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Currently there are no approved therapeutic vaccines for the treatment of chronic viral in-
fections in humans, which are associated with a wide variety of medically important diseases
that can arise with the primary infection or require months to decades to develop. Immuno-
suppressed individuals are uniquely susceptible to many of these diseases. The immune sys-
tem is targeted by HIV, human T cell leukemia virus, Epstein Barr virus, and
Cytomegalovirus; the gut by Hepatitis viruses, Adenoviruses, and Parvoviruses; the nervous
system by Herpes simplex 1 and 2, Varicella Zoster virus, and Measles; and the skin by Pap-
illomaviruses (Boldogh, 1996) and there is emerging evidence that viruses may play a role in
some neurodegenerative diseases (Blackhurst, 2 023). Globally, there are many vaccine candi-
dates in various stages of development for these chronic viral diseases as well as for other
chronic microbial infections.
In addition to communicable disease targets, there is a global need for widespread inter-
ventions for chronic noncommunicable diseases (NCD) that represent major sources of
morbidity and mortality, killing 41 million people each year causing 74% of all deaths glob-
ally (WHO, September 16, 2022). Cardiovascular diseases account for most NCD deaths (17.9
million people annually), followed by cancers (9.3 million), chronic respiratory diseases (4.1
million), and diabetes (2.0 million including diabetes-related kidney disease deaths). These
four groups of diseases account for over 80% of all NCD deaths. Chronic respiratory diseases,
hypertension, Alzheimer’s disease, dyslipidemia, asthma, and chronic obstructive pulmonary
disease further contribute to high rates of NCD deaths (Boutayeb, 2010; Kostova, 2021;
Kashutina, 2023). Approved preventive infectious disease vaccines can have indirect effects
on NCDs . For example, measles vaccination has been associated with less allergy and asthma
(Timmermann, 2015). Respiratory disease vaccinations (e.g., influenza, RSV, COVID-19, etc.)
help protect viral target tissues and organs from the disease-related effects of infection that
can have chronic sequelae, especially in individuals with preexisting conditions.
Of the many therapeutic vaccine targets being explored, cancer vaccines (active immuno-
therapies) are high-profile in recent news but have their origin in ancient history. Active
immunotherapy for cancer (in contrast to passive immunotherapy i.e., antibody administra-
tion or adoptive transfer of activated immune cells) was practiced more than 4000 years ago
by the Egyptian physician Imhotep, who described inducing an infection at a poulticed
incised tumor and the infection causing tumor regression (Jessy, 2011). In more modern times
(reviewed by Felgner, 2016; Carlson, 2020), the 1813 observations of tumor inhibition in can-
cer patients with gas gangrene and erysipelas (a recurrent disease caused by a bacterial infec-
tion defined by large, raised red patches on the skin, fever, and severe illness) led to a “clinical
trial” in 1863 by W. Busch and colleagues in Berlin who intentionally infected a female cancer
patient with erysipelas (the tumor regressed, but she died from the infection). The next ad-
vancements came with Coley, who read an account of a patient with an inoperable sarcoma
who experienced complete regression after developing erysipelas, and with Fehleisen, a
colleague of Busch who had identified Streptococcus pyogenes as the bacterium responsible
for erysipelas. From 1888 to 1933, Coley tested many preparations of “Coley’s Toxins” by
injecting sarcoma patients with Streptococcus pyogenes, some of which were useless, others
that worked but were highly infectious and killed patients, and some that looked promising.
He selected a combination of heat-killed Streptococcus pyogenes and Serratia marcescens,
treated more than 1000 cancer patients, and published over 150 papers on the therapy.
Following Coley’s death in 1936, the approach was generally out of favor until the 1960s
6. Introduction to vaccines and adjuvants206
II. Vaccines
and 1970s when small clinical trials were performed with formulations similar to Coley’s
toxin (e.g., Vaccineurin and others) with variable results (Hobohm, 2001). The observation
by Pearl (1929) that there was a lower incidence of bladder cancer in patients with tubercu-
losis, and animal studies in the 1950s that showed that BCG decreased cancer rates, led to the
use of intravesical (intrabladder) BCG being tested clinically a generation later (Morales et al.
1976). Since the late 1980s oncologists used intravesical BCG after primary tumor surgery to
prevent relapses of bladder cancer, ultimately leading to the 1990 approval of the treatment,
TheraCys, the first FDA-approved therapeutic vaccine (Table 6.11). Currently, there are only
a limited number of US-approved therapeutic vaccines that can be categorized as postexpo-
sure therapy, cancer prevention, or cancer treatment.
