Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5981_Библиотеки_им_академика_М_И_Перельмана
.pdf
the case for “a modular, flexible Master File type approach, similar to the Drug Master File
(DMF) procedure of the FDA, by extending the scope of already implemented EU ap-
proaches”. The paper says that instituting such a guideline would avert repeated resubmis-
sions and multiple evaluations of the same data relating to a platform technology used for an
authorized vaccine for the authorization of subsequent vaccines based on the same platform.
Are adjuvant platforms feasible?
One adjuvant paired with different vaccine antigens could be feasible depending upon the
desired immune response(s) for the diseases in question (type of innate immune response
triggered, humoral and/or cell-mediated immunity, durability of resp onse, etc.). For
TABLE 6.4 Pharmacology and biodistribution studies submitted to EMA for COVID-19 vaccine moderna
(now spikevax).
a
Study title Study number Test system
Pharmacology studies
Vaccination and protein re-stimulation in young BALB/c
mice with enhanced respiratory disease endpoint
monitoring
b
MOD-3937 BALB/c mice F only
Evaluation of immunogenicity and determination of titers
dynamic range of mRNA-1273 (SARS-CoV-2)
b
MOD-3938/
MOD-3940
BALB/c mice F only
Immunogenicity and protection from SARS-CoV-2
challenge of mice immunized with mRNA-1273
b
VRC01 BALB/cJ, C57BL/6J,
and B6C3F1/J mice
Efficacy of mRNA-1273 and enhanced disease in aged
BALB/c mice
b
VRC02 BALB/c mice, >12
months a
Evaluation of immunogenicity and efficacy of mRNA-
1273 in the Syrian golden hamster model
b
UTMB01
c
Syrian golden hamster
M and F
Immunogenicity and protective efficacy of mRNA-1273 in
rhesus macaques
b
VRC04 Rhesus macaques
Evaluation of immunogenicity and efficacy from
expanded dose range of mRNA-1273 in rhesus
Macaques
b
VRC07 Rhesus macaques
Biodistribution study
A single dose intramuscular injection tissue distribution
study of mRNA-1647 in male SpragueeDawley rats
d
5002121
Amendment 1
Sprague Dawley rat, M
only
a
Recreated from the 2021 EPAR found at https://www.ema.europa.eu/en/documents/assessment-report/spikevax-previously-covid-19-vaccine-
moderna-epar-public-assessment-report_en.pdf.
b
mRNA-1273 contains a single mRNA sequence that encodes for the full-length SARS-CoV-2 Se2P combined in a mixture of four lipids
(SM-102, PEG2000-DMG, cholesterol, and DSPC) and formulated in 20 mM Tris, 87 mg/mL sucrose, 10.7 mM sodium acetate, pH 7.5.
c
This study was designed by the Sponsor and conducted by the University of Texas Medical Branch.
d
mRNA-1647 contains six mRNAs which, encode the full-length CMV gB and the pentameric gH/gL/UL128/UL130/UL131A glycoprotein
complex. The six mRNAs are formulated at a target mass ratio of 1:1:1:1:1:1 in a mixture of four lipids (SM-102, PEG2000-DMG, choles-
terol, and DSPC) and formulated in 93 mM Tris,60 mM NaCl, and 7% PG.
6. Introduction to vaccines and adjuvants196
II. Vaccines
TABLE 6.5 Repeat-dose toxicology and other studies submitted to EMA for COVID-19 vaccine moderna
(now spikevax).
