Gregory A Poland, chiefa, Dennis Murray,
senior research fellowb, Ruben Bonilla-Guerrero,
senior research fellowa.
a Mayo Vaccine Research Group, 611C Guggenheim Building, Mayo
Clinic and Foundation, 200 First Street, SW, Rochester, MN 55905, USA, b Department
of Pediatrics and Human Development, Michigan State University, East Lansing,
MI, USA
Vaccines are hailed as one of the most important public health achievements
of the 20th century.1 In the next five to 15years,
new vaccines and new vaccine delivery technology will fundamentally
change how clinicians prevent and treat disease, with a substantial
impact on public health. This review describes recent developmentsin
the basic science underpinning the development of new vaccinesand
summarises the potential of these vaccines to treat and preventa
wide range of infectious and non-infectious diseases.2-5
Inaddition, research is being carried out on much needed vaccinesfor the developing world for diseases such as malaria, hookworm,dengue, enterotoxigenic Escherichia coli, shigella, and
tuberculosis,but these are beyond the scope of this brief review.
Summary points
New prophylactic and therapeutic vaccines will prevent and potentially
cure disease by providing people with the necessary immunological tools
Advances in current vaccines such as conjugated pneumococcal vaccines
for adults, nasal spray vaccines for influenza, and adult acellular
pertussis vaccines will provide an efficient way to produce longlasting
protective immunity
Development of vaccines against non-infectious diseases (such as
cancer, diabetes, and Alzheimer's disease) and nicotine and cocaine
dependence will provide alternative treatments
Vaccines against biological weapons will be possible by advances in DNA
vaccines
New vaccine delivery technology will provide easier delivery routes
(such as transcutaneous, depot, nasal, and oral delivery) without
compromising efficacy
Development of DNA vaccines
One approach generating great interest isthat of inducing protective
immune responses by injecting engineeredDNA sequences from
infectious organisms against which protectionis desired. If an
antigen can be identified it is possible toinsert the DNA sequence
coding for the protein antigen into acarrier genome (such as several
of the poxviruses or alphaviruses).Once delivered into the host, the
organism (and hence the insertedDNA) undergoes limited replication,
the protein of interest isproduced, and the host develops an immune
response against theprotein.
In a related strategy, so called naked DNA is injected directly into the host
to produce an immune response (fig 1). NakedDNA is
simply sequences of DNA inserted into bacterial plasmids(simple,
extrachromosomal rings of DNA found in bacterial cells)and injected
into the host. These have been effective in animalmodels, but
intramuscularly injected DNA in humans has failedto generate
vigorous immune responses, although transdermal orintradermal
delivery of DNA has been more encouraging. A clinicaltrial of
transdermally delivered microscopic gold beads coatedwith DNA coding
for hepatitis B surface antigen generated protectivelevels of
antibodies to the antigen.6 This vaccine has alsogenerated CD8 cytotoxic lymphocytes.6
Although efforts havebeen successful in animal models of vaccines
against several pathogens,progress in humans has been much slower.
To date, only DNA vaccinesagainst hepatitis B6
and malaria7 have induced immune responsesthought to be protective inhumans.
Development of therapeutic vaccines
Traditional vaccination is the preventionof a specific infectious
disease by delivering an immunogenicantigen derived from the surface
of the infectious agent, resultingin immunity against the foreign
organism replicating and establishingan infection. A therapeutic
vaccine, however, can limit or eradicatean already present and
established infectious agent or condition.The development of
therapeutic vaccines has depended in part onthe ability of DNA
vaccination to induce both humoral and cellmediated immune responses
by inoculation of plasmid DNA containingsequences for transcription
and translation, resulting in thein vivo synthesis of an immunogenic
peptide orprotein.
Attempts are being made to develop a therapeutic vaccine against HIV that
will induce virus-specific cytotoxic T lymphocytesagainst HIV, with
the goal of having activated T cells destroylatently infected cells.
Other efforts include developing therapeuticvaccines against
Helicobacter pylori, mucosal candidiasis, herpesviruses, and
human papillomavirus. DNA vaccination for hepatitisB virus has shown
great promise. The delivery of viral DNA sequencescan induce
longlasting humoral and cell mediated immunity in miceinfected with
hepatitis B virus. 89
In transgenic mice, atleast, there is a decrease in or clearance of
the hepatitis Bsurface antigen, with evidence of induction of
antibodies andproliferation of CD4 T cells.10
Clearly, the capabilities ofthe immune system to eliminate an
infectious agent even afteran infection or disease is established
could substantially improvehuman health.
Fig 1. Principle of DNA
vaccination. An immunogenic gene is inserted into an expression plasmid
(A), which is inserted into cultured cells (B). The cells are screened
for expression of the gene protein and then cultured. The plasmid DNA is
then extracted from the cells and purified before being used to immunise
a host (C)
Other important examples of therapeutic vaccine development include the
development of vaccines against certain cancers,11which is discussedlater.