Oncophage, a therapeutic vaccine that is only approved in Russia for treatment of renal
cell carcinoma, contains autologous tumor-derived gp96 heat shock protein-peptide in a non-
covalent complex with patient tumor-derived peptides. Provenge (Table 6.11) is based on
dendritic cell technology, (Anassi and Ndefo, 2011; Cheever and Higano, 2011), a technology
that also holds promise for therapeutic vaccines for chronic infectious and other noncancer
chronic diseases (Kastenmüller, 2014).
Dendritic cell (DC) vaccines are highlighted here because, as professional antigen-
presenting cells, they can be exploited for a variety of vaccines. After phagocytosing antigen,
DCs migrate to the draining lymph node where antigen is processed to peptides and the pro-
cessed peptides are loaded onto MHC molecules. Recognition of MHCII complexes by
antigen-specific CD4
þ
T helper cells enhance B cell expansion and antibody production.
Recognition of MHC I complexes by antigen-specific CD8
þ
T cells triggers proliferation
and activation to be cytotoxic (Cohn, 2014). DCs interact with B lymphocytes, as well as
with natural killer (NK) cells, to increase cytolytic activity and interferon-g (IFN-g)
production.
In order to make DC vaccines, the patient’s DCs are extracted from blood and immune
growth stimuli are used to expand the cells ex vivo. The DCs are then exposed to antigens
from the patient’s cancer (or other antigens depending upon the target). The combination
of DCs and antigens is then injected back into the patient and the DCs can then program
T cells. Antigens can also be targeted to DCs by complexing to monoclonal antibodies
directed to DC receptors and other novel approaches are being explored (Lee, 2023).
DCs are also involved in tolerogenesis, so also have potential to treat allergies (Jutel, 2016;
Nagy, 2021) and autoimmune diseases (Passeri, 2021). Non-cell-based allergy immunothera-
peutic treatments are essentially vaccines that induce tolerance. Current FDA-approved
CBER-regulated allergenics (US FDA, December 9, 2022) are administered by injection (allergy
shots), four products for pollen allergies are administered as sublingual tablets, and one is first-
in-class oral immunotherapy for peanut-allergic individuals who consume an increasing
amount of the allergen with the goal of reducing the risk of allergic reactions (Palforzia).
There are many review articles on cancer vaccines, mechanisms of action, antigens, plat-
forms, etc (Buonaguro, 2020; Jou, 2021; Fritah, 2022; Grimmett, 2022; Lin, 2022; Chang,
2023 and others), so these topics are only touched upon in this section and in Table 6.12,
which shows the types of antigens upon which most experimental cancer vaccine candidates
are based.
At one point in time, insufficient responses in clinical trials of cancer vaccines led to a cool-
ing off in the field. However, advances in tumor immunology led to understanding that the
Therapeutic vaccines 207
II. Vaccines
TABLE 6.11 Current FDA approved therapeutic vaccines and vaccine-like immunotherapies.
Vaccine Indication or use per respective label
Postexposure therapy
1980e1997:
Imovax
Rabavert
Rabies vaccine adsorbed
Postexposure prophylaxis for Rabies with human rabies immune globulin (also
for preexposure for those at high risk)
BioThrax 2015
Cyfendus 2023
Postexposure prophylaxis for Anthrax with appropriate antibiotics (also for
preexposure for those at high risk)
Jynneos
2022
Per CDC: “Postexposure prophylaxis is available for people exposed to mpox
virus and antiviral treatment(s) are available for people with mpox.” For
prevention per FDA
Cancer prevention
Cervarix
2009
Prevention of cervical cancer, cervical intraepithelial neoplasia (CIN) grade 2 or
worse and adenocarcinoma in situ, and cervical intraepithelial neoplasia (CIN)
grade 1, caused by oncogenic human papillomavirus (HPV) types 16 and 18, in
females 9 through 25 years of age
Gardasil-9
2014
Indicated in girls and women 9 through 45 years of age for the prevention of the
following diseases:
• Cervical, vulvar, vaginal, anal, oropharyngeal, and other head and neck
cancers caused by Human Papillomavirus (HPV) types 16, 18, 31, 33, 45,
52, and 58
• Genital warts (condyloma acuminata) caused by HPV types 6 and 11
and the following precancerous or dysplastic lesions caused by HPV types 6,
11, 16, 18, 31, 33, 45, 52, and 58:
• Cervical intraepithelial neoplasia (CIN) grade 2/3 and cervical
adenocarcinoma in situ (AIS)
• Cervical intraepithelial neoplasia (CIN) grade 1
• Vulvar intraepithelial neoplasia (VIN) grade 2 and grade 3
• Vaginal intraepithelial neoplasia (VaIN) grade 2 and grade 3
• Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3
Indicated in boys and men 9 through 45 years of age for the prevention of the
following diseases:
• Anal, oropharyngeal, and other head and neck cancers caused by HPV
types 16, 18, 31, 33, 45, 52, and 58
• Genital warts (condyloma acuminata) caused by HPV types 6 and 11.