a
Study title Study number Test system
Repeat-dose toxicology studies
Zika: A 1-month (3 doses) intramuscular injection toxicity study of
mRNA-1706 in SpragueeDawley rats with a 2-week recovery period
b,c
5002045 Sprague Dawley
rat, M and F
A 1-month (3 doses) intramuscular injection toxicity study of mRNA-
1706 in SpragueeDawley rats followed by a 2-week recovery period
b,c
5002231 Sprague Dawley
rat, M and F
A 1-month (3 doses) study of mRNA-1653 by intramuscular injection in
SpragueeDawley Rat with a 2-week recovery period
c,d
5002033 Sprague Dawley
rat, M and F
A 1-month (3 doses) intramuscular injection toxicity study of mRNA-
1893 in SpragueeDawley rats followed by a 2-week recovery period
c,e
5002400 Sprague Dawley
rat, M and F
A 6-week (4 doses) intramuscular injection toxicity study of mRNA-1647
in SpragueeDawley rats followed by a 2-week recovery period
c,f
5002034 Sprague Dawley
rat, M and F
A 6-week (4 doses) intramuscular injection toxicity study of mRNA-1443
in SpragueeDawley rats followed by a 2-week recovery period
c,i
5002158 Sprague Dawley
rat, M and F
Other toxicity study
A non-GLP repeat-dose immunogenicity and toxicity study of mRNA-
1273 by intramuscular injection in Sprague Dawley rats
h
2308e123 Sprague Dawley
rat, M and F
Genotoxicity studies
SM-102 bacterial mutation test in Salmonella typhimurium and
Escherichia coli
c
9601567 S. typhimurium
and E. coli strains
in vitro
SM-102 in vitro mammalian cell micronucleus test in human peripheral
blood lymphocytes
c
9601568 Human
peripheral blood
lymphocytes
Zika mRNA: mammalian erythrocyte micronucleus test in rat
b,c
9800399 Sprague Dawley
rat, M and F
NPI luciferase mRNA in SM-102-containing lipid
Nanoparticles: in vivo mammalian bone marrow
Erythrocyte micronucleus assay in the rat
g
AF87FU.125012
NGLPICH.BTL
Sprague Dawley
rat, M and F
a
Recreated from the 2021 EPAR found at https://www.ema.europa.eu/en/documents/assessment-report/spikevax-previously-covid-19-vaccine-
moderna-epar-public-assessment-report_en.pdf.
b
mRNA-1706 contains a single mRNA sequence that encodes the prME structural proteins of Zika virus combined in a mixture of four lipids
(SM-102, PEG2000-DMG, cholesterol, and DSPC) and formulated in 20 mM Tris, 8% sucrose, pH 7.4.
c
A Good-Laboratory Practice study.
d
mRNA-1653 contains two distinct mRNA sequences that encode the full-length membrane-bound fusion proteins of hMPV and PIV3. The
two mRNAs are formulated at a target mass ratio of 1:1 in a mixture of four lipids (SM-102, PEG2000-DMG, cholesterol, and DSPC) and
formulated in 93 mM Tris, 7% PG, 1 mM DTPA, pH 7.4.
e
mRNA-1893 contains a single mRNA sequence that encodes the prME structural proteins of Zika virus in a mixture of four lipids (SM-102,
PEG2000-DMG, cholesterol, and DSPC) and formulated in 100 mM Tris, 7% PG, 1 mM DTPA, pH 7.5.
f
mRNA-1647 contains 6 mRNAs which, encode the full-length CMV gB and the pentameric gH/gL/UL128/UL130/UL131A glycoprotein
complex. The 6 mRNAs are formulated at a target mass ratio of 1:1:1:1:1:1 in a mixture of four lipids (SM-102, PEG2000-DMG, cholesterol,
and DSPC) and formulated in 93 mM Tris,60 mM NaCl, and 7% PG.
g
NPI luciferase mRNA is combined in a mixture of four lipids (SM-102, PEG2000-DMG, cholesterol, and DSPC) and formulated in 25 mM
Tris, 123 g/L sucrose, 1 mM DTPA, pH 7.5.
h
mRNA-1273 contains a single mRNA sequence that encodes for the full-length SARS-CoV-2 Se2P combined in a mixture of four lipids
(SM-102, PEG2000-DMG, cholesterol, and DSPC) and formulated in 20 mM Tris, 87 mg/mL sucrose, 10.7 mM sodium acetate, pH 7.5.
i
mRNA-1443 contains a single mRNA sequence that encodes for a phosphorylation mutant of the CMV pp65 protein (i.e., deletion of amino
acids 435e438) combined in a mixture of four lipids (SM-102, PEG2000-DMG, cholesterol, and DSPC) and formulated in 93 mM Tris,
60 mM NaCl, and 7% PG.
