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_5703_Библиотеки_им_академика_М_И_Перельмана
.pdf
van der Laken CJ, Voskuyl AE, Roos JC, Stigter van Walsum M, de Groot ER, et al. Imaging and serum analysis of
immune complex formation of radiolabelled infliximab and anti-infliximab in responders and non-responders to
therapy for rheumatoid arthritis. Ann Rheum Dis 2007;66:253e6.
Vugmeyster Y, DeFranco D, Szklut P, Wang Q, Xu X. Biodistribution of 125I-labeled therapeutic proteins: application
in protein drug development beyond oncology. J Pharm Sci 2010;99:1028e45.
Wagner CL, Schantz A, Barnathan E, Olson A, Mascelli MA, Ford J, et al. Consequences of immunogenicity to the
therapeutic monoclonal antibodies ReoPro and Remicade. Dev Biol (Basel) 2003;112:37e53.
Walsh G, Walsh E. Biopharmaceutical benchmarks 2022. Nat Biotechnol 2022;40(12):1722e60.
Wang W, Chen N, Shen X, Cunningham P, Fauty S, Michel K, et al. Lymphatic transport and catabolism of therapeu-
tic proteins after subcutaneous administration to rats and dogs. Drug Metab Dispos 2012;40:952e62.
Wang W, Prueksaritanont T. Prediction of human clearance of therapeutic proteins: simple allometric scaling method
revisited. Biopharm Drug Dispos 2010;31:253e63.
Wang W, Wang EQ, Balthasar JP. Monoclonal antibody pharmacokinetics and pharmacodynamics. Clin Pharmacol
Ther 2008;84:548e58.
Wang J, Iyer S, Fielder PJ, Davis JD, Deng R. Projecting human pharmacokinetics of monoclonal antibodies from
nonclinical data: comparative evaluation of prediction approaches in early drug development. Biopharm Drug
Dispos 2016;37(2):51e65.
Wang H, Ma H, Sové RJ, Emens LA, Popel AS. Quantitative systems pharmacology model predictions for efficacy of
atezolizumab and nab-paclitaxel in triple-negative breast cancer. J Immunother Cancer 2021;9(2).
Wang Y, Zhu H, Madabushi R, Liu Q, Huang SM, Zineh I. Model-informed drug development: current US regulatory
practice and future considerations. Clin Pharmacol Ther 2019;105(4):899e911.
Ward ES, Ober RJ. Multitasking by exploitation of intracellular transport functions the many faces of FcRn. Adv
Immunol 2009;103:77e115.
Working P. Potential effects of antibody induction by protein drugs. In: Ferraiolo B, Mohler MA, Gloff CA, editors.
Protein pharmacokinetics and metabolism. New York: Plenum Press; 1992. p. 73e92.
Xiang H, Nguyen CB, Kelley SK, Dybdal N, Escandon E. Tissue distribution, stability, and pharmacokinetics of Ap02
ligand/tumor necrosis factor-related apoptosis-inducing ligand in human colon carcinoma COL0205 tumor-
bearing nude mice. Drug Metab Dispos 2004;32:1230e8.
Xu Y, Mehl JT, Bakhtiar R, Woolf EJ. Immunoaffinity purification using anti-PEG antibody followed by two-dimen-
sional liquid chromatography/tandem mass spectrometry for the quantification of a PEGylated therapeutic pep-
tide in human plasma. Anal Chem 2010;82:6877e86.
Xu Y, Hijazi Y, Wolf A, Wu B, Sun YN, Zhu M. Physiologically based pharmacokinetic model to assess the influence
of blinatumomab-mediated cytokine elevations on cytochrome P450 enzyme activity. CPT Pharmacometr Syst
Pharmacol 2015;4(9):507e15.
Yang BB, Kido A. Pharmacokinetics and pharmacodynamics of pegfilgrastim. Clin Pharmacokinet 2011;50:295e306.
Yu J, Karcher H, Feire AL, Lowe PJ. From target selection to the minimum acceptable biological effect level for human
study: use of mechanism-based PK/PD modeling to design safe and efficacious biologics. AAPS J 2011;13:169e78.
Zalevsky J, Chamberlain AK, Horton HM, Karki S, Leung IW, Sproule TJ, et al. Enhanced antibody half-life improves
in vivo activity. Nat Biotechnol 2010;28:157e9.
Zhang T, Androulakis IP, Bonate P, Cheng L, Helikar T, Parikh J, et al. Two heads are better than one: current land-
scape of integrating QSP and machine learning: an ISoP QSP SIG white paper by the working group on the inte-
gration of quantitative systems pharmacology and machine learning. J Pharmacokinet Pharmacodyn
2022;49(1):5e18.