and the following precancerous or dysplastic lesions caused by HPV types 6,
11, 16, 18, 31, 33, 45, 52, and 58:
• Anal intraepithelial neoplasia (AIN) grades 1, 2, and 3
Hepatitis B vaccines:
Recombivax HB 1986
Engerix-B 1989
Prehevbrio 2022
Heplisav-B 2023
These vaccines prevent acute, subchronic, HBV infection thereby preventing
cirrhosis and the development of HBV-related liver cancer
6. Introduction to vaccines and adjuvants208
II. Vaccines
tumor microenvironment can be immunosuppressive. The potential to turn “cold” tumors
(microenvironment has myeloid-derived suppressor cells and T regulatory cells that inhibit
reactive T cell infiltration) into “hot” tumors (those with inflammation/T cell infiltration)
by combining vaccination with checkpoint inhibitors that block inhibitory CTL-4 and PD-1
pathways (Chen, 2013; Mougel, 2019; Zabransky et al., 2023) has been a game-changer for in-
terest in and efficacy of cancer vaccines and immunotherapies. The publications by Igarashi
(2020), Chang (2023), and Zabransky et al. (2023) also review the state-of-the-art of cancer
vaccines, clinical vaccine candidates, and touch upon related immunotherapies including
tumor-infiltrating lymphocyte (TIL) therapy, TCR-T therapy (T cells transduced with
antigen-specific T cell receptors), CAR-T therapy (cancer antigen-recognizing antibody
gene, gene fragments from intracellular TCR domains, and other T cell costimulatory mole-
cules; Igarashi, 2020), and oncolytic viruses that are covered in other chapters in this book.
Complexity of vaccines from a product quality perspective
Needless to say, the chemistry, manufacturing, and controls (CMC)/quality aspects for
vaccines are very complex, and the adage for biologics, that “the process is the product,”
is especially true. Take as an example, a not-so-complicated hypothetical liquid tetravalent
conjugated vaccine produced by bacterial fermentation containing an adjuvant. There are
the four unconjugated antigen monovalent bulks, then four conjugated monovalent bulks,
and the adjuvant bulk. Then there is the pooled tetravalent bulk and the tetravalent bulk con-
taining the adjuvant. So, there is a total of 10 drug substances, the bulk “drug product,” and
the final filled product that must be monitored for and pass all CMC/quality requirements.
TABLE 6.11 Current FDA approved therapeutic vaccines and vaccine-like immunotherapies.dcont’d
Vaccine Indication or use per respective label
Cancer treatment
TheraCys
1990
TICE
1998
TheraCys (BCG live intravesical) was discontinued due to supply issues and
replaced with TICE in 1998. Indicated for intravesical use in the treatment and
prophylaxis of urothelial carcinoma in situ of the urinary bladder and for
prophylaxis of primary or recurrent stage Ta and/or T1 urothelial carcinoma
following transurethral resection
2010
Sipuleucel-T (PROVENGE;
Dendreon Corporation)
PROVENGE is an autologous cellular immunotherapy indicated for the
treatment of asymptomatic or minimally symptomatic metastatic castrate-
resistant (hormone refractory) prostate cancer
2015
IMLYGIC/T-VEC (talimogene
laherparepvec; Amgen)
T-VEC is a genetically modified oncolytic viral therapy considered a type of
therapeutic cancer vaccine that is indicated for the local treatment of unresectable
cutaneous, subcutaneous, and nodal lesions in patients with melanoma recurrent
after initial surgery
2022
Nadofaragene firadonevec
(Adstiladrin)
Approved for treatment of early-stage bladder cancers that have progressed
despite BCG therapy. It consists of an engineered, weakened virus that activates
an immune response in the bladder. Like BCG, it is delivered into the bladder
through a catheter
Complexity of vaccines from a product quality perspective 209
II. Vaccines
Then think about all of the vessels, tubings, filters, valves, O-rings, storage bags, columns,
centrifuges, and other equipment that the vaccine contacts during manufacturing. Filling of
final product is into a borosilicate glass vial with a siliconized or Teflon-coated rubber stop-
per, or a prefilled plastic or siliconized glass syringe/plung er stopper/needle/tip cap assem-
bly that is the final container. Finally, consider the ink and adhesive on the vial or syringe
label, and the ink on the label glued to the box in which the vial is packaged and stored.