CMV, cytomegalovirus; eCTD, electronic common technical document; ERD, enhanced respiratory disease; F, female; GLP, Good
Laboratory Practice; M, male; mRNA, messenger RNA; SM-102, heptadecan-9-yl 8-((2-hydroxyethyl) (6-oxo-6-(undecyloxy)hexyl)
amino)octanoate; Tris- HCl, tris(hydroxymethyl)aminomethane-hydrochloride; VRC, Vaccine Research Center.
example, aluminum salt-based adjuvants are used in many approved vaccines, but at the
time when many of these vaccines were deve loped the choice could have been because
alum was all there was, or it was “good enough,” or had the simplest regulatory path because
it was not novel.
MF59 oil-in-water adjuvant has been tested with many investigational candidate vaccines,
yet the only approved vaccines with MF59, to date, are Sequirus’ pandemic and seasonal
influenza vaccines. Dynavax CpG 1018 oligonucleotide adjuvant has also been aro und for de-
cades and is used alone in Heplisav-B and, recently, with aluminum adjuvant in Valneva’s
inactivated COVID-19 vaccine VLA2001. Dynavax CpG 7909, a different oligonucleotide
sequence, is used with aluminum adjuvant in Cyfendus postanthrax postexposure vaccine,
but this vaccine is rarely used. GSK’ s adjuvant systems that combine two or more adjuva nts
are components of approved vaccines only relatively recently. These adjuvants, and others
that are not yet used in approved adjuvanted vaccines, have been tested as components of
many other clinical vaccine candidates (Zhao, 2023; O’Hagan, 2017; Kozak, 2023) so there
are many options. But there are a number of important issues to consider other than whether
the adjuvant is effective in enhancing immune responses. Lykins and Fox (2023) suggest the
following:
1. “Derisk the environmental and supply chain sustainability of materials. Consider
alternate compounds or production methods to reduce dependency on animal or
unsustainable sources.
2. Incorporate thermostability approaches early in development.
3. Define the need that a new adjuvant would address (e.g., mucosal immunity and
durability of immunity) and tailor subs equent activities to this need.
4. Keep compositions as simple as possible but consider the added value of combination
approaches when necessary.
5. Employ experimental design methods and systems immunology approaches to
comprehensively characterize the immune profile of the new adjuvant.”
If an adjuvant has shown promise with several antigens, one mechanism by which adju-
vant manufacturers can document studies supporting the platform is via a DMF in the US.
This will streamline subsequent submissions and access to the DMF can be granted to other
companies that wish to license the adjuvant to use with their proprietary antigens. The Na-
tional Institute of Allergy and Infectious Diseases (NIAID, 2021) launched the continuously
updated Vaccine Adjuvant Compendium (VAC) Website “to foster collaborations between
NIAID-supported adjuvant researchers and the broader scientific community”. The intent
is to allow vaccine researchers and developers to access adjuvant metadata and contact the
intellectual property (IP) holder directly and to allow adjuvant developers to share their
metadata by depositing information about their adjuvant once a submitter account is estab-
lished by emailing DAITAdjuvantGrp@niaid.nih.gov.
To summarize, platforms can be cost effective by permitting sponsors to perform only key
product-specific nonclinical studies and leverage data from studies with other vaccines/adju-
vants based on the same platform(s). They can also be time effective in that review times may
be decreased by being able to cross-reference health authority reviews of other products. There
is also an important advantage from the animal welfare point of view because fewer studies,
therefore fewer animals, will be needed for every new candidate. Lastly, platform approaches
6. Introduction to vaccines and adjuvants198
II. Vaccines
are key to enabling rapid responses to emergent epidemics and pandemics as evidenced by the
rapidity with which some companies were able to respond to the outbreak of SARS-CoV-2.
“Outbreaks, they’re inevitable. But turning into a pandemic, that’s optional”
The quote above from Brilliant (2023) continues “It’s our option. If we find them quickly
and respond to them quickly, they will not become pandemics.” According to the WHO, the
viral diseases currently posing the greatest public health risk because of their potential to
cause an epidemic, and/or because there is no or insufficient countermeasure(s), include
the those shown in Table 6.6.