Zhao J, Cao Y, Jusko WJ. Across-species scaling of monoclonal antibody pharmacokinetics using a minimal PBPK
model. Pharm Res 2015;32:3269e81.
Zheng Y, Scheerens H, Davis JJC, Deng R, Fischer SK, Woods C, et al. Translational pharmacokinetics and pharma-
codynamics of an FcRn-variant anti-CD4 monoclonal antibody from preclinical model to phase I study. Clin Phar-
macol Ther 2011;89:283e90.
Zia-Amirhosseini P, Minthorn E, Benincosa LJ, Hart TK, Hottenstein CS, Tobia LA, et al. Pharmacokinetics and phar-
macodynamics of SB-240563, a humanized monoclonal antibody directed to human interleukin-5, in monkeys. J
Pharmacol Exp Ther 1999;291:1060e7.
5. Novel biopharmaceuticals: Pharmacokinetics, pharmacodynamics, and bioanalytics176
I. Development of biopharmaceuticals
Vaccines
SECTION II
This page intentionally left blank
6
Introduction to vaccines and
adjuvants
Deborah L. Novicki
DL Novicki Toxicology Cons ulting LLC, Marlborough, MA, United States
OUTLINE
Introduction 180
The two arms of the immune system 180
Regulation of vaccines 184
US FDA definition of a vaccine 185
Impacts of current vaccines on human
health 193
The science (and business) of
vaccinology 193
Vaccine platforms can accelerate
development and approval of new
vaccines 195
Are adjuvant platforms feasible? 196
“Outbreaks, they’re inevitable. But
turning into a pandemic, that’s optional” 199
WHO’s 10 major threats to global health 201
Other vaccines needed for serious
infectious diseases 201
Antimicrobial resistant bacteria 201
“There Was a Fungus Among Us” 202
Parasitic diseases 204
Therapeutic vaccines 205
Platforms for therapeutic vaccines 205
Complexity of vaccines from a product
quality perspective 209
Nonclinical testing 210
Vaccine development using the Animal
Rule 211
WHO threat #8dVaccine hesitancy
(and the importance of vaccinology
education) 213
Summary 217
References 218
CHAPTER
179
Nonclinical Development of Biologics, Vaccines and
Specialty Biologics, Second Edition
https://doi.org/10.1016/B978-0-443-13344-2.00014-6
© 2025 Elsevier Inc. All rights are reserved, including those for text
and data mining, AI training, and similar technologies.
Introduction
A simple introduction to the concepts of preventive and therapeutic vaccination is in a pa-
per by Sela and Hilleman (2004) where they state: “Vaccines are for healthy people, to pre-
vent them from getting sick. So perhaps the expression ‘therapeutic vaccine’ is an
oxymoron”. However, the term therapeutic vaccine, a vaccine intended to treat a disease
that is already acquired, is in our lexicon now, and research and development (R&D) for
both types of vaccines are rapidly expanding due to medical, social, and economic forces
currently in play. In very simple terms, vaccines work by presenting antigens as “non-self”
or “abnormal self” to the immune system. Initial interactions are with the innate immune sys-
tem, the well conserved, germline-encoded system of defenses that is triggered within mi-
nutes to hours, followed by the development of adaptive (specific) immune responses
within days to weeks.
A historical perspective is helpful to understanding the foundational science and the very
long path leading to the most recent successes in the development of vaccines. The History of
Vaccines website maintained by the College of Physicians of Philadelphia (2024) has a Chi-
nese image from the year 1000 showing devices for intranasal and dermal administration
of scratchings from smallpox lesions (variolation), and variations of variolation were prac-
ticed in Turkey, Africa, and Europe in the 1100s. The terms “vaccine” and “vaccinate”
were coined in 1803 when Edward Jenner described the technique he devised for preventing
smallpox by injecting people with cowpox virus, variolae vaccinae, which derives from the
Latin vaccinus, pertaining to cows or from cows, and vacca, cow (Douglas Harper, 2024).
The Institut Pasteur (2024) states that “Edward Jenner invented vaccination, Louis Pasteur
invented vaccines”, by Pasteur using the term for the prevention of diseases other than small-
pox. These pioneers planted the seeds for the innovators who followed including Koch, von
Behring, Ehrlich (introduced the concept of antigensdantibody generators) and Lister; the
twentieth century’s Calmette and Guerin, Salk and Sabin, and others; Hilleman, one of the
most productive vaccinologist s to date (Tulchinsky, 2018) VaccineNation’s “50 most influen-
tial people in vaccines” (2013)” and Time’s (2021) “Heroes of the Year” Corbett, Graham, Kar-
iko, and Weissman for their innovations enabling highly effective mRNA vaccines. The
multicentury history of vaccines is discussed in many publications and reviews, but in addi-
tion to the College of Physicians of Philadelphia website (2024), the Immunize.org website
(2024) is an excellent resource for the interested reader.
