Dermatologic Therapy, Vol. 22, 2009, 104–109 © 2009 Wiley Periodicals, Inc.

Printed in the United States · All rights reserved

DERMATOLOGIC THERAPY
ISSN 1396-0296

Vaccine immunology
Brenda L. Bartlett*, Anthony J. Pellicane‡ &
Stephen K. Tyring*†
*Center for Clinical Studies and †Department of Dermatology, University of
Texas Health Science Center, 6655 Travis St. #120, Houston, Texas, and
‡Rehabilitation Institute of Chicago, 333 E. Ontario St. #3008B, Chicago,
Illinois

ABSTRACT: This article provides a review of immunology to enhance understanding of vaccine effi-
cacy and use, and elaborates on the immune response to vaccination. The use of vaccines to prevent
infectious diseases represents a tremendous accomplishment of biomedical science, especially consid-
ering the complex interplay of the immune system with innumerable pathogens. Vaccines have allowed
for total eradication of one disease and have significantly reduced the incidence of other diseases. In
order to have a successful vaccine-based eradication program, the infection must be limited to humans
without an animal reservoir and only one or a few strains may exist in viral infection. These strains must
have constant antigenic properties. A number of vaccine types exist, both traditional and innovative,
and are described herein.

KEYWORDS: active immunity, humoral immunity, vaccine types, vaccinology

Introduction agents undergo little to no antigenic variation, or

drift, allowing for extraordinarily effective vaccines
Vaccinology dates back as far as 1796 when Edward (5). Prevention of disease through vaccination is
Jenner illustrated that inoculation of human skin the best way to control the spread of infectious
with cowpox virus was protective against subse- diseases. Although vaccines may not always pre-
quent smallpox infection (1). This phenomenon vent transmission of disease, they may modify the
gave rise to the term “vaccine,” which stems from severity of illness in those who become infected or
the Latin root “vacca” meaning cow. A vaccine is reduce transmission to susceptible people. In order
defined as a biological preparation that is used to understand how vaccinations accomplish such a
to establish or improve immunity to a particular feat, it is important to know how vaccines elicit an
disease (2). Vaccination is considered one of the immune response.
greatest public health achievements of the 20th
century by significantly decreasing global morbid-
ity and mortality caused by a number of infections, Discussion
including smallpox, polio, measles, and hepatitis
B among others (3,4). A remarkable decrease in Understanding the immune response/
these infections was seen after vaccines became developing immunity
available. For example, a 100% decrease was seen Vaccinology targets the humoral immune system,
in cases of indigenous poliomyelitis, and a 99% part of the adaptive/acquired immune system.
decrease was seen in cases of diphtheria, measles, The adaptive immune system, composed of the
mumps, and rubella. These particular infectious humoral and the cell-mediated immune systems,
has high specificity and memory. The humoral
Address correspondence and reprint requests to: Brenda L. immune system refers to immune responses that
Bartlett, MD, Center for Clinical Studies, 6655 Travis St. #120, involve antibodies generated by B cells. In contrast,
Houston, TX 77030, or email: [email protected]. cell-mediated immunity refers to T cell responses

104
 Vaccine immunology

in the absence of antibodies. Humoral immunity antibody-dependent cellular cytotoxicity or

can be transferred to another individual using complement-mediated lysis (7).
antibody-containing serum (6). Immunological memory or the anamnestic
An adaptive immune response ensues when the nature of the immune system allows for a rapid
pathogen is able to evade the innate immune increase in response after reexposure to an antigen
response whereby organisms are detected and (6). This feature plays a critical role in the function
destroyed rapidly by defense mechanisms that are of the immune system and is one of the principles
not antigen-specific and do not require prolonged of vaccination. After an infection, most effector
induction. A successful adaptive immune response cells die within 10–14 days. Some, however, persist
depends on the interaction of three key cell types: as highly reactive plasma cells (B cells) or memory
the antigen-presenting cell (APC), thymus-derived cells (B and T cells) to combat subsequent infec-
lymphocyte (T cell), and bone marrow-derived tion. Memory B cells have undergone Ig isotype
lymphocyte (B cell). Of the various antigen- switching and somatic hypermutation, a process
presenting cells, the dendritic cell (known as the that starts late in the primary immune response
Langerhans cell in the skin) is most important (8). Memory B cell production is initiated prior to
because they are specialized for the capture of anti- antigen elimination. With no antigen present,
gens, subsequent processing, and presentation at memory B cells divide slowly and do not produce
the cell surface for T cell receptor recognition. B antibodies. When a formerly recognized antigen
cell receptors however, may directly recognize (either from a pathogen or antigenic booster
foreign antigens (FIG. 1). Recognition of foreign vaccine) is reencountered, memory cells divide
antigen epitopes by immunoglobulin (Ig) receptors more rapidly and differentiate to form antibody-
on B cells leads to the production of plasma cells. secreting plasma cells. Antibody affinity is
Plasma cells subsequently secrete subclasses of increased during the ongoing secondary and sub-
antibodies (IgA, IgE, IgG, and IgM). These anti- sequent responses (9). The induction of memory
bodies function to prevent or limit initial infection cells, along with long-lasting antibodies to a spe-
and are involved in killing infected cells through cific pathogen, is the ultimate goal of preventative
vaccination (10–12).