Clemens and Clemens (2023), in their valuable review article on pandemics and their vac-
cines, state that research on vaccines for pathogens with pan demic potential has been limited
in the industry because of poor commercial opportunity (limited wealthy country market)
and in academia because of a lack of funding. The balance began to shift following the sev-
enth Ebola outbreak in Western Africa (2014/2016) that was 10 times larger (>28,600 infec-
tions and >11.300 deaths) than the six previous outbreaks comb ined, with approximately
10% of the healthcare workers dying. An unapproved Ebola vaccine that was subsequently
shown to be highly effective was available at the time (rVSV-ZEBOV, now approved
ERVEBO), but was not used until more than a year into the epidemic primarily because of
regulatory issues. To avoid a similar situation in the case of future pandemics, CEPI was
founded as a “an innovative global partnership between public, private, philanthropic, and
civil society organizations that was launched as the result of a consensus that a coordinated,
international, and intergovernmental plan was needed to develop and deploy new vaccines
to preve nt future epidemics.” (Bernasconi, 2020).
CEPI has estimated the annual global cost of moderately severe to severe pandemics to be
570 billion USD; in contrast, it was estimated that the minimum average cost for progressing
one vaccine against each of the WHO’s priority epidemic infectious diseases would be 2.8
billion USD (CEPI, 2024). In addition to CEPI, several other public-private partnerships
(PPPs) have been established to focus on other global priorities and address various gaps
in vaccines R&D and accessibility including, but not limited to, the Bill & Melinda Gates
Foundation and its Medical Research Institute, Global Alliance for Vaccines and Immunisa-
tion (GAVI), Wellcome Trust, European Commission, US Department of Health and Human
Services, GlaxoSmithKline (GSK) Vaccines’ Institute for Global Health, Hilleman
TABLE 6.6 WHO viral diseases with high public threat potential.
a
• COVID-19
• Crimean-Congo hemorrhagic fever
• Ebola virus disease and Marburg
virus disease
• Lassa fever
• Middle east respiratory syndrome
coronavirus (MERS-CoV)
• severe acute respiratory syndrome (SARS-CoV-1)
• Nipah and henipaviral diseases
• Rift valley fever
• Zika
• Disease X (a pathogen currently unknown to cause human disease
that could cause a serious international epidemic)
a
See https://www.who.int/activities/prioritizing-diseases-for-research-and-development-in-emergency-contexts (accessed April 15, 2024).
“Outbreaks, they’re inevitable. But turning into a pandemic, that’s optional” 199
II. Vaccines
Laboratories, Program for Appropriate Technology in Health (PATH), International Vaccine
Institute, the Jenner Institute, International AIDS Vaccine Initiative (IAVI), and the Human
Vaccines Project (Rappuoli, 2019a). Many readers will be familiar with COVID-19 Vaccines
Global Access (COVAX) the global initiative aimed at equitable access to COVID-19 vaccines
directed by GAVI, CEPI, WHO, and UNICEF.
As of 2024, CEPI has funded over 50 projects including vaccine candidates against its prior-
ity pathogens (Lassa, MERS, Rift Valley Fever, Nipah, Chikungunya, and Ebola), COVID-19
vaccines, broadly protective coronavirus vaccines, many enabling research projects, and “rapid
response platforms to develop vaccines against Disease X” (CEPI, 2024). “CEPI has overseen a
number of scientific breakthroughs, including the first Phase 3 trial of a Chikungunya vaccine”
(IXCHIQ approved in US as of November 2023) “and the advancement of the first ever Nipah
and Lassa virus vaccines into clinical trials. The advances that have been made in this short
period simply would not have been possible without CEPI” (CEPI, 2023). The active CEPI-
funded projects by phase of development can be found at. Other groups working on WHO pri-
ority disease vaccines can be found by searching the individual diseases.
Infectious disease by natural exposure is not the only epidemic/pandemic risk. A subset of
the WHO infectious disease organisms (Table 6.7 in bold) has been identified by the CDC as
having potential for use as bioterrorism weapons (CDC, April 4, 2018).
TABLE 6.7 CDC high priority bioterrorism agents.