The history of vaccines (discussed below) is intimately tied to the history of immunology,
and vice versa. Reviews by Kaufmann (2019), and Saleh (2021), and the American Association
of Immunologists timeline (2015), present seminal achievements in immunology. The focus
here is, by necessity, brief with a practical focus on key immunological concepts that are
fundamental to how vaccines work, currently approved vaccines, and diseases for which vac-
cines are still needed.
The two arms of the immune system
The innate immune system is the first line of the immune response and consists of four
barriers: anatomical (skin and mucous membrane), physiological (temperature, low pH,
and chemical mediators), cellular (endocytosis/phagocytosis), and inflammatory (vascular
6. Introduction to vaccines and adjuvants180
II. Vaccines
leak of antibacterial and chemoattractant proteins). Focusing on the cellular barrier, whether
the initiating stimulus is a microbe, an abnormal or damaged cell, or a vaccine, at the site of
infection, damage, or vaccine administration, defensive surveilling innate immune cells (pri-
marily macrophages and dendritic cells) have receptors (pattern recognition receptors, PRRs)
that recognize pathogen-associated molecular patterns (PAMPs) that are not expressed in the
host, or molecules released from damaged cells (damage associated molecular patters,
DAMPs) of the host (Li, 2021). PRRs fall into six general families, as shown in Table 6.1,
with a caveat: Innate immune sensing, the interactions between receptors and accessory pro-
teins, the downstream signaling, interfaces with the cells of the adaptive immune system, and
the elicited specific immune responses are all of increasing complexity, information is
evolving very rapidly, and there are hundreds of publications. Therefore, only select citations
that are heavily referenced are provided. Individual specificities for the Toll-like receptors
(TLRs) are shown in more detail than the other PRRs as they are the most well-
characterized, to date.
Upon PAMP or DAMP recognition, cell surface or intracellular PRRs signal the presence of
non-self or damaged self and proinflammatory responses are initiated via activation of intra-
cellular signaling pathways. These pathways include receptor complexing, adaptor mole-
cules, kinases, and transcription factors and comple x interactions of PRRs, including some
inhibitory interactions, are involved in immune responses, regulation, and disease (Kumar,
2024). PRR-induced signal transduction then results in the activation of gene expression
and the synthesis of compounds including cytokines, chemokines, cell adhesion molecules,
and immunoreceptors that together signal initiation of the second arm of the immune system,
the adaptive immune response (Brubaker, 2015; Jain, 2017). The adaptive immune response
recognizes non-self in the context of self (major histocompatibility complexes, MHC), is
antigen-dependent, antigen-specific, and has the capacity for immunological memory. It re-
quires complex interactions between antigen-presenting dendritic cells, macrophages, and
B cells, the main antigen-presenting cells (APCs) for T cells, or lymphoid follicular dendritic
cells, the main APCs for B cells. Reviews by Siegrist (2008), Clem (2011), and Pollard (2021)
provide excellent primers on how vaccines work. In very general terms, the process is sum-
marized by Patil (2020) as follows:
• Vaccine antigen is phagocytosed by APCs
• APCs travel to lymphoid tissue containing immature T and B cells
• Antigen is processed and binds to major histocompatibility complex class II (MHC II)
receptors and MHC I receptors on the cell membrane of the APC and is presented to
immature helper T cells and cytotoxic T cells through binding the MHC II (helper T) or
MHC I (cytotoxic T) to the T-cell receptor
• The T cells mature and proliferate, helper T cells activate B cells to proliferate and
produce antibodies specific to the antigen, and cytotoxic T cells destroy pathogens that
bear the antigen presented to them by the APCs
• Memory B and T cells are formed
The innate immune system is often referred to as the “nonspecific” immune system and
described as responding in the same way upon re-exposure to a foreign stimulus. However,
Netea et al. (2011) published a paper on “trained immunity” whereby innate immune cells
return to an inactivated state after an initial exposure to PAMPs and DAMPs but have
Introduction 181
II. Vaccines
TABLE 6.1 Pattern recognition receptor families.