The assessment of extractables (what can be extracted from contact materials under extreme
conditions) and leachables (what leaches from contact materials under conditions of use)
have become an important aspect of ensuring the safety of vaccines, in addition to controlling
manufacturing process impurities and residuals.
Nonclinical testing
The nonclinical programs for vaccines and adjuvants must, of course, demonstrate that the
vaccine is immunogenic and has the desired pharmacology (protection or therapy), but must
TABLE 6.12 Cancer vaccine antigen types.
Vaccine antigen type Where expressed Comments
Tumor-associated
antigens
(TAAs)
Preferentially or abnormally
expressed self-antigens on
tumor cells
Also expressed on normal cells, albeit at lower
levels, so have an autoimmunity risk and have not
been as successful because of induced weak and/or
short-lived immune responses in clinical trials
Tumor-specific
antigens
(TSAs)
Include antigens expressed by
oncoviruses or neoantigens
created by mutations in tumor
cells
TSAs are unique to tumor, so tend to be more
immunogenic than TAAs, and can activate CD4
þ
(helper) and CD8
þ
(cytotoxic) T cells to generate an
antitumor response. Oncoviral TSAs are expressed
in select tumor types in many patients (e.g., HPV E6
and E7 antigens in cervical cancer). Mutational
neoantigens can be unique to an individual patient’s
tumor or shared, i.e., found across different patients
and tumor types
Unique (personalized)
neoantigens
Require the creation of a
personalized (autologous)
product and can be based on
different platforms including
nucleic acid, dendritic cell,
tumor cell, or synthetic long
peptide platforms that deliver
the neoantigen(s) to prime the
patient’s immune system to
attack the tumor
Autologous vaccines are manufactured by resecting
tumor, genetically modifying tumor cells ex vivo to
increase immunogenicity then injecting them back
into the same subject or by genetically modifying
tumor cells in situ if tumor is accessible (Peng, 2019)
Shared neoantigens Some tumor-specific
neoantigens are common to a
subset of patients
Could theoretically be “off the shelf” so have the
advantage of being faster and cheaper than
personalized neoantigen vaccines but can be less
efficacious (Li, 2020)
6. Introduction to vaccines and adjuvants210
II. Vaccines
also address safety concerns related to the antigens, the platform (eggs, primary cells, cell
lines, immortal cell lines, bacteria, synthetic, etc.) used to manufacture the antigens, the ad-
juvants, the excipients and formulation components, novel delivery devices, and the target
human populations. Therefore, there is a complex matrix of factors with potential impacts
on efficacy and safety of vaccines, and nonclinical programs must be tailored and timed
appropriately to support the initiation of Phase 1 clinical testing, continued Phase 2 and Phase
3 testing, through to licensure. If clinical safety signals emerge pre- or postlicensure, investi-
gative studies may be needed in addition to the studies comprising the registration package.
Detailed reviews by Green and Al-Humadi remain excellent resources on nonclin ical study
design and assessments (2013, 2017), and detailed information on the pharmacology/toxi-
cology and related studies that are performed to enable clinical development, and to ulti-
mately support licensure of vaccines, are presented in Chapters 7 and 8. In addition to the
guidelines presented in the next chapter, there are a few additional documents that may
be helpful to consider in developing a nonclinical strategy (Table 6.13).
In some cases, nonclinical data forms the primary basis for approval when human vaccine
efficacy clinical trials cannot be conducted for ethical or feasibility reasons. To enable licen-
sure of therapeutics or vaccines for such situations, development under the “Animal Rule”
is an appropriate regulatory pathway (see US FDA 21 CFR 314 subpart I for drugs and 21
CFR 601 subpart H for biologicals).
