
liveattenuated, inactivated, subunit,
and RNA-based vaccines. In thisway, we can create new vaccinesthat tackle different antigens anddiseases, protecting even more
people against conditions that canotherwise be very difficult to treat.
Still, there’s another piece of the
puzzle. Vaccine development is acomplicated,time-intensive
process. Once a winning formula ismade - and passes through thevarious intensive stages of clinicalapproval - it’s important to ensure it
continues to be available and isn’tdelisted due to the lack ofcommercially available sustainable
ingredients. This is why designing
vaccinesusing
sustainable
ingredients is critical. Sudden
surges in demand could quickly leadtoshortages,
bringing
consequences that would derail our
vaccine access a decade or two
from now. Given the longdevelopment pipelines waiting until
then to find sustainable alternatives
will be too late.

www.crodapharma.com
www.crodapharma.com

Vaccines are a key tool for
protecting the planet and meeting
our sustainability goals. The
responsibility is on us all to not only
select sustainable ingredients, but
to secure supply chains andsources that will not deplete in the
future. It’s therefore essential that
our efforts are prioritised, to help
ensure that everyone gets thevaccines they need.
Emerging technologies
Keyformulation
ingredients
increase the likelihood of vaccine
success. For example, modern
vaccines
often
incorporateadjuvants and adjuvant systems,
which are ingredients that are used
to help induce a stronger immune
response. Adjuvants can amplify
vaccine efficacy by helping to raise
an early, long-lasting, and efficient
immune response to a vaccine. Inturn, this can provide significant
protection against the disease being
targeted. When combined withimmunostimulatory molecules, theresulting adjuvant systems can help
reach the same level of immune
protection with fewer injections or alower dose than when vaccinatingwith the non-adjuvanted antigen
alone. Adjuvant systems stimulate
immunity at various stages of theimmune response, for instance, byactivating chemokine signalling andtargeting specific types of immune
cells, such as dendritic cells and Thelper cells (typically Th1, Th2, orothers).
However,somevaccineformulations do not result in optimal
antigen delivery and presentation,
reducing vaccine efficacy as aresult. Thus, a diverse repertoire of
adjuvant systems is necessary tocreate better vaccines. Modern
vaccine development is focusing on
discovering and incorporating new
adjuvants to help address thosecountless conditions without current
vaccine solutions. Establishing new
adjuvants empowers us to achieve
new pathways of immunisation that
unlock new therapies – andtherefore help even more people. As
ongoing research continues toestablish a more extensive portfolioof adjuvant system technologies,
this enables us to not only address
more diseases, but helps us also
potentially improve the efficacy of
existing vaccines.

Aluminium salts are the most wellknown and widely used class ofadjuvants. Generally referring toaluminium
phosphateandaluminium hydroxide, they adsorb
the protein antigen and mediate its
presentation to innate immune
cells11,12.
Certain oil-in-water
emulsions (eg. MF59 and AS03)
mediatelocal
inflammatory
responses13.
Saponin-based
adjuvant systems, including MatrixM and QS 21, offer multiple effects
that support humoral and cellularimmuneresponses14.
Certaincomponents such as squalene areusedincombination
withsurfactants in specific adjuvant
formulations.
Meanwhile,
neoantigen vaccines that tackle cancer
are being explored as therapeutic
vaccines using the CAF family of
adjuvants, such as CAF09b.
Scientists
andvaccinemanufacturers are continuously
innovating to expand the repertoireof available adjuvant options. While
we work to discover novel adjuvant
formulations, we must use existing
options responsibly. The SBTN
(science-based targets for nature)high impact commodity list has
highlighted the need for moreawareness around the material
impact on nature of certain supply
chains. The use of raw materials
derived from these commodities as
key ingredients in vaccines will, in
the future, need to be better
understood and managed by raw
material
suppliers,
adjuvant
producers, and vaccine developers.
Beyond this, as we’ll share below,
the use of some of the mostprominent
andpromisingcomponents,
saponinsandsqualene, has been affected byother sourcing challenges – once
again highlighting the need forsustainable supplies.
Saponins: sustainable sourcing
from tree bark
Saponins, coined from the Latin
word sapo (meaning soap), areplant-derived chemicals with theability to form foams in water15. They
have primarily been sourced from
Quillaja saponaria Molina, a type oftree known for its saponin-rich bark.
Otherwise called quillay trees, they
are commonly found in Chile andother parts of South America.