Advances in current vaccines
The bacterium Streptococcus pneumoniae andinfluenza viruses
account for considerable morbidity and mortalityworldwide. Now
approved in several Western countries, S pneumoniaeconjugate
vaccines should help reduce the number of cases of invasiveS
pneumoniae disease (bacteraemia, meningitis, and sepsis) in
infants and young children. A live, attenuated influenza virus
vaccine is nearing approval in the United States. This vaccine,
administered as an intranasal spray, should stimulate both systemic
and mucosal immunity, while decreasing reliance on the use of
parenteral injections (see box for a list of potential vaccines).
Potential vaccination
in the 21st century (adapted with permission from Plotkin (2001)5)
New maternal vaccinesGroup
B streptococcus, respiratory syncytial virus
New vaccines for neonatesRespiratory
syncytial virus, hepatitis B
New vaccines for infants aged 2-6 monthsPaediatric
combinations (acellular pertussis (DtacP), Haemophilus influenzae
type b (Hib), hepatitis B, pneumococcal, meningococcal, hepatitis A, etc),
otitis (non-typable Haemophilus influenzae, Branhamella
catarrhalis), rotavirus (new), meningococcal conjugate
New vaccines for the developing worldEnterotoxigenic
Escherichia coli, shigella, malaria, dengue, tuberculosis
Vaccines for children aged 1-2 yearsMeasles-mumps-rubella-varicella
(MMRV), influenza (intranasal)
Vaccines for children aged 4-6 yearsMMRV
booster, paediatric combination booster, Streptococcus mutans (oral)
(anti-caries), Lyme disease and tick-borne encephalitis (endemic areas)
Vaccines for children aged 11-13 yearsHIV,
human papillomavirus, herpes simplex virus 2, Neisseria gonorrhoeae,
cytomegalovirus, parvovirus, Epstein-Barr virus
Vaccines for young adultsTetanus
and diphtheria toxoids, acellular pertussis, Helicobacter pylori
(anti-ulcer), Chlamydia pneumoniae (anti-atherosclerosis)
Travel vaccinesTherapeutic
vaccines against diabetes, multiple sclerosis, meningococcal conjugate
Vaccines for people aged
50 yearsInfluenza
(subcutaneous and intranasal), pneumonococcus (protein and polysaccharide),
herpes zoster, cancer (prophylactic and therapeutic vaccines)
Streptococcus pneumoniae
Multivalent polysaccharide vaccines for Spneumoniae have been
available in the United States since 1977,but they produce a poor or
inconsistent immune response in children,especially those less than
2 years old. Polysaccharide vaccinesinduce antibodies primarily by
mechanisms independent of the Tcells and are not long lasting and do
not induce an immune memoryresponse. For these reasons, a protein
carrier conjugated to apolysaccharide antigen of S pneumoniae
has now been developed,which causes the immune response to be
T cell dependent, allowinginfants and children to respond better to
the vaccine. The USlicensed heptavalent S pneumoniae
conjugated polysaccharide vaccinecontains the seven serotypes
(4, 6B, 9V, 14, 18C, 19F, and 23F)most commonly associated with
invasive disease among infants andyoung children. The new vaccine is
also expected to have the benefitof reducing nasopharyngeal carriage
of these seven S pneumoniaeserotypes.
Influenza virus
The only influenza vaccines currently licensedin the United States
are parenteral inactivated influenza virusvaccines prepared in chick
embryos. Because of changes in theinfluenza viruses circulating each
year (antigenic drift), protectionof high risk individuals requires
annualvaccination.
A live attenuated influenza virus vaccine being proposed for US approval
contains recombinant cold-adapted strains of influenzaA and B and is
given by intranasal spray. Several studies haveexamined the use of
live attenuated influenza vaccines in childrenand adults.12-14
In seronegative children more than 15 months oldantibody responses
to the influenza A and B components after asingle dose of vaccine
indicated an overall efficacy of 93%.12
Use of a live attenuated trivalent vaccine in adults significantly
reduced the occurrence of illness, visits to healthcare providers,
and days of work lost.14
When correctly targeted, an immune response can be used to eliminate cells
with aberrant behaviour (dysplasia) or aberrantgenomic function
(malignancy) or to reduce the amount of inflammationaffecting a
specific organ (such as in diabetes). 1516 Thisraises the possibility of
developing vaccines against diseasesnot known to be related to
infectious agents. Two of the mostexciting and promising areas in
this regard are vaccines againstcancer and autoimmune
diseases.