Category A
Highest priority agents
Category B
Second highest priority agents
Category C
Third highest priority agents
Pose a risk to national security
because transmitted from person to
person, lead to high mortality, and/
or have a high potential to cause
social disruption
Moderately easy to disseminate,
result in moderate morbidity rates
and low mortality rates, and require
specific enhancements of CDC’s
diagnostic capacity
Pathogens engineered for mass
dissemination in the future because
of availability, ease of production and
dissemination, and potential for high
morbidity and mortality rates and
major health impact
Anthrax
Botulism
Plague
Smallpox
Tularemia
Hemorrhagic fever viruses:
• Ebola
• Marburg
• Lassa
• Machupo
Brucellosis
Glanders
Q fever
Ricin toxin
Typhus fever
Staphylococcal enterotoxin B
Typhus fever
(Rickettsia prowazekii)
Viral encephalitis alphaviruses:
• Eastern equine encephalitis
• Venezuelan equine encephalitis
• Western equine encephalitis
Water safety threats:
• Vibrio cholerae
• Cryptosporidium parvum
Emerging pathogens:
• Nipah virus
• Hanta virus
Adapted from the CDC webpage last updated April 4, 2018 https://emergency.cdc.gov/agent/agentlist-category.asp.
6. Introduction to vaccines and adjuvants200
II. Vaccines
Focusing on the US, and expanding upon the remit of the CDC Office of Public Health Pre-
paredness and Response, the US Bio medical Advanced Research and Development Authority
(BARDA) plays a major role in epidemic and pandemic preparedness. BARDA, together with
the NIAID, supports the development of next generation medical countermeasures including
new approaches and technologies to accelerate the development of vaccines, therapeutic
products, and diagnostic tests needed to protect the US from public health security threats,
as does US FDA (February 15, 2023). BARDA works with partner organizations and funds
industry partners on technologies and products for public health medical emergencies
including chemical, biological, radiological, and nuclear accidents, incidents, and attacks,
antimicrobial resistance, pandemic influenza, and emerging infectious diseases (https://
aspr.hhs.gov/AboutASPR/ProgramOffices/BARDA/Pages/default.aspx; accessed April
15, 2024). As of April 10, 2024, just for COVID-19, BARDA has invested billions of dollars
in more than 149 projects including 22 vaccines, 63 diagnostics, 21 therapeutics, 15 rapidly
deployable capabilities, 20 support services, and 8 other type. BARDA’s Programs to Combat
Emerging Infectious Diseases include Ebola, Zika, pandemic influenza, and others.
The US Defense Advanced Research Projects Agency (DARPA) “ has held to a singular and
enduring mission: to make pivotal investments in breakthrough technologies for national se-
curity” (https://www.darpa.mil/about-us/about-darpa; accessed April 10, 2024) and their
decisions to fund nucleic acid vaccines and therapeutics research into Chiku ngunya and
Ebola over a decade ago enabled the remarkable achievement of 63 days from SARS-CoV-
2 Spike protein sequence selection to Phase 1 study dosing with Moderna’s mRNA vaccine
based on the NIAID prefusion-stabilized spike protein (Moderna, 2020). In parallel, DAR-
PA’S forward-thinking investments in rapid protective antibody identification technologies
enabled the first US FDA emergency use authorization for the monoclonal antibody therapy
developed by AbCellera with Eli Lilly and Company (DARPA, 2020). The goal of DARPA’s
P3 (prevention, protection, platform) program is to establish a robust technology platform for
pandemic response capable of developing field-ready medical countermeasures within
60 days of isolation of an unknown viral pathogen (DARPA, 2021).
WHO’s 10 major threats to global health
Prior to the emergence of the global COVID-19 pandemic, which is an obvious current
threat, the WHO had released a list of 10 major threats to global health (Table 6.8; NEJM,
2019). Among the 10 threats, several viral diseases (influenza, ebola, high-threat pathogens,
Dengue, and HIV) were listed. But there are addtional non-viral infectious disease threats
that are potential vaccine targets.