mart science to improve lives™
Smart science to improve lives™

Traditionally used as foaming
agents, Quillaja saponins are also
used in cosmetics, food products,
andvaccines.
Theirstrongimmunostimulatory activity, andcapacity to stimulate both cellmediated and humoral immunity,
have led to their popularity as
vaccine adjuvants.
Quil-A is a crude quillay extractcontaining a heterogeneous mix ofover 100 saponin components thatis exclusively used in veterinary
vaccines. To make the most of its
potent immunogenicity, a purified
fraction of Quil-A was created to be
used in human vaccines. Known as
QS 21, this adjuvant has recently
been the subject of multiple successstories in the pharmaceuticalindustry, as a component ofvaccines against shingles andmalaria – the world’s first!
This has inspired a new wave of
increasing interest and put a
spotlight on a looming shortage. For
decades,
Chile
has
been
harnessing quillay trees to meetdemand and deliver exports.
However, these trees only yield barkwith economic and clinical meritwhen they are over 25 years ofage16. This has led to subsequentecological damage and stricter
regulations. Chilean law prohibitsthedeforestationof Quillajasaponaria. Thus, special permits
are required to cut down the trees17.
Since landowners are allowed toprune 35% of their biomass every
five years, the market is moving
away from bark to biomass.
Although bark extract still exists,quantities are reducing, access islimited, and prices are rising18.
These limitations are having an
immediate effect on vaccine access:it has been reported that waitingtimes for shingles vaccines using
QS 21 in their formulations can evenexceed a year19.
Deforestation has a dramatic effecton nature, and the cascading threatofconsequencesmustbeprevented to preserve and protect
our planet. Thus, it is critical that we
find alternative technologies andsustainable solutions.
Toaddress
this,biotechcorporations like Desert King and
Botanical Solution Inc. (BSI) arewww.crodapharma.com
www.crodapharma.com

pioneering innovations in the field.
Desert King has cultivated their own
bark-enrich quillay trees thatgenerate greater yields and arenaturallymoresustainable.
Meanwhile, BSI has developed apatented R&D platform based onplant tissue culture that is able tocreatesustainablebotanical
products. One of these is ABM-01,
based on Quillaja spaonaria, whichis planned to act as a replacementin the production of QS 21. In thisway,ascalableandtruly
sustainable supply of QS 21 ispossible, helping create the next
generation of adjuvants in vaccine
development.
Squalene: from shark oil to asustainable source
Squalene is an organic compoundwith powerful bioactive properties20.
As a naturally occurring oil, it has
been used in skincare products, andcosmetics, as well as in various
vaccine adjuvant formulations. For
instance,thesqualene-based
emulsions MF59, AS03, and AF03
have been successfully utilised in flu
vaccines, helping initiate potent
innate and adaptive immune
responses21. Developing effective
flu vaccines is an ongoingchallenge, given that reduced
potency has been demonstrated incertain demographics, such as theelderly and young children, and that
their success depends on how well
the vaccine strains match thosecirculating during the season22.
History has shown us how theinfluenza virus can rapidly turn
pandemic,
highlighting
howimperative it is to have a repertoireof efficacious vaccines on hand.
Clearly, components like squalene
can be valuable in vaccine
development. This interest has shedlight on the need for alternative andmore sustainable sources that canconsistently meet demand.
Squalene is found in most living
microorganisms – but in very trace
amounts. Sharks are an exception.
Sharks store most of their lipids intheir livers, the majority of which ismade up of squalene. Harvestingsqualene from shark liver oil is arelatively straightforward process –a single distillation – such that thishas become the predominantsource.
However,there
aredramatic
environmental

consequences.
Oceanic
shark
populations have dropped by 71.1%
from 1970 to 201823. In fact, half ofoceanic shark species are now
endangered24. Sourcing shark liver
oil is furthering this state of peril. Not
only is this threatening shark
populations, putting pressure on
their already long reproductive
cycles, but it also means thatsqualene is in short supply.
This has inspired the search forsustainable alternatives. Some
organisations are advancing plantderived squalene, such as thatmade from amaranth. Meanwhile,
Amyris, a biotech company focusedonclean
chemistry,uses
fermentation to ensure high purity
for
their
pharmaceutical-grade
squalene. Using yeast isoprenoid
pathway
engineering,
theirsugar-derived
squaleneismolecularly
identicaltothat
harvested from sharks.
Creating the sustainablevaccines of tomorrow
Sustainability is a challenge thatneeds to be at the forefront of R&D
for vaccines today. The threat is
two-fold:
overlooking
theimportanceofprioritisingsustainable supplies can affect ouraccess to existing vaccines –through depleted sources andunreliable supply chains – and put
future vaccines at risk for decades
to come. The time it takes for
vaccines to be market-ready meansthat every delay in developing newsustainable ingredients will lead tosignificant repercussions for thehealth of subsequent generations.
Failing to act now threatens our
vaccine access and technologies –
effects that will only truly crystallise
after the 10 to 20-year-longdevelopment pipelines.
Success in this realm relies on
globalcollaboration.
Thus,
investment in worldwide vaccine
R&D, to develop better vaccines –for known diseases, new vaccine
platforms, and potential pandemic
threats – must be prioritised. By
supporting high-quality sustainablevaccineproductionin
local
communities and countries ofdifferent means, we can strengthen
the overall vaccine landscape. Our
healthsecurity
dependsonsolutions that are not only