Cancer
The identification of specific tumour antigens(tumour associated
antigens) that are present only in cancer cellssuchas those found in leukaemia, breast cancer, melanoma, prostate
cancer, and colon cancerprovide
immune targets for which immunogenicvaccines may conceivably be
designed. For example, the expressionof protein GPI-B7-1 transferred
onto membranes from a murine thymomatumour cell protects mice
against this kind of tumour.17 In
humans it is possible to stimulate T cell responses using isolated
membranes surgically removed from human tumour tissues that express
major histocompatibility complex (MHC) class II molecules, suggesting
the possibility of establishing an immune response that could
specifically target and eliminate tumour cells.18
Other efforts include therapeutic vaccines against melanoma, colorectal
cancer, leukaemia, and other cancers. 1920 Theability of DNA vaccines to
deliver precise and specific nucleotidesequences representing target
genessuch as the ALVAC
gp100 genefor melanoma and the ALVAC CEA-B7.1 gene for colorectal
cancerand
specific protein fragments such as the HER2/Neu peptide foundin
breast cancer cells 2122
have been studied as a potentialmeans with which to induce an immune
response. 1923
Autoimmune diseases
Diseases related to pathological immune activation,such as
autoimmune diseases and allergies, might be treatableor preventable
with vaccines. Efforts are being made to developvaccines against
rheumatoid arthritis, multiple sclerosis, myastheniagravis, food
allergies, and especially type 1 diabetes becauseof its associated
substantial morbidity andmortality.
In the case of type 1 diabetes, lymphocytes infiltrate the pancreatic islets
and selectively destroy the insulin secreting cells. One strategy for vaccine
development is to reduce thepathological lymphocytic infiltration by
tolerisation. 151624 Tolerisation involves the administration of
small amounts of thesame antigens that are the target of the
aberrant immune response,which, in the absence of cytokine
costimulation, fuels the activationof T cells, which reduceinflammation.
In disorders such as Alzheimer's disease, it may be possible to target the
amyloid protein that is
responsible for the neurodegenerativeplaques observed in this
disorder. In murine models vaccines havebeen shown to reduce and
prevent plaque formation, with some improvementin cognitive
function.25 Other examples of potential vaccinedevelopment include vaccines to prevent cocaine and nicotine addiction.With the use of immunopharmacotherapy, antibodies can be designedto neutralise a drug rather than target the receptors in the brain.Efforts are also being made to develop vaccines against atherosclerosisand to prevent conception.26-28
Vaccines against biological weapons of
mass destruction
Interest has increased in biological weapons of mass destruction as
terrorists look for methods with which to inflict harmon the
greatest number of people, with the lowest possible costand
technology needs, while creating mass panic. While vaccineshave been
licensed against smallpox, plague, anthrax, and others,only limited
amounts of anthrax vaccine are being produced inthe United States
for specific risk groups. Limited and ageingstockpiles of smallpox
and plague vaccine are available but areinsufficient for large
numbers ofpeople.
Because of the ability of biological weapons to infect and kill large numbers
of people, and the risk of person-to-persontransmission, vaccines
are likely to be the only practical meansof protection.
2930 Second
generation vaccines against anthrax,smallpox, and plague are being
developed, and vaccines againstother agents of bioterrorism such as
the haemorrhagic fever virusesand others are also in development.
However, major obstacles inproducing such vaccines for public use
include the need for afinancially viable market, the impossibility
of conducting humanefficacy trials, the intangible risk:benefit
ratio at the publichealth level, and governments' reluctance to face
the realityofbioterrorism.
Virtually all recommended immunisations require parenteral administration,
and many require a series of injections. To beeffective, vaccines
for some diseases will need to enhance mucosalimmunity as well as
systemic immunity. For these reasons, newvaccine delivery methods,
specifically alternatives to injections,are being sought. Topically
applied (transcutaneous) vaccines,transgenic edible plants that
contain genes for human vaccineantigens, and controlled delivery
depot systems with vaccine antigensencapsulated in biodegradable
polymers are possibilities currentlyunder study. Such new delivery
methods could decrease relianceon repeated injections, the need for
trained healthcare workers,and perhaps the need for a stringent cold
chain for vaccinestorage.