Vaccine development using the Animal Rule
Under the Animal Rule (US FDA, 2015) the developer must show that the candidate is
likely to benefit humans based on animal immunogenicity and efficacy studies and human
immunogenicity and safety trials. The use of the rule is critical for candidates against patho-
gens with high case fatality rates that prohibit human challenge trials, as well as diseases with
low/sporadic frequency of outbreaks that make human field trials very challenging to impos-
sible. Candidate vaccines for epidemic/pandemic outbreaks (Table 6.6) and medical counter-
measure diseases (Table 6.7) and are obvious candidates for developing vaccines or
postexposure treatments under the Animal Rule. Somewhat similar regulations exist in Can-
ada (see Health Canada reference) and the EU (EMA, Pre-authorisation Guidance).
Because of the complexities presented by different animal models for challenge/protection
studies and toxicity testing, different vaccine and adjuvant modalities, and the variety of dis-
eases that may fall under the Animal Rule, it is critical to select the appropriate animal
models and study endpoints in conjunction with FDA, agreeing on the number of species,
which studies must be performed under current GLPs, and expectations for compliance of
challenge and test materials to current Good Manufacturing Practices (cGMP).
Key factors when applying the Animal Rule are understanding the disease pathophysi-
ology, the qualitative and quantitative immune response(s) required for protection, and con-
ducting high-quality efficacy and toxicity studies using high-quality challenge and test
materials. Assays used to establish infection and protection, and which will be used to corre-
late human and animal immune respo nses, should also be of high quality.
In addition to requiring animal efficacy studies that must be powered to achieve the goals
described above, GLP toxicology studies are required, possibly in two species, and Phase I, II,
and III clinical immunogenicity/safety studies must be performed with the candidate
Vaccine development using the Animal Rule 211
II. Vaccines
vaccine. Therefore, sponsors should understand that this approach is no short-cut, and may
be more expensive than a “standard ” approach to licensure.
Extrapolation of animal protection data to humans (Burns, 2012) is accomplished by 1.
correlating the probability of survival of vaccinated/challenged animals with the titers of
organism-specific antibodies elicited by the vaccine, 2. plotting antibody titers obtained
from vaccinated clinical subjects as a “reverse cumulative distribution curve”, and 3. extrap-
olating the probability of survival from animals to humans by “bridging” the protective anti-
body titers in animals to the postvaccination human antibody titers. A similar approach could
be taken based on cell mediated immunity if it is the mechanism of protection.
The Sabin Vaccine Institute is developing candidate filovirus vaccines (Marburg virus and
Sudan virus), under the Animal Rule and has published two recent papers (Finch, 2022a, 2022b)
TABLE 6.13 Select documents for consideration in addition to guidelines in Chapter 7.
Guideline Year Comment on utility
a
Toxicity grading scale for healthy adult and
adolescent volunteers enrolled in preventive
vaccine clinical trials
2007 Helpful to consider clinically measured endpoints when
designing/interpreting nonclinical studies/data (https://
www.fda.gov/media/73679/download)
ICH S12 nonclinical biodistribution
considerations for gene therapy products
2023 Not strictly applicable to vaccines, but has points to consider
when designing biodistribution studies for vaccines/
adjuvants (https://www.fda.gov/regulatory-information/
search-fda-guidance-documents/s12-nonclinical-
biodistribution-considerations-gene-therapy-products)
Guidance for industry nonclinical studies for
the safety evaluation of pharmaceutical
excipients
2005 Not strictly applicable but has points to consider if
incorporating a novel or new excipient into a vaccine or
adjuvant formulation (https://www.fda.gov/media/
72260/download)
FDA’s Keith Peden’s views on considerations
for the quality, safety and efficacy of
prophylactic lipid nanoparticle mRNA
vaccines
2022 11 October Public Workshop on FDA Guidance to Industry
on Nanomaterial (https://www.fda.gov/drugs/news-
events-human-drugs/fda-nanoday-symposium-2022-
10112022)
General principles for the development of
vaccines to protect against global infectious
diseases guidance for industry
2011 Provides general recommendations and clarifications for
regulatory pathways to use in the development of vaccines
to protect against global infectious diseases for U.S. licensure
even when disease is not endemic to the US (https://www.