Receptor type Cellular location Receptor Primary PAMPs or DAMPs sensed Review article(s)
TLRs
Toll-like receptors
Cell surface TLR1 Triacyl peptides Fitzgerald (2020)
Sameer (2021)
Rodrigues (2024)
TLR2 Lipoproteins, peptidoglycans, porins, zymosan,
b-glycan, GPI mucin, envelope glycoproteins,
Diacyl lipopeptides and lipoteichoic acid
TLR4 Lipopolysaccharide, glycoinositol phospholipids,
envelope glycoproteins, host-derived Heat Shock
Proteins and HMGB1
TLR5 Flagellin
TLR6 Diacyl lipopeptides and lipoteichoic acid
TLR10 Controversial
Endosomal
compartment
TLR3 3-Double-stranded RNA and Poly I:C
TLR7 Single-stranded viral RNA
TLR8 Single-stranded viral RNA
TLR9 Unmethylated CpG and mitochondrial DNA
TLR10 Controversial
NLRs
Nucleotide-binding
oligomerization
domain (NOD)-like
receptors
23 members in 4
subfamilies in cytosol
of primarily immune
cells
NLRA Variously recognize PAMPS (peptidoglycans,
flagellin, viral RNA, fungal hyphae, etc.) and
DAMPs (host cell products including ATP,
cholesterol crystals, uric acid, etc., and
environmental stimuli such as alum, asbestos, silica,
metal particles, UV radiation, and dermal irritants)
Wade (2015)
Babamale (2021)
Almeida-da-Silva
(2023)
NLRB
NLRC
NLRP
CLRs
C-type lectins
receptors (have a
Ca2þ binding site)
CTLRs
C-type lectin-like
receptors (no Ca2þ
binding site)
Transmembrane and
soluble receptors
primarily on myeloid
and lymphoid cells
and lymphoid but also
on epithelial and
endothelial cells
>1000 proteins in
superfamily
categorized into 17
subgroups, per
phylogeny and
domain alignment
Together recognize most classes of human
pathogens (carbohydrates e.g., glucans, fucose, and
high mannose structures present in mycobacteria,
viruses, and fungi).
Some CLRs are activated by host-derived damage
signals
Geijtenbeek (2009)
Mnich (2020)
Ganguly (2021)
6. Introduction to vaccines and adjuvants182
II. Vaccines
RLRs
Retinoic acid-inducible
gene I (RIG-I)-like
receptors
Cytosol RIG-I Preferentially recognizes single-stranded RNA over
double stranded RNA
Rehwinkel (2020)
Solstad (2022)
Zheng (2023)
Melanoma
differentiation-
associated protein 5
(MDA5)
LGP2
ALRs
Absent in melanoma-
2-like receptors
Cytosol AIM2 Recognize double-stranded DNA Connolly (2014)
Garg (2023)
POP3
Nucleus IFI16
MNDA
PYHIN1
cGLRs
cGAS-like receptors
Cytosol cGASestimulator
of interferon genes
(STING) receptor
Recognizes double-stranded DNA Ge (2022)
Mosallanejad (2022)
Bordon (2023)
Introduction 183
II. Vaccines
undergone epigenetic changes as a result of the original encounter and are then able to mount
a faster and stronger response upon antigen re-ex posure. Trained immunity is also respon-
sible for the fact that certain infections and vaccinations can induce protection against other
pathogens, e.g., Bacillus CalmetteeGuérin (BCG) vaccine offers variable degrees of protection
against malaria, leishmaniasis, candidiasis, yellow fever, leprosy, sepsis, and various respira-
tory infections among other diseases (Dagenais, 2023). This may be desirable in the context of
infection or vaccination, but inappropriate training by endogenous (self) stimuli could lead to
inappropriate inflammation and immunopathology and plays a role in organ transplant
rejection (Marshall, 2018; Netea, 2020; Ochando, 2023).
An ideal vaccine will have or express the antigen(s) of interest as well as moieties that engage
the innate immune system sufficiently to trigger the cascade leading to a durable desired adap-
tive immune response but without causing an unacceptable degree of reactogenicity, the well-
known local sequelae of the inflammatory response to vaccination including injection site
pain, redness, swelling or induration, and systemic symptoms such as fever, myalgia, or head-
ache. In nonclinical studies reactogenicity can be assessed in vitro (e.g., cytokine studies) and
in vivo based on the evaluation of clinical signs, body weight and food consumption, injections
site reactions, body temperatures, clinical and anatomic pathology, acute phase reactants, and
cytokines (see Chapters 7 and 8 for more detail). Depending upon the clinical phase of testing,
many of the same physiological endpoints can be measured in humans (with the exception of
anatomic pathology) along with the collection of solicited symptoms (participants are actively
questioned about the occurrence of each symptom) or unsolicited symptoms (participants report
spontaneously). Vaccine adverse events beyond reactogenicity are discussed in a later section.