Other vaccines needed for serious infectious diseases
Antimicrobial resistant bacteria
Although there are many existing vaccines for bacterial diseases (Table 6.2), there are
many bacterial disease s for which vaccines are needed, especially considering the global
emergence of antimicrobial resistant/resistance (AMR) organisms (Tagliabue, 2018). AMR
is one of the WHO global health threats (Table 6.8) with 1.27 million deaths directly attributed
to AMR and another 4.95 million deaths indirectly associated with AMR (Kim, 2023). In 2022,
WHO’s 10 major threats to global health 201
II. Vaccines
the WHO published a report focusing on vaccine candidates in various stages of develop-
ment for priority AMR pathogens (Table 6.9).
The report highlights 61 vaccine candidates in various stages of clinical development, and
94 candidates in preclinical development. It is important to note that the immune responses
required to protect against or clear bacteria that cause extracellular infections will be different
than what is required to clear bacteria that infect the intracellular compartment. Intracellular
bacteria have evolved mechanisms to escape lysosomal degradation within target cells, and
replicate within cells, so require the elicitation of cellular immunity (Osterloh, 2022).
“There Was a Fungus Among Us”
The original 1958 song by Terry Noland had humorous intent, but 65 years later fungi
are no laughing matter. Per Dr. Hanan Balkhy, WHO Assistant Director-General of
TABLE 6.8 10 major threats to global health (WHO, 2019).
No. Major threat
Can be impacted by
vaccination?
a
Comments
a
1 Air pollution and
climate change
Not directly Vaccines can lessen the severity of infectious diseases in the
pollution-exposed populace and impact the prevalence and severity
of climate-sensitive diseases
2 Noncommunicable
diseases
Yes Therapeutic vaccines for chronic diseases and cancer
3Influenza Yes Seasonal and pandemic vaccines
4 Fragile and
vulnerable settings
Yes Detect and respond to outbreaks with immunization campaigns
5 Antimicrobial
resistance
Yes Block transmission of sensitive and resistant strains, prevent hard to
treat infections that reduces the chance of a pathogen mutating from
sensitivity to resistance; community spread; disease-related
complications by reducing the incidence of secondary infections, so
less antibiotic use
6 Ebola and high-
threat pathogens
Yes Vaccine platforms that are amenable to accelerated development
timelines
7 Weak primary care Not directly In 2023, 1 in 5 children worldwide are zero-dose (missed
vaccinations entirely) or under-vaccinated (partial routine
immunizations) levels not seen since 2008 (UNICEF, 2023)
8 Vaccine hesitancy Not directly Counteracting hesitancy with clear communication and education
strategies on efficacy and safety of vaccines is paramount
9 Dengue Yes One or two vaccines approved since 2015 depending upon
geography and indication
10 HIV Yes No vaccine despite >250 clinical trials
a
Author’s comments.
Six of the 10 major threats are active areas of vaccines R&D. Numbers 1, 4, and 7, while not directly impactable by vaccines, can
be indirectly impacted if vaccination of vulnerable individuals and populations is instituted. Number 8, vaccine hesitancy, is dis-
cussed in a later section.
6. Introduction to vaccines and adjuvants202
II. Vaccines
Antimicrobial Resistance, “Emerging from the shadows of the bacterial antimicrobial resis-
tance pandemic, fungal infections are growing, and are ever more resistant to treatments,
becoming a public health concern worldwide.” (GAVI, 2023). Fungi represent another class
of microorganisms that are emergent global threats that, in many cases, are amenable to vac-
cines but for which there are currently no approved products. Fungal diseases are increasing
TABLE 6.9 Vaccine pipeline for antimicrobial resistance (AMR) priority pathogens.
a
Pipeline feasibility
group A
(very high)
Pipeline feasibility
group B
(high)
Pipeline feasibility
group C
(moderate)
Pipeline feasibility
group D
(low)
Pathogens for which
licensed vaccines already
exist.
Pathogens for which a
vaccine candidate is in
late-stage development
(Phase 3) and vaccines are
suitable to target AMR
infections caused by
pathogens in the near
term.
Pathogens for which a
vaccine candidate has
either been identified in
early clinical trials or been
identified as a feasible
vaccine target during
expert review.
They may feasibly target
AMR infections, but are
in early stages of
development, so no
vaccine will be on the
market in the short term.
Pathogens for which no
vaccine candidate has
been identified in clinical
development, so vaccines
are not a feasible solution
for AMR infections in the
foreseeable future.