fda.gov/files/vaccines, blood & biologics/published/
Guidance-for-Industry–General-Principles-for-the-
Development-of-Vaccines-to-Protect-Against-Global-
Infectious-Diseases.pdf)
Guidance for industry for the evaluation of
combination vaccines for preventable
diseases: production, testing, and clinical
studies
1997 Provides guidance for nontherapeutic combination vaccines
to prevent multiple diseases or one disease caused by
different strains or serotypes of the same organism. (https://
www.fda.gov/regulatory-information/search-fda-
guidance-documents/guidance-industry-evaluation-
combination-vaccines-preventable-diseases-production-
testing-and)
a
All hyperlinks were accessed on (April 19, 2024).
6. Introduction to vaccines and adjuvants212
II. Vaccines
exploring the challenges of and approaches for developing vaccines under extraordinary circum-
stances. Theprograms for BioThrax (seebelow) and Zabdeno/Mvabea (Ebola prevention), which
wereapprovedinthe EuropeanUnionand inselectAfricancountrieswithouthuman efficacydata
are reviewed.
As of August 2, 2023, CBER has approved four products, including two vaccines, under
the Animal Rule:
• BAT [Botulism Antitoxin Heptavalent (A, B, C, D, E, F, G)d(Equine)] sterile solution for
injection for the treatment of symptomatic botulism following documented or suspected
exposure to botulinum neurotoxin serotypes A, B, C, D, E, F, or G in adults and
pediatric patients (Approval date: 3/22/2013)
• ANTHRASIL [Anthrax Immune Globulin Intravenous (Human)] sterile solution for
infusion for the treatment of inhalational anthrax in adult and pediatric patients in
combination with appropriate antibacterial drugs (Approval date: 3/24/2015)
• BioThrax (Anthrax Vaccine Adsorbed) suspension for intramuscular or subcutaneous
injection for postexposure prophylaxis of disease following suspected or confirmed
Bacillus anthracis exposure, when administered in conjunction with recommended
antibacterial drugs (Approval date: 11/23/2015)
• CYFENDUS (Anthrax Vacc ine Adsorbed, Adjuvanted) suspension for intramuscular
injection for postexposure prophylaxis of disease following suspected or confirmed
exposure to Bacillus anthracis in persons 18 through 65 years of age when administered
in conjunction with recommended antibacterial drugs (Approval date: 7/20/2023)
Nothing succeeds like success (Dumas, 1854), so the learnings from recent vaccines devel-
oped using alternative approaches, the promise demonstrated with platforms that can rapidly
respond with new vaccines, and the efforts and funding by important public-private collabo-
rations all suggest that there will soon be vaccine prototypes and approved vaccines for many
diseases that threaten humanity. But vaccines only protect those who take them.
WHO threat #8dVaccine hesitancy (and the importance of
vaccinology education)
“Without strategies that are evidence informed, we may find ourselves continuing to wonder why the
same COVID-19 vaccines that can reduce risk of death by up to 94% only managed to prevent 58% of deaths.”
Jones (2022).
Vaccine hesitancy, vaccine refusal in its extreme form, has had a heartbreaking impact on
the progression of the COVID-19 pandemic. We can continue to develop safe, efficacious vac-
cines for existing and emerging diseases but if there is a significant proportion of the popu-
lation that does no t get vaccinated, herd protection fails and there are unnecessary
hospitalizations and deaths. Only by educating healthcare providers and the public as to their
important benefits and true very low incidence of safety risks can vaccines reach their
potential.
Because vaccinology is the intersection of so many disciplines and diseases, a lack of
comprehensive vaccinology training for those in healthcare industries has been identified
WHO threat #8dVaccine hesitancy (and the importance of vaccinology education) 213
II. Vaccines
as an educational gap at university, postgraduate, and professional levels that has direct im-
pacts on global health (Lambert and Podda, 2018). To address the gap, many agencies and
institutions have established training courses ranging from free online tutorials to university
and postgraduate degree programs. Courses fall into three general groupings: Tutorials suit-
able for the general public are available from the US Food and Drug Administration (US
FDA, December 14, 2020), WHO (December 8, 2020), the CDC (March 30, 2023), and the
US Department of Health and Human Services (HHS, November 3, 2023) among others.