Regulation of vaccines
Vaccines for infectious diseases are regulated in the US by the Food and Drug Administra-
tion (US FDA) Center for Biologics Evaluation and Research (CBER) Office of Vaccines
Research and Review (OVRR). The relatively new Office of Therapeutic Products (OTP) over-
sees products that include gene therapies, therapeutic vaccines and other antigen-specificim-
munotherapies, xenotransplantation, stem cells, human tissue for transplantation, combination
products, bioengineered tissues, and certain medical devices. Vaccine authorization is sought
via the submission of a Biologics License Application (BLA). The US FDA participates in the
World Health Organization (WHO) prequalification program as the National Regulatory Au-
thority (NRA) for applicable US-manufactured vaccines (US FDA, March 23, 2018).
In the European Union and European Economic Area countries (EU/EEA) vaccines are
regulated by the European Medicines Agency (EMA) and country-specific agencies. The three
pathways (EMA, October 30, 2023) for approval are:
• Centralized procedure wherein the company submits a single Marketing Authorization
Application (MAA) to EMA that leads to the product’s approval in the EU/EEA
• Decentralized procedure wherein the company seeks authorization fo r a product that
has not been previously authorized in any EU country by simultaneously applying for
authorization in more than one, but not all, EU member states with one country serving
as the reference member state. Market authorization is granted if the other countries
agree wi th the reference state’s assessment.
6. Introduction to vaccines and adjuvants184
II. Vaccines
• Mutual recognition proced ure that allows a company whose product has already been
authorized in one EU nation (the reference state) to apply for approval in other EU
countries (target states).
In cooperation with the WHO, the EU-Medicines for All (EU-M4all, previously known as
Article 58) allows for the provision of scientific opinions on high priority human medicines,
including vaccines,to assistlow- andmiddle-income countries outside ofthe EU to achieveaccess
through WHO prequalification (https://www.ema.europa.eu/en/human-regulatory/marke
ting-authorisation/medicines-use-outside-european-union; accessed April 15, 2024).
The WHO maintains a list of global national health authorities (WHO Listed Authorities,
WLAs), which is relevant to vaccines, the framework for which is to “promote access and
supply of safe, effective, and quality medical products. The framework also provides for
the optimal use of limited resources by facilitating reliance on the work products and deci-
sions of trusted agencies in the decision-making of regulatory authorities, the WHO Prequal-
ification Program and procurement agencies.” (WHO, October 27, 2023).
US FDA definition of a vaccine
The CBER Guidance for Industry: Considerations for Developmental Toxicity Studies for
Preventive and Therapeutic Vaccines for Infectious Disease Indications (2006) describes vac-
cines as: “a heterogeneous class of preventive, in some cases therapeutic, medicinal products,
the administration of which is intended to elicit an immune response(s) that can prevent and/
or lessen the severity of one or more infectious diseases. A vaccine may be a live attenuated
preparation of bacteria, viruses,orparasites, inactivated (killed) whole organisms, living
irradiated cells, crude fractions or purified immunogens, including those derived from re-
combinant deoxyribonucleic acid (DNA) in a host cell, conjugates formed by covalent link-
age of components, synthetic antigens, polynucleotides (such as plasmid DNA vacci nes),
living vectored cells expressing specific heterologous immunogens, or cells puls ed with
immunogen. It may also be a combination of vaccines listed above. Antigens may be pre-
sented plain or delivered in combination with other antigens, adjuvants, additives and other
excipients.”
Select terms in the text above were bolded by the author to emphasize the variety of or-
ganisms, biological molecules, and cells that can be used to make vaccines. In addition to the
DNA vaccines mentioned in the quote, mRNA and other v accine types based on subsequent
novel technologies would be included were the guideline to be updated. Table 6.2 shows ex-
amples and the timeline of approved vaccines for prevention of infectious diseases by prod-
uct type and year.
From the 1700s to the 1980s, manufacturers produced vaccines based on inactivated whole
organisms, live attenuated organisms, and inactivated toxins (toxoids). These first-generation
vaccines contained moieties that stimulate the innate immune system leading to the adaptive
responses recognizing the exact structures, or immunogenic epitopes. However, around the
1980s, better characterized, purer second-generation vaccines (conjugates, subunits, recombi-
nant proteins, and synthetic peptides) were developed in order to decrease reactogenicity and
address other safety issues attendant with some first-generation vaccines. By comparing the
second half of the last century with the first 23 years of this century, it is clear that, while older
Introduction 185
II. Vaccines
Соседние файлы в папке Библиотека им академика М.И. Перельмана