Transcutaneous immunisation
Animal studies have shown the production ofboth systemic and mucosal
antibodies after topical vaccine application.Agents such as cholera
toxin and the heat labile enterotoxin ofEscherichia coli, in
combination with a vaccine antigen such astetanus toxoid, act as an
adjuvant and produce protective antibodiesafter being applied to the
skin of animals.31 Non-toxic mutantsor
subunits of cholera toxin and E coli enterotoxin would be needed,however, for any application on to human mucosal surfaces. Variousother adjuvants besides cholera toxin and E coli enterotoxin
(includingbacterial ADP-ribosylating exotoxins, interleukin -1
fragment, interleukin 2, and tumour necrosis factor -)
havealso been shown to produce an immune response after topical
application.32
Fig 2. Principle of delivering
vaccines in edible plants. A gene from a human pathogen is inserted into
a bacterium that infects plants (A). The bacterium then infects cultured
leaf segments of the selected food plant (B), which sprout into whole
plants containing the human pathogen gene (C). Once the plant is eaten,
it triggers an immune response to the pathogen
Additional educational
resources
Centers for Disease Control and Prevention (www.cdc.gov/)
Transgenic edible plants to deliver vaccines
The development of plants capable of expressingvaccine antigens is a
novel and promising strategy (fig 2). Such
genetically engineered plants would produce vaccine antigens intheir
edible parts and would, like subunit vaccine preparations,contain no
genes capable of replicating a whole infectious organism.33Because food plants can be regenerated rapidly, it may be possiblethat crops containing vaccine antigens could be produced indefinitelyand on a local basis. Potato and tomato plants have synthesised
antigens from Norwalk virus, enterotoxigenic E coli, Vibrio cholerae,and hepatitis B virus. A recently completed human study has shownthat a recombinant bacterial antigen, subunit B of heat labile
enterotoxin, produced in a potato and eaten resulted in productionof
both serum antibodies (IgG and IgA) and mucosal antibodies(sIgA) to
the antigen.34 Other plants, such as bananas, andother vaccine antigens, including tetanus and diphtheria toxoids,may be included in futurestudies.
Controlled delivery depot systems
The use of controlled delivery of vaccineantigen, or depot vaccine
technology, reduces the number of parenteralinjections while
potentially mimicking natural infection. Variousvaccine antigens
have been encapsulated in microspheres composedof biodegradable
polymers such as poly (lactic/glycolic) acid(PLGA), which can be
targeted to various cells in the immune systemor can form a depot at
the injection site, allowing slow releaseof the antigen over time.35
The release profile of vaccine antigendepends on the particle size
of the delivery vehicle, and a combinationof large and small
microspheres can create a pattern that mimicsthe antigen
concentration profile in conventional immunisation,combining both
primary and booster injections. A recent studyin animals found that
encapsulated tetanus toxoid or Haemophilusinfluenzae type b
polysaccharide elicited high antibody levelsthat persisted for
months.36
The future of vaccinology provides tremendous promise for controlling
diseases. Vaccines will be delivered orally, by nasalspray, or
transcutaneously by a minimally trained layperson andin a manner
that does not require expensive equipment. However,despite rapid
advances in the development of new vaccines, concernsabout vaccine
safety and a rise in anti-vaccine sentiment adverselyaffect
immunisation coverage, the willingness of manufacturersto develop
new vaccines, and the willingness of individuals andhealthcare
workers to use them. 3738
As advanced vaccines andvaccine technologies become available,
massive public educationefforts will be required to alleviate these
concerns. This isparticularly true for DNA vaccines, combination
vaccines, vectoredvaccines, and vaccines administered in a
parenteral depot fashion.The more distant potential for
person-specific vaccines basedon individual genotyping (vaccines
against a specific malignancyin a specific individual) will also
raise serious concerns. Nonethe less, the prospect of both
preventing and treating many seriousdiseases by the use of vaccines
portends an exciting era in publichealth andvaccinology.
Acknowledgments
We thank Kim Zabel for her excellent editorial assistance in the development
of this review. DM's current address is PediatricInfectious
Diseases, Medical College of Georgia, Augusta, GA,USA.
Footnotes
Funding: GAP and this work was supported in part by a grant from the Centers
for Disease Control and Prevention (AVA 001)and grants from the
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OF THE PUBLISHER, AND IS NOT TO BE CONSTRUED OR INTENDED AS PROVIDING MEDICAL OR
LEGAL ADVICE. THE DECISION WHETHER OR NOT TO VACCINATE IS AN IMPORTANT AND
COMPLEX ISSUE AND SHOULD BE MADE BY YOU, AND YOU ALONE, IN CONSULTATION WITH
YOUR HEALTH CARE PROVIDER.
"A foolish faith in authority is the worst enemy of truth."
-- Albert Einstein, letter to a friend, 1901
"I know of no safe depository of the ultimate powers of the society but the people themselves, and if we think them not enlightened enough to exercise control with a wholesome discretion, the remedy is not to take it from them, but to inform their discretion by education."
-- Thomas Jefferson, letter to William C. Jarvis, September 28, 1820
"What's the point of vaccination if it doesn't protect you from the unvaccinated?"
-- Sandy Gottstein
"Who gets to decide what the greater good is and how many will be sacrificed to it?"
Top
Methods
New vaccines
against infectious...
Group
B streptococcus, respiratory syncytial virus
50 years
cells. One strategy for vaccine
development is to reduce the pathological lymphocytic infiltration by
tolerisation. 
)
have also been shown to produce an immune response after topical
application.