For scientists there are postgraduate courses for those who wish for a career in the field
(see ADVAC, 2023 for a curriculum example), as well as advanced courses targeting profes -
sionals already skilled in vaccinology but who wish to play a leading role in decision-making
for vaccine development and global health. A google search on April 11, 2024 for ‘courses in
vaccinology’ yielded more than 40 training opportunities of varying levels offered
internationally.
It has been said by many that vaccines are victims of their own success, especially in weal-
thy countries. People may choose not to vaccinate their children or themselves because the
generations that dealt with the serious and lethal diseases prevaccines availability are now
elderly or gone, and younger generations have not lived through the infectious disease hor-
rors of the older generations. The CDC (September 15, 2022) describes 14 diseases that the
public has ‘almost forgotten about’ due to successful vaccination campaigns that are now un-
der threat. The antivaccine messaging by citizens of developed countries, who have the lux-
ury of taking advantage of herd protection, is impacting the developing world (Trujillo, 2021;
UNICEF, 2001) where the need to protect people with vaccines is so critical to maintaining the
reductions in mortality that have been gained in previous decades. But not only the devel-
oping world is at risk: as vaccination rates have declined in certain locales, there have
been outbreaks of measles, pertussis, and other diseases. In his book Deadly Choices: How
the Anti-Vaccine Movement Threatens Us All,” author Paul A. Offit (2011), one of the inventors
of RotaTeq rotavirus vaccine that has saved millions of lives globally, presents a historical
and broad review of the antivaccine movement and its consequences for children and adults.
The introduction to a special issue of the journal Health Psychology on vaccine hesitancy and
refusal (Bednarczyk, 2023) looks at the phenomenon from the perspective of health psychol-
ogy researchers and practitioners.
In the face of clear data that starkly illustrate the differences in COVID-19 deaths between
vaccinated and unvaccinated US populations (Fig. 6.1), it is hard for those in the field to un-
derstand delaying vaccination or refusal.
Traditional approaches to promote vaccine uptake among vaccine-hesitant parents, based
on highlighting the benefits and safety of the v accine and the dangers of the disease, did not
lead to an increased likelihood of vaccinating a child, even when misinformation was refut ed
(Jones, 2022). Counterintuitively, materials highlighting the dangers of the disease led to
more concerns about vaccines being harmful (Nyhan, 2014). Jones et al. (2022) conclude
that new strategies are needed and say that “Rebuilding trust is essential, and we need
evidence-informed strategies for achieving these critical goals. Identifying and implementing
effective interventions will require substantial and sustained investments in health commu-
nications research; an understanding of the influence of social media and information bubbles
on information spread and impact; public health infrastructure; and boots-on-the-ground,
targeted, and individualized approaches.” This is where vaccinology interfaces with social
6. Introduction to vaccines and adjuvants214
II. Vaccines
science and psychology. For interested readers, a Google search using “courses on vaccine
hesitancy” will yield several options, ranging from those for the general public to those for
academic and medical experts.
We shouldn’t be averse to adverse events . Reassuring the public that everything is being done,
researchwise, to understand the vaccines is more important than just saying everything is safe Murphy in
Couzin-Frankel (2022).
As with any medical intervention, vaccines are associated with side effects, the vast ma-
jority of which are very common (1 in 10) or common (1 in 100) and related to expected tran-
sient local reactions and generally mild systemic acute phase responses (injection site pain,
swelling, or redness; mild fever, chills, f atigue, headache ; muscle and joint aches) and initi-
ation of the immune response cascade. More serious adverse events are uncommon (<1in
100), rare (1 in 10,000), to very rare (<1 in 10,000), are vaccine-specific, and are reported in
the documentation for each appr oved vaccine. In 2011 (Stratton), the Institute of Medicine
(now National Academy of Medicine) reviewed the adverse effects of vaccines and
concluded “that while no vaccine is 100% safe, very few adverse events are shown to be
caused by vaccines”.AnupdatedreportbytheUS Agency for Healthcare Research and
Quality (2014) was again updated in 2021 and 16 vaccines that are recommended for routine
immunization in adults, pregnant people, children, and adolescents were reviewed. Signals
FIGURE 6.1 Differences in COVID-19 deaths between unvaccinated, vaccinated, and vaccinated þ bivalent-
boosted US populations. Reproduced without changes and with permission from Our World in Data, Creative Commons
BY license 4.0 https://creativecommons.org/licenses/by/4.0/.
WHO threat #8dVaccine hesitancy (and the importance of vaccinology education) 215
II. Vaccines
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