mart science to improve lives™
Smart science to improve lives™

sustainable, but also adhere to good
manufacturing practices (GMP)
standards.
The vaccines of tomorrow revolvearound sustainable supply chains
and access to scalable commercial
supplies that do not put undue
pressureonthenaturalenvironment. It is our responsibility
to future-proof vaccines by focusing
on longevity in our processes. Withcombined global efforts, we canenhancetheglobalhealthinfrastructure, leading us to develop
better vaccines against morediseases and supporting our
preparedness for future outbreaks.
We
believethatglobalcollaborations are the cornerstoneof creating a greener planet. Let’s
do all we can today, to generate asustainable future we’re proud of.

References
1 Extreme heat, widespread drought

typify European climate in 2022 |Copernicus
2 G7 2030 Nature Compact (PDF,
120KB 4 pages) (europa.eu)
3 The first science-based targets fornature – Science Based Targets
Network
4 UN, Department of Economic andSocial Affairs Population Division; World
Population Prospects, key findings andadvance tables; 20195 https://www.undp.org/sustainabledevelopment-goals
6 Eradicating polio | UNICEF

7 ia2030-draft-4-wha_b8850379-1fce-

4847-bfd1-5d2c9d9e32f8.pdf (who.int)

8 Vaccines for a sustainable planet |Science Translational Medicine

9 COVID-19 pandemic leads to major

backsliding on childhood vaccinations,
new WHO, UNICEF data shows
10 https://www.who.int/news/item/15-072021-covid-19-pandemic-leads-tomajor-backsliding-on-childhoodvaccinations-new-who-unicef-datashows
11https://books.google.co.uk/books?hl=en&lr=&id=rRebEAAAQBAJ&oi=fnd&pg=
PA214&ots=7vkRMPFhlI&sig=xVcNA4ja
Rf4e2XmkUfKzN03TtE&redir_esc=y#v=onepage&q&f=false
12 https://www.sciencedirect.com/
science/article/pii/S0165247812001599
13 https://www.tandfonline.com/doi/abs/
10.1586/14760584.2013.811188
14 https://www.ncbi.nlm.nih.gov/pmc/
Articles/PMC4874334/
15 Saponins from Quillaja saponaria andQuillaja brasiliensis: Particular Chemical
Characteristics and Biological Activities PMC (nih.gov)
16 Sustainable Production of Quillaja
Saponaria Mol. Saponins | SpringerLink
17 https://www.sag.cl/tramites/solicitudde-permiso-para-corta-explotacion-odescepado-de-quillay
18 Quillay, an endemic plant of Chile thatmakes its own in the agricultural andpharmaceutical industry - Redagrícola
(redagricola.com)
20 https://www.mdpi.com/14248247/15/3/265#B16-pharmaceuticals15-00265
21 https://www.tandfonline.com/doi/full/
10.1080/21645515.2017.1415684
22 Viruses | Free Full-Text | Selecting
and Using the Appropriate Influenza
Vaccine for Each Individual (mdpi.com)
23 https://doi.org/10.1038/s41586-02003173-9
24 https://doi.org/10.1038/s41586-02003173-9

ABOUT CRODA
At Croda, we are committed to using our smart science to promote healthy lives and wellbeing through the development and application of our ingredients and technologies, mostnotably with our excipients and vaccine adjuvants in the development of novel vaccines.
By being the most sustainable supplier of innovative ingredients, we will provide solutions tosome of the world’s biggest challenges while helping our customers achieve theirsustainability goals.
In 2022, Croda announced our ambition to be Net Nature Positive by 2030. Guided by theprinciples set out by the Science Based Targets for Nature (SBTN) we are working to better
understand the ways that our manufacturing sites, raw materials, and finished ingredients
impact or depend upon biodiversity and nature, including prioritising those materials on theHigh Impact Commodity List.
Croda’s partnerships with Amyris and BSI will expedite the commercial availability ofsqualene and QS 21, and are two examples of putting our commitment, to be Climate, Land,
People, and Nature Positive by 2030, into action. We are excited to be able to offer
sustainably sourced squalene and saponins soon.
Change happens when we each take small steps forward and do the best we can – with theplanet in mind.

www.crodapharma.com
www.crodapharma.com