Types of immunization
Most vaccinations induce active immunity by pro-
moting the development of antibody in the recipi-
ent, a response that is expected to be durable. The
goal of active immunization with a vaccine is to
stimulate the host to produce a primary immune
response, usually by inducing B cell proliferation,
antibody response, and T cell sensitization. Should
an individual subsequently be exposed to the
pathogen against which the vaccine is directed,
a secondary response, including increased B cell
proliferation and formation of antibodies, ensues
and protects the individual from developing
disease. Ideally, vaccine-induced immunity en-
dures throughout life. However, some vaccines
require boosters to sustain protection (13).
Passive immunization, which usually involves
the administration of a globulin product, produces
transient immunity for a specific exposure through
the transfer of antibody directly. It offers short-
term protection to individuals who have been
exposed to a particular antigen. For example, injec-
FIG. 1. Recognition of epitopes by B cells (permission tion of Ig against rabies virus can be used to
pending). Adapted from Delves and Roitt (7), Figure 6. This
picture was published in the New England Journal of Medicine prevent rabies infection in a person bitten by a
2000: 343: 37–49. New England Journal of Medicine. All rights rabid animal. Postexposure immunization of a
reserved. person exposed to rabies can be achieved with

105
Bartlett et al.

administration of both the rabies vaccine and anti- A monovalent vaccine is designed to immunize
rabies virus Ig (14). In general, passive immuniza- against a single antigen or single microorganism,
tion is not recommended for healthy adults whereas a multivalent or polyvalent vaccine is
because the majority of adults are capable of pro- designed to immunize against two or more strains
ducing a durable immune response through active of the same microorganism, or against two or
immunization (6). more microorganisms. Whereas most vaccines are
created using inactivated or attenuated com-
Assessing the immunologic response pounds from microorganisms, synthetic vaccines
to vaccination are composed mainly or wholly of synthetic pep-
tides, carbohydrates, or antigens. The simplest
A person’s immune response to specific vaccina-
types of vaccines are often administered with adju-
tions correlates with their ability to fight natural
vants to enhance immunogenicity. The most
infections. Evaluation of the person’s response is
common adjuvant, alum, enhances the production
critical in the assessment of the humoral immune
of antibodies by delaying the release of an antigen,
system. This assessment begins with the measure-
such as the hepatitis B vaccine (18).
ment of absolute levels of IgG, IgA, IgM, and some-
Four types of traditional vaccines exist: (i) vac-
times, IgE. A lack of response to vaccination is
cines containing live attenuated virus; (ii) vaccines
central to the diagnosis of several primary immu-
containing killed microorganisms; (iii) subunit-
nodeficiencies such as common variable immu-
based vaccines; and (iv) toxoid-based vaccines
nodeficiency and Wiskott–Aldrich syndrome.
(Table 1). A number of innovative vaccines are also
Defective vaccine responses are also features of
in development and use. These include conjugate
secondary immunodeficiencies such as splenic
vaccines, recombinant vaccines, and DNA vaccines
deficiency and human immunodeficiency virus
(2).
infection (15).
When assessing the immune response to a vac-
cination, specific antibody titers should be mea- Traditional vaccines
sured to the antigen of interest. If specific titers are