• Salmonella enterica ser.
Typhi
• Streptococcus
pneumoniae,
Haemophilus
• Influenzae type b
(Hib)
• Mycobacterium
tuberculosis
• Extraintestinal
pathogenic E. coli
(ExPEC),
• S. enterica ser.
Paratyphi A
• Neisseria gonorrhoeae
• Clostridioides difficile
• Enterotoxigenic E. coli
(ETEC)
• Klebsiella pneumoniae
• Nontyphoidal
Salmonella (NTS)
• Campylobacter spp.
• Shigella spp.
• Acinetobacter
baumannii
• Pseudomonas
aeruginosa
• Enterobacter spp.
• Enterococcus faecium
• Staphylococcus aureus
• Helicobacter pylori.
Recommendation
Increase the coverage of
authorized vaccines in
line with WHO
immunization targets to
maximize impact on
AMR.
Accelerate the
development of more
effective vaccines against
M. tuberculosis.
Accelerate the
development of a vaccine
for these pathogens.
Develop a vaccine for
these pathogens, expand
knowledge on the
potential for vaccine use
and impact and other
tools to combat the AMR
threat.
Focus on other
prevention and control
tools to combat AMR
threat linked to these
priority pathogens
b
.
a
Table adapted from WHO (2022) An analysis of bacterial vaccines in preclinical and clinical development: 2021. https://www.who.int/
publications/i/item/9789240052451 (accessed April 10, 2024).
b
Research and investment should explore alternative methods of control, including treatments and effective infection prevention and should
ensure access to clean water and adequate sanitation and hygiene facilities. This is even more urgent as the drug development pipeline for A.
baumannii and P. aeruginosa is currently also insufficient to adequately address the burden posed by these critical pathogens.
WHO’s 10 major threats to global health 203
II. Vaccines
worldwide, and the upswing suggests that this trend will continue. Increasing global temper-
atures may be letting infectious fungi in the environment grow in new areas that were once
non-permissive. Climate changes may also be exerting evolutionary pressure that could result
in new fungal infections. Some researchers believe climate change caused the emergence of the
deadly fungus C. auris (Hofer, 2019). The WHO fungal priority pathogens list (WHO FPPL,
October 25, 2022)is“the first global effort to systematically prioritize fungal pathogens, based
on their unmet R&D needs and perceived public health importance” (Table 6.10).
The WHO FPPL aims to “focus and drive further research and policy interventions to
strengthen the global response to fungal infections and antifungal” drug resistance. To high-
light the importance of these diseases, each year, the US CDC and partners dedicate Fungal
Disease Awareness Week to activities and outreach that encourage everyone to “Think Fun-
gus” (CDC, October 24, 2023).
Parasitic diseases
Like vaccines against fungal diseases, vaccines against parasitic diseases have “lagged cen-
turies behind those against viral and bacterial infections, despite the devastating morbidity
and widespread effects of parasitic diseases across the globe” (Pisarski, 2019). Like fungi,
the main hurdle to antiparasite vaccine development has historically been the lack of strate-
gies to elicit the complex types of immune responses needed to kill and clear the parasites
during their life cycle, during which different antigens can be expressed and the immune sys-
tem evaded. But inroads are being made: RTS,S/AS01 (RTS,S, Mosquirix), which WHO pre-
qualified in 2021, is the world’s first malaria vaccine against Plasmodium falciparum and is the
first approved vaccine to combat a human parasitic disease. It is approximately 30% effica-
cious, so other vaccine approaches are still needed. A second vaccine against Plasmodium fal-
ciparum, R21/Matrix-M adjuvanted malaria vaccine that is WHO prequalified and has better
efficacy (77%), was approved for use in Nigeria and Ghana having reached the WHO-
specified goal of 75% or greater efficacy over 12 months in the target population of African
children in a Phase 1/2b trial (Datoo et al., 2022). The trial was expanded to Phase 3 in Bur-
kina Faso (now approved), Kenya, Mali, and Tanzania, and 75% efficacy with a good safety
profile has been demonstrated (Datoo, 2024). Other parasitic neglected tropical diseases that
are recommended to be prioritized that could benefit from vaccines include intestinal
TABLE 6.10 WHO FPPL fungal priority pathogens.
a
Critical group High group Medium group
• Cryptococcus neoformans
• Candida auris
• Aspergillus fumigatus
• Candida albicans
• Nakaseomyces glabrata (Candida glabrata)
• Histoplasma spp.