Live attenuated vaccines are vaccines that do not
found to be protective (as defined by the laboratory
replicate well in human hosts, thereby inducing
performing the test), then the immune response to
immunity without inducing disease. An attenuated
it is normal and no further evaluation is required.
strain of the virus or bacteria is developed
Depending on the vaccine and the age of the
by selecting for strains that grow preferentially
patient, a single injection (e.g., pneumococcal
in nonhuman cells. These vaccines generate
polysaccharide vaccine in adults) or a series of
a robust immune response and a number of
injections (e.g., primary diphtheria, tetanus, and
effector mechanisms, including production of
pertussis series in children) may be indicated in
cytotoxic CD8+ T cells. Despite the multiple muta-
order to sustain adequate titers to confer protec-
tions in the genome of attenuated viral strains, a
tion (16). When measuring titers, it is important to
slight risk for reemergence of a pathogenic strain
know that only IgG is relevant to the assessment of
via a series of further mutations does exist (19).
vaccine response. Both infections and immuniza-
These vaccines also have the potential to cause
tions elicit IgM, IgA, and IgG antibody responses.
progressive disease in immunocompromised indi-
However, only IgG antibodies confer long-term
viduals and are ordinarily not given to pregnant
protection and are considered to be indicative
women because of potential damage to the fetus
of immunity. Of note, pre- and postvaccination
(20). Caution should be used in these populations.
titers should be at least 1 month apart to avoid low
Live attenuated viral vaccines are currently in use
postvaccination titers. A reliable evaluation of
for polio, smallpox, measles, mumps, rubella, vari-
an immune response to vaccination cannot be
cella, herpes zoster, influenza, and rotavirus (6).
obtained in patients who have received gamma-
Inactivated viral vaccines result from treatment
globulin replacement within the past 8 months or
of whole virus particles with chemicals such as
in those who have received single doses of immune
formaldehyde or heat, which renders them non-
globulins such as hepatitis A vaccine within the
infective but allows them to retain some un-
past 3–5 months (17).
changed epitopes. Inactivated bacterial vaccines
are made from entire organisms that have been
Types of vaccines
killed, making them harmless. The effector
Vaccines may be monovalent or multivalent, also response induced by inactivated vaccines is less
referred to as univalent or polyvalent, respectively. robust than the effector response generated by live

106
 Vaccine immunology

Table 1. Traditional vaccines used in active immunization

Type of Vaccine Composition of vaccine Examples
Killed whole organism Entire organism killed, thereby harmless Typhoid
Toxoids Protein of bacterial toxins are denatured; no Diphtheria, tetanus
longer pathogenic but antibody-inducing
epitopes remain
Surface molecules Surface molecules are isolated and purified Influenza, hepatitis B surface antigen
from pathogens
Attenuated bacteria Bacteria selectively cultured for strains that do Bacille Calmette–Guerin against
not replicate well in human cells Mycobacterium tuberculosis – not used in
the United States
Attenuated virus Viruses selectively cultured for strains that do Sabin oral polio vaccine, measles, mumps,
not replicate well in human cells rubella, varicella
Inactivated virus Treatment of whole virus particles renders Salk vaccine (polio)
them noninfective but retain some
unchanged epitopes
Adapted from Casadevall (6).