• Eumycetoma causative agents
• Mucorales
• Fusarium spp.
• Candida tropicalis
• Candida parapsilosis
• Scedosporium spp.
• Lamentospora prolificans
• Coccidiodes spp.
• Pichia kudriavzeveii
• Cryptococcus gattii
• Talaromyces marneffei
• Pneumocystis jirovecii
• Paracoccidiodes spp.
a
Table adapted from WHO FPPL (October 25, 2022).
6. Introduction to vaccines and adjuvants204
II. Vaccines
nematode infections, leishmaniasis, schistosomiasis, and lymphatic filariasis, as well as cryp-
tosporidiosis ( Pisarski, 2019). McAllister (2014) makes the case that there are many effective
veterinary antiparasitic vaccines that could serve as foundations upon which human vaccines
for e.g., malaria, Chagas’ disease, African trypanosomiasis, and giardiasis could be based.
Veterinary vaccines are outside of the scope of this chapter, but there is a shared history
with human vaccines (Aida, 2021) and veterinary medicine regulatory frameworks in the
US (Erdman, 2020) and EU that parallel the frameworks for human medicines (Munro, 2016).
Therapeutic vaccines
An introductory statement by Boukhebza et al. (2012) in their publication on therapeutic
vaccines is the following: “Therapeutic vaccination is a field still in its infancy when
compared with the two worlds from which it originates: prophylactic vaccination and
immune-therapeutics . Therapeutic vaccines combine features from both of these worlds
while also displaying specific ones.” The antigen and adjuvant approaches and platforms
used for preventive vaccines can translate to therapeutic vaccines, as do many of the princi-
ples of nonclinical assessment of efficacy and safety. Diseases that are targets for experimental
therapeutic vaccines (Wyman, 2011; PhRMA, 2020; Tian, 2022; Nature Research Cust om Me-
dia, 2024, and others) include but are not limited to chronic infectious diseases (e.g., HIV,
HBV, HCV, HSV, CMV, EBV); periodontitis; sexually transmitted diseases, noninfectious
conditions associated with metabolic derangements (dyslipidemia/cholesterol, hypertension,
obesity, cachexia); autoimmune diseases (type 1 diabetes, systemic lupus erythematosus,
rheumatoid arthritis, psoriasis, multiple sclerosis, myasthenia gravis, and transplant rejec-
tion); neurodegenerative diseases (Alzheimer’s and Parkinson’s diseases); addictions (smok-
ing, cocaine, nicotine); and asthma and allergies (allergen-specific immunotherapy).
Platforms for therapeutic vaccines
There are too many therapeutic candidate vaccines that have moved from nonclinical into
clinical development to review here, but the platforms used to produce the antigens are as
varied as the disease targets. Like preventive vaccine platforms, therapeutic vaccines can
include protein- or peptide-based antigens, RNA- and DNA-expressed antigens, and viral
vectors expressing antigens. One type of cell-based vaccine consists of antigen-presenting
dendritic cells loaded with DNA, RNA, or peptides, which is adaptable to either cancer or
noncancer targets. Cellular cancer vaccines can be autologous (derived from a patient’s
own tumor) or allogeneic (derived from a different patient source) and can consist of whole
cells that are unable to replicate or cell lysates. Autologous cell vaccines have the advantage
of containing all potentially relevant tumor-associated antigens for that particular patient
(Sondak, 2006) but are very challenging to manufacture. Allogeneic vaccines are easier to
manufacture, but the tumor-associated antigens present on the patient’s own tumor may
not be represented (Sondak, 2006). Like many preventive vaccines, therapeutic vaccines usu-
ally incorporate adjuvants and/or immunostimulatory compounds to enhance the immune
response to the therapy, the selection of which is dependent upon the desired immune
response.
Therapeutic vaccines 205
II. Vaccines
Соседние файлы в папке Библиотека им академика М.И. Перельмана