attenuated vaccines. Vaccines to prevent hepatitis antibody response to conjugate vaccines in young
A, hepatitis B, meningococcus, pneumococcus, children is predominately stimulated by the
typhoid, and rabies are examples of inactivated protein component and therefore reflects re-
vaccines. sponsiveness to protein antigens (FIG. 2). This
Subunit vaccines use fragments of a microorgan- approach is used in the Haemophilus influenzae
ism, rather than introducing a whole inactivated or type B and the Streptococcus pneumonie vaccines
attenuated microorganism, to create an immune (22).
response. Characteristic examples include the Combining the physiology of one microorgan-
subunit vaccine against hepatitis B virus (HBV) that ism and the DNA of the other, immunity can be
is composed of only the surface proteins of the created against diseases that have complex infec-
virus (produced in yeast) and the viruslike particle tion processes. There is an interest in developing
vaccine against human papillomavirus that is com- vaccines composed of attenuated viruses or bacte-
posed of the viral major capsid protein. ria as vectors of other antigens. The technique for
Toxoid vaccines are inactivated toxic com- incorporating DNA encoding an antigen from
pounds in cases where these, as opposed to the another infectious agent into vaccinia virus was
microorganism itself, cause illness. Proteins of described in 1982 (23). Antigen encoded by the
bacterial toxins are denatured so they are no longer foreign DNA was expressed after infecting an
pathogenic, but antitoxin antibody-inducing epi- animal with the chimeric poxvirus. The animal was
topes remain. If the host is exposed to the bacterial subsequently protected from infection by the
toxin postvaccination, the bacterial toxin is bound donor of the foreign DNA. Greater than 20 RNA and
by the antitoxin antibody, thus preventing toxin- DNA viruses, as well as bacteria, have been used as
mediated disease. Examples of toxoid-based vac- experimental vectors. Poxviruses are good candi-
cines include tetanus and diphtheria (21). dates as approximately 10% of the large genome
can be replaced by foreign DNA, potentially allow-
Innovative vaccines
ing for the development of multivalent vector
Conjugated vaccines contain polysaccharide vaccines (24).
antigens complexed to immunogenic proteins. In recent years, a new type of vaccine, created
These vaccines were developed because normal from an infectious agent’s DNA, referred to as DNA
children under the age of 2 years demonstrate vaccination, has been developed (25). It works by
poor responses to polysaccharide antigens alone insertion and expression of DNA into human or
because certain bacteria have polysaccharide animal cells, thereby triggering immune system
outer coats that are weakly immunogenic. By recognition of viral or bacterial DNA. Some cells of
linking these outer coats to proteins (e.g., toxins), the immune system that recognize the proteins
the immune system can be led to recognize the expressed will mount an attack against these pro-
polysaccharide as if it were a protein antigen. The teins and cells expressing them. These cells live

107
Bartlett et al.

FIG. 2. Antibody responses to polysaccharide antigens and polysaccharide–protein conjugates (permission pending). Adapted
from Ada (24), Figure 1. (a) A polysaccharide antigen binds to an IgM receptor on the surface of a B cell in lymphoid tissues. Once
B cells are activated, they produce and then secrete IgM antibody molecules. (b) Some polysaccharide–protein conjugates will be
taken up by dendritic cells, which present peptides from the protein portion of the conjugate to type 2 helper T (Th2) cells. Other
conjugate molecules bind to B cells that have IgM receptors specific for the carbohydrate moiety and will undergo endocytosis
and be processed by the B cell; the resulting peptides will be expressed with class II MHC molecules on the surface of the B cell.
This complex is recognized by the activated Th2 cell, which then secretes interleukin-4, interleukin-5, and interleukin-6. These
cause the B cell to differentiate and express IgG molecules with polysaccharide specificity. These cells mature in the lymphoid
follicles; only cells that express very-high-affinity IgG molecules become plasma cells and secrete high-affinity IgG that binds
strongly to the encapsulated bacteria and mediates opsonic activity and complement-mediated bactericidal activities. A recent
study suggests that the formation of memory B cells is a critical component of protective immunity against infection with
Haemophilus influenzae type b. (Ig) immunoglobulin. This picture was published in the New England Journal of Medicine 2000:
346: 1042–1053. New England Journal of Medicine. All rights reserved.

for a very long time so that if the pathogen that Conclusion

normally expresses these proteins is encountered
at a later time, they will be attacked instantly by the Vaccines have played and continue to play a sig-
immune system. One advantage of DNA vaccines nificant role in public health since their develop-
is that they are very easy to produce and store. A ment in 1796. An understanding of the immune
potential disadvantage of DNA vaccines is the pos- response facilitates understanding of the efficacy
sibility of DNA integration into the genome of the of vaccines. Traditional vaccines have been hugely
host cell. This could result in transformation or successful at eradicating and preventing infectious
tumorigenic events and the formation of anti-DNA disease. The continued effort to make innovative
antibodies (24). vaccines to new pathogens and the development of

108
 Vaccine immunology

novel methods of vaccine development will surely 13. Gardner P, Eickhoff T, Poland GA, et al. Adult immuniza-
lead to further success. The intelligent use of vac- tions. Ann Intern Med 1996: 124: 35–40.
14. Casadevall A, Scharff MD. Serum therapy revisited: animal
cines and the practice of other measures, hygienic models of infection and the development of passive anti-
and sanitary, contribute to general improvements body therapy. Antimicrob Agents Chemother 1994: 38:
in public health (6). 1695–1702.
15. Ochs HD, Buckley RH, Kobayashi RH, et al. Antibody
response to bacteriophage phi X174 in patients with
References adenosine deaminase deficiency. Blood 1992: 80: 1163–
1171.
1. Henderson D, Moss B. Smallpox and vaccinia. In: Plotkin 16. Committee on Infectious Diseases. Recommended immu-
SA, Orenstein WA, eds. Vaccines, 3rd ed. Philadelphia, PA: nization schedules for children and adolescents – United
WB Saunders, 1999: 74–97. States, 2008. Pediatrics 2008: 121 (1): 219–220.
2. Vaccines. Wikipedia. Available at: http://en.wikipedia.org/ 17. American Academy of Pediatrics. Active immunization. In:
wiki/vaccine. Accessed October 15, 2008. Pickering LK, ed. Red Book: 2006 report of the committee
3. CDC. Achievements in public health, 1900–1999: impact of on infectious diseases, 27th ed. Elk Grove Village, IL: Ameri-
vaccines universally recommended for children – United can Academy of Pediatrics, 2006: 445.
States, 1990–1998. MMWR Morb Mortal Wkly Rep 1999: 48: 18. Podda A. The adjuvanted influenza vaccines with novel
243–248. adjuvants: experience with the MF59-adjuvanted vaccine.
4. CDC. Ten great public health achievements: United States, Vaccine 2001: 19: 2673–2680.
1900–1999. MMWR Morb Mortal Wkly Rep 1999: 48: 241– 19. Fikrig E, Insel R, Knight A, Lolis E, Pawelec G, Vitetta E.
243. Manipulation of the immune response. In: Janeway CA,
5. Centers for Disease Control and Prevention. Summary of Travers P, Walport M, Schlomchik MJ, eds. Immunobiol-
notifiable diseases, United States, 1998. MMWR Morb ogy, 6th ed. New York, NY: Garland Science Publishing,
Mortal Wkly Rep 1998: 47 (Suppl): 1–92. 2005: 613–661.
6. Casadevall A. Resistance and immunization to infectious 20. Pirofski L, Casadevall A. The use of licensed vaccines for
diseases. In: Coico R, Sunshine G, Benjamini E, eds. Immu- active immunization of the immunocompromised host.
nology: a short course, 5th eds. Hoboken, NJ: John Wiley & Clin Microbiol Rev 1998: 11: 1–26.
Sons, Inc., 2003: 287–306. 21. McQuillan GM, Kruszon-Moran D, Deforest A, et al. Sero-
7. Delves PJ, Roitt IM. The immune system. First of two parts. logic immunity to diphtheria and tetanus in the United
N Engl J Med 2000: 343 (1): 37–49. States. Ann Intern Med 2002: 136: 660–666.
8. Gray D, Siepmann K, Wohlleben G. CD40 ligation in B cell 22. Sorensen RU, Leiva LE, Giangrosso PA, et al. Response to a
activation, isotype switching and memory development. heptavalent conjugate Streptococcus pneumoniae vaccine
Semin Immunol 1994: 6 (5): 303–310. in children with recurrent infections who are unresponsive
9. Arora A, Mendoza N, Tyring S. Vaccines. In: Gaspari A, to the polysaccharide vaccine. Pediatr Infect Dis J 1998: 17:
Tyring S, eds. Clinical and basic immunodermatology. 685.
London: Springer, 2008: 579–602. 23. Mackett M, Smith GL, Moss B. Vaccinia virus: a selectable
10. Ahmed R, Gray D. Immunological memory and protective eukaryotic cloning and expression vector. Proc Natl Acad
immunity: understanding their relation. Science 1996: 272 Sci U S A 1982: 79: 7415–7419.
(5258): 54–60. 24. Ada G. Vaccines and vaccination. New Engl J Med 2001: 345
11. Zinkernagel RM. On differences between immunity and (14): 1042–1053.
immunological memory. Curr Opin Immunol 2002: 14 (4): 25. McDonnell WM, Askari FK. DNA vaccines. N Engl J Med
523–536. 1996: 334: 42–45.
12. Storni T, Kundig TM, Senti G, Johansen P. Immunity in
response to particulate antigen-delivery systems. Adv Drug
Deliv Rev 2005: 57 (3): 333–355.

109